Reproductive Endocrinology For Gynaecologist S

Reproductive Endocrinology for Gynaecologists
Concepts and Practice
By
Mr. A. Abdel-Gadir PhD FRCOG

Consultant Gynaecologist and Fertility Specialist
Highgate Hospital, 17 View Road, London N6 4DJ
All rights reserved
Copyright © Abdel-Gadir, 2011
Abdel-Gadir is hereby identified as author of this

work in accordance with Section 77 of the Copyright, Designs
and Patents Act 1988
The book cover picture is copyright to Abdel-Gadir
This book is published by

Grosvenor House Publishing Ltd
28-30 High Street, Guildford, Surrey, GU1 3HY.
www.grosvenorhousepublishing.co.uk
This book is sold subject to the conditions that it shall not, by way of
trade or otherwise, be lent, resold, hired out or otherwise circulated
without the author's or publisher's prior consent in any form of
binding or cover other than that in which it is published and
without a similar condition including this condition being imposed
on the subsequent purchaser.
A CIP record for this book

is available from the British Library
ISBN 978-1-908105-73-8
Dedication
This book is dedicated to my mother, my brother Mohamed and to my

wife Hayat in recognition of the sacrifices they made on my behalf over
the years. My life would not have been the same without their very
generous love and encouragement.
Acknowledgment
I am immensely grateful to Mr. Oluseye A Oyawoye (Seye), MD MRCOG,

Consultant Obstetrician and Gynaecologist, Newham University
Hospital, London for proofreading the initial manuscript, and for his
professional remarks.
v
Table of Contents
Section Page
Introduction ix
Chapter 1
The Hypothalamo-Pituitary-Ovarian Axis 1
Chapter 2
Normal and Abnormal Puberty 23
Chapter 3
Primary and Secondary Amenorrhoea 41
Chapter 4
The adrenal glands in gynaecology 67
Chapter 5
Progestogens, Androgens and Oestrogens 89
Chapter 6
Polycystic Ovary Syndrome 113
Chapter 7
Induction of Ovulation 149
Chapter 8
Adipose Tissue and Reproduction 177
Chapter 9
The Climacteric, Menopause and HRT 193
Chapter 10
Premature Ovarian Failure 227
Chapter 11
The Thyroid Gland in Gynaecology 243
Chapter 12
Premenstrual Syndrome and Dysphoric Disorders 265
Chapter 13
Female Hormonal Contraceptives 279
Chapter 14
Endocrine Investigations in Gynaecology 311
Index 337
vii
Introduction
Reproductive Endocrinology is the medical discipline related to

hormones, neurotransmitters, paracrine and autocrine chemicals
involved with the control of sexual development, sexual behaviour and
reproduction. It is a fascinating subject to study and practise.
Furthermore, it has improved our understanding of many basic
gynaecological problems, which we used to take for granted without
knowing their molecular or biochemical background. During my medical
school years and PhD studies, an endocrine gland was defined as a
ductless organ which produced hormones. These were in turn defined as
chemicals carried by the blood, to cause their effects at distant sites.
These concepts proved to be incorrect over the years. Hormones are not
necessarily produced by ductless glands, and they could cause their
effects both locally and at distant targets. The functional perception has
also changed. Hormones and neurotransmitters are now considered as
chemical communication means between different parts of the body. The
local effects of hormones could be paracrine which denotes intercellular
communication between neighbouring cells, and autocrine which denotes
intracellular communication within the same cell. A new concept which is
known as intracrine relates to the effects of unsecreted substances which
bind to other intracellular substances within the same cell.
Providing contraceptive advice and hormone replacement therapy,

induction of ovulation, management of the premenstrual syndrome,
insulin resistance, hyperandrogenisation and premature ovarian failure
are few examples of our daily routine within a gynaecology clinic. They
all have a strong reproductive endocrinology background. Even without
derangement in reproductive hormones production, increased
oestrogen receptors activity coupled with genetic predisposition may
have some bearing on the development of endometriosis. Similarly,
increased skin androgen receptors and enzymatic activities have been
reported as local causes of idiopathic hirsutism. With this broader
application, it is evident that many gynaecological problems are in one
way or another affected by dysfunctional hormones, their receptors or
other related chemicals.
Accordingly, knowledge of the basic concepts of neuroendocrinology,

and the interrelationship between the different endocrine glands
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ABDEL -GADIR
especially the ovaries, adrenals and thyroid gland will improve our
medical practice, when dealing with gynaecological problems with
endocrine background. As gynaecologists, we need to understand how
the hypothalamo-pituitary-ovarian axis interacts with the
corresponding hypothalamo-pituitary-adrenal and thyroid axes, and
how the later two interact with each other. The effects of the extremes
of body weight on gynaecological practice are related mainly to their
endocrine effects, though the initial causes may be psychological. The
effects of different endocrine and non endocrine medications on
endocrine glands, and the neuroendocrine control of reproduction
should be appreciated. This is especially so for oestrogens,
progestogens and androgens. We should understand the effects of
oestrogens on the function of the thyroid and adrenal glands. This is
especially so if either or both glands are dysfunctional. Furthermore,
not all oestrogens are alike, not all progestogens are alike, and not all
androgens are alike. Subgroups within these steroids share similar
basic characteristics, but have different subsidiary effects, which are
very important within the gynaecological practice. Knowledge of such
information for instance may stop the common practice of repeated
prescriptions of the androgenic norethisterone, which is 17α ethinyl 19
nortestosterone, to women with abnormal uterine bleeding and
hyperandrogenic tendency. A non-androgenic progestogen can be
equally effective. Similarly, appreciating the mode of action of
clomiphene citrate as an oestrogen receptor modulator used to
stimulate endogenous FSH production may stop the practice of
prescribing it to women who already got high FSH levels because of
ovarian ageing. On the other hand, understanding the differences
between ovulatory and anovulatory dysfunctional uterine bleeding will
stop the practice of prescribing progestogens to patients with the
ovulatory type, which is useless and may even be harmful. These are
only few examples of how better understanding of reproductive
endocrinology can improve our gynaecological practice.
Hormones are produced in pulses, in a circadian rhythm, and with

physiological variations during the menstrual cycle. This should be
taken into consideration when requesting hormone investigations.
Furthermore, intercycle variations are also common, and occasionally
reported spurious results may not agree with the general clinical
picture. This later problem may follow wrong timing of blood samples,
use of undeclared medication by the patients, and the presence of
heterotypic antibodies, just as examples. Such information should be
taken into consideration during investigations of gynaecological
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REPRODUCTIVE ENDOCRINOLOGY FOR GYNAECOLOGISTS
problems, and the management plan should not be changed on the

merits of such results.
This book has been written to introduce reproductive endocrinology

with young gynaecologists in mind, and as a reference book for the
more seasoned ones. A practical clinical approach has been adopted for
presenting the information without using any mind twisters, and the
chapters are arranged in a logical sequence. Repetition has been
avoided by cross referring in-between chapters, when possible. A short
summary has been included at the end of each chapter to focus the
attention of the reader. Furthermore, a list of relevant references has
also been included after each chapter, for those who developed special
interest in any particular subject, and would like to have further
information. To make it more affordable to the targeted reader, it was
agreed that it should be printed in black and white and display the
colour pictures on the black cover. I hope it will be a useful addition to
the medical library.
Ahmed Abdel-Gadir
xi
Chapter 1
The Hypothalamo-Pituitary-Ovarian Axis
The pituitary gland is located at the base of the brain in the sella turcica
(Turkish saddle), covered by the diaphragma sellae which is an
extension of the dura matter. It is related superiorly to the optic
chiasma, laterally to the cavernous sinus and its contents, and inferiorly
to the sphenoid bone and sinus. These are important landmarks which
may be affected by large pituitary tumours. It varies widely in size in
normal adult females (1, 2), and may exceed 1 gram in weight in
multiparous women. It forms an important part of the neuroendocrine
system through which the brain controls an individual’s growth,
metabolism, wellbeing, reproduction, and many other vital functions.
This is affected through different neurotramitters which are conveyed
first to the hypothalamic nuclei, which receive signals from almost all
areas of the central nervous system. The hypothalamus in turn controls
the pituitary gland which is made of two developmentally and
histologically different parts, known as the neurohypophysis and
adenohypophysis. Arterial blood supply to the hypothalamus is
provided by the circle of Willis, whereas the neurohypophysis and
adenohypophysis receive blood from the inferior and superior
hypophyseal arteries respectively.
The neurohypophysis
The neurohypophysis develops from the ectoderm of the diencephalon

(mid brain). It is made of 3 different parts:
1. The neural lobe or infundibular process;
2. The median eminence of the tuber cinereum;
3. The infundibular stalk.
The neural lobe is connected to the median eminence by the
infundibular stalk which carries nerve axons arising in the
hypothalamus. The final terminals of these nerves end within the
vicinity of small blood vessels in the neural lobe itself. Similar to the
median eminence, this neurovascular association lacks the usual blood
brain barrier. The cell bodies of the nerves are located in the supraoptic
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ABDEL -GADIR
and paraventricular nuclei. Accordingly, the neural lobe is not a true

endocrine gland in the classical definition of the term. It is the terminal
stop for the release of oxytocin and antidiuretic hormone (vasopressin),
which pass down as granules in the nerve axons carried in the
infundibular stem. The main effects of oxytocin are carried at the
breasts myoepithelial cells, and uterine muscles. It is produced in
response to stimulation of the nipples and breast suckling, but its role
in the initiation of labour is not clear. Nonetheless, the mean plasma
concentration of oxytocin was consistently higher during the course of
spontaneous labour in comparison to levels observed 1 to 2 weeks
before the onset of labour (3). Furthermore, uterine muscles sensitivity
to oxytocin increases during pregnancy. Antidiuretic hormone helps in
water preservation by increasing the permeability of the renal collecting
tubules. It is mainly produced in response to increased osmotic
pressure as detected by osmorecptors in the hypothalamus, and by
volume depletion which is detected by baroreceptors in the carotid
sinus and carotid arch, left atrium and pulmonary veins. Other minor
stimulants include stress, vomiting, hypoglycaemia, exercise and
hypoxia. Certain drugs can stimulate vasopressin production and
release including β-blockers, prostaglandins and cholinergic drugs. On
the other hand, suppression of vasopressin release can be affected by
alcohol intake, α- blockers and glucocorticoid steroids. A detailed
description of the neurohypophysis structure and function is beyond the
remit of this chapter, which is mainly concerned with the development,
maturation, inter-relationships and aging of the hypothalamo-
adenohypophysis-ovarian axis, usually called the hypothalamo-
pituitary-ovarian (HPO) axis.
The adenohypophysis
The adenohypophysis originates from a diverticulum of the primitive

foregut, known as Rathke’s pouch, during the 4th week of fetal life. It
grows cranially and comes in contact with the neural diverticulum
which is destined to form the neurohypophysis by the 5th week. It
loses its connection to the foregut by the 6th week. The
adenohypophysis is fully developed by the 16th week of intrauterine
fetal life. By then it is tightly close to the neurohypophysis, but
remains functionally different. This is the time when a functional
connection between the hypothalamic gonadotrophin-releasing
hormone (GnRH) neurons and the hypophyseal portal circulation is
established (4). In an adult person, the adenohypophysis makes 80%
of the whole pituitary gland weight.
2
Like the neurohypophysis, it is also made of 3 different parts:

1. The pars distalis;
2. The pars intermedia;
3. The pars tuberalis.
The pars distalis forms the bulk of the gland and is responsible for the
production of follicle stimulating hormone (FSH), luteinising hormone
(LH), thyroid stimulating hormone (TSH), pro-opiomelanocortin
(POMC) which is the mother molecule for adrenocorticotrophic
hormone (ACTH), growth hormone (GH), prolactin, α-and-β
melanocyte stimulating hormone (MSH), endorphins, enkaphalins and
β-lipotropin (β-LPH). The secretion of these hormones is controlled
through both neural and humoral mechanisms. Endorphins and
enkaphalins are opioid molecules which can activate opioid receptors
in the central nervous system, but the function of β-LPH is not well
verified. Target glands controlled by the pituitary gland reciprocally
control their tropic hormones secretion through long negative
feedback mechanism, affected at the level of the pituitary gland and
hypothalamus. This prevents overproduction of the related tropic
hormones. Neural control of the pars distalis hormones is affected
through neurotransmitters which facilitate the production of these
tropic hormones, except for prolactin which is inhibited through
dopamine secretion. A short negative feedback mechanism is also
functional between the pituitary hormones and the hypothalamus to
control the production of the hypothalamic releasing hormones.
The pars intermedia is situated between the pars distalis and

infundibular process, hence its name, and is well developed during fetal
life. In contrast, it is usually not well developed and is non functional in
adults, though it may be involved with the production of pre-pro-
opiomelanocortin. It is normally separated from the pars distalis by the
hypophyseal cleft. The pars tuberalis forms a collar around the pituitary
stalk, and carries the portal vessels connecting the pars distalis with the
hypothalamus. Its exact endocrine function has not been conclusively
established, and may be different in different species. Nonetheless, its
role in mediating photoperiodically regulated changes in prolactin
secretion in seasonal mammals has been well investigated (5, 6). A
recent publication suggested that suprasellar pituitary tumours arising
from the pars tuberalis may stimulate prolactin secretion by producing
tachykinins, substance P and / or neurokinin A (7).
Unlike the neurohypophysis, the adenohypophysis has no direct arterial

blood supply. It receives its blood through short and long hypophyseal
3
ABDEL -GADIR
portal veins. The capillary plexus formed by the inferior hypophyseal

artery drains mainly into the dural venous sinuses, but some of
these capillaries form short portal veins within the pituitary stalk, and
provide 30% of the blood supply to the adenohypophysis. The main
blood supply to the adenohypophysis comes from the long portal veins.
These are exceptional vessels which also play a major role in the
neuroendocrine control of the adenohypophysis. They are unique in two
ways:
1. They start as a capillary plexus in the median eminence formed
by branching of the superior hypophyseal arteries, and end as a
capillary plexus in the adenohypophysis.
2. They are also fenestrated to improve neurotramitters release.
Venous blood from the adenohypophysis drains directly into the
cavernous sinus, thence into the superior and inferior petrosal sinuses
and into the jugular veins (8).
In the context of this chapter, the main script will concentrate on

the HPO axis, which is the main neuroendocrine system responsible
for the development of secondary sexual characteristics, and
reproduction.
The ultimate development of an adult female is controlled by the

following consecutive mechanisms:
• Chromosomal sex;
• Gonadal sex;
• Genital sex;
• Sex of rearing.
Any abnormality at any point along this trail can lead to physical and /
or psychological abnormalities which may affect sexual identity,
reproductive capacity, and quality of life of the individual concerned.
However, chromosomal sex is the most important and driving force
behind this sequence of developmental stages, depending whether a
sperm with a Y or X chromosome fertilises the egg. This will dictate the
development of the primitive gonad into a testicle or an ovary
respectively, which in turn controls the development of the genital
organs. Testicular production of testosterone and dihydrotestosterone
promote the differentiation of internal as well as external male genital
organs. Failure of testicular development, rather than ovarian
development, will allow differentiation of the urogenital sinus into
female external genitalia. According to genital sex assignment at birth,
an individual will be brought up as a boy or a girl by the parents and
4
society, which moulds his or her identity. Nonetheless, the issue of

gender identity is a complex one, especially in women exposed to
excessive amount of androgens during their intrauterine period of life,
as in cases of congenital adrenal hyperplasia.
Development of the ovaries
The initial step in primitive gonadal development entails genital ridge

formation by thickening of the coelomic epithelium on the medial
aspect of the mesonephros. This is followed by migration of
primordial germ cells from the wall of the yolk sac to the genital ridge
before and during differentiation of the gonad into a testicle or an
ovary. This early stage is similar in both sexes. Further development
of the primordial germ cells into the sex cords stage depends on the
presence of one X chromosome. However, further development of the
primitive gonads depends on the presence or absence of testicular
determining factor encoded in the sex determining region gene
(SRY). This is located in the short arm of the Y chromosome (9), and
converts the primitive gonads into testicles. Absence of this factor will
allow growth of the primitive gonads into ovaries instead. Further
development beyond the primary oocytes stage depends on the
presence of two X chromosomes. In the absence of a second X
chromosome, the primordial follicles will undergo rapid atresia
leading to degeneration of the ovaries into streak gonads. The
primitive gonad is normally destined to develop as an ovary by the
7th or 8th week of intrauterine fetal life.
Animal studies suggested that antimullerian hormone (AMH) plays a

critical role in both the morphological and endocrine gonadal sex
differentiation (10), beside its known inhibitory function on mullerian
system differentiation. Exposure of fetal ovaries to AMH resulted in
release of testosterone instead of oestradiol. This endocrine sex
reversal was attributed to suppression of aromatase enzyme activity,
as shown by the same authors. Furthermore, organ culture studies
showed that exposure of fetal ovaries to AMH induced the formation
of seminiferous cord-like structures.
Maturation of the HPO axis
Four different stages have been recognised leading to full maturation of

the HPO axis to its adult state:
1. Developmental stage;
2. Inhibitory stage;
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ABDEL -GADIR
3. Pubertal stage;
4. Adult stage.
The first or developmental stage begins with the differentiation of the
different parts of the axis during fetal life as described before. The
system becomes functional during the second trimester with
maximum secretion of gonadotrophins by the pituitary gland under
the control of the fetal hypothalamus. This coincides with a maximum
number of 7 million primordial follicles in the ovaries by the 24th
weeks of intrauterine life. The negative feedback mechanism
controlling gonadotrophins releasing hormone (GnRH) secretion starts
late during pregnancy and is coupled by progressive decline in
gonadotrophins secretion by the fetal pituitary gland. This phase is
characterised by increased oocytes atresia and loss of ovarian
primordial follicles, leaving behind only one million in both ovaries at
birth. Following birth and loss of the inhibitory placental steroids, the
neonatal hypothalamo-pituitary unit is reactivated resulting in more
gonadotrophins secretion which may exceed adult levels for about 3-
4 months. This again is followed by a slow decline in gonadotrophins
secretion to almost undetectable levels by the end of the second year
of life.
This is followed by an inhibitory stage which extends up to the age of

8-9 years. This juvenile hypothalamic pause is characterised by
minimal, if any, production of GnRH. The exact molecular changes
which lead to this arrest of the hypothalamic GnRH pulse generator
are not exactly known. Central neural suppression is frequently
quoted as the main cause. However, there is substantial evidence
now relating such arrest to an inhibitory gamma aminobutyric acid
(GABA) effect on the hypothalamus. There is increased level of the
hypothalamic mRNAs encoding for the enzyme glutamic acid
decarboxylase, which is responsible for the production of GABA, at
the time of GnRH generator arrest (11, 12). Reduction of this
inhibitory tone is associated with the onset of puberty (13, 14). A
similar effect has also been related to a high level of melatonin during
the inhibitory period of development (15). A reduction in melatonin
level to a critical value by the age of 10 years is associated with a
release of this inhibitory effect, and increased production of GnRH
and LH (16). Removing the ovaries during the inhibitory stage will not
lead to any increase in GnRH or gonadotrophins secretion, which is a
reflection of the extent of such hypothalamic pause. The pituitary
gland itself is less responsive to intravenous infusion or subcutaneous
administration of GnRH during this inhibitory stage of life. This is a
6
good indication that pituitary gland maturation is not totally

dependent on the hypothalamic GnRH pulse generation.
The pubertal stage follows the inhibitory phase, and signals the start of
the HPO axis maturation. It is an age dependent process which follows
genetically controlled CNS maturation necessary for the pulsatile release
of GnRH (17). However, changes in body weight and many biochemical
factors are also involved. For some time, onset of puberty was thought
to be initiated by adrenarche. This is especially so as there is gradual
increase in adrenal androgens secretion over a period of 2 years before
the onset of puberty. This is usually coupled by progressive increase in
the size of the adrenal cortex zona reticularis. However, this concept has
been challenged, and many other factors have emerged as more likely
initiators or facilitators of puberty onset. Attaining a minimum BMI with
minimum and critical body fat mass of about 17% is one such factor.
This results in an increase in the level of blood leptin which is a peptide
hormone produced by adipocytes. At a certain blood level threshold,
leptin facilitates the development of puberty, provided that other critical
control mechanisms are functional (18). Developmentally, leptin reflects
the amount of available energy reserves which are necessary for the
brain to start reproductive function. Its level starts rising by the age of
7 - 8 years and reaches a peak by the age of 13 – 15 years. Serum
levels subsequently shadow those of LH and oestradiol. Leptin has been
found to stimulate GnRH pulses, and accordingly induce gonadotrophins
production. It also stimulates the pituitary gland directly to produce
more LH than FSH. Another facilitatory factor for initiation of puberty is
a 54 amino acid peptide called kisspeptin which is encoded by the KiSS-
1 gene. Kisspeptin G protein-coupled receptor 54 (GPR54) is expressed
in GnRH neurons in the hypothalamus (19), and is considered as a
molecular gatekeeper for the HPO axis. It is the channel through which
kisspeptin directly stimulates GnRH release. This KiSS-1/GPR54 system
is an important regulator of puberty in all mammals. KiSS-1 mRNA and
GPR54 mRNA are both increased in the hypothalamus at the onset of
puberty, with high expression in the GnRH neurons (20). Nevertheless,
it is not clear yet whether this system is the actual trigger for the onset
of puberty (21). Its effect on gonadotrophins release can be blocked by
pre-adminstration of GnRH receptor antagonist (20). A wider role for
kisspeptin has been described in reproduction, as it is found in many
tissues in the body including the pituitary and ovaries. Its role in
metabolic control of puberty and fertility was shown by decreased KiSS-
1 gene expression in the hypothalamus in conditions with negative
energy balance (21, 22). Kisspeptin neurones are responsible for the
7
ABDEL -GADIR
suppression of puberty and reproductive disturbances in states of under

nutrition. This was thought to be the mechanism by which leptin
controls GnRH production, as it is a major metabolic regulator of the
KiSS-1 system. Furthermore, mutations which decreased or increased
GPR54 signalling caused isolated hypogonadotropic hypogonadism (23),
and gonadotropin-dependent premature puberty (24) respectively.
Kisspeptin neurones are also involved in the negative and positive
feedback mechanisms during the menstrual cycle, depending on their
location within the hypothalamus. Inhibition of KiSS-1 mRNA/kisspeptin
expression in the arcuate area is involved with the negative feedback
mechanism to oestrogen, whereas stimulation of the same system at
the periventricular nucleus is involved with the positive feedback
mechanism and LH surge at the middle of the cycle (25, 26).
Other important endocrine changes during early puberty include

increased levels of growth hormone releasing factor and the growth
hormone (GH) itself, mainly at night time. GH has been shown to
stimulate FSH induced granulosa cell differentiation. It also increases
intraovarian levels of IGF-1, and enhances ovarian response to
gonadotrophins. Together with IGF-1, they exert a paracrine
intraovarian control on steroidogensis.
This section can be summarised by the statement that changes in the

level of leptin and transduction of KiSS-1/GPR54 mRNA, coupled by
reduction in the hypothalamic GABA tone coincide with the onset of
puberty. All these factors, plus a genetically controlled CNS maturation
lead to release of the juvenile hypothalamic pause, allowing secretion of
large nocturnal GnRH and LH pulses which signify the onset of puberty.
With further development of the system into the fourth or adult

stage, these large nocturnal LH pulses become more frequent with
smaller amplitude. This may be due to increased nocturnal dopamine
activity at the same time. Further maturation leads to continuous
pulse production of both hormones during the whole day. This is
capped by maturation of the oestrogen positive feedback and LH
surge mechanisms. This usually occurs within 2 - 3 years after
menarche, and explains the anovulatory uterine bleeding commonly
seen during this period of time.
GnRH and gonadotrophins
GnRH is a decapeptide (10 amino acids) neurohormone produced

mainly in the preoptic area of the hypothalamus. It is secreted in
8
pulses into the hypophyseal portal vessels in the median eminence,

to be carried into the pars distalis of the pituitary gland. For
organised follicular development, FSH and LH should be produced in
tonic and cyclic patterns at different parts of the cycle, in response to
GnRH pulses. Tonic release indicates continuous production of both
hormones during the cycle, and the cyclic production is responsible
for the positive feedback mechanism at the time of ovulation.
Nevertheless, both tonic and cyclic production are pulsatile in nature.
The short plasma half life of LH which is about 20 minutes (27) allows
better perception of the pulsatile nature of its production than FSH,
which has a longer plasma half life of 45 – 60 minutes. This
difference is secondary to the amount of sialylated carbohydrate
moiety in the two hormones, being higher in FSH. On the other hand,
LH has higher sulphated structure than FSH. Such differences in half
life explain the lack of synchrony between the pulse patterns of both
hormones in relation to the short half life of GnRH pulses, which is
2.7 minutes. Furthermore, some GnRH pulses might not stimulate LH
production, due to temporary lack of response by the pituitary gland.
Other sources of GnRH in the peripheral blood include the pancreas,
and leakage from the organum vasculosum which is outside the blood
brain barrier. It is important at this point to differentiate between the
plasma and the biological half lives of any hormone. The plasma half
life denotes the time required by half of the hormone in circulation to
be metabolised or eliminated by natural means. Previous discussions
were related to this phenomenon. The biological half life is different,
and denotes the time for a certain hormone to lose half its
physiological or pharmacological effects. It is affected by receptor
interaction, activity of the hormone metabolites and its accumulation
in body tissues, beside the plasma half life itself.
Sustained large GnRH pulses desensitise the pituitary gland by

downregulating its own receptors on the surface of the gonadotrophs.
This suppression is always preceded by a short flare period, with
increased blood levels of gonadotrophins and oestradiol. GnRH
receptors are also found within the ovaries at the follicular level.
Accordingly, sustained non-physiological doses of GnRH can interfere
directly with ovarian function. They can reduce FSH induction of
follicular aromatase enzymatic activity, leading to reduced oestradiol
production. Furthermore, downregulation of ovarian LH receptors can
also result in reduced progesterone production.
Both FSH and LH are glycoproteins with an identical α chain having

92 amino acids. They have different amino acids sequence in their
9
ABDEL -GADIR
β chains, with 118 and 121 amino acids respectively in the two
hormones. This same α chain is also shared by the other glycoproteins,
mainly thyroid stimulating hormone (TSH) and human chorionic
gonadotrophins. FSH receptors are located in the granulosa cells,
whereas LH has receptors in both the granulosa and theca cells. As for
other protein hormones, these receptors are located in the cell
membrane and have short half life of 30 minutes, indicating rapid
turnover. Only about 2% of the receptors need to be occupied to initiate
a local response. Follicles are responsive to FSH stimulation only when
they reach or exceed 60-cell stage.
The characteristic functions of FSH can be summarised as follows:

• It stimulates granulosa cells hyperplasia;
• It stimulates accumulation of the liquor folliculi during
development of the antral follicles;
• It increases its own receptors as well as LH receptors;
• It induces the aromatase enzyme activity for the conversion of
androgens to oestrogen;
• It initiates the cumulus expansion and separation of the oocytes
and cumulus mass from the rest of the granulosa cells before
ovulation;
• FSH surge secures enough LH receptors to allow adequate
luteinisation after the LH surge.
On the other hand, the functions of LH include the following:
• It stimulates steroidogensis and production of progesterone and
androgens by the theca cells;
• LH surge is responsible for the actual act of ovulation. This is
dependent on the pituitary gland LH reserve, level of oestradiol
attained, and the duration of exposure of the hypothalamus to this
high oestrogen level;
• Luteinisation of the granulosa cells necessary for progesterone
production;
• It also stimulates resumption of meiosis with extrusion of the first
polar body just before ovulation.
The positive feedback and LH surge mechanism
Development of the positive feedback and LH surge mechanism is a

very intricate process, and forms the final maturation step in the
development of the HPO axis. With a mature positive feedback
mechanism, very small GnRH pulses upregulate their own receptors
10
in the pituitary gland, without causing any LH secretion. This pattern

is seen just before an LH surge, which is affected by a dose and
time controlled exposure of the hypothalamus and pituitary gland
to oestradiol, just before ovulation. Involvement of KiSS-1
mRNA/kisspeptin expression at the periventricular nucleus with the
positive feedback mechanism has been alluded to before. It takes 2
- 3 years for this mechanism to develop after menarche, and is one
of the reasons why early menstrual cycles are anovulatory, as
mentioned before. It is also the first to be affected adversely by
various abnormal endocrine conditions and medications which are
capable of affecting the production or action of the endogenous
hormones or neurotransmitters. This can lead to abnormal ovulation
and changes in menstrual cyclicity, abnormal uterine bleeding, and
ultimately anovulation and amenorrhoea. Different events occur at
the level of the hypothalamus, pituitary gland, and ovaries in
preparation for the LH surge:
• The hypothalamus secrets small and rapid GnRH pulses to
upregulate its own receptors at the level of the pituitary gland.
This is an oestrogen dose and duration of exposure dependent
process.
• This increase in pituitary GnRH receptors level is also associated
with an increase in the pituitary storage of LH itself. The LH surge
occurs when both attain a critical level, and the pituitary gland is
exposed to a critical level of oestradiol for a critical period of time.
• Changes within the ovary include increased production of
oestradiol before the LH surge, neovascularisation, increased
levels of prostaglandins and plasmin. These are also associated
with increased osmotic pressure and fluid influx into the follicle.
The actual LH surge starts at midnight, and peaks just before noon on
the following day. It lasts for about 48 hours, which corresponds to the
exhaustion of the accumulated pituitary LH reserve. Ovulation usually
occurs within 36-40 hours after the start of the LH surge.
The negative feedback
For completion purpose, the effects of oestrogen and progesterone on

the gonadotrophins negative feedback mechanism will be alluded to.
Both are capable of exerting a negative effect at the hypothalamus.
Increased level of oestrogen is associated with increased hypothalamic
dopamine and reduced adrenergic activity. Progesterone also increases
the level of hypothalamic endorphins. Accordingly, both steroids
can affect GnRH pulse generation. Significant inhibition of KiSS-1
11
ABDEL -GADIR
mRNA/kisspeptin expression at the arcuate nucleus of the

hypothalamus is also associated with the negative feedback as
mentioned before. At the level of the pituitary gland, both oestrogen
and progesterone can reduce gonadotrophins secretion by affecting
GnRH postreceptor activity, but not the receptors themselves. Inhibin
B is also important for the negative feedback control of FSH production.
The gradual increase in oestradiol and inhibin B secretion by the leading
follicle during the middle of the follicular phase is coupled by a gradual
decline in the level of FSH. These are important factors responsible for
securing monofollicular ovulation. A short loop negative feedback effect
is exerted by gonadotrophins on GnRH secretion at the level of the
hypothalamus. Furthermore, an ultrashort negative loop exists within
the brain with GnRH acting to suppress its own release (28).
Deterioration in the sensitivity of the hypothalamic negative feedback
mechanism with age has been considered as one cause for the increase
in follicular FSH levels in regularly menstruating women in their late 30s
and early 40s.
Factors affecting the HPO axis
Many environmental, neural and endocrine factors can affect the HPO
axis function, with variable consequences on the ovaries. The LH surge
is most vulnerable and is usually affected first. This may lead to
inadequate ovulation, dysfunctional uterine bleeding, infrequent
ovulation, and finally anovulation. The vulnerability of the HPO axis is
reflected by the fact that it is modulated by corticotrophins, cortisol,
adrenaline, noradrenaline, prolactin, dopamine, serotonin, thyroxine,
acetylcholine and gamma amino butyric acid, just as examples. This
explains how stress as well as thyroid or adrenal glands dysfunction can
be detrimental to the HPO axis function.
The most important environmental factors which can affect the HPO
axis are excessive weight gain or loss, bulimia even without weight
change, excessive exercise, morbid stress, depression and recreational
drugs. The hypothalamus GnRH pulse generation can be affected in
different ways. This will be discussed in more detail in other chapters in
this book.
The interrelationship between the different endocrine glands makes it

difficult, if not impossible, for a gynaecologist to practise reproductive
medicine without thorough knowledge of these interactions. This is
especially so for dysfunctions of the thyroid and adrenal glands as
well as hyperprolactinaemia. More information about these inter-
12
relations will be given in Chapters 3 and 4. Polycystic ovary syndrome

is the most common female endocrine dysfunction, and will be
discussed in chapter 6 in this book. Different LH and FSH pulse
patterns have been described (29), but there is general agreement
regarding increased LH pulse amplitude and probably pulse frequency
as well. However, the main endocrine characteristics of the syndrome
are hyperandrogenisation and anovulation.
Drugs both prescribed and recreational can affect the HPO axis.
Antipsychotic, H2-antagonists and certain anti-hypertensive drugs
can cause hyperprolactinaemia which can be symptomatic or
asymptomatic. Clinical consequences of high prolactin levels include
galactorrhoea, irregular menstruation, anovulation, amenorrhoea,
sexual dysfuncion, infertility and possibly osteoporosis. Atypical
antipsychotic drugs should be used instead, when indicated, as they
have negligible effects on prolactin dynamics. Reserpine, α-
methyldopa, labetalol, atenolol and clonidine should be changed for
newer anti-hypertensive drugs, after excluding other causes of
hyperprolactinaemia. On the other hand, alcohol forms the most
commonly used recreational chemical. It has a detrimental effect on
pubertal development, disrupts normal menstrual function, and affects
postmenopausal hormone levels (30). The effect of alcohol on puberty
involves the HPO axis, growth hormone and insulin growth factor-1
activities, which are functionally interrelated. Alcohol consumption
among adolescent girls between the ages of 12-18 years was shown to
suppress oestrogen levels for as long as 2 weeks, even after moderate
consumption (31). Lower LH (32) and growth hormone (33) blood
levels have been reported after alcohol consumption. Furthermore, the
development of regular menstrual pattern after menarche was
adversely affected by alcohol intake (34). The effects of alcohol on
oestradiol level after the menopause depended on the amount taken
and whether that individual was on HRT or not. Acute alcohol exposure
has been shown to cause temporary increase in oestradiol level in
women taking HRT. This was thought to follow decreased conversion of
oestradiol to oestrone (35). There was no similar effect on women not
using HRT. An opposite effect of chronic or high alcohol consumption
was noticed on the level of oestradiol in women using HRT (36).
Other drugs which can affect the HPO axis and cause irregular
menstruation and anovulation include heroin, cocaine, marijuana and
illegal steroids. They can reduce the fertility potential in men as well.
Narcotics in general increase signalling in the brain between
neurotransmitters, but the ultimate outcome is depletion of these
13
ABDEL -GADIR
chemicals including dopamine. This can affect the intellectual,

emotional and neuroendocrine activities of the brain. On the other
hand, sedatives and hypnotics reduce brain cell activity and accordingly
disrupt the neuroendocrine system.
Ageing of the HPO axis
The reproductive episode in human beings is very short. Maximum

fertility potential spans for only few years between the ages of 23-29
years. This episode is preceded and followed by times of reduced fertility
potential due to immaturity, to start with, and aging thereafter of the
HPO axis respectively. To be more accurate, aging of the HPO axis starts
during fetal life after the 24th week of pregnancy. Accelerated loss of the
primary follicles starts at that time, and drops from 7 million to one
million at birth as mentioned before. This is followed by further atresia,
and only 0.7 million will be found in both ovaries by the time of
menarche. It is estimated that about 100 follicles will be found by the
time of menopause. Such ovarian aging is also associated with increased
oocytes chromosomal abnormalities after the age of 35 years. This topic
has been reviewed by Pan et al in 2008 (37). The reported incidence of
aneuploidy in eggs from women in their 20s’ was about 2%, but
increased dramatically to 35% around the age of 40 years. This figure
can reach 50% of ovulated eggs in older women. These changes were
due to non-disjunction, errors during meiosis, and spindle abnormalities
as reported by the same authors. Accordingly, ovarian aging is marked
with the presence of fewer oocytes with higher chromosomal
abnormalities. The implantation capacity of embryos also declines with
age. A figure of 18.2% has been reported for women at the age of 25-
29 years. The corresponding figure was 6.1% for women 40-44 years
old (38). The earliest endocrine change to signal ovarian aging is a
significant decline in the production of antimullerian hormone by the
granulosa cells. This is followed after a variable period of time by a fall
in the circulating level of inhibin-B, with no significant changes in inhibin-
A or oestradiol. This will later progress on to a decline in inhibin-A and
oestradiol blood levels, and a rise in FSH level without any further
change in inhibin-B (39).
At the same time, an independent hypothalamic ageing process has

been suspected, not related to the ovaries. The responsiveness of the
hypothalamus to oestrogen negative feedback decreases with age,
which was attributed to elevation of the hypothalamic sensitivity
threshold. This was thought to follow an age related decrease in
hypothalamic catecholamines, decreased uptake of oestrogen by the
14
anterior and mediobasal hypothalamus, and diminished activity of the

pineal gland (40). All these factors contribute in causing the high FSH
blood levels and changes in LH pulse pattern detected during the early
follicular phase in regularly menstruating women in their late thirties,
compared to younger women. Further arguments have also been put
forward to support this concept of hypothalamic aging including:
• The occurrence of hot flushes in women between the ages of 35-
40 years, despite having regular menstrual cycles;
• The age dependent changes in FSH level could not be explained
by changes in the levels of inhibin B and oestradiol in all women.
Unfortunately, FSH is not a very reliable marker of ovarian ageing, at
least in its early stages. This is because of the following reasons:
1. It is produced in pulses and timing the blood sample within that
pulse can affect the FSH level. The peak, the trough or any point
in-between can be represented;
2. High FSH can be seen during some but not all cycles during the
early stages of the climacteric period. This pattern becomes
more frequent with time, till it becomes established during all
cycles;
3. High oestradiol in the early follicular phase can suppress FSH
production and leads to normal FSH blood levels. Accordingly,
oestradiol level should be tested in the same sample for
endocrine coupling. A high level ≥200 pmol/l is equally important
as a high FSH level in reflecting a reduced ovarian reserve.
Transvaginal ultrasound examination on day 2 or 3 of the cycle
may show:
• Rapid follicular recruitment with a single advanced or large

follicle. Such follicle can produce high oestrogen (>200 pmol/l)
which can affect FSH level. In such cases rapid growth and
maturation of the dominant follicle will lead to a short follicular
phase. This explains why polymenorrhoea is the first sign of the
climacteric period or incipient ovarian failure. Such short cycles
should be differentiated from those caused by short luteal
phase due to high prolactin level, thyroid dysfunction, and
polycystic ovary syndrome. Ultrasound cycle monitoring will
differentiate between the two categories.
• Multiple follicles recruitment, with many of them growing to a
medium size during the early part of the follicular phase,
can lead to high oestradiol level and falsely normal FSH blood
level.
15
ABDEL -GADIR
More information about other conditions which may affect FSH blood level
can be found in Chapter 14. Figure 1 shows 18.5 mm follicle in the left
ovary on day 5 of the cycle which was diagnostic of rapid follicular
recruitment. This patient had polymenorrhoea with short follicular phase.
Note the lack of any activity in the right ovary. Figure 2 demonstrates
multiple follicular recruitment on the 3rd day of the cycle. The patient was
31 years old. She had one 12 mm follicle in the left ovary and 3 others in
the right one measuring 14.5 mm, 12.5 mm and 10.5 mm respectively. She
also had short menstrual cycles. Note the small size of the left ovary. Her
FSH blood level was 6.8 IU/L and oestradiol 248 pmol/l on the same day.
Normally, a single dominant follicle produces enough oestradiol during

the mid follicular phase to switch off FSH production, causing demise of
the other recruited ones. This may not be the case during the late 30s
or early 40s as one follicle may not produce enough oestradiol to achieve
that purpose. This may be due to elevation of the hypothalamic negative
feedback sensitivity threshold as mentioned before. Accordingly, more
than one follicle will be needed to produce the necessary amount of
oestradiol. Consequently, two or more follicles will reach maturation and
ovulate in the same cycle, probably with a wide ovulation window,
depending on their size. This explains why binovular twins are more
common in women in their late 30s, than in younger ones. Accordingly,
such twining is a sign of reduced HPO axis integrity with compromised
negative feedback mechanism to oestradiol. It is definitely not a sign of
increased or enhanced fertility potential, as commonly thought.
Figure 3 shows double ovulation in a spontaneous monitored cycle with a

corpus luteum in each ovary, in a 37 year old woman. On the other hand,
16
Figure 4 shows a dominant follicle in the right ovary and a corpus luteum in
the left one. A colour Doppler copy of this picture on the back cover shows a
good vascular rim around the dominant follicle in the right ovary indicating
imminent ovulation in a different patient of almost similar age. This case
demonstrated a wide ovulation window with two follicles ovulating at different
times, which is not uncommon during natural cycles in women in their late 30s.
It can be safely stated that a single normal FSH test has a very low
diagnostic or even screening value for ovarian reserve, according to the
facts discussed above. In contrast, a single high level >13.0 IU/L
performed in a reputable laboratory indicates reduced ovarian reserve,
even if repeating the test in more than one occasion showed normal
values (41, 42). Accordingly, such repetition in subsequent cycles in a
woman who had a single high value is not indicated, and adds
unnecessary costs. Different ways have been tried to improve the value
of FSH as a predictor of ovarian reserve including:
• Multiple blood samples within the period of the FSH pulse (60-90
minutes);
• Repeating the blood test during consecutive cycles;
• Injecting a bolus dose of 100-200 μg of GnRH, and test the level
of FSH one hour after the injection, relative to the basal value.
Women with incipient ovarian failure usually have an exponential
rise in the level of FSH;
• The clomiphene citrate challenge test has been used extensively
for that purpose. Following a basal blood sample on day 3 of the
cycle, the patient is asked to take 100 mg of clomid for 5 days. By
day 10 of the cycle, the level of FSH is again assayed. Women with
reduced ovarian reserve are expected to have blood levels ≥10.0
IU/L. Normally, FSH level should be lower due to the negative
effect of oestradiol and inhibin B produced by the follicle at this
stage of the cycle. Higher cut-off FSH levels have been used by
different authors, including the summation of day 3 and day 10
blood levels. Further information can be found in Chapter 14.
These tests have been used as an indirect measurement of the ovarian
reserve or follicular pool, and to predict the clinical response to
ovulation induction in women >35 years of age, who are seeking to get
pregnant. They are not sensitive, and better tests are now available for
that purpose. Furthermore, they should not be used to predict the
exact time of cessation of natural fertility (43), or the age at
menopause. Inhibin B blood levels and antral follicle count on day 3 of
the cycle have been used for some time, but have been superseded by
antimullerian hormone (44) which has the added value of having a
17
ABDEL -GADIR
non-variable level at different times of the cycle. Accordingly, the test

can be requested at any time, and not restricted to the early follicular
phase. It is especially useful for the assessment of follicular pool in
young women with relatively high FSH and regular periods (incipient
ovarian failure) or high FSH and oligomenorrhoea (transitional ovarian
failure). Young women need to have their ovarian reserve tested after
a shorter period of infertility than usual in the following circumstances:
• Following ovarian surgery;
• Following ovarian irradiation;
• Women with a single ovary;
• Irregular periods with family history of early menopause;
• Associated autoimmune problems mainly of thyroid and adrenal
nature.
Other endocrine changes which occur with aging, but are not related to the
climacteric are progressive decline in the level of dehydroepiandrosterone
and dehydroepiandrosterone sulphate. Despite 50% fall in testosterone
level between the ages of 20-40 years, little if any changes occur during the
transitional perimenopausal period. Its level may even rise, after the
menopause (45).
Summary
It is evident that the function and integrity of the HPO axis as a single unit
can be affected by many factors, both from within or without the axis
itself. Accordingly, understanding the pathophysiology of this system
relies on thorough knowledge of normal function and dysfunction of other
endocrine glands, and how they may interact to disrupt its function. The
information provided in the subsequent chapters included in this book will
hopefully help in building up the necessary knowledge to allow the reader
to deal with all related problems. In essences this chapter was meant to
be a launching pad or platform for the rest of the book.
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22
Chapter 2
Normal and Abnormal Puberty
Normal pubertal development
Normal puberty is the transitional period between childhood and

adulthood, which is characterised by physiological, psychological and
physical changes in preparation to sexual maturation and
reproductive capability. These are usually coupled with changes in the
attitude of the pubertal girl toward her family and peers. To be able
to deal with abnormal pubertal problems, one should recognise and
understand the different stages leading to a fully functioning
hypothalamo-pituitary-ovarian (HPO) axis with intact and functioning
genital organs. Four such stages have been described in Chapter 1.
They are the developmental, inhibitory, pubertal and adult stages of
development in that chronological sequence.
Anatomical maturation
Variations in pubertal development in girls have been documented by

Marshall and Tanner in 1969 (1). Breast development (thelarche) is
usually the first visible sign of puberty following activation of the HPO
axis, and increased production of oestradiol by the ovaries. Thelarche
may occur at different times in different racial groups, but usually by
the age of 8-11 years. It may be unilateral initially, and follows pubic
hair growth in almost 15% of the cases. Racial differences have been
reported in this respect, and pubic hair growth preceded thelarche in
most African-American pubertal girls as reported by Herman-Giddens
et al (2). The same authors reported that 30% of African-American
girls had started pubertal development by the age of 7 years, and
50% by the age of 8 years. The corresponding figures for Caucasian
girls were 15% by the age of 8 years, and 40% by the age of 9
years. This racial difference may soon disappear or at least get
narrower as twice as many White American girls showed breast
development at the age of 7 years between 2004 and 2006 compared
to 1997. On the other hand, there was no difference in the
percentage of African American girls who showed early signs of
23
ABDEL -GADIR
puberty during the same period of time. Development of pubic hair

and the breasts, during puberty, has been documented by Tanner in
1962 (3) as shown in the table 1.
Table 1 shows the different development stages in Tanner’s classification of puberty (3).
stage Breast development Pubic hair development
1 No breast development No pubic hair
2 Breast bud stage Sparse labia major hair
3 More growth with appearance of areola Hair reaching mons pubis
4 Secondary mound of areola and papilla Adult hair not reaching medial
thighs
5 Areola recession with projecting papilla Hair reaching medial thighs
Normally, increased linear growth is caused by increased levels of

oestrogens and growth hormone. The role of adrenal androgens in this
respect has been challenged (4, 5). Some linear skeletal growth had
already occurred by the time of thelarche, but a peak adolescent growth
spurt of 8-9 cm/year usually corresponds to Tanner stages 2-3 breast
development (6). This rate usually falls down to 4 cm/year by the time
of onset of menstruation (menarche). Complete fusion of the epiphyses
usually occurs within 2 years after menarche.
Oestradiol plasma levels usually vary widely between one cycle and
another during the early stages of puberty, because of incomplete
development and maturation of the HPO axis and irregular ovulation.
Nevertheless, there is enough oestrogen to cause physiological and
anatomical changes in the vulva, vagina and uterus, increasing their
thickness and size. Vaginal skin colour also changes from red
prepubertal to well oestrogenised pink adult colour. Haber and Mayer
used ultrasound scanning to describe ovarian and uterine size from
birth to puberty in 1994 (7). Interestingly, they found that the uterus
started to increase in size two years before the ovaries, even before
any pubertal signs were present. They reported ovarian volumes of 0.8
cm3, 1.3 cm3, 3.7 cm3 and 6.7 cm3 at the ages of 7, 11, 13 and 15
years respectively. These are almost similar to figures reported by
other investigators. Two parameters were used by different
investigators to measure uterine size, mainly the uterus/cervical length
ratio and uterine volume. A fundal-cervical ratio equal to 1 was 100%
specific for identifying prepubertal girls but not pubertal ones (8).
Menarche usually takes place 2-3 years after the start of thelarche, at
an average age of 12-13 years. This can also be affected by familial and
racial factors which should be taken into consideration.
24
Before discussing abnormal pubertal development, it is important to

remember the following points:
1. Puberty is an age dependent maturation;
2. Pubertal CNS maturation is genetically dependent;
3. Onset of puberty differs in different families and racial groups.
Abnormal Pubertal Development
Initiation of puberty usually varies between the ages of 8-14 years, but
this age is getting lower over the last century. Even with this general
trend, racial, constitutional, and familial differences have been noticed.
This may be due to obesity and exposure to environmental chemicals.
Furthermore, girls growing in stressed families tend to reach puberty
earlier as reported by Moffitt el al in 1992 (9). The social effect is
complicated further by the finding that puberty may occur earlier if the
father is absent or a stepfather is present (10). These are only few
points to be taken into consideration when comparing information
between different reports. Signs of puberty can start early or
precocious before the age of 7-8 years, depending on the racial
differences mentioned before. Puberty can also be delayed in different
ways including:
• Absent secondary sexual characteristics by the age of 13 years;
• No menstruation by the age of 16 years with partial or complete
development of secondary sexual characteristics;
• Passage of 5 years between thelarche and menarche.
Delayed Puberty
For better understanding and management of delayed puberty, a simple

diagnostic classification will be used including simple delay, anatomical,
hypergonadotropic, and hypogondotropic causes. Unlike boys where
constitutional delay makes >50% of the cases, more than 80% of girls
with delayed puberty have pathological causes (11). The commonest in
this group is Turner’s syndrome.
Anatomical causes
Anatomical causes are mainly related to failure to menstruate, despite

normal secondary sexual characteristics. They can be further divided
into mullerian dysgenesis and distal genital tract obstruction. They are
very different developmentally, though they share a common diagnostic
subgrouping.
25
ABDEL -GADIR
Mullerian dysgenesis
Female genital anomalies occur in about 5% of women (12), and can

be asymptomatic in many cases. They are associated with other
malformations, especially of the kidneys and skeletal system in about
30% of the patients. Normal development of the fallopian tubes,
uterus, cervix and upper two thirds of the vagina depend on normal
differentiation, fusion and canalisation of the two mullerian ducts
during early fetal life. Such progression of normality can be disrupted
at different stages of development, leading to different anatomical
abnormalities. In the context of menstrual function, the final outcome
will be normal secondary sexual characteristics with no menstruation
due to partial or complete absence of the uterus, cervix or upper
vagina. In cases of cervical or upper vaginal agenesis with an intact
uterus, the condition will simulate lower genital tract obstruction with
cryptomenorrhoea and accumulation of blood into the uterus
(haematometra). This leads to an enlarged uterus which can be felt
abdominally. Obstructive genital tract anomalies can cause retrograde
menstruation, pelvic pain and possibly the development of
endometriosis (13). Elevation of the bladder with urethral elongation
and narrowing may lead to urine retention. Accordingly, suppression
of menstruation with an oral contraceptive pill is indicated in these
cases till surgical treatment is arranged.
A specific condition of complete or incomplete uterovaginal dysgenesis

is the Mayer-Rokitansky-Küster-Haüser’s syndrome (MRKH), with an
incidence of 1:4500 women. An absent vagina may be associated
with an absent or very small uterus with normal ovaries and normal
46XX peripheral karyotyping. Accordingly, the patient fails to
menstruate, although she has normal secondary female sexual
characteristics. Normally the mammalian HOX genes, which are a
subgroup of homeobox or transcription factor genes, are involved in
urogenital differentiation. However, a recent study showed that
mutations within these genes were not involved as a cause of MRKH
syndrome (14).
Distal genital tract obstruction
Embryologically, the lower part of the vagina and vulva are not part
of the mullerian system. They develop from the urogenital sinus. The
hymen separates the lumen of the vagina from the urogenital sinus
cavity till late in fetal development and ruptures during the perinatal
period (15). The two main anomalies in this group which can prevent
26
discharge of menstrual blood are an imperforate hymen, and

transverse vaginal septum.
Imperforate hymen
Imperforate hymen is usually an isolated random anatomical

abnormality, though familial cases have been reported (16). Its exact
incidence is not known, but a figure of one in 1000 newborn infants
has been quoted. In a small study, Heger et al in 2002 (17) found one
case in 147 premenarchal girls (<1%), with a mean age of 63 months.
It can be identified during the newborn physical examination or during
early neonatal life as bulging mucocolpos due to stimulation of mucus
production by maternal oestradiol (18). This will be absorbed over
time if undiagnosed, and identified only after the onset of puberty. The
patient may present with urinary retention due to elevation of the
bladder and narrowing or occlusion of the stretched urethra over
the distended uterus and vagina. More often, the typical presentation
will be cyclic lower abdominal pains, due to obstruction of menstrual
blood outflow. Examination may reveal a lower abdominal mass, but
the diagnosis is usually made when a bulging mass with blue
discolouration is seen during vulvar inspection. Treatment is usually
easy, with simple incision of the hymen. It should be done under
aseptic conditions to prevent ascending infection, as the collected old
blood is good media for bacterial growth. This should be done only
after affirmative diagnosis and exclusion of other causes of vaginal
obstruction. Careful examination might be necessary occasionally to
differentiate between an imperforate, cribriform and microperforate
hymen. In the later two cases, only small amount of menstrual blood
will be discharged at a time, leading to prolonged episodes of blood
loss. There is also a risk of accumulation of blood in the vagina above
the hymen.
Transverse vaginal septae
Transverse vaginal septae are less common than the imperforate

hymen with an estimated incidence of 1 per 70,000 women (19, 20).
They result from incomplete fusion between the urogenital sinus and
the mullerian duct components of the vagina, or failure of the initial
vaginal core to canalise completely (21). They can be found at
different levels; being 46%, 40% and 14% in the upper, middle and
lower parts of the vagina respectively (18). Upper septae are usually
perforate and allow discharge of some menstrual blood depending on
the degree of obstruction, but lower ones are more likely to be
27
ABDEL -GADIR
obstructive. Perforate septae can cause hypomenorrhoea,

dysmenorrhoea, dyspareunia, and infertility (22). On the other hand,
obstructive ones usually cause cryptomenorrhoea, which can lead to
vaginal and uterine distension which may be palpable abdominally.
Diagnosis is not difficult in such cases. Transabdominal ultrasound
scan examination will reveal a uterus and upper vagina distended
with altered fluid of mixed echogenicity. Surgical treatment is usually
more elaborate in comparison to simple incision of an imperforate
hymen. It should involve excision of the septum and the scarred
vaginal area surrounding it, to prevent future strictures formations.
Accordingly, it should be done by a gynaecologist experienced in
adolescent gynaecological surgery. Furthermore, an exact diagnosis is
necessary to ascertain the thickness of the septum and the patency
of the vagina proximal to it. MRI is the best modality for this
purpose. To reduce the risk of scar formation and hour-glass
constriction, vaginal dilators should be used after surgery. This is
valid even for perforate septae. A case report published by Nichols et
al in 2010 reported secondary amenorrhoea following excision of a
microperforate transverse septum in a woman who had regular
menstruation for 4 years before surgery (22).
Hypogondotropic delayed puberty
Unlike the anatomical anomalies group, patients with

hypogonadotropic hypogonadism usually fail to develop secondary
female sexual characteristics, and do not menstruate either. They
have normal internal and external genital organs, normal peripheral
karyotyping and low gonadotrophins and oestradiol blood levels.
Constitutional delay makes the most common diagnosis in this
diagnostic subgroup. Other causes include:
• Isolated gonadotrophin deficiency may be associated with
anosmia, as well as other somatic abnormalities as in Kallmann’s
Syndrome. Abnormal development of the olfactory bulbs has been
documented with MRI in these cases.
• Under-weight young females especially anorexics usually have
delayed pubertal development, and may not go through this
developmental stage at all, depending on the suppression level of
the HPO axis. Gymnasts usually fall within this subgroup.
• Chronic systemic diseases can also interfere with the onset of
puberty. Examples of such conditions include Crohn’s disease,
cystic fibrosis, tuberculosis, thalassaemia major, coeliac disease
and malnutrition.
28
• It is also important to exclude intracranial tumours mainly

pituitary adenomas and craniopharyngiomas.
• Isolated deficiency of GH can lead to pubertal delay. It may reduce
gonadal response to gonadotrophins. Normal pubertal growth can
be restored by GH administration.
• Suppression of the HPO axis may also follow hyperprolactinaemia,
hyperthyroidism and Cushing’s syndrome. Patients usually show
clinical features related to the specific endocrine dysfunction,
especially in the last two problems.
• Idiopathic panhypopituitarism is another possibility with other
tropic hormones affected, to different degrees.
Hypergonadotropic delayed puberty
This is a distressing situation, as it usually indicates gonadal failure with

little chance of normal recovery. Depending on the onset of the
condition, a patient can present with no or partial secondary female
sexual characteristics. The most common diagnosis in this group is
gonadal dysgenesis. Normal development of the primitive gonads
depends on the presence of one X chromosome. Further development
depends on the presence or absence of testicular determining factor,
encoded in the sex determining region gene (SRY). A primitive gonad
will progress into an ovary in the absence of this factor, up to the stage
of primary oocytes. Further development of these oocytes depends on
the presence of two complete X chromosomes; otherwise accelerated
atresia of the primary oocytes takes place leading to gonadal
dysgenesis, with fibrous streak gonads. Gonadal dysgenesis can be seen
in different forms including 45XO, 46XX, 46XY, and in different
combinations or mosaics. Further information about this subject can be
found in chapter 3. With pure gonadal dysgenesis, patients usually fail
to develop secondary sexual characteristics, but mosaics may present
with variable phenotypes depending on the presence or absence of a Y
chromosome.
Androgen insensitivity syndrome
In this diagnostic entity, patients with 46XY chromosomes develop

secondary female sexual characteristics including good size breasts and
body habitat. They usually have no or sparse axillary and pubic hair, and
will fail to attain menarche. Testicular development is complete with
normal production of androgens, but deficiency of androgen receptors
prevents masculinization of the urogenital sinus into a male gender. The
patient presents with normal looking vulva and short blind vagina.
29
ABDEL -GADIR
Internal genital organs will be missing due to suppression of the mullerian

ducts development. The testicles may be felt in the inguinal canals. The
main diagnosis in this group is testicular feminization syndrome which
should be differentiated from Mayer-Rokitansky-Küster-Haüser’s
syndrome (MRKH). The latter patients present with vaginal agenesis with
absent or very small uterus. They also have normal female 46XX
peripheral karyotyping and blood testosterone levels within the normal
female range, in contradistinction to patients with androgen receptors
insensitivity syndrome. On the other hand patients with partial rather
than complete androgen receptors insensitivity usually present with
variable degrees of pubertal masculinization.
Precocious or accelerated puberty
Young girls may start pubertal development before the age of 8 years.
Such precocity may be feminine (isosexual), or masculine (heterosexual),
and development can be complete or partial within the two main groups.
These groups can further be divided into the following subgrouping for
practical clinical application.
Complete isosexual precocity

Central type
Central complete isosexual precocious puberty is the most common type

and is seen in 70% of the cases. It follows gonadotrophins dependent
oestradiol secretion due to premature activation of the HPO axis. It is
interesting to note that such patients were found to have a high incidence
of polycystic ovaries, with clinical and biochemical hyperandrogenisation
when examined at least 3 years after attaining menarche (23). The
remaining 30% usually have neurogenic causes which are more common
in extremely young girls at onset of puberty. Identified lesions include
head trauma, hydrocephalus, postinfectious encephalitis, congenital
brain defects and tumours including pituitary adenomas, hamartomas
and astrocytomas (24), hence the need for brain MRI examination to
exclude such pathology. A recent study showed that MRI should be
performed in all patients with central isosexual precocious puberty, as
neither age nor any other clinical parameters differentiated between
patients with or without brain tumours (25).
Peripheral isosexual precocity
In this group, oestrogen production is not related to central activation

of the HPO axis. The most common causes are ovarian tumours,
30
especially the granulosa and theca cell types. Diagnosis can be

facilitated with the help of the relevant hormonal tests, and pelvic
ultrasound scan examination. Other causes include hypothyroidism
with high TRH production, which can lead to secondary stimulation of
gonadotrophins secretion by the pituitary gland. Early diagnosis and
treatment of the hypothyroid state will prevent the development of
such precocious puberty. This entails inclusion of thyroid indices in
the endocrine testing of these patients. Rarely, oestrogen producing
adrenal tumours can be the cause. Yet again, ingestion of neglected
hormones, especially the oral contraceptive pill can lead to abnormal
uterine bleeding, and some breasts development rather than full
blown precocious isosexual puberty.
This section will not be complete without mentioning McCune-Albright

syndrome (MAS) which has an estimated prevalence between 1 in
100,000 and 1 in a million. It is characterised by precocious puberty
due to autonomous oestrogen secretion by the ovaries, with low
gonadotrophins blood levels. It is not an inheritable disease, and is
usually identified by the café-au-lait skin patches, which are
characteristics of the syndrome, as well as fibrous dysplasia. Patients
may have facial or other single or multiple bone deformities which are
usually unilateral. It is caused by mutation in the alpha subunit of the
G protein (GNAS1) in few somatic cells (26). Such mutations have
been described in many tissues including pituitary adenomas, thyroid
adenomas, ovarian cysts, monostatic bone dysplasia and the adrenal
glands (27). Accordingly, it has been suggested that MAS, non-MAS
fibrous dysplasia, and the endocrine lesions mentioned before
represent a spectrum of phenotypic expression with different patterns
of somatic GNAS1 mosaicism (24). This point is supported by the fact
that patients with MAS also have a tendency to develop pituitary and
thyroid tumours, hyperparathyroidism, hyperthyroidism, gigantism
and adrenal abnormalities. Serum FSH and LH are usually low both
at the basal state, and after GnRH stimulation. Accordingly,
suppression with GnRH analogues will not be an effective treatment.
Medroxyprogesterone acetate is particularly useful for controlling
abnormal uterine bleeding. Aromatase enzyme inhibitors and
oestrogen receptor antagonists can be used to block oestrogen
production and effect respectively. Testolactone which is an
aromatase enzyme inhibitor has been used successfully for this
purpose (28). It resulted in significant reduction in oestradiol blood
levels, ovarian volume, and the mean rate of bone maturation.
Menstruation also stopped in 3 of 4 girls who were menstruating
regularly before medication was started.
31
ABDEL -GADIR
Incomplete isosexual puberty
This is the situation when only one secondary sexual characteristic

developed early, with no other sign of pubertal development. The three
main categories are:
1. Premature development of the breast (thelarche) before the
age of 8 years is the most common in this group. It is usually
unilateral and no treatment is required in most cases, other
than reassurance. A hormone test usually shows normal
oestradiol and LH levels, with occasional slight increase in FSH
level.
2. Premature adrenarche entails early development of axillary hair
before the age of 8 years. It can also be associated with early
change in body odour, due to activation of the apocrine axillary
sweat glands. This can be the first sign detectable by the parents.
It does not need any treatment if it stayed as an isolated non
progressive condition. Follow up will be needed to ascertain no
further development.
3. Premature pubarche indicates growth of pubic hair before the age
of 8 years as well. It is considered to be more sinister than
premature axillary hair development, as it may follow adrenal or
organic brain diseases. It is caused by functional increase in
adrenal gland androgens production in most cases. It can also
lead to complete heterosexual precocious puberty.
Heterosexual precocious puberty
Development of secondary male characteristics in an individual brought

up as a female has devastating effects on the patient and her family.
Many causes can be involved with such premature hyperandrogenisation,
but misuse of drugs should be excluded before indulging into any
complicated investigations. The most common cause of such
hyperandrogenisation is partial adrenal 21-hydroxylase enzymatic
deficiency. Other enzymatic defects can be involved less frequently.
Further information will be covered in Chapter 4, dealing with the adrenal
factor in gynaecology. Ovarian, and less frequently adrenal tumours, can
be seen in such cases and should be investigated especially in patients
with rapid and severe hyperandrogenisation. It is important to address
abnormal production of androgens as early as possible, because of its
negative impact on the patient and her parents. Early management is
more likely to prevent disfiguring skin lesions, and a final short adult
stature.
32
Management of abnormal pubertal development
The main priority in managing patients with abnormal pubertal

development is to distinguish between underlying pathological
conditions, and constitutional or benign pubertal changes. This is
especially so in cases with premature thelarche and isolated axillary
hair growth. More active approach will be needed in cases of early
heterosexual precocity, due to the long lasting implications of the
condition. Early referral to specialist care will be necessary in such
cases, if local expertise is not available. Only reassurance will be
necessary with little or no intervention in most cases presenting with
delayed pubertal development. Nevertheless, a well constructed
protocol should be at hand to investigate all these patients, and a
multidisciplinary team should be available to deal with their different
needs.
Clinical assessment
Thorough history should be taken including childhood disease,

especially in cases of delayed puberty. Nutritional history should be
ascertained in underweight girls. History of drug misuse, especially
neglected oral contraceptive pills is important to elicit, though it is
usually denied. The ages when the patient’s mother and her elder
siblings have gone through puberty are also important to know. Similar
pubertal developmental abnormality in other family members may
indicate a familial tendency. Family history of mental retardation and
other genetic diseases should be sought as well. Male mental
retardation and somatic characteristics including long face, prominent
ears, hyperflexible finger joints and double joint thumbs are few
characteristic related to fragile X syndrome.
Clinical assessment of the patients’ phenotype may reveal signs of

chromosomal abnormalities, and chronic systemic or endocrine diseases.
Examination should include height, weight, arms span and blood pressure.
The upper to lower (U/L) body length ratio is a simple parameter to test,
and can give very useful information. Normally this ratio is equal to 1.0 by
the age of 10 years, and falls to 0.9 in adult Caucasians, and 0.85 – 0.9 in
African Americans. Lower body length is usually longer in hypogonadal
patients, and the U/L body ratio will be reduced. The situation is reversed
in patients with hypothyroidism, and the ratio may exceed 1.0 which is a
reflection of the shorter long bones. On the other hand, a normal ratio is
usually seen in cases with constitutionally delayed puberty, growth
hormone deficiency and chronic diseases. Tanners’ breasts and pubic hair
33
ABDEL -GADIR
staging (3) should be documented as well (Table 1). The breast should also
be examined in the supine position, especially in overweight girls to guard
against errors caused by fat. Other somatic and endocrine signs should be
noted and included within the total management plan of the case. This is
especially so for hyperandrogenic signs, and signs of thyroid dysfunction.
Neurological examination should be conducted including examination of
the optic fundi, visual fields and sense of smell. It is important not to put
these young patients under undue stress during examination, and they
should not be overexposed. The presence of a female member of staff and
the mother usually gives reassurance during medical examination.
Inspection of the genital organs is important, but digital vaginal
examination should be done only if the patient is sexually active. It can
reveal a blind vagina. Rectal examination should not be attempted, as more
useful information can be obtained with ultrasound scan examination. Any
mass in the groin or anterior abdominal wall should raise the suspicion of a
dislocated testicle, and should be ascertained with imaging. For follow up
purposes, growth velocity should be plotted in a growth chart. This will
show the exact growth rate in a fixed time scale, and allows comparison of
current height with previous or old records. Follow up of development and
response to treatment can also be documented with digital photographs,
after seeking consent, and the photographs kept by the family. This would
reduce the usual denial of any improvement by the patients or their families
who usually seek dramatic changes within short periods of time.
Hormonal and genetic investigations
Investigations should depend on the patient’s age, her mode of

presentation and provisional clinical diagnosis. Hormonal tests should
include FSH, LH, oestradiol, thyroid indices, 17-hydroxyprogesterone,
androgens and prolactin, as indicated. A difference between FSH and LH
should be appreciated at this point. Both are produced in pulses with
progressive increase in the highest limit of each hormone during the
progressive stages of puberty. However, only the lower limit of LH
increases at the same time, but not FSH, and can be used for the
diagnosis of precocious puberty (29, 30). Dynamic testing of the pituitary
gland with a bolus dose of GnRH analogue can be helpful, but are rarely
necessary. A brisk response of both gonadotrophins will indicate delayed
puberty; whereas an exaggerated response of only FSH is a marker of
partial primary ovarian failure. With isolated thelarche, patients may also
have an exaggerated FSH response to GnRH challenge test, but lower
basal and post GnRH test LH levels than other girls with precocious
puberty (31). In contrast, central precocious puberty is usually
34
associated with higher LH response after this test, compared to

prepubertal girls.
Peripheral karyotyping is indicated especially in cases of heterosexual

precocity, suspected gonadal dysgenesis, hypergonadotropic
amenorrhoea and suspected cases of resistant androgen receptors
syndrome. It can help in many ways, as to the presence of numerical
chromosomal abnormalities, and in cases with XY instead of XX
chromosomes.
Imaging investigations
Pelvic and abdominal ultrasound scan examinations are necessary to

visualise the uterus and ovaries. Scanning can also help in cases with
suspected haematometra and haematocolpos. Bone age is important to
ascertain with X-ray examination of the left hand and wrist, against a
standard atlas. It should be used, rather than the chronological age, to
interpret the hormonal results related to the HPO axis. It is also useful in
differentiating between premature thelarche or adrenarche and true
precocious puberty. Furthermore, it helps in deciding when to start
treatment in cases of delayed and precocious puberty, and to monitor
response to treatment. A bone age 2 years more advanced than the
chronological age is a definite proof that puberty has already started. On
the other hand, a bone age within one year of the chronological age is an
indication that puberty has just started, or has not started yet. Recently,
ultrasound examination has been introduced instead of X-ray, for
assessing bone age.
Brain tumours and pituitary adenomas should be investigated with MRI,

when indicated. This is especially so in younger patients, and those with
neurological symptoms or signs. All patients with central isosexual
precocious puberty should also be similarly investigated (25). MRI
examinations are also very useful for the diagnosis of adrenal tumours.
Treatment of abnormal puberty
Treatment of abnormal pubertal development depends on the age of

the patient, her mode of presentation, bone age and diagnosis. Delayed
puberty should be treated expectantly with regular follow up. This is
especially so if there is delay in bone age relative to the chronological
age, which indicates further potential for growth. Oestrogen
replacement therapy may be needed ultimately to stimulate linear
growth and other secondary sexual characteristics. A small starting
35
ABDEL -GADIR
dose should be used till the expected height has been attained, before
increasing the dose to avoid premature closure of the epiphyses. The
age to start treatment is variable, and depends on the diagnosis at the
time. It should be started at a younger age when failure rather than
delay in pubertal development has been diagnosed. This includes
conditions such as gonadal dysgenesis, isolated growth hormone
deficiency, and idiopathic panhypopituitarism.
Central isosexual precocity should be treated with GnRH analogues to

suppress gonadotrophins and oestrogens production. This is especially
important in patients with advanced bone development in relation to
the chronological age. It has been reported that suppression of central
isosexual precocity with GnRH analogues is more difficult in girls than
boy (32). The opposite is true with delayed puberty as girls need less
GnRH to achieve similar pubertal development as boys. Gonadotrophin
independent isosexual precocity does not respond to GnRH, and should
be treated with blockers of sex steroid biosynthesis instead (33). The
use of Testolactone which is an aromatase enzyme inhibitor has been
alluded to before. Patients with heterosexual precocious puberty should
be treated as early as possible to prevent masculinization and ultimate
short stature. Non classic congenital adrenal hyperplasia is a good
example, and should be treated with hydrocortisone replacement
therapy. Medication should be monitored and titrated against serial
measurements of 17-hydroxyprogesterone and androstenedione blood
levels. The risk of reduced adult height should be kept in mind when
dealing with patients with precious puberty, in relation to under and
over treatment.
It is important to remove dysgenetic gonads in patients with 46XY

chromosomes, to prevent any chance of malignant transformation. It is
equally important not to address young patients who are brought up as
women in a male context, despite having 46XY chromosomes and the
presence of testicular tissue. They are destined to grow up as females
and should be shielded from this information, at least during their
teenage years. Surgical treatment of ovarian and adrenal tumours is
indicated when applicable.
The scope of surgical treatment of lower vaginal agenesis is beyond the

remit of this endocrine oriented chapter. It is definitely more
complicated than incision of an imperforate hymen, or excision of a
transverse vaginal septum. It should be performed in a specialised
tertiary unit. Medical suppression of ovulation with continuous use of an
oral contraceptive pill is necessary, till such referral can be arranged.
36
Pull-through vaginoplasty can be performed in patients with distended

upper vagina, which allows better mobilisation of the upper vagina
down to the hymeneal ring. Otherwise, skin grafts will be needed and
should be used to bridge the gap between the upper vagina and lower
part. In all cases, vaginal dilators will be needed to keep the new
vaginal canal patent.
Summary
This is a very important area of reproductive endocrinology which

deals with very sensitive issues involving vulnerable young girls.
The ultimate objective should be to maximise their chances of
leading satisfying and functional lives, as much as possible. This can
be fulfilled only after using the right management approach to
make the right medical diagnosis. The spectrum of causes
involved spans through constitutional, anatomical, endocrine and
chromosomal causes. Malignant tumours of the brain, ovaries and
adrenals can also be involved. Utmost care should be taken to use
simple and reassuring language, avoiding negative terms like ovarian
failure and testicles when applicable. Parents should also be actively
involved in all management considerations. They should understand
the exact nature of the problem, the management plan, as well
as any future implications. A multidisciplinary team including a
paediatrician, counsellor, dietician and a clinician experienced in
adolescentsí gynaecological surgery should be involved, as and when
necessary.
References
1. Marshall, W.A. and J.M. Tanner, Variations in pattern of pubertal

changes in girls. Arch Dis Child, 1969. 44(235): p. 291 - 303.
2. Herman-Giddens ME, Slora EJ, Wasserman RC, Bourdony CG,
Bhapkar MV Koch GG and Hasemeir CM. Secondary sexual
characteristics and menses in young girls seen in office practice:
a study from the Paediatric Research in Office Settings network.
Pediatrics, 1997. 99(4): 505 - 512.
3. Tanner JM. Growth at adolescence. 2nd ed. Oxford: Blackwell,
1962.
4. Culter Jr GB. The role of oestrogen in bone growth and maturation
during childhood and adolescence. J Steroid Biochem Mol Biol
1997; 61(3-6): 141 – 144.
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ABDEL -GADIR
5. Remer T and Manz F. The midgrowth spurt in healthy children is

not caused by adrenarche. J Clin Endocrinol Metab 2001; 86(9):
4183 – 4186.
6. Brook CGD. A Guide to the Practice of Paediatric Endocrinology;
Cambridge University Press, 1993.
7. Haber HP and Mayer EI. Ultrasound evaluation of uterine
and ovarian size from birth to puberty. Pediatr Radiol 1994; 24:
11 – 14.
8. Herter LD, Golendziner E, Flores JAM, Becker E, and Spritzer PM.
Ovarian and uterine sonography in healthy girls between 1 and 13
yeas old: correlation of findings with age and pubertal status. AJR
2002; 178: 1531 – 1536.
9. Moffitt TE, Caspi A, Belsky J and Silva PA. Childhood experience
and onset of menarche: a test of sociobiologica model. Child
Development 1992; 63: 47 – 58.
10. Ellis BJ, and Garber J. Psychological antecedents of pubertal
maturation in girls: parental psychopathology, stepfather
presence, and family and marital distress. Child Development
1992; 71: 485 - 501
11. Traggi C and Stanhope R. Delayed puberty. Best Pract Res Clin
Endocrinol Metab 2002; 16(1): 139-151
12. Oppelt P, von Have M, Paulsen M, Strissel P, Strick R, Brucker S,
Wallwiener D and Beckmann M. Female genital malformations
and their associated abnormalities. Fertil Steril 2007; 87(2):
335 - 342.
13. Sanfilippo JS Endometriosis in association with uterine anomaly.
Am J Obstet Gynecol 1986; 154(1): 39-43.
14. Burel A, Mouchel T, Odent S, Tiker F, Knebelmann B, Pellerin I,
Guerrier D.. Role of HOXA7 to HOXA13 and PBX1 genes in various
forms of MRKH syndrome (congenital absence of uterus and
vagina). J Negat Results Biomed. 2006; 5: 4
15. Troiano RN and McCarthy SM. Mullerian duct anomalies: Imaging
and clinical issues. Radiology 2004; 233(1): 19 – 34.
16. Breech LL and Laufer MR. Obstructive anomalies of the female
reproductive tract. J Reprod Med 1999; 44(3): 233 – 240.
17. Heger AH, Ticson L, Guerra L, Lister J, Zaragoza T, McConnell G,
and Morahan M. Appearance of the genitalia in girls selected for
nonabuse: review of hymeneal morphology and nonspecific
findings. J Pediatr Adolesc Gynecol 2002; 15(1): 27 – 35
18. Elyan A and Saeed M. Mullerian duct anomalies: clinical concepts.
ASJOG 2004; 1: 11 – 20.
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19. McKusick VA, Bauer L, and Koap CE. Hydrometrocolpos as a

simply inherited malformation. JAMA 1964; 189: 813 – 816.
20. Mitchell DG, and Outwater EK. Benign gynaecologic disease:
application of magnetic resonance imaging. Top Magn Reson
Imaging 1995; 7: 26 – 43.
21. McKusick VA. Transverse vaginal septum (hydrometrocolpos).
Birth Defects Orig Artic Ser 1971; 7: 326 – 327.
22. Nichols JL, Bieber EJ and Gell JS. Secondary amenorrhoea
attributed to occlusion of microperforate transverse vaginal
septum. Fertil Steril 2010; 94(1): 351.
23. Franceschi R. Gaudino R, Marcolongo A, Gallo MC, Rossi L,
Antoniazzi F AND Tatò L. Prevalence of polycystic ovary syndrome
in young women who had idiopathic central precocious puberty.
Fertil Steril 2010; 93(4): 1185 - 1191.
24. Cisternino M, Arrigo T, Pasquino AM, Tinelli C, Antoniazzi F,
Beduschi L, Bindi G, Borrelli P, De Sanctis V, Farello G, Galluzzi F,
Gargantini L, Lo Presti D, Sposito M, Tatò L. Etiology and age
incidence of precocious puberty in girls: a multicentric study. J
Pediatr Endocrinol Metab, 2000. 13 Suppl 1: p. 695-701.
25. Ng SM, Kumar Y, Cody D, Smith CS and Didi M. Cranial MRI scans
are indicated in girls with central precocious puberty. Arch Dis
Child 2003; 88: 414 – 418.
26. Bianco P, Riminucci M, Mjolagbe A, Kuznetsov SA, Collins MT,
Mankani MH, Corsi A, Bone HG, Wientroub S, Spiegel AM, Fisher LW
and Robey PG. Mutaions of the GNAS1 gene, stromal cell dysfuncion,
and osteomalacia changes in non-McCune-Albright Fibrous dysplasia
of bone. J Bone Miner Res 2000; 15(1): 120 – 128.
27. Diaz A, Danon M and Crawford J. McCune-Albright syndrome and
disorders due to activating mutations of GNASS1. J Pediatr
Endocrinol Metab 2007; 20(8): 853 – 880.
28. Feuillan PP, Foster CM, Pescovitz OH, Hench KD, Shawker T, Dwyer
A, Malley JD, Barnes K, Loriaux DL, Cutler GB Jr. Treatment of
precocious puberty in the McCune-Albright syndrome with the
aromatase inhibitor testolactone. N Engl J Med. 1986; 315(18):
1115 - 1119.
29. Apter D, Cacciatore B, Alfthan H, Stenman UH. Serum luteinizing
hormone concentrations increase 100-fold in females from 7 years
to adulthood, as measured by time-resolved immunofluorometric
assay. J Clin Endocrinol Metab. 1989; 68: 53 - 57.
30. Brito VN, Batista MC, Borges MF, Latronico AC, Kohek MB, Thirone
AC, Jorge BH, Arnhold IJ, Mendonca BB. Diagnostic value of
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fluorometric assays in the evaluation of precocious puberty. J Clin

