February 26, 2013

MENOPAUSE
Dr. Songco
Outline:
I.
II.
III.
IV.
V.
VI.
VII.
VIII.
IX.
X.

Menopause
The Age of Menopause
Physiology of Menopause
Pathophysiology of Menopausal Transition
Stages of Reproductive Aging Workshop (STRAW)
The Symptoms of Menopause
Pathophysiology of Menopause Organ Changes
Approach to the Woman in Menopause
Treating the Woman in Menopause
CHUCHU
a.
Premature Ovarian Failure (POF)
b.
Turner Syndrome
c.
Fragile X

PHYSIOLOGY OF MENOPAUSE
Estrogen levels from Puberty to Post-menopause

MENOPAUSE
Permanent cessation of menstruation resulting from
loss of ovarian follicular activity (WHO)
FINAL menstrual period (not LAST menstrual period)
12 months amenorrhea without any other cause
DEFINITION OF TERMS
Perimenopause menopausal transition
o Duration of 2-8 years (ave. 5 years)
o Hot flushes, depressed mood, irritability
Menopause
Climacterium
o Encompasses perimenopause, menopause, and
postmenopause
Premature Ovarian Insufficiency/Failure (POF/POI)
THE AGE OF MENOPAUSE
Average age
Western countries
Malay women
Thai women
Filipinas

51 y/o
51-52 y/o
45 y/o
49-50 y/o
47-48 y/o

Genetically predetermined
Early
Later
Smoking
Higher parity
Low socioeconomic status
Prior use of OCP
Women at high altitudes
High BMI
Vegetarians/thinner women High
consumption

Too much estrogen from the ovaries Inhibin B

release negative feedback on the anterior pituitary

decreased FSH release

Androgen production from the ovary continues beyond the

alcohol

The age at menopause appears to be genetically determined

and is unaffected by race, socioeconomic status, age at
menarche, or number of prior ovulations. Factors that are
toxic to the ovary often result in an earlier age of
menopause; women who smoke experience an earlier
menopause (1), as do many women exposed to
chemotherapy or pelvic radiation. Women who have had
surgery on their ovaries, or have had a hysterectomy,
despite retention of their ovaries, also may experience early
menopause (2). Premature ovarian failure, defined as
menopause before the age of 40 years, occurs in
approximately 1% of women. It may be idiopathic or
associated
with
a
toxic
exposure,
chromosomal
abnormality, or autoimmune disorder. [Berek and Novaks]

menopausal transition because of sparing of the stromal

compartment. Androgen concentrations are lower in
menopausal women than in women of reproductive age.
This finding appears to be associated more with aging and
decreased functioning of the ovary and adrenal glands over
time rather than with menopause per se. Menopausal
women continue to have low levels of circulating estrogens,
principally from peripheral aromatization of ovarian and
adrenal androgens. Adipose tissue is a major site of
aromatization, so obesity affects many of the sequelae of
menopause. The ovarianhypothalamicpituitary axis
remains intact during the menopausal transition; thus, FSH
levels rise in response to ovarian failure and the absence of
negative feedback from the ovary. Atresia of the follicular
apparatus, in particular the granulosa cells, results in
reduced production of estrogen and inhibin, resulting in
reduced inhibin levels and elevated FSH levels, a cardinal
sign of menopause.

PATHOPHYSIOLOGY OF MENOPAUSAL
TRANSITION

have no clinical consequences except for the

increased
risk
of
endometrial
proliferation,
hyperplasia, and cancer associated with continued
endogenous estrogen production or administration
of unopposed estrogen therapy in menopausal
women. The possible effects of declining androgen
concentrations that occur with aging are an area of
both controversy and active investigation.
The major consequences of menopause are related
primarily to estrogen deficiency. It is very difficult to
distinguish the consequences of estrogen deficiency
from those of aging, as aging and menopause are
inextricably linked. Studying the effects of estrogen
deficiency and replacement in young women with
ovarian failure or of drugs that suppress estrogen
synthesis (such as gonadotropin-releasing hormone
antagonists) helps to distinguish between the effects
of aging and estrogen deficiency. These models are
imperfect, though, and differ from natural
menopause in many ways.