Endocrinol Metab. 1999; 84(10): 3539 - 3544.
31. Della Manna T, Setian N, Damiani D, Kuperman H, Dichtchekenian
V. Premature thelarche: identification of clinical and laboratory
data for the diagnosis of precocious puberty. Rev Hosp Clin Fac
Med Sao Paulo. 2002; 57: 49 – 54.
32. Donaldson MD, Stanhope R, Lee TJ, Price DA, Brook CG, and
Savage DC. Gonadotrophin responses to gonadotrophin releasing
hormone in precocious puberty treated with gonadotrophin
releasing hormone analogue. Clin Endocrinol (Oxf) 1984; 21:
499 – 503.
33. Bridges NA, Christopher JA, Hindmarsh PC and Brook CGD. Sexual
precocity: sex incidence and aetiology. Arch Dis Child 1994; 70:
116 – 118.
40
Chapter 3
Primary and Secondary Amenorrhoea
Amenorrhoea is the term used to describe permanent or transient

absence of menstruation for a period of 6 months or more during the
reproductive period of life. It is physiological before puberty, during
pregnancy or lactation, and after the menopause. Occasionally, a
period of 3 months is used to make the diagnosis. Amenorrhoea can
be divided into primary or secondary types relative to its onset in
relation to menarche, but this classification does not have a
diagnostic bearing in many cases (1). They share common causes in
most cases, but specific ones are also identifiable for each category.
Primary amenorrhoea
Primary amenorrhoea is a term used to indicate failure to menstruate

in the following two situations:
1. Failure to attain menarche by the age of 16 years by a female
with complete or partially developed secondary female sexual
characteristics;
2. Failure to menstruate by the age of 14 years by a girl who failed
to develop any secondary sexual characteristic.
It is evident that both criteria are arbitrary, and are only used to
indicate a reasonable time when to start clinical and laboratory
investigations. This is especially so as the age of onset of puberty is
getting lower. Young girls should be investigated if menstruation failed
to start 5 years after the onset of the first signs of puberty. This can be
done at the age of 14 years, or even at a younger age. About 0.3% of
women fail to start menstruation all together, and present with primary
amenorrhoea (2). So, it is not a very common problem within a general
gynaecology outpatient department. Nevertheless, it is important that
all gynaecologists should have a diagnostic chart and management
plan in place, especially in areas where subspecialists are not available.
This is a sensitive area and both the patient and her parents will be
worried about future prospects. This is especially so in cases where
hyperandrogenic signs are also involved.
41
ABDEL -GADIR
The most common causes of primary amenorrhoea have not changed

over the years, including primary ovarian failure (48.5%), congenital
absence of the uterus and vagina (16.2%), GnRH deficiency (8.3%),
and constitutional delay of puberty (6.0%) (3).
Secondary amenorrhoea
Pathological secondary amenorrhoea is defined as failure to menstruate

for a period of 6 months or more by a woman in her reproductive age
who had menstruated previously. This is to differentiate it from the
physiological type seen during pregnancy, lactation and after the
menopause. Secondary amenorrhoea is almost 10 times more common
than the primary type. The respective incidence of the two versions in
the United States was reported as 0.3% and 3.0% respectively (2). A
figure of 3.3% was quoted for secondary amenorrhoea in one Swedish
study (4). Early intervention is indicated in patients who present with
other associated symptoms including hyperandrogenisation, and in
those who are keen to get pregnant.
General overview
It may be more practical to think of amenorrhoea as failure at one or

more points along the hypothalamo-pituitary-ovarian axis, or failure of
the uterus and vagina to respond to the cyclic stimulus of this axis and
discharge menstrual flow in the non pregnant state. With this vision,
amenorrhoea can be divided into the following categories:
1. Anovulatory amenorrhoea due to HPO axis dysfunction;
2. Failure of the endometrium to respond to oestrogens and
progesterone;
3. Failure of uterine development or genital tract obstruction;
4. Other endocrine glands dysfunction.
Anovulatory amenorrhoea
This section will deal with problems related to the hypothalamus,

pituitary gland and ovaries in that sequence. The detrimental effect of
other dysfunctional endocrine glands on the HPO axis will be mentioned
separately.
Hypothalamic anovulation
Hypothalamic amenorrhoea may be associated with many neuroendocrine

changes including:
42
• Change in the pulsatile secretion of LH, growth hormone and

prolactin;
• High plasma levels and lack of the diurnal variations of cortisol;
• Delayed or absent response of gonadotrophins to GnRH stress
test,
• Delayed or absent response of prolactin to thyrotrophin releasing
hormone stress test;
• Abnormal thermoregulation.
The hypothalamus can be affected by direct neural or biochemical
messages from other brain centres. Different methods have been used
to characterise adverse hypothalamic conditions leading to disruption
of GnRH pulse generation, but the following 4 subgroups are more
clinically oriented:
• Functional disorders;
• Psychological or psychiatric disorders;
• Anatomical or organic disorders;
• Isolated gonadotrophins deficiency syndrome.
Functional hypothalamic disorders
Functional hypothalamic disorders indicate abnormal GnRH and

gonadotrophins production, resulting in ovulatory dysfunction in the
absence of any known organic, endocrine or systemic cause. Increased
activation of the hypothalamo-pituitary-adrenal axis with some
resistance in cortisol feedback mechanism has been suggested in
women with functional hypothalamic amenorrhoea and normal body
weight (5). Higher cerebrospinal fluid cortisol levels have been found in
these women compared to a control group of normally menstruating
women, despite having similar blood free cortisol index. The most
common two causes in this category are weight related disorders, being
excessive weight gain or loss, though it can also be seen in other
women.
Amenorrhoea can follow anorexia nervosa and obesity whereas bulimia

is associated more often with abnormal uterine bleeding and delayed
menstruation, despite the fact that there is no significant weight loss.
Both anorexia and obesity have a central endocrine effect. Anorexia is a
psychological problem with endocrine manifestations, whereas
obesity can be nutritional or may follow compulsive eating due to
psychological problems. It is evident that both conditions can come under
the psychological subheading as well. Anorexic women become
amenorrhoeic even before they become unduly thin, which emphasises
43
ABDEL -GADIR
the psychiatric role in such cases. This is different with simple nutritional
weight loss which does not fulfil the same psychiatric criteria as anorexia.
In these cases, women can become amenorrhoeic mostly after going
below a certain critical BMI specific for each individual. Furthermore, they
usually regain some menstrual function as soon as they approach that
BMI, unlike patients with anorexia who may regain a lot of weight yet
remain amenorrhoeic. Nutritional obesity can cause loss of menstrual
function through different mechanisms, not involving a psychiatric
component. This can be affected through disturbed prolactin secretion
and increased brain endorphins, dopamine, and opioids. There is also
reduction in the hepatic production of SHBG, which can lead to increased
levels of free androgens which are converted to oestrone by peripheral
fat. All these factors can affect the hypothalamus negatively to different
degrees, reduce GnRH pulse generation, and lead to disturbed
gonadotrophins secretion. Loss of weight should be the priority to
reactivate the HPO axis, rather than induction of ovulation. Some
menstrual activity can be expected after losing 10% of the body weight
by some obese patients.
Exercise induced amenorrhoea also falls under this diagnostic

subgroup. These patients usually have the triad of amenorrhoea,
eating disorders, and osteoporosis. Excessive competitive exercise is
usually associated with increase in stress hormones mainly ACTH and
cortisol which have direct effect on the hypothalamus, reducing GnRH
pulse frequency. They also have direct effect on the pituitary
gonadotrophs making them less responsive to the GnRH pulses. This is
compounded by the fact that there is a high incidence of eating
disorders in athlete women (6). Different rates of amenorrhoea have
been reported with different types of exercise. Furthermore, pubertal
girls are more prone to develop amenorrhoea than older women. Rates
of 5 - 66% had been noted with competitive athletes and 19 - 44% with
ballet dancers.
Drug induced hypothalamic dysfunction can follow prescribed

medication or misuse of recreational drugs. Most of them affect brain
neurotramitters, and interfere with the proper functioning of the
hypothalamic nuclei. Normally, GnRH secretion is affected by
norepinephrine, dopamine, serotonin, acetylcholine, endorphins,
enkaphalins, glutamate and aspartate. Any drugs which affect these
neurotramitters will modulate GnRH pulse generation and consequently
gonadotrophins secretion. Increased brain opiates activity can lead to
hypothalamic inhibition and amenorrhoea, which can be reversed by
prolonged use of opiates receptors antagonists like naltrexone. Such
44
medication was found to counteract the inhibition of GnRH pulse

generation in these cases (7).
The role of depoprovera in causing amenorrhoea will be singled out in

this chapter, as it is becoming more popular as a long acting
contraceptive and for the treatment of endometriosis. It is debo-
medroxyprogesterone acetate which is given by deep intramuscular
injections every 3 months. As a potent progestogen, it directly affects
the hypothalamus reducing GnRH pulse frequency and hence reduces
gonadotrophins secretion. It can induce amenorrhoea for variable
periods of time after repeated injections. Almost 50-70% of women will
have long periods of amenorrhea after using depoprovera for one year
or more. It may take up to 18 months before regular ovulation is
resumed following the last injection, though return of fertility has been
quoted to occur 9 months after the last injection (8). Other side effects
include irregular uterine bleeding, functional ovarian cysts, and
osteoporosis. Accordingly, patients should be made aware of these side
effects, before committing themselves to this medication. Other drugs
in common use which can cause amenorrhoea include high doses of
corticosteroids, isoniazid, and danazol which is a synthetic 2, 3 isoxazole
derivative of 17α-ethinyl testosterone.
Psychological and psychiatric hypothalamic anovulation
Patients with severe and protracted anxiety states and depression are
liable to have menstrual irregularities including amenorrhoea. Short
term stressful conditions may not have an adverse effect on the
hypothalamus, but prolonged periods of stress or depression can affect
the brain neurotramitters. This is especially so for corticotrophin
releasing hormone which is an important neurotransmitter and can
interfere with GnRH pulse generation. This is affected through an
increased central opioids activity, as it can be suppressed by the opioids
antagonist naloxone (9). On the other hand, the effect of short term
tress depends on the stage of the menstrual cycle and oestrogen level.
It could stimulate premature LH release during the second half of the
cycle, or inhibit follicular growth if it occurred during the early follicular
phase (10). Both effects could be detrimental to the normal process of
ovulation.
Depressed patients are more liable to develop hypothalamic

amenorrhoea due to increased concentration of opioids and dopamine
in the brain. Evidence of involvement of both chemicals in causing
hypogonadotropic amenorrhoea has been known since 1980 (11).
45
ABDEL -GADIR
Treatment with antidepressants and anxiolytics can also affect

hypothalamic function. Accordingly, it is important to check for any
medication a patient may be using during the clinical interview. Further
information should be sought from the patient’s primary care doctor,
when in doubt. Increased blood levels of cortisol due to increased pulse
amplitude, and decreased levels of DHEA-S have been reported in
women with psychogenic amenorrhoea, compared to women with
normal cycles. Furthermore, loss of cortisol circadian rhythm and early
escape from dexamethasone suppression have been reported in
depressed patients by Sacha et al in 1973 (12) and Amsterdam et al in
1983 (13) respectively. On the other hand, major affective disorders
have also been reported in many amenorrhoeic runners, or in their first
or second degree cousins (6).
Anatomical hypothalamic causes of amenorrhoea
Anatomical hypothalamic lesions are not common but can interfere with
the hypothalamic brain connections, obstruct the pituitary stalk, or
even damage the sella turcica itself with the enclosed pituitary gland.
The most important and well known tumours are craniopharyngiomas.
Patients may present with amenorrhoea and very high prolactin levels,
due to interruption of the pituitary stalk. Involvement of the optic
chiasm and optic nerves can lead to visual symptoms.
Other intracranial tumours not involving the hypothalamus include

gliomas and astrocytomas which can affect the brain connections with
the hypothalamus. Pituitary tumours will be considered separately in
this chapter. It is important to conduct a proper neurological
examination, including the optic discs and visual fields. This is
especially important in patients with neurological symptoms, high
prolactin levels, and those with precocious isosexual puberty.
Isolated gonadotrophins deficiency
Isolated gonadotrophins deficiency syndrome is not common, and

patients usually fail to develop secondary sexual characteristics. They
are usually tall and eunuchoid with long arms and legs bones and
longer arms span than height. Development of the axillary and pubic
hair may be normal, as the adrenocorticotrophic axis is normal. Many
patients may have defective sense of smell, as in Kallmann’s
syndrome, due to abnormal development of the olfactory bulbs.
Failure of migration of the GnRH neurons from the embryonic
olfactory placode into the brain during fetal life, or lack of
46
establishment of a functional connection with the hypophyseal portal

system may account for the hypogonadotropic state in patients with
Kallmann’s syndrome (14).
Pituitary causes of amenorrhoea
Failure of the pituitary gland to produce gonadotrophins can be a primary

problem within the pituitary gland itself, or can be secondary to failure of
stimulation by GnRH. It can be an isolated gonadotrophins deficiency, but
panhypopituitarism can also be seen. Patients with hypopituitarism can be
deficient in growth, thyroid and adrenal hormones. They can present
with amenorrhoea, as well as symptoms related to other hormonal
deficiencies. Such symptoms include easy fatigability, cold intolerance,
weakness and loss of axillary and pubic hair. Failure of pubertal girls to
grow is an important sign which indicates neurological testing and MRI
examination of the brain. Hypopituitarism can follow any of the following
conditions:
• Non functioning pituitary tumours;
• Pituitary infarction;
• Empty sella syndrome;
• Sheehan syndrome following postpartum haemorrhage;
• Pituitary granulomas including tuberculosis and histiocytosis X;
• Head injury can lead to damage of the pituitary gland, with partial
or total loss of endocrine function. Severe loss of ACTH may lead
to shock due to loss of adrenal hormones. On the other hand,
symptoms related to gonadotrophins loss can be delayed and
may show after some time, depending on the degree of cellular
damage.
Ovarian causes of amenorrhoea
Direct ovarian or gonadal causes are related more often to primary

amenorrhoea, and premature ovarian failure with secondary
amenorrhoea. At the same time, chromosomal abnormalities are more
likely to be the cause the younger the patients are. The following
gonadal causes are more likely to be seen within this group:
• Gonadal dysgenesis
Gonadal dysgenesis is the term used to describe atresia of gonadal

germ cells leading to streak gonads. Development of the ovaries has
been described in some detail in the previous chapter. Patients with
gonadal dysgenesis or streak gonads can have 46XX, 46XY, 45XO, or
47
ABDEL -GADIR
different combinations of these chromosomes. Development of the

primitive gonad into a testicle depends on the presence of the sex
determining region gene (SRY) on the short arm of the Y chromosome.
Total absence of this gene in a 46XX fetus allows development of the
primitive gonads into ovaries in females. Mutations in the SRY gene
account for 20-30% of Swyer Syndrome cases with 46XY pure gonadal
dysgenesis. Most cases may follow mutations in other genes necessary
for the normal development of the testicles (15). In such cases, failure
of the testicles to develop leads to failure of testosterone and
antimullerian factor production. Accordingly, no internal or external
male genital organs develop, and the mullerian ducts progress into full
internal female genitals instead. The urogenital sinus also fails to
masculine, and develops into a vulva and lower vagina. Adequate pubic
and axillary hair growth is stimulated by adrenal androgens at puberty.
Most cases of Swyer syndrome are sporadic, but exceptionally familial
cases are seen in women with complete or partial gonadal dysgenesis,
in an autosomal recessive manner (16). Pure gonadal dysgenesis, with
46XX or 46XY chromosomes, is usually associated with female
hypogonadism with high FSH levels and primary amenorrhoea. Patients
with mixed gonadal dysgenesis and chromosomal combinations may
have one streak gonad on one side, plus a testicle or germ cell tumour
on the other side. A good example for such asymmetrical gonadal
development is seen in 45XO / 46XY mosaics. On the other hand, some
patients may have more than one cell line in different tissues, with
normal development of secondary female sexual characteristics, yet
they develop primary ovarian failure in their 20s or early 30s. In one
such case peripheral karyotyping was normal, yet an abnormal cell line
was found at the ovaries by Abdel-Gadir and Ramadan in 1990 (17).
Women with triple X chromosomes syndrome can also present with
secondary amenorrhoea. They usually have normal secondary female
sexual characteristics, and are able to have children. They are also
liable to have tall stature and lower IQ than women with 46XX
chromosomes. This can show as delayed speech and learning
difficulties. About 10% of affected females have kidney abnormalities
or seizures. It has been estimated that 1 in 1000 newborn girls have
triple X chromosomes. In most cases, this usually follows random
nondisjunction during oocytes division and is not inherited from
parents. The level of physical and functional changes usually relates to
the number of affected cell lines, as patients with 46XX / 47XXX
mosaicism have been described. To conclude this subsection, it is
important to mention that the most common chromosomal aberration
in patients with gonadal dysgenesis is 45XO or Turner’s syndrome. The
48
diagnosis can be suspected in these cases from the characteristic

somatic phenotype, even before peripheral karyotyping is analysed.
Fragile X syndrome will be considered separately in this section. Carriers

of the permutations of the familial mental retardation gene (FMR1) which
is located in the long arm of the X chromosomes (Xq27) have 50-200
repeats of the cytosine-guanine-guanine trinucleotide in the gene,
instead of the normal rate of 5-50 repeats. They have 20% chance of
developing primary ovarian failure. It was diagnosed in 6% of women
with premature ovarian failure and normal 46XX chromosomes (18; 19).
This percentage reached 14% in cases with similar family history (19).
Affected patients may not show any mental or somatic signs of the
syndrome. Family history of mental disability can be elicited more
commonly in male siblings. There is a 50% chance that each offspring of
a female carrier inherits the gene permutation. Somatic characteristics
include a long face, prominent ears, high arched palate, hyper-extensible
finger joints, double jointed thumbs and flat feet. There is no specific
treatment for this condition. This diagnosis should be confirmed by
chromosomal testing for FMR1.
Few enzymatic and receptor signal defects have been described as

causes of both primary and secondary amenorrhoea depending on the
degree and severity of the condition. Gene mutation of the FSH
receptor which is a member of the G-protein-coupled-receptors group
can cause streak gonads and primary amenorrhea, when present in the
most severe form. Lesser variants may lead to arrest of follicular
development at different stages, ranging from antral to the later stages
of development. This may be associated with some degree of secondary
sexual characteristics development and early secondary amenorrhoea.
More information about other mutations can be found in Chapter 10.
• Ovarian irradiation and chemotherapy
Pelvic irradiation and use of chemotherapeutic agents for malignant

conditions can lead to damage of the germ cells within the ovaries, with
subsequent ovarian failure and hypergonadotropic amenorrhoea. The
older the woman is at the time of exposure, the more chance she will
develop irreversible ovarian damage. Transposition of the ovaries
during radiation can help in saving ovarian function. It is estimated that
800 rads exposure leads to permanent ovarian failure irrespective of
the age group. Lower doses may be associated with partial or complete
recovery in younger patients. It is current practice that most young
women with breast cancer receive adjuvant cytotoxic chemotherapy, as
49
ABDEL -GADIR
well as hormonal treatment for oestrogen receptor-positive tumours.

This brought the issue of preservation of later fertility potential to light.
The older the patient at the time of treatment, the higher the chance
she will have permanent amenorrhoea after chemotherapy. Rates of
21-71% and 49-100% have been quoted for women younger and older
than 40 years (20). However, these wide variations in incidence are
most likely related to the type of drug and dosage used as reported by
Minton and Munster in 2002 (21).
• Ovarian tumours
Hormonally active ovarian tumours can lead to long periods of

amenorrhoea depending on the type of hormone produced by the
tumour cells. The list is long and includes granulosa cell tumours,
fibrothecomas, βhCG producing teratomas, and androgen producing
tumours. A recent case report of 8 years secondary amenorrhoea
caused by a parasitic ovarian leiomyoma which produced high levels of
inhibin B has been documented by Abdel-Gadir et al in 2010 (22). The
patient resumed regular menstruation one month after removing the
mass. In all these cases pelvic ultrasound scanning can show an ovarian
mass, and a blood hormonal profile may reveal the nature of the
chemicals produced
Genital anatomical factors
The first 4 subheadings shown below have already been covered in

chapter 2. They all cause primary amenorrhoea, and should be
considered early, especially in women with cyclic pelvic pain and
menstrual-like symptoms. The last subheading, which is a cause of
secondary amenorrhoea or hypomenorrhoea, will be addressed in this
chapter.
• Imperforate hymen;
• Transverse vaginal septum;
• Partial or complete mullerian agenesis;
• Vaginal agenesis involving the urogenital sinus part of the vagina;
• Endometrial damage.
Traumatic amenorrhoea may follow endometrial damage subsequent to
uterine surgery or infections. It can follow dilatation and curettage,
termination of pregnancy, caesarean section, myomectomy, and
manual removal of the placenta. An underlying pregnancy is involved in
most cases. All these procedures can lead to complete or partial
obstruction of the uterine cavity with adhesions, depending on the
50
degree of endometrial destruction. Nonetheless, minimal adhesions

may be associated with total damage of the basal endometrial layer
leading to amenorrhoea, not responsive to any hormonal treatment or
surgical correction. This pattern may also be seen with tuberculosis
infection of the endometrium, leading to failure of endometrial growth
and shedding in response to the rise and fall of oestrogen and
progesterone during a menstrual cycle. On the other hand apical
adhesions covering the lower part of the uterus may cause
amenorrhoea without any significant damage to the endometrium. This
may follow a caesarean section, as shown in figure number 5.
Previous history of uterine surgery is the main clue to a proper

diagnosis in this group of women presenting with hypomenorrhoea or
secondary amenorrhoea. Ultrasound scan examinations and saline
infusion sonohysterography may give some clues to the site and extent
of intrauterine adhesions.
Figure 5 shows an oblique

ultrasound view of a uterus full of
menstrual blood due to apical
adhesion following caesarean
section.
Other endocrine dysfunctions
Functional integrity of the HPO axis may be adversely affected even by

the most subtle changes in other pituitary or target endocrine glands
hormones. The correlated problems we most see as gynaecologists are
associated to:
• Thyroid gland dysfunction;
• Hyperprolactinaemia;
• Adrenal gland dysfunction;
• Polycystic ovary syndrome (PCOS).
Thyroid dysfunction
Thyroid gland disorders are very common in women, and may cause
different types of menstrual irregularities. Accordingly, a high degree
of suspicion should be exercised. This is especially so when dealing
51
ABDEL -GADIR
with women >40 years old, and younger ones with similar family
history. The function of the HPO axis is closely interlinked to that of the
thyroid gland. Both, an underactive or overactive thyroid gland may
affect ovulation by different means. TSH and gonadotrophins are
glycoproteins with very similar structure. They even have identical
amino acids sequence in their alpha chains. In vitro studies showed that
thyroid hormones increased granulosa cells division, and enhanced
their production of oestradiol. This was more noticeable for T3 than T4
(23). On the other hand, any change in the level of circulating
oestrogens can also affect the thyroid gland. High oestradiol blood
levels stimulate the liver to produce more thyroxine binding globulin
which is the carrier molecule of thyroxine. Normally this leads to a drop
in the level of free T4, calling on the thyroid gland to produce more
thyroxine to compensate for that effect. This can be seen during
pregnancy, or after exogenous administration of oestrogens including
the combined contraceptive pills, and hormone replacement therapy.
Childhood hypothyroidism may lead to delayed or precocious puberty,

as discussed in Chapter 2. In the later case, secondary stimulation of
the pituitary gland by TRH increases gonadotrophins production.
Elevation of TRH can also lead to hyperprolactinaemia, and affects the
HPO axis adversely. There is also reduced production of SHBG in cases
of hypothyroidism, which leads to increased levels of free testosterone
and oestradiol in circulation. High free androgens are converted to
oestrone in the hypothalamus which can modulate GnRH generation.
Nonetheless, gonadotrophins levels may be normal, but a blunted or
delayed response of LH to GnRH stimulation may be seen in patients
with hypothyroidism (24; 25)
On the other hand, high thyroxine levels increase the pituitary

gonadotrophs sensitivity to GnRH with significant increase in the
production and secretion of LH during both phases of the cycle. A similar
effect has been reported for FSH, but not by all investigators. This effect
may be sustained for up to 4 months after initiating antithyroid
treatment, which explains the lag period between normalisation of
thyroid indices and resumption of normal ovulatory function. High
thyroxine blood levels also increase the production of SHBG by the liver
which reduces the metabolic clearance of oestradiol. There is also
increased production of oestradiol by the granulosa cells in response to
thyroxine (22). Accordingly, there is 2-3 folds increase in oestradiol level
during the follicular and luteal phases of the cycle. There is also increased
production of testosterone and androstenedione, with significant increase
in their conversion rates to oestradiol and oestrone respectively. Even
52
with regular menstrual cycles, progesterone levels during the luteal

phase were found to be low in women with hyperthyroidism compared to
control groups.
Hyperprolactinaemia
Circulating human prolactin can be found in 3 different molecular

weights of 23, 60 and 100 kilodaltons. They are called little, big and big-
big prolactin respectively. The major circulating form is little prolactin
which is also the biologically active hormone. The big-big variety is
known as macroprolactin (26), and is made of little prolactin and
immunoglobulin G antibody. This complex structure interferes with the
hormone/receptor interaction (27) and renders prolactin biologically
inactive. Macroprolactinaemia may be found in 18-42% of patients
with high prolactin blood levels (28). These patients are usually
asymptomatic and have regular menstrual cycles, as the hormone is
biologically inactive. Recently, a suggestion has been made to test the
biological activity of prolactin in all patients with hyperprolactinaemia,
as this may affect the management plan (29). This practice is not yet
universal and symptomatic patients with hyperprolactinaemia are
treated accordingly. The rest of the text in this section relates to the
biologically active prolactin.
About 15% of amenorrhoeic women have increased prolactin blood

levels, which can affect the HPO axis directly at all levels. Increased
prolactin production can follow any of the following conditions:
• Prolactin producing pituitary tumours may be micro or
macroadenomas, with <10 mm and >10 mm size respectively.
Such tumours are usually autonomous, and the amount of
prolactin produced depends on their size. They should be excluded
with MRI during investigations of hyperprolactinaemia.
• Certain drugs functionally block the inhibitory effect of dopamine on
the pituitary gland lactotrophs, allowing autonomous production
and release of prolactin. Oestrogens have been shown to restrict
access of dopamine into the lactotrophs granules. This explains the
exaggerated prolactin response after TRH stimulation test following
oestrogen medication.
• Traumatic stalk transection or disruption of the vascular
connections between the hypothalamus and pituitary gland by a
craniopharyngioma, pituitary tumour, or any other intracranial
growth can prevent delivery of prolactin inhibitory factor to the
pituitary gland.
53
ABDEL -GADIR
• Increased production of prolactin by the pituitary gland may follow

increased production of TRH due to hypothyroidism. It can also
follow the use of such drugs as metoclopramide and cimetidine
which act as dopamine antagonists, and allow more prolactin
secretion by the pituitary gland. This effect can also be augmented
by prior exposure to oestrogen medication. It is interesting that the
effect of cimetidine on prolactin secretion is blunted in patients with
hyperthyroidism (30). This may be an indication that cimetidine
affects prolactin secretion by more than one means. Chronic
oestrogen medication can also enhance prolactin secretion, in
isolation, by increasing lactotrophs mitotic activity and number.
Other conditions which can increase prolactin secretion include
nipples manipulation, chest surgery, herpetic inflammation of the
intercostal nerves and renal failure.
• Hypothalamic dopamine deficiency may follow inflammatory
brain condition such as sarcoidosis, arteriovenous malformations
and medical treatment with drugs such as reserpine and alpha
methyldopa.
Hyperprolactinaemia can alter GnRH pulse generation, and ultimately
reduce gonadotrophins production, mainly LH. Alteration or abolition of
the LH surge may lead to inadequate ovulation, abnormal luteal phase,
polymenorrhoea, polymenorrhagia and menorrhagia. Pituitary
adenomas and craniopharyngioma are more likely to cause
amenorrhoea, as they lead to very high prolactin levels with severe
gonadotrophins deficiency and hypoestrogenic state. Moderate
elevation in prolactin levels following hypothyroidism or drug
medication can cause oligomenorrhoea and abnormal uterine bleeding
in some patients, but may also cause amenorrhoea. It may also act
directly at the ovaries and reduce the effect of gonadotrophins on the
follicles at a post-receptor level. This can lead to inappropriate
folliculogenesis, long follicular phase and abnormal ovulation. Low
luteal phase serum progesterone may also follow an abnormal effect at
post LH receptors level. The clinical effects of hyperprolactinaemia can
be summarised as follows:
↑ Dopamine → ↓ gonadotrophins production → ↓ follicular stimulation

→ ↓ steroidogensis → ↓ oestradiol → ↓ positive feedback mechanism
→ ↓ LH surge → anovulation/oligomenorrhoea → amenorrhoea
High prolactin levels can also interfere with adrenal enzymatic

activity leading to increased production of androgens, which have
detrimental effects on the ovaries and endometrium. Changes in
54
3β-hydrtoxysteroid dehydrogenase activity may reduce the conversion

of Δ5 precursors into Δ4 products. This leads to increased production of
17α-hydroxypregnenolone and DHEA-S, with the later precursor
changed into more potent androgens in peripheral tissues. It is not
usual for an isolated mild deficiency of this enzyme to cause total
amenorrhoea. Patients are more likely to present with some
hyperandrogenic symptoms and signs.
Adrenal gland dysfunction
Detailed information about the adrenal hormones can be found in

Chapter 4. In the context of amenorrhoea, women with adrenal
dysfunction can fall into 2 major groups
1. Enzymatic deficiencies which are autosomal recessive problems;
2. Cushing’s syndrome which is a rare presentation in the
gynaecology clinic.
The lack of a strong evidence associating adrenarche to the onset of
puberty in normal girls has been discussed in Chapter 2. Nonetheless,
excessive production of adrenal androgens due to 21-hydroxylase
deficiency may lead to precocious puberty. Severe untreated conditions
can result in primary or secondary amenorrhoea due to the effects of
very high androgens at different parts of the HPO axis, and the uterus.
Women with 21-hydroxylase deficiency are more prone to develop
secondary polycystic ovaries. They may also show signs of
hyperandrogenisation including acne and excessive hair growth. The
less common 11-hydroxylase deficiency may cause similar problems,
with an occasional added risk of high blood pressure. Deficiency of 17α-
hydroxylase occurs in 1: 50,000 to 1: 100,000 newborns (31). It
usually occurs in combination with 17/20 lyase enzymatic deficiency, as
they are controlled by the same cytochrome P450c17 enzyme.
Nonetheless, they might occur separately depending on the type of
mutation (32). It has more dramatic effects than the other two
enzymatic deficiencies mentioned before. Deficiency of 17α-
hydroxylase reduces or even totally blocks the conversion of
progesterone to 17α-hydroxyprogesterone, and pregnenolone to
17α-hydroxypregnenolone. With reduced synthesis of 17α-
hydroxyprogesterone, less 11-deoxycortisol and cortisol will be
produced. Deficiency of 17/20 lyase enzymatic activity will compound
matters further by reducing the conversion of the available 17α-
hydroxyprogesterone and 17α-hydroxypregnenolone to androgens,
which are the substrates for oestrogens. The ultimate clinical outcome
of these changes will be:
55
ABDEL -GADIR
• Failure of cortisol production will lead to increased production of

ACTH, with excessive stimulation of the adrenal gland and further
accumulation of the pre-block precursors. Excessive progesterone
will be converted more readily to deoxycorticosterone and
corticosterone. This may lead to hypertension and hypokalaemic
alkalosis. The age of onset and degree of severity of hypertension
vary between the affected individuals (33)
• Failure to produce androgens and oestrogens will result in failure
to develop secondary sexual characteristics, and primary
amenorrhoea.
The biochemical picture will be high levels of FSH, LH, progesterone,
deoxycorticosterone and corticosterone, but low oestradiol level.
Aldosterone and plasma rennin activity may also be reduced. The
ovaries may show multicystic pattern, but ovarian biopsies showed no
evidence of follicular maturation. Despite failure of spontaneous
follicular growth, patients with 17α-hydroxylase (34) and isolated
17/20 lyase (35) enzymatic deficiencies had positive response to
exogenous gonadotrophins stimulation with adequate follicular
growth, oocyte maturation and fertilisation during in vitro fertilisation
programmes. These studies demonstrated the need for a proper
diagnosis to differentiate these patients from others with high FSH
and low oestradiol levels due to primary ovarian failure.
Individuals with 46XY karyotyping and severe or homozygous 17β-

hydroxysteroid dehydrogenase 3 mutations may be born with external
female genitals, and are raised as females. They will fail to menstruate,
and develop hyperandrogenic habitat at the time of puberty. This topic
will be discussed in more details in Chapter 4.
Cushing’s syndrome is usually diagnosed in a medical department rather

than a gynaecology clinic. The main endocrine problems are excessive
ACTH induced, or independent cortisol production by the adrenal glands.
There is also loss of the cortisol circadian rhythm, together with the
hypothalamo-pituitary-adrenal negative feedback mechanism. The
clinical manifestations may be subtle in the early stages and many of the
symptoms are shared by other endocrine dysfunctional conditions. The
full blown picture may show central obesity, purple wide striae,
hyperandrogenisation, facial plethora, mooning of the face, muscle
wasting, diabetes and high blood pressure. Patients may also present
with secondary amenorrhoea, even at the early stages of the syndrome.
Accordingly, it should be kept in mind during the investigations of
patients who present with amenorrhoea associated with any of the other
56
symptoms or signs described before. It is important not to confuse this

condition with the pseudo Cushing state related to excessive alcohol
abuse and depression. These patients present with clinical and
biochemical changes reminiscent of Cushing’ syndrome. They may even
fail to respond to a dexamethasone suppression test. Treatment is
different in these cases, and should only target the two underlying
problems.
Polycystic ovary syndrome
This is the most common female endocrine disorder and has been
reported in 3.5-11.2% of all women. Almost 50% of all female
endocrine problems are related to PCOS. The spectrum of symptoms
includes hyperandrogenisation anovulation, obesity, and infertility.
Menstrual dysfunction is variable, with oligomenorrhoea being most
common, but primary and secondary amenorrhoea may be seen. A new
consensus has been agreed for the diagnosis of PCOS in 2003 (36), but
still needs to gain universal approval. The Rotterdam expert group
stated that PCOS is an ovarian dysfunctional condition characterised by
hyperandrogenism, anovulation and the presence of 12 cystic areas in
one or both ovaries. Other causes of hyperandrogenic states should be
excluded first, before making the diagnosis. A more detailed account
will be given about PCOS in Chapter 6.
Management of amenorrhoea
Thorough medical history should be taken and physical examination

and investigations should be performed according to the patient’s
age, pubertal development, general phenotype and the presence or
absence of other endocrine physical signs. The main objectives
should be to exclude medical problems which can affect the patient’s
general health. This is especially so for intracranial, ovarian or adrenal
tumours. The management plan ought to have purposeful treatment
oriented objectives. It must seek to distinguish between the following
conditions:
1. Hypogonadotropic hypogonadism;
2. Hypergonadotropic amenorrhoea with or without gonadal
dysgenesis;
3. Hyperandrogenic amenorrhoea;
4. Anatomical amenorrhoea.
The following action plan is suitable for most patients, and can be
modified as necessary to suit each individual case:
57
ABDEL -GADIR
• Personal biodata including weight, height, arms span and blood

pressure should be recorded.
• Tanner’s breast and pubic hair staging should be performed.
• Look for hyperandrogenic signs, central obesity, and purple wide
striae.
• Signs of hypo or hyperactive thyroid gland should be ascertained.
• The vulva should be inspected in cases of primary amenorrhoea.
• Digital vulvar examination of sexually active patients with primary
amenorrhoea should be done.
• Neurological examination including the optic discs and visual fields
should be conducted.
• Transabdominal and transvaginal ultrasound pelvic scan
examinations may show the presence or absence of the uterus
and ovaries. Distension of the uterus and vagina with blood may
be demonstrated in cases of haematometra and haematocolpos,
secondary to genital tract obstruction. These are the findings
mostly seen in younger patients. Few women with amenorrhoea
or dysfunctional uterine bleeding may show polycystic ovaries and
the endometrium may be hyperplastic and thick. This is a pattern
seen more often in obese women as shown in figure 6.
Figure 6 shows sagittal and axial

transvaginal ultrasound views of a
uterus with 18 mm thick hyperplastic
endometrium following 5 months
of amenorrhoea in a patient with
PCOS. Small empty vacuoles of
different sizes are dispersed amid
the echogenic endometrium.
Intrauterine adhesions can show in many different ways including a

thin endometrium with bright neighbouring echoes, as shown in
figure 6. Loss of the endometrial / myometrial interphase may be the
only ultrasonic finding. This could be more discernable during the
luteal phase of the cycle because of the contrast between the
remaining part of the echogenic secretory endometrium and the
normally hypoechoic inner part of the myometrium. The diagnosis is
best concluded with saline infusion sonohysterography. Failure of
uterine distension may indicate total obliteration of the cavity.
Alternatively, distortions of the cavity with echogenic bridges, or
failure of a specific part of the cavity to distend with saline may be
58
seen. Saline infusion sonohysterography is an outpatient procedure

which can be used in isolation in most cases, or in conjunction with
office hysteroscopy. It should be performed under aseptic conditions,
and should be covered with antibiotics.
Figure 7 shows a sagittal

ultrasound view of a uterus with
thin endometrium and bright
endometrial echoes in the lower
and middle parts of the cavity,
cranial to a caesarean section scar.
Figure 8 shows an indiscriminate endometrial / myometrial interface, marked by

an arrow head, which proved to be due to intrauterine adhesions as shown by
saline infusion sonohysterography in Figure 9. The intact part of the cavity is
revealed by the hypoechoic saline with adhesions shown as bright bridges dividing
the cavity. The catheter used for saline infusion is shown as two bright parallel
lines in the cervical canal.
• MRI of the pituitary gland and brain are necessary in cases of

hyperprolactinaemia, and in cases of delayed and precocious
isosexual puberty. This is especially important in patients with
neurological symptoms, or abnormal findings on neurological
examination. Plain skull X-ray examinations are not sensitive
enough to be used for this purpose.
• Peripheral karyotyping is important in cases of primary or
secondary amenorrhoea with high FSH blood levels. It is also
useful in cases of suspected androgen receptor insensitivity
(46XY) and Mayer-Rokitansky-Küster-Haüser’s syndrome (46XX).
• X-ray of the left hand and wrist for bone age should be requested
for women with delayed or precocious puberty, and the film
compared to a standard atlas.
59
ABDEL -GADIR
• An endocrine profile should be requested including:

• FSH, LH, and oestradiol can differentiate between hypo and
hypergonadotropic amenorrhoea;
• TSH and free T4 are needed to investigate thyroid function.
• Testosterone, androstenedione and SHBG are useful in cases of
hyperandrogenic amenorrhoea and in cases suspected of
androgen insensitivity syndrome. Very high testosterone levels
may point towards ovarian or adrenal tumours.
• 17-hydroxyprogesterone is the main precursor necessary for
the diagnosis of 21-hydroxylase deficiency.
• DHEA-S, androstenedione and cortisol should be assessed, as
necessary, to give more information about the adrenal gland.
Very high DHEA-S may indicate the presence of an adrenal
tumour.
• Pituitary dynamic tests for FSH, LH, TSH, ACTH and growth
hormone can be performed to test the integrity of all trophic
hormones in cases suspected of hypopituitarism.
• Stimulation of the adrenal gland with a bolus dose of synacthen
should be utilised to diagnose 21-hydroxylase enzymatic
deficiency in marginal or doubtful cases. Excessive increase in the
level of 17-hydroxyprogesterone will confirm the diagnosis. A
similar test is also available for the less common 11β-hydroxylase
deficiency with metyrapone.
Treatment of primary and secondary amenorrhoea
The main objective of managing patients with amenorrhoea is to exclude

serious organic causes which may affect their future wellbeing.
Identifying patients with hypo or hypergonadotrophic amenorrhoea is the
next important objective. It is also important to remember that endocrine
glands are biochemically interlinked, and a derangement in one gland
may affect many others. Accordingly, the diagnostic workup should be
thorough and purposeful to detect such changes. A good example is the
elevation of prolactin level in response to hypothyroidism. Treating
hyperprolactinaemia in such cases entails dealing with the causative
hypothyroidism first. Management of amenorrhoeic patients in general
depends on the patient’s age, definitive diagnosis, associated symptoms
and fertility demands as shown in the following examples:
• Development of young hypogonadal pubertal girls should be
enhanced with small doses of oestrogen to allow linear growth
and development of secondary sexual characteristics. The dose
60
should be maintained and a progestogen should be added to

allow regular endometrial shedding, once the patient is fully
developed. This will also allow the normal attainment of
maximum bone density by the age of 20 years, and prevent
osteoporosis. Dysgenetic gonads should be removed in
individuals with a Y chromosome, to guard against malignant
transformation. Induction of ovulation with gonadotrophins is
the standard treatment in patients with hypogonadotropic
hypogonadism, when pregnancy is desired. Pulsatile GnRH
medication is also possible in cases of hypothalamic
amenorrhoea with an intact pituitary gland.
• Patients with hyperprolactinaemia usually respond well to
bromocripine which is a dopamine D1 and D1 receptor agonist.
It should be started in a small dose of 2.5 mg every day with
food. The dose should be increased slowly over few days
and titrated against prolactin level. A positive response of
80% is expected in cases of amenorrhoea caused by
hyperprolactinaemia. Some menstrual activity may resume after
a short period of time, but it usually takes many weeks or
months before a full ovulatory response is seen. Accordingly,
additional medication to stimulate ovulation should not be
rushed. Bromocripine is indicated even in cases of pituitary
macroadenoma as a first line of management. The tumour size
may shrink, which makes it easier to remove surgically. Tumours
which already involved neighbouring structures, especially the
optic chiasm need surgical decompression first. Regular follow
up with MRI and visual field examinations should also be done
together with serial estimations of prolactin blood levels. There
is a risk of pituitary tumours increasing in size during
pregnancy. Longer acting dopamine agonists are available if
bromocripine is not well tolerated, and for maintenance purpose
for long periods of time in patients who are not keen to get
pregnant. Single weekly doses of cabergoline (dostinex 0.5 - 1.0
mg) can improve compliance with taking the drug.
• Patients with hypo and hyperthyroidism should be managed
accordingly. Thyroxin treatment should be started with a small
dose and built up against TSH levels, to reduce side effects
especially cardiac ones. It is important to remember that
menstrual function and more importantly regular ovulation may
take much longer time to resume after correction of the peripheral
blood levels of thyroid indices. Similarly, other medications to
induce ovulation should not be rushed. The relationship between
61
ABDEL -GADIR
hypothyroidism and hyperprolactinaemia has been mentioned

before.
• Eating disorders are common in young women, and should be
treated as psychological rather than endocrine problems. These
patients usually have negative body image, and intense fear of
gaining weight. They may also suffer from depression, anxiety
and obsessive compulsive disorders. Treatment should focus on
cognitive behavioural therapy and behaviour modification,
personal and family counselling, nutritional advice, as well as
individual and group counselling sessions. Antidepressants and
hormone replacement therapy should be prescribed in severe
cases suffering from depression, and to prevent bone loss
respectively.
• A diagnosis of hypothalamic dysfunction is usually made in
amenorrhoeic patients with normal gonadotrophins, oestrogens,
prolactin, thyroid indices and adrenal hormones. This is fitting
with the WHO group 2 classification of amenorrhoea. Patient with
PCOS can show clinical and / or biochemical hyperandrogenisation.
Treatment is almost the same in both groups depending on the
following parameters as far as menstruation is concerned:
1. Patients who are not keen to get pregnant should have regular
progestogens withdrawal bleeding every 6-8 weeks, to prevent
endometrial hyperplasia. Alternatively, they can be offered an
oral contraceptive pill to have monthly withdrawal bleeding, and
prevent unwanted pregnancies at the same time.
2. Patients who wish to conceive should be offered induction of
ovulation with clomiphene citrate as a first choice. Gonadotrophins
injections can be used when a good response is not attainable.
They are more expensive, and need expert serial monitoring to
reduce the risk of excessive response and hyperstimulation.
Summary
It is evident that primary and secondary amenorrhoea share many

similar causes, and fit into almost identical management strategies. A
logical clinical, hormonal and imaging approach will elucidate most
cases with minimal need for advanced investigations. The sensitivity of
the problem especially with primary amenorrhoea in young pubertal
girls and in older patients who wish to get pregnant makes it necessary
for all gynaecologists to have a clear management plan, as stated
before. Dealing with the anatomical abnormalities involved with
primary amenorrhoea can pose greater difficulty, and liaison with a
62
gynaecologist experienced in this form of surgery is important. As a

whole, a multidisciplinary approach will be needed to cover the different
needs of these patients.
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35. Pellicer A, Miró F, Sampaio M, Gomez E and Bonilla-Musoles A. In
vitro fertilization as a diagnostic and therapeutic tool in a patient
with partial 17, 20 desmolase deficiencies. Fertil Steril 1991; 55:
970 - 975.
36. Revised 2003 consensus on diagnostic criteria and long-term
health risks related to polycystic ovary syndrome. Fertil Steril
2004; 81(1): 19 – 25.
66
Chapter 4
The adrenal glands in gynaecology
The adrenal glands are part of the neuroendocrine hypothalamo-

pituitary-adrenal (HPA) axis, which is involved with almost all body
functions. This is especially so for cortisol which has receptors in all
tissues in the body. The importance of the adrenal hormones is
reflected by the fact that the HPA axis is functional by the 6th week
of intrauterine fetal life. Furthermore, each adrenal gland is richly
supplied by 3 suprarenal arteries, despite their small size. During
fetal life, each gland is made of an inner medulla, and an outer cortex
which is made of a small outer adult zone and an inner and much
larger functional fetal zone. This fetal zone shrinks after birth, and is
replaced by the zona reticularis by the 4th or 5th year of life. The
outer adult zone, on the other hand, increases in size with time. The
inner medulla is derived from the neuroectoderm, and the outer
cortex is formed from mesoderm. Nonetheless, histological work
showed that such strict anatomical distinction was not correct, as
chromaffin cells were seen dispersed all over the cortex (1). The
medulla is responsible for the secretion of epinephrine and
norepinephrine, and will not be covered in this text.
Adrenarche is a term used to indicate the start of androgens production

by the adrenal glands. It usually starts by the age of 6-8 years
with increased production of dehydroepiandrosterone (DHEA) and
dehydroepiandrosterone sulphate (DHEAS), followed after one year by
increased production of androstenedione. There has been contradictory
evidence regarding the initiating stimulus for adrenarche. A small role has
been confirmed for adrenocorticotrophic hormone (ACTH) in this respect
(2), as there was no corresponding ACTH dependent increase in cortisol
level, compared to androgens. The main factors involved included an
increase in body weight, and the related increase in insulin and leptin levels.
On the other hand, Weber et al (3) showed diminished adrenal androgens
secretion in familial glucocorticoids deficiency, which they took as an
indication for the importance of ACTH contribution in the induction of
adrenarche. Furthermore, a genetic cause was suggested by Dardis et al in
1999 (4). They showed decreased expression of 3β-hydroxysteroid
67
ABDEL -GADIR
dehydrogenase type 2 (HSD3B2) gene and 3β-hydroxysteroid

dehydrogenase (3βHSD) enzymatic activity as functions of age in
prepubertal and early pubertal normal human adrenal tissues. This slows
conversion of Δ5 precursors into Δ4 products, leading to increased
production of DHEA by the adrenal glands at adrenarche. This finding was
a direct confirmation to a previous study conducted by Gell et al in 1996
which showed age-dependent decease in immunohistochemically localised
3βHSD in the adrenal zona reticularis during prepuberty (5).
The zona glomerulosa is responsible for the production of

aldosterone, whereas cortisol is produced by the middle zona
fasiculata. Adrenal androgens are produced mainly by the inner zona
reticularis, and partly by the fasiculata. Understanding the effects of
the adrenal glands in reproductive medicine hinges on the knowledge
of the different steps and enzymes involved in the production of the
adrenal steroids. The two main hormones produced by the adrenal
cortex are aldosterone which is a mineralocorticoid, and cortisol
which is a glucocorticoid hormone. Changes in the level of these two
hormones are fine tuned in response to the body needs. Cortisol
production is controlled mainly by the hypothalamic corticotrophin
releasing hormone (CRH), but also by antidiuretic hormone (ADH)
during stress. They are both produced by the paraventricular nuclei.
CRH is produced by the small or parvocellular neurosecretory cells
and released into the portal circulation, before reaching the
adenohypophysis. This pattern is different with ADH which is
produced by the large or magnocelluar neurosecretory cells. The
axons of these cells carry ADH and terminate in the infundibular
process, before it is released into the general circulation. Aldosterone
production is controlled by changes in the renin angiotensin system,
with a small role being played by ACTH. On the other hand,
androgens are produced as byproducts during the production of these
hormones, and their absence will not initiate any pituitary response
to increase their production. At the same time, they do not possess
an active negative feedback mechanism to shut down their excessive
production by the adrenal glands. This is because the rate limiting
step in adrenal steroidogensis is triggered and slowed down according
to the level of free cortisol in circulation.
Biochemistry
The initial step in the adrenal gland steroidal chains involves the
conversion of cholesterol into pregnenolone by cholesterol side chain
cleavage enzyme, catalysed by cytochrome P450scc. This is the rate
68
limiting step, and is controlled by ACTH production by the pituitary

gland. Only 20% of cholesterol is synthesised locally and the rest is
retrieved as LDL cholesterol from the general circulation. The next step
involves further incorporation of pregnenolone into the Δ5 or Δ4
pathways. The term delta is used to indicate the location of the double
bond within the steroid ring. The Δ4 molecules have a double bond
between carbons 4 and 5 in ring A, whereas the double bond is between
carbons 5 and 6 in ring B in Δ5 molecules. This is illustrated by the
progesterone and pregnenolone molecules shown by Figures 10 and
11 respectively. Conversion of Δ5 precursors into Δ4 molecules is
affected by the enzyme 3β-hydroxysteroid dehydrogenase/Δ5-Δ4
isomerase, which is also known as 3βol-dehydrogenase (3β HSD).
Unlike other adrenal enzymes, it is not a member of the cytochrome
P450 family.
The Δ5 pathway
The final products of this pathway are weak androgens which can be
converted to more potent ones peripherally. Meanwhile the
intermediate products are incorporated into the Δ4 pathway as well.
This conversion can be demonstrated as follow:
Pregnenolone → 17α-hydroxypregnenolone by 17α-

hydroxylase enzyme
17α-hydroxypregnenolone → dehydroepiandrosterone by 17/20

lyase enzyme
Dehydroepiandrosterone → androstenediol by 17β-hydroxysteroid

dehydrogenase
The gene responsible for regulation of the 17α-hydroxylase enzyme is

located in the long arm of chromosome number 10 (10q24) and is
coded as CYP17A1.
69
ABDEL -GADIR
The Δ4 pathway
The initial step in this pathway is the conversion of pregnenolone and

17α-hydroxypregnenolone (which are Δ5 precursors) into progesterone
and 17α-hydroxyprogesterone respectively, by the enzyme 3β HSD. It
is also responsible for conversion of dehydroepiandrostenedione
(DHEA) to androstenedione and androstenediol to testosterone. There
are two 3β HSD isoenzymes; type 1 is present in the adrenals and
gonads and type 2 is present in the placenta and peripheral tissues
(6). The gene responsible for regulation of 3β-hydroxysteroid
dehydrogenase type 2 enzyme is located in the short arm of
chromosome number 1 (1p13), and is coded as HSD3B2.
Cortisol production
The following steps are involved in cortisol production:

• 17α-hydroxyprogesterone → 11-deoxycotisol by 21α-hydroxylase
enzyme.
The gene controlling 21α-hydroxylase enzyme is located in the short

arm of chromosome number 6 (6p21), and has the gene symbol
CYP21A2. Mutations in the function of this enzyme make more than 90%
of all enzymatic deficiencies in the adrenal gland. The final outcome will
be accumulation of the precursor 17α-hydroxyprogesterone ready for
conversion into androgens, as shown below in the section dealing with
androgens and oestrogens production. Severe deficiencies in this
enzyme can lead to very low cortisol and aldosterone production, with
salt wasting and ambiguous genitals at birth. Milder forms may present
after birth with symptoms mainly related to elevated androgens level.
The next step in cortisol synthesis is:
• 11-deoxycortisol → cortisol by 11β-hydroxylase enzyme.
Mutations in the gene controlling 11β-hydroxylase enzyme are the

second most common after the 21α-hydroxylase type. They make
about 8% of all adrenal enzymatic deficiencies. The effective gene is
located in the long arm of chromosome number 8 (8q21), and coded
as CYP11B1. Gene mutation and partial block at this stage can lead
to accumulation of 11-deoxycortisol, and deoxycorticosterone which
needs the same enzyme to be converted to corticosterone as shown
in the aldosterone production section. Severe enzymatic deficiency
can also lead to ambiguous genitals at birth. Milder forms may cause
hyperandrogenic symptoms and signs, as well as high blood pressure
70
later on in life. The association of hypertension with low plasma renin

activity follows deoxycorticosterone induced sodium retention and
volume expansion. Hypokalaemia may also be an issue.
Aldosterone production
The following steps are responsible for the final production of

aldosterone:
• Progesterone → deoxycorticosterone by 21α- hydroxylase
enzyme;
• Deoxycorticosterone → corticosterone by 11β-hydroxylase
enzyme;
• Corticosterone → aldosterone by aldosterone synthase enzyme.
It is evident that an important step in aldosterone synthesis involves
the enzyme 21α-hydroxylase, which is also involved in cortisol
synthesis. Deficiency in the production of this enzyme by the zona
glomerulosa is usually not severe enough to cause major block in
aldosterone production. However, with homozygotic patients such
severe deficiency may occur, and can lead to the classical salt wasting
adrenal hyperplasia.
Androgens and oestrogens production
Androgens are byproducts and act as precursors to oestrogens, as

shown by the following steps:
• 17α-hydroxyprogesterone → androstenedione by 17/20 lyase
enzyme;
• Androstenedione → testosterone by 17β-hydroxysteroid
dehydrogenase;
• Androstenedione → oestrone by the aromatase enzyme;
• Testosterone → oestradiol by the aromatase enzyme.
Enzymatic deficiencies
It is easy now to see how enzymatic blocks or deficiencies can halt the
progress of the steroidal chain, and affect the type of precursors that build
up behind that block. Theoretically, any of the enzymes involved in the
steroidal chains can be deficient and may lead to clinical effects depending
on which hormone is deficient, and the alternative channels taken by the
precursors at the bottleneck. Some of these deficiencies are not
compatible with life, if not treated immediately after birth, especially the
rate-limiting step involved with the conversion of cholesterol to
71
ABDEL -GADIR
pregnenolone. It is also evident that different enzymes are controlled by

genes located at different chromosomes. Nerveless, all mutation
abnormalities involving the adrenal enzymes have autosomal recessive
inheritance.
Total block of any enzyme will cause maximal effect. The time, mode
and severity of manifestations depend on which hormone is deficient,
and the accumulated byproducts. Accordingly, enzymatic deficiencies
can be categorised into four subgroups according to their severity:
1. The classical or salt wasting types follow severe enzymatic
deficiencies leading to aldosterone and cortisol deficiency, and
excessive androgen production. This can follow severe
deficiencies of 21α-hydroxylase, 11-hydroxylase and 3β-
hydroxysteroid dehydrogenase. The affected neonate will also
show different degrees of ambiguous genitalia. The HPA axis
starts functioning by the 6th week of intrauterine life.
Malfunctioning of the adrenals with excessive production of
androgens will affect the urogenital sinus normal sexual
differentiation, which occurs few weeks later. Excessive
intrauterine exposure to androgens can also have many effects on
the attitude of an exposed female during childhood and adulthood
periods of life. This will be addressed in more detail later on.
2. The nonclassical salt sparing or simple virilizing type follows partial
enzymatic blocks, not including aldosterone and may present at
birth or any time thereafter. With 21α-hydroxylase deficiency,
Orta-Flores et al (7) showed one system with 2 different active
sites; one on progesterone only and a second one on either
progesterone or 17α-hydroxyprogesterone indiscriminately. They
suggested that both sites are defective in the salt-losing variety,
and only the second site is involved in the non salt losing type.
3. The late onset or attenuated adult form can lead to different
degrees of acne and / or hirsutism and menstrual dysfuncion
depending on the severity of the enzymatic block.
4. Cryptic type is seen in patients with biochemical evidence of 21α-
hydroxylase deficiency without any clinical evidence of
hyperandrogenisation, amenorrhoea, or infertility (8).
Specific types of enzymatic deficiencies
21α-hydroxylase deficiency
This is the most common type and makes >90% of all cases, as
mentioned previously. Gynaecologists are more likely to deal with this
72
version than the other types; hence it will be described in more detail.
The main biochemical diagnostic parameter is a high blood level of 17α-
hydroxyprogesterone. This can be tested in a morning blood sample in
the basal state, or combined with an ACTH stimulation test in marginal
cases. In the later scenario, 17α-hydroxyprogesterone level should be
measured before and 60 minutes after a bolus dose of ACTH. An
exaggerated increase in the level of 17α-hydroxyprogesterone confirms
the diagnosis. As for all other enzymatic deficiencies, the time and
severity of presentations depend on the degree of the enzymatic block.
Neonatal manifestations
Normal development of the external genitals depends on the presence

or absence of a testicle, and the production of testosterone and
dihydrotestosterone. More information about this subject has already
been given in Chapters 2 and 3. Enzymatic deficiencies may affect the
adrenal glands and gonads at the same time. Accordingly, when dealing
with a newborn with ambiguous genitals the provisional diagnosis
should include the following possibilities:
• Undermasculinized male;
• Masculinized female;
• True hermaphrodite.
This is an emergency situation in the labour room, which causes great
anxiety and distress to the parents. The condition is usually handled by
a paediatric endocrinologist, and later on by a paediatric surgeon if
necessary. Exclusion of the classical type of 21α-hydroxylase deficiency
with aldosterone deficiency should take priority, because the electrolytes
deficiencies can be fatal. The level of 17α-hydroxyprogesterone may give
false results if tested within the first 24 hours after birth. It has been
mentioned before that severe deficiency of 11β-hydroxylase and 3β-
hydroxysteroid dehydrogenase may give a similar picture at birth. The
masculinized vulva takes one of the following 5 stages as described by
Prader as far back as 1955 (9):
1. Cliteromegaly with no labial fusion;
2. Cliteromegaly with posterior labial fusion;
3. Larger clitoris with almost complete fusion of the labia, and a
single perineal urogenital orifice;
4. Phallic clitoris with urethra-like urogenital sinus at its base and
complete labial fusion;
5. Penile clitoris with urethral meatus at its tip, and scrotum like
labia.
73
ABDEL -GADIR
Confirmation of the biochemical abnormalities and peripheral

karyotyping are necessary to exclude the possibility of an
undermasculinized male. This later anomaly may follow one of the
subsequent scenarios:
1. Partial deficiency of the hormone 5α-reductase which is
necessary for the complete masculinization of the urogenital
sinus;
2. Partial receptor insensitivity may also present in a similar
manner;
3. Patients with mixed gonadal dysgenesis should also be
considered in the provisional diagnosis.
Childhood and Pubertal period
The classical types of adrenal enzymatic deficiency are outside the

remit of gynaecologists, unless surgery is performed by gynaecologists
experienced in this field. Cases with the less severe forms may show
slow growth and development during childhood years. They may
suddenly show accelerated growth when the adrenals start producing
excessive amounts of androgens at premature adrenarche. Children
overdosed during replacement therapy may also show signs of
underdevelopment, and may even show some cushingoid features due
to excessive glucocorticoid replacement.
Within the gynaecological remit, children with the milder forms may have
premature adrenarche, and start heterosexual precocious puberty before
the age of 8 years. The most common presentation in girls <10 years is
premature pubarche which was seen in 92% of the cases at presentation.
Clitoromegaly and acne were seen in only 20% at this age group as
reported by Moran et al (7). Parents may notice change in their
daughter’s body odour, due to early activation of the apocrine axillary
sweat glands. There is also rapid linear growth, and the child will be taller
and more mature than her siblings, but the final height will be shorter
than expected. This is the usual final outcome despite meticulous control,
in many cases. With excessive androgen, progesterone and 17-
hydroxyprogesterone production menarche may be delayed, and the
patient may even have primary amenorrhoea. The most common
symptoms beyond the age of 10 years are hirsutism (59%),
oligomenorrhoea (54%), acne (33%), infertility (13%), clitoromegaly
(10%), alopecia (8%) and primary amenorrhoea (4%) (10). The same
authors found significant increase in prevalence of hirsutism with age
which suggested a progressive nature for nonclassic adrenal hyperplasia.
74
Treatment with hydrocortisone or any other glucocorticoid should be

started early, and titrated against 17α-hydroxyprogesterone and
androstenedione blood levels. Patients with 21α-hydroxylase deficiency
are likely to develop polycystic ovaries, secondary to the increased
adrenal androgens production. This may lead to anovulation and
abnormal uterine bleeding. Finally, infertility can be an issue, and
induction of ovulation may be needed despite good adrenal control. In
general, hydrocortisone is preferable to dexamethasone or
prednisolone, especially in patients who are seeking to conceive as it is
inactivated in the placenta. Accordingly, the fetus will not be exposed
to any significant amounts of exogenous steroids.
11β-hydroxylase deficiency
The less common deficiency of 11β-hydroxylase may follow a similar

pattern of severity, and association to aldosterone, as 21α-hydroxylase
deficiency. This can be in classical or non-classical forms, as mentioned
before. It may lead to different grades of hyperandrogenisation either at
birth or at any other time with high blood pressure on occasions, but not
in all cases. Diagnosis is usually confirmed by having a high 11-
deoxycortisol blood level. Occasionally, a definitive diagnosis may be
difficult and a stimulation test with metyrapone is necessary. This can
cause further block of the enzyme 11β-hydroxylase, and stimulates
ACTH production. An exaggerated increase in the level of 11-
deoxycortisol will clinch the diagnosis. Patients with this enzymatic
deficiency may have different health related problems due to the high
blood pressure, which can be severe at times. Treatment also involves
hydrocortisone replacement therapy titrated against the level of 11-
deoxycortisol.
17α-Hydroxylase Deficiency
Patients presenting with 17α-hydroxylase deficiency may have delayed

or no signs of pubertal development, and primary amenorrhoea. This is
secondary to failure of conversion of progesterone to 17α-
hydroxyprogesterone, and pregnenolone to 17α-hydroxypregnenolone.
These are the precursors to androgens and later on oestrogens, as
shown before. Deficiency of the commonly associated 17/20 lyase
enzymatic activity will compound matters further by reducing the
conversion of the available 17α-hydroxyprogesterone and 17α-
hydroxypregnenolone to androgens which are the substrates for
oestrogens. They may also show high blood pressure and hypokalaemic
alkalosis, due to the conversion of the excessive progesterone to
75
ABDEL -GADIR
deoxycorticosterone and corticosterone. The age of onset and

degree of severity of hypertension can vary between different
individuals (11).
A different biochemical picture may be seen in this type of enzymatic

deficiency compared to the first 2 versions, with high blood levels
of FSH, LH, progesterone, deoxycorticosterone and corticosterone. On
the other hand, oestradiol and aldosterone levels, as well as plasma
renin activity will be reduced. The ovaries may be multicystic, with
no evidence of follicular maturation on ovarian biopsies. Beside the
specific steroidal treatment, management entails oestrogen
replacement therapy to allow normal development of secondary sexual
characteristics.
17β-Hydroxysteroid dehydrogenase deficiency (17HSD)
Different isoenzymes of this parent molecule are found in different

tissues of the body. They are involved with oestradiol and oestrone
interconversions, conversions of androstenedione to testosterone, and
dehydroepiandrosterone to androstenediol. The enzyme 17HSD1 is
expressed in the ovaries, and is responsible for oestradiol production
from oestrone, which is a product of androstenedione. On the other
hand 17HSD3 is found in the testicles and is responsible for the
conversion of androstenedione to testosterone. Other isoenzymes are
distributed widely in peripheral tissues (12).
Genetic mutations in 17HSD3 are rare, and may lead to reduced

testicular production of testosterone, and consequently reduced or
absent peripheral dihydrotestosterone conversion. In homozygous or
severe cases, failure of virilization of the external genitalia is likely to
occur. The prostate may not develop either, because of the resultant
deficit in dihydrotestosterone production. These individuals will be
raised as females till puberty when signs of androgenisation start to
show, because of increased conversion of androstenedione to
testosterone by peripheral 17β-hydroxysteroid dehydrogenase
isoenzymes. Gynaecomastia may also be seen because of increased
conversion of the high androstenedione to oestrone and oestradiol.
Patients with less severe mutation may be born with ambiguous
genitals. In all cases they have normal 46XY male chromosome
complement, with low plasma testosterone to androstenedione ratio.
The testicles may be felt in the inguinal canal, and no internal female
genitals will be seen. The prostate may be absent as mentioned before,
depending on the degree of dihydrotestosterone deficiency.
76
3β-hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase deficiency (3βHSD)
3βHSD deficiency is a rare disorder which was discovered first in male

infants. The hormone is responsible for the oxidation of Δ5 3β
hydroxysteroid precursors into Δ4 ketosteroids, which is an essential early
step in the formation of glucocorticoids, mineralocorticoids, and sex
steroids. At least 37 mutations in HSD3B2 gene have been identified to
cause different amino acid changes in 3βHSD enzyme (13). This in turn will
reduce its biological activity to different grades and affect the production of
cortisol and aldosterone accordingly. In severe cases the newborn may
have the classic salt losing or nonclassic virilizing versions with ambiguous
genitals, due to the conversion of the accumulated Δ5 precursors
peripherally to more potent androgens (DHEA to androstenedione and
androstenediol to testosterone). Steroids biosynthesis may be impaired in
the ovaries as well, affecting oestrogen production. Mild cases may present
as late onset hyperandrogenisation. Older children present with acne,
premature pubarche, and accelerated linear growth, whereas adolescent
girls may show hirsutism, acne and clitoromegaly. Ultrasound scan
examination usually reveals polycystic ovaries.
Hormone investigations of patients with the late onset type may

show normal morning basal blood levels of pregnenolone, 17-
hydroxypregnenolone and DHEA. Elevated Δ5/Δ4 steroids ratios were
considered diagnostic of this problem, specifically pregnenolone/
progesterone, 17 hydroxypregnenolone/17 hydroxyprogesterone and
DHEA/androstenedione ratios. However, the most accurate diagnostic
test is a plasma level of 17-hydroxypregnenolone >100 nmol/L
following ACTH stimulation (6).
Other considerations
It is usual for gynaecologists to deal with teenage girls and young adult
women who present with irregular periods and hyperandrogenic
symptoms or signs. The level of 17α-hydroxyprogesterone should be
tested in a morning sample of blood to check for adult onset 21α-
hydroxylase deficiency, even in the presence of ultrasonically diagnosed
PCO. Beside the ambiguous genitalia and precocious puberty alluded to
before, high androgen levels can lead to
• Primary or secondary amenorrhoea;
• Skin hyperandrogenisation including acne, excessive growth of
facial and body hair in a male distribution pattern, and androgenic
alopecia;
77
ABDEL -GADIR
• Severe hyperandrogenic or virilizing signs are seen only in severe

undiagnosed cases;
• Ovulation dysfunction including, inadequate ovulation, short luteal
phase with polymenorrhoea, menorrhagia, oligomenorrhoea and
dysfunctional uterine bleeding;
• Infertility may be an important issue due to the following
detrimental effects of the high androgens:
• Polycystic ovary conversion;
• Reduced oocytes maturation capacity;
• Reduced granulosa cells mitotic activity;
• Reduced FSH induced aromatase activity;
• Reduced follicular response to ovulation induction with clomid
or gonadotrophins;
• Endometrial dysfuncion and reduced pregnancy rate.
• Intrauterine exposure to high levels of androgens has been shown
to affect the gender behaviour and attitude of the exposed
females, both as children and during adult life. They tend to be
less gentle with greater physical aggressive behaviour, and may
show less interest in infants (14). They were also shown to have
less heterosexual interest, and were not satisfied with their sexual
assignment as females. These behavioural changes were different
in different patients in comparison to normal controls (15).
Accordingly, it was not possible to predict across different
behaviours. Nevertheless, it is generally agreed that severe
intrauterine exposure to androgens, especially with the classical
types of adrenal hyperplasia, is more likely to cause behavioural
masculinization during childhood and male psychosexuality during
adult life. Adolescent girls tend to have delayed or absent
heterosexual attractions to young men such as dating and falling
in love.
In 1999, Meyer-Bahlburg (16) reviewed the causes of infertility in
patients already under treatment for congenital adrenal hyperplasia.
Non-optimal hormonal control of the adrenal glands was considered to
be the most frequent cause, beside reduced sexual intercourse
secondary to the psychological factors mentioned before. Inadequate
control may be attributed to the fact that excessive steroids secretion
in these patients may be affected by other factors beside the adrenal
enzymatic block induced ACTH overproduction (17, 18). Other
recognised causes include:
1. Mild degree of ACTH hyper-responsiveness to corticotrophin-
releasing hormone stimulation;
78
2. Altered enzyme kinetics with reduced catalytic efficiency of

21-hydroxylase, which results in increased production of
progesterone and 17-hydroxyprogesterone by the adrenal glands
despite of excessive glucocorticoid adminstration;
3. Up to 40% of the patients have evidence of adrenocortical
hyperplasia;
4. Overactivation of the renin-angiotensin-aldosterone axis increases
adrenocortical steroidogenesis in patients with salt-wasting and in
some patients with simple virilizing adrenal hyperplasia;
5. Alteration of the hypothalamo-pituitary-ovarian axis can result in
abnormal gonadotrophins production, and excessive ovarian
production of progesterone and 17-hydroxyprogesterone.
Accordingly, suppression of both the ovaries and the adrenals
may be necessary for optimum steroidogenic control (17).
An important cause of infertility is patients with classic adrenal
hyperplasia is inadequate vaginal reconstruction which can compromise
the width of the introitus, width and depth of the vagina itself, as well
as the erotic functions of the labia minora and clitoris. The role of
clitorectomy which was the standard practice during early childhood in
the past has been criticised and clitoral reduction and / or recession
have been suggested instead.
Hormonal Treatment
The main objective in managing patients with adrenal enzymatic

deficiency is to provide adequate cortisol replacement. This in turn will
suppress overproduction of ACTH, and reduces adrenal cortex
overactivity with suppression of excessive androgens production.
In gynaecological practice, the most commonly encountered

problems related to adult onset 21α-hydroxylase deficiency are
menstrual irregularities and skin hyperandrogenisation. Normal
menstruation usually resumes some time after normalisation of 17α-
hydroxyprogesterone, which is used to monitor response together with
androstenedione. Hydrocortisone is the most widely used mediction in
a daily dose of 10-20 mg/m2. This dose can be increased to 20-30
mg/m2 every day in divided doses in case of poor response.
Alternatively, a synthetic glucocorticoid hormone may be used.
Treatment with dexamethasone 0.25-0.5 mg at bedtime for 1-2 years
can restore normal ovulatory cycles, even after stopping medication
(19). Prednisolone may also be used in a dose of 5 – 10 mg every day
in 2 divided doses. Some patients may have persistently high serum
79
ABDEL -GADIR
progesterone levels, despite the correction of the enzymatic

problem (20). This can lead to anovulatory cycles (21), or failure of
the endometrium to develop despite good follicular maturation (22).
The role of the ovaries in producing excessive amounts of
progesterone and 17-hydroxyprogesterone in patient with adrenal
hyperplasia has been alluded to before, and suppression of the
adrenals and ovaries may be necessary for optimum control. A difficult
subgroup includes patients with altered enzyme kinetics which can
result in increased progesterone and 17-hydroxyprogesterone
production independent of ACTH. Accordingly, these chemicals may
remain above normal levels even in the presence of excess
glucocorticoid adminstration (17). To cater for unforeseen emergency
problems, each patient on glucocorticoid treatment should be provided
with a card to state the diagnosis, the type of drug and the dose used.
Furthermore, an injection kit with 50 – 100 mg hydrocortisone should
be provided depending on age, to cater for emergency situations at
home.
Family considerations
All adrenal enzymatic deficiencies are inherited as autosomal recessive

disorders. With carrier parents, the likelihood is that one of four children
will be affected (25% chance), two will be carriers (50% chance), and
one will have normal genes (25% chance). Severity of the mutation will
also affect penetration. A severely affected allele may be inherited as a
severe abnormality with classic adrenal hyperplasia. This subject was
studied by Moran et al in 2006 (23). The risk of a mother with non
classical 21-hydroxylase deficiency giving birth to a child with the
classical type is 2.5%. The risk of spontaneous miscarriages was 25.4%
and 6.2% (P<0.002) before and after the diagnosis respectively.
Premarital or preconception screening can be useful, especially if one
prospective parent proved to be a carrier. This is especially so in
communities known for intermarriages, or for marriages within the
same ethnic group. Similarly, a female sibling of a hyperandrogenic
patient diagnosed with such an adrenal defect should be offered proper
screening, especially if she showed similar symptoms or signs. Genetic
testing for mutations and gene deletion or conversions is now available
for definitive screening of patients and carriers.
Parents of a previously affected child or carrier parents may seek

preconception advice. Two methods can be used to deal with this
problem including preimplantation genetic screening and prenatal
genetic diagnosis.
80
1. Preimplantation genetic screening
With preimplantation genetic screening, in vitro fertilisation will be

necessary to create embryos which can be biopsied and tested for the
enzymatic deficiency. Only normal embryos should be replaced into the
patient’s uterus. This may create ethical issues of creating embryos and
then destroying them. Normal embryos may also be destroyed during
the procedure, which is not 100% accurate. On the other hand, such
screening gives parents a better chance of having healthy children, and
prevents the potential sufferings of the affected children. There is also
the option of prenatal genetic diagnosis which may be too late to make
a diagnosis in time to prevent virilization of a female fetus. Accordingly,
providing thorough information counselling is necessary, and patients
need ample time and support to make their own minds without any
pressure.
2. Prenatal genetic diagnosis
Prenatal molecular genetic studies of fetal DNA retrieved by chorionic

villus sampling (CVS) are ideal for diagnosing 21α-hydroxylase
deficiency (24). However, this is rather late to prevent the exposure of
the urogenital sinus to excessive fetal androgens. This is especially so,
as the fetal adrenal glands start functioning by the 6th week of
pregnancy, well before a CVS can be done. Accordingly, a glucocorticoid
should be started as soon as pregnancy is diagnosed, and not later than
the 9th week (25, 26). Chorionic villus sampling can be done as usual,
and medication should be stopped if the fetus proved to be normal. The
recommended dose of dexamethasone is 20 μg /kg pre-pregnancy
weight / day in divided doses.
Adrenal insufficiency
The detrimental effects of excessive cortisol production on the

hypothalamo-pituitary-ovarian axis and menstrual function have been
discussed in Chapter 3. On the other hand, failure of cortisol production
can cause serious medical problems, depending on the degree of
deficiency. Such failure may be caused by many factors, not related to
the enzymatic deficiencies mentioned before. Partial adrenal
insufficiency may be suspected or diagnosed in the gynaecology clinic,
especially during investigations of premature ovarian failure or
autoimmune thyroid dysfunction. Furthermore, patients already on
glucocorticoid replacement therapy may present with different
gynaecological problems. A short summary about adrenal insufficiency
81
ABDEL -GADIR
will be given here, as it is primarily a medical rather than a reproductive

endocrine disorder.
Beside their metabolic, immunological / ani-inflammatory and

haematological effects, corticosteroids augment the cardiovascular
effects mediated by the sympathetic nervous system during stress
(27). Accordingly, corticosteroids deficiency may result in hypotension
or shock in response to different types or degrees of stress. Aldosterone
on the other hand is the main mineralocorticoid and it regulates sodium
plasma levels, blood volume and blood pressure. It also increases
urinary potassium secretion, and low aldosterone levels are usually
associated with hyperkalemia and mild metabolic acidosis. Other
sodium retaining chemicals including angiotensin II and norepinephrine
can compensate for mildly reduced aldosterone blood levels (28).
However, severe deficiency may lead to salt wasting and hypotension.
Primary adrenal insufficiency is usually caused by underactive or
damaged adrenal glands, and may affect both cortisol and aldosterone
production. Conversely, secondary insufficiency is caused by pituitary
dysfuncion or damage and affects mainly cortisol production.
Autoimmune adrenal insufficiency is the most common primary type,
and may be associated with other autoimmune disorders including
autoimmune thyroid dysfuncion and premature ovarian failure, vitiligo,
coeliac disease and pernicious anaemia. Beside the low plasma cortisol
levels, high titres of adrenal antibodies may be found during endocrine
investigations. In fact such antibodies may be detected in a woman’s
blood many years before she becomes symptomatic. More information
about this subject can be found in Chapter 10. The most common
secondary adrenal insufficiency follows sudden cessation of
glucocorticoid medication after prolonged suppression of the HPA axis.
Recovery may take weeks or months before normal function is
resumed, depending on the level and duration of suppression. This may
lead to refractory hypotension during acute medical problems and
surgical procedures, if adequate care has not been taken of the
extra need for exogenous cortisol. Examples of the gynaecological
scenarios which may lead to this problem include sepsis, haemorrhage,
childbirth and gynaecological surgery. Other causes of primary
adrenal insufficiency include destruction of the adrenal glands by
tuberculosis, sarcoidosis, amyloidosis, haemochromatosis, sepsis and
adrenal haemorrhage. About 70-80% of the adrenals need to be
damaged before clinical symptoms may develop. Certain drugs
including metyrapone which is an aldosterone antagonist
(Alliance Pharmaceuticals), and ketoconazole which is an antifungal
82
(Janssen-Cilag) may cause adrenal insufficiency. Failure of the pituitary

gland to produce ACTH due to pituitary damage by a tumour or empty
sella, or the hypothalamus to produce corticotrophin releasing hormone
can lead to secondary and tertiary adrenal insufficiency respectively.
Symptoms and management of adrenal insufficiency
Symptoms of adrenal insufficiency are usually insidious and vague in

mild cases, and patients may present with weakness, fatigue, fainting
attacks and dizzy spells, postural hypotension, unexplained weight loss,
muscular pains, sparse or absent axillary and pubic hair, and increased
pigmentation. A high degree of suspicion is needed especially in
patients with personal or family history of autoimmune disorders. Blood
chemistry may show low sodium and high potassium levels,
eosinophilia and occasionally low blood sugar, with low plasma cortisol.
The short ACTH stimulation test is very sensitive in diagnosing primary
but not secondary adrenal insufficiency. Doubling of basal plasma
cortisol level after ACTH injection is the minimum normal response.
Similar results were generally reported after the 250 μg and 1 μg tests
(29), though Abdu and Clayton (30) showed good reproducibility and
higher sensitivity with 1 μg synacthen tests. A similar conclusion was
drawn by Tordjman et al, who suggested regular use of the 1 μg test
instead of the standard one (31). Regarding the duration of the test,
Edavalath et al showed more false positive results with the 30-minute
test compared to the 60-minute version (32). Further endocrine
investigations may be carried out by a medical endocrinologist, and
usually include blood tests for ACTH, aldosterone, noradrenaline and
plasma renin activity. Imaging of the adrenals and pituitary gland may
be necessary.
Replacement therapy with hydrocortisone tablets is necessary in

established cases, and a mineralocorticoid will also be required in cases
of aldosterone deficiency. The normal cortisol production rate in women
is 9.12 mg/day which is equivalent to 5.28 mg/m2/day (33). Body
surface area in m2 can be calculated using the Mosteller formula (vweigh
(kg) x height (cm)/3600) (34). The usual dose of hydrocortisone is 10
mg in the morning and 5 mg before lunch and the evening meal,
depending on body surface area. This dosage is meant to give blood
levels which simulate the normal circadian changes in plasma cortisol.
In general, the correct dose is the lowest that allows the patient to feel
well without producing symptoms of hypercortisolism as stated by
Zelissen (35). The main side effect of prolonged mild overdosage with
corticosteroids is osteoporosis. However, steroid induced osteoporosis
83
ABDEL -GADIR
was found to be substantially reversible after restoration of normal

cortisol levels as demonstrated in patients with Cushing’s disease (36).
Fludrocortisone (Bristol-Myers Squibb) should be used in a dose of 0.05-
0.3 mg every morning in cases of aldosterone deficiency, depending on
the age and weight of the patient, and severity of the condition. The
recommended starting dose is 0.1 mg/day, to be reduced to 0.05
mg/day should the patient develop high blood pressure. Hydrocortisone
booster doses should be given during episodes of severe stress, acute
medical conditions, and surgical procedures. The duration of this extra
medication depends on the nature of the medical problem and the extent
of the surgical procedure involved, and should also be tapered slowly
thereafter. Patients should have an emergency injection kit at home to
be used especially after excessive vomiting which needs emergency
treatment.
In gynaecological practice, 100 mg hydrocortisone should be given

intramuscularly just before induction of anaesthesia for major
gynaecological surgery and caesarean section, and at the onset of normal
labour. The same dose should be given every 6 hours till the patient is
able to eat and drink normally following major surgery. Thereafter, double
the usual oral dose should be taken every day for 48 hours, before
tapering it slowly down to the normal dose. Following vaginal delivery and
minor surgery, double the oral dose should be taken for 24-48 hours
before returning to the normal daily dose. This regimen should be
prolonged as necessary in case of complications.
Summary
This short manuscript has been written to address the problems posed
by dysfunctional adrenal glands, as seen by gynaecologists. The
relationship between adrenal dysfunction and the risks of ambiguous
genitalia, abnormal pubertal development, anovulation, dysfunctional
uterine bleeding, hyperandrogenic skin manifestations, and infertility
are too many to be ignored by any gynaecologist. Furthermore, the
presentation of non classical adrenal hyperplasia can not be
distinguished clinically from any other hyperandrogenic disorder,
mainly polycystic ovary syndrome. It has been reported that 1 - 10%
of all hyperandrogenic women are likely to be affected by 21
hydroxylase adrenal enzymatic deficiency. The exact rate is different in
different societies, being 1 in 1000 in the White population in general.
A more frequent rate of 1 in 27 has been reported in Ashkenazi Jews,
with 1 in 63 Croats, and 1 in 330 Italians (37). Accordingly, assessment
of 17α-hydroxyprogesterone should be included during the
84
investigations of all hyperandrogenic women. Blood samples should

be collected early in the morning, to cater for the circadian changes in
its blood levels. Borderline levels should be investigated with a
synacthen test, which shows an exaggerated 17α-hydroxyprogesterone
response in patients with partial enzymatic defects. Total reliance
on high DHEA-S (Δ5) blood levels to screen for all adrenal
enzymatic defects is not appropriate. Less than 12% of patients
with such biochemical changes had concurrently elevated 17α-
hydroxyprogesterone (Δ4) in the basal state or after synacthen tests,
as reported by Abdel-Gadir et al (38).
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Shaikh G, Clayton P, Grötzinger J, Holterhus PM and Riepe FG.
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prenatal androgen exposure Hormones and Behaviour 2009;
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15. Sheri A. Berenbaum and J. Michael Bailey Effects on Gender
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18. Sánchez LA, Morán C, Reyna R, Ochoa T, Boots LR and Azziz R.

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androgen and elevated progesterone levels in women treated for
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21. Nimkarn S and New MI. Steroid 11 beta-hydroxylase deficiency
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22. Holmes-Walker DJ, Conway GS, Honour JW, Rumsby G and Jacobs
HS. Menstrual disturbances and hypersecretion of progesterone in
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deficiency. Clin Endocrinol 1995; 43 (3): 291 - 296.
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Marcondes JAM, Pugeat M, Speiser PW, Pignatelli D, Mendonca BB,
Barchega TAS, Escobar-Morreale HF, Carmina E, Fruzzetti F and
Kelestimur F. Reproductive outcome of women with 21-
hydroxylase-deficient nonclassic adrenal hyperplasia. J Clin
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hydroxylase deficiency. Endocr Rev 2000; 21: 245 - 291.
25. Mercado AB, Wilson RC, Cheng KC Wei JQ and New MI. Extensive
personal experience: Prenatal treatment and diagnosis of
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deficiency. J Clin Endocrinol Metab 1995; 80: 2014 - 2020.
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Congenital adrenal hyperplasia: update on prenatal diagnosis and
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27. Sapolsky RM, Romero M and Munck AC. How do glucocorticoids
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29. Dorin RI, Qualls CR and Crapo LM. Diagnosis of adrenal

insufficiency. Ann Intern Med 2003; 139: 194 – 204.
30. Abdu TAM and Clayton R. The low-dose synacthen test for the
assessment of secondary adrenal insufficiency. Curr Opin
Endocrinol and Diabetes 2000; 7(3): 116 – 121.
31. Tordjman K, Jaffe A, Trostanetsky Y, Greenman Y, Limor R and
Stern N. Low dose (1 μg) adrenocorticotrophin (ACTH) stimulation
as a screening test for impaired hypothalamo-pituitary-adrenal
axis function: sensitivity, specificity and accuracy in comparison
with high dose (250 μg) test. Clin Endocrinol 2003; 52(5):
633 – 640.
32. Edavalath M, Hudson P and Leigh J. Comparison of 30 minute
short synacthen test and 60 minute short synacthen test for
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33. Vierhapper H, Nowotny P, and Waldäusl W. Sex-differences in
cortisol production rates in humans. Metabolism 1998; 47(8):
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34. Mosteller RD. Simplified calculation of body-surface area. N Eng J
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35. Zelissen PMJ, Croughs RJM, van Rijk PP, and Raymakers JA. Effect
of glucocorticoid replacement therapy on bone mineral density in
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36. Manning PJ, Evans MC and Reid IR. Normal bone mineral density
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Dokmetas HS, Atmaca h, Bahceci M, Balci MK, Comlekci A, Bilen
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88
Chapter 5
Progestogens, Androgens and Oestrogens
This chapter has been written to give a functional account of

progestogens, androgens and oestrogens, rather than a biochemical
script to compare their structural similarities and differences.
Understanding their metabolic and morphological effects and their
interactions with each other and with other endocrine glands forms the
final objectives behind writing this chapter.
Progestogens, androgens and oestrogens are steroidal compounds made

of 4 interconnected cyclic hydrocarbons rings designated as A, B, C and
D rings respectively. They can be natural or synthetic. All steroidal
hormones attach to intracytoplasmic receptors, before being carried into
the nuclei to exert their specific effects. Different hormones have different
potency, depending on the duration of time a single dose of steroid-
receptor complex occupies the nucleus of the target cell. In their natural
forms, they are produced by the adrenal glands and ovaries in non
pregnant women. Peripheral conversions also play an important role in
the synthesis and degradation of oestrogens and androgens. The
placenta is a major source during pregnancy
Progestogens
Progesterone was discovered in 1934. It is a natural 21-carbon

molecule formed from pregnenolone by the microsomal enzyme 3β-
hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase. Pregnenolone itself is
made from cholesterol through a reaction catalysed by cytochrome
P450scc, as described in Chapter 4. In a way, progesterone is a mother
molecule of androgens and oestrogens, as shown by the following
chart:
Progesterone → 17α-hydroxyprogesterone
↓
Androstenedione → Oestrone
↓
Testosterone → Oestradiol
89
ABDEL -GADIR
The importance of this interrelationship has been discussed in

Chapter 4, where failure of conversion of progesterone to 17α-
hydroxyprogesterone can lead to failure of androgens and oestrogens
production.
The three molecules shown in Figures 12 - 14 represent progesterone,

testosterone and oestradiol respectively. Note the small differences in the basic
two dimensional structures of the three molecules.
Natural progesterone is produced by the corpus luteum, adrenal glands

and the placenta. Synthetic progestogens, on the other hand, are
mainly the derivatives of:
• 17α-hydroxyprogesterone which are non-androgenic;
• 19-norprogesterone derivatives which are also non-androgenic;
• 19-nortestosterone derivatives which are androgenic.
Natural progesterone is >95% bound to plasma proteins, mainly
albumen and transcortin. Once in the blood, it has a short half-life of 5-
20 minutes. Accordingly, the efficacy of exogenous progesterone
depends more on the route of administration and its absorption half-
life, rather than its elimination rate. It is metabolised in the liver
successively into pregnanedione, pregnolone, and finally pregnandiol.
The effects of natural progesterone can be divided into the following
categories:
1. Endocrine or chemical effects

• Following ovulation, progesterone produced by the corpus luteum
modulates the function of the hypothalamo-pituitary units. It affects
GnRH pulse generation leading to slower LH pulse pattern with high
amplitude during the luteal phase. The central effect of
progesterone is affected at the level of the hypothalamus itself (1).
Patients with reduced hypothalamic sensitivity to progesterone will
have rapid GnRH and LH pulses, as seen in patients with polycystic
ovary syndrome (2).
• It depletes oestrogen receptors as well as its own. This is
important at the endometrial level, as prolonged endometrial
90
exposure to progesterone can lead to endometrial atrophy, and

possibly dysfunctional uterine bleeding. It also affects oestradiol
metabolism by increasing its conversion to oestrone. This is
affected through activation of the enzyme 17-hydroxysteroid
dehydrogenase.
• It competes weakly with testosterone at its receptors level.
• It has a thermogenic effect by increasing the core body
temperature during the luteal phase.
2. Morphological effects
• The immediate morphological effect of progesterone after
ovulation is to increase cervical mucous viscosity, which reduces
migration of bacteria and sperm into the cervical canal.
• It converts the oestrogen primed endometrium into a secretory
one. This is one of the most commonly used indications for
progesterone medication. It can be given by deep intramuscular
injections, or vaginally during fertility treatment, especially with
assisted reproduction. Cyclogest pessaries and crinone gel are just
two examples in common use. A meta-analysis published by
Zarutskiea and Phillips in 2007 (3) showed that transvaginal
progesterone medication in the right daily dosage is equally
effective as the intramuscular route in this respect. Micronization
of progesterone increased its surface area, and improved its
absorption through the stomach. It has been licensed by the
American Food and Drug Administration (FDA) for the
management of secondary amenorrhoea and for hormone
replacement therapy since 1998.
• It has an effect on tubal peristaltic activity, and reduces the
number of cilia and mucous production by the fallopian tubes.
• The antioestrogenic effect of progesterone has a direct effect in
reducing myometrial sensitivity and contractility.
• It augments the effect of prolactin in preparing the breasts for
lactation, but also inhibits lactation during pregnancy. The
dramatic decline in the blood level of progesterone following
childbirth triggers milk production.
3. Metabolic and immunological effects of progesterone

• Progesterone has an immunosuppressant effect which is not
mediated through progesterone or glucocorticoid receptors. This
effect was thought to be secondary to non-receptor mediated
activity, conversion of progesterone to another steroid within
the microenvironment of the immune cell, and interaction of
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ABDEL -GADIR
progesterone with other members of the steroid and thyroid

hormone receptor superfamily (4).
• It has a catabolic effect, as shown by a rapid decline in the plasma
concentration of many amino acids after progesterone
administration (5). There is also increased total urinary nitrogen
excretion without aminoaciduria.
• It may induce hyperinsulinaemia by acting directly on the
pancreas and promotes hepatic storage of glycogen. Its also
antagonises the effect of insulin on glucose metabolism in adipose
tissues and muscles (6). This is coupled by increased deposition
of fat in the breasts and adipose tissue. It also reduces the
hypertriglyceridaemic effect of oestrogen.
• It has an anti aldosterone effect, and increases sodium loss.
• It increases the respiratory minute tidal volume, hence reduces
the alveolar and blood CO2.
Synthetic progestogens
Synthetic progesterone analogues have been produced, as

progesterone is poorly absorbed from the gastrointestinal tract unless
it is micronized. Such progestogens have different structures and
characteristics, but they all share the common ability to induce
secretory changes in an oestrogen primed endometrium. Unlike natural
progesterone, many of them can be taken orally. Like natural
progesterone, they modify oestrogen effects but have different
characteristics otherwise:
• Progestogens derived from 19-nortestosterone have different
degrees of androgenicity. The sequence of ascending androgenicity
is: ethynodiol diacetate, norethindrone, norethindrone acetate,
norgestimate and desogestrel in that order, with levonorgestrel
and gestodene having the highest androgenicity.
• Derivatives of 19-norprogesterone are referred to as pure
progestational molecules, as they have no androgenic,
oestrogenic or glucocorticoid activity. They bind almost
exclusively to progesterone receptors. This group includes
nestorone, trimegestone and nomegestrol (7).
• Mild corticoid effect has been attributed to cyproterone acetate
(8), but it also competes with cortisol at its receptor sites (9).
Furthermore, it has mild inhibitory effect on the enzyme 21-
hydroxylase and to a lesser extent 3βol-dehydrogenase (10).
Accordingly, it can inhibit the production of both cortisol and
aldosterone at the same time. The degree of inhibition is
92
dependent on the metabolic clearance rate of the drug, and the

degree of the genetic mutations of the two enzymes in the
individual concerned. Because of adrenal glands suppression and
their reduced response to ACTH, cyproterone acetate should be
withdrawn slowly to prevent adrenal failure, especially if it has
been used in a high dose for a long period of time.
• The new progestogen drospirenone is a derivative of
spironolactone, and has an anti mineralocorticoid effect.
Accordingly, it decreases salt and water retention with a potential
for lowering blood pressure (6). It also has a mild antiandrogenic
effect.
• Progestogens have anti gonadotrophin effect when given in a high
dose.
• Most progestogens suppress the production of endogenous
progesterone by affecting the corpus luteum enzymatic activity, if
used during the luteal phase. There is no actual luteolytic
activity, as suppression can be reversed by human chorionic
gonadotrophin injections. The lowest total dose necessary to
produce such an effect was 30 mg for northisterone, 12 mg for
norgestrel, 300 mg for chlormadinone acetate and 360 mg for
medroxyprogesterone acetate (11).
Most synthetic progestogens are derived from testosterone, especially
those used in oral contraceptives. More information about their
biochemical subgrouping will be found in Chapter 13. They have different
effects on lipids and lipoproteins, depending on their androgenicity and
the dosage used (12). They increase LDL production, but increase its
clearance rate as well. Accordingly, they have no significant effect in this
respect when used with oestrogen. Androgenic progestogens, such as
levonorgestrel, decrease triglyceride levels by reducing secretion of very-
low density lipoprotein (VLDL). On the downside, they can also
counteract the beneficial effect of oestrogen on HDL (13). Conversely,
non-androgenic progestogens have variable effects on oestrogen induced
increase in HDL level. Dydrogesterone, as an example, has little negative
effect (14), whereas medroxyprogesterone acetate reduces this effect. In
general, C-21 progestogens do not prevent the increase in triglycerides
induced by oral oestrogens.
The derivatives of 17α-hydroxyprogesterone and 19-norprogesterone

are antioestrogenic and antigonadotrophic. They have no androgenic
effect, which makes them favourable to use in patients with
hyperandrogenic tendency. They can be given orally or by injection. The
two main subgroups of 17α hydroxyprogesterone are:
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ABDEL -GADIR
• 17α-hydroxyprogesterone caproate which is given

intramuscularly;
• 6α-methyl-hydroxyprogesterone acetate which is also known as
medroxyprogesterone acetate or provera can be used orally. It
can also be used intramuscularly in a depo form which increases
its duration of action (depo-medroxyprogesterone acetate).
Depo-medroxyprogesterone acetate is used mainly as a long acting
injectable contraceptive, and for ovulation suppression in cases of
endometriosis. The term medroxy is an abbreviation for methyl-
hydroxy. Deep intramuscular injections can be repeated every 3
months in doses of 150 mg. More frequent injections do not improve
the efficacy of the drug, but may result in more side effects. The main
side effects even when the drug is used in the recommended doses
include:
• Prolonged amenorrhoea may occur even after suspending
medication. The average period for the return of normal fertility
has been quoted as 9 months (15), but it may take even longer
time after prolonged use of the drug.
• Risk of abnormal uterine bleeding is also an issue. Prolonged
periods of bleeding both heavy and light may be encountered.
• There is a risk of developing ovarian cysts.
• The prolonged anti oestrogenic effect on the brain may lead to
lower mood spells, and occasionally depression.
• Other anti oestrogenic side effects may be a problem, mainly
osteoporosis.
• There is also a risk of weight gain after prolonged use of the drug.
Other long acting 17-hydroxyprogestogen derivatives have been
used for:
• Supplementing pregnancy following repeated miscarriages and
premature labour has been one indication for using 17-
hydroxyprogesterone caproate. The brand mostly used was
Delalutin, which has been withdrawn in 1999. In 2008, the
American FDA regarded 17-hydroxyprogesterone caproate as a
category D drug, which indicated evidence of fetal harm, when this
drug was used during pregnancy. Nonetheless, many articles have
defended the safety of 17- hydroxyprogesterone during pregnancy
on theoretical basis, as it is produced in large amounts by the
placenta, and according to the results of animal and clinical studies.
Most of these publications dated back to the 60s, 70s and 80s.
• A well known member of this subgroup is cyproterone acetate.
It has a very potent anti androgenic effect by competing with
94
testosterone and dihydrotestosterone at their receptors. It also

has a strong antigonadotrophic effect. It is most commonly used
for treatment of female hyperandrogenisation in a reversed
sequential therapy in severe cases. Because of its depo effect, it
may lead to menstrual irregularities or dysfunctional uterine
bleeding, unless it is combined with an oestrogen. It can be used
in a dose of 10-50 mg every day plus 30 μg of ethinyl oestradiol
for 10 days, to be followed by unopposed ethinyl oestradiol for 15
days. In milder cases, it can be used in a small dose of 2 mg
combined with 35 μg ethinyl oestradiol in a designated
contraceptive pill called Dianette (Bayer plc). Cyproterone acetate
can cause breast tenderness, lethargy, depression, loss of libido
and adrenal suppression. An important side effect is dysfunctional
uterine bleeding. Accordingly, it should not be used in the second
half of the cycle. The objective of using oestrogen is to regulate
the monthly withdrawal bleeding. Cyproterone acetate is
contraindicated in cases of liver disease, severe depression,
history of deep vein thrombosis and during pregnancy.
In most cases, further progestogen medication will not stop progestogen
induced abnormal uterine bleeding, and may even make it worse. This is
especially so after using long acting progestogens. During mild to
moderate bleeding episodes, oral oestrogen helps in building up the
endometrium and gives it some structural integrity, before bleeding
stops. In severe cases, only intravenous oestrogen may be effective.
Premarin can be used in a dose of 25 mg every 4 hours for 24 hours,
followed by oral oestrogen for further 10 – 14 days. A progestogen is
needed during the last 5-7 days of therapy to induce secretory
endometrial changes, before suspending treatment to provoke a
medically controlled withdrawal bleeding. Blood loss usually eases off
substantially, or even stops after the 3rd or 4th premarin intravenous
dose. Progestogens are also useful for treating patients with anovulatory
irregular or abnormal uterine bleeding. However, luteal progestogens
medication is not useful for controlling ovulatory abnormal uterine
periods. They may even be detrimental, and cause more menstrual blood
loss (16; 17). In contrast, longer regimens from days 5-25 of the cycle
are equally effective as levonorgestrel intrauterine devices, but only have
30% acceptability by patients for repeated prescriptions (18).
Transvaginal ultrasound scan examination can be very useful in setting
the management plan. Patients presenting with abnormal uterine
bleeding and a thin endometrium should have oestrogen to build up the
endometrium, and to benefit from its local haemostatic effect. The
indiscriminate use of progestogens for all patients should be avoided.
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Androgenic progestogens are mainly testosterone derivatives, after

removal of the C19 methyl group (19-nortestosterone). The most
commonly used one outside the contraception field is norethisterone
(primolut N) which is a 17α-ethinyl derivative of 19-nortestosterone. It
is mainly used for inducing withdrawal bleeding after periods of
amenorrhoea, and for treatment of anovulatory menorrhagia. The
other commonly used derivative is 13 ethinyl-17α-ethinyl-19
nortestosterone (norgestrel). This and other androgenic progestogens
are mainly used in minute amounts either as progestogen only pills, or
as part of combined contraceptive pills. The mirena system is a
levonorgestrel loaded intrauterine contraceptive device which is used
for contraception, control of excessive uterine bleeding, and in cases of
endometriosis for pain control. It is impregnated with 52 mg of
levonorgestrel, and releases 20 μg of the hormone into the uterine
cavity every day. Only a small fraction reaches the general circulation,
though it has been detectable in significant amounts in the peritoneal
fluid in the pelvis. It has also been shown to have anti-inflammatory
and immunomodulatory effects (19). Furthermore, levonorgestrel
decreases and then blocks DNA synthesis and mitotic activity (20). In
addition, it increases endometrial apoptotic activity by reducing
expression of the Bcl-2 gene which has an anti-apoptotic effect (21).
It is advisable to avoid androgenic progestogens use in hyperandrogenic

women, as they may worsen this condition. This is especially so for
norgestrel and levonorgestrel as they can suppress the production of sex
hormone binding globulin by the liver, and increases the level of free
testosterone. High doses of norethisterone acetate for long periods of time
in repeated cycles, to control abnormal uterine bleeding, are better
replaced with medroxyprogesterone acetate which is equally effective
when used in the right dose. Furthermore, many 19-nortestosterone
derivatives are capable of reducing HDL cholesterol level, and inducing
insulin resistance. This is also valid for gestational diabetes mellitus
(GDM), as shown by Hedderson et al in 2007 (22). Their results suggested
43% increased risk of GDM associated with pre-pregnancy use of high
androgen hormonal contraceptives.
Human testing of progestogens
Progestogens potency was measured in different ways including:

• The progestational dose is the one capable of converting an
oestrogen primed endometrium into a secretory one. Secondary
amenorrhoeic women were prescribed unopposed oestrogen for
96
two weeks, followed by combined oestrogen and progestogen

medication for 10 days. The endometrium by the end of this
period was assessed for different grades of secretory changes.
The limitations of this test were discussed by Swyer in 1984 (23),
who argued that no data satisfied the standards of acceptability,
on his opinion, by the time his paper was published.
• The cycle delaying dose was documented first by Greenblatt et al
in 1958 (24). It is the progestogen dose capable of delaying
menstruation when started 7 days after ovulation, and continued
for 3 or more weeks. Bleeding should only start 2-3 days after
stopping the effective progestogen therapy, and not during
medication.
• Other parameters used to test progestogens potency included
depression of the vaginal karyopyknotic index, inhibition of
oestrogen induced cervical mucous changes, inhibition of
ovulation, and withdrawal bleeding after 5-days courses in
women with secondary amenorrhoea and oestrogen primed
endometrium.
These tests were utilised as a guide for selecting the right doses of
progestogens to be used in new contraceptives, with standardized
doses of ethinyl oestradiol. They are also helpful in selecting the
effective dosage to control abnormal uterine bleeding. They should not
be used for delaying menstruation for social or religious occasions.
Such practice may lead to abnormal uterine bleeding, especially if the
correct cycle delaying dose is not used.
Table 2: shows the total progestational dose (TPD), and the daily cycle delaying
dose (CDD) during natural cycles of testes progestogens.
Progestogens TPD (mg) CDD (mg)
Pure progesterone im 200 1000
Norethisterone 100-150 15
Medroxyprogesterone acetate 60 20
Cyproterone acetate 20 -
Levonorgestrel 07 05
Androgens
Androgens are C19 steroidal hormones which are capable of initiating

and maintaining secondary male sexual characteristics. They may be
natural or synthetic in origin. They are also capable of inducing nitrogen
retention, and have high affinity to certain cytoplasmic prostate cell
receptors. They are produced in women by the ovaries, adrenal glands,
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and by peripheral conversion in the skin, fat, and by the liver. The two
main circulating androgens are testosterone and androstenedione (Δ4-
A). However, in a decreasing order of production in adult women, the
major androgens are dehydroepiandrostenedione sulphate (DHEAS),
dehydroepiandrostenedione (DHEA), androstenedione, androstandiol
(Δ5A-diol), testosterone and dihydrotestosterone (DHT) (25). At skin
level, dihydrotestosterone is the main functional androgen molecule,
and is made by peripheral conversion from androstenedione (70%) and
testosterone (20%), as well as other precursors by the enzyme 5α-
reductase. Such conversion is not required at other tissues including the
brain or muscles, as testosterone is the main active molecule in these
sites. Only a small amount of dihydrotestosterone is actively produced
by the ovaries.
Normally, the ovaries and adrenals produce 20-25% of circulating

testosterone each, with the remaining 50% produced by peripheral
conversion of androstenedione. On the other hand 35% of circulating
androstenedione is produced by the ovaries and 25% by the adrenals,
with the rest through peripheral conversion. Almost 80% of circulating
testosterone is bound to SHBG, 19% to albumen and 1% is free as an
active fraction. The blood level of androgens depends on the production
rate, available SHBG receptor sites and the metabolic clearance rate by
the liver, skin, peripheral fat and other tissues.
Many routes are available for androgens metabolism. Peripheral fat and
muscles are two main tissues involved with aromatisation of androgens
to oestradiol and oestrone. Testosterone is also metabolised to
androsterone and aetiocholanolone in peripheral tissues, before being
conjugated in the liver to glucuronide and sulphate by-products. These
are water soluble and excreted in urine. Such conjugation occurs mainly
at C-17 and C-3 sites in the androgen molecules. In general hepatic
extraction of androgens is inversely related to their SHBG binding.
About 40-60 % of testosterone and 30-40% DHT are extracted by the
liver (26; 27).
Generally androgens have the following functions in the human

female:
• Classical teaching attributed the initiation of puberty and growth
in linear height to adrenal androgens. This concept has been
challenged recently, and both phenomena were related instead to
increased levels of oestrogen and growth hormone, as discussed
in Chapter 2.
98
• They are responsible for the growth of ambisexual axillary and

pubic hair, which needs only small amount of androgens.
• They act as substrate for oestrogens production.
• They are involved in maintaining female fertility, mainly through
regulation of the hypothalamo-pituitary axis in a dose dependant
manner (28);
• They play a role in regulating follicles development and ovulation
at the level of the ovaries. This is partly affected through down
regulation of FSH receptors in the small follicles to promote
monofollicular ovulation.
• They can help in increasing libido at the time of ovulation.
The biological activity of androgens is controlled mainly by their free
fraction in circulation which is controlled by their production rate,
metabolic clearance rate, and interaction with other hormones. In
normal circumstance, this is mainly affected by the level of SHBG
which is produced by the liver. SHBG production is increased by
oestrogens, thyroxine and reduced by obesity, hypothyroidism and
high androgens production. It protects androgens against rapid
degradation, and accordingly controls their metabolic clearance rate.
It also has a role in controlling interconversions between androgens,
and the peripheral conversion of testosterone to oestradiol. In this
respect, measurement of total testosterone does not reflect the
free and effective fraction during investigations of female
hyperandrogenicity. Accordingly, the testosterone / SHBG ratio,
usually known as the free androgen index, is a better measure of
clinically relevant androgenicity than the total testosterone level.
Certain androgens have higher affinity to SHBG sites than others, and
displace testosterone from its binding sites, leading to high levels of the
biologically active free testosterone. Norgestrel is one example with
higher tendency in smaller doses than northisterone. Small doses of
300 μg of northisterone may not affect SHBG level, but daily doses of 5
mg, which are usually used to control abnormal uterine bleeding, can
do so. On the other hand, cyproterone acetate does not affect SHBG.
Timing the blood test for androgens level assessment is important in

relation to the time of the day, and relative to the menstrual cycle.
Androgens are produced in circadian pattern, especially the adrenal
ones, and are higher in morning blood samples. Afternoon samples may
give erroneously low values. Furthermore, blood samples should be
timed to the early or mid follicular phase, as testosterone level can be
high in the middle of the cycle. An example of such a scenario is that
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ABDEL -GADIR
high LH and testosterone blood levels on days 5-7 of the cycle can
represent PCOS. In contrast, even higher LH and testosterone levels at
the middle of the cycle will be a normal physiological finding at the time
of the LH surge.
Excessive androgens may affect a female patient during the different

stages of her life differently, as follows:
• Excessive exposure of a female fetus to androgens during
intrauterine life can lead to ambiguous genitalia at birth. Similar
exposure of the fetal brain may adversely affect gender identity
during childhood and adulthood life. It can also impinge on the
heterosexuality of the adult woman.
• Excessive androgens exposure during childhood can lead to
precocious heterosexual puberty as discussed in Chapter 2. It
may also cause primary or secondary amenorrhea and skin
hyperandrogenic signs.
• During adult life excessive androgens exposure leads to general
hyperandrogenic symptoms and signs including weight gain, acne,
hirsutism, androgenic alopecia, and other masculinization signs.
Severe cases will show virilization signs including cliteromegaly,
frontal hair recession and coarse voice. Occasionally, excessive
sexual hair growth and acne may occur despite normal levels of
circulating androgens. In such cases increased production of DHT
can follow high tissues 5α-reductase activity. This is reflected by
increased production of 5α-androstandiol-3α, 17β-diol glucoronide
which is a byproduct of DHT (29).
• Excessive androgens can also affect the HPO axis and uterus, and
cause luteal phase defects, polymenorrhoea, menorrhagia,
dysfunctional uterine bleeding, oligomenorrhoea and amenorrhoea.
Detrimental direct effects at the level of the oocytes and
endometrium have also been confirmed. Androgens can reduce
oocytes maturation capacity, reduce granulosa cells mitotic activity,
and FSH induced aromatase activity.
Management of hyperandrogenaemic states
The most important steps in the management of hyperandrogenaemia

are:
• Stop any medication which can lead to hyperandrogenism.
• Exclude adrenal or ovarian tumours as a cause, especially in
women with adults’ onset conditions, rapid progressive signs, and
very high blood levels of androgens.
100
• Stop or reduce the production of the androgens, being ovarian or

adrenal in origin. Different drugs are available for this purpose.
Adrenal enzymatic deficiencies are treated with glucocorticoids and
ovarian sources are managed with oral contraceptive pills, or
gonadotrophin releasing hormone analogues
• Increase the level of blood SHBG which reduces the level of free
testosterone. This can be affected through the oestrogen fraction
of an oral contraceptive pill. It has been shown that 30 μg ethinyl
oestradiol did not increase SHBG level beyond levels seen in
normal ovulating women. The effect was more dramatic with 50
μg doses.
• Antiandrogens should be used to counteract the effects of the
androgens on peripheral tissues. The most widely used drugs are
spironolactone and cyproterone acetate. They compete with
androgens at their receptor sites.
• Patients with polycystic ovary syndrome may benefit from
metformin which can reduce ovarian production of excessive
androgens.
• Skin care and proper use of cosmetic aids are important parts of
the management plan, to support the antiandrogenic treatment.
• Assess the psychological impact of the problem and the basis for
presentation. Counselling may help as well.
Clinical use of androgens in female reproductive medicine is limited by
their side effects, which can be disfiguring and not acceptable. Danazol,
which is an isoxazole derivative of 17α-ethinyl testosterone, used to be
popular for the treatment of endometriosis. It has also been used for
the treatment of mastalgia in a daily dose of 50-100 mg during the
luteal phase. Testosterone implants were also used to supplement
oestrogen HRT in women with low libido, but are not popular now.
Recently, the transdermal route has been tested as well. Intrinsa
patches (Procter and Gamble) provide 300 μg of testosterone every
day, and each patch can be used for 3-4 days. They are licensed for
women with hypoactive sexual disorder on concomitant oestrogen
therapy, after bilateral oophorectomy. Beside acne, excessive hair
growth and weight gain, androgens can cause migraine, insomnia,
breast pain, and dyslipidaemia with low HDL cholesterol and high LDL
cholesterol.
Oestrogens
Oestrogens are biologically defined as chemicals which promote sexual

heat or oestrous in ovariectomised premature rats. They are also
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ABDEL -GADIR
defined as substances that promote vaginal cornification or uterotropic

effects in the oophorectomised rat or mouse. In a clinical context,
oestrogens are known as chemicals that stimulate and maintain growth
of female secondary sexual characteristics. As for progestogens, they
are also classified as naturally occurring, and synthetic. It has been
shown earlier in this chapter that oestradiol and oestrone are steroidal
compounds produced from androgens, both in the ovaries and adrenal
glands in non pregnant women. Peripheral conversion of androgens in
the skin and fat also contributes to the level of these two hormones. The
placenta is a major source of oestriol during pregnancy.
Structurally oestrone, oestradiol and oestriol have 18 carbon atoms

each, but differ in the number of the hydroxyl groups within the
molecule.
Figures 15 - 17 show oestrone, oestradiol and oestriol molecules showing one,

two and three hydroxyl groups respectively. Note the ketone group (=O)
attached to the D ring instead of a hydroxyl group in oestrone.
Oestrogen production and clearance are affected by the stage of the

menstrual cycle in premenopausal women. Furthermore, more than 95%
of the circulating oestradiol is produced by the ovary containing the
dominant follicle or corpus luteum (30). After the menopause, ovarian
oestrogen production and clearance decline substantially. Most of the
circulating oestradiol and oestrone production result from extra glandular
aromatisation of testosterone and androstenedione. Increased body fat
will increase such aromatisation, resulting in higher circulating levels of
oestradiol and oestrone (31).
Oestradiol is the main biologically active oestrogen in premenopausal

women. It circulates in the blood in 3 forms, bound to proteins,
conjugated in bile salts, and 2% as a free active fraction. About 60%
of oestradiol in circulation is bound to albumen, and 38% to SHBG. On
the other hand, oestrone is not strongly bound to plasma proteins,
with a higher metabolic clearance rate than oestradiol. At the same
time, oestrone forms the first step in the biological inactivation of
102
oestradiol. This is followed by its conversion to oestrone sulphate,

catechol oestrogens, as well as oestriol and epioestriol (32). Catechol
oestrogens are so named because of their structural similarity to
catecholamines of having two hydroxyl groups on the aromatic A ring
(33). The main compounds in this subgroup are 2-hydroxyoestrone
and its metabolite 2-methyloestrone. The oestrogenic effects of
catechol oestrogens are limited to the central nervous system, but
have antioestrogenic effect in other oestrogen sensitive organs. All
metabolites are biologically less active than oestradiol itself (34).
Oestrogens function through genomic or non-genomic effects. The

genomic effect is imposed through their nuclear receptors, leading to
specific changes in gene transcription. As for progestogens and
androgens, the effects of oestrogens will be studied under 3 headings:
1. Chemical and endocrine;
2. Morphological;
3. Metabolic.
Chemical and endocrine effects of oestrogens
Oestradiol is the main oestrogen in the non-pregnant young female. It is

mainly produced by the granulosa cells during the follicular phase and the
corpus luteum during the luteal phase. The rising levels of oestrogen
during the middle of the follicular phase reduce FSH production by the
pituitary gland through the negative feedback mechanism. This allows
mono-follicular growth, as the dominant follicle continues growing in
response to lower levels of FSH, unlike the smaller ones which stop
growing and become atretic. This is because the dominant follicle has
more FSH receptors, and higher aromatase enzyme activity which allow
easy conversion of androgens to oestradiol. It also has more LH receptors
and a rich micro vascular capillary network. Accumulation of androgens in
the smaller follicles is an important factor leading to their demise. The
ability of the dominant follicle to produce enough oestradiol to initiate the
negative feedback mechanism is important for mono-follicular ovulation.
This may not be the case in older women in their late 30s or early 40s, due
to the age related change in hypothalamic sensitivity. Accordingly, the
pituitary gland continues producing more FSH till 2 or 3 follicles are
capable of producing enough oestradiol to initiate the negative feedback
mechanism, and reduce FSH production. This is the scientific reason why
women in their late reproductive years are more likely to have
spontaneous multiple pregnancies.
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Metabolic effects
Oestradiol is responsible for inducing hepatic production of SHBG,

thyroxine binding globulin and transcortin which are carrier molecules for
androgens and oestrogen, thyroxine, and cortisol respectively.
Accordingly, it has an important role to play in regulating the free
fractions of these hormones, and their metabolic clearance rate. Other
non-genomic effects of oestrogens include protein anabolic activity,
though to a lesser extent than that of androgens. They also have anti
osteoporotic effect as they promote bone deposition and reduce its
resorption. Oestrogen receptors have been isolated in bone. Oestradiol is
also known to cause vasodilatation, due to its direct activation of the
potassium channels in the plasma membranes. This leads to potassium
exit and relaxation of the vascular smooth muscle fibres. High doses of
oestradiol can cause excessive sodium and water retention, and lead to
high blood pressure.
Morphological effects of oestrogens
The main effects of oestradiol in this respect are:

• Oestrogens in general have no direct or indirect role in the
development of female organs during intrauterine fetal life.
Nonetheless, maternal use of exogenous synthetic oestrogens
may lead to abnormality of the vagina and shape of the uterus, as
shown by the diethylstilbestrol effect. Offsprings of these mothers
developed vaginal polyposis, as well as T-shaped uterine
configuration;
• Initiation of breasts development and its growth to adult size with
the help of other hormones including progesterone and prolactin;
• Linear acceleration in height at puberty and final closure of the
epiphyseal plates;
• Cornification of the vaginal skin, and increase in total vaginal size;
• Increasing the size of the cervix, uterus and tubes in preparation
to reproductive function;
• Deposition of fat in certain areas of the body which is a female
physical characteristic;
• Oestradiol increases endometrial cells hyperplasia and proliferation
during the follicular phase. Together with progesterone they
sustain endometrial secretory changes and activity in preparation
for implantation during the luteal phase;
• Oestradiol induces midcycle changes in the quantity and quality of
the cervical mucus to facilitate sperm migration into the upper
104
uterine cavity. The cervix also acts as sperm reservoir to facilitate

continuous sperm availability for many hours after intercourse.
Natural non-human oestrogens
The most commonly used oestrogen in this group is premarin which is

a conjugated equine product. It is isolated from mares’ urine. The
composition of this product is made of:
• 48% oestrone sulphate;
• 26% equilin sulphate which is the major circulating oestrogen in
women using conjugated equine oestrogens. It is 4 times more
potent than the oestrone part, and is stored in the adipose
tissues;
• 15% 17α-dihydroequilin sulphate.
Premarin has been used extensively orally as hormone replacement
therapy mainly for vasomotor symptoms, and as vaginal cream for
postmenopausal vulvovaginal atrophic changes. Injectable forms are also
available, and the use of intravenous premarin in acute cases of severe
uterine bleeding has been mentioned before in this chapter.
Synthetic oestrogens
These chemicals are divided into steroidal and non-steroidal compounds,

and have different functional characteristics in comparison to natural
oestrogens. The most commonly used steroidal ones are ethinyl oestradiol
and mestranol which is 3-methyl ether of ethinyl oestradiol. Examples of
the non-steroidal group include diethylstilbestrol, chlorotrianisene,
clomiphene citrate and tamoxifen. Few of these synthetic oestrogens have
very long nuclear retention. They act accordingly as oestrogens in a single
dose, but as oestrogen receptor modulators in repeated doses. This is
secondary to downregulation of the cytosol receptors, and inhibition of
messenger RNA transcription, due to prolonged nuclear occupation.
This effect can also be tissue specific, as these drugs act as anti
oestrogens in one tissue, and as oestrogens in others. A good example
is tamoxifen which has a very potent antioestrogenic effect on the
breast tissues, through its metabolite hydroxyl tamoxifen. A similar
antioestrogenic effect at the level of the hypothalamus is utilised for
induction of ovulation, by stimulating gonadotrophins secretion.
Conversely, it has an oestrogenic effect on the myometrium and
the endometrium, through different metabolites. This explains the
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endometrial hyperplasia, polyps and carcinoma risks reported with

prolonged use of tamoxifen by patients who had breast cancer.
Many drugs inhibit oestrogens synthesis directly by interfering with the

aromatase enzyme activity, without any direct effect on the cytoplasmic
receptors. The most commonly known ones in this group are letrozole
and anastrozole which are non-steroidal drugs. They can be used as
anti oestrogens for different purposes including induction of ovulation,
and for the treatment of endometriosis.
Oestrogens potency
Oestrogens potency depends on the time the oestrogen-receptor

complex occupies the nucleus of the target organ, after a single dose.
Oestrone and oestriol occupy the same receptors as oestradiol, but
have shorter nucleus retention time. Accordingly, they have weaker
biological effects than oestradiol, but repeated doses of either
hormone may have equivalent effects as a single oestradiol dose (35).
The nuclear retention time of oestradiol was found to be 1-4 hours.
Diethylstilbestrol had a longer time of 6-24 hours, and tamoxifen
retention time was 24-48 hours. Oestrogens potency has been tested
against the following parameters in postmenopausal women:
• The ability to build up a proliferative endometrium;
• The ability to induce cornification of the vagina;
• The ability to reduce FSH and LH levels.
For these tests to be of any value in comparing different oestrogens,
many factors should be taken into consideration:
• The type and dose of the oestrogen used;
• The route of administration is very important. Conversion of
oestradiol to oestrone takes place after oral administration by
the enzyme 17-keto reductase, which is available in the
gastrointestinal tract, but not in the vagina. Accordingly, vaginal
administration is more likely to increase oestradiol rather than
oestrone blood level. Similarly transdermal administration has
a similar effect, as oestradiol escapes the first pass through
the gastrointestinal tract and the liver, and its conversion to
oestrone;
• The absorption rate and whether it is affected by other factors;
• The metabolic clearance rate which depends on the blood level of
the carrier molecules, and hence the free fraction of the hormone;
• The particular system under evaluation.
106
Use and side effects of oestrogen therapy
The most common uses for oestrogens in female patients in

chronological age order are:
• To initiate pubertal development in cases of delayed puberty;
• In different contraceptives in combination with progestogens;
• For the treatment of dysfunctional uterine bleeding;
• In preparation of the endometrium during ovum donation cycles;
• Hormone replacement therapy in cases of surgical or natural
menopause, and in cases of gonadal dysgenesis.
Side effects of synthetic oestrogens cover a wide range of organs and
effects. The most publicised risks following unopposed oestrogen use
are endometrial hyperplasia and carcinoma of the endometrium.
Accordingly, a progestogen should be used for a minimum duration of
12- 13 days with oestrogen HRT. This is not necessary in patients who
already had a hysterectomy. Further discussions about the relationship
between HRT and breast cancer, or cardiovascular disease will be found
in Chapter 9. Other side effects of synthetic oestrogens include:
1. Hypertension is a risk in susceptible patients, due to increased
plasma renin activity and renin substrate. There is also increased
aldosterone production and sodium retention.
2. There is a two-fold increased thromboembolic tendency, caused by
increased production of factors II, VII, X and fibrinogen. This is
coupled with decreased antithrombin III activity. The final outcome
is a hypercoagulable state. This risk is especially high in heavy
smokers, diabetics, and with previous history of thrombosis.
Certain conditions may also increase this risk including
immobilisation, trauma or surgical procedures, sepsis and obesity.
The route of administration also has an important effect. There is
more thrombosis risk with the oral route than the transdermal or
vaginal routes, because of the first hepatic pass of oestrogens, and
increased production of coagulation factors with the oral route.
3. Ischaemic heart disease risk is also increased because of the
increase in triglycerides level, despite the favourable effects of
oestrogens on HDL cholesterol and LDL cholesterol.
4. Cholelithiasis is also a side effect of synthetic oestrogens. The
relative risk in postmenopausal women is 2.5, compared to those
who are not using HRT. This effect may follow:
a. Alteration in lipid balance;
b. Alteration in bile salts content;
c. Alteration in HDL cholesterol.
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Contraindication to oestrogen use
Taking into account all the metabolic, endocrine and anatomical points
mentioned before, oestrogens should not be used in the following
conditions:
• During pregnancy;
• With undiagnosed genital bleeding;
• In case of acute liver disease;
• Present or past history of oestrogen dependent cancer;
• History of thromboembolism.
Few conditions should be taken into consideration in a risk / benefit
assessment, before prescribing oestrogens. These conditions include:
• History of liver disease;
• Diabetes mellitus;
• Hypertension;
• Uterine fibroids;
• Familial porphyria cutanea tarda.
Antioestrogens
Antioestrogens are substances that compete with oestrogens at their

binding receptor sites. This effect can be universal, or specific to few but
not all tissues. Clomiphene citrate and tamoxifen are the classical
examples in this group. Tamoxifen acts as an antioestrogen at the
breasts, but stimulates oestrogen receptors in the uterus, which may
result in hyperplasia and polyps, or even endometrial carcinoma. The
role of catechol oestrogens as antioestrogens outside the central
nervous system (CNS) has been mentioned before. Within the CNS,
they compete with catecholamines for the enzyme catechol-
methyltransferase, which results in reduced degradation of CNS
catecholamines. This will prolong the effects of catecholamines
within the brain, with consequent modulation of catecholamines
sensitive hypothalamic releasing and inhibiting factors (32). Though
progestogens are usually considered to have an antioestrogenic effect,
they tend to exhaust rather than occupy oestrogen receptors. So
strictly speaking progestogens modify oestrogen effects, but do not
compete with them for their receptor sites.
Summary
It is evident that progestogens, androgens, and oestrogens have similar

basic steroidal rings, yet subtle changes in those molecules gave them
108
different endocrine, morphological and metabolic characteristics. Such

features may even be different within the different subgroups of each
hormone. This depends on the chemical structure, half-life and
bioavailability, affinity to receptors, potency and metabolic clearance
rate. More clinical information will be provided in Chapters, 9, 10, 12 and
13. It is also important to take the information provided in this chapter
into consideration, when reading the chapters dealing with hormone
replacement therapy and contraception.
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neuroendocrine control. In: Knobil E, Neill J. Eds. The Physiology
of Reproduction. New York: Raven Press, 1994; 711 - 749.
2. Blank SK, McCartney CR and Marshall JC. The origins and
sequelae of abnormal neuroendocrine function in polycystic ovary
syndrome. Hum Reprod 2006; 12(4): 351 – 361.
3. Zarutskiea PW and Phillips JA. Reanalysis of vaginal progesterone
as luteal phase support (LPS) in assisted reproduction (ART)
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4. Schust DJ, Anderson DJ, and Hill JA. Progesterone induced
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5. Landau RL and Lugibihl K. The effect of progesterone on the
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16(12): 1114 – 1122.
6. Kalkhoff RK. Metabolic effects of progesterone. Am J Obstet Gynecol
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7. Sitruk-Ware R. Pharmacological profile of progestogens. Maturitas
2009; 47(4): 277 - 283.
8. Städtler F, Langner V. The effect of cyproterone and gonadotrophins
on the adrenal gland of juvenile and adult rats. A morphological and
morphometrical study. Pathol Res Pract 1985; 179 (4-5): 493 – 498.
9. Honer C, Nam K, Fink C, Marshall P, Ksander G, Chatelain R,
Cornell W, Steele R, Schweitzer R, Schumacher C. Glucocorticoid
receptor antagonism by cyproterone acetate and RU486′′. Mol
Pharmacol 2003; 63 (5): 1012 – 1020
10. Pham-Huu-Trung M, de Smitter N, Bogyo A, Girard F. Effects of
cyproterone acetate on adrenal steroidogenesis in vitro. Horm Res
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11. Johansson EDB. Depression of the progesterone levels in women

treated with synthetic gestagens after ovulation. Acta Endocrinol
1971; 68(4): 779 – 792.
12. Stevenson JC. Hormone replacement therapy and lipids.
Menopause Review 1997; 2: 15–20.
13. Crook D, Cust MP, Gangar KF, Worthington M, Hillard TC,
Stevenson JC, Whitehead MI, Wynn V. Comparison of transdermal
and oral oestrogen-progestin replacement therapy: effects on
serum lipids and lipoproteins. Am J Obstet Gynecol. 1992;
166(3): 950 - 905.
14. Crook D, Godsland IF, Hull J, Stevenson JC. Hormone replacement
therapy with dydrogesterone and 17 beta-oestradiol: effects on
serum lipoproteins and glucose tolerance during 24 month follow
up. Br J Obstet Gynaecol. 1997; 104(3): 298 - 304.
15. Depoprovera Product Monograph. Depoprovera. Pfizer, Canada
Inc, 2006.
16. Preston JT, Cameron IT, Adams EJ and Smith SK. Comparative study
of tranexamic acid and northisterone in the treatment of ovulatory
menorrhagia. Br J Obstet Gynaecol 1995; 102: 401 - 406.
17. Irvine GA, Campbell-Brown MB, Lumsden MA, Heikkilä A, Walker
JJ, Cameron IT Randomised comparative trial of the
levonorgestrel intrauterine system and northisterone for
treatment of idiopathic menorrhagia. Br J Obstet Gynaecol 1998;
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18. Andersson JK, Rybo G. Levonorgestrel-releasing intrauterine
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19. Vercellini P, Viganò P, Somigliana E The role of the levonorgestrel-
releasing intrauterine device in the management of symptomatic
endometriosis. Curr Opin Obstet Gynecol. 2005; 17(4): 359 - 365.
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progesterone in the endometrium during the luteal phase in
preparation for nidation. Hum Reprod 2000; 15 (Suppl 1): 119 - 128.
21. Vereide AAB, Kaino T, Sager G, Orbo A. Scottish Gynaecological
Clinical Trial Group, Bcl-2, BAX, and apoptosis in endometrial
hyperplasia after high dose gestagen therapy: a comparison of
response in patients treated with intrauterine levonorgestrel and
systemic medroxyprogesterone. Gynecol Oncol 2005; 97: 740 - 750.
22. Hedderson MM, Ferrara A, Williams MA, Holt VL and Weiss NS.
Androgenicity of progestins in hormonal contraceptives and the
risk of gestational diabetes mellitus. Diabetes Care 2007; 30(5):
1062 – 1068.
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23. Swyer GIM. Determination of progestational potency: a review.