STAGES OF REPRODUCTIVE AGING WORKSHOP

(STRAW)

Study the chart in detail!

The number of follicles is highest at 20 weeks of
age. At birth, there are 1-2 million follicles.
In menopausal women, there is a low estrogenic
environment that gives rise to a high
androgenic environment. Thus, menopausal
women may experience acne and hair growth.
Anti-Mullerian Hormone (AMH) may be given
anytime during the cycle. In the Philippines, it
is very expensive, and only available at St.
Lukes Global.
The menopausal transition is characterized by
elevated FSH levels associated with variable cycle
lengths
and
missed
menses,
whereas
the
postmenopausal period is marked by amenorrhea.
The menopausal transition begins with variability in
menstrual cycle length accompanied by rising FSH
levels and ends with the final menstrual period.
Menopause is defined retrospectively as the time of
the final menstrual period followed by 12 months of
amenorrhea. Postmenopause describes the period
following the final menses
The pathophysiologic consequences of menopause
may be best understood by considering that the
ovary is a women's only source of oocytes, her
primary source of estrogen and progesterone, and a
major source of androgens. Menopause results in
infertility secondary to oocyte depletion. Ovarian
cessation of progesterone production appears to
Apale,Aquino E., Aquino J. Arceo,

Constantino
Page 2 of 7

Study this chart in detail, especially the last row,

Endocrine!

1.
2.
3.
4.
5.
6.
7.
8.
9.

THE SYMPTOMS OF MENOPAUSE

Vasomotor symptoms
Sleep disturbance
Depressed mood
Skin and urogenital atrophy
Decline in cognitive function
Menstrual disturbances
Osteoporosis/ostepenia
Cardiovascular disease
Sexual dysfunction

Systemic estrogen therapy is the most effective

treatment available for vasomotor symptoms
and associated sleep disturbance
o
Because vasomotor symptoms appear to be the
result of estrogen withdrawal, rather than
simply low estrogen levels, if cessation of
estrogen therapy is desired, the dose should be
reduced slowly over several months
Vasomotor symptoms affect up to
75% of
perimenopausal women. Symptoms last for 1 to 2
years after menopause in most women, but may
continue for up to 10 years or longer in others. Hot
flashes are the primary reason women seek care at
menopause and request HT. Hot flashes not only
disturb women at work and interrupt daily activities
but also disrupt sleep
A
central
event,
probably
initiated
in
the
hypothalamus, drives an increased core body
temperature, metabolic rate, and skin temperature;
this reaction results in peripheral vasodilation and
sweating in some women.
o

These are all due to follicular depletion and

decreased estrogen. These women are secreting
ESTRONE.

Vasomotor Symptoms
Hot flush
o Starts from the chest, upwards
o Occurs in the middle of the early mornings
(a time that should be for deep sleep)
Increase in awake and asleep SBP
Increase in HR
Loss of sleep
Depressed
Irritable
Rapid decreases in estrogen levels (estrogen
withdrawal) causes:
o Increase norepinephrine stimulation
o Increase serotonin activation
o Increase activity of central opioid peptides
These factors added together causes narrowing
of
the
thermoneutral
zone
in
the
thermoregulatory center
o The upper threshold is decreased, which
means smaller increases in core body
temperature can trigger mechanisms to
dissipate heat such as vasodilation and
sweating
o The lower threshold is increased, which
means
smaller
decreases
in
core
temperature can trigger mechanisms to
preserve heat, such as shivers and chills
Hot flushes start with core temperature rising
above
the
narrow
upper
threshold
vasodilation in the peripheral vasculature
increase skin temperature increase systolic
BP increase HR
Can be accompanied by anxiety and palpitations
o Reflex cooling from the improved skin
surface heat dissipation causes chills after
flash
o Commonly occur at night, which leads to
sleep dysfunction and reports of fatigue
because of disruptive symptoms
Estrogens effective for treatment of vasomotor
symptoms