J Roy Soc Med 1984; 77: 406 – 409.
24. Greenblatt RB, Jungck EC and Barfield WE. Anew test for
efficiency of progestational compounds. Ann N Y Acad Sci 1958;
71(5): 717 - 721.
25. Longcope C. Adrenal and gonadal androgen secretion in normal
females. Clin Endocrinol Metab1986; 15: 213 – 228.
26. Longcope C, Sato k, McKay C and Horton R. Aromatization by
splanchnic tissue in men. J. Clin Endocrinol Metab 1984; 58: 1089
– 1093.
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extraction and conversion of testosterone and dihydrotestosterone
in man. J Clin Endocrinol Metab 1978; 46: 528 – 533.
28. Walters KA, Allan, and Handelsman DJ. Androgen actions and the
ovary. Biol Reprod 2008; 78: 380 - 389.
29. Aziz R, Carmina E and Sawaya ME. Idiopathic hirsutism. Endocr
Rev 2000; 21: 347 – 362.
30. Baird DT and Frase IS. Blood production and ovarian secretion
rates of oestradiol-17/3 and oestrone in women throughout the
menstrual cycle. J Clin Endocrinol Metab 1974; 38: 1009 – 1017.
31. Jud HL. Hormonal dynamics associated with the menopause; Clin
Obstet Gynecol 1976; 19(4): 775 – 788.
32. Ruder HJ, Loriaux L and Lipsett MB. Oestrone sulphate:
Production rate and metabolism in man. J Clin Invest 1972; 52:
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33. Fishman J. The catechol oestrogens. Neuroendocrinology 1976;
22(4): 363 – 374.
34. Buster J. Oestrogen kinetics for clinicians. Glob libr women’s med.
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the oestrogen receptor. J Biol Chem 1983; 258(13): 8113 - 8117
111
Chapter 6
Polycystic Ovary Syndrome
Polycystic ovary syndrome (PCOS) is the most common female

endocrinopathy, with reported prevalence of 3.5-17.8% in all women
within their reproductive years (1, 2). This variation may reflect actual
differences in the different populations studied, but also reflects the
different diagnostic criteria used. This is demonstrated by the different
rates reported after using the National Institute of Health (8.7%), the
Andrology Excess Society (12%), and Rotterdam (17.8%) diagnostic
criteria in the same group of women (2). Furthermore, PCOS was
diagnosed in 28% and 5% of unselected obese and lean women
respectively (3). Accordingly, any reported community incidence will
be affected by the prevalence of obesity as one factor. Ethnicity has
also been shown as an important variable, with Greeks and Native
Americans having higher prevalence than Caucasians and African
Americans. On the other hand, ultrasonically diagnosed polycystic
ovaries have been documented in 16-25% of women with regular
menstruation (4-6). More women will be expected to show polycystic
ovaries with the newly adopted less stringent Rotterdam criteria (7),
as will be discussed later. Variable familial expressions have been
reported, and both autosomal dominant and sex linked transmission
modes have been described. Most women with PCOS showed normal
46XX chromosomes, but many also showed dermatoglyphic male
pattern. Unusual dermatoglyphic patterns usually relate to genetic
disorders (8, 9), but excessive intrauterine exposure to androgens was
thought to be the cause in patients with PCOS. Genetic studies have
shown increased expression of type 6 17 β-hydroxysteroid
dehydrogenase (HSD17B6) gene in PCOS ovarian theca cells (10). At
the same time, allele distribution for the single nucleotide
polymorphism rs898611 in HSD17B6 was significantly different
between PCOS and control subjects (11). Such polymorphism was
associated with higher body mass index and insulin resistance. Other
alleles (rs10459247 and rs10876920) have been similarly implicated
(10). A distinction between PCOS and the mere ultrasound diagnosis
of PCO is clinically necessary, but some significant evidence showed
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ABDEL -GADIR
that such distinction in many cases may not be as strict as previously

suggested (5, 12, 13).
Historic considerations
Certain milestones exist in our current understanding of PCOS. The first

known description of polycystic ovaries was recorded by Antonio
Vallisneri in 1721. The English translation of the Italian text was
reported as follows: ‘Young married peasant women, moderately obese
and infertile, with two larger than normal ovaries, bumpy, shiny and
whitish, just like pigeon eggs’ (14). This was followed by a description
of sclerocystic ovarian changes by Lisfranc in 1830. A similar pattern
was then described respectively by Chereau in 1844, Tilt in 1850 and
Gallard in 1873, as reported by O’Dowd et al in 2000 (15). In 1935, the
syndrome had its name and fame in modern medicine when Stein and
Leventhal (16) described a combination of amenorrhoea, obesity and
hirsutism in women with enlarged ovaries. Adhering to this combination
of symptoms and signs before making a diagnosis will exclude many of
the patients with the syndrome as we know it now.
The endocrine changes in patients with PCOS were first explored by

McArthur et al in 1958 (17). They described high LH levels in the urine
of patients with polycystic ovaries. High androgen levels were first
documented by De Vane et al in 1975 (18). This was followed by the
documentation of normal luteinising hormone blood levels in women
with PCOS by Rebar in 1976 (19). Ultrasound reporting of the ovarian
polycystic pattern was first described by Swanson et al in 1981 (20),
followed by Hann et al in 1984 (21), before been objectively quantified
by Adams et al in 1985 (22). Finally the association of PCOS with insulin
resistance was described by Kahn et al (23), and became a major issue
in the aetiology and morbidity of PCOS. Further discussions of all these
parameters will be found in the corresponding parts of this chapter.
Traditionally, an ovary was described as polycystic when it showed 10

or more small cystic areas less than 10 mm in diameter in one
ultrasound plane (22). Most of the clinical, endocrine, biochemical and
Doppler ultrasound research was conducted in patients diagnosed on
the basis of this criterion, plus the other clinical and biochemical
parameters of anovulation and hyperandrogenism. A new consensus
has been agreed by the Rotterdam Study Group in 2003 (7), that 12 or
more cysts in the whole ovary should be used as a new parameter for
the ultrasonic diagnosis of PCO. This new ultrasound criterion is less
stringent than the previous one, and many normal patients will be
114
included in such a diagnosis. A recent study by Duijkers and Klipping

published in 2010 (24) showed that 83-84% of normal women between
the ages of 18-22 years showed PCO when these new ultrasound
characteristics were applied. The prevalence decreased with age, and
reached 0-33% in women 38-40 years old. They suggested that these
new diagnostic criteria should be reconsidered and adapted to the
woman’s age.
Development of polycystic ovaries
Normally, as many as 10-20 follicles are recruited each cycle, but most
of them arrest before reaching full maturation. This is because of
reduced FSH production by the pituitary gland, secondary to the
negative feedback effect of oestradiol and inhibin B produced by the
leading follicle, by the mid-follicular phase. The dominant follicle
continues to grow because it had already developed a good
microvascular blood flow, and enough FSH receptors, with adequate
aromatase enzyme activity to maintain an oestrogenic intrafollicular
environment. Smaller follicles stop growing because of their dominant
androgenic hormonal milieu. Many researchers have documented 2-3
fold increased development of pre-antral and antral follicles in
polycystic compared to normal ovaries (25-27). Most of these follicles
stop growing because of the abnormal hormonal signalling, and the
high androgenic environment within the ovaries (28). Accumulation of
such small cysts (underdeveloped follicles) leads to the characteristic
polycystic appearance which was more common under the age of 35
years than in older women as reported by Abdel-Gadir et al in 2009
(29). These cystic areas form a wide spectrum of growing follicles and
atretic cysts, which may explain the different clinical response of
patients with PCOS to induction of ovulation. Women with more follicles
are expected to respond more quickly than those with atretic cysts. The
final destiny of the atretic cysts theca cells will be an addition to form
extra secondary ovarian stoma. It is not possible to differentiate
between small follicles and atretic cysts using ultrasound scanning.
Better pictures became available with the advent of transvaginal

ultrasound scan technique, showing different patterns of cysts
distribution within the ovaries:
• Cysts may be arranged under the capsule giving the classical
subcapsular pattern which is featured in almost all articles and
books;
• Cysts may be universally dispersed all over the ovarian stroma;
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ABDEL -GADIR
• One ovary may have a universal and the other subcapsular

pattern of cysts distribution;
• Few patients may have only one polycystic ovary;
• Cysts may be localised to only one part of an ovary.
A view was held previously that cysts distribution within the polycystic
ovaries could be a reflection of different endocrine patterns (30). This
was not the case as Abdel-Gadir et al in 1991 (31) showed that basic
and pulsatile patterns of FSH, LH and testosterone were not related to
the pattern of cysts distribution. This later view was upheld by the
recent consensus meeting on PCOS held in Rotterdam in 2003 (23),
which also recommended that increased stromal echogenicity should be
excluded from the diagnostic criteria. A volume ≥10 ml has been
reaffirmed as a diagnostic criterion. Furthermore, the expert panel
suggested that one ovary showing a polycystic pattern is enough to
make the diagnosis in the presence of other diagnostic criteria. The
significance of volume has been shown in a previous study by Abdel-
Gadir et al 1990, (32) which documented better and quicker response
of patients with PCOS and larger ovaries to induction of ovulation with
gonadotrophins than others with smaller yet polycystic ovaries. No
differences could be detected in the duration of symptoms, basal LH or
testosterone blood levels or the pulse pattern in relation to ovarian
volume, as documented by the same last group (31). This observation
was in agreement with a previous statement made by Givens et al in
1976 (33) that normal size polycystic ovaries had similar histological
and biochemical abnormalities as enlarged ones. In this context,
volume can be more useful as a prognostic parameter for better
response to induction of ovulation with gonadotrophins, rather than a
reflection of the extent of derangement of the hormonal milieu, or
severity of the PCOS condition.
Figures 18 and 19 demonstrate two ovaries with classical subcapsular and

universal cysts distribution respectively. On the other hand, Figure 20 shows one
polycystic and one normal ovary. Note the difference in size between the two
ovaries (11.0 vs. 2.7 cc respectively). All three patients were hyperandrogenic
and had irregular periods.
116
Prolonged use of a combined oral contraceptive pill may affect

ovarian morphology and volume, which may mask the polycystic
pattern. A dominant follicle or corpus luteum can have a similar effect
on the corresponding ovary. Accordingly, patients with reasonably
regular menstrual cycles should be scanned during the early follicular
phase to guard against this artefact. Patients with oligomenorrhoea
may need to be rescanned if their initial examination showed a
dominant follicle or corpus luteum. Nonetheless, the presence of
polycystic changes in the non-active ovary will be adequate to make
the diagnosis.
Figures 21 and 22 show the same ovaries before and 8 months after using a
combined oral contraceptive pill respectively. Note the loss of PCO pattern in
figure 18. Figure 23 shows two polycystic ovaries. The mature follicle in the right
ovary did not conceal the PCO pattern on that side in this case.
The syndrome
Diagnosis of PCOS has also gone through different stages with different
criteria being proposed by consensus rather than universal agreement:
1. In 1990 the National institute of Health (NIH) included oligo-
ovulation and clinical or biochemical signs of hyperandrogenisation
as obligatory criteria for the diagnosis of PCOS, after exclusion of
other related causes. Ultrasound polycystic pattern of the ovaries
was not included as a diagnostic parameter (34).
2. In 2003 the Rotterdam Consensus criteria (7) recommended at
least two of the following three criteria to be used for the diagnosis
of PCOS, after exclusion of other related causes: a) oligo-
ovulation and /or anovulation b) signs of hyperandrogenisation c)
polycystic ovaries on pelvic ultrasound examination.
3. In 2006 the Androgen Excess Society position statement stated that
PCOS should be considered first as a disorder of androgen excess or
hyperandrogenism after exclusion of other related causes (35). The
group also stated explicitly that women with oligomenorrhoea and
polycystic appearing ovaries on ultrasonography but no evidence of
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ABDEL -GADIR
hyperandrogenism do not have PCOS, and should be considered of

having a different disorder.
It is clear that the only common ground between the 3 consensus
statements is the presence of hyperandrogenisation, though it is not a
necessity for diagnosing PCOS in the Rotterdam criteria if the other two
parameters are fulfilled. These differences may have important clinical
consequences, and major impact on comparing research findings.
Patients with PCOS diagnosed by the NIH criteria have more adverse
metabolic profile including greater total and abdominal obesity, higher
incidence of insulin resistance and risk factors for type II diabetes
mellitus and cardiovascular disease than hyperandrogenic ovulatory
and nonhyperandrogenic anovulatory PCOS patients (36). The last two
groups can fit into the Rotterdam criteria for diagnosing PCOS. These
differences, among others, fuelled the controversy regarding the
diagnosis of PCOS in the following situations:
• Hyperandrogenic women with polycystic ovaries and regular
cycles;
• Anovulatory women with polycystic ovaries, but no evidence of
excessive androgens production;
• Using the new ultrasound criteria suggested by the Rotterdam
group for diagnosing polycystic ovaries (12 cystic areas in the
whole ovary rather 10 in one ultrasound ovarian plane).
PCOS has a familial tendency as 40 % of sisters and 35% of mothers of
affected women also have the syndrome (37). It should be seen as a life
long general medical condition, rather than just a fertility issue. A fetal
origin has been proposed for PCOS, as animal studies showed that
intrauterine exposure to high doses of androgens led to the development
of many of the PCOS characteristic features (38). It usually has
prepubertal onset, especially in girls with premature pubarche before
the age of 8 years. Normally, there is a bell-shaped endocrine and
morphological phenomenon during the different stages of puberty, with
some endocrine hyperfunction to allow normal growth and development.
This includes growth hormone, insulin, insulin growth factor-1 and LH
which increase during puberty and settle to normal adult levels
thereafter. One theory postulates that PCOS may represent amplification
of these maturation changes, which do not end by the end of puberty.
This may be related to obesity, insulin resistance, stress, and
dopaminergic dysregulation. A hypothalamic dysfunction has also been
suspected, as pubertal girls with PCOS have their LH surge at midday,
rather than at midnight. Furthermore, impaired hypothalamic sensitivity
to progesterone has been suggested as a cause for the rapid GnRH and
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LH pulse pattern in patients with PCOS. This was thought to be

secondary to increased levels of androgens, as normal sensitivity was
restored by the androgen receptor antagonist, flutamide (39). On the
other hand, a dysfunctional pituitary gland has also been implicated as
a cause of the syndrome, because of the increased LH response to GnRH
stimulation (40). Furthermore, an ovarian role has been suggested
related to abnormal 17α-hydroxylase and 17/20 lyase enzymatic activity
(41). Over the years the emphasis on the study of polycystic ovaries
changed from a histological, to a pure hormonal, then genetic and
ultrasound oriented, and lately metabolic causation. This is a good
indication that the exact cause or causes behind the development of
PCOS are not yet established. It also proves that the condition is a
heterogeneous one, with possibly different causes in different patients.
Nevertheless, once PCOS develops, the ovaries assume a prime role in
producing androgens (42, 43). Logically one can think of polycystic
ovaries in 2 different ways; as normal ovaries with abnormal
gonadotrophins drive, or as abnormal ovaries showing abnormal
morphology and response, irrespective of the gonadotrophins drive.
The essential histological features described for PCO were reported as:
• Arrest of follicular growth;
• More atretic cysts;
• Relative deficiency of healthy granulosa cells;
• Predominance of theca cells;
• Increased fibroblasts deposition in the follicles basal lamina, due
to increased intraovarian androgens levels, was thought to reduce
the passage of FSH into the follicles and reduce aromatase
activation.
The biochemical changes related to PCOS were reported as:
• Theca cells are hypersensitive to LH stimulation, with 20 times
more production of androstenedione, compared to normal
ovaries (44). Increased ovarian cytochrome P450c 17α activity
is a characteristic of polycystic ovaries, with enhanced 17α
hydroxylase and 17, 20 lyase activities. This promotes more
conversion of progesterone to 17α-hydroxyprogesterone, which is
a substrate for androgens. Such increased activity was shown
after GnRH stimulation by Barnes et al in 1989 (40).
• There is increased inhibin B production by the granulosa cells in
response to androgens, with the highest response following
dihydrotestosterone exposure. This selectively affects FSH
production.
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ABDEL -GADIR
• At the endometrial level, patients with PCOS were shown to have

lower expression of G protein-coupled oestrogen receptors
(GPR30), and low α and β oestrogen receptors (ERα and ERβ
respectively) during the implantation window of the cycle. This
may lead to lower endometrial receptivity, low pregnancy rate,
and higher spontaneous miscarriages rate (45).
• Exaggerated production of LH by the pituitary gland was related
to low hypothalamic dopamine activity (46). Dopamine infusion in
such patients reduced LH levels significantly more than in normal
women.
• There is also dissociation of central opioids neurological activity in
patients with PCOS as shown by the lack of any effect of β-
endorphins, which normally inhibit LH release in normal women.
• Hyperinsulinaemia due to abnormal peripheral resistance has also
been described. Insulin resistance has been defined as abnormal
target tissues response to a given amount of insulin (47). This is
especially important for such tissues as muscles and fat which
require insulin to absorb and metabolise glucose, and for hepatic
glycogen synthesis and storage. The effect of insulin resistance on
fat metabolism results in reduced uptake of circulating fat,
increased hydrolysis of stored lipids, and increased blood levels of
plasma fatty acids and triglycerides. The hepatic effect results in
increased production of glucose by the liver, which contributes to
the metabolic syndrome of dyslipidaemia, and high insulin and
glucose blood levels. Other risk factors of insulin resistance which
are beyond the remit of this manuscript include several disorders
of coagulation and low fibrinolytic activity (48). Tissue
plasminogen activator (tPA) activity was found to be inversely
correlated to insulin resistance and serum triglycerides (49).
Insulin has an essential role in ovarian function. It is necessary for
normal follicular growth and maturation, as well as oestradiol
production by the granulosa cells. These phenomena may be defective
in patients with insulin deficiency. In contrast, excessive ovarian insulin
exposure can enhance theca cells androgenic activity to produce more
androstenedione, creating a hyperandrogenic intraovarian environment
which can lead to anovulation and PCO formation. Insulin resistance is
caused by excessive serine phosphorylation in the insulin receptor, in at
least 50% of patients with PCOS (50). Another explanation involved
decreased action of chiro-inositol which is an important secondary
messenger for transduction of insulin signalling (51). No insulin
receptors mutations have been described in patients with PCOS (52).
High fasting insulin levels can be detected during the early phases of
120
insulin resistance. Failure of this compensatory mechanism due to

exhaustion of the pancreatic β cells over time may lead to low insulin
production, and increase in blood glucose levels. Accordingly, normal
fasting insulin blood levels may not exclude this metabolic problem. The
homeostasis model assessment (HOMA) was originally introduced by
Matthews in 1984 and was modified since (53, 54). Currently two
mathematical equations are used to test for insulin resistance (HOMA-
IR) and pancreatic B cell reserve (HOMA-B). Increased HOMA-IR
indicates insulin resistance and reduced HOMA-B indicates reduced
pancreatic B cells reserve. HOMA-IR is calculated using the equation
‘insulin level x glucose level / 22.5’. HOMA-B is calculated by the
equation ‘20 x insulin level / glucose level – 3.5’.
Different reports described increased and normal blood levels of leptin

in patients with PCOS. Nonetheless, no difference could be found
between patients with PCOS and normal controls of similar BMI (55).
Furthermore, Leptin blood levels were found to be directly correlated to
those of insulin, and high leptin has been suggested to contribute to
insulin resistance (56). This was thought to be affected through
attenuation of hepatic tyrosine phosphorylation of the insulin receptor
substrate-1 (IRS-1), which is a docking protein for several tyrosine
kinase receptors. It also down-regulates gluconeogenesis. In contrast,
leptin increased the activity of IRS-1-associated phosphatidylinositol 3-
kinase (57). Persistent activation of this enzyme caused insulin
resistance due to accelerated insulin receptor substrate-1 degradation in
adipocytes (58). Furthermore subcutaneous fat has been shown to be
more effective than intra-abdominal fat in causing high leptin levels
(59). Another adipocytokine produced solely by adipose cells is
adiponectin which is a 244 amino acid protein. It is thought to have a
protective role against insulin resistance (60). Its level has been
reported to be low in women with PCOS, irrespective of BMI or insulin
level (61).
Clinical presentation of women with PCOS
Women with PCOS may present with different problems at different age
groups, and treatment is usually tailored differently to suit their
different needs. This reflects the changes in the range and severity of
symptoms over the years, and the emphasis on fertility demands by
older women with irregular ovulation. Depending on the diagnostic
criteria used, PCOS may be associated with hyperandrogenic symptoms
and signs, obesity, irregular periods and infertility. Some patients may
have all the listed problems, but show concern to one or two of them
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ABDEL -GADIR
without any concern about the other signs. This is especially so in

teenage girls who are more concerned about their weight and skin
problems than irregular periods. Infertile older women are more
concerned about fertility issues, with minor if any concerns about
excessive hair growth or acne. They often choose to have induction of
ovulation to help them getting pregnant rather than antiandrogens to
help with their skin problems. Despite of the immense psychological
impact caused by obesity, women in the older age group may try to
neglect its implications, and seek advice to conceive nevertheless. This
pattern of presentation is not rigid, and patients in different age groups
may present with the same concerns. Clinically, patients with insulin
resistance may present with general fatigue, sleepiness and difficulty to
concentrate especially a couple of hours after meals. They may also
complain of bloating sensation, carbohydrates cravings and difficulty to
lose weight.
Androgenic skin problems
Young women may present with acne, excessive weight gain and
irregular periods, but the first two problems usually rank higher in their
own minds. The disfiguring facial spots can affect their lives, as well as
their relationship with parents and peers, and may lead to some
psychological problems. Hirsutism is also frequently seen in both young
and older women. It entails growth of dark terminal hair in a male
distribution pattern, which is not socially acceptable. Different ethnic
groups have different numbers of hair follicles per unit area of skin.
Oriental women tend to have the least number, compared to other
races. Furthermore, the perception of how much hair is unacceptable is
different among different ethnic groups and families. Accordingly, any
scoring system should take these points into consideration when
making a diagnosis of excessive hair growth. Nonetheless, a score of
more than 8 in the Ferriman-Gallwey scoring system (60) is usually
considered abnormal. Terminal hair growth on the upper lip, chin,
chest, upper back, lower back, upper abdomen, lower abdomen, upper
arms, forearms, thighs and lower legs should be graded on a severity
score from 0 – 4, with 0 indicating no hair growth and 4 being the
worst. However, one study showed more terminal hair growth on the
buttocks / perineum, sideburn and neck areas, rather than on the
upper back, upper abdomen and upper arms (62). Nevertheless, the
buttocks/perineum, neck and sideburns are not part of the Ferriman-
Gallwey scoring system, and hence may not be examined. Irrespective
of the number of areas examined the system remains subjective with
122
poor interobserver agreement (63). Nevertheless, it is good enough for

follow up of individual patients within a clinical setup by the same
observer.
Hirsutism is generally related to exposure of the hair follicles to

excessive androgens, resulting in prolongation of the growth phase
(anagen) of the facial and body hair cycle. An opposite effect may be
seen on scalp hair follicles. Hair loss resulting in androgenic alopecia is
more common than the more severe frontal hair recession, which is one
of the signs of virilization. With androgenic alopecia, there is gradual
transition from the normal thick, pigmented terminal hair to thinner,
shorter, indeterminate hair and finally to short, soft, nonpigmented
vellus hair in the crown area. This is due to shortening of the anagen
phase, which is coupled with a normal telogen (resting) phase. This
results in increased hair shedding and thinning of the hair in the
involved area, rather that total baldness. Furthermore, the frontal hair
line is usually preserved, unlike the more severe hair recession.
Hirsutism must be differentiated from hypertrichosis which indicates
excessive growth of ambisexual hair, mainly in the arms and legs of
both women and men. It is common as a familiar or genetic trait seen
in different racial groups, but can also follow glucocorticoid therapy.
Other androgenic skin problems including greasy skin and dandruff may
also be seen. Skin pigmentation known as acanthosis nigricans is more
common in insulin resistant women. It is made of velvety dark patches
behind the neck, in the axillae and under the breasts. Skin tags or flaps
which are known medically as acrochordons or cutaneous papillomas
may also be present. Other less commonly used names include
cutaneous tags and fibroma molluscum.
Obesity
Recording the body mass index (BMI) is important in all patients

presenting with anovulation or hyperandrogenic signs. It is a good
reflector of the amount of body fat, but is not a perfect one.
Nevertheless, it is a good parameter to use in a clinical setup. Its
significance should be related to the fat distribution areas, and the
presence of other risk factors for cardiovascular diseases. The normal
range is between 18.5 – 24.9 kg/m2, overweight range is 25-29.9
kg/m2, obesity 30-34.9 kg/m2, and severe obesity >35.0 kg/m2.
Patients with PCOS are at risk of developing obesity, and figures
between 40-50% have been quoted (64, 65). It may even be a
triggering factor during early puberty for the development of the
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syndrome itself. It is usually of the android type, which is a male

characteristic, with increased abdominal fat deposition. A waist to hip
ratio >0.85 in women indicates increased risk of cardiovascular
diseases. Alternatively, and simply, the waistline can be used instead.
A figure >88 cm (35 inches) is a reliable measure of abdominal
obesity in women.
Women with PCOS are prone to metabolic problems related to

obesity, high blood pressure, insulin resistance, high insulin level,
type II diabetes, high LDL cholesterol and triglycerides levels, low
HDL cholesterol, low fibrinolysis and alteration in plasminogen
activator inhibitor 1 (PAI-1). All these factors are related to
Syndrome-X which is known to increase the risks of cardiovascular
accidents. Though both obese and non-obese women with PCOS are
prone to insulin resistance and type II diabetes mellitus (66), this
problem is amplified by obesity. In general insulin resistance is
considered as a pathophysiological contributor in around 50-80% of
women with PCOS (67). Furthermore, Insulin resistant patients with
PCOS have significantly higher plasma homocysteine levels than their
non-insulin resistant counterparts (68). High homocysteine plasma
levels have been implicated with cardiovascular disease, recurrent
miscarriages and pre-eclampsia. Recent evidence showed that PCOS
independent of obesity and insulin resistance is the strongest
predictor of elevated high sensitivity C-reactive protein level (hs-
CRP), which is a marker of increased cardiovascular risk. Obesity and
age increase this risk in patients with PCOS (69).
In spite of all these studies, epidemiological data did not show

increased risk of mortality or morbidity from coronary heart disease in
women with PCOS (70, 71). This has been attributed to the high
oestrogen environment with its vasodilatory effects, and high levels of
vascular endothelial growth factor in women with PCOS. Oestrogen acts
on blood vessels wall eliciting release of nitric oxide, which is a potent
vasodilator and improves blood flow (72). Larger epidemiological data
are necessary to confirm these basic findings. Women with PCOS are 30
times more likely to experience obstructive sleep apnoea syndrome
(OSAS), in comparison to matched controls (73). Insulin resistance was
a stronger risk factor of the condition than BMI or testosterone level.
Women with OSAS are also more liable to snoring, interrupted night
sleep, excessive daytime sleepiness and easy fatigability. The last
authors also suggested that progressive deterioration of PCOS leads to
OSAS. High incidence of cholithiasis has also been found in women with
PCOS, even at a young age.
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Beside its effect on insulin level, obesity may aggravate the endocrine
abnormalities in patients with PCOS through the following means:
• High levels of endorphins and dopamine in circulation;
• High hypothalamic opiates can alter GnRH pulse generation;
• Tendency to high prolactin levels;
• High conversion rate of androstenedione to oestrone creating a
hyperoestrogenic status;
• Reduction of SHBG production by the liver leading to high free
testosterone.
It is important to remember that not all obese women with high insulin
blood level are hyperandrogenic. This emphasises the importance
of local ovarian abnormalities, which can make them more liable
to produce excessive amounts of androgens in response to
hyperinsulinaemia. On the other hand, not all patients with PCOS are
insulin resistant. A review article published by Moran and Teede in 2009
addressed this issue (36). Hyperandrogenic anovulatory women with
PCOS are more likely to have insulin resistance than hyperandrogenic
ovulatory patients and nonandrogenic anovulatory ones. They stated
that hyperandrogenic ovulatory PCOS women are liable to be adversely
metabolically affected when abdominally obese. There was also little
evidence that non-hyperandrogenic anovulatory PCOS women matched
for abdominal obesity had a more adverse metabolic profile than
controls.
Problems with ovulation
The reproductive capacity of women with PCOS may be compromised

with increased risk of anovulation, menstrual abnormalities, ovarian
hyperstimulation syndrome, miscarriages, and cancer of the
endometrium. Ovulatory problems may show as inadequate or short
luteal phase, menorrhagia, polymenorrhoea, dysfunctional uterine
bleeding, oligomenorrhoea and amenorrhoea. It is more often for these
patients to present with oligomenorrhoea and dysfunctional uterine
bleeding than any of the other mentioned problems as reported by
Abdel-Gadir et al in 1992 (5). This point was further confirmed by
Brassard et al in 2008 (74) as 80-90% of patients who present with
oligomenorrhoea have PCOS. Conversely, only 40% of patients who
present with amenorrhoea will be diagnosed with PCOS, as
hypothalamic amenorrhoea is also a common cause (75). The major
impact of PCOS on ovulation is affected through increased intraovarian
hyperandrogenic milieu, as well as the effect of increased circulating
androgens on the hypothalamo-pituitary unit. Excessive androgens are
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known to have a direct detrimental effect on ovulation at the level of

the ovaries as they can:
• Reduce granulosa cells mitotic activity;
• Reduce FSH receptors on the granulosa cells;
• Reduce the FSH induced aromatase activity in the granulosa cells;
• Reduce LH receptors leading to reduced progesterone production
during the luteal phase, which can lead to abnormal uterine
bleeding;
• Reduce oocytes maturation capacity and ability to undergo normal
embryonic development as shown by animal studies (76);
• Compromise normal growth and secretory activity of endometrial
epithelial cells. This was shown for androstenedione which
specifically reduced glycodelin secretion in cultured endometrial
epithelial cells (77). A similar effect was shown for testosterone
which reduced uterine and plasma glycodelin concentration (78);
• Suppress expression of HOXA-10 gene which is a hormone-
regulated endometrial transcription factor. It is essential for
endometrial development and receptivity (79), and its suppression
may compromise pregnancy rate.
All these problems can lead to disturbed menstrual function, reduced
fertility potential, and miscarriages. Nevertheless, 60% of women with
PCOS are fertile as diagnosed by their ability to conceive within 12
months, but may take longer time to do so (74). Obesity is an important
factor in this respect as almost 90% of infertile women with PCOS are
obese. The reported prevalence of obesity in patients with PCOS in
general is 40 – 60%. The reproductive capacity of patients with PCOS
is also compromised by a higher risk of hyperstimulation and multiple
pregnancies, after induction of ovulation. Furthermore, increased
miscarriage rates have been documented by many authors in relation
to obesity and high LH, androgens, PAI-1, insulin resistance and
hyperinsulinaemia. Lower levels of glycodelin and insulin like growth
factor binding protein 1 (IGFBP-1) have been reported in patients with
PCOS during the first trimester of pregnancy (80), and in the non-
pregnant state (81). These two proteins are necessary for proper
implantation, by inhibiting the immune response of the endometrium to
the embryos. Nevertheless, no association has been firmly documented
between PCOS and recurrent miscarriages, despite over representation
of the presence of PCO in these cases as reported by Essah et al (82).
These same authors related all the risk factors mentioned above to
insulin resistance and hyperinsulinaemia. Reducing insulin blood level
resulted in reduction of LH, androgens and PAI-1, and increase in the
126
level of glycodelin and IGFBP-1 blood levels. In addition, patients with

PCOS were shown to be at greater risk of gestation diabetes (odd ratio
2.94) and high blood pressure during pregnancy, irrespective of being
insulin resistant or not. Conversely, the risk of pre eclampsia was high
only in patient who were insulin resistant before getting pregnant.
Newborns from PCOS pregnancies were significantly more often
delivered by caesarean section, and transferred to neonatal intensive
care units than controls (83). Reduced miscarriage rate has been
documented after using metformin (84)
As many as 21% hyperandrogenic regularly menstruating women with

PCO were found to have anovulatory cycles by Carmina and Lobo in
1999 (12). Similarly asymptomatic regularly menstruating women with
ultrasonically diagnosed PCO had low luteal serum progesterone level as
documented by Abdel-Gadir et al in 1992 (5). This later group of
patients might represent the first stage in a continuous chain of events,
passing through a phase of regular anovulatory cycles (12), before they
develop irregular and anovulatory menstruation. This puts further
emphasis on the point that the presence of PCO even in women with
regular menstrual cycles should not be considered as a normal finding.
These patients may benefit from having regular medical follow up, as
some of them were shown to have occult hyperandrogenism and subtle
metabolic changes similar to those seen in patients with PCOS (13, 85)
Psychological effects of PCOS
Women with PCOS are at risk of mood swings, anxiety, and

depression with impaired quality of life (86). Obesity, hirsutism,
irregular periods, and subfertility are major sources of psychological
morbidity, depending on the age and other personal circumstances of
the individual patient. Nevertheless, obesity was reported to be the
most prevalent cause of mental distress, while the impact of the
other symptoms proved to be less well defined (87, 88). A positive
correlation has been reported between the degree of insulin
resistance, even before the development of type II diabetes, and the
severity of depression (89). Such psychological difficulties may
represent disturbed response to stress by patients with PCOS,
manifested by enhanced hypothalamo-pituitary-adrenal axis and
heart rate reactivity, as well as reduced upregulation of interlukein-6
in response to stress as reported by Benson et al in 2009 (90). This
was reflected biochemically by significantly increased ACTH and
cortisol response to stress by PCOS patients, in comparison to BMI-
matched healthy controls. The same authors concluded that altered
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ABDEL -GADIR
PCOS patients’ reactivity to stress may be a link between depression,

overweight, and the cardiovascular and diabetes risks associated with
the diagnosis. To improve the quality of life of this subgroup of
patients, attention should be paid to the psychological impact of the
disorder.
Management of patients with PCOS
Management of patients with PCOS is usually directed towards their

mode of presentation. The psychological impact of the problem should
be assessed and addressed, irrespective of the age group. The reason
why patients seek medical advice is strongly affected by their age,
fertility needs and the psychological impact of the problem. Control of
symptoms, being irregular menstruation or hyperandrogenisation is
usually possible, but permanent cure may be unlikely. Furthermore,
therapies usually change with the age and needs of the patient.
Accordingly, prolonged follow up is necessary to prevent long term
medical problems, and the management strategy should focus on:
• Reduction of body weight and control of the metabolic
dysfunction;
• Treatment of peripheral hyperandrogenisation;
• Control of abnormal uterine bleeding;
• Treatment of infertility.
It is not unusual for many patients to present with two or even all 4
problems together. Weight reduction is beneficial for all the other three
problems, and induction of ovulation is indicated when the patients are
keen to get pregnant. Progestogens and the combined contraceptive pill
are generally adequate to control anovulatory abnormal uterine
bleeding, but treatment of skin hyperandrogenic signs usually clashes
with infertility treatment. It usually entails the use of antiandrogens and
drugs which block ovulation, or are not safe to use during pregnancy.
Loss of Weight
Excessive weight should be addressed as a priority, through significant

changes in life style, including more physical activity and healthy
eating. Self starvation should be avoided, as most women who lose
weight this way usually regain their initial weight within 2-3 years.
Adequate weight loss leads to significant improvement in insulin
resistance, and reduction in the level of circulating free androgens. It
can also help in regulating ovulation and improving the chances of
conception. This can be done with the help of a dietician, and through
128
regular follow up visits to the clinic over a long period of time to

encourage compliance. Information about the obstetric and fetal risks
related to obesity can be found in Chapter 8.
Unfortunately, many women with PCOS find it difficult to lose weight

despite their serious efforts, because of the anabolic effects of insulin
and androgens. Insulin also improves appetite by acting directly at the
hypothalamus, and increases lipogenesis and reduces lipolysis.
Excessive androgens can also lead to masculinization. Accordingly,
sustained self motivation, and professional help will be needed.
Metformin can be prescribed to obese patients with insulin resistance.
It helps with insulin utilisation at tissue level, especially the liver and
muscles. It also reduces gluconeogenesis and glucose absorption from
the gastrointestinal tract. It may cause gastrointestinal side effects,
and is better taken with food. The dose should be built up slowly to
avoid side effects, and to encourage compliance. The usual dose is 500
mg twice daily, but 850 mg tablets can be taken with food 3 times every
day by non-responsive patients. Metformin should be suspended few
days before any major surgical procedure. Reports of liver damage
have been published (91-93), and severe elevation of hepatic enzymes
gives a good indication. Ideally, all patients should be tested few times
during the first year of medication and annually thereafter. A rare
complication of metformin therapy is lactic acidosis.
Metformin use is contraindicated in patients with compromised

hepatic or renal function tests. Other contraindications include severe
infections, dehydration, alcoholism, heart failure, recent myocardial
infarction and use of X-ray contrast media. An important side effect of
metformin is reduction of vitamin B12 absorption, especially in patients
who are at risk, mainly vegetarians. It does not cause hypoglycaemia,
but can do so if taken with alcohol. Nevertheless, it can normalise blood
glucose levels. To have a good impact on insulin resistance and obesity,
changes in life style and good feeding habits, as well as ample physical
exercising are necessary. A final note to remember in this section is that
metformin is not a slimming drug.
Treatment of skin hyperandrogenic signs
The 5 main strategies used in the treatment of female skin

hyperandrogenisation not related to exogenous androgens are:
1. Assess the psychological impact of the problem especially in
young patients, and offer the necessary support when needed;
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ABDEL -GADIR
2. Reduce the adrenal and ovarian androgens production;

3. Increase the hepatic production of SHBG, which reduces the free
fraction of androgens;
4. Block 5α-reductase activity with antiandrogens at the level of the
pilosebaceous organs, and reduce the conversion of testosterone
to 5-dihydrotestosterone.
5. Use cosmetic means both personally and through professional
help.
Any androgenic medication should be changed or suspended.
Predisposing medical problems including adrenal hyperplasia,
hyperprolactinaemia or thyroid dysfunction should be addressed first.
Ovarian androgens production can be reduced by blocking ovulation
with an oral contraceptive pill. In certain circumstances a glucocorticoid
will be necessary, especially when a combined adrenal enzymatic
deficiency has been diagnosed. The oestrogen fraction in any combined
oral contraceptive pill stimulates the liver to produce more SHBG. This
reduces the free fraction of circulating androgens. The reported levels
of SHBG following the use of 30 μg ethinyl oestradiol pills were
equivalent to levels recorded in women with regular menstrual cycles.
A significant increase was documented after using a daily dose of 50 μg,
which is a high dose not commonly used in most present day oral
contraceptives. It is good practice to avoid pills with androgenic
progestogens. This is especially so as they can induce or worsen insulin
resistance, and may induce dyslipidaemia. This is particularly so, as
many pills devoid of such androgenic progestogens are now available.
Examples of PCOS friendly pills include mercilon, yasmin, cilest,
marvelon, femodene, femodette and minulet. Metformin has also been
shown to reduce androgens production by acting directly on the
ovaries, and can help with skin problems even in hyperandrogenic
patients with PCOS who are not insulin resistant.
The most widely used antiandrogen nowadays is spironolactone, which

is an aldosterone receptor antagonist. Though initially used as a diuretic
for treatment of hypertension, it proved to have excellent anti
androgenic characteristics, with minimal side effects. It usually takes
few months before seeing a significant effect, and it sustains its effect
through the following mechanisms:
• It reduces testosterone production by interfering with cytochrome
P450 activity. Specifically, it inhibits 17α-hydroxylase and 17-20
desmolase activity (94);
• It promotes the conversion of testosterone to oestradiol in the
liver;
130
• It reduces the activity of the enzyme 5α-reductase necessary for

the conversion of testosterone to 5-dihydrotestosterone;
• It competes with 5-dihydrotestosterone at the skin receptors.
The main side effect of spironolactone is intermenstrual bleeding, which
usually settles with continued use. This is not a problem for patients using
an oral contraceptive pill at the same time. Using spironolactone during
the early weeks of pregnancy can lead to feminization of male fetus
genitalia. This is due to reduction in the concentration and activity of 5-
dihydrotestosterone, which is necessary for the development of male
external genitals. Accordingly, it should be used with an oral contraceptive
pill, or any other efficient method of contraception, by sexually active
women during their reproductive years. Changes in blood electrolytes are
not common but should be kept in mind, as spironolactone has an anti
aldosterone effect.
Other antiandrogens include cyproterone acetate, flutamide, finasteride

and dutasteride. The most widely used one in this group is cyproterone
acetate, either in a reversed sequential therapy as mentioned in
Chapter 4, or as part of an oral contraceptive pill as in dianette (Bayer
plc). It has a potent antigonadotrophic effect, and hence reduces
ovarian androgens production. It also has a direct effect at the skin
level by competing with 5-dihydrotestosterone for the receptor sites. It
is important to combine it with an oestrogen, and should be used only
during the first half of the treatment course. This is because of its long
debo effects, which may cause menstrual dysfunction and excessive
uterine bleeding. It should not be used for a very long period of time
after the symptoms have subsided. This is even true for dianette,
despite the small dose of cyproterone acetate, as it may cause
depression after prolonged use. Accordingly, dianette should not be
used primarily for contraception purposes by non hyperandrogenic
women. Spironolactone in a daily dose of 100 mg has been shown to
be more effective on the skin than dianette which contains 2 mg
cyproterone acetate and 35 μg ethinyl oestradiol. Other drugs are also
potent but have significant hepatic toxicity and should be used only
sparingly, and only when really necessary. Flutamide is an androgen
receptor blocker given in a dose of 250 mg once or twice daily. It has
hepatic toxicity, and can alter liver function tests. It may also cause
anorexia, pruritis, dry skin and dark urine. It is mainly used for
resistant cases of androgenic alopecia. Liver function tests should be
performed before and regularly during the treatment. 5α-reductase
inhibitors are not very popular in treating female hyperandrogenisation,
and may be less effective than other antiandrogens. Finasteride
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ABDEL -GADIR
(proscar) in a dose of 5 mg every day can be used for the treatment

of hirsutism as it is mainly a type 2 isoeznyme inhibitor. On the other
hand, dutasteride (avodart) in a dose of 0.5 mg every day inhibits both
type 1 and 2 isoenzymes and causes a dramatic reduction in
dihydrotestosterone level within a short period of time. It has been
portrayed as an effective treatment for androgenic alopecia.
All these medications should be combined with good skin care and
professional help for hair removal. Skin irritants should be avoided. It is
always advisable that patients should take photographs of the affects
areas before starting treatment, and at regular intervals thereafter to
monitor response. Laser treatment proved to be effective in dealing with
excessive hair growth, but should be part of a general management plan
involving medical treatment of excessive androgens production.
A diagnosis of PCOS should be considered in hyperandrogenic women

with ultrasonically diagnosed polycystic ovaries, despite having regular
menstruation. Nonetheless, other causes of hyperandrogenism should be
excluded first. Furthermore, a high level of LH is no longer considered
necessary to confirm the diagnosis. It may be elevated in up to 60% of
the patients, but its level can be affected by recent ovulation, ingestion
of certain medications and BMI; being higher in leaner patients. It is
secreted in 90- minute pulses, and the level depends on the timing of the
sample within a pulse. In addition, the unreliability of single blood sample
hormone estimations in representing the true endocrine milieu has been
known since 1973 (95). The reliability of a single LH estimation was
undermined by a variability of 38% and 92% in accuracy to represent the
6-hour mean value, following 20 minutes blood sampling during the
follicular and luteal phases of the cycle respectively. The same authors
suggested a minimum of 3-hour multiple sampling to detect changes of
40% or less in LH concentrations. Such variability has since been
confirmed for LH as well as testosterone by Abdel Gadir et al in 1991 (30).
In this respect, a high LH level is significant, but a normal level will not
exclude LH hypersecretion. This is a reflection of a stronger positive
predictive value, but a low negative one. The significance of measuring
LH blood levels in anovulatory hyperandrogenic women with PCOS is
reflected by its prognostic value for selecting patients for ovarian
electrocautery, as patients with high LH levels had a better response (96).
Idiopathic hirsutism
This is a term used to describe excessive hair growth which can not be
explained by measurable excessive circulating androgens level. Many of
132
these patients have a mild adrenal enzymatic deficiency. In many

patients only the free androgen fraction is increased, despite having
normal total testosterone and androstenedione levels. This may be due
to low levels of the carrier molecule SHBG, and is reflected by a high
testosterone/SHBG ratio. Hepatic production of SHBG is reduced by
obesity, high blood insulin and androgens, as well as low thyroid
hormone levels.
Increased end tissue (skin) sensitivity has also been described as a

cause of excessive hair growth in many cases of idiopathic hirsutism.
This was related to rapid turnover of androgens at the skin level,
due to increased numbers of androgen receptors. It can also follow
increased conversion rate of testosterone to the more biologically
active dihydrotestosterone, secondary to increased 5α-reductase
enzymatic activity. This is reflected by increased blood levels of
dihydrotestosterone metabolite 3α-androstandiol glucoronide (3α-diol
G). Oral contraceptives do not usually affect this end byproduct, which
is usually reduced by spironolactone and cyproterone acetate, which
act as antiandrogens at the skin level. This increased tissue turnover of
androgens explains why women with the same levels of circulating
androgens may have different degrees of excessive hair growth. In this
context, hirsutism is not a reflection of the circulating level of
androgens, but rather an expression of the skin turnover of 5-
dihydrotestosterone, as reflected by the increased level of 3α-diol
glucuronide. This metabolite byproduct is also produced by many other
tissues in the body, which reduced its value as a reliable biomarker for
the diagnosis of idiopathic hirsutism.
Infertility treatment of patients with PCOS
Infertile obese women with PCOS should be offered fertility treatment only
after a good effort has been invested in losing weight. This has been shown
to improve ovulation and increase their chances of natural conception,
even without any medication. The risk of increased miscarriages in obese
women with PCOS after induction of ovulation should be kept in mind (31,
97). This is on top of the real risks of gestational diabetes, and the
associated fetal and maternal complications in patients with body mass
index >35 kg/m2. More information about the effects of body weight on
pregnancy outcome can be found in Chapter 8.
Induction of ovulation should be attempted first with clomiphene citrate

under supervision, because of the risks of multiple ovulations. A 5-day
course of 50 mg every day can be started on the 3rd day of withdrawal
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ABDEL -GADIR
bleeding. Ovulation usually occurs about 7 - 10 days after the last

tablet, but may occur a couple of days earlier in some women. A higher
dose of 100 mg every day for 5 days may be needed, in non-responsive
patients. Higher doses are usually ineffective and can affect the cervical
mucus fluidity, increase the histological age of the endometrium
relative to the follicle, and interfere with tubal motility and fluid
chemistry as an antioestrogen. Treatment with clomiphene should not
be continued for more than 6 cycles. Gonadotrophins can be used in
nonresponsive cases, but they need special expertise, and easy access
to professional ultrasound monitoring. Attempts should be made to aim
at monofollicular ovulation by starting medication with a single
ampoule for 7-10 days, before increasing the dose in half an ampoule
doses, at equal time spacing. The cycle should be abandoned if multiple
follicles are recruited. The risk of multiple follicular development
exceeds 50% and 80% with clomiphene citrate and gonadotrophins
therapy respectively in patients with PCOS. Ovarian diathermy has
been advocated as an alternative to gonadotrophins, with good
outcome. In fact 52.1-84.0% of patients with the sole problem of PCOS
conceived after such a procedure (30, 98). It has also been shown by
Abdel-Gadir et al in 1990 (32) to be equally effective as gonadotrophins
in inducing ovulation with a similar pregnancy rate, lower risk of
miscarriages, and no risk of hyperstimulation or multiple pregnancies.
In a different article, the same authors reported better endocrine
response in patients with PCOS and high LH level compared to
those with normal LH level, but high LH:FSH ratio (89). A further benefit
of laparoscopy in these cases is that it offers a good chance to examine
the pelvis for other infertility factors at the same time. The risk of
developing pelvic adhesions after ovarian drilling should be
weighed against the prospective benefits expected in these patients.
Such risk may be reduced by adopting principles used during
microsurgery (99):
• Insert the needle at right angle to the surface of the ovary to
prevent slit cauterisation and reduce the damaged ovarian surface
area;
• Apply the current only when the needle touches the ovary to
prevent arcing and charring of the ovarian surface which can lead
to adhesions formation;
• Use the minimum number of points according to ovarian size;
• Cool the ovary with a physiological solution as soon as that side is
done;
• Avoid electrocautery in women with evidence of PID or during
extensive pelvic surgery with large raw areas especially on the
134
pelvic sidewall, as this may encourage ovarian adhesions to these

areas.
Metformin has been shown to be highly effective in augmenting
clomiphene citrate activity for induction of ovulation in previously
resistant patients (100). It reduces androgen production by the
ovaries, improves ovulation, and reduces miscarriage rates.
Reduction of insulin level has been shown to reduce ovarian
cytochrome P450c17α activity, and serum free testosterone (101).
Furthermore, it has been shown to reverse the metabolic and
endocrine risk factors associated with increased miscarriage rate in
women with PCOS. It reduces the levels of PAI-1, and luteinising
hormone, but it may take 4 months before a full molecular effect is
achieved. Recent reports suggested that it may have a direct effect
on the ovaries, even in women who are not insulin resistant (102).
Metformin has also been shown to reduce the risk of ovarian
hyperstimulation syndrome in patients with PCOS undergoing IVF or
ICSI treatment cycles, but did not improve pregnancy rate when
taken before or during the treatment cycles (103). Nevertheless, the
authors suggested that large controlled trials were needed to verify
this last point. Despite all these positive reports, some scepticism has
been voiced regarding the benefit of metformin in the treatment of
infertility and menstrual disturbance.
Implications of ultrasonically diagnosed PCO in non-PCOS

patients
Normal women with polycystic-appearing ovaries
It has been reported that 16-25% of ‘normal’ women had polycystic-

looking ovaries without any specific symptoms or signs (4-6). Many
of them had increased risks, and similar morbidity as related to
PCOS. They may show subtle metabolic (73) and endocrine (5, 12)
abnormalities including:
• Low high density lipoprotein-cholesterol;
• Evidence of insulin resistance;
• Androgenic ovarian response to stimulation with gonadotrophins;
• Low serum progesterone during the luteal phase of natural cycles,
indicating ovulatory dysfunction;
• Similar risks of excessive response to induction of ovulation, and
ovarian hyperstimulation syndrome as patients with PCOS.
In addition, they have similar uterine and ovarian blood flow as patients
with PCOS (104) as revealed by Doppler studies. Accordingly, the
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notion that the presence of PCO in this group of women is totally

‘normal’ should be revised.
Other endocrine problems associated with ultrasonically diagnosed

PCO
Polycystic ovaries may be seen in women with a wide range of different

endocrine problems including:
• High prolactin level;
• Hypothyroidism;
• Adrenal enzymes deficiencies;
• Hypothalamic dysfunction.
Accordingly, total reliance on ultrasonography alone will create a
diagnostic problem, and wise utilisation of endocrine investigations is
always necessary in patients presenting with menstrual dysfunction (5).
Hyperprolactinaemia
Polycystic ovaries have been reported in 50.0% of patients

with hyperprolactinaemia (5). High prolactin can affect the ovaries in
different ways:
• It can change GnRH and gonadotrophins production;
• It has a direct effect on the follicles at a postreceptor level,
reducing their response to gonadotrophins;
• It increases adrenal androgens production by causing partial
enzymatic block, leading to a hyperandrogenic state.
Hypothyroidism
As many as 36.4% patients with hypothyroidism showed PCO on

ultrasound scan examinations (5). Hypothyroidism is generally
associated with low levels of SHBG, and increased levels of free
androgens. This may lead to hyperandrogenic skin problems which may
confound the diagnosis. Free androgens can also be aromatised to
excessive amounts of oestrogens in the hypothalamus, which can
adversely affect GnRH and gonadotrophins secretion. Secondly, high
androgens can affect the ovaries directly leading to the development of
PCO, as discussed before. Additionally, hypothyroidism can lead to TRH
induced secondary hyperprolactinaemia, which compounds the risk of
anovulation. The presence of PCO in patients with hypothyroidism may
partly explain the increased risk of ovarian hyperstimulation syndrome
during induction of ovulation in this group of patients. More information
136
about hypothyroidism can be found in Chapter 11, which deals with the
thyroid gland in gynaecology.
Adrenal enzymatic deficiencies
Partial adrenal enzymatic deficiencies have been discussed thoroughly

in Chapter 4. They can present first at puberty or early adult life, and
are described as ‘adult onset’. The most common variety seen in >90%
of the diagnosed cases is partial 21α-hydroxylase deficiency. The
pattern of presentation includes symptoms and signs similar to those
described for PCOS. In fact the ovaries may be polycystic in virtually
100% of the cases (5). The American College of Obstetrics and
Gynaecology recommended that all women with a suspected diagnosis
of PCOS should be screened for 17α-hydroxyprogesterone levels. As
mentioned previously, morning blood samples should be examined to
cater for the circadian rhythm of the adrenal hormones.
Hypothalamic dysfunction
Hypothalamic dysfunction is a diagnosis of omission, after excluding all

known factors capable of causing ovulatory dysfunction. Many non
quantifiable causes may be implicated in these cases, such as severe
stress which can affect GnRH pulse generation. Excessive weight loss
can affect the ovaries, but it has been associated more with multicystic
rather than polycystic ovaries. Different medications have a similar
effect, especially antiepileptic drugs and other drugs capable of affecting
the brain neurotransmitters, and accordingly GnRH pulse generation.
Despite the lack of an overt endocrine dysfunction that could be

revealed by a peripheral blood test, polycystic ovaries were reported in
23.7% of anovulatory patients with hypothalamic dysfunction (5). Such
ovaries behave the same way as any other polycystic ones, with
increased risk of hyperstimulation during induction of ovulation.
Treatment of patients in this group should be tailored to their symptoms
and needs. This may involve induction of ovulation to facilitate
conception. An oral contraceptive pill can be used to induce regular
withdrawal bleeding, and protect against unwanted pregnancies.
Regular progestogen withdrawal bleeding every 8 weeks will guard
against endometrial hyperplasia in patients who are not sexually active.
Effect of age on patients with PCOS
With advancing age, women with PCOS tend to have more regular periods
and lower circulating androgens as reported by Winters et al in 2000 (105).
137
ABDEL -GADIR
At the same time women over the age of 35 years showed lower prevalence
of PCO pattern during transvaginal ultrasound scan examinations, as
reported by Abdel-Gadir et al in 2009 (29). These changes may be
secondary to the age related reduction in the total number of recruitable
follicles, and the increase in FSH level leading to a more favourable LH / FSH
ratio. Over the years, more obese patients with PCOS are likely to develop
type II diabetes. A figure of 80% risk has been quoted in this subgroup.
They are also at higher risk of carcinoma of the endometrium than normal
women, especially in the presence of other risk factors including
amenorrhoea, endometrial hyperplasia, and high blood pressure.
Summary
PCOS is a heterogeneous condition involving interlinked metabolic,

endocrine and reproductive problems. Its exact causes are not well known,
but many theories have been introduced to explain its development. It has
a familial predisposition, though an exact genetic or chromosomal cause
has not been established. More evidence is accumulating relating it to
abnormal insulin resistance and hyperinsulinaemia. Nonetheless, not all
patients with hyperinsulinaemia have PCOS, and not all patients with PCOS
have high insulin blood levels. A recent article published by Jovanovic et al
in 2010 confirmed increased cardiovascular and metabolic risks in
hyperandrogenic women with the classic PCOS, but ovulatory patients
with PCOS appear to be less affected. On the other hand, the
nonhyperandrogenic phenotype was the least affected group, if at all (106).
PCOS should be treated as a general medical problem, rather than just a

fertility issue. Controlling the metabolic disorder, when applicable, by
reducing body weight and insulin resistance should be the primary
management objective. This will impact favourably on the
endocrine and reproductive sides of the syndrome. The presence of
ultrasonically diagnosed PCO in patients with menstrual irregularity and
hyperprolactinaemia, or thyroid and adrenal dysfunction, stresses the
need for a proper endocrine assessment. This will help in making a
definitive diagnosis before starting any form of medical or surgical
treatment, solely on the ultrasonic findings.
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Chapter 7
Induction of Ovulation
Induction of ovulation is a term used to describe stimulation of part or

the whole of the hypothalamo-pituitary-ovarian (HPO) axis by
exogenous means to produce follicles and ultimately eggs. Normally the
ultimate objective is to develop one follicle, and to shed one oocyte to
reduce the risks of multiple pregnancies and hyperstimulation
syndrome. Stimulation can be at the level of the hypothalamus,
pituitary gland, or directly at the level of the ovaries. It is only indicated
in women who are keen to conceive, but are not ovulating regularly, or
frequently enough to give them a good chance of doing so. This is
different from controlled ovarian hyperstimulation, when multiple
follicles are stimulated during an in vitro fertilisation treatment cycle.
The objective here is to produce multiple oocytes to be fertilised in vitro,
to create embryos which can be replaced into the uterus. Certain
conditions must be satisfied before induction of ovulation can be
provided:
• The exact cause of anovulation should be diagnosed, to allow
proper selection of the appropriate medication to stimulate
ovulation. The indiscriminate prescription of clomiphene citrate
to all women with oligo-ovulatory cycles without reaching a
diagnosis is not appropriate.
• There should be no medical or social reasons to contraindicate
pregnancy. Medical conditions should be addressed first, and social
factors are better dealt with in collaboration with a counsellor.
• At least one fallopian tube should be patent.
• Specific endocrine problems including thyroid and adrenal glands
dysfunction, and hyperprolactinaemia should be addressed first.
Spontaneous ovulation may restart without the need for active
stimulation of the HPO axis.
• Obese and underweight patients should be encouraged to regain
an appropriate body mass index between 18.5 – 24.9 kg/m2. This
is more likely to kick-start the HPO axis to resume functioning
spontaneously. More information about this subject can be found
in Chapter 8.
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• There should be no contraindication to use the specific drug

selected.
• Monitoring facilities and experienced medical supervision
should be available to maximise chances of patients’ safety.
This will reduce, but does not abolish altogether excessive
ovarian response, ovarian hyperstimulation syndrome or multiple
pregnancies risks.
• Hospital backup should be available to deal with any complications,
especially ovarian hyperstimulation syndrome.
Treatment rationale
Different drugs are available to work at different levels of the HPO axis.
They can be summarised as follows:
1. Drugs acting at the level of the hypothalamus [anti oestrogens];
2. Drugs acting at the level of the pituitary gland [pulsatile GnRH];
3. Drugs acting directly on the ovaries [gonadotrophins].
Disease rationale
The type of drug selected depends on the category of the anovulation

problem encountered. The WHO anovulation subgroupings will be used
as examples in this case:
1. Hypogonadotropic hypogonadism [WHO type 1];
2. WHO type 2 (non PCOS);
3. Polycystic ovary syndrome which makes more than 50% of all the
cases.
Aetiology of anovulation
Polycystic ovary syndrome has been described as the most common

endocrinopathy in women during their reproductive life (1). This view
has been shared by many other authors, and the following percentages
of endocrine dysfunctions have been reported in one series (2):
• PCOS was diagnosed in 50.8% of all anovulatory women
investigated.
• Hypothalamic dysfunction was reported in 26.2% of the cases.
Anovulation was linked to weight related problems, psychological
problems, or excessive physical exercise. No specific association
was noted in many patients.
• Ovarian failure was reported in 8.7% of the patients as diagnosed
by high FSH blood levels. Induction of ovulation is not a viable
option in these patients.
150
• Hypo-or-hyperthyroidism was diagnosed in 4.2% of all patients

who presented with anovulation, or anovulatory menstrual
dysfunction. As stated before, treating the underlying condition
allows spontaneous resumption of ovulation in most cases.
Adequate ovulation may take longer time to resume after the
biochemical correction of the deranged thyroid indices.
• Secondary amenorrhoea due to hypogonadotropic hypogonadism
was diagnosed in 4.0% of the cases mainly due to empty sella
syndrome. The diagnosis was made with the help of MRI.
• Hyperprolactinaemia was reported in 3.1% of the cases.
• Different other causes made the remaining 3.0%.
The exact percentages may be different in different populations, and
care should be taken to establish the correct diagnosis before
commencing patients on any specific medication.
Specific medications
Antioestrogens
Antioestrogens are the most commonly used drugs for induction of

ovulation. They are only effective in patients with anatomically intact
HPO axis, as in cases of PCOS and other types of WHO type 2
anovulatory problems. They occupy oestrogen receptors at the level of
the hypothalamus; hence creating a false impression of central
hypoestrogenic state. This will induce the hypothalamus to produce
more GnRH pulses to stimulate gonadotrophins production by the
pituitary gland. They are not effective in treating patients with
hypogonadotropic hypogonadism (WHO type 1), or hypergonadotrophic
hypogonadism (cases of ovarian failure) who already have high blood
FSH levels.
Clomiphene citrate (clomid) is the most widely used drug in this group.
It is a non-steroidal antioestrogen used for induction of ovulation since
1961 (3). It has a long 1/2 life, so it occupies cytoplasmic oestrogen
receptors for a long period of time, rendering them unavailable after an
initial stimulation phase. Such downregulation of oestrogen receptors
ultimately creates a hypoestrogenic state, which the hypothalamus
rectifies by producing more GnRH pulses to increase gonadotrophins
production. The manufacturer’s product monograph reported that only
51% of an oral dose of clomiphene citrate was excreted after 5 days,
mainly in the stools. The remaining part stayed in the body for a long
period of time, mainly in the enterohepatic circulation. Less than 1% of
the drug was still being excreted every day in faecal or urine samples
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collected 31 to 53 days after its administration (4). This explains the

protracted antioestrogenic effects of the drug on the different systems
of the body.
Since its discovery, various protocols have been tried before settling with
the classical 5 days courses. Treatment is usually started after
progestogen withdrawal bleeding. Extended therapy for 10 days has
been reported to be effective in patients who failed to ovulate after 5-
day courses. Fluker et al in 1996 (5) reported that 47% of initially
resistant patients ovulated after daily 100 mg doses, used between days
3-12 after withdrawal bleeding episodes. They reported 65% of the
treatment cycles to be ovulatory in this group, with no significant side
effects.
Ovulation usually occurs 7-10 days after the last clomiphene citrate
dose, but may occur a couple of days earlier. About 15-20% of patients,
mainly with PCOS, may not respond or only have an inadequate
response. Furthermore, only 30-40% of the patients who manage to
ovulate usually conceive (6), and the pregnancy rate is generally
inversely related to the dose used. Doses >100 mg/day are not usually
indicated, and clomid should not be used for more than 6 cycles (4).
The discrepancy between ovulation rate and pregnancy rate is related
to its antioestrogenic effects, and reduced uterine receptivity. Different
detrimental effects have been reported following clomiphene citrate
therapy including:
• Thick and non-watery cervical mucous reduces colonisation of the
cervical crypts with sperm, which is necessary for the continuous
migration of sperm into the uterine cavity.
• Patients on clomid were found to have advanced histological
maturation of the endometrium relative to its chronological age.
• Changes in fallopian tubes fluid chemistry and motility can affect
the transport of the sperm and / or embryos.
More recent studies showed reduced endometrial thickness, and
unfavourable endometrial pattern on ultrasound monitoring. This was
coupled by reduced uterine arteries, subendometrial and endometrial
blood flow in patients with PCOS using clomiphene citrate (7). Beside
these specific antioestrogenic effects, clomid has been shown to increase
the blood level of circulating androgens in patients with PCOS. This may
have some bearing on the quality of the eggs produced, and the
receptivity of the endometrium. Some women may also notice skin
eruptions while on treatment. In fact all body systems can be affected by
clomiphene citrate, though significant systemic complications are not
152
common. The range of reported side effects included headaches, low

mood, nausea and vomiting, fever, hot flushes, tinnitus, chest pain,
shortness of breath, tachycardia, urticaria, arthralgia, back pain and
myalgia, among many others. More serious side effects included visual
symptoms including visual spots and blurred vision, due to intensification
and prolongation of the after-images in brightly lit areas. Diplopia,
scotoma, photosensitivity and reduced visual acuity have all been
described. Treatment should be stopped immediately, and not repeated
in these cases. Changes in liver enzymes and hepatitis have also been
mentioned. It is important to reiterate that systemic side effects are not
common, despite this long list of possible complications.
One of the more common side effects of clomiphene citrate therapy is

multiple pregnancies. This follows multiple follicular recruitment and
multiple ovulations in >30% of the patients. Ultrasound scan follow up
should alert the treating doctor to this possibility. These patients should
abstain from sexual intercourse during that cycle. Twin pregnancies
have been reported in 5-10% of all pregnancies following clomiphene
citrate therapy, but much lower figures were reported for twins (1 in 400
cases, 0.25%) and triplets (1 in 800 cases, 0.12%).
Figure 24 shows monofollicular ovulation in a patient with polycystic ovaries

after induction of ovulation with clomiphene citrate. A corpus luteum is seen in the
right ovary, while the left one shows polycystic changes. In contrast, Figure 25
shows a total of 11 recruited follicles of different sizes.
Other side effects include:

• Clomiphene citrate has a thermogenic effect, which may give a
false impression of thermal shift in non-responsive patients using
temperature charts to document ovulation.
• Premature LH surge with small follicles is not uncommon after
clomiphene citrate induction of ovulation. Such occurrence can
only be detected if ultrasound monitoring is used.
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• Increased incidence of luteinized unruptured follicles (LUF)

syndrome has also been reported after using clomiphene citrate
therapy. It can be diagnosed when a follicle fails to collapse or to
shows internal changes reminiscent of a corpus luteum. Colour
Doppler monitoring may show poor neovascularisation around the
luteinized follicle, and serum progesterone may be low as well.
The reported incidence of LUF ranged between 6-25% during the
first cycle of clomiphene citrate use. Higher percentages were
reported in women with unexplained infertility and regular cycles
who received clomiphene citrate during intrauterine insemination
treatment cycles. Figures of 78% and 90% were reported during
the second and third cycles respectively in this group of women
(8). This detrimental effect on follicular rupture was considered an
indication for a possible role for clomiphene citrate in the aetiology
of LUF, either by central or local means.
Clomiphene citrate should not be used by patients with liver disease
and ovarian cysts, and by patients who had previous complications or
hypersensitivity to the drug. Accordingly, before prescribing any further
doses of clomiphene citrate, care should be taken to exclude the
presence of undiagnosed pregnancy, and ovarian cysts which follow
14% of the induced cycles. Such cysts are functional and usually
resolve spontaneously. It is also contraindicated in women with
undiagnosed vaginal bleeding, and for the management of menstrual
disorders in women who are not keen to get pregnant.
Other drugs have been combined with clomiphene citrate to improve

its efficacy including corticosteroids, bromocripine, as well as oral and
injectable oestrogens. Many studies have reported the efficacy of
these medications in improving the response of patients who were
initially resistant to clomiphene citrate. Pre-treatment with an oral
contraceptive pill, and combined treatment with oestradiol benzoate
injections (9), corticosteroids (10), bromocripine, and human chorionic
gonadotrophin for the final triggering of ovulation have all been used
with different claims of success, after an initial poor response. On the
other hand, a Cochrane review published in 2009 showed no extra
benefit of adding human chorionic gonadotrophin to clomiphene citrate
(11). Nevertheless, the same review showed improved pregnancy rate
when clomiphene citrate was combined with dexamethasone, or
followed a course of oral contraceptives.
Other antioestrogenic drugs have also been used for induction of

ovulation. The most commonly reported one is tamoxifen, which can be
154
given in a dose of 10 – 20 mg every day for 5 days, starting on day 3

of a progestogen withdrawal bleeding. It is not very popular in
comparison to clomiphene citrate. Recently, aromatase inhibitors have
also been documented as effective drugs for induction of ovulation,
either separately, or in combination with clomiphene citrate. By
inhibiting the aromatase enzyme, they reduce the conversion of
androgens to oestrogens, and hence create a hypoestrogenic effect.
This can lead to increased production of GnRH pulses by the
hypothalamus and gonadotrophins by the pituitary gland. The most
commonly used drug in this group is letrozole which is a third
generation aromatase inhibitor. It is given in a dose of 2.5 mg/day for
5 days, starting on day 3 of a progestogen withdrawal bleeding as well.
A single dose of 10 – 30 mg was found to be equally effective as the 5-
day course. Letrozole has been shown to be effective in clomiphene
citrate resistant cases. It has another advantage of a short half life of
45 hours compared to the very long half life of clomiphene citrate which
could occupy nuclear oestrogen receptors for 6-8 weeks. Accordingly, it
is less likely to have significant detrimental effects on the cervical
mucous and endometrium. Letrozole has also been used with
gonadotrophins for induction of ovulation in poor responders with some
good effect. It may also be used to augment the effect of
gonadotrophins, hence reducing their total dose for cost saving. Other
drugs within this group include anastrozole and exemestane. All
aromatase inhibitors have similar antioestrogenic side effects as
clomiphene citrate. They are not yet as popular as clomiphene citrate,
but are potentially useful for patients who can not take clomiphene
citrate, and in resistant cases (12).
There is some controversy regarding the value of ultrasound monitoring

after using antioestrogens induction of ovulation, mainly clomiphene
citrate. Unavailability of the service and the cost of repeated ultrasound
scan examinations were the main factors responsible for the historical
use of clomiphene citrate without monitoring. Many of the benefits in
following patients with serial ultrasound scan examinations before and
during clomiphene citrate medication have been discussed before,
including:
• To avoid taking the drug in cases with residual corpus luteal cysts.
This is especially important during follow up cycles after previous
use of the drug. Such cysts were reported in 14% of the cases as
mentioned before;
• Assurance of follicular growth as ò20% of the patients may not
respond;
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ABDEL -GADIR
• To detect multiple follicular development with increased risk of

multiple ovulation (30 %) and multiple pregnancy (5 – 10%);
• To detect ovulation of small follicles due to premature LH surge;
• To confirm ovulation which is necessary for selecting the optimum
time for intercourse or artificial insemination;
• To detect cases with LUF syndrome (25 – 90%) as discussed to
before.
One drug which gained great notoriety is metformin (glucophage),
which is an insulin sensitising biguanide drug, used for the treatment of
type II diabetes mellitus. It had an equal effect in improving
anovulatory menstrual irregularities in both insulin resistant and insulin
sensitive PCOS patients (13). A direct effect on the ovaries has been
reported even in women who were not insulin resistant (14). A good
account has been given about its mode of action, dose, and side effects
in Chapter 6. It proved effective in the treatment of anovulatory PCOS
patients by inducing regular menstrual cycle and fertility. It was also
effective in converting clomiphene citrate resistant patients into
responsive ones (15), and reduced early miscarriage rate (16, 17). The
usual dose is 500 mg twice daily with food to reduce gastrointestinal
side effects. It also has a favourable local effect at the level of
the uterus, besides its other favourable endocrine effects on
hyperinsulinaemia and hyperandrogenaemia. Such effects include
improved endometrial thickness as well as uterine, subendometrial and
endometrial blood flow to levels usually seen in a non PCOS control
groups (18). It is inevitable that many patients on metformin, which is
classified as category B drug for use during pregnancy, will fall pregnant
while taking the drug. Recent work showed that it reduced the
development of gestational diabetes in women with PCOS (19), and
was safe to use during pregnancy (20)
Gonadotrophins
Human pituitary gonadotrophins were isolated in 1958, and utilised

successfully for induction of ovulation. They have been withdrawn from
the market because of their limited supplies, and the association of
Creutzfeldt-Jacob disease with human pituitary growth hormone.
Products prepared from postmenopausal women urine have been used
since the 1960s, and recombinant products were the latest to be
produced. This incurred major changes in prices for patients, in return for
more pure products and stable batch to batch consistency. Nonetheless,
no significant differences in odds of pregnancy outcome or complications
have been found between urinary and recombinant FSH during induction
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of ovulation in patients with PCOS in a Cochrane review conducted by

Bayram et al in 2003 (21). The situation was rather different during
assisted reproduction treatment cycles in a different Cochrane review
conducted in the same year by Daya and Gunby (22). They reported
significant increase in the odds of clinical pregnancy and live birth or
ongoing pregnancy for recombinant FSH versus urinary FSH. This view
has been challenged by a more recent randomised controlled multicentre
study published by Abate et al in 2009 (23). They found no difference in
oocyte or embryo quality produced by patients using either medication.
Furthermore, there was no difference in the fertilisation, cleavage and
implantation rates, or pregnancy and miscarriage rates between the two
groups. Interestingly, less urinary FSH was needed for a shorter period of
time than the recombinant FSH during the same study to give a similar
clinical response. Combined drugs with equal proportions of FSH and LH,
or only FSH medication are available in the market. Despite many claims
and counter claims in the past, it is now evident that there is no significant
superiority of one product over the others, in relation to induction of
ovulation or pregnancy rate.
Gonadotrophins are currently used as primary medication in WHO

group 1 and clomiphene citrate resistant patients. They act directly
on the ovaries, with about 20% chance of multiple pregnancies.
Hyperstimulation occurs despite strict monitoring, as follicles are
produced in sequence rather than in parallel. It is usually advisable to
start with the smallest dose, and to step it up as necessary. Doses and
response may differ in different cycles, even in the same patient; hence
the need for strict monitoring. Pre treatment counselling is necessary
regarding the need for repeated visits to the clinic for monitoring, and
to discuss the risks of hyperstimulation and multiple pregnancies. The
need to cancel a cycle should be stressed clearly to the patient, in case
of excessive response. Smaller doses should be used in the subsequent
cycles.
Gonadotrophins dosage
One should always aim at monofollicular ovulation taking into account

the endogenous FSH. Patient with WHO group 1 usually need higher
doses, with lower risk of OHSS than women with PCOS or PCO.
Treatment should be started with one ampoule of the preferred
gonadotrophin for 5 – 7 days, and the dose should be increased by half
or one ampoule every 5 - 7 days, if necessary. The minimum effective
dose should be maintained till a mature follicle has developed. With
excessive recruitment, the dose should be stepped down, or even
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abandon the cycle if multiple follicles have already developed. The

minimum effective dosage should be used in subsequent cycles.
Regular monitoring with ultrasound scanning is adequate without the

need for oestradiol estimations, in most if not all cases. If oestradiol is
used, the ideal daily rise in serum level was shown to be a factor of 1.3
- 1.4, as seen during natural cycles. Exponential rise indicates
increased risk of excessive response and hyperstimulation. Follicles
may be recruited and grow in sequence, rather than in parallel in
response to gonadotrophins medication during controlled ovarian
hyperstimulation. Accordingly, new follicles may be seen each time a
scan examination is preformed. A folliculogram is best suited to show
this response as follicles would be spread along the whole column,
rather than being grouped together as siblings of similar size. There is
a higher chance of multiple follicles development with gonadotrophins
(>60%), in comparison to clomiphene citrate (>30%). It is also
noticeable that different patients hyperstimulate at different oestradiol
levels. Accordingly, ultrasound scanning is a better parameter than E2
in predicting multiple pregnancies and OHSS. This depends on the total
number of stimulated follicles, especially intermediate size ones, as will
be discussed later on in this chapter.
The primary objectives for monitoring ovulation are:

• To secure patients’ safety by detecting early signs of excessive
response which precedes hyperstimulation;
• To evaluate patients’ response to therapy in an attempt to secure
monofollicular ovulation whenever possible;
• To document changes in the endometrial thickness and
echotexture;
• To time hCG injection to trigger ovulation;
• To document ovulation has taken place.
It has been established that all these requirements can be fulfilled using
ultrasound monitoring. This is because of the close relationship between
follicular development and endometrial changes as documented by
ultrasound on one hand, and oestradiol level on the other. Furthermore,
ultrasound scanning can be used to time the hCG injection, whereas
oestradiol is not useful in this respect. It can be useful for withholding
the hCG injection, if the blood tests showed exponential rise in
oestradiol levels. The reason why hyperstimulation occurs at different
oestradiol levels depends most probably on the maturation index of the
follicles at the time of the hCG injection. Monitoring ovulation should
begin before starting medication to rule out the presence of ovarian
158
cysts or any other pathology. The following scan should be performed

5-7 days after starting medication. The number of recruited follicles
should be counted, and marked in a specially designated folliculogram.
This should be filled serially, as it gives a visual picture regarding the
number and the rate of follicular growth. The maximum endometrial
thickness should be measured in the sagittal plane, during each
examination. Its texture pattern should also be noted, being isoechoic
to the myometrium, hypoechoic or echogenic. A trilaminar pattern with
hypoechoic texture is considered to be the most receptive.
Figures 26 – 28 represent thin menstrual, midcycle trilaminar, and echogenic

secretory endometrium respectively. Cervical mucous can also be seen as a dark
line occupying the cervical canal in Figure 27.
Ovulation can be predicted biochemically by measuring the LH surge.

This can be done by urine prediction kits or by serial measurements
of LH blood levels, once a follicle has reached 16 mm in diameter.
Neovascularisation of the dominant follicle, as detected by colour
Doppler mapping, is a good predictor of imminent ovulation as well.
All this might be academic, as an exogenous hCG injection is usually
given to help with ovulation and timed intercourse. A recent study
published by Farhi et al in 2010, showed that pregnancy rate was
affected by follicular size when hCG was administered to trigger
ovulation (24). The rate was highest (13.6 – 18.6%) when the follicles
were 18-22 mm in diameter and lowest with 17 mm (8.8%), 23 mm
(8.8%), and 24 mm (5.7%) follicles respectively. Most important,
there was no difference in pregnancy rate between cycles with one or
two follicles. In general, serum progesterone estimation one week
following ovulation helps to indicate adequate ovulation or otherwise.
Different levels have been used, but in general a blood level ≥30
nmol/l is considered to reflect adequate ovulation. On the other hand,
ultrasound scanning can show the following signs of ovulation:
• Collapse of the monitored follicle;
• The follicle becomes smaller with thicker wall;
• The follicle outline becomes irregular with the appearance of intra-
follicular echoes due to the presence of blood clots and serum;
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ABDEL -GADIR
• There is increase in the amount of fluid in POD;

• The endometrium shows an echogenic texture.
The corpus luteum has different looks depending on the amount of haemorrhage into
the sac itself, and the time lag between ovulation and transvaginal ultrasound scan
examination. Figure 29 shows a solid corpus luteum shortly after ovulation. A blood
clot occupies the whole sac. Figure 30 shows a corpus luteum with a blood clot and
irregular haemolysed areas in the middle, few days after ovulation. Figure 31
depicts a corpus luteum with a resolving blood clot showing reticular texture, may
days after ovulation. In general, a corpus luteum behaves like any other haematoma
as related to the texture, resolution and disappearance of the blood clot.
Occasionally a follicle may fail to ovulate despite increased oestradiol level,

occurrence of an LH surge and rise in the level of luteal phase serum
progesterone. This can occur in cases of luteinized unruptured follicle
syndrome (LUF), which is seen more common in infertile women. In such
cases, ultrasound scan examination may show a persistent follicle after the
LH surge, with minimal vascular markings of the luteinized follicle during
colour Doppler mapping. In the pre-ultrasound era, diagnostic laparoscopy
was the main tool to diagnose LUF through failure to see ovulation ostium,
and low serum progesterone in the peritoneal fluid during the luteal phase
of the cycle. In cases of premature LH surge, ultrasound scanning can show
ovulation of a small follicle with a thin endometrium. This can occur during
both natural and clomiphene citrate induced cycles.
Figure 32 and 33 are laparoscopic views of two ovaries with a new ovulation
ostium, and a corpus luteum respectively. Copies of the two photographs in colour
160
are shown in the back cover. Yellow discolouration of the corpus luteum is very
clear in figure 33 copy on the back cover.
The role of Doppler Ultrasound
Doppler ultrasound has been studied extensively in relation to the

uterine, endometrial and ovarian vasculature during spontaneous and
induced ovulation. The uterine artery had more dominance in these
studies, and basic findings can be summarized as follows:
• The uterine arteries can be identified just lateral to the cervix;
• Typically they have moderate to high blood flow velocity;
• Their resistance index depends on the phase of the cycle;
• They have small end diastolic flow during the proliferative phase;
• The resistance index declines before ovulation, and stays low till
menstruation.
Basic Doppler studies of the ovarian arteries can be summarized as
follows:
• Ovarian vessels can be seen lateral to the upper pole of ovaries;
• They are more difficult to visualize than the uterine arteries;
• They do not show prominent colour flow on colour Doppler
mapping;
• They typically have low velocity;
• Their resistance index depends on the phase of cycle.
Doppler studies at the middle of the cycle can show the following
characteristics:
• Reduced resistance index of the uterine arteries and increased
vascularisation of the dominant follicle in normal cycles;
• Low or absent subendometrial and endometrial perfusion in
infertile women;
• Absent uterine arteries diastolic flow in some infertile women.
Certain sonographic parameters have been considered as favourable
when documented during induction of ovulation:
• An endometrial thickness ≥8 mm;
• A hypoechoic endometrium with trilaminar echotexture;
• A dominant follicles 18-22 mm in diameter (24)
• Uterine artery pulsatility index < 3;
• High degree of endometrial blood perfusion as shown by colour
Doppler or 3D power Doppler histograms reflect favourable
endometrial receptivity (25).
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Figure 34 shows a midcycle transvaginal ultrasound sagittal view of a uterus

with thick endometrium and good endometrial and subendometrial blood flow,
as shown by colour Doppler mapping. Figure 35 demonstrates a mature follicle
with peripheral colour markings revealed during colour Doppler examination.
Better views of the colour markings are shown in the corresponding copies of
both photographs on the back cover. Figure 36 shows favourable uterine
artery Doppler pulse waveform, representing both the systolic and diastolic
parts. The pulsatility index was 2.05 as shown in the lower right corner by the
electronically generated data. Absence of the early part or the whole diastolic
pulse had been associated with increased impedance, low tissue perfusion and
infertility (26, 27).
Triggering ovulation with hCG injection
It is usual to trigger ovulation with an exogenous dose of hCG, rather

than wait for a spontaneous LH surge. This can be a necessity in the
following conditions:
1. For patients with hypogonadotropic hypogonadism;
2. Following pituitary downregulation with a GnRH-analogue;
3. For better timing of ovulation in cases of intrauterine
insemination;
4. When a follicle has reached 20-22 mm in diameter without
evidence of an LH surge, or a good colour rim demonstrable by
colour Doppler mapping.
The usual hCG doses used for triggering the final act of ovulation are
5000 and 10000 IU, and ovulation usually occurs 36-40 hours later. The
ovulation window can last for 3 or more days, as follicles of different
sizes may take different times to ovulate. Secondary follicles continue
to grow for a day or more with the production of more oestradiol, before
ovulating. This group is the one more likely to cause OHSS, and multiple
pregnancies. Smaller follicles usually luteinize immediately after hCG,
and become atretic. The drug may stay in circulation for up to 10 days
after a dose of 10000 IU. So it can trigger ovulation, and maintain luteal
support. Such a high dose is more likely to have a wide ovulation
window, so it is not ideal for patients with multiple follicles. Accordingly,
a dose of 5000 IU should be used to trigger ovulation, and to reduce the
162
risk of OHSS. Similarly, luteal hCG injections to support the corpus

luteum can also increase the risk of OHSS. When necessary,
progesterone supplements will be a better option, and should be used
instead.
The triggering dose of hCG affects rupture of the dominant follicle

through different mechanisms:
• It increases follicular fluid volume;
• It also increases collagenase and plasmin activity;
• It increases the level of prostaglandins F2α;
• It increases the contractility of myoepithelial cells in the ovary.
At the same time, the triggering hCG injection affects oocytes
maturation. Normally oocytes meiosis is inhibited by the enzyme oocyte
maturation inhibitor (OMI) produced by the granulosa cells. This OMI
does not act directly on the oocytes, but through the cumulus cells. It
is inhibited by the natural LH surge or hCG injection used to trigger
ovulation of a mature follicle. They cause withdrawal of the cumulus
cell mass, resulting in break down of the cumulus cells-oocytes
communication.
A different role for hCG has been reported within the setup of controlled
ovarian hyperstimulation protocol which is used during assisted
reproduction treatment cycles. Small daily doses of 200 IU were found
to support growth and maturation of follicles >12 mm in diameter,
without any detrimental effects on the quality of the follicles. Such
medication was associated with reduced number of small preovulatory
follicles, resulted in more oestrogenic intrafollicular environment, and
reduced FSH/HMG consumption (28)
Induction of ovulation with pulsatile GnRH
GnRH is a decapeptide produced by the hypothalamus. It can be used in

cases of hypothalamic failure or dysfunction. The best results should be
expected in women with WHO type 1 anovulation [hypogonadotropic
hypogonadism]. It is given through a pulsatile pump in a dose of 5-15
μg/pulse, every 90 minutes. Smaller doses are used when the intravenous
route is used, rather than the subcutaneous one. It has the least risk of
producing OHSS or multiple pregnancies, which should be taken into
consideration when weighing its advantages and disadvantages.
Usually an exogenous hCG injection is not necessary to trigger the

final act of ovulation, as a spontaneous LH surge usually occurs.
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ABDEL -GADIR
Furthermore, luteal support can be maintained with the same pulse dose
of GnRH. Alternatively, an exogenous progestogen can be used, to give
the patient a break from continuous use of the pump.
The drawbacks of using pulsatile GnRH for induction of ovulation

include:
• Treatment can only be given within a dedicated infertility unit with
staff available to respond to patients’ problems;
• Patients must be motivated with good sense of hygiene to reduce
the risk of infection;
• The needle site should be changed regularly. This should be
done weekly for subcutaneous sites, to avoid infection. More
frequent changes will be needed with the intravenous route of
administration, depending on dislodgment of the needle, or
appearance of local signs of phlebitis;
• The cost of the pump and the dedicated type of needles should be
taken into consideration;
• It may take longer to respond to pulsatile GnRH medication than
to gonadotrophins depending on the dosage.
Ovarian electrocautery for induction of ovulation
Laparoscopic ovarian electrocautery is useful as a second line

management for patients with PCOS not responsive to clomiphene
citrate therapy. It is most effective in patients with blood LH levels >
12 IU/L, as reported by Abdel-Gadir et al in 1993 (29). Both LH and
testosterone were reduced after the procedure, and it was equally
effective as gonadotrophins for ovulation induction, as reported by the
same authors. Almost 50% of the conceptions occurred within 6
months in patients with no other fertility problem. Nevertheless, about
25% of the patients did not respond, but got more sensitive to
clomiphene citrate. A recent study reported by Amer et al in 2009 (30)
found that patients with high AMH level ≥ 7.7 ng/ml had reduced
chance of ovulation after the procedure. This can be used as another
parameter, beside LH, to counsel patients regarding chances of
response before surgery.
Ovarian drilling has many merits in comparison to other methods of

induction of ovulation. It is a simple procedure which is easy to learn,
and does not need strict ultrasound or oestradiol monitoring. There
were also no increased risks of OHSS or multiple pregnancies, as
documented in all the reports published so far. Many patients will
continue to have regular periods for a long time, without the need for
164
any further medication. Nonetheless, there is a danger of misusing the

technique in patients who are not seeking to get pregnant. There is also
the risk of ovarian adhesions if the technique used is not perfect. Using
microsurgical principles can reduce this risk (31). The exact details
have already been described in Chapter 6. Proper patients’ selection
using LH and AMH blood levels will increase the success rate, as
mentioned before.
Figure 37 is a laparoscopic view of a

polycystic ovary after ovarian drilling.
No slit cauterisation could be seen.
Also note the characteristic dilated
blood vessels usually seen on the
surface of polycystic ovaries. A better
view is shown by a colour copy of the
same photograph on the back cover.
The risk of primary ovarian failure has been raised, but never
materialised in any prospective study. Ovarian reserve markers were
found to be lower after ovarian drilling, compared to women with PCOS
who did not have the same procedure (32). The changes in FSH, inhibin
B and antimullerian hormone blood levels, which were used as
measures of ovarian reserve, should be considered as signs of
normalisation of ovarian function rather than a reduction of ovarian
reserve as suggested by Murat in 2009 (33). It is understandable that
over cauterisation of the ovaries can lead to non-reversible damage.
Accordingly, the number of drills should always be guided by the size of
the ovary itself, and the duration of the current application should not
exceed 4 seconds each time a drill is made.
Induction of ovulation in women with regular periods
Induction of ovulation in women with regular cycles raises many

medical and ethical questions. This is especially so as drugs meant to
stimulate the ovaries can unnecessarily lead to multiple pregnancies
and OHSS. They may not improve the fertility potential in women
<35 years, but can increase the multiple pregnancy rate. On the
other hand, increasing the number of follicles in older women with
gonadotrophins injections can increase cycle fecundity rate. This is
usually done within a protocol of timed intercourse or intrauterine
insemination (IUI). Nevertheless, the delivery rate in women over 40
years of age was less than 5%, following gonadotrophins injections
165
ABDEL -GADIR
and IUI as reported by Tsafrir et al in 2009 (34) Furthermore,

induction of ovulation is not beneficial and should be avoided in
patients with regular cycles and high FSH blood levels. There is
always a risk that unnecessary use of clomiphene citrate in regularly
cycling women may reduce cycle fecundity, due to its antioestrogenic
effects on the cervical mucous, endometrium and fallopian tubes as
mentioned before. Furthermore, there is increased risk of LUF (8).
Early pregnancy scanning
Following adequate ovulation and a positive pregnancy test, early

pregnancy ultrasound monitoring should concentrate on the following
points:
• Confirm a diagnosis of intrauterine pregnancy;
• Exclude the possibility of an empty uterus with positive βhCG;
• Exclude or ascertain a diagnosis of multiple pregnancy;
• Ascertain chorionicity of multiple pregnancies. A thick septum
between the two sacs during early pregnancy usually indicates
binovular twining. The lambda sign is useful in this respect in the
second trimester;
• Help with monitoring of disturbed pregnancies;
• Can be used for embryo reduction in cases of higher order multiple
pregnancies.
Ovarian hyperstimulation syndrome
Ovarian hyperstimulation syndrome is the most serious complication to

follow induction of ovulation, and may lead to significant morbidity or
even mortality. It is characterised by marked ovarian enlargement,
high serum sex steroids, and extravascular exudation of fluid and
protein due to increased vascular permeability. This can result in
intravascular volume depletion, haemoconcentration, diminished organ
perfusion and increased thrombotic tendency (35). It is usually more
common with gonadotrophins than clomiphene citrate induced cycles
(36). Paradoxically, it is more common with induction of ovulation than
with superovulation utilised during IVF treatment cycles, as the risk is
reduced by follicular aspiration during oocytes retrieval. Certain
patients are more at risk than others, and the following factors increase
the risk independently as reported by the Practice Committee of the
American Society of Reproductive Medicine (36):
• Young age;
• Polycystic ovaries;
166
• Low body weight;

• Higher doses of exogenous gonadotrophins;
• High absolute or rapid rise in serum oestradiol;
• Previous episodes of OHSS;
• Exogenous hCG injections to trigger ovulation;
• With hCG injections for luteal support;
• During conception cycles because of endogenous hCG production.
It is generally noticeable that a patient’s characteristics determine her
individual response, more than the stimulation protocol. Of all these
risk factors polycystic ovaries stand out as the most important entity.
The risk is also higher during the first treatment cycle, and in patients
with hypothyroidism and hyperprolactinaemia. It is also higher in
downregulated cycles. GnRH analogues increase the risk by blocking
the spontaneous LH surge and luteinisation which are the self
protecting mechanisms against further follicular development (37). At
the molecular level, it has been shown Mayorga et al (38) that ovarian
response to FSH stimulation depends on the patient’s FSH receptor
(FSHR) genotype. The same authors suggested that the number of
FSH ampoules needed by each patient could be predicted from a linear
combination of basal FSH level and the type of FSHR polymorphism.
The exact incidence of OHSS is usually difficult to ascertain, because

of under reporting, and the different diagnostic criteria used.
Furthermore, mild forms may even pass unnoticed or unreported by
the patients themselves. A figure of 4% has been reported after
standard ovulation induction with gonadotrophins with < 1.0% in its
severe form. The overall incidence of moderate and severe OHSS
during IVF cycles was reported by Brinsden et al in 1995 (39) as 1-
10%, but only 0.5 – 2% of the cases were in the severe form. A
figure of 38% was quoted by Asch et al in 1991 (40) when oestradiol
level exceeded 10,000 pmol/l on the day of hCG administration.
Furthermore, the higher the number of eggs collected, the higher was
the risk. This risk exceeded 20% when 30 oocytes were collected, as
reported by the same last authors. Different oestradiol cut off figures
have been quoted when the risk of OHSS increased. In contrast, the
rate of increase in oestradiol blood levels, rather than the absolute
values, has been reported to be more important in this respect (37).
This could reflect the hypersensitivity of the ovaries to stimulation.
At the same time, the value of oestradiol levels in predicting
OHSS has been questioned in different reports (41, 42). Accordingly,
a combination of different parameters should be used during
monitoring, including the following:
167
ABDEL -GADIR
• The number of follicles;

• The rate of rise in oestradiol level;
• The actual level of oestradiol;
• The ratio of mature vs. intermediate follicles which denotes
follicular maturation index on the day of hCG adminstration.
Figure 38 shows excessive ovarian

response during IVF treatment cycle.
More than 10 follicles were recruited in
each ovary. The cycle was cancelled to
prevent the development of OHSS.
Patients with more secondary than tertiary follicles are more at risk
to develop OHSS. This was demonstrated by a report published by
Blankstein et al, as far back as 1987 (43). In mild OHSS, 68.7% of
the follicles were 9 – 15 mm in diameter. On the other hand, 95% of
the follicles were <16 mm in diameter, most of them (54.7%) <9 mm
in cases of moderate to severe OHSS. This last point can explain the
different oestradiol levels reported in the literature when the risk of
OHSS increased, without taking note of the ratio of the number of
secondary and tertiary follicles.
It seems that certain women are more liable to develop OHSS than others.
Figures 39 – 41 belong to a patient who developed moderate OHSS with
ultrasonically diagnosed ascites during an IVF treatment cycle, in spite of normal
ovarian response and normal oestradiol blood levels. Furthermore, despite the
presence of significant ascites, her blood chemistry was not significantly
affected. Figures 39 and 40 show transabdominal pictures of the right and left
ovaries with only few residual corpus luteal cysts. Excessive amount of fluid is
visible around the right ovary and uterus as shown in figure 40. The right and
left ovaries were only mildly enlarged with diameters of 6.8 x 4.8 cm and 7.2 x
5.1 cm respectively. Figure 41 shows some fluid under the diaphragm and on
168
top of the liver. This case shows that ovarian size, blood chemistry and the
presence of significant ascites may not correlate in the same patient.
The exact cause of OHSS is not known, but certain factors were
implicated in the development of OHSS, and have been summarised as
follows (36):
• High follicular fluid level of proteins and renin;
• Angiotensin mediated increased capillary permeability;
• Excessive exudation of protein-rich fluid from the peritoneal
surface and enlarged ovaries.
Though only the ovarian protein-renin-angiotensin system is mentioned
in this list, other ovarian vasoactive factors are also involved in
mediating increased capillary permeability. The list includes the kinin
kallikrein system, selectins, von Willebrand’s factors, prolactin,
prostaglandins, but the most important one is vascular endothelial
growth factor (VEGF) (37). This was shown by a major impact of
recombinant VEGF antiserum in neutralising capillary permeability
activity (44, 45). Further work showed significantly high free or
unbound VEGF, and lower plasma and follicular fluid levels of the
corresponding binding protein in patient with OHSS (46, 47). On the
other hand it, is has been suggested that activation of the renin-
angiotensin system in patients with OHSS may be a secondary response
rather than a primary factor in the pathogenesis of OHSS (37).
The syndrome typically starts approximately one week after ovulation,

but the affected patients may not show any specific symptoms to start
with. The spectrum of abnormalities ranges from ovarian enlargement,
to severe multiple systems failure. Patients may present with abdominal
pain, feeling bloated and tired, diarrhoea and thirst, and abdominal
distension in the early stages. In most cases the condition is self-
limiting, and strict observation and reassurance will be adequate. The
range of severe clinical and biochemical problems can be grouped into:
• Volume depletion, hyponatraemia and ascites;
• Haemoconcentration & thrombotic tendency;
• Renal and hepatic dysfunction and respiratory distress.
For such a self-limiting problem, unnecessary intervention can cause
more harm than benefit. Accordingly, the management plan should
focus on the following points:
• Proper assessment of the severity of the condition, bearing in mind
its dynamic nature which can change from one day to another;
169
ABDEL -GADIR
• Provision of symptomatic relief and reassurance to the patient;

• Avoidance of haemoconcentration;
• Prevention of thromboembolism;
• Maintenance of cardiorespiratory and renal function.
These are easy objectives to set, but can be very taxing in cases with
severe OHSS. Different methods have been used to classify its severity
since 1967, when the first classification was introduced by Rabau et al
(48). Various clinical, ultrasound and biochemical parameters have
been combined into many subgrades which made them rather difficult
to use. For clinical purposes, the following simplified classification has
been used in many fertility units for many years, with good effect:
• Mild OHSS when the ovaries are < 8 cm in diameter, and the
patient complains of abdominal bloating, heaviness and mild pain;
• Moderate OHSS entails ovaries 8-12 cm in diameter with
increased abdominal discomfort, nausea and vomiting, and
ultrasound evidence of ascites;
• In severe cases of OHSS, the ovaries exceed 12 cm in diameter, with
clinical evidence of ascites, hypovolaemia, haemoconcentration,
electrolyte imbalance, decreased renal perfusion and liver
dysfunction. All these systems dysfunctions need regular blood
chemistry assessments to determine their severity and progression.
The ascites can be tense, and there may be evidence of hydrothorax
and generalised oedema.
Not all patients with OHSS need daily hospital supervision, or
admission to hospital. These will incur unnecessary inconvenience
and expenses to the patients. In mild cases, outpatient management
entails adequate oral fluid intake, at least 1 litre per day. The patient
should also weigh herself daily, and any excessive weight gain of
more than 2 pounds per day should be reported to the hospital for
further investigations. She should also observe her own urine output.
Any reduction in daily output or passage of concentrated urine should
likewise be reported to the hospital. Furthermore, strenuous exercise
should be avoided to prevent trauma or torsion of the enlarged
ovaries. It is advisable to see the patient every few days to measure
her abdominal circumference at a fixed point each time, and to
ascertain her general condition. In cases of moderate to severe
OHSS, the major cardinal monitoring parameters should include:
• Signs of dehydration and fluid retention with deranged blood
electrolytes;
• Haematological signs of haemoconcentration including PCV >
50% and WBC >25 X 103;
170
• Signs of decreased renal perfusion and renal failure, as shown by

decreased urine output and changes in blood chemistry;
• Signs of liver dysfunction with deranged liver function tests;
• Signs of adult respiratory distress syndrome which may be difficult
to diagnose initially. The patient may present with rapid pulse,
shortness of breath with no abnormal signs on chest examination.
The condition may deteriorate fast, and the patient could
become hypoxic or even cyanotic, and in need of positive pressure
ventilation. Arterial blood gas assessment is indicated in hypoxic
patients at risk even in the absence of physical signs.
Management of moderate and severe OHSS
Strict initial clinical, ultrasound and biochemical assessment will give a

clear picture of how much a patient’s systems are deranged. This helps
regarding further management plans, and whether the patient should
be referred to a unit with intensive care facilities. It is important to bear
in mind that the general clinical appearance and the extent of ovarian
enlargement are not good indicators of the patient’s biochemical
derangement. The following guidelines should be followed:
• Aim at reassurance to reduce anxiety;
• Keep a strict fluid chart and start crystalloid solutions 100-150 ml/
hour, if the urine output < 400 ml/day or the PCV > 45%;
• Add low salt human albumin in a dose of 100 gm every 3-12 hours
by intravenous infusion, if the PCV has not improved or the patient
has developed oliguria;
• To reduce the risk of deep venous thrombosis, patients should be
encouraged to use full length thrombo-embolic deterrent (TED)
stockings, and to mobilise as soon as possible;
• Subcutaneous heparin in a dose of 5000 IU twice/day should be
used to guard against thromboembolic problems;
• A diuretic (furosemide) should be used only if PCV has improved,
but there is no diuresis yet. Otherwise, it should be avoided as it
can lead to further dehydration of the intravascular compartment
and electrolyte derangement;
• Dopamine infusion can be used in a dose of 5 μg / kg body
weight / min, in patients with impending renal failure despite
implementation of all the above measures;
• Patients with tense ascites which is interfering with breathing should
have ultrasonically guided paracentesis of the peritoneal fluid. This
will reduce its splinting effect on the diaphragm, and can help with
urine output as well in patients suffering from oliguria. This fluid is
171
ABDEL -GADIR
very rich in plasma proteins, and can lead to proteins deprivation if

large amounts of the ascitic fluid are removed.
It is important to remember that OHSS is a self-limiting condition, and
resolves spontaneously in the majority of cases. Accordingly, treatment
should fundamentally be supportive. More damage can be incurred
through prescribed fluid overload. On the other hand, management of
severe cases can be difficult, and should be conducted with the help of
physicians experienced in the management of severe fluid and
electrolytes imbalance.
Summary
Induction of ovulation is an art, as much as being a science. Even strict

vigilance and attention to details will not prevent complications
altogether. Accordingly, doctors involved with this discipline should
have good experience in prescribing the drugs used for induction of
ovulation. They should also be competent in monitoring patients to
optimise response, and to prevent or detect early signs of any
complication. It is always important not to prescribe gonadotrophins if
there are no competent monitoring facilities in place, and there is no
hospital backup support to deal with any complication which may result
from such medication.
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176
Chapter 8
Adipose Tissue and Reproduction
No Reproductive Endocrinology book will be complete without a chapter

addressing the effects of adipose tissue on reproductive function. Both
underweight and overweight states have been recognised for a long
time to have detrimental effects on development, menstrual function,
fertility potential and pregnancy outcome. This is over and above their
effects on general health. The body mass index (BMI), which represents
the ratio of weight in kilograms over height in metres squared, has been
used in clinical setups to measure the effects of adiposity.
The World Health Organisation in 2000 (1) defined a normal BMI to cover
a range between 18.5 – 24.9 kg/m2, overweight range >25 – 29.9 kg/m2,
obesity >30 kg/m2 and morbid obesity >35 kg/m2. Figures <18.5 kg/m2
were defined as underweight. However, BMI is not a very exact reflection
of body fat, as it can be affected by age, bone density and muscles mass.
More important, it does not reflect the regional distribution of fat which
proved to be more important clinically in many respects. Furthermore,
the agreed cut off ranges may not be equally important in different ethnic
groups. Nevertheless, it is an easy formula to use with reasonable
accuracy, and its efficacy can be improved by measuring the waist
circumference, and the waist: hip ratio at the same time. Waist
circumference is the most accurate clinical parameter for estimating intra
abdominal fat, but the cut off figures also vary with ethnic origin. A value
>80 cm for waist circumference, and >0.85 for waist-to-hip ratio have
been associated with increased morbidity (2). Waist measurement should
be taken with the patient standing up, with the tape at the narrowest part
of the abdomen, after expiration.
Before going into the clinical implications of obesity and underweight,

it is important to describe the structure and function of adipose tissue
which forms the largest endocrine gland in the body. It is made of
adipocytes (fat cells), preadipocytes, endothelial cells, pericytes,
macrophages, monocytes, and fibroblasts. During infancy and early
childhood, brown adipocytes are dominant, but are rare during adult
life. They are multilocular, brown in colour, and are mainly concerned
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ABDEL -GADIR
with basal heat production. On the other hand, white adipocytes or

white fat cells are unicellular, and form the main energy stores for the
body. They are 95% made of triglycerides. They can grow in size up
to a certain critical threshold, before triggering preadipocytes
differentiation into adipocytes. Once adipocytes are formed, they
remain permanently for life. This process of lipogenesis is facilitated by
the enzyme lipoprotein lipase (LPL), and in reverse lipolysis is affected
by the enzyme hormone sensitive lipase (HSL). The expression of this
late enzyme is increased during very low calories dieting (3)
Adipose tissue function
Adipose tissue is essential for human survival and has many vital
functions:
• It has a major endocrine capacity through production of leptin,
adiponectin, and aromatisation of androgens to oestrogens.
• It is involved with energy reserve especially during times of
starvation. This can be affected through different means, but
especially so through the sympathetic nervous system. Lipolysis
to generate free fatty acids into the circulation is achieved by
stimulation of the β-adrenergic receptors, and is inhibited by
stimulation of α2A-adrenoceptors. Insulin also has an anti-
lipolytic effect.
• Various metabolic functions are affected through different
chemicals produced by adipocytes. Leptin reduces hunger and
food intake and acts as an antiobesity hormone. Together with
adiponectin and omentin, they promote insulin-stimulated
glucose uptake in the muscles and liver. On the other hand,
tumour necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) can
disrupt insulin signalling in skeletal muscles, leading to insulin
resistance.
It has already been discussed in Chapter 2 that puberty does not start
until a critical BMI with a certain adipose tissue mass has been attained.
This effect is an important one, since failure to attain such BMI on one
hand, or accumulation of excessive body fat on the other, can affect
normal development at puberty. The hormone leptin has been identified
as the main messenger to the brain to report adequate energy reserves
to facilitate the initiation of pubertal development.
Leptin is a protein hormone produced by adipocytes. It is made of 167

amino acids and is involved with regulation of appetite, energy
expenditure and maintenance of body weight by decreasing hunger and
178
food intake. Its involvement in reproduction has been highlighted by

the discovery of leptin receptors in the hypothalamus, pituitary gland,
ovaries and endometrium. It stimulates GnRH production by the
hypothalamus, and also acts directly at the pituitary gland to enhance
gonadotrophins production; LH more than FSH. Nonetheless, it has a
paradox effect at the ovarian level. In high concentrations it can inhibit
follicular development and steroidogensis (4). On the other hand, the
capacity of adipocytes to produce leptin is enhanced by oestrogens (5)
and suppressed by androgens (6). In this respect it can be appreciated
how adipocytes affect pubertal development and menstrual function
through production of extra or reduced amounts of leptin, depending on
the adipose tissue mass. Its blood level starts rising by the age of 7-8
years in girls and reaches a peak by the age of 13-15 years. This
corresponds to the time of onset of puberty, and the age at menarche
is inversely related to serum leptin levels. It has a permissive effect, but
does not trigger pubertal development. This was shown by the fact that
it can permit normal development at the appropriate age (7), but does
not stimulate early onset on puberty in young children (8). Its level was
found to shadow those of LH and oestradiol during the later part of
puberty, being lowest during the early follicular phase and peaks during
the luteal phase. Congenital absence of leptin (9), and leptin receptor
mutations (10) have been shown to prevent pubertal development.
Another important endocrine function of adipocytes is to convert

androgens to oestrogens. Aromatisation of androstenedione leads to
the production of oestrone which is a weak oestrogen. Nevertheless, it
can disrupt the function of the hypothalamo-pituitary-ovarian axis
(HPO), and causes anovulation when produced in excessive amounts.
With anovulation, continued exposure of the endometrium to oestrone
may result in endometrial hyperplasia and abnormal uterine bleeding
as well. Adipocytes also possess the enzyme 11β-hydroxysteroid
dehydrogenase type 1, which catalyzes the conversion of the inactive
cortisone into the active cortisol. This conversion can be excessive with
the accumulation of high cortisol levels in the adipose tissue, in obese
patients (11).
Other chemicals produced by adipocytes which can affect the endocrine

system or body homoeostasis in general include:
• Adiponectin is a 30 KDa protein which improves insulin sensitivity.
It also has anti-inflammatory and anti-atherosclerotic effects
(12). In vitro studies showed that it may inhibit GnRH and LH
secretion, but its main action is to increase insulin dependent
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ABDEL -GADIR
glucose uptake by the muscles and liver cells. This is affected by

decreasing serum free fatty acids and triglycerides, and by
suppression of hepatic glucose production (13, 14). A good review
about adiponectin has been published by Haluzík et al in 2004
(15), and will be summarised here. Fibronectin is the only
adipokine which has an inverse relationship to obesity. Normally,
its plasma level is about 1000-fold higher than leptin, but its level
is decreased in diabetics and insulin resistant patients. Few results
showed an inverse relationship between adiponectin plasma level
and BMI, triglycerides, as well as fasting and postprandial plasma
glucose concentrations. Adiponectin gene expression is reduced
by obesity, glucocorticoid, β-adrenergic agonists, TNFα, exposure
to cold and leanness. On the other hand, a positive correlation has
been shown between its plasma level and insulin stimulated
glucose disposal. Animal studies have shown promising results
that adiponectin replacement may be useful in the treatment of
insulin resistance and atherosclerosis.
• Plasminogen activator inhibitor- type1 (PAI-1) is the main inhibitor
of the fibrinolytic system. It is a glycoprotein which inhibits tissue
plasminogen activator (tPA), thus preventing the conversion of
plasminogen to plasmin and reducing fibrinolysis. This can increase
the risk of thrombus formation. Excessive increase in PAI-1 activity
is associated with venous thrombosis, cardiovascular disease,
recurrent miscarriage and other pregnancy complications. It is
produced more by visceral adipocytes than peripheral adipose
tissue, and is positively regulated by glucocorticoids. There is a
significant positive linear relationship between PAI-1 and 11β
hydroxysteroid dehydrogenase mRNA expression (11). Its level is
positively correlated to body fat mass, and is reduced by loss of
weight and metformin medication.
• TNF-α is important for fat metabolism, as it promotes lipolysis and
increases plasma free fatty acids. It is also involved with the
development of insulin resistance
• IL-6 can increase the production of the inflammation markers C-
reactive proteins, hence increasing the risk of thromboembolism.
It also has a negative effect on insulin signalling, which may lead
to insulin resistance as mentioned before.
Effects of adipose tissue location
In the context of this chapter adipose tissue location will be discussed

in relation to upper or lower body fat distribution. Upper body adipose
180
tissue includes areas above the waistline. This is divided into

subcutaneous (extra-abdominal) and visceral (intra abdominal)
distribution. Measurement of the waistline has already been alluded to
for the documentation of the visceral type. Lower body adipose tissue
distribution falls below the waist line, mainly in the hips and thighs.
The significance of this distinction in adipose tissue distribution relates

to the differences in the biochemical activities of the adipocytes in
these different areas. This is reflected by the fact that upper body
obesity is more of a male trait linked to androgenic profiles, whereas
women tend to have lower body obesity. Accordingly, the two types are
called android and gynaecoid obesity, respectively. This brings the issue
of BMI in focus again, as it can not distinguish between the two types.
Furthermore, as visceral adiposity is more significant in relation to
metabolic and reproductive abnormalities than global fat distribution,
care should be taken to ascertain the waistline circumference as a
routine procedure in all examinations.
Central obesity in women can lead to a hyperandrogenic state through

the following mechanisms:
• It can induce insulin resistance and hyperinsulinaemia, as well as
increase free fatty acids concentration.
• Hyperinsulinaemia can act directly at the level of the ovaries
increasing testosterone production, by acting as a co-gonadotrophin.
It can also increase the level of free androgens in circulation by
reducing hepatic production of sex hormone binding globulins
(SHBG).
• High free fatty acids (FFA) concentration can contribute to female
hyperandrogenism by causing insulin resistance, or by acting
directly on the adrenal glands without ACTH intervention, to
stimulate androgens production (16).
Unfortunately, central obesity and hyperandrogenism form a vicious cycle
in women, as androgens also promote central obesity (17). Androgens
were shown to induce lipogenesis through augmentation of the enzyme
lipoprotein lipase activity. In fact a direct correlation has been found
between free testosterone level in obese women and lipoprotein lipase
activity. Oestrogens on the other hand, have an opposite effect.
Postmenopausal women who have a low oestrogen/androgen ratio tend
to develop central obesity. This pattern is reversed in women using HRT
who usually maintain their gynaecoid premenopausal fat distribution
pattern (18).
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ABDEL -GADIR
General endocrine effects of adiposity
Before describing the clinical effects of excessive or reduced body fat on

human reproduction, a short account on the effects of body weight on
endocrine glands, other than the HPO axis, will be described.
Growth hormone (GH) levels have been found to be low in obese

patients, mainly due to reduced production by the pituitary gland. This
is valid both in the basal state, and after stimulation with growth
hormone releasing hormone, growth hormone releasing peptides and
arginine. This pattern was reversed by weight loss. The clinical
significance of this finding is not clear, as the level of insulin like growth
factor 1 (IGF-1) which is the main mediator of GH effects, is not
affected by obesity (19, 20). This last statement is not valid with
visceral obesity as the level of IGF-1 was found to be low, even in
patients with normal BMI.
Thyroid function has been scrutinised over the years in relation to BMI.
Hypothyroidism and hyperthyroidism may be associated with weight
gain and weight loss respectively. Accordingly, all obese patients and
women with excessive weight loss should have their TSH and free
thyroxine levels measured. On the other hand, no association has been
found between subclinical hypothyroidism and excessive weight gain,
though an exaggerated TSH response to TRH stimulation was seen in
many obese patients. Further information about the effects of deranged
thyroid function on the other endocrine glands can be found Chapters
3 and 11.
The relationship between the hypothalamo-pituitary-adrenal axis and

BMI has been studied intensively, because of the relationship between
Cushing’s syndrome and obesity. Nutritional obesity may be associated
with decreased level of cortisol binding globulin, increased level of urine
free cortisol, increased non ACTH dependent peripheral production of
cortisol, increased cortisol response to ACTH stimulation test, increased
ACTH pulse amplitude and decreased cortisol suppression after 1 mg
dexamethasone suppression test. In general there are fundamental
alterations in the function of the HPA axis with obesity. They include
increased sensitivity to stimulation, but decreased negative feedback or
reduced sensitivity to inhibition. The direct effect of free fatty acids on
the adrenal glands has been alluded to before.
The relationship between obesity and insulin resistance is a well

known fact. This is irrespective of the cause of the obesity itself. This
182
is especially so for the visceral type which is characterised by reduced

peripheral glucose uptake, and increased glucose production by the
liver. This will result in increased insulin production by the pancreas
which gradually fails with time. This may result in reduced insulin
production after a glucose load to start with and ultimately in the
basal state (21). The role of TNF-α, IL-6 and free fatty acids in
causing insulin resistance has been mentioned before.
It is evident from the above sections that body fat can affect different
hormones, but this is mainly so for visceral obesity. On the other
hand different hormonal dysfunctions can cause excessive deposition
of adipose tissue leading to obesity. The relationship between
hypothyroidism and obesity has already been mentioned. Cushing’s
syndrome is another example leading to central obesity. Other rare
conditions include insulinomas and neuroendocrine tumours.
Clinical implications of high and low BMI
The effects of BMI on the reproductive endocrine system span from

puberty to the postmenopausal period. The effects of obesity will be
addressed first in relation to the different stages of life.
Childhood and pubertal obesity
It has already been mentioned that onset of puberty depends on the

presence of a critical adipose tissue mass. Underweight girls may fail
to start their pubertal development, or have a delayed onset with
incomplete development. Increasing body weight has been shown to
reverse this pattern. The role of leptin in this context has been shown
by the successful increase in GnRH pulsatility in low weight women
with hypothalamic amenorrhoea, after administration of recombinant
leptin (22).
On the other hand childhood obesity may be associated with early onset
of pubertal development. At the same time, excessive teenage obesity
can lead to oligomenorrhoea or even amenorrhoea following an early
menarche. This is occasionally seen in patients with the polycystic ovary
syndrome (PCOS). More seriously, adolescence obesity has been
associated with increased likelihood of lifelong nulliparity, in comparison
to women with normal adolescent BMI (23). An earlier cohort study
showed that obesity at the age of 7 years was associated with increased
risk of irregular menstruation at the age of 33 years, stressing the
importance of childhood obesity (24).
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ABDEL -GADIR
Adulthood obesity
Adulthood obesity can lead to anovulation problems and dysfunctional

uterine bleeding which are mediated through increased insulin level,
hyperandrogenaemia and deranged gonadotrophins secretion.
Excessive leptin production has also been shown to have a detrimental
effect on follicular development and steroidogensis (4). Other
mechanisms which can affect the function of the HPO axis in obese
patients include:
• Disturbed prolactin secretion;
• Increased level of endorphins;
• Increased level of dopamine and opioids;
• Increased oestrone level due to increased androgens
aromatisation;
• Low SHBG resulting in high free androgens levels.
An important reason for failed induction of ovulation with clomiphene
citrate is obesity. The higher the body mass index, the higher the
dose of clomiphene citrate needed. It is also a general observation
that overweight and obese women usually need higher doses of
gonadotrophins for a longer period of time to induce ovulation, with
inadequate response. There is also a higher risk of cycle cancellation
and lower oocytes retrieval rate among obese women within an IVF
programme (25)
Despite the universal agreement on the detrimental effects of obesity

on anovulation, contradictory literature has been published about its
risks on infertility, recurrent miscarriages and other obstetrical
complications. This may be due to the following reasons:
• The clinical significance of the BMI ranges set by the WHO is
different in different ethnic groups.
• The effects of central and peripheral obesity are not usually
separated during assessment of the different reproductive risk
factors related to obesity.
• The initial cause of obesity may not be taken in consideration in
different reports e.g. hypothyroidism, PCOS or adrenal enzymatic
deficiency.
• The different effects of obesity in nulliparous and parous women in
relation to pregnancy outcome have only been ascertained recently.
Higher risks of elective preterm operative delivery, perinatal mortality
and long term disability have been shown in obese nulliparous, but
not parous women in a retrospective cohort study (26).
184
Many articles have also documented reduced fertility potential in obese

women with regular menstrual cycles, and the need for prolonged time
to achieve a pregnancy (27- 29). This was quantified by one study
which showed 4% decline in the probability of natural conception per
kg/m2 in women with BMI >29 kg/m2 (30). Furthermore, a 30%
decrease in average cycle fecundity was found for 0.1 unit increase in
waist / hip ratio in women undergoing donor insemination (31). Some
controversy exists on the effects of obesity on IVF outcome. The
general impression is that obese women needed larger doses of
gonadotrophins for longer duration, with a smaller yield of oocytes.
Embryo quality is not affected by obesity, with inconsistent results on
clinical pregnancy rate.
The detrimental effects of obesity on pregnancy outcome have been

shown by many publications, and have been reviewed by the ASRM
Practice committee in 2008 (2). This included early pregnancy loss, and
later obstetrics complications. The relationship between miscarriage
rate and BMI has been demonstrated by a meta-analysis of 16 studies
which documented 67% increased miscarriage risk in overweight
women in comparison to women with normal BMI (32). Other problems
related to a BMI >30 kg/m2 included pre eclampsia, gestational
diabetes, and caesarean section (33). With severe obesity and a BMI
>40 kg/m2, increased obstetrics risks also included hypertension, large
for gestational age infants, meconium aspiration, shoulder dystocia,
fetal distress, stillbirth and early neonatal death (34, 35). Furthermore,
obesity has been associated with increased birth defects. Neural tube,
ventral wall and cardiac defects and multiple congenital anomalies were
found to be significantly increased (36). In addition it has been reported
that the usual fortification of folic acid did not reduce the incidence of
neural tube defects in obese women (37).
It is evident that obesity affects reproductive function through

anovulation and infertility, as well as increased miscarriage, stillbirth
and neonatal death rates. Accordingly, it has been recommended that
women with a BMI >35 kg/m2 should not be offered fertility treatment.
Ideally this figure should be reduced to 30 kg/m2, as all the
complications mentioned above were still significantly high below that
level. This recommendation is not usually heeded as many obese
women are not infertile, and infertile patients always raise this point
during consultation, when asked to reduce their weight first. The other
problem with obesity is that slight reduction in weight of 5-10% may
induce ovulation and regular menstrual function, despite the patient
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ABDEL -GADIR
being still within the obese or even gross obesity range. The difficulty
here is that any pregnancy will still be at risk of all the complications
mentioned before. Accordingly, a suggestion has been made that
grossly obese and obese women should use barrier methods of
contraception while losing weight till they attain an acceptable BMI
(38). As most complications were more significant in nulliparous than
parous women, the pressure of infertility and urgency to conceive will
make this suggestion difficult to implement, though it is scientifically
sound.
A change in life style rather than dieting is more appropriate to lose

weight, and to prevent rapid regain of the adipose tissue. This should
be affected by regular exercise, increased every day routine activity,
and walking or cycling instead of using the car or public transport for
reasonable distances. The advice of a dietician should be sought to help
with healthy eating, and to prevent consumption of high carbohydrate
food. Insulin resistant patients may find it difficult to lose weight.
Metformin can be used to control this problem and to allow better
utilization of glucose by the muscles, and to reduce gluconeogenesis. It
can also cause modest weight loss when used in high doses, with an
average of 5 kg over 8 months period (38). Better results were
documented for orlistat (Roche) which helped with 5% weight loss in 3
months, compared to 1% for metformin (39).
The effects of obesity in older women have gained notoriety because of

its association with the development of type 1 endometrial carcinoma
(40). Beside the sustained production of oestrone by the adipose tissue,
obesity is also associated with anovulation, nulliparity and
hyperlipidaemia, which are also considered as risk factors for the
development of endometrial carcinoma. Diabetes mellitus and
hypertension are two other risk factors closely related to obesity as
well. Nonetheless, no correlation has been found between obesity or
skin fold thickness and the age of onset of the menopause. On the other
hand, lean postmenopausal women are more likely to develop
osteoporosis than overweight ones. This can reflect reduced peripheral
oestrogen production, which is the major source for postmenopausal
oestrone, in the former group.
Effects of low BMI
A body mass index <18.5 kg/m2 has been described as low by the WHO
(1). Many medical and reproductive abnormalities have been
associated with such low body weight. In a reproductive function
186
context, reduced adipose tissue mass has been associated with absent
or delayed puberty, anovulation and menstrual dysfunction, infertility
and obstetrics complications as well.
Though anorexia nervosa comes to mind first, many underweight

women do not fit that diagnosis. Excessive exercise, malnutrition and
chronic illnesses can also contribute to the spectrum of the problem.
Furthermore, the extent of reproductive failure depends on the extent
of adipose tissue loss, as well as the psychological predisposition of
the individual patient. With malnutrition and chronic illnesses,
attainment of near normal BMI may lead to resumption of menstrual
function. This is not usually the case in patients with anorexia, due
to the dominant psychological block of the HPO axis. On the other
hand, professional women athletes may regain their menstrual
function, without putting on weight, during the closed season and
when injured and out of action. This emphasises the predominant
effect of stress in these cases, but the discriminating line here is very
vague as professional athletes usually have the triad of amenorrhoea,
eating disorder and psychological stress.
The major condition related to extreme weight loss and loss of

adipose tissue is anorexia nervosa which affects up to 1% of
adolescents (41). The diagnosis relies on demonstrating the following
points:
1. Disturbed body image;
2. Intense fear to gain weight;
3. Starvation;
4. Amenorrhoea.
An important consequence of this condition is the loss of bone
density, which can lead to osteoporosis and the risk of bone stress
fractures. As the maximum bone density is usually attained by the
age of 20 years, these patients lead a life with low bone density
despite using HRT and calcium supplements. One study suggested
that using dehydroepiandrostenedione may have a positive effect on
bone turnover (42).
Despite the major endocrine effects of anorexia nervosa, the condition

remains to be a psychological one and should be treated as such.
Management should aim at dietary advice, personal and family
counselling, advice on behaviour modification, as well as individual and
group psychotherapy. Hormone replacement therapy (HRT) to
counteract the effects of the severe hypo-oestrogenic state, especially
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ABDEL -GADIR
osteoporosis is indicated. This can be in the form of dedicated HRT

combination drugs, or as an oral contraceptive pill. Anti depressant
treatment is necessary in severe cases suffering from depression.
Ultimately, hospital admission may be necessary to save the patient’s
life with forced feeding.
Summary
This chapter was meant to deal with the inter-relationship between

adipose tissue and reproductive function, without laying much
emphasis on the metabolic and general health issues. It is clear that fat
cells have a major endocrine role during the whole life span of women
from the onset of puberty through the reproductive years, up to the
postmenopausal age. Thorough understanding of the endocrinology of
the adipose tissue and its chemical products leptin, ANF-α, IL-6,
fibronectin, free fatty acids on the HPO axis, HPA axis, insulin and
hepatic function is necessary for the Reproductive Endocrinologist.
Appreciating the differences in the detrimental effects of central vs.
peripheral obesity will also improve our understanding of the effects of
obesity in reproductive function. This is currently clouded by the
indiscriminate use of the BMI in research projects which lead to many
discordant results.
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2004; 19: 2523 - 2528.
26. Smith GC, Shah I, Pell JP, Crossley JA and Dobbie R (2006).
Maternal obesity in early pregnancy and the risk of spontaneous
and elective preterm birth: a retrospective cohort study. Am J
Public Health 2007; 97 (1): 157 - 162
27. Gesink Law DC, Maclehose RF, Longnecker MP. Obesity and time to
pregnancy 2007; 22: 414 - 420.
28. Jensen TGK, Scheike T, Keiding N, Schaumburg I and Grandjean P.
Fecundity in relation to body mass and menstrual pattern.
Epidemiology 1999; 10: 422 - 428.
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Body mass index and delayed conception: a European multicentre
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30. Van de Steeg JW, Steures P, Eijkemans MJ, Habbema JD, Hompes
PG, Burggraaff JM, Oosterhuis JE,. Bossuyt PMM, van der Veen
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VrieswijK B and Karbaat J. Fat and female fecundity: prospective
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index increase the risk of miscarriage after spontaneous and
assisted conception? A metaanalysis of the evidence. Fertil Steril
2008; 90: 714 - 726.
33. Dokras A, Baredziak L, Blaine J, Syrop C, Van Voorhis BJ
and Sparks A. Obstetric outcomes after in vitro fertilization in
obese and morbidly obese women. Obstet Gynecol 2006; 108:
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Maternal obesity and risk of adverse pregnancy outcome.
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Chapter 9
The Climacteric, Menopause and HRT
The climacteric
The climacteric is the period of time which precedes the final cessation
of menstruation, and may last for 1-10 years. It indicates a gradual
decline in ovarian function and reproductive capacity during the late
30s and early 40s, even in women with regular menstrual function. In
contrast to puberty, which represents the development of reproductive
capability, the climacteric signifies the beginning of the end of that
capability.
Both ovarian and hypothalamic ageing have been documented as

causes for the onset of the climacteric period. Few related endocrine
changes can be seen during the late thirties and early forties:
1. The earliest changes reflect the gradual decline in the number of
preantral and small antral follicles. The level of antimullerian
hormone drops first, followed after some time by reduction in
inhibin B production. This later change reduces the inhibitory
effects on the hypothalamus and pituitary gland, leading to
increased production of follicle stimulating hormone (FSH). There
are no significant changes in the levels of oestradiol, inhibin A or
luteinising hormone (LH) at this early stage.
2. Higher levels of FSH start rising earlier during the luteal phase of
the cycle, resulting in early recruitment of follicles for the
subsequent cycle, even before the start of menstruation in the
current one. Accordingly, the recruited follicle will be more
advanced during the early follicular phase of the subsequent
cycle, and will only need a short period of time to attain full
maturation. This leads to a short follicular phase and
polymenorrhoea, which are early signs of incipient ovarian
failure. The level of oestrogen may be high during the whole cycle
in some cases, with the possibility of luteal phase dysfunction.
The increase in FSH level usually affects few cycles only initially.
More cycles will be slowly affected, till ultimately a high FSH level
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becomes detectable in all cycles. This can still happen while the
patient has regular menstruation.
3. With further decrease in the number of follicles, excessive FSH is
produced coupled with slower response by the remaining less
sensitive ones. This results in a longer follicular phase,
inadequate ovulation, and occasionally dysfunctional uterine
bleeding. The cycles become less frequent and anovulatory over
time, before total cessation of menstruation.
Coinciding with the decline in oocytes numbers, cytogenetic studies and
in vitro fertilisation treatment cycles showed the following problems:
• Abnormal arrangement of the chromosomes on the myotic spindle
in metaphase II oocytes;
• Increased incidence of aneuploidy in the resulting embryos.
Independent of ovarian aging, changes in the negative feedback
mechanism due to hypothalamic ageing have also been suspected to
occur in regularly menstruating women in their late 30s and early 40s.
This can initiate or at least be a contributing factor to the high FSH
levels documented during the early follicular phase in these women.
Certain observations have been mentioned in support of this point:
• Changes in the level of inhibin B and oestradiol do not explain
changes in the level of FSH in all women in their late thirties and
early forties who have regular menstrual cycles;
• The occurrence of hot flushes in women between the ages of 35-
40 years despite having regular cycles and normal oestradiol
level;
• Failure of the pituitary gland to respond to an oestrogen challenge
test with LH surge is a common observation in women during the
climacteric period (1);
• Reduced LH pulse frequency and increased pulse width during the
mid follicular phase in regularly menstruating women in their
forties can be related to changes in the negative feedback
mechanism, and partly explain the age related changes in
reproductive potential (2).
The menopause
Natural menopause is a term used in retrospect to indicate the last

menstruation, one year after its occurrence in women >45 years of
age. In contrast to puberty, the age at menopause has not changed
over the last century and remained stable in different communities
and families. In western countries, the average age at the
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menopause is 51 years. Permanent cessation of menstruation before

the age of 40 or 45 years is termed premature and early menopause
respectively. Nonetheless, the term premature menopause is not
acceptable by many patients, and can be medically incorrect as will
be discussed in Chapter 10. On the other hand, surgical menopause
can occur when the ovaries are removed, at any time, before the
average age of natural menopause.
Certain factors have been documented to affect the age at which the
natural menopause may occur. A woman’s age at menopause is very
much affected by the age her mother reached the menopause,
reflecting the importance of genetics in this respect. This familial trait
has been supported by twins’ studies. Smoking, lower educational
attainment, being separated, divorced or widowed, unemployment and
history of heart disease have been reported to be independently
associated with earlier natural menopause. On the other hand, parity,
prior use of oral contraceptives and Japanese race/ethnicity were
associated with a later age at natural menopause (3). Similarly, a
multiethnic study which involved 103,893 women in 2008 (4) showed
that race/ethnicity was a significant independent predictor of the timing
of natural menopause. All other factors including smoking, age at
menarche, parity and body mass index did not significantly alter the
effect of race/ethnicity-specific hazard ratio. This is agreeable with a
previous report which showed that all lifestyle and reproductive factors
explained the difference in age at natural menopause in less than 10%
of the cases, after studying 2182 twin pairs (5). Accordingly single
ethnic group studies are liable to miss this important effect of
race/ethnic origin.
Despite all the research conducted in this field of reproductive

endocrinology, there are no set reliable biochemical criteria to predict
the exact age at the menopause. Measuring early follicular phase FSH
levels is useless in this respect, as high levels can be detected many
years before the menopause. This test may be useful in showing a low
ovarian reserve and fertility potential, when a high level is reported.
Even in this context, a normal level in women in their late thirties does
not indicate normal fertility potential. The following general points have
been found to be helpful in predicting an early menopause:
• Maternal history of early menopause;
• Twelve or more months of amenorrhoea at or beyond the age
of 45 years is associated with 90% chance of no further
menstruation;
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• History of 3-11 months of amenorrhoea at or beyond the age of

45 years is associated with 95% chance of the menopause within
4 years,
• Poor response to controlled ovarian hyperstimulation at the first in
vitro fertilisation (IVF) treatment cycle has been associated with a
higher risk of early menopause (<46 years), in comparison to
women who developed more than 3 follicles (6, 7).
Endocrine changes associated with the natural menopause

Androgens
The menopause is followed by a hypoestrogenic state due to ovarian

failure, with peripheral adipose tissue producing a major fraction of the
circulating oestrone, which is the main oestrogen in this age group. This
depends on the BMI of the individual patient. There is little progressive
decline in adrenal androgens production after the menopause, following
the maximum decline which occurs between the ages of 20 - 40 years.
This results in 70-80% reduction in dehydroepiandrosterone (DHEA)
production rate by the age of 70 years (8). This decline in adrenal
androgens production is not matched by any decline in cortisol
production as reported by Liu et al in 1990 (9). They found
decreased DHEA/17-hydroxypregnenolone and androsdenedione/17-
hydroxyprogestgesgterone ratios which they attributed to decreased
17, 20-desmolase enzymatic activity. Furthermore, they attributed the
decline in DHEA blood levels to reduced pulse amplitude without any
changes in its circadian (daily) or ultradian (pulse frequency) secretion
patterns. On the other hand, ovarian androgens production normally
decline over the reproductive years with the maximum decline rate
being just before the menopause (10). There is 50% reduction of the
daily production rate of androstenedione mainly from the ovaries, with
the adrenals being the main source in postmenopausal women. There
is also a small decline in the level of sex hormone biding globulin
(SHBG), but not significant enough to affect the free androgen index.
DHEA forms the main circulating androgen during the postmenopausal
period, and it is readily converted to oestrogen and testosterone. This
forms the theoretical background for using it as a food supplement after
the menopause to provide a form of hormone replacement therapy, and
as an anti-aging agent as well.
Thyroid indices
Thyroid gland dysfunction is also more frequent during the late

reproductive years, and after the menopause. Women are almost 8
196
times more likely to have such problems in comparison to men of the

same age group. Clinical and subclinical thyroid diseases have been
reported in 2.4% and 23.2% of postmenopausal women respectively
by Schindler in 2003 (1). Among those with the subclinical disease,
73.8% were hypothyroid and 26.2% were hyperthyroid. Accordingly,
this same author recommended routine screening of thyroid function
in the climacteric period to determine subclinical thyroid diseases.
This is especially so as subclinical hypothyroidism may be associated
with dislipidaemia in the form of high total cholesterol, high low
density lipoprotein (LPL) cholesterol, and low high density lipoprotein
(HDL) cholesterol. Such a deranged lipid profile can increase the risk
of cardiovascular problems in these patients. The risk is also
increased because of the reduced oestrogen / androgen ratio.
Oestrogen medication can affect the thyroid status by increasing the
level of thyroxine binding globulin (TBG); hence reducing the level of
free thyroxine in circulation. This may aggravate problems in women
with subclinical hypothyroidism. Conversely, transdermal HRT has no
similar effect on TBG, as it has no first hepatic pass and should be
used by patients with hypothyroidism on HRT. On the other hand,
hyperthyroidism has a detrimental effect on bone density, and can
induce osteoporosis. This effect has been documented even in healthy
postmenopausal women with persistently low normal thyroid
stimulation hormone (TSH), by Kim et al in 2006 (12). The same
authors suggested that low normal TSH levels may not be
physiological for postmenopausal women, and during treatment of
hypothyroidism, and may not be adequate for avoiding osteoporosis.
Changes in LH dynamics
Beside the changes in FSH level alluded to before, more subtle

changes have also been documented in LH secretion. Increased LH
pulse frequency and amplitude have been documented during the
luteal phase of the cycle during the late reproductive years. Different
reports documented changes or no changes during the follicular
phase. Nevertheless, the evidence is more compelling towards
decreased LH pulse frequency and amplitude during the mid follicular
phase in older women during their reproductive years (2). This was
attributed on one side to ageing or enhanced hypothalamic-pituitary
negative feedback mechanism, or to increased oestradiol level at that
point of the cycle. This later point can be a reflection of the rapid
recruitment and larger follicles occasionally seen during the early part
of the cycle in women with polymenorrhoea, as alluded to before.
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Eventually, elevated LH levels throughout the cycle are observed in

ovulatory women by the age of 45 years (13).
Changes in body habitat
A noticeable observation is the change in body composition during the

late climacteric period, and after the menopause. This is manifested in
the form of central obesity which may be due to:
1. Reduced oestrogen / androgen ratio favours an android or central
body fat deposition, which can be reversed by oestrogen
medication.
2. Decreased energy expenditure due to
a. Reduced resting metabolic rate;
b. Decreased physical activity;
c. Higher risk of hypothyroidism.
Postmenopausal symptoms
Following the menopause oestrogen withdrawal symptoms can be

acute, intermediate or delayed. The most distressing symptoms are the
acute ones which can affect the patients’ quality of life, but the delayed
ones carry more long term medical risks.
Acute symptoms
Nearly 80% of postmenopausal women experience acute symptoms

which can be vasomotor or psychological in nature, but not all of
them seek medical advice. The two main vasomotor symptoms are
hot flushes and night sweats, but many women may present with
headaches, palpitations and fainting attacks. A wide range of
psychological symptoms can be seen including depressed mood, sleep
disturbance, mood swings, lack of concentration, loss of memory,
fatigue and anxiety state. Many younger women in their late thirties
and early forties, who have regular menstrual cycles, may also have
oestrogen deficiency symptoms mainly premenstrually. It is important
to exclude other medical conditions which can give similar symptoms,
especially in patients not responsive to HRT. Such conditions include
anaemia, sleep apnoea, panic attacks and hyperventilation, thyroid
dysfunction, clinical depression, diabetic autoimmune dysfunction,
carcinoid syndrome and phaeochromocytoma.
Hot flushes make the most important and distressing acute vasomotor
symptom, which can affect patients’ lives negatively in many ways.
198
They may be associated with night sweats which disturb the patient’s
sleeping pattern, leading to fatigue and inability to perform every
day life duties. Nearly 20% of women can be badly affected and will
need medical help. Though they are mainly related to oestrogen
withdrawal, oestrogen levels have not been found to be significantly
different in women with and without hot flushes (14). Furthermore,
stimulation of the sympathetic nervous system can also start an
episode of hot flushes, indicating its importance in this respect. In fact
increased catecholamines production in the brain has been documented
in women during episodes of hot flushes (15). Sociocultural factors are
most likely involved as well, as the incidence of hot flushes was
reported as 82% in American women (16), 60% in Swedish women
(17), with yet lower figures in developing countries (18). More recent
publications almost duplicated this trend. The effect of ethnic origin has
also been shown by an article published by Monterrosa et al in 2009
(19). They found that impairment of quality of life in postmenopausal
women varied according to race in different Columbian groups.
Urogenital symptoms were more severe in indigenous and black
women, whereas somatic and psychological symptoms were more
severe in Hispanics.
Each hot flushing episode may last 1-5 minutes, but can be longer. The
patient feels warmth or heat in the face, shoulders and neck area
depending on the severity of the attack. This may be associated with
reddening of the skin and profuse sweating, which corresponds to the
distribution of the cervical sympathetic trunk. Such visible changes are
usually seen in approximately 50% of the patients. It is usually followed
by feeling cold and shivering. The intensity of the symptoms varies
between women, and at different times in the same woman. In general,
surgical menopause is usually associated with more severe symptoms
than the natural one. Prolonged and repeated flushing episodes may
lead to telangiectasia and classical rosacea of the face (20).
Occasionally, symptoms may follow intake of spicy food or caffeine, hot
bath or shower, cigarette smoking, alcohol consumption, and anxiety
state. Women perception of the menopause and its implications on
health, family relations and sexuality depends on their cultural
background and own personality. This may have direct bearing on their
coping abilities, and how they react to oestrogen deficiency symptoms.
Other predisposing factors include family history of hot flushes, and a
high body mass index. Episodic hot flushes may last for up to 5 years
in 65%, 6 – 10 years in about 25% and >11 years in 10% of affected
postmenopausal women.
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The exact causes for hot flushes are still speculative and many factors
have been implicated. In a recent review in 2009, Andrikoula et al (21)
discussed few possible factors related to women predisposition to hot
flushes.
• The mean blood pressure was found to be higher in women who
had hot flushes than in those who did not have similar episodes.
This is despite of the fact that the blood pressure may drop during
the episodes themselves.
• Furthermore, postmenopausal women with hot flushes were
found to have higher electrodermal activity during stress.
• Lower total plasma antioxidant activity, lower concentration of
reduced sulfhydryl groups, and higher plasma concentration of
lipoperoxides have also been found in women who had hot
flushes, compared to those who were not similarly affected (22).
All these factors are known to increase cardiovascular disease risks in
women with hot flushes. A recent report by the Women’s Health Across
the Nation Heart Study (23) showed that women who had hot flushes
had reduced brachial artery flow-mediated dilation, and greater aortic
calcification.
Control of body temperature
Body temperature is controlled by thermoregulatory means of

neuroendocrine and autonomic structures that keep the core body
temperature within certain range of threshold values (24). The upper or
‘sweating’ threshold is involved with release of heat, and the lower or
‘shivering’ threshold with heat conservation and renewed production.
These thresholds maintain the thermoneutral zone (25), which is
regulated by different parts of the central nervous system (CNS),
including the spinal cord, brain stem, limbic system and the preoptic
area of the hypothalamus. The initial impulses about body core
temperature are sent by sensors found in different parts of the body,
including the spinal cord, intra-abdominal veins and the gastrointestinal
tract. The final role is played by peripheral blood vessels which dilate or
constrict to lose or preserve heat respectively, in response to impulses
form the CNS. This system is modulated by serotonergic and
noradrenergic impulses. Hot flushes occur when the core body
temperature increases above the sweating threshold, which leads to
peripheral vasodilatation with increased blood flow to lose heat. On the
other hand, when the core body temperature falls below the shivering
threshold, peripheral vasoconstriction leads to heat conservation within
the body. The question to ask now is why some and not all women have
200
hot flushes, and to different degrees of intensity? It has been suggested

that women prone to hot flushes have a narrow thermoregulatory zone
(core body temperature range), at which neither sweating nor shivering
occurs (24). This zone may be further narrowed by sympathetic
stimulation, which explains why stressful stimuli bring about hot flushes.
On the other hand, drugs that suppress the sympathetic tone widen this
zone. A similar effect is also caused by oestradiol. (26). The differential
diagnosis of vasomotor symptoms includes anxiety state, thyrotoxicosis,
carcinoid syndrome and phaeochromocytoma. Accordingly, usual
medical acuity should be exercised to exclude these possibilities before
assuming oestrogen deficiency symptoms, especially in younger
women. Older symptomatic women not responding to HRT should also
be investigated for these possibilities. Twenty four hours urine 5-HIAA
(5-hydroxyindolacetic acid) should be measured in suspected cases of
carcinoid syndrome. False negative results are not uncommon, as the
excretion rate is variable, and the test may need to be repeated. On the
other hand, false high urine 5-HIAA can be caused by certain types of
food including bananas, pineapples, coffee and chocolates. Suspected
cases of phaeochromocytoma should be investigated with plasma and
24 hour urine catecholamines and metanephrines. These tests have got
certain limitations. Catecholamines have got short half-life which may
lead to a false negative result if a single assay is performed during
intervals between surges of high blood pressure (27). Accordingly,
measurement of metanephrines is preferred as they act as direct tumour
markers and indicators of catecholamine release (28). Inaccuracy of 24
hour urine collection can lead to false positive and false negative results,
if the collection time exceeded or was less than 24 hours respectively. In
a recent study Lenders et al found plasma metanephrines measurement
had 100% sensitivity for diagnosing phaeochromocytoma, compared to
89% for the urinary products (29). This discrepancy caused by problems
with urine collection was corrected by measuring the urinary
metanephrines-to-creatinine ratio, which improved the sensitivity to
100% (28).
Intermediate symptoms
These symptoms usually occur within 1-3 years after the menopause,
and about 50% of women may have them by the 5th – 8th year. They
are mainly related to loss of skin and joints collagen and urogenital
atrophy; the later one being more distressing.
Prolonged lack of oestrogen can lead to atrophy of the vaginal skin and
the area of the vestibule, and may affect 60% of postmenopausal
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women. This figure may be an underestimation of the real incidence, as

it is usually an under diagnosed and inadequately treated condition
(30). It can lead to burning sensation, irritation and rawness which may
affect sexual relationship. Superficial dyspareunia can be a real
problem, which can progress to vaginismus, loss of libido and
apareunia. A figure of 32% has been quoted for women who lost sexual
relations because of vaginal skin dryness and atrophy (31). The
problem can be magnified by atrophy of the epithelium covering the
urethra and trigone, as they share an embryonic origin with the lower
vagina from the urogenital sinus. This can lead to increased frequency
of micturition, and other voiding problems. Unlike hot flushes,
symptoms of vaginal atrophy tend to get worse with time and may show
for the first time 10 years after the menopause. Some statistics have
been reported by Dennerstein et al in 2000 (32) in relation to the
development of vaginal dryness. They quoted an incidence of 3% in
perimenopausal women, and 21% and 47% incidence one and three
years after the menopause respectively.
Sexual dysfunction in mid-life women has also been positively

correlated to depressive symptoms and poor general health. It is
remarkable that women who showed higher total testosterone and
free testosterone index, but not oestrogen, had better sexual drive
and relationship (33). This may justify the use of testosterone
supplements to improve this aspect of patients’ lives. Intrinsa (Procter
and Gamble) transdermal patches can be used every 3-4 days, and
provide 300 μg testosterone every day. Patients should be warned
against androgenic side effects which can be permanent. Other adverse
effects include migraine headaches, insomnia, weight gain and breast
tenderness.
Changes in collagen fibres can affect tendons tensile strength, leading

to painful joints on movement. This is usually a neglected problem,
and occasionally a diagnosis of arthritis is made. Certain women are
liable to lose their skin moisture and elasticity more than others,
which results in wrinkles and premature ageing. This can have
devastating psychological effects. Skin ageing is usually affected by
many factors being genetic, environmental or hormonal. Natural or
intrinsic ageing is usually characterised by smooth pale finely
wrinkled skin, and dryness. On the other hand, photo-ageing which
follows excessive exposure to the sun is characterised by severe deep
wrinkles, as well as pigmentation changes, such as solar lentigo and
mottled pigmentation (34). A woman in her 50s may look much older
than her siblings, especially those on HRT which is known to preserve
202
skin moisture, as well as collagen and elastic tissues integrity.