Apale,Aquino E., Aquino J. Arceo,

Skin and Urogenital Atrophy

Urogenital atrophy
Vulvovaginal aging
Lack of estrogen on the urogenital epithelium
Dryness, itching, burning, dyspareunia
Decreased blood flow, collagen, elastic fibers,
vaginal elasticity

Systemic estrogen therapy is effective for the relief of

vaginal
dryness,
dyspareunia,
and
urinary
symptoms. For women who should not or choose not
to use estrogen therapy, another option is topical
application. Because systemic absorption is low,
endometrial stimulation is minimal; thus vaginal
estrogen therapy may be appropriate even for
symptomatic women with breast cancer. Low doses
of estrogen cream (Premarin, Estrace) (0.5 g) are
effective when used only 1 to 3 times weekly (27).
An estradiol vaginal tablet (Vagifem) (25 g)
inserted twice weekly, which may be less messy and
easier to use than estrogen cream, is available. An
estrogen containing vaginal ring (Estring) (7.5
g/day), which is placed in the vagina every 3
months and slowly releases a low dose of estradiol,
also is available

Skin
Skin aging
Lack of estrogen
Decline in skin collagen
Decline in Cognitive Function
Estrogen is protective for the CNS
o Estrogen
protects
against
neuronal
oxidative stress/cytotoxicity
o Decreases the amount of amyloid protein
deposits Alzheimers disease
o Enhances cerebral blood flow 3
Thus, in menopause, there is decreased blood
flow to CNS
Menstrual Disturbances
Anovulation
o Perimenopausal
women
should
NOT
experience heavy menstrual bleeding
Longer cycles in between, heavy bleeding

Constantino
Page 3 of 7

 Rule out organic pathology/neoplasia

Cardiovascular Diseases

Dyslipidemia
Total and low density lipoprotein (LDL)
cholesterol increase with age
Accelerated by menopause
High density lipoprotein (HDL) decreases
Lead to increase rates of corononary heart
disease, myocardial infarction and stroke in
post-menopausal women
CVD risk for menopausal women is higher than
in men of equal age
CVD is the most common cause of death in
Filipino women
o Withdrawal of estrogen dyslipidemia,
which sets in at an increased rate, as
compared to women of reproductive age

Bone Issues: Osteopenia vs. Osteoporosis

Those with osteopenia have a 10x increased risk
of fracture
Osteopenia leads to osteoporosis if undiagnosed
or uncontrolled
Estrogen is responsible for promoting osteoblast
(bone-forming cell) activity.
It also inhibits bone remodeling and balances
osteoblast and osteoclast (bone-resorbing cell)
activity.
As levels of serum estrogen decline in
menopause, there is an increase in the rate of
bone loss
Increase in bone turnover increases serum
calcium
Affects trabecular bone defect in bone mineral
density
Menopause causes primary osteoporosis :
estrogen decrease
Increased osteoclast formation
Bone resorption > bone formation
Bone turnover increases serum calcium
Loss of estrogen also sensitizes bone to respond
highly to parathyroid hormone
When serum calcium becomes low, the
parathyroid releases PTH to stimulate vitamin
D production
o Vitamin D increases absorption of calcium
in the kidney and the intestine as well as
stimulating osteoclasts
Apale,Aquino E., Aquino J. Arceo,