Nevertheless, the last author (34) questioned the use of HRT for the
sole indication to prevent or reverse skin ageing. This view may well
change with time, especially as topical conjugated oestrogen cream
medication resulted in significant improvement of fine facial wrinkles
in postmenopausal women (35). Beside the cosmetic issues, decrease
in skin collagen and thickness have been found to correspond to
reduction in bone mineral density (36). Accordingly, it can be used as
an early indication for investigating bone density, to pre-empt future
osteoporosis.
Long term effects of oestrogen deficiency
The two main problems in this group are osteoporosis and coronary
heart disease (CHD). The mostly affected bones are the femur neck and
vertebral column. Long term hypo-oestrogenism can be complicated
with femoral neck and vertebral crush fractures, as well as wrist and
Colles fractures. It is estimated that 1 in 7 postmenopausal women
sustain a fractured neck of femur. Furthermore, 40-50% will sustain
such a fracture before the age of 75 years. The serious point about
these statistics is that about 3 of 5 postmenopausal women will not lead
an independent life after a fractured hip, and there is 20% mortality
within one year. This is on top of the large expenses necessary to care
for these women. With advancing years after the menopause,
osteoporosis gets worse but more so in the following groups of patients:
• Family history of osteoporosis;
• Low peak bone mass by the age of 20 years;
• Early age at the menopause;
• Low production of oestrone by adipose tissue in underweight
patients;
• Cigarettes smoking;
• Excessive alcohol intake;
• Sedentary life style;
• Prolonged used of corticosteroids;
• Subclinical hyperthyroidism.
The relationship between osteoporosis and hypo-oestrogenism can be
related to excessive parathyroid hormone activity, and reduced
calcitonin secretion with increased osteoclastic activity. Oestrogen
counteracts parathyroid hormone and 1, 25 dihydro vitamin D bone
resorbing action. It also stimulates calcitonin secretion. On the other
hand, oestrogen receptors are found in bone. Accordingly, it can act
directly by increasing proliferation of osteoblasts through production of
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IGF-1 and TGF-β, and inhibits osteoclasts differentiation from their

bone marrow precursors.
The other important effect of long term oestrogen deficiency is on

cardiovascular disease (CVD), which accounts for 1 in 4 deaths in women
after the age of 50 years. There are more deaths from breast cancer in
women under the age of 50 years than from strokes and ischaemic heart
disease combined. This pattern is reversed after the menopause.
Furthermore, the life time risk of death from heart attacks, stroke and hip
fractures is greater than the risk of death from breast cancer. The risk of
CVD increases with time, irrespective of the age when the menopause
occurred. However, endothelial-dependent vasodilatation usually
deteriorates after the menopause and attains similar levels to older men
by the 6th decade of life (37). This follows a significant decline in the
oestrogen protective effect on vascular endothelial function, which is a
critical factor in causing CVD. Oestrogen modulates endothelial function by
enhancing nitrous oxide (NO) release and by promoting vasodilatation
(38). The postmenopausal state is also associated with higher levels of
inflammation markers including interleukin-6 (IL-6) and tumour necrosis
factor-α (TNF-α), as well as reduced antioxidants which indicate increased
oxidative stress (39). Many other factors increase the risk of CVD including
obesity, high blood pressure, diabetes mellitus, smoking, raised
triglycerides and LDL cholesterol and reduced HDL cholesterol levels.
Management
It is clear that quality of life can be affected in different ways at

different stages of the climacteric and postmenopausal periods. This
is a distressing situation, as more women now live well beyond their
70th birthday. Such a long life is associated with increased risk of
postmenopausal medical problems. Central obesity and its
detrimental effects on CVD have already been alluded to. On the
other hand, there is a tendency for blood pressure to increase with
age in women. By the age of 69 years, almost 80% of women have
hypertension (40). Even a high normal blood pressure of 140/90 is
associated with increased risk of CVD, and small reductions in blood
pressure result in major reduction in CVD risk. In mathematical
terms, it has been suggested that reduction of 10 mm Hg in systolic
pressure during the menopausal transition results in 25% reduction
in cardiovascular events. It is evident that many factors can be
addressed to reduce the risk of CVD through changes in life style,
loss of weight, regular exercise, strict control of diabetes and high
blood pressure.
204
It is unfortunate that a lot of confusion has clouded the management of

the menopause with HRT, because of much publicised increased risk of
breast cancer, and coronary heart disease. This is partly due to the
initial conclusions drawn from the Women Health Initiative Study (41),
and other similar publications. Unfortunately, the medical profession
fell into the traps set by the Media, and magnified the negative points
in these reports, in spite of the known flaws with those studies. Many
young women, even those with premature ovarian failure have been
deprived of HRT, and are leading miserable lives. Alternative remedies
of unquantified benefits found the right void in the market to fill, and
understandably their unproven alleged safety has been magnified by
the selling vendors.
Many well balanced articles have been published to put things into their real
perspective in relation to HRT use. In 2008 an expert group (42) published
important key practice points, in relation to HRT use. They suggested that
the risks involved with HRT should be conveyed in absolute numbers rather
than percentages. Furthermore, they recommended HRT for young
postmenopausal women to maintain quality of life, and for primary
prevention of cardiovascular risks. They even recommended testosterone
supplementation for women with hypoactive sexual desire disorder (HSDD)
and unexplained tiredness. Regarding breast cancer risk, they suggested
that young postmenopausal women who are about to start HRT for the first
time should be counselled that breast cancer risk does not increase for the
first 7 years. They also stated that unopposed oestrogen replacement
therapy for hysterectomised women does not increase breast cancer risk,
and may even lead to a small reduction in the risk. On the other hand, they
stated that phytoestrogens and herbs are less effective than classical HRT,
and their quality control is questionable. It is important here to reiterate the
beneficial antioxidant and anti-inflammatory effects of oestrogen alluded to
before. Furthermore, adequate exposure to oestrogen during the
menopause transition is believed to reduce or even prevent vascular
endothelial dysfunction by the expression of functioning oestrogen
receptors α (ERα) which are mediators of nitrous oxide release (39).
Transdermal testosterone
The benefit of transdermal testosterone system (TTS) in a low daily

dose of 300 μg has been confirmed by many clinical trials without any
significant virilizing effects even after 2 years of use. However, its effect
on metabolism, the breasts or endometrium is not elucidated yet as
discussed by Rymer et al in 2010 (4£). Appropriate patient’s selection
is also important, to reduce the unwanted complications. It is indicated
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mainly for women with hypoactive sexual desire disorder as part of a

total management plan, as the condition itself is multifactorial. It may
be related to psychiatric conditions or temporary psychological issues,
medical conditions and the use of pharmacological agents. Reduced
sexual desire disorder is more common in women who had surgical
menopause compared to premenopausal women and those who had
natural menopause (44). Oral testosterone formulations should be
avoided, as they undergo first-pass hepatic metabolism. Prolonged use
may lead to hepatic dysfuncion, hepatomas and hepatocelluar
carcinoma. Oral medication has also been shown to reduce high density
lipoproteins (HDL), and increases triglycerides blood levels in oestrogen
treated women. It is good practice to perform liver function tests and a
fasting lipid profile before starting testosterone mediction, and at
regular intervals while on medication. It has also been stated that
testosterone medication could not be recommended without
concomitant oestrogen therapy (45).
Contraindication to HRT use
HRT is contraindicated in the following conditions, and other methods

should be considered instead:
• Active liver disease;
• Undiagnosed genital bleeding;
• Current, past or suspected breast cancer;
• Oestrogen dependent malignancy e.g. endometrial carcinoma;
• Endometrial hyperplasia;
• Active or recent venous or arterial thromboembolic disease;
• Untreated hypertension;
• Porphyria cutanea tarda.
In these circumstances another non-hormonal medication should be
used:
• Clonidine, which is an α adrenergic agonist, was the only
alternative available in the past. It is no longer a second line
medication, because of its many side effects which include
hypotension, fatigue, drowsiness, insomnia, constipation and dry
mouth.
• Selective serotonin reuptake inhibitors (SSRI) have proved useful,
in combination with noradrenaline reuptake inhibitors (SNRI).
Venlafaxine proved useful in relieving vasomotor symptoms and low
mood without having a sedative effect, but is not useful in relation
to bone density preservation. It can be started in a dose of 37.5 mg
206
every day. With inadequate response the dose can be stepped up to

75 mg daily. This may reduce side effects and improves compliance.
The dose should also be tapered before stopping the drug
altogether.
• Gabapentin has also been shown to improve vasomotor symptoms.
This was a coincidental observation in postmenopausal women
who had chemotherapy for breast cancer. This observation has
since been followed prospectively in controlled studies. Guttoso et
al in 2003 found no difference between gabapentin and conjugated
equine oestrogens in the management of hot flushes (46). A
similar conclusion has been reached by Aguirre et al in 2010 who
found gabapentin in a daily dose of 600 mg to be as effective as
low dose transdermal oestradiol (25 μg/day) in controlling
moderate to severe hot flushes (47)
• Anti depressants can be used when clinical depression is
diagnosed.
• Phytoestrogens, on the other hand, can improve menopausal
symptoms, but their safety in patients with contraindications to
classical HRT has not been studied.
DHEA
The use of DHEA as a form of nutritional HRT supplement has been

alluded to before. It has been used in daily doses of 25 mg and 50 mg by
Genazzani et al (6) and Stomati et al (48), respectively. They reported
increased blood levels of oestrogens, DHEA, androstenedione,
testosterone, allopregnenolone, and β-endorphins in postmenopausal
women. Beside the beneficial effects of the steroidal hormones,
allopregnenolone and β-endorphins have anxiolytic effect and promote
relaxation and feeling of wellbeing. Using the lower dose of 25 mg/day
resulted in significant improvement in vasomotor symptoms and
psychological disturbances during the early and late postmenopausal
years respectively (6). Furthermore, there were no detrimental
endometrial changes even after 12 months of medication, as shown by
thin endometrial echoes during repeated ultrasound scan examinations.
The exact effective and safe daily dose of DHEA is not yet established. A
case report published by Sahelian and Borken in 1998 reported cardiac
arrhythmia as a side effect of DHEA when used in a daily dose of 25 mg
(49). Another important drawback of this medication is that monitoring
blood or saliva DHEA levels do not reflect its biological effects at tissue
level. Even a more important fact is that a Cochrane review published in
2006 found little evidence from controlled studies to support a beneficial
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effect of DHEA supplementation on cognitive function of non-demented

middle-aged or elderly people (50). However, it did not find consistent
evidence of any adverse effects. Currently doses of 5-50 mg tablets are
marketed through various venues including the Internet, with no medical
control.
Contested recommendations
It has been recommended that HRT should be used in the smallest

effective dose for the shortest period of time. Setting a short time limit
has been criticised as false, and treatment should be continued as long
as it is needed by the patient. Nevertheless, regular reassessment of
the indication and the dose should be done on an annual basis, at least.
The minimum effective daily starting doses for oral oestradiol have
been reported as 0.5-1.0 mg, and 0.3-0.45 mg for conjugated equine
oestrogen. The equivalent doses for transdermal oestradiol patches and
oestradiol gel are 25.0-37.5 μg, and 0.5-1.0 mg respectively.
Assessment of response should be done after 2 – 3 months. About 20%
of patients may not have an adequate response, and the dose will need
to be increased. The route of administration should be carefully
selected. Patients with high triglycerides blood levels and migraine
headaches should avoid oral HRT, and should have transdermal
medication instead.
It is noticeable that the recommendations put forward by many official

bodies regarding the use of HRT after the publication of the WHI study
(41) have not been changed, despite the critical reviews and the
published evidence against many of these recommendations. This is
especially so for the inappropriate conclusions regarding cardiovascular
disease and breast cancer, as the results had been generated from older
postmenopausal women above the age of 60 years. In a very critical
editorial, Pines et al (4) criticised the planning and the initial conclusions
drawn from the WHI study (41), which lead to dramatic decline in the
number of women using HRT. Unfortunately, the extrapolation of results
from older women and their generalisation to symptomatic younger
patients who have just gone through the menopause has lead to a sharp
decline in the number of women using HRT. Many other reviews criticised
the study on similar grounds. The same authors (51) came to the
conclusion that women should be reassured regarding oestrogen
therapy as safe when initiated near the menopause, and under the age
of 60 years. There is also a potential to improve quality of life in
symptomatic women, and reduce their risk of future heart disease and
premature death. Furthermore, they recommended that symptomatic
208
perimenopausal women with no inherent breast cancer risk factors can

safely use HRT for 7 years.
Thromboembolic risks
The only sticky point concerns an increased risk of thromboembolism

with age and obesity in postmenopausal women using oral HRT.
Younger overweight patients are at risk as well. To put things
into perspective, the number of additional cases of venous
thromboembolism over a 5-year period was 2-6 per thousand women
aged 50-59 years, as reported by the WHI study itself (41). This
increase was seen only during the first 2 years of oral medication, in
women with a body mass index above 25 kg/m2. Accordingly, women
with such body habitat who develop vasomotor symptoms should have
thorough counselling, and other non hormonal medications can be used
instead. Nonetheless, the quality of life should always be considered in
the equation when counselling these patients. Transdermal HRT can be
used in cases with severe symptoms not responsive to other
medications. Production of vitamin K-dependent coagulation factors by
the liver is directly correlated to the dose of oral oestrogen used.
Furthermore, oral medication can induce activated protein C resistance
in some patients. Both effects were not seen in patients using
transdermal oestrogen HRT. Moreover, oral oestrogens reduce the level
of anti-thrombin III which inhibits activated coagulation factors (52). A
recent review of the available biochemical and clinical data by Birge in
2008 (532) suggested that women on low dose transdermal oestrogen
medication are not at increased risk of cardiovascular disease, stroke,
venous thrombotic disease, or even breast cancer. In fact Canonico et
al in 2007 showed a decrease in venous thromboembolism in patients
using transdermal menopausal hormone replacement therapy (54).
However there was no decrease in acute CHD attacks in women with
angiographically demonstrable ischaemic heart disease (55).
Endometrial cancer risk
The risk of endometrial cancer is a real one in women using unopposed

oestrogen replacement therapy (ERT). Accordingly, the endometrium
should always be protected with 12-13 days of a progestogen
medication. Alternatively, the mirena system is a good alternative for
this purpose, with the high local concentration of levonorgestrel. This is
especially useful, as continuous ERT can be given without a break,
especially for patients who developed bad vasomotor symptoms during
the HRT free one week episode. It is important to mention here that a
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case control study published in 2010 showed increased risk of breast

cancer, whether the mirena system was used alone or together with ERT
(56). This is a significant finding which could sway many gynaecologists
and patients from recommending and using the mirena system
respectively. However, more studies are needed to confirm this finding.
Doctors may start looking again to alternative progestogens to use. It
has been mentioned that progestogens derived from natural
progesterone and dydrogesterone have lower risk for promoting breast
cancer than synthetic progestogens derived from C21 progesterone
and 19-nortestosterone (57), used during combined therapy.
Younger symptomatic women, especially those with premature ovarian

failure, usually need a higher dose of oestrogen compared to patients
who went through the natural menopause. For non smoker healthy
patients in this group, an oral contraceptive pill will be a reasonable
option to provide the necessary oestrogen replacement, and to
maintain regular withdrawal bleeding. Older women can have dedicated
HRT combined medication, either orally or in a transdermal form. The
later form is more physiological as it does not have the first hepatic
pass, in contrast to the oral route. Women on continuous combined HRT
are more at risk of having breakthrough bleeding, which may cause
alarm especially in older postmenopausal women. Accordingly, they
should have endometrial assessment if they continue to have irregular
bleeding for the first 6 months of treatment, or if they develop
abnormal uterine bleeding for the first time after long uneventful use of
HRT (58).
The ideal drug to deal with postmenopausal medical problems should

have the following characteristics, as discussed in the literature:
• It causes no detrimental haematological or biochemical changes;
• It controls all the acute and intermediate symptoms effectively;
• It does not lose efficacy through tachyphylaxis after prolonged
use;
• It has good safety margin when used for long periods of time;
• It does not cause abnormal uterine bleeding;
• It reduces risks of cardiovascular diseases;
• It does not increase the risk of uterine cancer;
• It does not increase breast cancer rate;
• It prevents osteoporosis and reduces bone fracture risks.
Obviously, none of the available drugs has all these attributes, and we
should make the best out of what is available to us currently. Most
important is the fact that hypo-oestrogenic women should not be denied
210
medical help and left to suffer because of our current misinformation

regarding the magnitude of the potential risks involved. Patients should
be involved in decision making, because quality of life is a personal
choice. This is especially so, as the medical evidence against using HRT
is far from compelling.
Selective oestrogen receptor modulators
Selective oestrogen receptor modulators (SERM) are non steroidal

compounds which have an oestrogenic effect on one or more target
tissues, with anti oestrogenic effect on others. The first generation
SERM tamoxifen is widely used for the treatment of breast cancer.
Other second generation drugs have been produced for the treatment
of osteoporosis, especially in patients over the age of 60 years.
However, they have similar thromboembolic risks like oestrogens (59).
Bisphosphonates
Bisphosphonates are used for the treatment of osteoporosis. They

reduce bone turnover and accordingly reduce spontaneous bone
fractures and bone pain (58). However, reports of osteonecrosis of the
jaws have been published. The risk factors for such complication
included old age, prolonged use of the drugs, dental disease, dental
extraction, prolonged use of steroids and diabetic state. Accordingly, it
has been advised by Goss (60) that before commencing treatment with
a bisphosphonate, a patient should be dentally fit and should have
regular dental checks while on treatment.
It is evident that many alternatives to HRT are available for the

treatment of osteoporosis in postmenopausal women. They have
different effects on the vertebrae and femur. Alendronate, ibandronate,
intranasal calcitonin, parathyroid hormones, raloxifene, risedronate,
strontium ranelate and zoledronate reduce the risk of vertebral
fractures. At the same time alendronate, risedronate, strontium
ranelate and zoledronate reduce the risk of hip fractures as well (61).
Accordingly, there is a wide choice for selecting the more suitable
treatment, without the need to prescribe HRT for women over the age
of 60 years, and those with higher risks of breast cancer or cardiac
disease. Other important measures to reduce the risk of fractures
include intake of calcium and vitamin D, as well as appropriate weight
bearing exercise. It is also important that patients with osteoporosis
should be careful with their life style, because of their increased liability
to sustain fractures on trivial trauma.
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Urogenital atrophy
A special note will be made at this point about the management of

patients with urogenital atrophy. It has already been stated that the
condition is under diagnosed, despite its immense negative effects on
the patients’ health and sexuality. This is especially so in patients who
had breast cancer, as the use of HRT is considered inappropriate or not
a preferred option by the patient, because of safety issues. It may not
be appreciated that almost 45% of patients on systemic HRT still suffer
from urogenital symptoms (62). In both groups of patients vaginal
oestrogen medication can be used to reverse the atrophic skin changes
and relieve the associated symptoms. It is also effective in increasing
the number of periurethral blood vessels in postmenopausal women
(63). This may explain the significant improvement in urinary stress
incontinence felt by patients while on similar treatment, shown by a
metaanalysis conducted by Cody et al in 2009 (64). Paradoxically, the
same authors reported that systemic conjugated equine oestrogen
replacement therapy made incontinence worse in some patients. This
was in disagreement with a randomised prospective study conducted by
Long et al in 2006 (65). They found improved blood flow around the
bladder neck and mid-urethra, and almost equal relief of symptoms of
overactive bladder and stress incontinence following oral and
transvaginal oestrogen replacement therapy, despite lower serum
oestradiol levels following vaginal medication.
There is no evidence that transvaginal oestrogen replacement therapy

increases the recurrence rate of breast cancer, as shown by a small
study (66). Larger controlled randomized trials are necessary to
confirm its absolute safety. Long term follow up studies showed no need
to recommend the use of progestogens with this medication, as no
evidence of endometrial proliferation could be shown even after 6-24
months of treatment (27). A distinction should be made between
oestriol and conjugated equine oestrogen cream on one hand, and
oestradiol tablets and low dose oestrogen rings on the other, as the first
two can cause small increase in serum oestradiol (67). A metaanalysis
published by Suckling et al in 2006 (68) reported significant uterine
bleeding, breast pain and perineal pain following conjugate equine
oestrogen use when compared to vaginal tablets in one study. It also
reported significant endometrial stimulation by one study following the
use of the same cream when compared to the vaginal ring. Accordingly,
one should use oestradiol tablets (vagifem 25 μg, Novo Nordisk) or low-
dose oestrogen rings (estring, Pfizer) for long term HRT, to guard
against these side effects. Oestrogen vaginal tablets and cream are
212
licensed for continuous use for 3-6 months in the United Kingdom,
whereas low-dose vaginal ring is licensed for two years. One study
showed that most women preferred using the ring over other vaginal
medications because it was convenient and under their own personal
control (69). The ring should be changed every 3 months. In a more
recent literature review, Santos and Clissold (70) recommended the
use of vaginal promestriene which is a synthetic analogue of oestradiol
by patients who present with severe vulvo-vaginal symptoms and
history of breast cancer. This view can be explained by previous findings
by Wolff et al in 1982 (71) who documented a good local anti-atrophic
effect following vaginal promestriene with no oestrogen-like systemic
effects.
Endometriosis, fibroids and HRT
Two other special groups of patients need to be addressed as well;

those with history of endometriosis and those with uterine fibroids. The
first group is usually made of younger women who had radical surgery
to remove the endometriosis, including bilateral oophorectomy. Older
women with history of endometriosis who were treated medically or by
conservative surgery before the menopause may also need HRT. A
small undefined risk of recurrence or malignant transformation of
endometriosis had been suggested, but the general consensus is that
the benefits of using HRT far outweigh the risks, as suggested by
Soliman and Hillard (72). This is especially so for patients who had
surgery at a young age. It is generally advisable to use combined HRT
with both oestrogen and progestogen, as unopposed oestrogen
imposes a higher risk for recurrence. Nonetheless, there are no clinical
trials to address the role of progestogens in this respect, as stated by
the same authors.
The effect of HRT on fibroids is similarly not well quantified, and the risk
of increase in fibroids size has been used as a factor to deny women
HRT, especially those who were symptomatic before the menopause. An
increase (73) and no change in the size of the fibroids (74) have been
reported after using oral HRT, in doses of 0.625 conjugated equine
oestrogens, with 5.0 mg or 2.5 mg medroxyprogesterone acetate
(MPA) respectively. The first authors documented the change in size
only during the first 2 years of medication (73). On the other hand, a
randomized study showed significant increase in fibroids size after
using transdermal 50 μg of ethinyl oestradiol and 5 mg MPA for one
year. Tibolone (xxxx) which has oestrogenic, progestogenic and
androgenic effects did not cause an increase in fibroids size in the same
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study (75). This fact has been confirmed by other studies (76, 77),
which makes it a good option for postmenopausal women with fibroids
who need HRT. Even with increased fibroids size, there are no related
symptoms usually. Nonetheless, intracavitary fibroids can behave
differently, and can cause abnormal uterine bleeding (78), but this was
not a universal observation for all patients with similar lesions.
Following a hysteroscopic study, Perrone et al (79) described
intrauterine lesions in 37% and 26% of the patients who did or did not
have abnormal uterine bleeding respectively while on HRT. Other
benefits attributable to tibolone are that it reduced blood pressure,
TNF-α and glycaemia levels in healthy postmenopausal women without
any bad effect on other inflammatory factors. It did, however, reduce
HDL-cholesterol levels (80). These factors should be considered when
prescribing HRT.
Benign breast conditions and HRT
Women with histologically diagnosed atypia have 4-5 fold increased risk
of developing breast cancer (81). The Women’s Health Initiative Study
showed increased diagnosis of benign breast conditions associated with
combined and unopposed HRT use (82). However, neither HRT method
was shown to impose a higher risk of cancer in patients with benign
breast conditions than the observed general population risk (83, 84).
Current evidence shows that HRT, both combined or unopposed, does
not affect the prophylactic effect of bilateral oophorectomy until the age
of 50 years in premenopausal women with BRCA1 and BRCA2
mutations (85). There is no data for postmenopausal women to make
affirmative conclusions. More information will be available after the
publication of the Epidemiological Familial Breast Cancer, Cancer
Research UK report.
Breast examinations and mammography
Women should have a full general examination before starting HRT,

including weight and blood pressure. The role of repeated breast
examinations is controversial, as it did not reduce breast cancer
mortality in different studies. It can also result in a high number of false
positive results, which may lead to unnecessary investigations and
anxiety (86). Similarly, routine baseline mammography is not indicated
before starting HRT, as recommended by the Royal College of
Radiologists (87, 88). The situation is rather different in patients with
personal history of benign breast disease with atypia, or first degree
family history of premenopausal breast cancer (86). Patients between
214
the ages of 50-65 years should be encouraged to have regular 3-yearly

mammograms. Both combined and unopposed oestrogen HRT reduce
the diagnostic sensitivity and specificity of mammography (89, 90).
Reduced sensitivity could lead to increased interval cancer rates, delays
in diagnosis, and worsens prognosis. On the other hand, reduced
specificity may lead to increased positive false diagnostic rates.
Oestradiol implants and tachyphylaxis
A final note is due at this point about oestradiol implants which were
very popular in the past in doses of 25, 50 and 100 mg. They were
mainly used after surgical removal of the ovaries to deliver oestradiol
in a controlled manner over prolonged periods of time, hence reduce
the need for frequent medication. They were also used for general
management of postmenopausal symptoms, at a time when other
non-oral medications were not available. However, they are not as
popular now and many young doctors may not even have seen any
being inserted. Unfortunately, a few women using oestradiol implants
develop tachyphylaxis, which indicates recurrence of postmenopausal
symptoms despite high plasma oestradiol levels. This was related to
the rate of fall in oestradiol blood level, rather than the absolute level
itself (91). Such phenomenon was seen more often in patients who
had history of psychopathology or surgical menopause (92), and had
more frequent implant insertions. Prevention of tachyphylaxis should
be an important objective, even before initiating this type of
medication, as treatment is difficult once the problem is already
established. Templeman et al in 1998 found no relationship between
the recurrence of symptoms and oestradiol blood level (93). They
also found that repeating implants adminstration without taking
notice of oestradiol blood level resulted in continuous increase in its
basal level. This should be expected as implants usually continue
releasing oestradiol for much longer periods of time than the 6
monthly gaps usually used between medications. This was shown by
a case report published by Wardle and Fox in 1989 (94). Oestradiol
levels were 1211 pmol/l, 673 pmol/l and 169 pmol/l one year, 18
months and 3 years after the last implant insertion respectively.
Counselling patients regarding the lack of agreement between
symptoms score and oestradiol blood levels, and the medical risks
related to high oestradiol blood levels was shown to reduce the
possibility of developing tachyphylaxis (93). Patients should
understand that the main biochemical objective of HRT is to restore
premenopausal oestradiol blood levels with exogenous medication,
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and no extra oestradiol will be administered when blood levels >400

pmol/l. Such levels were maintained by 50 mg oestradiol implant
insertions every 9.7 – 11.7 months as reported by Buchler et al in
1995 (95). They concluded that there was no need for more frequent
prescriptions of oestradiol implants, and suggested annual
adminstration instead.
There are no controlled studies regarding treatment of established

cases of oestradiol tachyphylaxis. Further implant insertions should be
avoided, as long as oestradiol blood level is high. The importance of
thorough patients’ counselling regarding the medical risks of super
physiological oestradiol blood levels has been alluded to before.
Symptoms may be controlled by prescription of small doses of
transdermal oestradiol, testosterone implants, or combined
noradrenaline / serotonin reuptake inhibitors (Venlafaxine). The later
treatment modality may be combined with a smaller implant (25 mg
instead of 50 mg) in difficult cases, and progressively prolonging the
period between implant insertions. Patients with psychiatric
manifestations who are more prone to develop tachyphylaxis should
receive psychiatric help.
Summary
Women live longer nowadays after the menopause, and expect better
quality of life than their mothers and grandmothers. Accordingly, good
control of the acute vasomotor symptoms, and reduction of the long
term problems related to osteoporosis and CVD became a pressing
medical necessity. This will also reduce the national budget necessary
to cater for women who have already developed such problems. The
current available options of different medications, both hormonal and
non hormonal are wide enough to suit different needs. Proper selection
and regular follow up on one hand, and adequate education of the
patients on the other, are necessary. Family history and other risk
factors of breast cancer, thrombophilia, and dyslipidaemia should be
taken into consideration.
It is important to differentiate between women below and above the

age of 60 years, when dealing with HRT. The effect of age in relation
to breast cancer risk is well known. Furthermore, HRT is considered
a promoter of pre-existing malignancy rather that an initiator of
malignant transformation (96, 97), and promotes oestrogen receptor
positive tumour (98). It is also associated with low grade invasive
cancer at diagnosis. The review article published by Hodis and Mack
216
in 2009 (99) explicitly addressed the risk of coronary heart disease

(CHD) in relation to HRT. The main difference between the outcome
of randomised controlled studies and the observational ones, mainly
the WHI, was the age of the patients studied. The first group dealt
with younger women, whereas the later ones dealt with older ones in
relation to the menopause. Both HRT and SERMs reduced the risk of
CHD in women <60 years, and in those who started treatment within
10 years of the menopause. Similarly, the current data showed no
increased risk of stroke with HRT in younger (50–59 years)
normotensive postmenopausal women, particularly when lower doses
were prescribed soon after menopause (100). A major support for the
use of HRT in young women during the menopause transition, or soon
after the menopause came from the writing group on behalf of the
Workshop Consensus Group of the International Menopause Society
in 2009 (40). These recommendations agree with the scientific
finding that oestrogens have beneficial and protective effects on the
vascular endothelium. Such effect is even evident during the normal
menstrual cycle in premenopausal women because of the variations
in circulating oestrogen levels. Endothelial-dependent vascular
dilation is greater during the later part of the follicular phase
compared to the earlier part of the cycle (101). Beside its
vasodilatation effect, oestrogen also has direct antioxidant and anti-
inflammatory effects, both in vivo and in vitro (39).
At this point it is important to re-emphasise the need to convey risks in

absolute numbers rather than percentages (42) to avoid needless alarm.
This is well illustrated by the data related to breast cancer risk. The
calculated risk by the age of 50-70 years for women who never used HRT
is 45 cases per 1000 women. Using HRT for 5, 10 and 15 years is
expected to result in 2, 6 and 12 extra breast cancers per 1000 women
respectively, by the age of 70 years (102). Expressing these figures as
percentages of the basal risk of 45 cases per 1000 will give alarming
increased risks of 4.4%, 14.2% and 26.6% respectively.
It is high time for the regulatory authorities to change their

recommendations which were made after the publication of the WHI, to
match the new evidence and critical appraisal of that study and other
similar ones. This view has been voiced before by many experts in the
field (103, 104). HRT is safe and beneficial, when used by the right
patient, and under the right supervision. Furthermore, women should
be treated as individuals, and their views should be taken into
consideration when they request HRT. The risk-benefit ratio should be
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assessed and discussed with them, before prescribing any type of

medication.
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226
Chapter 10
Premature Ovarian Failure
Premature ovarian failure is a term used to indicate a syndrome of

amenorrhoea, low oestradiol, and high gonadotrophins levels in
women under the age of 40 years. A statistical definition has been
suggested which related these clinical and endocrine parameters to
an age group two standard deviations below the mean age of the
menopause, estimated for the reference population (1). This is rather
a complicated definition, and the fixed age-related one is more
popular in clinical practice.
It is not only the definition of the syndrome which drew some

debate. The name itself has been a subject of some controversy. The
terms premature menopause, premature ovarian dysfunction and
hypergonadotrophic hypogonadism have all been used. Each of these
terms has its drawbacks, and may not represent all aspects of
the syndrome. Premature menopause is definitely not a suitable
option, as the term menopause indicates permanent cessation of
menstruation. Ovarian activity can resume in many patients, at
different times. In fact 50% of patients with POF may menstruate (2,
3), but the exact timing or pattern of such intermittent recovery can
not be predicted. Furthermore, the term itself has devastating
psychological effects on young women in their early 20s or 30s. It is
a term usually related to mothers and grandmothers and not to
young women in the prime of their youth. Furthermore, many women
with POF may have primary amenorrhoea, and the term premature
menopause will not be a valid one to use. Hypergonadotrophic
hypogonadism and premature ovarian insufficiency sound softer on
the patients. The later term was used first by Albright et al in 1942
(4), and seems to be the most appropriate. It is also suitable to cover
many women who had regular menstruation, polymenorrhoea or
oligomenorrhoea and a hypergonadotropic state. Though they are not
amenorrhoeic, they still have reduced fertility potential and can be
hypo-oestrogenic at different times. Few of them may even have hot
flushes. Nonetheless, premature ovarian failure stood the test of
time, and remained the most popular term to use, though the word
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failure also gives a bad psychological impact of insufficiency and

personal inadequacy.
To complicate matters yet further, there is no general agreement on the

criteria necessary to make a diagnosis. Different authors have
documented different durations of amenorrhoea (3-6 months), and
levels of follicle stimulating hormone (FSH) from 10 – 40 IU/L, before
making a diagnosis. All these points lead to hesitancy on the part of
clinicians to make a diagnosis. It can take a patient many years, and
seeing many doctors before a diagnosis is finally made. Alzubaidi et al
(5) reported that 50% of young patients who had secondary
amenorrhoea needed to see three or more clinicians before
investigations were started. Accordingly, it is imperative that any young
patients with history of 3 months secondary amenorrhoea or irregular
menstruation should be investigated (6), especially those with
significant personal or family history, as will be discussed later on in this
chapter.
The incidence of premature ovarian failure has been reported differently

in different societies and in relation to age as well. A total prevalence of
0.3 – 1.0% has been frequently quoted. It affects 1.0% of women
younger than 40 years, 0.1% under the age of 30 years, and 0.01% of
women under the age of 20 years (7). These figures can be affected by
all the points discussed before in relation to the definition, as well as the
delays in diagnosis. Furthermore, more young women are expected to be
diagnosed with POF, due to the higher success rates for treating childhood
malignancies (8). Also ethnic differences may have an impact as reported
by Luborsky et al in 2002 (9). An incidence of 1.4% was quoted for
African-Americans and Hispanics, 1.0% for Caucasians, 0.5% for
Chinese, and 0.1% for Japanese. Both mono and dizygotic twins are more
liable to develop POF. A combined Australian and British study involving
832 sets of twins showed 3- to 5-folds increased prevalence of POF in
twins than the general population at age thresholds 40 and 45 years. No
specific factors were found to account for this higher risk of early
menopause. In spite of significant differences within monozygotic twins,
the age range at the menopause was more harmonious than for dizygotic
twins, confirming a hereditary component to the timing of the
menopause (10).
Patients with POF can present with primary amenorrhoea, secondary

amenorrhoea, or even irregular and delayed menstruation. About 10-
28% of patients with primary amenorrhoea may have POF vs. a
prevalence of 4-18% in women with secondary amenorrhoea (11).
228
Causes of POF
Premature ovarian failure can occur spontaneously, or may follow

certain medical interventions. No specific cause may be found in more
than 90% of spontaneous cases, but the following explanations were
suggested:
1. There was reduced differentiation of the cohort of oocytes in the
ovaries during fetal life.
2. There was rapid exhaustion of the oocytes pool during fetal life,
childhood or early adult life. Up to the stage of sex cords
development within the ovaries, one X chromosome is needed,
but two X chromosomes are necessary for further development
beyond the stage of primary oocytes. In the absence of all or part
of the second X chromosome, rapid atresia of the follicles occurs,
leading to the formation of streak gonads or premature ovarian
failure, depending on the atresia rate.
3. Resistance of the follicles to gonadotrophins stimulus is mostly
related to mutations in FSH and LH receptors genes.
The first two points can be related to problems with the oocytes
themselves, and have been discussed in great details in Chapters 2
and 3, especially in relation to gonadal dysgenesis and different
chromosomal combinations. This chapter has been written with this
information in mind, and further repetition will be avoided. On the other
hand, the third point relates to granulosa cells dysfunction.
The aetiology of spontaneous POF will be discussed in relation to the

following causes:
1. Genetic or familial causes;
2. Autoimmune factors;
3. Infections.
On the other hand, iatrogenic causes are easier to diagnose, and may
follow one or more of the following interventions:
1. Pelvic surgery;
2. Pelvic irradiation;
3. Use of cytotoxic drugs.
Spontaneous POF
There are differences between sporadic and familial cases of

spontaneous POF, which should be taken into consideration when
counselling or investigating these patients. Accordingly, thorough
229
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history should be taken to prevent excessive and unnecessary

investigations and exhaustion of resources, as only 20-30% of the
spontaneous cases are familial (12).
Chromosomal and genetic factors
Most of the associated genetic disorders are related to the X

chromosome (13), though autosomal dominant and recessive
abnormalities have been documented as well (14). Such chromosomal
abnormalities and other genetic causes were more common in patients
with similar family history, and in patients presenting with primary
amenorrhoea. Most patients usually have normal 46XX karyotyping.
Abnormal results were reported in 50% and 13% of the patients with
primary and secondary amenorrhoea respectively (15). A critical region
in the long arm of the X chromosome, Xq13 to 26, excluding section
Xq22, is critical for ovarian development and function (16). Accordingly,
translocations in this region, and X chromosome deletions, and
duplications, as well as balanced translocations are likely in patients
with spontaneous POF. The most commonly known chromosomal
abnormality in this condition is 45XO (X chromosome monsomy or
Turner’s syndrome), or a mosaic combination including such cell line.
Patients with 45XO premature ovarian failure usually have significant
physical characteristics which may even obviate the need for
chromosomal analysis. They have short stature, webbing of the neck,
increased carrying angle of the elbows, widely separated nipples, low
set ears and hair line, high arched palate and coarctation of the aorta.
Another specific condition is trisomy X syndrome (47XXX) which is
caused by non-disjunction of the X chromosome, but its prevalence as
a cause of POF is unknown. Other conditions include deletions in either
the short or long arms of the X chromosome, and balanced X
chromosome translocations. The last two authors (16) suggested that
all patients with POF should have their peripheral karyotyping tested.
This advice is valid in cases with familial POF. It may not help with the
management of sporadic individual patients, except in the presence of
a Y chromosome which increases the risk of gonadal malignancy.
Furthermore, patients may carry two cell lines, with the abnormal one
being at the ovarian level. This has been shown by a report published
by Abdel-Gadir and Ramadan in 1990 (17) regarding a 32 year old
nulliparous patient who presented with secondary amenorrhoea of 7
years duration. This was preceded by 12 years of oligomenorrhoea
dating back to menarche, which she attained at the age of 13 years.
She had normal 46XX peripheral lymphocytic karyotyping. Ovarian
tissues karyotyping revealed reciprocal translocation 45XOt
230
(3:20)(q22:q12)t(13:15) (q14:q13). Accordingly, normal peripheral

karyotyping may not reflect the exact abnormality, especially in
mosaics with two cell lines. Therefore, it is not indicated as a routine
test in sporadic POF cases. Despite history of some ovarian function,
almost 90% of the patients were nulliparous at the time of POF
diagnosis (16).
Growth differentiation factor 9 (GDF9) and bone morphogenetic protein

15 (BMP15) genes are necessary for normal human reproduction. This
subject was reviewed by Hoekstra et al in 2008 (18). Higher mutation
frequency in both genes was reported in patients with POF, when
compared to controls. A slight increase in POF was also noted in
mothers of dizygotic compared to monozygotic twins (19, 20). This was
related to increased frequency of mutations in GDF9 and BMP15,
though different variants of mutations were detected in patients with
POF and dizygotic twins (18).
Premutations in the fragile site mental retardation 1 (FMR1) gene,

which is responsible for fragile X syndrome, have been diagnosed in 6%
of women with 46XX karyotyping and POF (21, 22). Such risk was found
to be higher in cases with similar family history (14%), in comparison
to sporadic cases (2%), as reported by Sherman in 2000 (22). About 5-
10% of these patients may conceive spontaneously following
resumption of ovarian function, but carry a high risk of having mentally
retarded children (23). Accordingly, they should be referred for genetic
counselling as well as those with known family history of fragile X
syndrome, unexplained mental retardation, tremor / ataxia syndrome
and dementia (23). Frequency of miscarriages is also increased in
females with fragile X syndrome.
Other rare enzymatic causes and signal defects have been described,
but are not frequent enough to warrant routine testing in sporadic
cases. The most known conditions in this group are gene mutations of
the FSH receptor (FSHR), luteinising hormone receptor, and galactose-
1-phospate uridylytransferase (GALT) in patients with galactosaemia.
Despite good dietary control of galactosaemia, 70-80% of the patients
develop POF (24). Patients with complete or partial FSHR mutation are
more likely to have primary or early secondary amenorrhoea
respectively. The later group are more likely to show follicles during
ultrasound examinations of the ovaries than other patients with POF
(25). On the other hand, LH receptors gene mutation is usually
associated with primary amenorrhoea. One further problem is partial or
complete deficiency of 17α-hydroxylase which occurs in 1:50,000 –
231
ABDEL -GADIR
100,000 newborns, usually in combination with 17/20 lyase deficiency.

Due to failure of androgens and oestrogens production, these patients
usually fail to develop secondary sexual characteristics and present
with primary amenorrhoea and hypokalaemic hypertension. More
related information has already been given in Chapter 3.
Autoimmune factors
Patients with POF are at risk of having other autoimmune disorders

(26). A figure of 20% has been quoted for such an association by
Goswami and Conway in 2005 (27). The syndrome has been
associated mainly with autoimmune thyroid dysfunction, adrenal
insufficiency, and diabetes. Other associations included systemic lupus
erythematosus, Sjogren’s syndrome, pernicious anaemia, vitiligo,
Crohn’s disease and rheumatoid arthritis. Autoimmune lymphocytic
oophoritis has been suggested as the cause of ovarian failure, related
to steroidogenic cell autoimmunity. Nonetheless, ovarian antibodies
have not proved to be useful for the screening or diagnosis of POF.
They were reported in a wide range of 10 - 69% of patients with POF,
but also in a significant number of controls (28). A study by Yan et al
in 2000 (29) showed significant increase in CD8 density in T
lymphocytes. Though ovarian biopsy can be more diagnostic of
autoimmune oophoritis, it is not justifiable because of the lack of
definitive treatment as suggested by Khastgir et al in 1994 (30). On
the other hand, identification of patients with adrenal antibodies
allows proper follow up of patients at risk of developing adrenal failure
or even adrenal crisis. About 4% of women with spontaneous POF
tested positive for adrenal antibodies (31), and asymptomatic adrenal
insufficiency was reported in 2% of patients with spontaneous POF.
This last group would have been especially at risk of adrenal crisis had
they conceived spontaneously, or through ovum donation. In contrast,
Turkington and Lebovitz (32) reported that 23% of patients who
already had adrenal insufficiency had POF at the same time. In these
cases, POF preceded the development of clinical Addison’s disease by
five to fourteen years. This fact confirms the need for regular follow
up of these patients. Autoimmune hypothyroidism is another common
risk, and a figure of 20% has been reported by Kim et al in 1997 (33).
Accordingly, all patients diagnosed with spontaneous POF should have
their thyroid stimulating hormone (TSH), free thyroxine (T4), and
thyroid peroxidase antibodies tested at regular intervals. Screening for
the other autoimmune problems mentioned previously is not
necessary, unless clinically indicated.
232
Other changes in the immune system which reflect its association with
POF have been reviewed by Anasti (11). Increased number of activated
T cells and reduced number of natural killer (NK) cells are two examples.
Increased numbers of activated T cells have been described in other
autoimmune endocrine disorders, which suggested a similar pathology in
POF. Furthermore, reduced number of NK cells has also been shown in
patients with Grave’s disease. This can affect the function of B and T cells,
leading to increased production of autoantibodies, which could lead
ultimately to tissue damage. The same author reviewed reports of
resumed ovarian function after immunotherapy in patient with such
diseases as myasthenia gravis, systemic lupus erythematosus, adrenal
failure and poly glandular failure. No clinical parameters or biochemical
criteria could be identified to predict who would respond or not, including
the presence or absence of ovarian autoantibodies. Accordingly, the
current evidence in the literature is not strong enough to support the use
of immunotherapy for the treatment of patients with POF.
Infections
POF has also been related to various infections, but the incidence or the
magnitude of the problem is not known. Mumps has been associated
with 3-7% risk of viral oophoritis, during epidemics (34). Other
infections included cytomegalovirus infection in patients with
compromised immune systems, secondary to lymphoma or acquired
immunodeficiency syndrome (AIDS), and in organ transplant patients
on anti-rejection treatment (34). There are no specific tests to relate
POF to these infections and patients’ history is the only clue to such
infections. A figure of 3.5% for such infections has been reported by
Rebar and Connolly in 1990 (2), and they included varicella, shigellosis
and malaria, as possible causes as well.
Iatrogenic causes of POF

Pelvic surgery
As mentioned previously, surgery, pelvic irradiation, and the use of

cytotoxic drugs are the main causes of iatrogenic or induced POF.
Removal of the ovaries leads to abrupt loss of ovarian function, and
causes severe oestrogen deprivation. This can follow bilateral
oophorectomy performed because of ovarian tumours or severe pelvic
endometriosis. Busacca et al in 2006 (35) reported 2.4% incidence of
POF following laparoscopic excision of bilateral endometriomas.
Furthermore, early loss of ovarian function may follow a hysterectomy
233
ABDEL -GADIR
(36, 37), as almost 30% of the blood flow into the ovaries is provided
by the uterine arteries. Ovarian damage following ovarian drilling has
been suggested as a possibility, but has not materialised as a reality
with increased incidence of POF after the procedure, despite the
widespread use of the technique. Nevertheless, care should be taken to
avoid excessive use of the energy during this procedure, and to restrict
the punctures to a reasonable number, depending on the size of the
ovaries. More information can be found about this subject in Chapter 7.
Cytotoxic and pelvic radiation therapy
With the recent success in the treatment of childhood malignancies,

many of these children are expected to reach adult life. The risk of
POF is high in this group of women, secondary to the use of
chemotherapeutic agents and radiotherapy. This is on top of those who
have already had surgical treatment. A recent study addressed the risk
factors involved with the development of non surgical POF in these
patients (38). These factors included patient’s age, ovarian exposure to
increasing doses of radiation, the number of cytotoxic drugs used and
their cumulative dose, and the diagnosis of Hodgkin lymphoma. The
authors reported a figure of 30% incidence of POF for patients who were
treated with alkylating agents plus abdominopelvic radiation. Older
patients can be affected more, as the risk of POF following such
treatment increases with the patient’s age after puberty. It is a known
fact that chemotherapy reduces the number of oocytes, but also affects
the structure of the granulosa cells and oocytes at the same time. These
effects depend on the type of drug and dosage used (39).
Adjuvant chemotherapy for the treatment of breast cancer is becoming

an important factor in the development of POF in older women within
their reproductive years. Rates of 21-71% and 49-100% have been
quoted for women younger and older than 40 years respectively (40).
These wide variations in incidence are most likely related to the type of
drug and the dosage used. Some reports showed that simultaneous
medication of gonadotrophin releasing hormone agonist can reduce the
toxic effects of these drugs, but this is not well verified yet, and is not
routinely used in these cases.
As for chemotherapy, the age of the patient and the dose of

radiotherapy used affect the risks of POF, with prepubertal ovaries being
more resistant to the damage. The older the patient is at the time of
exposure to radiotherapy, the more her chances will be to develop
irreversible ovarian damage. Exposure to 800 rads can lead to
234
permanent ovarian failure, irrespective of the age group. Lower

doses may be coupled with partial or complete recovery in younger
patients. Transposition of the ovaries before radiation can save
some ovarian function, and preserve fertility in many patients.
Furthermore, freezing oocytes and ovarian tissue are two other
available options to preserve future fertility, before using cytotoxic
drugs or radiotherapy.
Clinical implications
The major clinical effects of POF result from the hypoestrogenic state
and deficiency of androgen production by the ovaries. This is
compounded by substantial psychological problems caused by loss of
menstrual function, and more importantly a substantial reduction in
fertility chances. These changes are usually perceived as loss of
femininity with strong feelings of grief and anger, as well as being
worthless and insecure. These are the immediate effects following the
diagnosis, which should be handled with great care. As for natural
menopause, hypoestrogenism exposes patients with POF to immediate,
intermediate and delayed problems, but these effects will be worse in
the long term as the patients have lost their ovarian function at a
younger age. Vasomotor symptoms can disrupt the patients’ lives,
and may start even before cessation of menstruation, mainly
premenstrually. This may be compounded by night sweats, headaches,
and loss of concentration and mood swings, as for the natural
menopause. There is a chance for these symptoms to be worse to start
with, due to the severe psychological trauma inflicted on the patient
by the diagnosis itself. Sexual difficulties due to vaginal dryness and
aging skin changes also take their toll. Nevertheless, the main long
term problems are CVD and osteoporosis. The increased risk of CVD
may follow accelerated endothelial dysfunction, which precedes
atherosclerosis. This process was reversed by cyclical HRT use (41, 42).
Hu et al in 1999 (43), observed a significant association between
younger age at the menopause and higher risk of coronary heart
disease only in women who never used hormone replacement therapy.
Since the increased risk was seen only in current smokers, but not in
women who never smoked before, it was suggested that such increased
risk reflected only a confounding effect of smoking. The risk of
osteoporosis may be worse in women with POF than those who go
through a natural menopause, because of the prolonged duration of
oestrogen deficiency, if HRT had not been used. This can be even worse
in patients who develop POF at a very young age, as the maximum bone
density is usually set around the age of 20 years.
235
ABDEL -GADIR
Management of POF
This is a very difficult subject that needs to be addressed with great

care and compassion. Young women with 3 or more months of irregular
menstrual function should be investigated. It is important to elicit any
family or personal history of autoimmune problems. Family history of
POF, mental retardation, ataxia or dementia should be sought.
Symptoms of oestrogen withdrawal, even in patients with regular
menstrual cycles, can give a clue to the hypoestrogenic state. Usually
physical and pelvic examinations are not remarkable during the early
stages. Signs of autoimmune disorders may be seen in few patients
including vitiligo, thinning of the axillary and pubic hair, butterfly facial
skin rash etc. At the same time, vaginal skin atrophy can be seen in long
standing cases. Transvaginal scan examination may show a small
uterus with thin endometrium and small non active ovaries, but may
not be helpful in many cases. A hormone test for FSH, LH, oestradiol,
prolactin, TSH and T4 should be done. It has been recommended that
women with a high FSH level ≥40 IU/L should have the blood test
repeated after one month time, before making a definitive diagnosis of
POF. Such rise in FSH level can be episodic and is usually late, in
comparison to the decline in the level of inhibin B and antimullerian
hormone (AMH). In fact the decline in AMH starts first while women still
have regular menstrual cycles, and has a strong positive correlation to
the antral follicles count (44). Adrenal and thyroid peroxidase
antibodies should be tested at regular intervals, even if reported
negative during the initial endocrine assessment.
The adverse psychological effects have already been mentioned before,

and counselling should be an integral part of the management plan.
Patients should be seen more frequently to answer all their doubts and
queries. The differences between natural menopause as a permanent
process and POF should be explained. It is very important to choose the
right words when addressing these patients. Words such as menopause
and failure should be avoided. Chances of intermittent resumption of
ovarian function should be addressed, as 50% of the patients have
intermittent menstrual cycles, as mentioned before. Nevertheless, the
exact timing of these cycles can not be predicted before hand, and
patients who wish to conceive should have regular intercourse.
Excluding women with familial POF due to fragile X chromosome
syndrome, there is no increased risk of congenital abnormalities when
these patients manage to conceive. Furthermore, the course of the
pregnancy is usually not different to other women with regular
236
menstrual cycles. Nonetheless, the presence of autoimmune problems

should be taken into consideration, especially for the adverse effects of
adrenal insufficiency. Postnatal adrenal crisis is also a risk factor. These
risks stress the importance of the point raised before regarding
screening patients with POF for adrenal autoantibodies before they get
pregnant. Any medication to increase the chances of pregnancy will be
ineffective, and can interfere with the intermittent chances of
spontaneous resumption of ovarian function. This is especially so for
attempts to induce ovulation with antioestrogens or gonadotrophins. A
note about immunosuppressants has already been mentioned before.
The normal 5 -10% chance of spontaneous pregnancy rate (6) should
be conveyed to the patients.
Hormone replacement therapy (HRT) makes the cornerstone for the

management of patients with POF. There are no controlled studies as yet
for the best HRT to be used in these young women. They usually need
double the dose of oestrogen to control their vasomotor symptoms,
compared to other postmenopausal women (20). Both the oral and
transdermal routes can be used effectively. Progestogens will be
needed for at least 12 days every month to prevent endometrial
hyperplasia. This can be used in a cyclic HRT form, which is preferred by
many patients as it gives the reassurance of the monthly withdrawal
bleeding. Continuous HRT can also be used, but there is a higher risk of
breakthrough bleeding with this type of medication. The oral
contraceptive pill can be used instead, in areas where dedicated HRT
drugs are not available, despite the high dose of the synthetic oestrogen
used. Some authorities advocate its use, as it can provide contraception
for patients who are not keen to get pregnant. Others are against its use,
as it can mask detection of natural remission of ovarian function.
Moreover, it does not offer very good contraception, and pregnancies did
occur while patients with POF were taking the pill regularly.
The debate regarding the use of HRT has been addressed in Chapter 9,
and will not be repeated here. It is enough to say that young women
with POF should be encouraged to use HRT till the age of the natural
menopause, without any significant risk of breast cancer or CVD. On the
contrary, it can improve their quality of life and prevent osteoporosis,
CVD, sexual difficulties and premature aging. The same advice
regarding diet and weight bearing exercises should be given, as for
postmenopausal women. Furthermore, they should be treated the
same way as other postmenopausal women once they reach the age of
51 years.
237
ABDEL -GADIR
Summary
Premature ovarian failure is a distressing problem which can not be
reversed medically. Patients usually feel neglected, and 71% of
women with POF were not satisfied with the manner in which the
diagnosis had been relayed to them (45). It is always important to avoid
using the words menopause or ovarian failure. Furthermore, patients
should be informed about the possible intermittent resumption of
ovarian function, and the risk or chance of spontaneous pregnancy,
even while on the pill or HRT. The services of a counsellor are most
important, and patients should be directed to join a support group of
patients with a similar diagnosis. It is important to ascertain similar
family history, as it has some bearing on the management plan of the
concerned patient. In addition, regular follow up of patients with
spontaneous POF should include regular screening for adrenal
autoantibodies and thyroid function. Women with family history of POF
should be referred for genetic counselling, and those with positive
adrenal antibodies should see a medical endocrinologist for further
assessment of their adrenal glands function. It is evident that a
multidisciplinary team is needed for the proper management of patients
with premature ovarian failure who need support and compassion, as
well as HRT. The adverse effects of HRT reported in older women do not
apply in this young age group.
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BJ, Shawker TH and Merino MJ. Development of luteinized
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18. Hoekstra C, Zhao ZZ, Lambalk CB, Willemsen G, Martin NG, BDI
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20. Gosden RG, Treloar SA. Martin NG, Cherkas LF, Spector TD.
Faddy MJ and Silber SJ. Prevalence of premature ovarian failure
in monozygotic and dizygotic twins. Hum Reprod 2007; 22:
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21. Marozzi A, Vegetti W, Manfredini E, Tibiletti MG, Testa G,
Crosignani PG, Ginelli E, Meneveri R and Dalpra L. Association
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25. Aittomaki K, Herva R, Stenman UH, Juntunen K, Ylostalo P,
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35. Busacca M, Riparini JR, Somigliana E, Giulia O, Stefano I Michele
V, Massimo C Post surgical ovarian failure after laparoscopic
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on the age of ovarian failure: identification of a subgroup of
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37. Khastgir G and Studd J. Hysterectomy, ovarian failure and
depression. Menopause 1998; 5(2): 113 - 122.
38. Sklar CA, Mertens AC, Mitby P, Whitton J, Stovall M, Kasper C,
Mulder J, Green D, Nicholson HS, Yasui Y and Robison LL.
Premature menopause in survivors of childhood cancer: a report
from the childhood cancer survivor study. J Natl Cancer Inst 2006;
98(13): 890 - 896.
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41. Kalantaridou SN, Naka KK, Bechlioulis A, Makrigiannakis A,
Michalis L and Chrousos GP. Premature ovarian failure, endothelial
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42. Kalantaridou A, Naka KK, Papanikolaou E, Kazakos N, Kravariti M,
Calis KA, Paraskevaidis EA, Sideris DA, Tsatsoulis A, Chrousos GP
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risk of cardiovascular disease. Arch Intern Med 1999; 159: 1061

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242
Chapter 11
The Thyroid Gland in Gynaecology
The importance of the thyroid gland in gynaecological endocrinology is

reflected by the fact that it has been mentioned in almost all chapters
in this book. It produces triiodyothyronine (T3), thyroxine (T4) and
calcitonin. Its effects span from intrauterine fetal life to the
postmenopausal period. It is involved with development, growth,
reproduction, and general body homeostasis in all age groups. Beside
the endocrine effects which will be discussed in more details in this
chapter, T4 and T3 have metabolic and cardiovascular effects. The
metabolic ones involve rapid cellular uptake of glucose, increase
glycolysis and gluconeogenesis, boost lipid mobilisation increasing free
fatty acids levels, promote protein synthesis and increase the number
and size of mitochondria in most cells. They also increase the basal
metabolic rate, oxygen consumption by most tissues, as well as heat
production. Other important metabolic effects include enhancement of
intestinal glucose transport, and reduction of plasma cholesterol level,
mainly low density lipoproteins. A detrimental effect on low-density
lipoprotein cholesterol has been shown even in subclinical
hypothyroidism (1). The cardiovascular properties involve both
genomic and non genomic effects. They increase heart rate with
reduced isovolumic relaxation time, and increase left ventricular
ejection fraction and cardiac output (2). They also increase the
sympathetic nervous system tone. On the other hand calcitonin is
produced by the parafollicular or C- cells and is involved with the
regulation of calcium metabolism. It counteracts the effect of the
parathyroid hormone and reduces calcium blood level. This effect is
utilised clinically for long-term treatment of postmenopausal patients
with osteoporosis to reduce the risk of vertebral fractures.
Thyroid gland dysfuncion usually, but not always presents during the
reproductive years in women. It is the second most common female
endocrinopathy (3), following polycystic ovary syndrome. Accordingly,
gynaecologists cannot possibly avoid seeing patients with thyroid
disease. Both hypo-and-hyperthyroidism can be insidious without any
thyroid gland enlargement, which usually leads to delayed diagnosis and
243
ABDEL -GADIR
treatment. Furthermore, they can present for the first time during
pregnancy. The prevalence of hypothyroidism varies between 2-4%
during the reproductive years, with autoimmune thyroid disease being
the most common cause. Hyperthyroidism is less common in this age
group. Many patients may have subclinical hypothyroidism, with or
without thyroid peroxidase antibodies. The diagnosis of this entity is
usually made in asymptomatic women with normal free thyroxine (T4),
but thyroid stimulating hormone level (TSH) >5.0 mIU/L, though a figure
of 2.5 mIU/L has been advocated by many authorities. It was reported by
McDermott and Ridgway in 2001 (4) that 13.7% of these patients had
different symptoms usually seen in patients with overt hypothyroidism.
The list included dry skin (28%), poor memory (24%), slow thinking
(22%), muscle weakness (22%), fatigue (18%), muscle cramps (17%),
cold intolerance (15%), puffy eyes (12%), constipation (8%) and
hoarseness (7%). These are vague symptoms, and were seen in 12.1%
of the euthyroid women involved in the same study. More information
about this subject will be discussed later on in this chapter.
The fetal thyroid gland
During its early intrauterine life, the fetus depends entirely on maternal
thyroid hormones for its development, growth and survival. Maternal
thyroid hormones play an essential role in the development of the fetal
brain. This is affected through the placenta which regulates the
amounts of thyroid hormones reaching the fetus, depending on its
stage of development (5). Significant amounts of thyroxine have been
found in fetal tissues before the fetal thyroid gland starts functioning,
reflecting its importance in fetal development even at this early stage
of development. Accordingly, any maternal thyroid dysfunction, or
abnormality with the placental transport mechanism can lead to fetal
compromise especially of the fetal brain, and developmental delay in
children after birth. These changes may be seen even in mild
hypothyroid cases, but their severity is directly related to the severity
of the condition itself. The placenta lacks the ability to boost the transfer
of maternal thyroid hormones into the fetus in pathological conditions
of thyroid hormone deficiency (5).
The fetal hypothalamo-pituitary-thyroid axis starts functioning by the

12th week and is fully developed by the 16th week of intrauterine fetal
life. The level of free thyroxine usually reaches adult levels by 16
weeks of fetal life, and continues to increase with gestational age.
Similarly thyroid stimulating hormone (TSH) reaches adult levels by
the 20th week, and peaks by the time of birth (6). The fetus becomes
244
more dependent on its own thyroid hormones during the second half
of the pregnancy. Assessment of fetal thyroid function has been made
possible with cordocentesis, as documented by Thorpe Beeston and
Nicolaides in 1993 (7). Administration of thyroid releasing hormone
to pregnant women showed rapid increase in the level of fetal TSH
from the 25th weeks of pregnancy. Fetal TSH levels have been found
to be higher in hypoxic growth retarded fetuses, anaemic fetuses
from red cell isoimmunized pregnancies, and chromosomally
abnormal fetuses especially those with trisomy 21. These changes
were agreeable with previous results reported by the same group two
years earlier (8). Higher levels of TSH and lower T4 and free T4 were
detected in fetal blood from small for gestational age, than those with
appropriate weight at a comparable age. They also reported
significant associations between increased TSH level and low T4, and
the degrees of fetal hypoxia and acidaemia respectively.
Thyroid function during pregnancy
There is almost 30-50% increased demand for thyroid hormones during

pregnancy. This may not be fulfilled if the thyroid gland is dysfunctional.
Beside the increased metabolic needs, certain biochemical changes
occur during pregnancy which increase the demand for more thyroxine
production:
• Increased production of oestrogens by the placenta during
pregnancy increases the hepatic production of thyroxine binding
globulin (TBG) which results in lower levels of free T4.
• There is increased renal blood flow, glomerular filtration rate and
loss of iodine in urine starting from early pregnancy.
• There is increased stimulation of the thyroid gland during the first
trimester by the high levels of human chorionic gonadotrophin,
which has thyrotrophic effect.
• Changes in peripheral metabolism of thyroid hormones occur
during pregnancy under the effect of placental type 3 iodothyronin
deiodinase.
The relationship between maternal hypothyroidism and fetal brain
development is well documented. Children born to women with
untreated or inefficiently managed hypothyroidism had lower IQ levels.
They also had more difficulty in schools, compared to other unaffected
siblings. Such impairment may occur even after mild or even subclinical
maternal hypothyroidism as reported by Pope and Glinoer in 2003 (9).
In general, the more severe the maternal condition, the worse the fetal
and newborn outcome. Women living in parts of the world deficient in
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iodine, and without iodine supplementation are also at risk. The ideal
situation will be for all women to start their pregnancies in a well-
compensated thyroid function. This is especially so since the increased
demand for thyroxine was evident as early as the 5th week of gestation,
as shown by patients already on thyroxine replacement therapy (10).
This increased demand was shown to start even earlier in patients who
conceived after in vitro fertilisation treatment. This is due to the high
level of oestrogens which usually follows controlled ovarian
hyperstimulation with gonadotrophins. There is a parallel increase in
the level of TBG as well, with significant reduction in the level of free
T4. Oestrogen levels as high as those seen during the mid trimester of
pregnancy (4000 – 6000 pg/ml) have been reported in these cases by
the time of human chorionic gonadotrophin injection (11). This will put
a strong argument in favour of screening women at risk of having
subclinical hypothyroidism with TSH and free T4 before controlled
ovarian hyperstimulation is started. The group includes patients
with personal or family history of autoimmune disorders including
vitiligo, past history of thyroid disease, lipid disorders and chronic
anovulation. Regular screening of these women during pregnancy can
be useful as well. On a different subject, a detrimental effect of
hypothyroidism on maternal blood pressure has also been recorded.
Pre-eclamptic patients had significantly elevated TSH level, and those
with low total T4 / total T3 ratio had significantly higher plasma urate
concentration (12).
There is immense controversy regarding the role of subclinical

hypothyroidism with or without thyroid peroxidase antibodies on
human reproduction. More evidence has now been published showing
that both conditions could be associated with infertility, early pregnancy
loss, and preterm labour. Furthermore, women with thyroid peroxidase
antibodies are liable to develop postpartum thyroiditis (13).
Nevertheless, it is generally known that an association does not always
mean causation. In a recent report, Duliére et al in 2009 (14)
recommended that thyroid peroxidase antibodies positive pregnant
women should be supplemented with 50 μg / day of thyroxine, unless
the TSH level is < 1.0 mIU/L.
In contrast, subclinical hyperthyroidism during pregnancy has fewer

clinical consequences, and no treatment is usually required (15). On
the other hand, Grave’s disease is rare during pregnancy, and may
affect 0.1-0.4 pregnant women, usually during the first trimester
and/or after delivery. Fetal hyperthyroidism may follow passage of the
246
related TSH receptor antibodies through the placenta. The treatment

plan for patients with hyperthyroidism, and those with nodular goitre at
the time of initial diagnosis should be arranged with a medical
endocrinologist; whereas management of hypothyroidism can be
arranged locally.
Endocrine effects of thyroid dysfunction

Hypothyroidism
Thyroid gland hormones play an important role in modulating the

hypothalamo-pituitary-ovarian axis function, which could be affected
negatively in cases of thyroid gland dysfunction. Thyroxine has
receptors at the level of the ovaries (16), and has also been shown to
exert a direct effect on granulosa cells function (17). Such direct action
has been documented previously by Channing et al in 1981 (18), in
cultured granulosa cells. They showed that thyroxine augmented the
action of gonadotrophins on granulosa cell luteinisation and secretion
of progesterone. Histologically, women with high TSH were shown to
have reduced progesterone effect at the level of the endometrium, with
higher incidence of out of phase biopsies than women with normal TSH
(19). On the direct hormonal side, hypothyroidism is associated with
high prolactin levels due to the secondary increased production of TRH,
which stimulates prolactin production. This can have a direct effect on
the hypothalamus affecting the pulsatile release of gonadotrophin
hormones releasing hormone (GnRH). This in turn can lead to abnormal
gonadotrophins production, mainly LH. In severe cases this leads to
disruption of the hypothalamo-pituitary-ovarian axis, with resultant
anovulation, and occasionally abnormal uterine bleeding. Furthermore,
secondary hyperprolactinaemia can have direct effects on the
gonadotrophs and ovaries, at post receptors level. The LH surge is
usually first to be affected leading to abnormal ovulation with a short or
inadequate luteal phase. This can lead to polymenorrhoea, heavy
menstruation or even infertility in the long term. The long-standing
effect in severe cases is hypoestrogenic amenorrhoea, which can affect
bone density as well. Other secondary effects of hyperprolactinaemia
can be seen in the adrenal glands, through direct inhibition of adrenal
enzymes. One example is reduction in the activity of 3β-ol
dehydrogenase. This will result in reduced incorporation of the Δ5
precursors into the Δ4 pathways, resulting in increased production of
DHEA which is converted peripherally into more potent androgens. The
other enzyme mostly quoted to be affected by hyperprolactinaemia is
21-hydroxylase.
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Low thyroxine levels also lead to reduced hepatic production of sex

hormone binding globulin (SHBG), reducing the binding sites for
androgens and oestradiol. This leads to decreased total plasma
concentration of testosterone and oestradiol, with an increase in their
free fractions. There is usually decreased metabolic clearance rate of
androgens, despite their increased peripheral aromatisation to
oestrone (20). This can also occur at the level of the hypothalamus
leading to abnormal GnRH pulse production, with disrupted
gonadotrophins secretion. Occasionally, basal production of
gonadotrophins is not affected, but a blunt or delayed response of LH
to GnRH is seen in patients with hypothyroidism (21, 22). This
alteration in the level of gonadotrophins is restored back to normal
following medication with thyroxine, and achievement of euthyroid
state (23). At the level of the ovaries, high free androgens can reduce
oocytes maturation capacity, and granulosa cell mitotic activity. They
also reduce FSH and LH receptors as well as the activity of the
aromatase enzyme, with ultimate anovulation and development of
polycystic ovaries. Androgens also have detrimental effects at the level
of endometrium.
Effects of hypothyroidism
The diagnosis and management of neonatal and childhood thyroid

diseases are the domain of paediatricians and paediatric
endocrinologists, and are beyond the remit of this chapter. Suffice to
say that fetal hypothyroidism does not affect the development of the
reproductive tract, whilst untreated congenital hypothyroidism can lead
to dwarfism, mental retardation, and lack of sexual maturation. The
effect of hypothyroidism on pubertal development has already been
discussed in Chapter 2. Starting before the age of puberty,
hypothyroidism can delay the onset of pubertal development. In a few
cases isosexual precocious puberty follows stimulation of the pituitary
gonadotrophs by the increased level of TRH, leading to increased
production of gonadotrophins, mainly LH. This point should be
considered when dealing with patients presenting with abnormal
pubertal development.
It is more usual for gynaecologists to see patients with

hypothyroidism presenting with menstrual dysfunction. This can be in
the form of polymenorrhoea, menorrhagia, oligomenorrhoea or even
amenorrhoea. Excessive bleeding can be due to altered hepatic
production of factor VII, VIII, IX and XI (24). The reported incidence
of menstrual irregularities in women with hypothyroidism declined
248
over the years. Figures of 50-70% were quoted previously, but a

figure of 23.4% has been recently quoted in a group of 171 patients
by Krassas in 2000 (25). These differences may be a reflection of the
early diagnosis of these problems in recent years, before they
became severe enough to adversely affect the HPO axis. Accordingly,
thyroid indices should be investigated in all women who present with
menstrual dysfunction. All the biochemical / endocrine changes
associated with hypothyroidism, mentioned before, can also result in
involuntary infertility. The exact incidence of this problem is difficult
to ascertain, as infertility clinics’ statistics do not represent the exact
population prevalence. Furthermore, the problem is confounded by
the fact that symptomatic hypothyroid patients are usually treated in
primary care clinics. This may occur even before infertility becomes
an issue. Moreover, such treatment restores normal fertility in most
patients. The issue here will be antenatal monitoring instead.
The situation is even more difficult with subclinical hypothyroid cases,

because of the differences in the criteria used by different authors to
reach a diagnosis, mainly the upper normal TSH cut-off level. More cases
of subclinical hypothyroidism were diagnosed when a TRH stimulation
test was used rather than a basal TSH level. In a different approach,
Raber et al used the TRH stimulation test to follow the reproductive
performance of patients with mild hypothyroidism already on thyroxine
medication. Patients who never achieved a basal TSH <2.5 mIU/L or
TRH stimulated TSH <20 mIU/L had lower conception rate in a 5 year
follow up study (26). Furthermore, they also reported more frequent
miscarriages in women with higher basal TSH levels. Many cases of
subclinical hypothyroidism were associated with ovulatory dysfunction,
with a prevalence of 1-4% in infertile patients. In one study, Bohnet et
al (27) reported improvement of luteal serum progesterone, and 20%
pregnancy rate after treating women with subclinical hypothyroidism
with levothyroxine in a daily dose of 50 μg. The problem regarding the
association of subclinical hypothyroidism and infertility has been
plagued by the lack of well designed randomized and controlled clinical
trials as suggested by Poppe et al in 2007 (28). However, there is enough
evidence to show that patients with subclinical hypothyroidism are more
vulnerable during induction of ovulation and controlled ovarian
hyperstimulation for assisted reproduction treatment. The increased
oestradiol level increases TBG production as mentioned previously, and
reduces free T4 level, inducing a state of hypothyroidism especially
during conception cycles. A similar effect can be induced by HRT, and by
using the combined oral contraceptive pill for family planning or cycle
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control for abnormal uterine bleeding. Even women with normal thyroid
gland function may show high TSH and total thyroxine blood levels in
these circumstances. Nevertheless, the free T4 fraction will be
unaffected. In previous years, free thyroxine index was used to
investigate thyroid status during pregnancy and in women using HRT or
oral contraceptives, because of the high oestrogen-induced TBG levels.
It was obtained by multiplying total T4 times T3 uptake. This has been
replaced nowadays by direct measurement of the free T4 fraction.
On a different note, care should be taken when investigating tubal

patency in patients with subclinical hypothyroidism, as they are at risk
of developing clinical hypothyroidism after hysterosalpingoraphy, using
oil–soluble iodinated contrast medium (lipiodol) (29).
Thyroid autoantibodies
Euthyroid patients with thyroid peroxidase antibodies will be discussed

separately in this section. Autoimmune thyroid antibodies are found in
5-10% of women within the reproductive period, and make the most
common autoimmune disorder in women. Such autoantibodies are
more often associated with infertility in patients with endometriosis
(30) and polycystic ovary syndrome (31). Furthermore, the pattern in
most studies showed increased incidence of such autoimmune
antibodies in infertile women compared to parous controls with a
relative risk of 2.1 (27). The most dramatic association of these
autoantibodies has been with pregnancy outcome and postpartum
thyroiditis. This subject is still shrouded with controversy, but more
evidence now points toward a detrimental association. Most work
showed normal pregnancy rates in patients with thyroid autoantibodies.
Nonetheless, increased incidence of early pregnancy loss has also been
documented in these cases. Miscarriage rate figures of 53% and 23%
were reported for patients with and without thyroid autoantibodies
respectively, following assisted reproduction treatment cycles (32).
Three to five folds increase in miscarriage rates have also been reported
in euthyroid patients with thyroid autoantibodies (33, 34). This risk was
independent of the presence of anti nuclear or anti cardiolipin
antibodies for miscarriages in spontaneously pregnant women (35, 36).
Furthermore, Abbassi-Ghanavati et al in 2010 have reported a
detrimental effect of antithyroid peroxidase antibodies on the placenta
(37). They documented threefold higher placental abruption rate in
antibodies positive (1.0%) compared to antibodies negative pregnant
women (0.3%).
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An association between thyroid autoantibodies and reduced thyroid

reserve has been shown, with a tendency of these patients to become
hypothyroid during pregnancy and controlled ovarian hyperstimulation.
Higher levels of TSH and lower levels of free T4 have been reported in
patients after controlled ovarian hyperstimulation, in comparison to
pre-treatment levels (38). Furthermore, significantly higher TSH and
lower free T4 levels were seen during the first 10 weeks of pregnancy
in women with thyroid autoantibodies compared to antibodies negative
women (39). These endocrine changes figured in one of the three
theories used to explain the increased risk of early pregnancy loss in
patients with thyroid autoantibodies by Kaprara and Krassas in 2008
(40). Another hypothesis suggested that the presence of such
antibodies was just a reflection of a more generalised autoimmune
problem which resulted in fetal tissues rejection. The third hypothesis
suggested that women with thyroid antibodies usually conceived at an
older age than others who had no autoantibodies, because of the
related infertility. Consequently, the increased risk of age should be
taken into consideration in these cases. Many arguments have been put
forward in support of each of these different theories, which are beyond
the remit of this chapter. However, it was evident that there were no
contradictions between these 3 hypotheses. They might be variably
functional together or separately in different individuals, to different
degrees. It remains to be said that the real pathophysiological
association between thyroid autoantibodies and early pregnancy
miscarriages awaits further clarification. Reduction of thyroid reserve in
patients with thyroid peroxidase antibodies is further demonstrated by
a relative risk of 12.9 for developing long-term thyroid dysfuncion if a
patient developed postnatal hypothyroidism as well. This relative risk
reached 32 in patients who also showed hypoechoic thyroid changes on
ultrasound scans (41).
Various reports documented contradictory outcome following thyroxine

medication during pregnancy on the miscarriage rate in euthyroid
women with thyroid autoantibodies. This was true even for the same
investigators as a beneficial effect was reported when larger numbers
of patients were re-examined (42, 43). Negro et al reported
miscarriage rates of 3.5% and 13.8%, and premature delivery rates of
7.0% and 22.4% in the thyroxine treated and untreated groups
respectively; p<.05 (43). On the whole, some beneficial effects for
thyroxine treatment on pregnancy outcome have been shown, but
further work needs to be done to establish this fact beyond any doubts.
This is especially so for pregnancies that followed assisted reproduction
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treatment, as the strain on the thyroid gland had already started during
controlled ovarian hyperstimulation with gonadotrophins.
Selenium and thyroid function
Many articles have been published in recent years regarding the

importance of selenium in relation to thyroid function. A positive
correlation was reported between selenium blood levels and the volume of
the thyroid gland (44). Its importance stems from the fact that
selenoproteins play an important role in the redox system, and for
enzymatic reduction of hydro-peroxidase in the thyroid gland, thus
protecting it from excessive hydrogen peroxide and reactive free oxygen
species (45, 46). Furthermore, selenium dependent enzymes have
modifying effects on the immune system (47), especially on the
development of autoimmune thyroid disorders (44). In addition, selenium
deficiency during pregnancy and the puerperium may trigger postpartum
thyroiditis (45). Similarly, many articles have also demonstrated reduction
in thyroid peroxidase antibodies (48 - 50), as well as well as improvement
in mood and general wellbeing (51) following selenium medication.
Supplementation during pregnancy and the postpartum period reduced
thyroid inflammatory activity and the incidence of hypothyroidism as
reported by Negro et al in 2007 (49). Withdrawal of supplementation
resulted in sharp drop in selenium blood level, and marked increase in the
level of the thyroid peroxidase antibodies (50). This is a an important
subject as supplementation of women with subclinical hypothyroidism and
peroxidase positive euthyroid women with daily doses of 100 – 200 μg of
selenium may help in slowing down the progress of the disease. However,
unlike levothyroxine medication, selenium supplementation during
pregnancy did not reduce the incidence of preterm deliveries as reported
by a recent Cochrane database review (52).
Effects of hyperthyroidism
Hyperthyroidism is defined as a TSH concentration <0.10 mIU/L with an

elevated free T4 level (53). It may affect 2% of women between the ages
of 20 and 50 years. The majority of cases are due to Grave’s disease, with
15-20% caused by nodular goitre (54). Uncontrolled thyroxine
medication can be an important factor as well. Hyperthyroidism leads to
increased hepatic production of SHBG, as well as blood haemostatic
factors. Such hypercoagulable state is evident even in patients with
subclinical hyperthyroidism (55), which is generally diagnosed when TSH
levels are persistently <0.10 mIU/L with normal free T4 concentration.
Thyroxine also modifies GnRH pulsatility, and increases the sensitivity of
252
the pituitary gland to GnRH stimulation. This may result in increased

production of gonadotrophins by the pituitary gland, mainly LH.
Consequently, there is increased production of testosterone and
androstenedione by the ovaries. There is also reduced clearance of
oestradiol leading to a hyperoestrogenic state with hyperthyroidism. The
final outcome is 2-3 fold increased production of oestradiol during both
the follicular and luteal phases of the menstrual cycle. Despite these
biochemical changes, many women with hyperthyroidism ovulate
regularly, as shown by endometrial biopsies (56). Nonetheless, they have
low luteal phase serum progesterone, despite having regular
menstruation. As for hypothyroidism, the quoted incidence of menstrual
irregularities in women with hyperthyroidism declined over the yeas for
the same reason. A figure of 21.5% has been quoted within a group of
214 thyrotoxic patients by Krassas in 2000 (57).
Information regarding the prevalence of infertility in women with

hyperthyroidism is not readily available. A figure of 5.8% has been
reported by Joshi et al in 1993 (58). Menstrual irregularities were
reported in 22% of hyperthyroid patients, with hypomenorrhoea
and polymenorrhoea being the most common (52% and 32%
respectively). The prevalence of hypomenorrhoea reflects the
increased concentration of the clotting factors alluded to before. Such
menstrual abnormalities were 2.5 times more common in hyperthyroid
patients in comparison to a control group (59). Patients usually respond
well to treatment with carbimazole, but it should not be used by women
who are planning to get pregnant. Propylthiouracil should be prescribed
instead, as it is safer to use during pregnancy. Management of
hyperthyroidism should be agreed with a medical endocrinologist, who
should set the general management plan. Normal ovulatory function
may not resume quickly, despite correction of the blood TSH and free
T4 levels. The effect of hyperthyroidism on the pituitary gland may take
longer time to correct. These patients may still show exaggerated LH
production by the pituitary gland in response to GnRH stimulation test,
for many weeks after initiating treatment with carbimazole, and the
correction of the peripheral biochemical blood picture.
It is usually easy to diagnose overt hyperthyroidism because of the

associated symptoms of weight loss, sweating, tremors, palpitations
and occasionally eye signs. Nonetheless, many women may live with
subclinical hyperthyroidism without being aware of its existence. The
incidence of subclinical hyperthyroidism has been reported as 1.5% in
the general population (59, 60). Accordingly, the condition should be
kept in mind in gynaecology clinics when dealing with patients
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presenting with menstrual irregularities, especially hypomenorrhoea or

polymenorrhoea. This is especially so in the presence of high blood
levels of FSH, LH and oestradiol. On the other hand, subclinical
hyperthyroidism is less detrimental during pregnancy and treatment
does not improve pregnancy outcome, with an increased risk of fetal
exposure to antithyroid drugs.
The thyroid gland and menopause
The incidence of thyroid disease increases with age, more so in women

than men. The prevalence of overt and subclinical conditions in
postmenopausal women has been reported as 2.4% and 23.2%,
respectively by Schindler in 2003 (61). Within the subclinical group,
73.8% were hypothyroid and 26.2% hyperthyroid, as reported by the
same author who recommended routine screening of thyroid function
during the climacteric period.
The importance of thyroid gland dysfunction during the postmenopausal

period is related to the following three points:
1. Many symptoms of thyroid gland dysfunction are similar to
hypoestrogenic ones, and can be missed accordingly. A long list
includes memory loss, depression, neuromuscular complaints,
loss of energy, dry skin, cognitive impairment in hypothyroid
patients, and vasomotor symptoms with hyperthyroidism. All
these symptoms can be seen even with mild thyroid dysfunction.
2. Many cases of thyroid dysfunction are subclinical, and both the
doctor and the patient may not be aware of the condition.
Accordingly, there is real danger of converting a subclinical case
of hypothyroidism into an overt one by prescribing HRT.
3. Thyroid dysfunction at this age group is associated with different
health risks including cardiac problems and osteoporosis.
Increased cardiac risks are related to increased serum
cholesterol and low density lipoprotein cholesterol, as well as
reduced levels of high density lipoprotein. The most common
symptom related to subclinical hyperthyroidism in this age group
is cardiac arrhythmia, and 15% may develop thromboembolic
complications. An adjusted hazard ratio of 1.98 was reported for
atrial fibrillation in 65 year old women with subclinical
hyperthyroidism in comparison to a normal control group (62). A
population based study published by Parle et al in 2001 (63)
showed 2-3 folds increased mortality in women aged 60 years or
older with subclinical hyperthyroidism within 2-5 years after a
254
single measurement of low TSH. Yet again, in another population

based study involving older women with an average age of 69
years, Hak et al (64) found subclinical hypothyroidism to be a
strong indicator or risk factor for atherosclerosis and myocardial
infarction, with odd ratios of 1.7 and 2.3 respectively. The
association was even stronger for thyroid autoantibodies positive
women with subclinical hypothyroidism. The corresponding odd
ratios for atherosclerosis and myocardial infarction were 1.9 and
3.1 respectively. On the other hand, a significant increase in
osteoporosis risk is related to hyperthyroidism, both clinical and
subclinical. This stresses the need for strict control of the
hyperthyroid state, and for oestrogen replacement therapy to
counteract this detrimental effect.
It is evident by now that both overt and subclinical thyroid dysfunctions

could pose significant health related issues on postmenopausal women.
The involvement of gynaecologists in well woman and postmenopausal
management clinics dictates that thorough knowledge of this
information is essential. There is reduced need for thyroxine with
advanced age. Accordingly, care should be taken when prescribing
thyroxine, because of the age related increased incidence of
cardiovascular diseases. Accordingly, a small starting dose of 25 μg /
day should be used, when indicated. The dose can be increased slowly
with equivalent amounts every few weeks to avoid cardiovascular
complications. Similarly, overdosing with thyroxine can lead to
osteoporosis. The situation is rather reversed with HRT. Oestrogen
medication though beneficial for both the acute and late menopausal
symptoms, it can convert patients with subclinical hypothyroidism into
clinical cases. In return, the thyroxine dose may need to be increased
for patients already on medication. All this information stresses the
need to ascertain thyroid function and cardiovascular status before
starting such medications in patients at risk of clinical or subclinical
hypothyroidism or hyperthyroidism. Though treatment of patients with
subclinical thyroid dysfunction is controversial, it has been
recommended that such treatment should be considered in women
with TSH ≥10 mIU/L, symptomatic women with subclinical
hypothyroidism and TSH value <10 mIU/L, and in women with
subclinical hyperthyroidism who have TSH level <0.1 mIU/L (65).
Interpretation of thyroid indices
Within a gynaecology outpatient setup, thyroid gland investigations

are usually indicated in patients with abnormal pubertal development,
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ABDEL -GADIR
menstrual dysfunction, infertility, recurrent miscarriages,

galactorrhoea and high prolactin level, premature ovarian failure,
excessive weight gain, and during investigations of symptomatic
postmenopausal women. This is especially so in patients with family
history of thyroid disease, personal or family history of autoimmune
dysfunction, history of thyroid surgery, thyroid enlargement, and in
patients with symptoms or signs suggestive of thyroid dysfunction.
Serum TSH and free T4 are the basic investigations usually started
with. The effect of HRT and oral contraceptives on TSH and total T4 has
been alluded to before. In certain cases assessment of free T3 and
thyroid peroxidase antibodies will be needed. These indices can be
interpreted as follows, as documented by MacFarlane in 2000 (54):
• Blood tests should be repeated in asymptomatic patients with high
TSH level > 10 IU/L and free T4 <10 pmol/L to confirm the
diagnosis, guard against laboratory errors and to avoid treatment
of patient with transient thyroiditis.
• Secondary hypothyroidism should be excluded in patients with
persistent low free T4 and normal TSH.
• TSH blood levels > 5 mIU/L with normal free T4 indicate
subclinical hypothyroidism in asymptomatic women. These tests
should be repeated together with thyroid peroxidase antibodies.
Patients with confirmed readings but negative peroxidase
antibodies should have regular follow up with similar blood tests.
In contrast, patients with similar readings and positive peroxidase
antibodies need treatment with thyroxine.
• High TSH level with normal free T4 in a patient already on
thyroxine usually reflects irregular medication. She should be
encouraged to take her medication regularly, and to test
compliance with further blood tests.
• Normal free T4 and T3 with undetectable TSH level in a patient
taking thyroxine is not an indication to reduce the dose.
• A normal TSH level usually excludes thyrotoxicosis, except with
TSH producing pituitary tumours.
• Undetectable or low TSH blood level should suggest a diagnosis of
thyrotoxicosis, if confirmed with high levels of free T4 and T3. In
some cases only T3 level is raised.
At this point it is important to emphasise the need for regular follow up
of patients with subclinical hypothyroidism. Within a 10-years follow up
period, 34% of 154 women with a similar diagnosis progressed to overt
hypothyroidism (66). The most important predictor for such conversion
was the presence of thyroid peroxidase antibodies. In a clinical
256
perspective published as early as 2001, McDermott and Ridgway (4)

emphasised the clinical importance of this entity and recommended L-
thyroxine treatment for symptomatic patients, those with relevant
cardiovascular risk factors or goitre, those who tested positive to
thyroid peroxidase antibodies, and pregnant women.
Summary
This chapter has been written with gynaecologists and the

gynaecological patients in mind. Women with frank hypo-or-
hyperthyroidism are usually diagnosed and managed in-between the
primary care unit and a hospital medical endocrinologist. Nevertheless,
many patients with thyroid dysfunction present for the first time with
gynaecological problems. At the same time, many others will be seen
by gynaecologists while under treatment, or had previously been
treated for a thyroid problem. The high incidence of hypothyroidism
both overt and subclinical in women, and their correlation to disturbed
reproductive function dictate that gynaecologists should be aware of
the diagnosis and management plan of such patients, both in the
pregnant and non-pregnant states. This entails thorough awareness of
the several interactions between the HPT axis with the corresponding
ovarian and adrenal ones. The effects of exogenous oestrogens
including the oral contraceptive pills and HRT, other medications,
assisted reproduction treatment and pregnancy on the function of the
thyroid gland should be appreciated. Other autoimmune disorders
should be kept in mind when dealing with patients with personal or
family history of autoimmune thyroid disease. Common autoimmune
disorders tend to coexist and cluster in families. The frequency of
another autoimmune disorder was reported by Boelaert et al as 9.67%
and 14.3% in patients with Grave’s disease and Hashimoto’s thyroiditis,
respectively (67). The list included Addison’s disease, vitiligo, coeliac
disease, systemic lupus erythematosus and pernicious anaemia.
Accordingly, the same authors recommended that patients with
autoimmune thyroid disease should be screened for other autoimmune
disorders, especially when they present with new or nonspecific
symptoms.
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263
Chapter 12
Premenstrual Syndrome and Dysphoric Disorders
It is estimated that 80-90% of women develop some premenstrual

symptoms, mainly emotional (1), during their reproductive years which
indicate imminent start of menstruation. They are usually referred to
as premenstrual moliminal symptoms, which can be physical,
psychological or behavioural. They cause transient discomfort in the
majority of cases, and are relieved by the onset of menstruation.
Conversely, 30-40% of these women are significantly affected and need
to seek medical advice. A diagnosis of premenstrual syndrome (PMS) is
made in these cases. A definition suggested by Magos and Studd for
PMS in 1984 (2) was: ‘a condition which manifests with distressing
physical, behavioural and psychological symptoms in the absence of
organic or underlying psychiatric disease, which regularly recurs during
the luteal phase of each menstrual (ovarian) cycle and which
disappears or significantly regresses by the end of menstruation’.
Traditionally, these patients were considered to have abnormal or
excessive reaction to the normal premenstrual withdrawal of oestrogen
and progesterone. They almost always have used different remedies
including evening primrose for many months, before seeking medical
advice. The symptoms may be severe enough to affect quality of life in
2-9% of menstruating women (3). These are mainly in the form of
major mood disorders which completely disrupt every day-to-day
activity; hence the name premenstrual dysphoric disorder (PMDD) has
been introduced. This name replaced the term ‘late luteal phase
dysphoric disorder (LLPDD)’ in 1993, on the recommendation of the
American Psychiatric Association. Obese women who performed less
exercise, and had lower academic achievement were thought to be
more at risk. A lower prevalence is usually seen in women who use
hormonal contraception (4). The most frequent PMDD symptoms
include anger/irritability, anxiety/tension, feeling tired and lethargic,
mood swings, feeling sad and depressed, and increased interpersonal
conflicts. Such premenstrual problems are not a creation of present day
women, as they have been known since the times of Hippocrates who
wrote ‘shivering, lassitude and heaviness of the head denote the onset
of menstruation’. Most likely with delayed childbirth pattern and smaller
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family size nowadays, more women are exposed to repeated

menstruations than their ancestors who were more likely to be
pregnant or breast feeding more frequently at the same age group.
Accordingly, they were less exposed to a similar predicament. It is
usually forgotten that 5-15% of women have positive changes
premenstrually, with improved physical activity and sexuality (5). There
are no known criteria to distinguish this group from those who usually
suffer premenstrually.
Aetiology of PMS
The range of premenstrual symptoms is wide and includes physical,

psychological, and behavioural problems. Headaches, forgetfulness,
lack of concentration, insomnia or hypersomnia, fatigue, apathy, hot
flushes, irritability, anger, panic attacks, mood swings and loss of self
control are common. Other symptoms include clumsiness, being tearful
and over sensitive, food cravings, breast tenderness, bloating
sensation, swelling, constipation and diarrhoea. It is noticeable that
almost >90% of the symptoms are psychological or behavioural, which
may be a reflection of some chemical changes in the brain during that
period of the cycle.
Two different major endocrine theories have been put forward over the
years as possible causes of PMS and PMDD:
• The ovarian hormones theory hypothesised that lack of
progesterone or reduced progesterone / oestrogen ratio during
the late luteal phase are responsible for these adverse symptoms.
This was the basis why progesterone medication has been used
for many years and in different forms in an attempt to control
these premenstrual symptoms. Evidence from meta-analysis of
randomised controlled studies showed that progesterone was not
more effective than placebo in this respect, and did not support
the use of progesterone in the management of patients with
premenstrual syndrome (6)
• The serotonin theory is more plausible, as lower platelets
serotonin content and maximum velocity (Vmax) of serotonin
uptake by platelets have been shown during the luteal phase in
women affected by PMS than a normal control group, as reported
by Ashby et al in 1988 (7). The importance of this finding relates
to the fact that platelets are believed to be a peripheral model for
central serotoninergic neurones, as stated by the same authors.
Furthermore, the serotonin theory has been supported by good
266
clinical response after medical treatment with selective serotonin

reuptake inhibitors (SSRI) to replenish brain serotonin activity.
According to this theory, normal cyclic fluctuation in the level of
oestrogen and progesterone triggers brain biochemical changes in
susceptible individuals. A relationship has been found between a
decline in oestrogen level and altered serotonin brain activity (8).
This concept has been supported by the observation that 85% of
women with PMS had hot flushes at the same time, compared to
15% of women with no PMS (9, 10). Furthermore, oestrogen
therapy has been shown to improve clinical depression by double
blind clinical trials in oestrogen deficient patients (11, 12).
Other non-endocrine theories have been put forward as well, but they
are beyond the remit of this chapter. They included sociocultural,
psychosocial, as well as cognitive and learning theories. Suffice to say
that they had related most premenstrual symptoms to psychological
causes, internal conflicts and previous experiences, which could lead to
maladaptive strategies to cope with the onset of menstruation.
A recent breakthrough came with a discovery of genetic predisposition

to PMDD in a preliminary report published by Huo et al in 2007 (13). A
variant of oestrogen receptor alpha gene, together with a variant form
of catechol-o-methyltransferase gene (COMT), were found in women
with PMDD. COMT is an enzyme involved with prefrontal lobe activation,
which is an important regulator of mood. This genetic finding may
explain the familial predisposition to PMDD. About 70% and 36% of the
daughters of affected and unaffected women respectively were
similarly inflicted with PMDD (14). This discovery does not contradict
with the general consensus accepting the serotonin hypothesis as the
most credible cause of PMDD. Women with these genetic variants may
be more prone to react badly to CNS serotonin deprivation.
All age groups between menarche and the menopause can be affected
with PMS or PMDD, though they are more common in the third and
fourth decades of life. This can be genuine statistics, but may be a
misrepresentation of reality. Younger women especially teenagers may
be affected, but their symptoms can be related falsely to unstable
teenage hormonal changes and indiscretions. Due to restrictions in
medical services, information is lacking regarding the incidence of PMS
and PMDD in developing countries. Furthermore, talking about
menstruation related issues is a taboo not to be discussed. Most of the
research relates to richer societies. Nevertheless, community studies in
these richer nations showed no racial differences in the prevalence of
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PMDD, though some differences were reported in the mode of

presentation, and type of symptoms. Food cravings were reported more
frequently by black women (15), whereas mood changes and weight
gain were more common in white women (16).
It is always important to make sure that the presenting symptoms are

not just premenstrual magnification of chronic depression, or some
other psychiatric disorder. PMS and PMDD start after ovulation and are
relieved after the onset of menstruation. Few women may have
different levels of chronic or background psychiatric diseases, which get
worse premenstrually. Accordingly, a prospective diagnostic calendar
will be more appropriate to help in making the right diagnosis. The
patient should document the nature of her symptoms, and rate their
severity on daily basis for a period of at least 2 cycles in relation to
menstruation. She should also record their effects on her personal
wellbeing. This will help in excluding patients with predominantly
psychiatric problems including depression, anxiety, panic and bipolar
affective disorders being treated in a gynaecology outpatient clinic. It
is also important to appreciate that all mild forms of these problems are
considered to be risk factors for the development of PMDD. Other
predisposing factors include history of sexual abuse and domestic
violence. Medical problems which can simulate PMS and PMDD should
be sought and excluded. Examples of such diseases include anaemia,
thyroid diseases and hyperprolactinaemia. Pelvic endometriosis is
another disease which can confound the picture, as it may be
associated with migraine headaches and bloating sensation.
Diagnosis of PMDD
It is not unusual for a patient to see many practitioners before her

symptoms are taken seriously. There was general acceptance at one
time that such symptoms are normal part of menstruation.
Retrospective history may not show the exact extent of the problem, or
the range of symptoms suffered by the patient, hence the need to keep
a prospective calendar as mentioned before.
General history and medical examination can be useful in directing the

diagnosis toward a specific medical problem. Weight loss, tremors,
sweating, shortness of breath, dry skin and excessive or painful
menstruation, premenstrual dyspareunia and dyschezia are helpful
symptoms or signs to elicit. They can direct the clinician to such medical
conditions as thyroid disease, anaemia and endometriosis just as
examples. Maternal or family history of PMDD and history of sexual
268
abuse, infertility, family violence, previous psychiatric diseases, and

alcohol abuse are also important to elucidate.
Imaging techniques are not useful, and there are no confirmatory

endocrine tests pathognomonic of the condition. Nevertheless, blood
tests will be necessary to exclude medical conditions such as anaemia,
thyroid disease and hyperprolactinaemia. Furthermore, serum
progesterone level estimations in women who had a hysterectomy can
be used to relate the patients’ symptoms to their ovarian cycle.
Transvaginal ultrasound scanning may show a corpus luteum.
Frequently, thorough medical history and a charted calendar of
symptoms may prove to be more diagnostic in this respect. The most
important symptoms are irritability, anxiety, anger and depression.
According to the American Psychiatric Association, the presence of 5 or
more of the following symptoms is necessary to make a diagnosis of
PMDD (17), after ruling out other possible causes. Furthermore,
symptoms should be severe enough to affect the quality of life, and at
least one of the first four symptoms should be included in a 2-months
prospective study:
1. Marked depressed mood;
2. Marked anxiety;
3. Marked affective lability;
4. Persistent and marked anger;
5. Decreased interest in usual activities;
6. Lethargy;
7. Marked change in appetite;
8. Hypersomnia or insomnia;
9. Sense of being overwhelmed or out of control;
10. Physical symptoms.
Treatment
Treatment of patients with PMS and PMDD should start with the
recognition of the problem itself by the doctors involved. Patients do not
need to see many practitioners before their problems can be addressed.
PMS and PMDD are not imaginary problems in the heads of the inflicted
patients. In most cases these patients had different medications for
many months if not years, while waiting to find proper medical
attention.
Patients should be encouraged to change their lifestyle. This should

involve changes in eating habits, as small and frequent meals can
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reduce the risk of mood swings. It has been shown that intracellular
uptake of glucose can be impaired during the premenstrual period (18).
More physical activity, especially aerobic exercising reduces stress and
has temporary favourable effect on mild cases. All these attempts are
less likely to be effective in moderate or severe cases. Historical advice
given to these patients included reduction of caffeine intake and
smoking to reduce irritability and insomnia. Increased consumption of
salt and sugars to satisfy premenstrual cravings can result in bloating
sensation and rapid weight gain (19). Accordingly, these items should
be avoided and high fibre food used instead.
Definitive medical treatment
All medical problems, mentioned before, which may be contributing to

the patients’ sufferings should be treated effectively. Excessive
menstrual bleeding and dysmenorrhoea should be addressed as well,
as they add to the patients’ sufferings. Endometriosis is one problem
which can demoralise these patients. Waiting in expectation for
premenstrual and menstrual pain may have a negative impact on the
patient’s morale in anticipation of her periods. Changes in most
dimensions of quality of life were significantly associated with pain as
reported by Cox et al in 2007 (20). They also found that role limitation
due to emotional problems and mental health were associated with pain
during sexual intercourse and bladder and bowel function.
Furthermore, the repeated sense of disappointment of having a period
by an infertile woman who is keen to conceive should be taken into
consideration. This is especially so with the undue family pressure
endured by women in certain circumstances, and after repeated
unsuccessful infertility treatment attempts. The role of counsellors in
such cases is very important, and patients should be encouraged to see
one, despite the common reluctance shown by many patients.
There is enough evidence to treat patients with PMDD with one of the
many selective serotonin reuptake inhibitors (SSRIs) available. They
have direct effect by improving the brain serotonin deficiency. Few
patients may not be agreeable to use antidepressants, because of the
stigma attached to them. Fluoxetine is the most widely used SSRI for
PMDD, in a dose of 20 mg/day. It can be used continuously during
the whole month to start with, before being restricted to the
symptomatic luteal phase of the cycle. This later luteal phase regimen
can be effective for many women as a primary protocol from the start
of medication (21). Fluoxetine has been found to be more effective in
patients suffering mainly from premenstrual depression and fatigue.
270
Patients suffering from irritability, anxiety and insomnia are better

treated with sertraline. It is evident that SSRIs are not equally
effective in all aspects of PMDD. Accordingly, changing the brand with
another one is indicated if a patient does not respond to the initial
medication. The only tricyclic antidepressant with any benefit in the
treatment of PMDD is clomipramine, because of its potent
serotoninergic activity. An important side effect of SSRIs is loss of
libido, which can be a problem for a patient already suffering from
PMDD. This can worsen what is remaining of her marital relationship.
An alternative line of management should be pursued in these cases,
and for patients not agreeable to use antidepressants.
Despite the fact that PMDD is related to ovulatory cycles, blocking

ovulation with oral contraceptive pills may not cause significant relieve
of symptoms in all cases (22, 23). There is even increased incidence
of headaches, pelvic pain, bloating sensation and breast tenderness
during the hormone free intervals, compared to the 21 days while the
pill has been taken (24). This negative effect was attributed to the
progestogen fraction of the pill, irrespective of it chemical type. In fact
one community based study published by Joffe et al in 2003 (25)
reported mood deterioration in 16.3% of women who took the pill.
Previous history of depression was found to be the only significant
predictor of this effect in this study (odds ratio, 2.0; 95% CI, 1.1-3.8).
Shortening the hormone free period can be of benefit in many cases,
as well as using extended or continuous contraceptive regimens.
Contraceptive pills with the progestogen fraction changed to
drospirenone, which is a mild diuretic, have been shown to be
effective with both the physical and psychological symptoms (26, 27).
Accordingly, they can be used as the first line of treatment by willing
patients, and those who are seeking contraception as well.
Drospirenone also has antimineralocorticoid effect, and can counteract
oestrogen induced aldosterone production. This can potentially reduce
water retention and weight gain. A further option is to insert a mirena
system, and to use transdermal oestradiol patches or gel continuously.
The mirena system liberates 20 μg of levonorgestrel daily into the
uterine cavity, and protects the endometrium against the sustained
effect of continuous oestradiol medication. It has secondary
beneficial effects by reducing menstrual blood loss and improving
dysmenorrhoea, and accordingly the patient’s morale.
Vitamin B6 (pyridoxine) is another medication which has been used

for many years for the treatment of PMS. Conclusions from published
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randomised placebo controlled trials were limited by the low quality

of most of those trials (28), but in daily doses of 100 mg it is likely
to relieve symptoms related to PMS and premenstrual depression.
Nevertheless, it can lead to peripheral neuropathy, and patients
should be advised to stop taking it, if they had any peripheral tingling
sensation or numbness. The routine use of diuretics in the
management of patients with PMDD or PMS is not indicated. Loss of
salt and water stimulates several hormonal systems to compensate
for the changes in sodium and water balance. This includes the renin-
angiotensin-aldosterone system, vasopressin secretion, and the
sympathetic nervous system which may have important clinical
implications (29). Rebound fluid retention and weight gain may occur
when medication is stopped. The only exception for a useful diuretic
is spironolactone which has been shown to affect both mood swings
and physical signs related to PMS or PMDD (30, 31). This effect was
thought to be related to the steroidal structure of the spironolactone
molecule rather than its diuretic effect (26, 27). This explains the
beneficial effect of oral contraceptive pills containing drospirenone
which is a derivative of spironolactone. Yasmin (Bayer plc) is one pill
with 30 μg ethinyloestradiol and 3 mg drospirenone.
There is also a place for gonadotrophins releasing hormone (GnRH)

analogues in downregulation of the pituitary gonadotrophs, and
reducing the production of gonadotrophins, mainly LH. This leads to
anovulation, and a hypoestrogenic state. Prolonged use of such
medication is not recommended, because of its effect on reducing bone
mineralization. When needed for more than 3-6 months, an add-on
medication is necessary to sustain normal oestrogenisation. This can be
offered in the form of continuous oestrogen and progestogen
medication, or in the form of livial (Schering-Plough) which is made of
oestrogen, progestogen and androgens. Another disadvantage of this
medication is the expensive cost of repeated GnRH injections, but it can
be used for a short period of time to give another medication, used in
parallel, ample time to take effect.
Treatment of specific types of symptoms
It is not unusual for women to present with one or two specific

premenstrual problems in repeated months. Dealing with such patients
is occasionally difficult, but success is very rewarding. It is usually
easier to monitor and rank symptoms when dealing with one or two
problems than in patients presenting with vague unrelated symptoms.
In most cases, relapse can occur if medication is suspended.
272
Occasionally, patients may be symptomatic during few months only for

no obvious reasons. The most common of these problems are
premenstrual breast pain, premenstrual migraine headaches, severe
anxiety and insomnia, panic attacks, and severe bloating sensation.
The help of a fellow psychiatrist may be needed for patients

presenting with anxiety, depression or panic attacks as they may be
part of genuine psychiatric problems not revealed during the
gynaecological clinic interview, or by the symptoms chart filled by the
patient. Different medications other than SSRIs are available, and the
patient may need to stay on one or more of them for a long period
of time, rather than just premenstrually. Buspiron hydrochloride is a
useful drug in cases of anxiety, especially for patients who developed
sexual dysfunction on SSRIs medication (32). It acts on 5-HT1A
receptors, and it usually takes a couple of weeks before response to
treatment is noticed.
Premenstrual mastalgia
It has been estimated that about 70% of women affected with PMS
present with premenstrual mastalgia as their main symptom. Breast
examination usually reveals no abnormality, except for extreme
tenderness. The inflicted patient may not be able to wear her usual
brassier. Different studies showed no specific endocrine derangement
to account for this presentation, including prolactin estimations.
Similarly, different medications have been tried with different effects
including tocopherol (vitamin E), evening primrose, bromocripine and
danazol. Despite its popularity as a prime medication for this specific
problem, evening primrose has generally not shown significant
beneficial effects on PMS or PMDD symptoms in controlled clinical trials
(33). A useful drug in this respect is danazol which can be used in a
small daily dose of 50-100 mg during the luteal phase of the cycle. It
should be avoided in women with hyperandrogenic tendency, but it
showed no detrimental effect in normal women. Similarly, bromocripine
proved to be useful in treating premenstrual mastalgia. Paradoxically,
luteal phase medication in a dose of 1.25 mg twice daily proved to be
more effective in the management of breast pain than a similar dose
given continuously (34).
Premenstrual migraine
Premenstrual migraine headaches may be the only problem a woman

presents with. It is occasionally seen in women taking different brands of
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oral contraceptive pills. Stopping the pill may or may not resolve the
problem, and the patient may get disheartened in persistent cases.
Ultimately, she will have MRI and other investigations to exclude brain or
other intracranial pathologies. It is not unusual for migraine headache to
be a manifestation of oestrogen withdrawal in many women.
Nevertheless, the initial treatment should be similar to that provided for
migraine occurring at other times during the cycle. This should include
lifestyle modifications, and use of appropriate therapy to reduce the
attack symptoms, its duration and disability (35). Eventually a time
contingent therapeutic trial of oestrogen therapy during the luteal
phase and menstruation time can relieve the headache in many women
(36-38). Continuous, but not cyclic, use of combined oral contraceptives
reduces the hormonal fluctuations during the cycle, and can
reduce menstrual migraine attacks frequency. This medication has
extra hormonal effects by acting on associated comorbidities like
dysmenorrhoea, menorrhagia and endometriosis. A study by Ferrero et
al in 2004 (39) showed that women with endometriosis were twice at risk
of having migraine headaches, and at a younger age than a control group
(38.3% vs. 15.1% respectively). In a different study, Tietjen et al (40)
looked at women with migraine as the primary study group, and reported
higher prevalence of endometriosis than in non headache controls.
Furthermore, they showed that women with endometriosis and migraine
had more frequent disabling attacks of migraine than women with
migraine but no endometriosis. Additionally they had more menorrhagia,
dysmenorrhoea and infertility than other patients with migraine only and
normal controls. Nonsteroidal anti inflammatory drugs can be used when
oestrogen medication is contraindicated, and can also help with any
coexistent dysmenorrhoea. Acute attacks may be better controlled by a
tryptamine based drug, including sumatriptan and rizatriptan. They can
abort an attack within 30-90 minutes in the majority of patients, but
recurrence of the migraine even within the same day is a possibility. They
act by binding to 5-HT1 receptors in cranial blood vessels and nerve
terminals; hence causing vasoconstriction and reduce pain. For safety
reasons, they should not be used at the same time with SSRIs. Together
they can cause the serotonin syndrome (serotonin toxicity). Patients may
present with nausea, diarrhoea, headache, sweating, muscle twitching,
tachycardia, high blood pressure, hyperthermia, tremors, hyperreflexia,
mental confusion, hallucinations, and might end up in coma (41). The
main treatment strategy in such cases is to stop all serotoninergic
medication, and the syndrome will resolve spontaneously. In more severe
cases supportive care should be provided to the patient as necessary,
depending on her symptoms and signs.
274
Summary
Premenstrual dysphoric disorders are disabling medical problems which

can affect the quality of life of up to 9% of menstruating women. They
also increase the risk of major depressive disorders and postpartum
depression. They are an important cause of family disruption, and
should be taken seriously. Patients should be followed prospectively
with a symptoms chart for two months, to make a detailed and proper
diagnosis. Normally the symptoms are present only during the second
half of the cycle, and disappear after the onset of menstruation.
Patients with symptoms spilling into the follicular phase suffer from
other psychiatric conditions, which should be managed within that
context. Different medications are available for different symptoms,
and supportive counselling should be offered when necessary. Patients
should also be encouraged to change their life style in relation to
healthy dieting, more exercise, and to avoid smoking, caffeine intake,
pure sugars and salt. There is no evidence that most of the alternative
therapies taken by many patients have any benefit more than a placebo
effect. It is important not to neglect the effects of the comorbidities
associated with PMDD, and patients should be treated within a total
multidisciplinary management plan.
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B, Nordenström S. Oral contraceptives in premenstrual syndrome:
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278
Chapter 13
Female Hormonal Contraceptives
A functional account about progestogens, androgens and oestrogens

has already been given in Chapter 5. It included the metabolic,
morphological and endocrine effects of these three different steroids. It
will be an impossible task to write about all brands of the hormonal
contraceptives available worldwide. Many good brands are licensed in
certain but not other countries. Accordingly, this chapter is not
meant to give a detailed account of such different variations, or the
instructions on how to use different contraceptives. It is written with the
following objectives in mind, avoiding repetition of previously discussed
issues:
1. A broad account of the different types of female hormonal
contraceptives and their mode of action;
2. The non-contraceptive benefits of hormonal contraceptives;
3. Use of hormonal contraceptives by patients with known medical
problems;
4. Complications and risks of hormonal contraceptives;
5. Emergency contraception;
6. Perimenopausal contraception.
Types of hormonal contraceptives and their mode of action
Despite the great advances in the field of family planning over the last
30 years, oestrogens and progestogens remained the cornerstones for
hormonal contraceptives, though newer means for their delivery have
been introduced. Beside the oral route, transdermal, transvaginal and
intrauterine routes have been used effectively, and with great
acceptance by women. Progestogens played the major part in hormonal
contraception, and are mostly derived from three parent steroid
molecules which are estranes, gonanes and pregnanes. These molecules
differ in relation to their half lives, and their antioestrogenic effect.
Furthermore, gonanes have 17 carbon atoms, whereas estranes have
18. The range of progestogens used includes norethindrone,
norethindrone acetate, ethynodiol diacetate, norgestrel, levonorgestrel,
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norethynodrel, desogestrel, norgestimate, and gestodene. The last

three are derived from the gonane molecule, and are known as the third
generation progestins. Other gonane derivatives include norgestrel
and levonorgestrel. Estranes include norethindrone, norethindrone
acetate, ethynodiol diacetate, and lynestrenol. Pregnanes include
medroxyprogesterone acetate and megestrol acetate, and they have no
androgenic activity. They are used in the injectable forms of hormonal
contraceptives. The sequence of ascending androgenicity of the
different progestogens used is: ethynodiol diacetate, norethindrone,
norethindrone acetate, norgestimate and desogestrel, in that order.
Levonorgestrel and gestodene have the highest androgenicity in all
groups. This information is of great value when selecting a specific brand
of contraceptive pill, especially when dealing with hyperandrogenic
patients. Furthermore, progestogens of lower androgenic capability
are less likely to oppose the oestrogen induced hepatic production
of sex hormone binding globulin and high density lipoprotein (HDL).
A new spironolactone analogue (drospirenone) which has anti-
mineralocorticoid, anti-androgenic and progestational activities has
been used in oral contraceptive pills, mainly for women with polycystic
ovary syndrome and premenstrual dysphoric disorder.
In contrast to the long list of progestins, only two oestrogens are used
in the majority of combined hormonal contraceptives; ethinyl oestradiol
and mestranol. Ethinyl oestradiol is pharmacologically active, whereas
mestranol has to be converted into oestradiol first before gaining
biologically activity. Oral contraceptives currently in the market contain
20 - 35 micrograms of oestrogen. Pills with 50 μg ethinyl oestradiol
are still available, but are used for the management of certain
gynaecological problems when high doses of oestrogen are needed,
rather than for regular contraceptive purposes. Unlike all the other
routes, orally taken ethinyl oestradiol is absorbed rapidly from the
intestines and undergoes rapid metabolism in the liver during the first
hepatic pass which reduces its biological efficacy by almost 40%. It has
plasma half life of 10-27 hours, with a longer half-life in tissues, such
as the endometrium. This first hepatic pass affects different liver
functions, including increased production of clotting factors, sex
hormone binding globulin, transcortin, thyroid binding globulins, as well
as changes in the lipid profile. This may have direct positive or negative
effects on different individuals, depending on their own circumstances,
such as patients with hypothyroidism on thyroxine replacement
therapy. Such hepatic first pass does not occur with the transdermal
route, which can be of benefit especially for patients at risk of
thromboembolism.
280
Hormonal contraceptives can be used in different forms:
Oral contraceptives
Oral contraceptives can be used either in a combined oestrogen and

progestogen form, or as progestogens only pills. Regular brands of the
combined form have 21 pills, either in monophasic, biphasic or triphasic
combinations. Monophasic pills have the oestrogen and progestogen in a
fixed dose in the same pill for the whole 21 days. Biphasic and triphasic
brands have oestrogen and progestogen pills in two or three different
doses to be taken in sequence respectively. The idea behind these different
combinations was to reduce the total amount of hormones used, and to
simulate the variations in oestrogen and progesterone which occur during
a natural ovulatory cycle. Newer brands of oral contraceptives have been
manufactured to reduce the hormone free period by increasing the
number of pills to be taken each cycle. Brands with 24 or 26 instead of 21
pills have been marketed. The main objective behind this regimen was to
have better control of the bleeding episodes, and to reduce the
premenstrual symptoms suffered by the patients during the hormone free
period. Such brands are sold in the United States, but are not licensed yet
in the United Kingdom. An extended protocol to use oral contraceptive pills
for 84 days before having a withdrawal bleeding proved useful for patients
with endometriosis and severe premenstrual syndrome. Seasonale
(Duramed Pharmaceuticals, Inc) is a brand which contains 30 μg ethinyl
oestradiol and 150 μg levonorgestrel. Yet again, despite the wide increase
in the number of brands of combined hormonal contraceptives currently
available, suppression of ovulation and local uterine changes remained to
be the most important modes of action. These are affected through the
synergistic effects of both oestrogen and progestogen. Nonetheless, in
most cases the contraceptive efficacy is linked to the progestogen part,
with oestrogen controlling regular bleeding.
Unlike oestrogens, progestogens can be used separately to provide

adequate contraception. Progestogens only pills have been available for
a long time, and are sometimes known as mini pills. They are mainly
used when oestrogen is contraindicated. This is especially so in cases
at risk of cardiovascular diseases and venous thromboembolism. They
are also a good choice for lactating women requiring contraception, as
they do not affect milk production, and do not influence the infant’s
growth or development. Unlike the combined forms, they should be
used continuously and at the same time every day without a break.
Different brands are available and their main contraceptive effects have
been related to the following points:
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• They increase cervical mucus viscosity which reduces

transcervical sperm migration into the uterine cavity. This effect is
maximal four hours after intake. The pills should be taken at the
same time every day, as serum levels fall to baseline levels within
24 hours after ingestion. Other precautions should be taken for 48
hours if taking a pill is delayed for more than 3 hours.
• They can inhibit activation of the enzymes necessary for sperm
capacitation which is required for ovum penetration.
• They slow ovum transport through the fallopian tubes, which may
increase the risk of tubal pregnancies.
• They reduce embryos implantation due to their progestational
histological effects on the endometrium. Progestogens deplete their
own receptors and oestrogen receptors in the endometrium.
Biochemically, progestogens reduce the production of glycogen in the
endometrium, and accordingly reduce the ability of the blastocyst to
survive in the uterine cavity.
• Small doses of progestogens as used in the progestogen only pills
do not usually inhibit ovulation, and many women continue to
ovulate normally. Occasionally, only the LH surge is affected
despite growth of the follicles to a mature size. This explains the
increased risk of functional ovarian cysts seen in patients using
progestogen only pills.
Injectable contraceptives
The two main injectable forms are depo-medroxyprogesterone acetate

(depoprovera) and combined injectable contraceptives (CICs), both
being long acting contraceptives. Depoprovera can be used in a dose of
150 mg every 3 months. Its blood level peaks approximately 10 days
after drug administration, and sustain high blood levels capable of
inhibiting ovulation by direct action at the hypothalamus and pituitary
gland. It also has a strong progestational effect at the level of the
endometrium. Amenorrhoea is common after the third dose in almost
50% of the users, with the majority of the remaining group having
irregular bleeding episodes (1). After one year of use, about 75% of the
users will be amenorrhoeic. It may take up to 200 days for the drug to
clear off the circulation following a single injection, as documented in the
Depoprovera Product Monograph (2). This slow decline in the level of
serum progestogen is responsible for the long period of amenorrhoea and
delayed return of fertility. It took 9 months after the last injection on
average for women to conceive as reported in the same Monograph (2).
In comparison to intrauterine contraceptive devices (IUCD) and
oral contraceptives, 92% of women conceived within 2 years after
282
discontinuing depoprovera, 93% after IUCD and 95% after stopping the
pill (2). Partial reactivation of the hypothalamo-pituitary-ovarian axis
may allow basic folliculogenesis to restart leading to development of
mature follicles, with failure of the LH surge mechanism. This will prevent
the final act of ovulation, or may lead to abnormal ovulation and
dysfunctional uterine bleeding. Being a strong antioestrogen, it has been
associated with the development of osteoporosis. This effect has been
quantified by the Product Monograph alluded to before (2), which
reported 5-6% reduction in the spine and hip bone mass density after 5
years of depoprovera use. This decline was more pronounced during the
first two years of medication. This effect was not carried through during
the postmenopausal years as shown by a World Health Organisation
study, which showed similar bone mass density in women who did or did
not use depoprovera (3). Furthermore, young women in their teenage
years are more likely to regain their bone mass density within 12 months
after stopping medication. An advantage of depoprovera is that it has no
androgenic effect. Furthermore, it does not affect the level of triglycerides
or total cholesterol (4), and has no significant detrimental effect on the
liver function, coagulation factors, fibrinolysis, or blood pressure.
Alterations in carbohydrate metabolism similar to those imposed by the
oral contraceptive pill can follow depoprovera administration, but to a
lesser extent and with minor clinical significance (5). More information
about depoprovera has been given in Chapter 5. Another injectable
progestogen is Noristerat, which is made of 200 mg norethisterone
enanthate. It should be given by deep intramuscular injection on the fifth
day of the cycle for short term effective contraception, when patient’s
compliance is not guaranteed regarding the pill. It can be repeated after
eight weeks if necessary. It has similar mode of action to depoprovera,
but menstrual irregularities are less common.
Combined injectable contraceptives (CICs) contain both oestrogen and

progestogen, and are given by monthly intramuscular injections. Their
mode of action is similar to that of the combined oral contraceptive pill,
with similar range of side effects and contraindications, but without the
first hepatic pass. They offer better cycle control and quicker return of
fertility after suspending medication than the progestogen only
injections. There are three main types of CICs including Cyclofem,
Mesigyna and Deladroxate. Cyclofem (cyclo-provera) contains 25 mg
depo-medroxyprogesterone acetate, plus 5 mg oestradiol cypionate.
Mesigyna is made up of 5 mg oestradiol valerate and 50 mg
norethisterone enanthate. Deladroxate contains 10 mg of oestradiol
enanthate and 150 mg dihydroxyprogesterone acetophenide. The first
dose should be given within the first 5 days of menstruation, and
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repeat injections administered every 28 days. They offer an error

margin of 5 days only. Because of their depo effect, ovulation and
fertility usually return 2-3 months after the last administered dose (6).
A recent Cochrane database systemic review showed that more women
using CICs had normal bleeding, and fewer of them stopped using
them because of bleeding reasons than progestin-only users (7).
Another advantage of CICs is that there is low incidence of
amenorrhoea, after their prolonged use. Despite all these advantages,
this method is not very popular yet, and is not licensed in many
countries. Nevertheless, it can be very useful in developing countries
as it needs less compliance than the oral contraceptive pill.
Subdermal contraceptives
Research in subdermal implants started in 1967 which resulted in the

introduction of Norplant in 1983 in Finland, before being used in other
countries. It was licensed for 5 years, but has been withdrawn from the
UK in 1999. Another discontinued brand was Jadelle, which was made
of two rods each containing 75 mg levonorgestrel. The only licensed
brand in the UK now is Implanon, which is a single subdermal 4 cm rod
with 68 mg etonogestrel dispersed in ethylene vinyl acetate core. It is
covered by 0.06 mm rate-controlling membrane. During the initial
stages, it releases 60 - 70 μg/day, which declines to 25 - 30 μg/day by
the end of the third year. It is licensed to be used for 3 years after
insertion, and should be inserted subdermally usually in the upper arm
under aseptic conditions. The same incision used for removing the old
rod can be use to insert the new one. It has the same mode of action
as depoprovera, and almost similar indications as well. There is also
increased risk of irregular uterine bleeding, which makes the
commonest cause for removing the rod. In all, good cycle control was
reported by only 28% of women over a period of 3 years (8). Other
statistics showed 30-40% amenorrhoea throughout the 3 years, 30%
infrequent bleeding and 10-20% prolonged bleeding episodes. Its
contraceptive and cycle control efficacy is decreased if hepatic enzymes
inducing drugs such as rifampin, carbamezapine, phenobarbitol and St.
John’s Wort are used at the same time.
Transdermal contraceptives
In recent years transdermal combined oestrogen and progestogen

contraceptive patches became available. They have the same mode of
action and efficacy as the combined pill, regarding suppression of
ovulation, cycle control and cervical mucous viscosity (10). They have
284
an extra advantage, as the absorbed hormones do not pass through the

liver first. This reduces the production of all oestrogen dependent
hepatic factors, which occurs following the first pass through the liver. A
once-weekly Evra patch (Janssen-Cilag Ltd) can be used for 3 weeks
starting on the first day of menstruation, followed by one patch-free
week. Each patch delivers 33.9 μg ethinyl oestradiol and 203 μg
norelgestromin daily into the systemic circulation. To reduce the risk of
ovulation the patch should be changed every 7 days irrespective
whether menstruation has not started or bleeding has not stopped yet.
A new patch may need to be replaced in less than 2% of the cases
because of complete detachment. Contraindications for using combined
oral contraceptives are valid for the patch as well. Furthermore, one
follow up study showed that women younger than 20 years of age were
less likely to use the patch properly, compared to the contraceptive pill
(11). This method is more suitable for women in their twenties or thirties
who are not very compliant with the daily routine of the oral
contraceptive pill, and are not keen on other methods.
Intrauterine devices
The mirena system (Bayer) is a levonorgestrel impregnated intrauterine

system which is becoming widely used for contraceptive purposes, as well
as for control of excessive menstrual blood loss. It is made of a polymer
cylinder containing 52 mg of levonorgestrel mounted on a T-shaped
frame. It releases 20 μg of levonorgestrel every day into the uterine
cavity, through a hormone rate limiting membrane covering the device.
It acts as a contraceptive through the same 4 mechanisms described for
other progestogens earlier on in this chapter. It does not inhibit ovulation
in the majority of cases. There is occasionally an initial period of abnormal
uterine bleeding which usually settles within 3 months. Patients should
be counselled accordingly to prevent unnecessary premature removal of
the device. Eventually, the amount of blood loss and bleeding days will be
reduced, and 20% of women may become amenorrhoeic after one year
(12). This beneficial effect has been used to avoid surgery with
reasonable results in patients with uterine fibroids. Few studies showed
reduction in blood loss and regression of the uterine size, with or without
diminution in the fibroids mass (13, 14). This effect was thought to be
secondary to inhibition of the endometrial growth factors. Nevertheless,
such devices can be used only when the cavity is not significantly
affected by any fibroid. The system is licensed for 5 years following its
insertion into the uterine cavity. Unlike cupper containing intrauterine
contraceptive devices, it is not licensed for postcoital emergency
contraception.
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ABDEL -GADIR
The mirena system has no metal component and accordingly different ultrasound
characteristic to CuT devices, but still more echogenic than a Vcu200 device.
Figures 42 - 44 show sagittal uterine transvaginal ultrasound views with a
CuT device, mirena system and Vcu200 device correctly sited inside the
cavity respectively. Note the progressively softer echogenic patterns created
by the mirena system and Vcu200 device compared to the sharp echo created by
the CuT.
When available, 3D ultrasonography can be helpful in showing the exact

type of IUCD, especially with the less commonly used and less
echogenic Vcu200 device.
Figure 45 shows a transvaginal

ultrasound scan coronal view of a uterus
with a normal looking triangular cavity
and a Vcu200 contraceptive device in
situ.
Intravaginal contraceptives
Vaginal rings with combined oestrogen and progestogen, and

progestogen only medication are gaining popularity as reversible
contraceptive means in certain parts of the world. One example of a
combined oestrogen and progestin ring is NuvaRing (Schering), which
is available in the United Kingdom market. It is a flexible one size ring
(54 mm) made of ethylene vinylacetate copolymers and magnesium
stearate. It liberates 15 μg ethinyl oestradiol and 120 μg etonorgestrel
daily into the vagina. It should be inserted into the vagina on the first
day of menstruation by women who did not use hormonal contraception
in the preceding cycle. On the other hand, women who are using any
form of combined hormone contraception can switch to use the ring on
any day, the latest being the day following the usual hormone free
interval. It can be used for 3 weeks, followed by seven ring-free days
286
every month. Personal application is easy by squeezing the ring during

its insertion into the vagina, while squatting, lying down, or with one leg
lifted up on a chair. It does not need to stay in any specific shape or
position within the vagina. Its mode of action is similar to other
combined contraceptives. The ring can be removed for cleaning but
replaced within 3 hours to maintain proper contraception. Good cycle
control was reported by 98% of users (15). Nevertheless, 2-5%
reported device-related problems including vaginal discharge, vaginal
discomfort and problems during intercourse in the same study. This last
problem can easily be overcome by removing the ring during
intercourse, but replacing it immediately thereafter. The grace period
for changing vaginal rings is longer than for transdermal patches.
Accordingly, one ring can be used continuously for 4 weeks, and
changed immediately on the same day after that with a new one, to
avoid onset of menstruation if desirable. Leaving the same ring in the
vagina for more than 4 weeks reduces its contraceptive efficacy, as
advised by the manufacturer’s patient information sheet. There is also
a small risk that NuvaRing can be accidentally expelled from the vagina
during intercourse, with straining during a bowel movement, and while
removing a tampon.
Progestogen-only vaginal rings are also available in certain countries,

with different durations of action. They act through their progestational
effects on the cervical mucous and endometrium, as for other
progestogen contraceptives. Progering (Andromaco Laboratories,
Chile) is a brand suitable to extend the contraceptive effectiveness of
lactation in breastfeeding women. It was initially tested for 3 months
(16), but a more recent study showed that it is effective for 4 months
without affecting breast-feeding or the rate of infant growth. It also
prolonged the period of lacational amenorrhoea (17). The ring can be
removed for comfort during sexual intercourse, but additional
contraception will be necessary for one week if it has been removed for
more than 3 hours. Bleeding disturbances are common, as for other
progestogen only contraceptives.
Efficacy of hormonal contraceptive
The statistics used to compare the efficacy of different contraceptive

methods is usually documented as failure per hundred women years.
This estimate of efficacy refers to the first year of use, though the
longer a woman uses a contraceptive method, it is less likely for that
method to fail. It is important to understand that failure rate depends
on many factors which can reduce the efficacy of the contraceptive
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ABDEL -GADIR
method. Parts of these factors are related to the method itself, but a
major part is related to the way it has been used. This is reflected by
failure in relation to the typical use and perfect use of the specific
contraceptive. Perfect use is a measure of efficacy when the method
has been used perfectly according to the manufacturer’s guidelines,
without fail. Failure in such cases reflects the inherent capabilities of the
method itself. On the other hand, typical use failure rate reflects the
probability of pregnancy during the first year, allowing for non-
compliance and incorrect use of the method. This is the statistics
usually quoted in the literature, which is obviously affected by many
confounders. It is understable why long acting contraceptive methods
which rely less on patients’ compliance offer similar typical and perfect
use failure rates. The perfect use failure rates of depoprovera and
Norplant are 0.03% and 0.05% respectively, with the typical use failure
rates being almost identical. This is in contrast to the other methods
which depend on the patients’ compliance. The combined oral
contraceptive pills perfect use failure rate is approximately 0.1-0.5%,
but the typical failure rate is as high as 5% (18).
Non contraceptive uses of hormonal contraceptives
Family planning remains to be the most common indication for using

hormonal contraceptives. Nonetheless, patients who need such
protection may have other gynaecological or chronic medical problems,
which make proper selection of a specific brand with a specific route of
administration more important. These issues will be discussed in the
following sections of this chapter.
1. Cycle control in oligomenorrhoea or amenorrhoea is an indication
to prevent endometrial hyperplasia and hypo-oestrogenic state.
This should be done after making a proper diagnosis of the initial
cause of anovulation. This is especially so for thyroid dysfunction
and hyperprolactinaemia, as treatment of these conditions is
most likely to correct the menstrual problem. Oligomenorrhoeic
and amenorrhoeic women with polycystic ovary syndrome are at
risk of developing endometrial hyperplasia. This increases the risk
of endometrial carcinoma. Using an oral contraceptive pill to
induce regular monthly withdrawal bleeding will reduce this risk.
Alternatively, a mirena system can be used instead. On the other
hand, young women with hypo or hyper gonadotrophic
hypogonadism are at risk of developing hypoestrogenic side
effects including osteoporosis. One option to deal with this
problem is to use a low dose oral contraceptive brand.
288
2. Treatment of abnormal uterine bleeding especially excessive

blood loss is also an indication for using an oral contraceptive
pill, or the mirena system. This is especially so in patients with
dysfunctional uterine, when no specific treatable endocrine or
organic uterine causes can be detected. This subject has been
discussed in detail before in this chapter under the subtitle
‘Intrauterine contraceptive devices’.
3. Treatment of hyperandrogenisation is an important indication
for using non androgenic oral contraceptive pills. This is affected
by inhibiting ovulation, reducing ovarian androgens production,
and increasing the level of SHBG which reduces the level of free
testosterone. It is also important to exclude other specific
treatable conditions which may increase the level of serum
androgens, including ovarian and adrenal tumours. Adult onset
adrenal hyperplasia should also be excluded, as treatment
usually entails suppression of the adrenal androgens as a
priority. The highest level of SHBG is reported after using a
combined pill with cyproterone acetate as the progestogen
fraction (Dianette, Bayer plc). The role of non androgenic
progestogens has already been discussed in this chapter. Pills
with low progestogen / oestrogen activity are preferable in the
treatment of patient with acne, but may not give the best cycle
control, and breakthrough bleeding is more likely. The direct
antiandrogenic effect of drospirenone in reducing 5α reductase
activity is well utilised in the combined pill Yasmin (Bayer plc).
4. Using an oral contraceptive pill to inhibit ovulation has been
shown to reduce the risk of developing functional ovarian cysts
while under treatment (19). This effect has been well
documented for high dose older contraceptives with 50 μg
ethinyl oestradiol, but not for the lower dosage group. Once a
cyst was formed such treatment achieved similar results to
expectant management (20, 21). A significant similar effect
has also been found with other benign ovarian tumours
including serous and mucinous adenomas, teratomas and
endometriomas (22). The reduction in risk was related to the
duration of use. Similar to functional cysts, oral contraceptives
are not useful for the treatment of these benign ovarian cysts
once they already developed.
5. Oral contraceptive pills are also used in cycle preparation during
assisted reproduction treatment cycles. This is done usually in
cases with irregular menstruation for good planning of the
treatment cycles. One protocol involves the use of an oral
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contraceptive pill after a progestogen withdrawal bleeding

episode. This is followed by daily injections of a gonadotrophin
releasing hormone (GnRH) agonist, from day 17 of the cycle to
affect down regulation of the pituitary gland. Nasal sprays can
be used instead. Controlled hyperstimulation is started within a
day or two after the withdrawal bleeding has started, usually
within a week after stopping the pill. There will be less risk of
developing an ovarian cyst following the GnRH agonist
during such a protocol. Accordingly, a similar protocol can be
prescribed for patients who developed ovarian cysts following
GnRH agonist use during previous assisted reproduction
treatment cycles.
6. The use of oestrogens and combined oral contraceptive pills in the
management of young women with absent or delayed pubertal
development has been discussed in Chapter 2. Unopposed
oestrogen is usually a priority for some time till normal height has
been attained, before converting to an oral contraceptive pill.
7. Low dose combined contraceptive pills can also be used as
hormone replacement therapy in cases of premature ovarian
failure as discussed in Chapter 10. These patients usually need
a higher oestrogen dose than women who went through natural
menopause. Furthermore, having regular withdrawal bleeding
has a good psychological effect on these patients. Neither the
combined contraceptive pills nor any designated hormone
replacement therapy are effective as contraceptives in these
cases. Pregnancies have been reported in young women with
premature ovarian failure while on the pill. This information
should be conveyed to all patients in such a situation who
are adamantly keen not to get pregnant. Women with
anorexia nervosa are at special risk of severe hypoestrogenism.
Using a low dose combined contraceptive pill will provide the
missing oestrogen, while the patient is having the necessary
psychological treatment. This is also valid for professional
women athletes, who are at risk of the triad of amenorrhoea,
anorexia and osteoporosis.
8. Medical treatment of endometriosis also involves using different
types of hormonal contraceptives. Cyclic or continuous use of
oral contraceptive pills are two options. Recently, the extended
use of an oral contraceptive pill for 84 days has been introduced.
Depoprovera and the mirena system are also useful in this
respect. The dominant progestational effect of all these drugs is
the main factor in controlling endometriosis growth and
290
symptoms. This does not give permanent cure, and symptoms

and signs usually recur after medication is suspended.
Furthermore, such medication is not suitable for women who
are keen to conceive, which is a real limitation for this therapy.
9. The role of hormonal contraceptives in the management of
premenstrual dysphoric disorders has been discussed in
Chapter 10. Suffice to say that mixed results have been
reported about the effect of the oral contraceptive pill, and the
risk of worsening symptoms during the pill free period. This
resulted in the release of brands with 24 and 26 pills to
reduce the pill free period. Using an extended brand for 84
days, like Seasonale (Duramed Pharmaceutical, Inc), has also
been shown to improve premenstrual dysphoric disorders. It
contains 84 active pills, each containing 30 μg ethinyl
oestradiol and 0.15 mg levonorgestrel, with 7 inert tables. A
pill which gained notoriety in this respect is Yasmin (Bayer
plc), as the progestogen fraction has been replaced with
drospirenone which is a spironolactone derivative. Each pill
contains 30 μg ethinyl oestradiol and 3 mg drospirenone, and
used for 21 days with one pill-free week. Another pill with 20
μg ethinyl oestradiol and 3 mg drospirenone with 24 active
pills is marketed in America, and used especially for
premenstrual dysphoric disorders. In very severe cases, the
mirena system can be used, together with continuous
transdermal oestrogen.
10. The mirena system has a wide range of non contraceptive
benefits which have been alluded to before in this chapter.
One benefit not mentioned before, is its role in protecting
the endometrium against the chronic hyperplastic effect of
tamoxifen during treatment of breast cancer. Other benefits
include control of endometriosis induced pelvic pain, and
for endometrial protection in postmenopausal women on
continuous oestrogen replacement therapy. An extra important
benefit of the mirena system is its effect in reducing the
symptoms and size of endometriotic lesions in the rectovaginal
septum (23). This will obviate the need for the difficult
surgery necessary to deal with this pathology in most cases.
Furthermore, suggestions have been put forward to use it
immediately after endometriosis surgery to reduce the need for
further operations in the future (24). Levonorgestrel has been
found in the peritoneal fluid in significant amounts,
approximately two thirds of the serum level, in women who
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showed improvement in their symptoms after six months of

using a mirena (25). Similarly, the level of the serum marker
CA-125 showed equivalent decline after long term use of
the device as for GnRH-a, when used for the treatment
of endometriosis (26). All these effects were related to the
high levels of peritoneal levonorgestrel causing increased
programmed cell death (apoptosis), atrophy of the ectopic
endometrial glands, and decidual transformation of the stroma.
It has also been reported to have anti-inflammatory and
immunomodulatory effects (27). Furthermore, levonorgestrel
has been shown to decrease and then block DNA synthesis and
mitotic activity (28).
Other coincidental benefits of hormonal contraceptives
There are many coincidental health benefits related to the use of the
oral contraceptive pills including:
• An epidemiological study reported by Schlesselman in 1991 (29)
showed a duration-related protective effect of combined oral
contraceptive pills against endometrial cancer. The risk before the
age of 60 years was reduced by about 38% with two years of use.
Longer use for 4, 8, and 12 years, conferred 51%, 64%, and 70%
reduction in endometrial cancer risk respectively. Such protective
effect lasted for ≥15 years after stopping medication.
• Many reports documented a protective effect of oral contraceptives
against ovarian cancer in general. This risk also decreased with
increased duration of use. The adjusted odd ratio for ovarian
cancer with any past use of oral contraceptives was 0.5 (95 CI 0.3
– 0.8). A 60% risk reduction was noted after 6 years of use or more
(30). Such protective effect was noted even in carriers of BRCA1
(odd ratio, 0.5; CI 0.3 – 0.9), and BRCA2 mutations (odd ratio, 0.4;
CI 0.2 – 1.1)
• Reduced risk of functional ovarian cysts is another benefit related
to suppression of ovulation. Risk reduction was also related to the
duration the oral contraceptives use. Such benefit persisted for at
least 15 years after stopping using the pill. The protection rate in
comparison to non-users has been estimated as 30% for women
who used the pill for 4 years or less. This figure increased to 50%
and 80% for 5 – 11 years, and >12 years of the pill use
respectively (31, 32).
• Reduced risk of colorectal cancer has been documented for
patients who used oral contraceptives with 50 μg ethinyl
292
oestradiol, with a relative risk of 0.6 after 96 months of use. The

effect of low dose brands has not been verified.
• Decreased incidence of benign breast diseases including
fibrocystic changes and fibroadenomas has been attributed to
the use of oral combined contraceptives. This effect was seen
even after only one or two years of use (33), and lasted for one
year after stopping the pill (34). Conversely, the ESHRE Capri
Workshop Group in 2005 (35) thought there were significant
problems with bias, study design and interpretation of results
related to this topic. Furthermore, they thought there was no
evidence of biological plausibility. In short, they did not endorse
the idea of a beneficial effect on the breasts.
• The subject relating bone mass density to hormonal
contraception has generated a lot of contradictory results. The
osteoporotic effect of depoprovera has been discussed already.
Oral progestogens only pills do not inhibit ovarian function,
and do not have similar effect on bone density. The difficulty
with studies which addressed bone mass density has been
confounded by different factors which affect bone. Examples of
such factors included hereditary factors, age, body mass index,
smoking, level of physical exercise and diet. On the other hand,
there is some evidence of a little favourable effect of the
combined oral contraceptives on bone mineral density and
fracture risk in women of reproductive age as concluded by the
ESHRE Capri Workshop Group (35). This is despite of the fact
that oestrogen blood concentrations over the whole month are
lower in women using the combined oral contraceptive pill than
during natural ovulatory cycles. They did not endorse any
benefit on bone mass density in patients with anorexia nervosa.
Use of hormonal contraceptives by women with known medical

problems
Young women with different non gynaecological medical problems may

need contraceptive advice to prevent unplanned or unwanted
pregnancies. This occasionally creates different difficulties, because of
the direct effect of the method used on the medical condition, or its
interaction with the different drugs necessary to control her basic
medical problem. The most likely conditions to be encountered in this
age group include obesity, high blood pressure, diabetes mellitus,
migraine, hypothyroidism, pituitary adenomas and thrombophilias.
Patients with certain risk factors may also request contraceptive advice.
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This group includes women with previous history of deep vein

thrombosis, and those with personal or family history of breast cancer
Obesity
It is not uncommon for obese patients to seek contraceptive advice.