With no estrogen, the bone now releases

more calcium for the same amount of PTH
stimulation
further
weakening
the
structure
Standard Tx: bisphosphonates, not calcium
Bone mineral density (BMD) measurements may
be used to diagnose osteoporosis, determine
fracture risk, and identify women who would
benefit from therapeutic interventions. Dual xray absorptiometry (DXA) of the hip and spine
is the primary technique for BMD assessment.
Women should receive 1,000 to 1,500 mg of
calcium and 400 to 800 IU of vitamin D daily.
Hormone therapy is effective in preventing and
treating osteoporosis. In observational studies,
estrogen therapy has been shown to reduce
osteoporosis-related
fractures
by
approximately 50% when started soon after
menopause and continued long term.
o

The World Health Organization (WHO) has

established the following definitions:
Normal BMD as a T-score > - 1 standard
deviation of the mean
Osteopenia as BMD between -1 and 2.5 SD
Osteoporosis as a T-score < -2.5 SD

Constantino
Page 4 of 7

The National Osteoporosis Foundation

recommends testing in BMD:
Women > age 65 years
Post-menopausal women age 50-69 years with
an increased risk profile
Women > age 50 years with fracture
Women
with
a
medical
condition
(eg.
Rheumatoid arthritis) or taking a medication
(eg. Glucocorticoid > 5mg daily dose
prednisone or equivalent for > 3months) that
will pre-dispose to low BMD
Women being considered for pharmacological
therapy for osteoporosis
Women being treated for osteoporosis, to
monitor their progress
Post-menopausal women discontinuing estrogen
therapy
PATHOPHYSIOLOGY OF MENOPAUSE ORGAN
CHANGES

Calcitonin Salmon (Miacalcin or Fortical)

200IU intranasal spray daily

4.MHT

Estrogen
5.PTH

Recombinant
PTH(1-34)
Teriparatide
( Forteo) 20 g SQ daily
6.Hormone replacement therapy
7.Conjugated equine estrogen 0.625 mg
8.Estrogen creams
9.Estrogen ring
10. Estrogen patch

PREMATURE OVARIAN FAILURE

(This chart is reproduced at the end of this
trans)
APPROACH TO THE WOMAN IN MENOPAUSE
History and physical examination
Appropriate laboratory tests
o Pap smear
o Lipid profile
o FBS
o FOBT
o CBC
o Urinalysis
o Liver enzymes
o Ultrasound
o DEXA
o Mammogram
TREATING THE WOMAN IN MENOPAUSE
Vasomotor symptoms
Lifestyle change
Non-hormonal
medications:
phytoestrogens,
SSRIs, gabapentin
Estrogen replacement therapy
o Give COMBINED estrogen/progesterone
Otherwise, unopposed estrogen in
endometrium will predispose one to
having CA
Osteopenia vs Osteoporosis
1.Bisphosphonates

Alendronate (Fosamax) 10 mg daily tablet,

70 mg weekly tablet or liquid formation

Risedronate ( Actonel) 5 mg daily tablet,

35 mg weekly tablet or 75 mg on 2
consecutive days tablets or 150 mg
monthly tablet

Ibandronmate (BOniva) 2.5 mg daily

tablet, 150mg monthly tablet or 3 mg IV
therapy every 3 months

Zoledronic Acid ( Reclast) 5 mg IV thertapy

yearly
2.SERMs

Raloxifene HCl (Evista) 60 mg daily

3.Calcitonin
Apale,Aquino E., Aquino J. Arceo,

Commonly referred to as premature ovarian

failure (POF) but this is a misnomer as there is
varying ovarian function in 50% of patients
with POI
Formal
diagnoses
made
via
history
of
amenorrhea for >4 months + 2 serum FSH
levels gathered >1 month apart in a woman
POI is ovarian failure with a high FSH level
(primary hypogonadism)
o Loss of oocytes lack of folliculogenesis
lack of ovarian estrogen production
o Clinical presentation is a per menopause
when at the full end of the spectrum of
insufficiency amenorrhea and estrogen
deficiency symptoms
Recommend karyotyping for relatives
Women with POI tend to be smaller, and their
ovaries go into atresia early on.