They may even have pre perceived ideas against using barrier methods
for different reasons. A more urgent situation can arise when an obese
patient presents with irregular or excessive menstrual blood loss, which
needs immediate hormonal treatment and cycle control in the long
term. Obesity is a known risk factor for venous thrombosis, pulmonary
embolism, insulin resistance, and diabetes mellitus. There is increased
risk of thromboembolism in women with BMI >35 kg/m2. The Royal
College of Obstetricians and Gynaecologists considered a BMI of 40
kg/m2 or more as a contraindication to use oral contraceptives. In fact
the risks of using oral contraceptives generally outweigh their benefits
for women with BMI of 35 to 39 kg/m2. This is coupled with a negative
correlation between BMI and the contraception effectiveness of
transdermal patches and the vaginal ring, leading to higher failure
rates. This may be due to altered steroid metabolism, and / or dilution
of the steroid dose in a larger blood volume. The evidence for an
association between oral contraceptives failure and obesity has been
conflicting. This subject has been reviewed by Brunner et al in 2006
(36). They confirmed a negative association, but the results were
largely attenuated after adjustments for age, ethnicity and parity.
Taking all the risks involved into consideration, it seems that the
preferred option for obese women is a mirena system. The revised
Depoprovera Product Monograph in 2006 (3) reported variable results
related to weight gain after using the product. The majority of studies
reviewed showed weight gain of 5.4 lbs (2.5 kg) at the end of one year.
Other studies reported weight gain of 8 lb (3.5 kg) by the end of the
second year, but 20-40% of depoprovera users actually lost weight
during treatment.
High blood pressure
High blood pressure is another possibility in patients seeking

contraceptive advice. It is a risk factor for cardiovascular events and
stroke, even in young women, who are normally expected to have a low
risk (37). The estimated annual incidence of myocardial infarction and
strokes has been reported as 1.7 and 34.1 cases per 1 million
respectively, for normotensive women aged 30–34 years. These rates
increased to 10.2 for myocardial infarction and 185.3 for stroke among
294
hypertensive women of the same age group (38). Women using

combined oral contraceptives are at increased risk of developing high
blood pressure. Certain factors are known to increase this risk,
including a strong family history of high blood pressure especially in
female relatives, and history of high blood pressure during a previous
pregnancy. Other risk factors include racial origin, age, obesity,
smoking and alcohol abuse. Duration of the oral contraceptives use is
also important. There were higher age-adjusted blood pressure levels
after 8 years of use than in women who used the pill for shorter periods
of time as reported by Lubianca et al in 2003 (39). The same authors
concluded that hypertensive women on oral contraceptives had
significant elevation of diastolic blood pressure and poor blood pressure
control, independent of age, weight and antihypertensive drug
treatment. In a subsequent publication Lubianca et al in 2005 (40)
reported reductions of 15.1+/-2.6 mm Hg and 10.4+/-1.8 in systolic
and diastolic blood pressure respectively after stopping oral
contraceptives use. They recommended stopping such medication as
an effective antihypertensive intervention in such a clinical setting.
This finding was agreeable with another study reported by Atthobari et
al in 2007 (41) who showed worsening of high blood pressure with
hormonal contraceptives and its improvement after discontinuation of
medication. It also showed some deterioration in renal function during
usage of hormonal contraceptives. Urine albumin excretion increased
by 14.2% in starters (P = 0.074), and fell by 10.6% after stopping
medication (P = 0.021). On the other hand, the glomerular filteration
rate fell by 6.3% in starters (P < 0.001), and did not recover after
stopping the contraceptive. The same authors reviewed previous
studies for the correlation between hormonal contraception and renal
function, in relation to these findings. Two previous studies proposed
that contraceptives use may be associated with an increased risk of
microalbuminuria, independent of the blood pressure effect. On one
hand, higher levels of albuminuria are considered as an early marker of
vascular endothelial damage, but there is no significant evidence
relating renal disease to the use of hormonal contraception. Both
pathologies are related to an increased risk of progressive renal failure
and excess cardiovascular morbidity and mortality (41).
This section can be concluded that the combined oral contraceptive pill
is better avoided by hypertensive patients, and by women liable to
develop high blood pressure. Progestogen only contraceptives can be
used instead. Nonetheless, controlled mild high blood pressure as an
isolated problem is not an absolute contraindication against using a low
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dose oral contraceptive pill. Readjustment of the antihypertensive

treatment dose may be necessary, due to stimulation of the renin
angiotensin system and aldosterone production by oestrogens. At the
same time, regular medical supervision will be needed, if the
patient opted to continue with the same medication, rather than
using an alternative method. Conversely, uncontrolled or complicated
hypertension is an absolute contraindication to use the combined oral
contraceptive pill. Other risk factors like obesity and smoking should be
taken into consideration when making the decision.
Thrombophilia and history of thromboembolism
Thrombophilia is a term used to indicate increased tendency to

intravascular coagulation. It may follow hereditary or acquired
causes. Congenital factors include factor V Leiden mutation,
prothrombin, protein C and S, and antithrombin III deficiencies. High
homocysteine and sickle cell disease are other factors to consider.
Thombophilia can also be acquired due to antiphospholipid
antibodies. Factor V Leiden forms the most common inherited
thombophilia, and 3 – 8% of Caucasians carry a copy of the mutation
in each cell. Furthermore, 1 in 5000 individuals carries 2 copies of the
mutation. The risk of thromboembolism for Factor V Leiden is >10
times more (80%) in this group than for the heterozygous state
(7%). It is less common in other ethnic groups. It is important to
note that not all thrombophilias carry the same risk of venous
thromboembolism. The lowest risk is attributed to a single mutation
such as Factor V Leiden, and the highest to antithrombin deficiency
(42). Using the combined oral contraceptive pills is associated with a
small increase in thrombosis and pulmonary embolism risks. In
numerical terms, about 20 – 30 women in every 100,000 pill users
may develop deep vein thrombosis or pulmonary embolism. Previous
history of either problem or a personal history of thrombophilia will
increase the risk. Despite the controversy regarding the increased
risk with third compared to second generation oral contraceptives,
epidemiological data confirmed this increased tendency for venous,
but not arterial thrombosis (43). Furthermore, the increased risk of
venous thromboembolism is more pronounced during the first year of
use. Other contributing factors included obesity, cigarette smoking,
immobility, fractures, surgery and cancerous conditions especially of
the pancreas. There is an exponential increased risk when genetic
factors are combined with these conditions. Accordingly, great care
should be taken to identify patients with such genetic risk factors, but
296
screening all women is not indicated before prescribing oral or other

hormonal contraceptives. Additionally, oestrogen containing pills
should be avoided in these cases when contraception is needed.
Though progestogen contraceptives, whether oral or injectable, do
not increase the thrombosis tendency in the general female
population, their role in individual women with thrombophilia has not
been investigated. Accordingly, there is an opinion that a copper
IUCD should be the first-line contraceptive method for women with a
history of deep venous thrombosis, pulmonary embolism, or coronary
events (44).
Diabetes mellitus
Classical teaching has always associated combined oral contraceptives,

and in some cases even the progestogen only brands, with changes in
carbohydrate metabolism. Such changes included decreased glucose
tolerance and increased insulin resistance, which are risk factors for
type II diabetes mellitus and cardiovascular disease. This issue has
been addressed by a meta-analysis published by Lopez et al in 2009
(45). They concluded that the current evidence showed a limited effect
for hormonal contraceptives on carbohydrate metabolism in women
without diabetes. Furthermore, they criticised many of the published
articles because of the small numbers of women involved, lack of
comparison between different types of contraceptives, and lack of
information regarding the effects among overweight women. In the
same year, Cagnacci et al (46) found that vaginal contraceptive rings
were less likely to change insulin resistance than combined oral
contraceptives. They concluded that a vaginal ring may be a better
choice for long-term contraception in women at risk for developing
diabetes mellitus or the metabolic syndrome. In a study which
addressed the effect of depoprovera injections, Xiang et al found
increased risk of diabetes which they explained by three factors (47):
1. The drug was used by women with increased baseline diabetic
risk;
2. There was associated weight gain during medication;
3. The drug was used in cases with high baseline triglycerides
and/or during breast-feeding.
All this information indicates that proper selection of the suitable
contraceptive should always take into consideration the inherent
characteristics of the drug to be used, and the risk factors shown by
each individual woman.
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Contraception is an important issue for diabetic women, as unplanned

pregnancy can induce major maternal and perinatal complications. There
was little evidence that changes in blood sugar control induced by
combined oral contraceptives had any clinical consequence as reported by
Shawe and Lawrenson 2003 (48). Furthermore, low dose combined
contraceptive pills have minimal effect on the lipid profile which may even
by beneficial. Conversely, there is some concern regarding the effect of
oral and injectable progestogens on HDL and LDL cholesterol levels.
Diabetes mellitus is a risk factor for thromboembolism and cardiovascular
diseases, but well controlled diabetes is not an absolute contraindication
for using the oral contraceptive pill. The same authors (48) stated that
short term studies of young women with uncomplicated diabetes who
were taking low-dose combined oral contraceptives have been reassuring.
On the other hand, patients with complicated diabetes and macrovascular
or microvascular changes should be prescribed nonhormonal
contraceptive methods. The same is valid for cases with uncontrolled
diabetes, or in the presence of other risk factors like obesity, hypertension
or smoking. In a different approach Nikolov et al in 2005 (49) made a clear
distinction between types I and II diabetics in relation to contraceptive
advice. They recommended the use of low dose combined contraceptive
pills in women with uncomplicated type I diabetes of less than 15 years
duration. A change in the insulin dose and control of body weight will be
needed to maintain good glycaemic control. Conversely, they advised
against using combined oral contraceptives in women with type II
diabetes, because they may provoke clinical changes and worsen the
progress of the disease itself. This last point is very much valid for
prediabetics and diabetics controlled only by diet. Further deterioration of
the glycaemic condition, which may follow using combined contraceptives,
adds a further burden on the patient to take hypoglycaemic drugs, which
also adds cost and the need for more strict compliance.
Complications and risks of hormonal contraceptives
This section will be dealt with in bullets form to focus the attention of
the reader, as most points have already been addressed before in this
chapter. Few of the complications are gynaecological in nature, but
systemic and organ specific complications or risks will also be
addressed.
• Dysfunctional uterine bleeding may follow inappropriate or
prolonged use of oral contraceptives. This is also valid for
progestogen only contraceptives whether oral, injectable or
implants. It is not unusual for dysfunctional uterine bleeding
298
following depoprovera to be unresponsive to treatment with

oestrogen or tranexamic acid. Use of further progestogens either
as norethisterone or medroxyprogesterone acetate may even
increase the bleeding problem.
• Long term amenorrhoea and delayed return of fertility potential
can follow depoprovera injections. Though 9 months after the last
dose was a figure usually quoted for return of fertility, many
women do not menstruate for much longer periods of time.
• There is increased risk of thromboembolism in obese patients and
smokers and in women >35 years of age, especially with the
combined contraceptives as discussed before.
• Osteoporosis with long term injectable progestogens is a risk
factor. It can be more significant in very lean young teenage girls
as the maximum bone density is usually attained by the age of 20
years.
• Unfavourable changes in cervical cytology have been seen in
women using combined oral contraceptive pills. Furthermore,
prolonged use of these pills has been associated with a small
increased risk of cervical cancer. Among current users of the pill,
the relative risk (RR) after 5 years of use was 1.9 (95% CI, 1.69-
2.13) compared to those who never used the pill. There was
gradual decline in the risk, which returned to normal 10 years
after stopping the pill. This pattern was seen in invasive and in situ
cancers and for women who tested positive for the high risk
human papilloma virus, as reported by the International
Collaboration of Epidemiological Studies of Cervical Cancer in
2007 (50). The same group estimated an increased cumulative
incidence of cervical cancer from 3.8 to 4.5 per 1000 women by
the age of 50 years in women who used the pill for 10 years
between the ages of 20 and 30 years, in developed countries. The
corresponding increase was from 7.3 to 8.3 per 1000 for
developing countries. The reason for this increased risk of cervical
cancer was not well elucidated, but was thought to be an
association rather than a cause and effect relationship. Women
using the pill are more likely to be sexually active and may not use
barrier contraceptive means regularly. This can put them at
increased risk of contacting human papilloma virus, which is the
likely cause of cervical cancer. Accordingly, it is important that all
women on combined oral contraceptive pills should have regular
cervical smear screening, especially if human papilloma virus
infection was detected (51). A note should be documented here
about the effect of depoprovera. An overall non significant relative
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ABDEL -GADIR
risk of 1.11 (95% CI, 0.96 – 1.29) has been reported for invasive
sqaumous cell cervical carcinoma in women who ever used the
drug. This was not affected by the duration of use, or the times
since the initial or most recent injection (2).
• The issue relating breast cancer risk to the oral contraceptive pill is
more complicated than the pill’s relationship to cervical cancer. It
is a subject which had attracted, and still attracts the attention of
the media and public. Many scares have hit the public in waves
since the 1970s, which lead to thousands if not millions of
unplanned or unwanted pregnancies, and equally distressing
terminations of pregnancies. The relationship has been
confounded by the multifactorial nature of breast cancer, which is
affected by many variables. The odd ratio is 200 for those with the
BRAC gene mutation. A figure of 3 has been reported for women
with familial history of breast cancer (52). Furthermore, many life
style and other related variables have been known to increase the
risk. The list includes lack of exercise, excessive alcohol intake,
cigarette smoking, postmenopausal obesity, early menarche, late
menopause, first full-term pregnancy after the age of 35 years,
and reduced breast feeding (53). Each of these factors increased
the risk of breast cancer more than the risks reported for combined
oral contraceptives (53). As an example of such confounders,
women who had their menarche before the age of 12 years had
30% higher risk of developing breast cancer than those who
started menstruating by the age of 15 years, as reported by ESHRE
Working Capri Group (35). A meta-analysis published by
Kahlenborn et al in 2006 (54) examined 34 studies that met
stringent inclusion criteria since 1980, for an association between
using oral contraceptives and premenopausal breast cancer in
general. A small increased risk with an odd ratio (OR) of 1.19 was
found (95% CI, 1.09-1.29). Both parous (OR, 1.29; 95% CI, 1.20-
1.40) and nulliparous (OR, 1.24; 95% CI, 0.92-1.67) women were
affected. Prolonged use did not change the OR risk for nulliparous
women. The risk was stronger when the pill was used before the
first full term pregnancy. Furthermore, the maximum risk was seen
when the pill was used 4 years before the first full term pregnancy,
with an OR of 1.52 (95% CI; 1.26-1.82). Despite all these figures,
the risk of breast cancer remains to be small, and the benefits of
using the oral contraceptive pill outweigh their risks in most
women. To put this statement into mathematical perspective,
there will be 0.5 additional breast cancers per 100,000 women 16-
19 years of age, during the time of use and 10 years follow up. The
300
corresponding figures for women in the age groups 20-24 years

and 25-30 years are 1.5 and 4.7 additional cancers per 100,000
respectively as reported by Reid in 2007 (53).
Emergency contraception
Emergency or postcoital contraception should be used to prevent

unwanted pregnancy after unprotected intercourse. It is an occasional
method and should not be used as a regular means of contraception.
Copper intrauterine contraceptive devices are the most efficient means
if inserted within 5 days of unprotected intercourse, with a failure rate
<1.0% (55). They act mainly by preventing fertilisation through the
toxic effect of copper on sperm, but impede implantation at the same
time. TT380 Slimline (Durbin PLC, South Harrow, Middlesex, UK) and T-
Safe 380A (Williams Medical Supplies Ltd, Rhymney, Gwent, UK) are
the most effective, and have the lowest failure rate. They are the
preferred method for women using liver enzymes inducing drugs, such
as barbiturates, carbamazine, rifampicin and phenytoin. Nulliparous
women could be offered the Mini TT380 Slimline, which has a small
plastic frame.
The two main hormonal means are Levonorgestrel 1500 μg tablets and
ulipristal acetate which is a synthetic second generation selective
progesterone receptor modulator. The levonorgestrel contraceptive pill
(Levonelle 1500, Bayer Schering) is licensed for use within 72 hours of
intercourse. It prevents pregnancies in 95%, 85% and 58% of the
cases if used within 24, 24 – 48 and 48 – 72 hours after the first
intercourse respectively (56). It interferes with follicular development
and impairs ovulation, with little evidence regarding inhibition of
implantation. Another tablet should be taken if vomiting occurs within
3 hours after taking the pill. It is also recommended that a woman on
liver inducing enzymes should take 2 tablets soon after unprotected
intercourse, if she is not agreeable to use a copper IUCD. Ulipristal
acetate (30 mg tablet) could be used up to 120 hours after intercourse,
and is more effective than levonorgestrel for inhibiting ovulation (57,
58). It also affects implantation, and accordingly could be used for
emergency contraception after ovulation but before the expected time
of implantation. No teratogenic effects have been attributed to either
drug, and termination of pregnancy is not indicated on this context in
cases of failed contraception. Both drugs could lead to menstrual
irregularities and delay of menstruation, which may cause patients
some concern.
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ABDEL -GADIR
An alternative method of emergency hormonal contraception is to take

4 combined oral contraceptive pills immediately after intercourse and
repeat the dose 12 hours later. Microgynon 30 (Bayer Schering) has
been recommended for this purpose (59). This may lead to nausea and
vomiting, and an anti-emetic drug may be needed in these cases. This
method is indicated if the single-tablet protocols or copper IUCD are not
available or unacceptable.
Perimenopausal contraception
Previous studies showed lower tendency by women over the age of 40

years to use contraception, with 40% opting for sterilization in the
United Kingdom (60). This pattern may change because of the
introduction of newer methods of contraception. It is important to
emphasise that no method of contraception is contraindicated on the
basis of age only, in the absence of risk factors or medical problems.
Perimenopausal women are more likely to develop high blood pressure,
diabetes mellitus, obesity and dysfunctional uterine bleeding which
make selection of an appropriate contraceptive method rather difficult.
At the same time, pregnancy at this age carries great risks for the
mother and fetus, and appropriate contraception should be guaranteed
to prevent unplanned pregnancies. The following points should be
taken into consideration when offering contraceptive advice to women
in this age group:
• It is most important to take a woman’s preference into
consideration and to discuss with her the merits and drawbacks of
her chosen method of contraception to improve compliance.
Certain taboos may be attached to the use of certain methods
which make them less acceptable in different areas and cultures.
• Women above the age of 40 years can use combined hormonal
contraceptives up to the age of 50 years, unless there are
coexisting risk factors. They should be switched to another form
by that age. The last statement is also valid for women using
injectable progestogen only contraceptives, but inherent
predisposition to osteoporosis should be taken into consideration
even in younger women.
• Smoking is a significant cardiovascular risk factor even at the age
of 35 years and in younger obese women. This risk falls
significantly one year after stopping smoking and almost
disappears 3-4 years later.
• There is 50% increased risk of thromboembolic attacks among
cigarette smokers independent of oral contraceptives use or age (61).
302
• Women with migraine, history of stroke or cardiovascular disease

should not be prescribed combined hormonal contraceptives.
• The progestogen only pill and mirena system are good options,
but there is a higher risk of dysfunctional uterine bleeding with
the former method, which made it unsuitable for many
perimenopausal women (62). They are not associated with
increased risk of thromboembolism (61, 63). Both methods can be
used by patients with previous history of ischaemic heart disease
and stroke, but the progestogen only pill should not be used
during an active thrombotic episode. The risks involved by using
injectable progestogen only contraceptives outweigh their
benefits in these conditions. The role of copper IUCD in such cases
has already been mentioned before (44).
• Monophasic contraceptive pills with ≤30 μg ethinyl oestradiol and
low dose northisterone or levonorgestrel are good first line options
for women with no risk factors who opted to use a combined pill.
The risk of venous thrombosis decreases with lower oestrogen
dose and duration of use.
• The non-contraceptive health benefits of low dose contraceptive
pills alluded to before, justify their use in healthy perimenopausal
women (63). Kaunitz viewed their use in this age group as a
general strategy not only to provide effective contraception, but
also to improve perimenopausal symptoms and to enhance quality
of life (64).
• Oral contraceptive pills with desogestrel, gestodene or
drospirenone have significantly higher risk of venous thrombosis
than other brands containing levonorgestrel, as confirmed by
Lidegaard et al in 2009 (65).
• In general, the risk of cerebral thromboembolic attacks is reduced
by >30% when using low dose pills compared to 50 μg
preparations (61). This is equivalent to one additional death per
one million low dose pill users per year in comparison to IUCD
users (66). On the other hand the General Practice Research
Study (67), and the WHO Collaborative Studies of Cardiovascular
Disease and Steroid Hormone Contraception (68, 69) showed no
increase in mortality rate from stroke or venous thrombosis in low
dose pill users.
• A copper IUCD is an alternative non-hormonal method of
contraception, but may exacerbate menstrual problems in this
age group (70). The T380 device offered contraceptive
effectiveness equivalent to surgical sterilization (71). Accordingly,
such a device may be offered to women free of any pre-existing
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menstrual problems, otherwise the mirena system should be used

if this mode of contraception is preferred (72).
• Combined HRT does not provide effective contraception and
women on such medication should use effective contraception till
the age of 55 years. This can be provided by the progestogen only
pills or a mirena system. Two FSH blood level estimations will be
needed 6 weeks after stopping HRT for confirmation of the
menopause, before contraception can be stopped (73).
Summary
The subject of hormonal contraception has been a prime issue in the

public domain many times over the last 30 years, but mostly for the
wrong reasons. Women who seek contraceptive advice are mostly
young and healthy, and can use hormonal contraceptives safely in the
majority of cases. This is a different scenario to other patients who have
known risk factors, or are currently under treatment for one or another
chronic illness. An unwanted pregnancy can cause more damage than
the small risks of inducing cardiovascular problems or breast cancer,
which are not very common in this young age group. Furthermore, the
thromboembolic risks of pregnancy exceed those related to the use of
the combined oral contraceptive pill. The medical and psychological
risks involved with termination of pregnancy should be taken into
consideration as well. Many women can not even consider the option of
having a termination, because of ethical or religious reasons, and get
stuck with an unwanted pregnancy. Accordingly, the most appropriate
contraceptive should be selected for each individual woman taking into
account her own preferences, any available risk factors, the issues
of expenses, compliance, and ease to see a medical or nursing
professional when necessary. The other non contraceptive benefits
mentioned before in this chapter should be added to the whole package
when discussing the issues related to contraception with patients.
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women under 40 years using low oestrogen oral contraceptives
and intrauterine devices in Finland form 1975 to 1984. Am J
Obstet Gynecol 1990; 163: 281 – 284.
67. Jick H, Jick SS, and Gurewich V, Myers MW and Vasilakis C.
Risk of idiopathic cardiovascular death and nonfatal venous
thromboembolism in women using oral contraceptives with
differing progestogen components. Lancet 1995; 346: 1589 –
1593.
68. WHO Collaborative Study of Cardiovascular Disease and Steroid
Hormone Contraception. Venous thromboembolic disease and
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combined oral contraceptives: results of international multicentre

case-control study. Lancet 1995; 346: 1575 – 1582.
69. WHO Collaborative Study of Cardiovascular Disease and Steroid
Hormone Contraception. Ischaemic stroke and combined and
combined oral contraceptives: results of international multicentre
case-control study. Lancet 1996; 348: 498 – 505.
70. Gebbie A. Contraception in the perimenopause. J Br Menopause
Soc 2003; 9(3): 123 -128.
71. Alexander IM. Contraceptive options for perimenopausal women.
Contracept Technol Update 1999; 20(10): 122 – 124.
72. Bhathena RK and Guillebaud J. Contraception for the older
woman: an update. Climacteric 2006; 9()4): 264 – 267.
73. FHRPHC Guidance: contraception for women aged over 40 years.
J Fam Plann Reprod Health Care 2005; 31(1): 51 – 63.
310
Chapter 14
Endocrine Investigations in Gynaecology
The term endocrine investigations is usually used erroneously synonymous

to hormonal blood tests. This concept should be changed, and the term
should be used instead to include all the available means to examine and
diagnose endocrine related problems. This is especially so as the
biochemical results are usually used to complement other diagnostic
means, and may be useless as stand alone indices. This chapter will
promote this broader concept and address history taking, clinical
examination and imaging means, as well as the biochemical tests used in
this respect. There are many different clinical scenarios when
gynaecologists need to request specific hormonal tests during the
investigations of certain cases. In other words, hormonal tests are usually
requested to verify or exclude a provisional diagnosis. These tests can also
be used to monitor patients’ response to treatment, or the progression of
the medical condition itself. There is an intricate interrelationship between
the normal physiology and pathophysiology related to the pituitary gland,
ovaries, adrenals and thyroid gland. Furthermore, many medications can
affect the function of these glands, and change their peripheral blood
indices. An important role for autoimmune disorders has already been
addressed in the previous chapters in this book, especially in relation to the
adrenals and the thyroid gland. Accordingly, gynaecologists must be able
to appreciate and address the broader clinical problems, and request the
right imaging and biochemical hormonal and non-hormonal investigations.
They should also be able to couple these numerical results together, and in
relation to the general clinical picture.
Most endocrine investigations are conducted within a gynaecological

unit because of the following reasons:
1. Abnormal pubertal development, being delayed or precocious;
2. Menstrual dysfunction being polymenorrhoea oligomenorrhoea,
amenorrhoea, or menorrhagia;
3. Hyperandrogenisation problems including acne, hirsutism,
obesity and androgenic alopecia;
4. Infertility investigations including ovarian reserve, and
monitoring ovulation induction;
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5. Management of abnormal pregnancies including ectopic or molar

gestation;
6. Perimenopausal symptoms including premature ovarian failure.
Medical history and physical examination
As for all medical problems, a thorough medical history forms the platform
for all endocrine investigations, depending on the nature of the problem
itself. The more usual questions should include the pattern of onset of the
problem being sudden or gradual, duration and progression, any relevant
related symptoms, history of excessive change in weight, exercise level,
medication or surgery, as well as the results of any previous
investigations. Symptoms suggestive of specific endocrinopathy should
also be explored, including hyperandrogenisation, fatigue, forgetfulness,
lethargy, fainting and dizzy spells, increased pigmentation, excessive hair
loss, polyurea and polydipsia. Childhood disease and developmental
history are important in relation to abnormal pubertal development,
whether delayed or precocious. History of malnutrition, chronic anaemia,
tuberculosis and other endemic diseases can give good clues to the origin
of delayed puberty in developing countries. Any significant family history,
especially of maternal age at the menopause should be elucidated.
Another good example is history of mental retardation in male siblings,
especially in cases of premature ovarian failure and fragile X syndrome.
General examination is important as well. The patient’s general look,

height, weight, and arms span are important parameters to be ascertained.
Blood pressure measurement is also important, as high levels can be seen
in patients with delayed puberty due to 17-hydroxylase deficiency, and in
patients with Cushing’s syndrome. Obesity and underweight conditions are
very important to ascertain with BMI calculations. It is difficult to give
specific scenarios about different physical outlooks, but the following
specific signs may indicate an endocrine dysfunction:
• Facial plethora may be due to alcoholism or increased cortisol
levels;
• Slow speech and reactions, lack of concentration and
forgetfulness may indicate severe hypothyroidism;
• Exophthalmos, warm damp palms, and hand tremors as signs of
hyperthyroidism;
• Very tall or short stature in relation to age, are important clues
during investigations of puberty related problems;
• Discrepancy between height and arms span are important signs to
verify; Upper to lower body ratio is also important;
312
• Greasy or dry skin could be secondary to hyperandrogenisation or

hypothyroidism respectively;
• Signs of hyperandrogenisation including, acne, hirsutism and
alopecia should be recorded;
• Excessive hair growth should be scored using the Ferriman and
Gallwey scoring system (1). A score > 8 is considered abnormal.
More information about this system and its limitations can be
found in Chapter 6.
• Enlarged thyroid gland can be a normal sign during puberty and
pregnancy;
• Breast development and staging using Tanner’s stages during
investigations of pubertal development problems;
• Sparse development or absence of axillary and pubic hair in cases
of autoimmune adrenal insufficiency. This can also be seen in
women with well developed breasts, as seen in cases of androgen
insensitivity (testicular feminisation) syndrome;
• Acanthosis nigricans at the back of the neck, in the axillae and
under the breasts have been associated with insulin resistance;
• The presence of vitiligo, which indicates autoimmune dysfunction,
is important when dealing with such cases as premature ovarian
failure;
• Low set ears, webbing of the neck, bone deformities and other
abnormal chromosomes signs;
• Galactorrhoea may be present in about 50% of cases of
hyperprolactinaemia, but can be seen in women with normal
prolactin levels;
• Purple striae ≥ 1.0 cm wide can indicate Cushing’s syndrome;
• Trunk obesity and high waist / hip ratio as signs of androgenic
obesity;
• Enlarged clitoris as a sign of marked increase in androgens
production as seen in cases of virilization, together with deepening
of the voice, body masculinization and frontal hair recession;
• Neurological signs especially in cases of precious puberty.
These are just examples of the physical signs seen in patients
presenting with problems which may have gynaecological endocrinology
background or origin. Gynaecological pelvic assessment should be
performed, when indicated.
Imaging tests
Different imaging examinations are available, depending on the condition

being investigated. Transabdominal and transvaginal ultrasound scan
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examinations are widely used to ascertain the presence and normality of

the internal genital organs. Testicles can be detected within the inguinal
canals in patients with testicular feminization syndrome. Diagnosis of
polycystic ovaries is a common objective, depending on the patient’s
presentation. The presences of 12 cysts in one or both ovaries, or an
ovarian size ≥10 cc are the two ultrasonic criteria adopted for the
diagnosis of polycystic ovaries (2). Diagnosis of functional ovarian cysts,
and endocrinologically active solid ovarian masses can be helpful in
certain cases. Adrenal masses can also be detected ultrasonically, but are
better diagnosed with MRI. Pituitary adenomas are diagnosed with MRI
which superseded the use of plain skull X-ray and CT scanning, even as
a first line imaging technique. Patients with high prolactin levels are a
prime target for this technique within the gynaecology clinic. MRI of the
brain is also indicated in cases with abnormal pubertal development to
exclude brain tumours, especially in the presence of neurological
symptoms or signs. The role of left hand and wrist X-ray in the
investigation and monitoring of abnormal pubertal development has
already been addressed in Chapter 2. Monitoring ovulation with
transvaginal ultrasound scan examination is important both for natural
cycle tracking and during induction of ovulation. A monitored natural
cycle can also reveal the length of the follicular and luteal phases,
especially in patients with short cycles. Other useful parameters include
endometrial thickness and texture, and Doppler assessment of uterine
and endometrial blood flow. The superior role of ultrasound scanning for
monitoring induction of ovulation in comparison to serial oestradiol
estimations has already been discussed in Chapter 7.
Hormonal tests
A thorough account has been given about biological testing of

oestrogens and progestogens effects and potency in Chapter 5. In a
clinical setup, the most practical similar bioassay test is the
progestogen challenge test, which is a diagnostic test for oestrogen
exposure. The most commonly used version of the test is to administer
oral progestogens for 5-7 days, before being withdrawn. An oestrogen
primed endometrium will bleed following the withdrawal of the
progestogen. This positive response is used to indicate good oestrogen
exposure, and to exclude hypoestrogenism. Negative results can occur
in well oestrogenised patients with endometrial adhesions, or other
causes of genital tract obstruction, and in cases of endometrial
tuberculosis. Accordingly, many authorities advised against the routine
use of the test, and recommended the use of blood hormone tests
instead. Pregnancy is a physiological cause for negative tests.
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Following an appropriate clinical assessment, a hormone test may be

necessary to verify or refute a provisional diagnosis. It is not
uncommon for a hormonal test to be contradictory with a well reached
clinical impression. This may be due to different causes including:
1. Most hormones are produced in pulses, and one test may not be
a true representation of the hormonal milieu. Examples of such
difficulty can be seen with FSH, LH, testosterone, oestradiol and
insulin which are the more commonly requested tests. The
coefficients of variation (SD/Mean%) for a single estimation of
these hormones relative to multiple samples examined within 6
hours have been reported as 14.7 % for FSH, 26.8 % for LH, 31.9
% for testosterone, 15.4 % for oestradiol and 31.3 % for insulin
by Abdel-Gadir et al in 1990 (3). In the same year, serial
screening with basal FSH estimations in different cycles has been
suggested by Scott et al (4), to compensate for the limited
diagnostic and predictive values of single FSH estimations.
2. Hormones have a circadian pattern. Few hormones have higher
levels in the morning, and timing the test for an afternoon
slot will give an erroneous result. Good examples are 17-
hydroxyprogesterone which is used for the diagnosis of 21-
hydroxylase deficiency, androstenedione and testosterone.
These hormones are usually higher in morning blood samples
following the adrenal circadian rhythm. The circadian variations
in cortisol levels are well known.
3. Hormone levels vary during the different stages of the menstrual
cycle and give different results at different times. Early follicular
phase assessment reflects the basic gonadotrophins levels,
before the expected rise during the follicular phase and midcycle.
High LH and testosterone blood levels during the early follicular
phase are usually associated with the polycystic ovary syndrome,
while higher levels of the same hormones during the midcycle
are normal physiological findings indicating ovulation. A further
example is FSH which needs to be tested on the 2nd or 3rd days
of the cycle, as the blood levels increase toward the middle of
the follicular phase. One further example is mid luteal phase
serum progesterone which needs to be tested about 7-9 days
before the next period. Accordingly, conducting the test
arbitrarily on day 21 of a 35 day cycle is not be useful, and gives
a wrong diagnosis.
4. Hormone blood tests are affected by many drugs, and the patient
should be asked about such medication. This is especially so
for hormonal treatment including contraceptives, which can
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interfere with the endogenous endocrine milieu. This is even

valid for a progestogen challenge test which may affect
gonadotrophins blood levels, mainly LH. Induction of ovulation
with clomid can have a similar effect. It is a well known fact that
LH level is lower in cases of PCOS after induction of ovulation,
because of the modulatory effects of progesterone. Accordingly,
such hormonal treatment needs to be stopped for a month or two
before conducting meaningful hormonal tests. This statement is
not valid for patients on treatment for hyperprolactinaemia and
hypo or hyperthyroidism, when a hormonal test is performed to
monitor response to treatment and compliance.
5. Certain blood tests need to be performed after overnight fasting
such as fasting insulin and glucose levels, and the fasting lipid
profile when investigating women for insulin resistance.
6. Serum prolactin level can be affected even by the venepuncture
used to collect the blood sample itself. Furthermore, marginal
elevations of TSH are not uncommon, and usually settle with
time. This can be a reflection of mild transient thyroiditis, or
even laboratory errors due to cross reaction with other
glycoproteins. In both these scenarios the blood test needs to
be repeated.
7. Heterotypic antibodies can affect immunoassays, and give
spurious results. Repeating the test using a different method will
be necessary.
8. Marginally elevated hormonal results are inconclusive, and
should be repeated. Examples of minor elevations of TSH and
prolactin levels have already been given. Dynamic tests may be
necessary to reach a definitive diagnosis in some cases. The mostly
used test within a gynaecological setup is the short synacthen test
(Alliance Pharmaceuticals), which is used for confirmation or
exclusion of adrenal enzymatic deficiency. In this scenario 17-
hydroxyprogesterone level is measured before and 60 minutes
after a bolus dose of synthetic ACTH (synacthen). An exaggerated
response of 17-hydroxyprogesterone indicates adult onset 21-
hydroxylase deficiency. The result should be read according to the
laboratory normal ranges, as there are overlaps between normal
responses and heterozygous enzymatic deficiency. This test is also
useful within a general endocrinology setup, as a test for adrenal
insufficiency. Different cortisol cut-off levels have been used to
indicate normal and abnormal responses after a synacthen test
(5). Studies using 1 μg synacthen showed good reproducibility and
higher sensitivity compared to the standard test with 250 μg as
316
reported by Abdu and Clayton in 2000 (6). The same authors

reported that post synacthen cortisol levels <400 nmol/L were
diagnostic of adrenal insufficiency and Levels >600 nmol/L
practically excluded the condition. Conversely, levels between 400
and 600 nmol/L were doubtful and should be interpreted in the
light of the clinical data. The appropriate timing for the post
synacthen blood test has also been investigated, and 60 minutes
tests were found to be essential to avoid false results retrieved
after 30-minute short synacthen tests (7).
Specific clinical examples
1. Hormonal tests for delayed and precocious pubertal development

include FSH, LH, and oestradiol. In these cases LH is more
important than FSH to detect the initiation of puberty, as the upper
and lower levels of the pulse increase with the progressive pubertal
stages. In case of FSH, it is only the upper limit of the range which
increases during the initial stages of puberty. It is sometimes
difficult to ascertain whether normal pubertal development has
started or not. This is the case with isolated premature breast
development (thelarche). In such cases there is exaggerated FSH
response to the GnRH challenge test. There is also a tendency
toward lower basal and post GnRH test LH levels than in other girls
with precocious puberty as shown by Della Manna et al in 2002 (8).
In contrast, girls with central precocious puberty had higher LH
peak levels after GnRH injection, compared to prepubertal girls as
shown by the same authors. Nonetheless, this dynamic test is not
usually necessary, as baseline LH assessments are adequate to
make a diagnosis, and to monitor response after initiation of
treatment. This is especially so as Pescovitz et al in 1988 (9)
showed that girls with early central precocious puberty frequently
had LH and FSH responses to GnRH stimulation similar to the
FSH predominant response of girls with isolated thelarche.
Measurement of testosterone and 17-hydroxyprogesterone blood
levels is necessary in cases of precocious heterosexual puberty.
This is mainly to detect 21-hydoxylase deficiency, which makes
more than 90% of all cases of adrenal enzymatic deficiencies. In
all cases bone age assessment is an integral part of the work
scenario as discussed in Chapter 2. Furthermore, ultrasound scan
examination can show increased uterine and ovarian volumes, in
addition to breast enlargement in cases of normal or central
precocious puberty (8).
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2. The range of hormonal investigations in patients with anovulatory

menstrual dysfunction depends on the presence of collateral
symptoms. Basic investigations should include gonadotrophins,
oestradiol, thyroid stimulating hormone (TSH), free thyroxine (T4)
and prolactin estimations. In the presence of hyperandrogenic
symptoms or signs, adrenal and ovarian precursors and androgens
should be investigated. This should include morning blood tests for
17-hydroxyprogesterone, androstenedione, testosterone and sex
hormone binding globulin (SHBG). This will allow calculation of the
free androgen index (the level of testosterone divided by SHBG).
With mild elevation of 17-hydroxprogesterone level, a synacthen
test is necessary. With adult onset 21-hydroxylase deficiency, there
is an exaggerated increase in the level of 17-hydroxyprogesterone.
The result should be compared to the values set by the laboratory
for normal, heterozygous and homozygous response, as
mentioned before. Basic morning 17-hydroxyprogesterone blood
levels should also be used to monitor adequate response to
glucocorticoids replacement therapy in patients with 21
hydroxylase deficiency. In all cases of suspected anovulation,
transvaginal ultrasound scan examination should be performed to
ascertain the presence of polycystic ovaries, as mentioned before.
3. The presence of insulin resistance may be explored in cases of PCOS,
especially in obese women and those with history of gestational
diabetes or family history of type II diabetes mellitus. Fasting insulin
level on its own is not a satisfactory method to test for insulin
resistance, because of the wide variability in the results, and an
isolated fasting glucose measurement is utterly useless in this
respect unless the patient is already diabetic. The oral glucose
tolerance test (OGTT) is generally recommended for that purpose.
However, for practical clinical purpose the fasting glucose /insulin
ratio can be used instead, as it had good predictive value of insulin
response during OGTT, and highly correlated with insulin sensitivity
(10, 11). A fasting glucose (mg/dL) / insulin (μU/mL) ratio <4.5 had
positive and negative predictive values of 87% and 94% respectively
for diagnosing insulin resistance (11). So, it is more useful in
excluding the diagnosis than confirming it, which is still important
information for patients’ management. The homeostasis model
assessment of insulin resistance (HOMA-IR) is another method
which also proved to be useful in this respect (12). It correlated
highly with estimates obtained by using the euglycaemic and
hyperglycaemic clamps and fasting insulin concentration (13). A
cutoff level >2.5 was considered to be diagnostic of insulin resistance
318
in adults. HOMA-IR proved to be more reliable than fasting

glucose/insulin ratio and quantitative insulin sensitivity check index
as shown by Keskin et al in 2005 (14). A higher cutoff point of 3.16
was considered to be diagnostic for insulin resistance in adolescents
by the same authors. HOMA-IR can be calculated by multiplying
fasting insulin level in μU/mL by fasting glucose level in mmol/l, and
divide the outcome by 22.5. The concept of homeostasis model
assessment is extended to include HOMA-B which measures changes
in pancreatic B-cell function. It is mostly used in research projects
and is calculated by the equation (20 x insulin level in μU/mL) /
(glucose level in mmol/L – 3.5). High HOMA-IR and Low HOMA-B
were found to be independently associated with increased diabetic
risk in a multiethnic cohort of women, reflecting the value of HOMA
indexes in epidemiologic studies (15).
4. Infertility hormone investigations depend on the age of the
patients, and their mode of presentation. Patient with irregular
menstruation should be investigated for anovulation as discussed
in section 2 above. Patients with regular periods need only mid
luteal serum progesterone assessment to document adequate
ovulation. The length of the cycle should be taken into
consideration, as day 21 progesterone assessment will give wrong
results in patients with regular cycles longer than 28 days. The
length of the follicular and luteal phases can be accurately
documented by ultrasound scan monitoring of the cycle. Women in
their mid or late 30s need to have their ovarian reserve assessed,
irrespective of their menstrual pattern. A recent study by Gleicher
et al (16) investigated the aetiology of premature ovarian aging,
which is another name for reduced ovarian reserve. They reported
that 16.2% of women had genetic, 38.8% autoimmune and 12.2%
combined causes, whereas 33.8% were idiopathic with no
identifiable cause. They concluded that premature ovarian aging
and premature ovarian failure should be considered as continuum,
and should be investigated accordingly. In a different context, it
should be appreciated that such testing is not only necessary
during infertility investigations, but is indicated also to screen
women in their 30s who would like to delay childbearing.
Assessment of ovarian reserve

Follicle stimulating hormone
Over the years great efforts have been made to assess the number and
quality of oocytes prior to assisted reproduction treatment cycles. The
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emphasis has now moved to include assessment of infertile women

during basic hormonal investigations. Age as a single parameter is weak
predictor of ovarian reserve and response to controlled ovarian
stimulation with gonadotrophins (17). For many years, FSH assessment
on the 3rd day of the cycle was the only available investigation to assess
ovarian reserve. The value of high basal FSH level during assisted
reproductive treatment cycles has been reflected by a high cancellation
rate due to poor response. As a single indicator, it was shown to have
better predictive value than age alone in this respect (18). On the other
hand, chronological age was associated with lower implantation rates
owing to poor oocyte quality (19, 20). Such reduced embryos
implantation capacity with age has been related to increased aneuploidy
rate (21). This pattern was shown by other studies as well (22, 23). At
the same time, Levi et al in 2001 (24) related high FSH levels to increased
rate of pregnancy loss, regardless of the woman’s age. They advised that
patients should be counselled regarding the low probability of conception,
and low live birth rates. This view has not been supported by other
articles when young women with high FSH blood levels have been
examined. This was shown by a study published by van Rooij et al in 2003
(20) which examined young women with high FSH blood levels, against
women older than 40 years of age with normal FSH levels. The young
group with high FSH had more cycle cancellation than the older group
with normal FSH. Nevertheless, the young group with high FSH had
better implantation rate per embryo, and higher ongoing pregnancy rate
per cycle and embryo transfer, than the older age group with normal FSH
levels. Poor responders in both groups had lower pregnancy rate than
good responders.
It is an established observation that normal FSH levels are unreliable

predictors of ovarian reserve. This can be a reflection of the following
points:
1. FSH is produced in pulses, and timing of the blood sample may
coincide with the peak or the bottom of the pulse, giving different
results. As discussed previously, the coefficient of variation
(SD/Mean%) for a single FSH reading relative to multiple samples
examined within 6 consecutive hours on the same day has been
reported as 14.7 % by Abdel-Gadir et al in 1990 (3).
2. There is intercycle variability of basal FSH blood levels, being
higher in few but not all cycles. Normally cycling women over the
age of 40 years who had a normal day 3 FSH level have 50%
chance of having an elevated day 3 FSH level in a subsequent
cycle (25).
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3. FSH levels rise late in comparison to inhibin B and antimullerian

hormone, following the decline in the number of follicles.
4. FSH level can be negatively affected by the level of oestradiol in the
same blood sample. A high oestradiol level >200 pmol/l on the 3rd
day of the cycle carries similar bad prognosis as high FSH. This can
be a reflection of rapid recruitment, with a follicle reaching a larger
size than usual on day 3 of the cycle. This is usually seen in patients
with polymenorrhoea and short follicular phases, as the follicle has
started growing earlier during the luteal phase of the previous
cycle. This is a reflection of the early rise in FSH level at that time
of the previous cycle. Alternatively, the high oestradiol level follows
recruitment of multiple intermediate size follicles by day 3 of the
cycle; each producing its share of oestradiol. Transvaginal scan
examination will help in making a diagnosis, and can differentiate
between these two possibilities.
The following techniques have been used to improve the predictive
value of FSH:
• Repeat the test during successive cycles, which is time wasting for
patients who need to start fertility treatment;
• Take 3 samples within a short period of time on the same day to
cover for the pulse variability;
• The clomiphene citrate challenge test has been used as well. It
entails FSH estimation on the 3rd day of the cycle, followed by 100
mg clomid every day from day 5 to 9 of the cycle. FSH level should
be examined again on day 10 of the cycle. A level >10 IU/L
indicates a bad prognosis with reduced ovarian reserve, as it is
expected to be suppressed by the rising oestradiol level. Higher
cut-off levels of FSH have been suggested in the literature. The
test has no additional value in women who already showed high
basal FSH levels. Few studies have shown significant intercycle
variability of the clomiphene citrate challenge test results in the
same patients (4, 26). Furthermore, the predictive or clinical
value of the test was not superior to that of a basal FSH level in
combination with antral follicles count (27).
• Both intranasal and subcutaneous GnRH stress tests have been used
to check the ovarian reserve. The injectable test entails measuring FSH
blood levels before and one hour after a bolus dose of subcutaneous
or intravenous dose of GnRH. An exaggerated increase in the level of
FSH relative to the basal measurement indicates reduced ovarian
reserve. The intranasal test entails 6 hourly administration of GnRH
after measuring the basal levels of FSH and oestradiol. These same
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hormones should be measured 24 hours later. Similarly exaggerated

increase in FSH level, and reduced oestradiol response are taken as
markers of reduced ovarian reserve. These tests are hardly used in
clinical practice nowadays, and will not be discussed any further.
It is evident that high early follicular phase FSH blood levels are more
reliable than normal levels in predicting the ovarian reserve. Certain
conditions should be excluded from this general statement. FSH blood
levels can be increased physiologically during puberty, after using oral
contraceptives and during lactation. Other conditions associated with
elevated FSH levels include excessive smoking, during recovery from
hypothalamic amenorrhoea, and after unilateral oophorectomy (28).
Patients with hyperthyroidism can also have mild elevation of both FSH
and oestradiol, as discussed in Chapter 11.
High FSH may be caused by direct ovarian problems related to several

granulosa cells FSH receptors polymorphisms, but 2 of them located at
codon 307 and 680 are more frequent. The amino acid asparagine (Asn)
is replaced by serine (Ser) at position 680 (N680S), and threonine (Thr)
is replaced by alanine (Ala) at position 307. The two most common
allelic combinations are Thr307/Asn680 and Ala307/Ser680 as reported by
Théron-Gérard et al in 2007 (29). Patients are usually classified as
homozygous (Ser/Ser or Asn/Asn) or heterozygous (Asn/Ser).
Homozygous patients for the Ser680/Ser680 variant (N680S) have
longer follicular phase of the cycle and higher basal FSH blood levels
(29, 30). The later being a natural compensation to stimulate normal
follicular growth despite reduced FSH receptors sensitivity. These
patients also need higher doses of gonadotrophins and produce lower
levels of oestradiol during induction of ovulation, though they have
normal number of follicles (31). Accordingly, Greb et al (31) suggested
more studies to investigate the role of routine genotyping for N680S
polymorphism to help with tailoring ovarian stimulation protocols to
individual patient’s needs.
Mothers of familial dizygotic twins showed high basal FSH blood levels and
pulse frequency, not related to the normal age-induced reduction of
negative feedback mechanism, as reported by Lambalk et al in 1998 (33).
Hypothalamic and/or pituitary neuroendocrine factors not related to GnRH
were suggested as possible causes. There was no change in FSH pulse
amplitude or response to GnRH stimulation, compared to control
groups. At the same time, there were no differences in basal or GnRH
induced LH levels, oestradiol, inhibin A or inhibin B levels between
mothers of dizygotic twins and controls. Genetic studies so far failed to
322
pinpoint the exact mutations which may lead to dizygotic twining. No

linkage was found in correlation to mutations in the gene coding
transmembrane FSH receptors (FSHR) as reported by Montgomery et
al in 2001 (34). Furthermore, rare mutations in growth differentiation
factor 9 (GDF9) may affect twining chances, but dizygotic twining is not
associated with common variations in GDF9 (35).
False high FSH results can also follow the presence of heterotypic
antibodies in a patient’s blood, which can interfere with the
immunoassay. Spurious high FSH level was reported in a 33 year old
women who had regular cycles by Cahill et al in 1992 (36). She proved
to have normal levels when an alternative laboratory method was used.
Such antibodies are not species specific. They can be found in patients
regularly exposed to animals or their products. Blood transfusions and
autoimmune diseases, especially the rheumatoid factor, have also been
mentioned as possible causes.
Antral follicles count
To overcome the limitations of FSH in predicting ovarian reserve, many

other parameters have been introduced as alternatives, or to
complement its role in this respect. Transvaginal ultrasound scan
examination is one such parameter. Ovarian size and antral follicles
count during the early follicular phase have been used.
Reduction of ovarian size, irrespective of parity, after the age of 40

years has been documented by Andolf et al in 1987 (37). As
expected, a substantial decline in ovarian size has also been noticed
after the menopause (38). These points were taken further by Lass
et al in 1997 (39), who assessed ovarian response to induction of
ovulation with gonadotrophins in relation to ovarian volume. Women
with ovaries <3.0 cc in volume needed higher dosage of
gonadotrophins, had higher cancellation rate, and produced less
follicles than women with larger ovaries. Accordingly, the authors
recommended that assessment of ovarian size to be an integral part
of the infertility evaluation. This concept was taken even further by
Tomás et al in the same year (40). They found that patients with <5
antral follicle (2 - 5 mm in diameter) in each ovary had lower
response to gonadotrophins than patients with more antral follicles.
This parameter was found to be more sensitive than ovarian volume
or patients’ age alone. Accordingly, they recommended antral follicles
count, rather than ovarian volume, for counselling patients regarding
their expected response to induction of ovulation. Using the same
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parameter, Frattarelli et al in 2003 (41) confirmed the high

cancellation (41%) and low pregnancy (23%) rates in women with ≤
4 antral follicles. The more important finding was that no antral
follicles count absolutely predicted pregnancy or cycle cancellation.
Nevertheless, a meta-analysis published by Hendriks et al in 2005
(42) showed a superior predictive value of antral follicles count over
basal FSH toward poor response. These points put together support
the recommendation made earlier by Bancsi et al in 2002 (43) that
antral follicles count should be used together with other endocrine
parameters for the assessment of ovarian reserve.
It is evident that patients with small ovaries and those with low antral
follicles need higher gonadotrophins doses to secure a response, and to
reduce the risk of cycle cancellation, during assisted reproduction
treatment cycles. This should be taken into consideration especially with
the increased cost involved. A step-down induction protocol with initial
high dosage may be a better option to secure the initial recruitment of
follicles before reducing the dose, if that proved to be necessary.
Inhibin B
Inhibin B is another product of the granulosa cells. A substantial decline in

its blood levels with no significant changes in inhibin A or oestradiol has
been reported in early perimenopausal women with regular cycles (44,
45). This was followed after a period of time, and changes in menstrual
cyclicity, by marked fall in inhibin A and oestradiol levels, and a rise in FSH
level, without any further changes in inhibin B. This is another sign that
basal FSH and oestradiol levels are not reliable markers of the early decline
in ovarian reserve. The value of inhibin B as a measure of ovarian reserve
has been shown by many studies. Women with blood levels less than 45
pg/ml on day 3 of the cycle had lower oestradiol levels after induction of
ovulation, higher cancellation rate and lower number of oocytes collected,
in comparison to women with higher blood levels (46). This finding was
contradicted by a study published by Corson et al in 1999 (47), who failed
to find any clinical value for testing inhibin B. This was not a common
observation, as many other articles confirmed its value in predicting
ovarian response to induction of ovulation. On the other hand, it has the
same drawback as basal FSH, because of the physiological variability
during the different stages of the same menstrual cycle. Accordingly, it
must be assessed on days 2 or 3 of the cycle.
In a different approach, Kwee et al in 2004 (48) tested the intercycle

variability of basal inhibin B and oestradiol levels before and after
324
injecting 300 IU of recombinant FSH subcutaneously. There were no

significant differences in the increment of either hormone, when the
test was performed during different cycles. Because of the
reproducibility of the results, they considered this test to be more
reliable than basal FSH assessment and the clomiphene citrate
challenge test. Both tests gave significantly variable results when
performed during different cycles. Nevertheless, like all other invasive
dynamic tests, it did not attract much interest, and has not commanded
popular use in routine clinical setups.
Antimullerian hormone
Antimullerian hormone (AMH) is produced by the granulosa cells in

close proximity to the oocytes, and by few cells surrounding the antrum
of 4 – 6 mm antral follicles. These cells continue producing AMH till
further recruitment and development of the follicles into dominant ones
or their ultimate atresia. Human AMH is a dimeric glycoprotein with a
molecular weight of 140 kdaltons, and it is a member of the
transforming growth factor beta (TGF-β) family of growth and
differentiation factors (49). At the ovarian level, AMH is involved with
follicular steroidogensis, and regulation of ovarian activity. It reduces
granulosa cells aromatase activity and the number of LH receptors in
cultured granulosa cells, and regulates testosterone production by the
theca cells (50). Reduction of the aromatase enzymatic activity affects
the intraovarian androgen / oestrogen ratio, hence oocyte function. A
high ratio leads to follicular degeneration, whereas a low ratio causes
germinal vesicles rupture (51-53). On the other hand, AMH reduces
follicular sensitivity to FSH. Furthermore, oocytes upregulate AMH
expression in granulosa cells, depending on their developmental stage
(54). This led to the hypothesis that oocytes in growing follicles control
primordial follicles recruitment and development through the inhibitory
effects of AMH.
AMH level has a direct correlation with the number of antral follicles;
hence it is a good marker of ovarian reserve. It was more consistently
correlated with the degree of follicular depletion than inhibin B and
antral follicles count, even in young patients with high FSH levels (55).
Furthermore, it has relatively stable serum concentration within one
year in premenopausal women, and can be measured with good
reproducibility using commercial kits (56). Additionally, blood levels do
not change during the menstrual cycles, and the test can be performed
at any time irrespective of the stage of the cycle. A meta-analysis
published by Broer et al in 2009 (57) showed that AMH is at least as
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ABDEL -GADIR
accurate as the antral follicle count in predicting poor response and

non-pregnancy during IVF treatment cycles. However, most of the
present data stress the fact that AMH is the best currently available test
for ovarian reserve. Nevertheless, like all other parameters it does not
reflect the quality of the eggs, which is controlled by the patient’s age.
Furthermore, it was not a better predictor of pregnancy when compared
to the other available tests (49). It is interesting that a recent report
showed that AMH levels were affected by ethnicity. Its blood levels were
found to be 25.2% and 24.6% lower in Afro-Caribbean and Hispanic
women respectively, when compared to White women, after adjusting
for age, body mass index and smoking (58). This raises the need to
establish different cut-off levels for different ethnic groups, which
allows better utilisation of the test results in modern day cosmopolitan
societies.
A recent publication showed that AMH level was significantly reduced

during oral contraception use, with a trend toward lower levels during
metformin therapy (59). The question here would be what is the
recovery time to normal levels once such mediation is stopped? This is
necessary to know if patients who come off the pill need to have their
ovarian reserve established. The same authors came to the conclusion
that AMH is an accurate marker of antral follicles pool in WHO-2 / PCOS
women, but its measurement is not likely to be helpful in the
management of these patients (59). This may not be true when dealing
with PCOS cases, as patients with high AMH blood levels (≥ 7.7 ng/ml)
are less likely to respond to ovarian drilling (60). Accordingly, AMH can
be used together with LH to select PCOS patients who are more likely
to respond to this procedure.
Figure 46 shows a small right ovary with 3 antral follicles (2-5 mm in diameter)
marked by asterisks on day 3 of the cycle. Figure 47 shows a very small left ovary
with no antral activity at all. These two pictures belong to a 24 years old woman
who had regular monthly cycles. Her day 3 FSH level was 7.3 IU/L, but her AMH
326
level was only 4.2 pmol/L. She needed 450 IU of human menopausal
gonadotrophin every day for 13 days to produce 3 follicles. Three oocytes were
collected and injected with her husband’s sperm, during intracytoplasmic sperm
injection treatment cycle. Two oocytes were fertilized, and were replaced on day 2
of the procedure. She conceived a single intrauterine pregnancy and delivered a
healthy baby at term. This case reflected the unreliability of a normal day 3 FSH
blood level in predicting the ovarian response during an assisted reproduction
treatment cycle. It also showed the value of both transvaginal ultrasound scan
examination and AMH in this respect.
Figure 48 shows two small ovaries with a

single antral follicle in the left one. This
37-year old patient had regular menstrual
cycles with normal day 3 FSH blood
levels (<10 IU/L). Her AMH was only 1.73
pmol/L. She failed to respond to
controlled ovarian hyperstimulation with
high doses of gonadotrophins injections.
It was a further example of how normal
FSH blood levels failed to predict her
ovarian response.
Other clinical conditions
Human chorionic gonadotrophin is another glycoprotein hormone which

is used for the diagnosis of normal and abnormal pregnancies, and as a
tumour marker. The total molecule cross-reacts with other glycoproteins
due to the similarity of their α chains. Accordingly, the β subunit is used
because of its specificity. The three more common pathological
conditions related to high human βhCG blood levels are ectopic
pregnancies, gestational trophoblastic tumours, and ovarian teratomas.
Ectopic pregnancies
With ectopic pregnancies, a positive βhCG test is associated with an

empty uterus, and occasionally a positive ultrasonic identification of an
ectopic mass outside the uterine cavity. Transvaginal ultrasound scan
examination can give a very high positive predictive value and helps
with the diagnosis in 90% of the cases, when performed by
experienced personnel. An empty uterus with βhCG level of 1500-2000
IU/ml indicates an ectopic pregnancy, as an intrauterine sac should be
seen at such levels. The most common ultrasound finding is the
presence of a mass beside the uterus on the same side as the corpus
luteum, in almost 80% of the cases. Viable ones with fetal heart
327
ABDEL -GADIR
activity are the least common type. Depending on the stage at

diagnosis, variable amounts of fluid with floating particles can be seen
in the pouch of Douglas indicating intra-peritoneal leak of blood from
the ectopic pregnancy. βhCG blood levels are usually lower than those
expected for the period of amenorrhoea, and the rate of increase over
a period of time is also lower than expected for normal intrauterine
pregnancies. The level of βhCG usually doubles, or at least increases
by 1.66 fold every 2 – 3 days in 85% of normal intrauterine
pregnancies. In recent years, serum progesterone has been used as
an extra parameter for the diagnosis of ectopic pregnancies, as it has
a constant blood level during the whole of the first trimester. A blood
level ≥ 25 ng/ml is usually diagnostic of an intrauterine pregnancy. It
excludes an ectopic pregnancy with 97.4% certainty, in spontaneously
conceived cycles. Conversely, a level < 15 ng/ml has been reported in
81% of ectopic and 93% of abnormal intrauterine pregnancies. It is
also seen in 11% of normal intrauterine pregnancies. It is evident that
the higher the progesterone blood level, the stronger its negative
predictive value will be in excluding a diagnosis of ectopic pregnancy.
Accordingly, all three parameters (clinical, scan examination and
hormonal tests) should be combined to reach a diagnosis. The use of
hormonal tests in the follow up of cases managed conservatively, and
in the management of pregnancies of unknown location has reduced
the need for unnecessary surgery in many cases.
Gestational trophoblastic tumours
Very high blood βhCG levels are suggestive of gestational trophoblastic

tumours (GTT), which can be benign or cancerous. The group includes
molar pregnancy, persistent trophoblastic disease, placental site
trophoblastic tumours (PSTT), and choriocarcinomas. The intrauterine
contents can show a snowstorm appearance in cases of a complete
mole, during transvaginal ultrasound scan examination. Conversely,
partial molar pregnancy may look almost normal during ultrasound
scanning. The ovaries are usually enlarged with multiple corpora luteal
cysts. Serial estimations of βhCG levels are used for monitoring
response to treatment. Patients usually need other investigation
modalities including X-ray chest, CT scans, MRI, and even lumbar
puncture. A complete account about this subject is beyond the remit of
this chapter.
The use of βhCG as a tumour marker is not limited to trophoblastic

diseases, as the level can also be elevated in patients with other
gynaecological neoplasms. Teratomas, dysgerminomas and germinal cell
328
tumours are such examples. In these cases, the diagnosis is usually made
with the help of ultrasound scan examinations or MRI. Paradoxically, high
βhCG levels have been reported in patients with vulvovaginal and cervical
cancers. The prognosis was found to be worse for patients with higher than
normal βhCG levels (61). Other malignant and benign non gynaecological
conditions were also associated with high blood βhCG levels. The list
included melanomas, colonic, breast and renal tact carcinomas (62-64).
Despite the high βhCG levels, trophoblastic cells were not present in
biopsies retrieved from these tumours. Benign conditions associated with
high βhCG levels included liver cirrhosis, duodenal ulcer, and inflammatory
bowel disease. Accordingly, these conditions should be taken into
consideration when a high βhCG level is detected in non pregnant women.
However, βhCG is not a recognised method for the diagnosis or monitoring
of any of these conditions.
Many other hormones can also be used electively for detecting pelvic
tumours, or are chance findings in correlation to certain gynaecological
problems. AMH can be a biomarker of increased breast cancer risk (65),
and a marker of granulosa cell tumours which also produce very high
levels of oestradiol. This can cause long periods of amenorrhoea
followed by excessive breakthrough uterine bleeding. Such tumours
also result in precocious isosexual pubertal development. On the other
hand, case reports of parasitic ovarian leiomyomas presenting with
endocrine related problems have been published. Hyperandrogenic skin
and hormonal changes have been reported in postmenopausal women
with ovarian leiomyoma due to theca cell reaction (66), and hilus cells
hyperplasia (67). Similarly a case report of secondary amenorrhoea
caused by high inhibin B level secondary to a parasitic ovarian
leiomyoma has been published by Abdel-Gadir et al in 2010 (68). This
patient resumed menstruating within one month after excision of the
ovarian fibroid.
Summary
This chapter has been written to complement the information given in

the previous chapters, with gynaecologists in mind. It is meant to give
a general overview of the different endocrine investigations used in
gynaecological practice. In many cases clinical history, physical
examination and imaging techniques provide the necessary information
to reach a diagnosis, with minimal need for elaborate hormone tests.
Special efforts have been made to emphasise the strength and
limitations of the common hormone tests used in gynaecological
practice. The need for proper timing of blood samples collection within
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ABDEL -GADIR
the day, and in relation to the stage of the menstrual cycle has been
stressed. Any medication taken by the patient should be taken into
consideration when requesting a hormone test, and during the
interpretation of the results. Such tests should be used to complement
the clinical impression, and to extend the clinical judgement necessary
for the management of any particular case. Many results can be
spurious for different reasons, and may not agree with the general
clinical picture. In such cases the examination should be repeated for
confirmation purpose, using a different method if possible, before
changing the patient’s management plan. Adequate knowledge of the
relevant basic Reproductive Endocrinology will allow better utilisation of
the available diagnostic means, facilitates proper patients’ care, and
eliminates misuse of resources.
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93 – 95.
336
Index
A Aneuploidy, 16
Abnormal Pubertal Development, 31 Anorexia nervosa, 51, 220, 221,
342, 345
Acanthosis nigricans, 146, 167
Anovulatory amenorrhoea, 51
Adenohypophysis
Antiandrogens, 145, 152, 154,
pars distalis, pars intermedia, pars
156, 158
tuberalis, 3
Antidiuretic hormone, 2, 80
Adipocytes, 8, 144, 209, 210, 211,
Antimullerian hormone, 383
213
Antioestrogens, 130, 179
Adiponectin, 144, 210
Anti-thrombin III, 247
Adipose tissue, 178, 209, 210, 212,
Antral follicles count, 381
213, 216, 219, 220, 221, 222, 241
Anxiety, 53, 72, 86, 151, 202, 235,
Adipose tissue function, 210
236, 238, 311, 314, 315, 316,
Adrenal antibodies, 273, 280
317, 320
Adrenal enzymatic deficiencies, 83,
Aromatase inhibitors, 39, 184
94, 162, 375
Assessment of ovarian reserve, 377
Adrenal gland dysfunction, 64
Autoimmune hypothyroidism, 273
Adrenal insufficiency, 96
Autoimmune lymphocytic oophoritis,
Adrenarche, 8, 39, 43, 46, 64, 79
273
Adulthood obesity, 217
Aetiology of anovulation, 178 B
Aetiology of PMS, 312 Benign breast conditions, 253
Ageing of the HPO axis, 16 Binovular twins, 19
Aldosterone, 65, 80, 83, 89 Bisphosphonate, 250
Ambisexual axillary and pubic hair, Bisphosphonates, 249
118 Bone age, 43, 70, 375
Ambisexual hair, 146 BRCA1 and BRCA2 mutations, 253
Anastrozole, 127, 184 Bromocreptine, 71, 183, 320
Anatomical amenorrhoea, 67 Bulimia, 14, 51
Androgen insensitivity syndrome, 36
Androgenic alopecia, 91, 120, 146,
C
156, 367 Cabergoline, 72
Androgenic skin problems, 145 Café-au-lait skin patches, 38
Androgens, 117 Carcinoid, 235, 238
Androgens and oestrogens Catecholamines, 17, 123, 130, 236,
production, 84 238
337
ABDEL -GADIR
Catechol-o-methyltransferase gene, Diabetes mellitus, 350

313 Diagnosis of PMDD, 315
Causes of POF, 269 Dianette, 114, 341
Central obesity, 66, 67, 216 Diethylstilbestrol, 127
Chemotherapy, 58, 275, 276 Dihydrotestosterone, 5, 86, 90,
Childhood and pubertal obesity, 216 114, 117, 134, 142, 154, 155,
Childhood hypothyroidism, 61 156, 158
Cholithiasis, 148 Distal genital tract obstruction, 33
Climacteric, 229 Dizygotic twins, 269
Cliteromegaly, 86 Dopamine, 4, 9, 14, 52, 53, 54,
Clomiphene citrate, 130, 180, 182, 62, 63, 71, 142, 148, 217
183 Doppler ultrasound, 191
Clomiphene citrate challenge test, Drospirenone, 111, 318, 319, 330,
20, 379, 383 341, 343
Coagulation factors, 129, 247, 334 Dysfunctional uterine bleeding, 14,
Combined injectable contraceptives, 91, 99, 109, 114, 120, 128, 149,
333 217, 230, 333, 352
Complete isosexual precocity, 37
E
Complications and risks of
hormonal contraceptives, 351 Eating disorders, 72
Control of body temperature, 237 Ectopic pregnancies, 386
Core body temperature, 109, 237 Effects of hyperthyroidism, 296
Corticotrophin releasing hormone, Effects of hypothyroidism, 291
53, 80 Effects of low BMI, 220
Cortisol production, 82 Efficacy of hormonal contraceptive,
Cryptomenorrhoea, 32, 34 339
Cushing’s syndrome, 66 Emergency contraception, 354
Cycle delaying dose, 116 Endocrine effects of adiposity, 214
Cyproterone acetate, 111, 114, Endocrine effects of thyroid
119, 121, 132, 156, 158, 341 dysfunction, 289
Cytochrome P450scc, 81, 107 Endocrine Investigations, 367
Cytotoxic and pelvic radiation EDndometrial carcinoma, 130, 220,
therapy, 275 227, 244, 340
Endometriosis, 32, 53, 113, 115,
D 121, 127, 133, 252, 274, 293,
Delayed Puberty, 32 315, 321, 327, 331, 342, 343
Depoprovera, 53, 333, 334, 335, Endorphins, 4, 13, 52, 53, 143,
345, 347, 350, 352, 353 148, 217
Development of an adult female Endothelial growth factor, 147
chromosomal sex, gonadal sex, Enzymatic deficiencies, 84
genital sex, sex of rearing, 5 Evening primrose, 311, 320
Development of the ovaries, 5 Evra patch, 336
338
F Hormone replacement therapy, 61,

72, 126, 131, 277, 342
Factor V Leiden, 348
Hormone sensitive lipase, 210
Factors affecting the HPO axis, 14
Human testing of progestogens,
Familial dizygotic twins, 380
116
Familial mental retardation gene, 57
Hyperandrogenic amenorrhoea, 67
Ferriman-Gallwey scoring system,
Hypergonadotrophic hypogonadism,
145
180, 267
Fetal thyroid gland, 286
Hypergonadotropic amenorrhoea, 67
First hepatic pass, 129, 233, 248,
Hypergonadotropic delayed
330, 334
puberty, 36
Fragile X syndrome, 57, 75, 272
Hyperinsulinaemia, 148, 150, 164,
Functional ovarian cysts, 53, 333,
185, 214
341, 344, 370
Hyperprolactinaemia, 62
Functions of FSH, 11
Hyperstimulation syndrome, 149,
Functions of LH, 12
160, 161, 197
G Hypertrichosis, 146
Hypogonadotropic hypogonadism, 67
Galactorrhoea, 370
Hypogondotropic delayed puberty, 35
Galactosaemia, 272
Hypokalaemic alkalosis, 65, 89
Gamma aminobutyric acid, 7
Hypothalamic ageing, 17, 229, 230
Gestational trophoblastic tumours,
387 Hypothalamic anovulation, 51
Gluconeogenesis, 144, 153, 219 Hypothalamic dysfunction, 163
Glycodelin, 150 Hypothalamo-pituitary-adrenal axis,
51, 151, 215
GnRH, 10
Hypothalamo-pituitary-ovarian axis,
GnRH stress tests, 379
3, 50, 211, 290, 333
Gonadal dysgenesis, 56
Gonadotrophins, 186 I
Gonadotrophins dosage, 187 Iatrogenic causes of POF, 274
Granulosa cell tumours, 58, 388 Idiopathic hirsutism, 157
Grave’s disease, 274, 289, 296, 302 Imaging investigations, 43
Gynaecoid obesity, 213 Immunotherapy, 274
Gynaecomastia, 90 Imperforate hymen, 33
H Implanon, 335
Inadequate ovulation, 14, 63, 91, 230
Heterosexual precocious puberty, 40
Incipient ovarian failure, 18, 20,
Heterotypic antibodies, 381
21, 229
Heterotypic antibodies, 373
Incomplete isosexual puberty, 39
Hirsutism, 145, 146
Induction of Ovulation, 177
Hormonal Contraceptives, 329
Induction of ovulation with pulsatile
Hormonal tests, 371 GnRH, 194
339
ABDEL -GADIR
Inhibin A, 26, 229, 382 Management of POF, 277

Inhibin B, 14, 17, 20, 58, 137, Masculinized female, 86
142, 196, 229, 230, 277, 378, Masculinized vulva, 86
382, 383, 384, 388 maternal hypothyroidism, 288
Injectable contraceptives, 333 Maturation of the HPO axis, 6
Insulin like growth factor binding Maximum bone density, 71, 221,
protein 1, 150 277, 352
Insulin receptors mutations, 143 Mayer-Rokitansky-Küster-Haüser’s
Insulin resistance, 116, 135, 136, syndrome, 37
141, 143, 144, 147, 150, 151, Mayer-Rokitansky-Küster-Haüser’s
153, 154, 155, 161, 164, 213, syndrome, 33, 70
214, 215, 346, 350, 369, 373, 375 McCune-Albright syndrome, 38
Intrauterine adhesions, 68 Medroxyprogesterone acetate, 39,
Intrauterine devices, 336 53, 112, 113, 116, 252, 330,
Intravaginal contraceptives, 338 333, 334, 352
Intrinsic ageing, 240 Menorrhagia, 63, 91, 115, 120,
Irregular periods, 91, 145, 151 149, 291, 321, 367
Isolated gonadotrophins deficiency, Metformin, 121, 151, 153, 185,
55 213, 220
Isosexual precocious puberty, 37, 291 Migraine, 122, 240, 246, 315, 320,
321, 327, 346
K Mineralocorticoid, 80, 111, 330
Kallmann’s Syndrome, 35 Mini TT380 Slimline, 354
Killer cells, 273 Mirena system, 115, 248, 318,
KiSS-1/GPR54, 8, 9 336, 340, 342, 343, 347
Monozygotic twins, 268
L
Morphological effects of oestrogens,
Leptin, 211 125
Letrozole, 127, 184 Mullerian ducts, 32, 37, 56
Levonelle 1500, 355 Mullerian dysgenesis, 32
LH surge, 10, 12, 13, 14, 63, 64, Multiple follicles recruitment, 18
141, 189, 192, 230, 332, 333 Multiple pregnancies, 124, 150,
Lipoprotein lipase, 210, 214 159, 177, 178, 182, 186, 187,
Low density lipoprotein, 112, 233, 193, 194, 195, 196, 197
298
Lower body obesity, 213
N
Luteinized unruptured follicle Natural non-human oestrogens,
syndrome, 190 126
Negative feedback, 4, 7, 13, 17,
M 19, 80, 124, 137, 215, 230, 231,
Mammography, 253 234, 380
Management of OHSS, 202 Neurohypophysis
340
The neural lobe, The median 57, 87, 271

eminence, infundibular stalk, 2 Peripheral obesity, 218
Non contraceptive uses of hormonal Phaeochromocytoma, 235, 238
contraceptives, 340 Photo-ageing, 240
Normal pubertal development, 29 Phytoestrogens, 245
Norplant, 335, 339 Pituitary causes of amenorrhoea, 55
NuvaRing, 338 Pituitary dynamic tests, 70
Pituitary macroadenoma, 72
O
Plasma renin activity, 83, 89, 129
Obesity, 147
Plasminogen activator inhibitor-,
Objectives of monitoring ovulation, 187
212
Obstructive sleep apnoea
Polycystic ovaries, 37, 64, 88, 91,
syndrome, 148
135, 136, 137, 138, 141, 142,
Oestradiol implants, 254
157, 163, 166, 167, 173, 182,
Oestrogen replacement therapy, 198, 291, 370, 375
89, 247, 264, 299, 343
Polycystic ovary syndrome, 60, 66,
Oestrogens, 122 135, 178
Oestrogens potency, 127 Polymenorrhoea, 18, 63, 91, 120,
Oligomenorrhoea, 21, 63, 91, 120, 149, 229, 234, 267, 290, 291,
139, 149, 216, 267, 271, 291, 367, 378
340, 367 Positive feedback, 10, 12, 64
Oocyte maturation inhibitor, 193 Postmenopausal symptoms, 235
Oral contraceptives, 331 Postpartum thyroiditis, 289, 293,
Osteoporosis, 52, 53, 71, 113, 220, 295, 307
221, 233, 240, 241, 249, 250, Precocious or accelerated puberty,
255, 277, 279, 298, 299, 333, 37
340, 342 Preimplantation genetic diagnosis,
Ovarian autoantibodies, 274 95
Ovarian causes of amenorrhoea, 56 premarin, 114, 126, 261
Ovarian electrocautery, 157, 195 Premature adrenarche, 87
Ovarian leiomyoma, 58, 388 Premature LH surge, 182
Ovarian tumours, 58 Premature Ovarian Failure, 267
Oxytocin, 2 Premature ovarian insufficiency,
267
P
Premenstrual dysphoric disorder,
Paraventricular hypothalamic 311, 326, 330
nuclei, 80 Premenstrual Syndrome, 311
Pars distalis, 3, 4, 10 Prenatal genetic diagnosis, 95
Pars intermedia, 4 Primary amenorrhoea, 49
Pars tuberalis, 4 Progestational dose, 116
Peripheral isosexual precocity, 38 Progestogen withdrawal bleeding,
Peripheral karyotyping, 33, 35, 37, 163, 180, 184, 341
341
ABDEL -GADIR
Progestogen-only vaginal rings, 339 Subdermal contraceptives, 335

Progestogens, 107 Synthetic oestrogens, 126
Prolactin, 4 Synthetic progestogens, 110
Protein C resistance, 247 T
Psychological effects of PCOS, 151
Tachyphylaxis, 254
Pubarche, 39, 141
Pure gonadal dysgenesis, 36, 56 Tanner’s classification of puberty, 30
Terminal hair, 145
R Testicular determining factor, 6, 36
Rapid follicular recruitment, 18 The Δ4 pathway, 82
Renin angiotensin system, 80, 348 The Δ5 pathway, 81
Risk of breast cancer, 242, 279, The menopause, 231
353, 388 The neurohypophysis
The infundibular stalk, 2
S
The median eminence, 2
Secondary amenorrhoea, 50, 179 The neural lobe, 2
Selective oestrogen receptor Thelarche, 29, 30, 31, 39, 40, 42,
modulators, 249 43, 374
Selenium, 295 Thermoregulatory zone, 238
Serotonin, 14, 53, 313, 314, Thombophilia, 349
317, 322 Thyroid autoantibodies, 293, 294,
Serotonin reuptake inhibitors, 295, 299
244, 313 Thyroid autoantibodies, 293
Serotonin toxicity, 322 Thyroid dysfunction, 60
Sex determining region gene, 6, Thyroid function during pregnancy,
36, 56 287
SHBG production, 119, 148 Thyroid gland and menopause, 298
Short luteal phase, 91, 149 Thyroid indices, 300
Signs of ovulation, 189 Thyroid peroxidase antibodies, 273,
Solar lentigo, 240 278, 286, 289, 293, 294, 295,
Spironolactone, 111, 121, 155, 300, 301, 306, 307, 308
158, 319, 326, 330, 343 Thyroxine binding globulin, 61, 233
Spontaneous POF, 270 Transcortin, 108, 124, 330
Stein and Leventhal, 136 Transdermal contraceptives, 335
Step-down induction protocol, 382 Transient thyroiditis, 300, 373
Streak gonads, 6, 36, 56, 269 Transitional ovarian failure, 21
Subclinical hyperthyroidism, 289, Traumatic amenorrhoea, 59
297, 298, 300 Treatment of abnormal puberty, 43
Subclinical hyperthyroidism, 297 Triggering ovulation, 192
Subclinical hypothyroidism, 215, Triglycerides, 112, 129, 147, 210,
233, 285, 286, 288, 289, 292, 212, 242, 246, 334, 350
293, 299, 300, 301 Triple X chromosomes, 57
342
Trophoblastic diseases, 387 Vellus hair, 146

Trophoblastic tumours, 386, 387 Visceral obesity, 216
True hermaphrodite, 86
W
T-Safe 380A, 354
TT380 Slimline, 354 Waist / hip ratio, 218, 370
Tumour necrosis factor alpha, 210 Waist measurement, 209
Waist to hip ratio, 147
U WHO anovulation subgrouping, 178
Ulipristal acetate, 355 Women Health Initiative Study,
Undermasculinized male, 86 242, 246, 247
Urogenital symptoms, 250
Y
V Yasmin, 319, 341, 343
Vasomotor symptoms, 126, 238,
Z
244, 245, 247, 248, 255, 278,
298 Zona fasiculata, 80
Vasopressin. See antidiuretic Zona glomerulosa, 80, 83
hormone Zona reticularis, 79, 80
343

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Reproductive Endocrinology for Gynaecologists

Concepts and Practice

Mr. A. Abdel-Gadir PhD FRCOG

Abdel-Gadir is hereby identified as author of this

The book cover picture is copyright to Abdel-Gadir

This book is published by

A CIP record for this book

This book is dedicated to my mother, my brother Mohamed and to my

I am immensely grateful to Mr. Oluseye A Oyawoye (Seye), MD MRCOG,

Reproductive Endocrinology is the medical discipline related to

Providing contraceptive advice and hormone replacement therapy,

Accordingly, knowledge of the basic concepts of neuroendocrinology,

Hormones are produced in pulses, in a circadian rhythm, and with

problems, and the management plan should not be changed on the

This book has been written to introduce reproductive endocrinology

The Hypothalamo-Pituitary-Ovarian Axis

The neurohypophysis develops from the ectoderm of the diencephalon

and paraventricular nuclei. Accordingly, the neural lobe is not a true

The adenohypophysis originates from a diverticulum of the primitive

Like the neurohypophysis, it is also made of 3 different parts:

The pars intermedia is situated between the pars distalis and

Unlike the neurohypophysis, the adenohypophysis has no direct arterial

portal veins. The capillary plexus formed by the inferior hypophyseal

In the context of this chapter, the main script will concentrate on

The ultimate development of an adult female is controlled by the

society, which moulds his or her identity. Nonetheless, the issue of

Development of the ovaries

The initial step in primitive gonadal development entails genital ridge

Animal studies suggested that antimullerian hormone (AMH) plays a

Maturation of the HPO axis

Four different stages have been recognised leading to full maturation of

This is followed by an inhibitory stage which extends up to the age of

good indication that pituitary gland maturation is not totally

suppression of puberty and reproductive disturbances in states of under

Other important endocrine changes during early puberty include

This section can be summarised by the statement that changes in the

With further development of the system into the fourth or adult

GnRH and gonadotrophins

GnRH is a decapeptide (10 amino acids) neurohormone produced

pulses into the hypophyseal portal vessels in the median eminence,

Sustained large GnRH pulses desensitise the pituitary gland by

Both FSH and LH are glycoproteins with an identical α chain having

The characteristic functions of FSH can be summarised as follows:

The positive feedback and LH surge mechanism

Development of the positive feedback and LH surge mechanism is a

in the pituitary gland, without causing any LH secretion. This pattern

The negative feedback

For completion purpose, the effects of oestrogen and progesterone on

mRNA/kisspeptin expression at the arcuate nucleus of the

Factors affecting the HPO axis

The interrelationship between the different endocrine glands makes it

relations will be given in Chapters 3 and 4. Polycystic ovary syndrome

chemicals including dopamine. This can affect the intellectual,

Ageing of the HPO axis

The reproductive episode in human beings is very short. Maximum

At the same time, an independent hypothalamic ageing process has

anterior and mediobasal hypothalamus, and diminished activity of the

• Rapid follicular recruitment with a single advanced or large

Normally, a single dominant follicle produces enough oestradiol during

Figure 3 shows double ovulation in a spontaneous monitored cycle with a

non-variable level at different times of the cycle. Accordingly, the test

1. Syvertsen A, Haughton VM, William L and Cusick JF. The

3. Fuchs AR, Goeschen K, Husslein P, Rasmussen AB and Fuchs F.