Ovarian failure occurs before 40 years of age in 1% to

5% of women and is considered pathologic
(premature ovarian failure). Early failure may be
caused by decreased follicular endowment or
accelerated follicular atresia. If ovarian failure occurs
before puberty, the patient's breasts will not develop
(i.e., Turner syndrome), and gonadal agenesis results

ETIOLOGY AND PATHOGENESIS

Two broad categories:
1. Follicle depletion lack of follicles due
to inadequate initial pool of primordial
follicles, increased
expenditure,
or
destruction
because
of
a
follicle
targeting toxin
2. Follicle dysfunction follicles present
but non-functional in steroid production
due to a pathological mechanism
Follicle depletion
Depletion due to genetics ( X chromosome
disorders or somatic chromosome mutations),
autoimmune cause, and ovarian toxins
Turner syndrome
Genotype is XO; can be a mosaicism with
expected range of clinical presentation

Constantino
Page 5 of 7

 Turner fetuses contain normal number of

primordial follicle germ cells up to week 12 of
gestation with subsequent decease in number
therefore it is accelerated atresia during the
gestational period
Ovaries described as streak gonads with
extensive connective tissue infiltration and
absent to few atretic follicles

FRAGILE X SYNDROME
X-linked form of severe intellectual disability
affecting 5 untranslated portion of the FMR1
gene
o Full mutation (affected): >200 CGG
repeats in the FMR1 region
No POI
o Premutation: 55 200 CGG repeats
Can expand to a full mutation in one
generation of transmission
Associated with POI increasing
number of repeats decreases age at
menopause
o Gray zone: 40 CGG repeats
Can be associated with POI
When a female passes on her permutation it can
increase the number of CGG repeats and
develop into a full mutation, whereas in males
the mutation can regress, expand (shy of a full
mutation), or stay the same
Mechanism for initiation of POI in permutations
of Fragile X syndrome is unknown
o Potentially
increased
FMR1
mRNA
expression and decreased FMR1 protein
Full mutation phase reduced
Mean follicular phase FSH increased
Inhibin B (follicular phase), inhibin
A/progesterone (luteal phase) reduced
Mechanism for initiation of POI in permutations
of Fragile X syndrome is unknown
o Potentially
increased
FMR1
mRNA
expression and decreased FMR1 protein
Full mutation phase reduced
Mean follicular phase FSH increased
Inhibin B (follicular phase), inhibin
A/progesterone (luteal phase) reduced
Women with intellectual disability at onset.
Some have large breasts but with muscular
dystrophies.
Fragile X syndrome is the most common cause of
inherited (Xlinked) mental retardation. It is
caused by inactivation of the FMR1 gene located on
Xq27.3 as a result of expansion of a CGG triplet
repeat of more than 200 copies. The normal
population has an average size repeat of 30. Female
carriers of the disorder have between 60 to 200
repeats (premutations) and are not mentally
retarded.
Women who have premutations have a 15% to 25%
chance of premature ovarian failure (91,92).
Interestingly, women with full mutations are not at
higher risk for premature ovarian failure. It is
hypothesized that expression of abnormal FMR1
mRNA produced by patients with the premutation
causes dysfunction in the ovary, which does not
occur when the FMR1 gene is inactivated and not
Apale,Aquino E., Aquino J. Arceo,

Constantino
Page 6 of 7

transcribed (91,92). Patients with premature ovarian

failure have a 4% to 5% chance of having the
premutation for fragile X . If premature ovarian
failure is present in another family member, the
chance of finding a premutation increases to 15%

END
You will never be happy if you continue to
search for what happiness consists of. You will
never live if you are looking for the meaning of
life. Albert Camus
Being sorry is the highest act of selfishness,
seeing value only after discarding it. -Douglas
Horton

Hi IRG! Hi bears!!!

The reason a lot of people do not recognize

opportunity is because it usually goes
around wearing overalls looking like hard
work.

Apale,Aquino E., Aquino J. Arceo,

Constantino
Page 7 of 7