HUMAN

PHYSIOLOGY
FOR MEDICAL STUDENTS

I ENDOCRINE GLANDS & REPRODUCTION I

MAGDI SABRY, MD
professor of physiology
Faculty of Medicine
AI-Azhar University
CAIRO
 All rights reserved, no part of this book may be reproduced in any
manner without ~t •ritten permission from the author or publisher.
For information, please call Tel. 6342854.

DEDICATED TO

MY TEACHERS THROUGHOUT MY LIFE, particu/ur(r the

.fir.\1 2 teuc:hers. my late pc11·ent.\·.

MY FAITHFUL LATE WIFE, the light that disappeared

fhnn l~fe hut i..,. el•erla.'iling inside me.

MY SONS, SHERIF, AMR AND ESSAM, AND THEIR WIVES,

thl'ir lol'e gil•c•s me.: !tope am/ inleresl in file am/ malw.\· their
lwppiue..,...,. my chic~{gottl.

MY GRANDCHILDREN, AHMED, NOURHAN AND SAMA

SHERIF, YASMIN AND MOHAMMED AMR, AND A YA ESSAM.
tlu• beautiful yomtg angel.-; that ftm•t• added a new kind of
lwppine.'is to my life.
 PREFAC
With recent adwmces in the field of human physiology, it has
becom e urgent to prm•ide till up to date re1•iew 011 the subject.

T/li' book is prrJI'ided to help medical .\tudent' in uml£'n tanding

modem human phys iology./t presents th e 11'/t olt .\ f(bjecf in a
brief, comprehensive, and up to date form.

Great effort was done to perfect s uch a vast s ubject in a11 easily
understandable expressio11 and in a suc:lt reasomtiJ/e bulk. It includes
as muc:lt simplified am/ clear illustrations a.\ possiiJ/e.a11d to maintai11
simplicio•. they have been presented 111 a diagrrt111111atic form,
photographs 11•ere greatly excluded.

Tlt e major part of my g ratitude sh ould be gh•e11 to all 11•110 taug ht

me, am/ to my late '"~fe and so11s 11'/to, patient~)'. supported me duri11g
prepamtio11 t~f litis book

A11y suggestions, remarks or criticism will be great~)' welcomed,

ltearfiZI' appreciated and l 'f!I:J' much considered.

I !tope this book will be a reallte/p to umlergraduate medical student'

as well a.\ to postgraduates and candidates of ltiglt t•r degrees, ill the
field ofllllmtm physiology.
:vlAGDI SABRY 1989

Seco nd edition 1994

Third ed itio n 2000
I ' d un· 111 l hl· fmul h ~ clili un
Hli\ IIL' II' etfition i\ oriJ,:illa/ hmh ill \/lllpi! llll(/ COIIIt'l/(\. fl/ tfwptc•r.. hlll'l.'
ht'l'll t''J;It mil·cly re,•i,rtl uml tlfltltllt•d. Hort' ./h:ttre:o. ami illmtrllliom art'
illlrmlttl't'tl, ant! rcn'llf dam urc• m!t/C'tl i!f,cwllt'N' v~t•dal(r llhoutthr mt• ·lumi"'"
of action of ll onnont'\, ant! a/m f/\1 all \llhjcct' l1111't' ht t'l l t'OIIIf lll'lt'(l' rcll'rilft'll.
 I CONTENTS I

SECTION I : THE ENDOCRINE GLANDS page

Chapter 1 : The hor1nones ................................................................... !

Chapter 2: The pituitary gland (the hypophysis).......................... lO

Chapter 3 : The thyroid gland. ... ..... ............... .. ...... ... ....... 33

Chapter 4 : The adrenal (suprarenal) cortex................................ 49

Chapter 5 : The adrenal (suprarenal) medulla............................ 66

Chapter 6: The parathyroid glands & calcium metabolism 72

Chapter 7 : Endocrine fi.m ctions of the pancreas ....................... 84

Chapter 8 : The pineal gland (the epiphysis) ............................... 96

SECTION II : REPRODUCTION
Chapter 1: Sexual deve/poment and puberty .... .. .. .... .... .. ... 97

Chapter 2 : The male reproductive system............................ ...... I 03

Chapter 3: The female reproductive system............................. 116

SECTION I

ENDOCRINE GLANDS
CHAPTER 1
LTr·- ·'ORMCNF<=' 1
In the human body, there arc 2 systems that regulate the functions of other
systems. These arc th e nervous and the endocrine systems. The endo-
crine glands are ductless glands that secrete lwrmones directly into the
bloodstream through which they reach other s it~:s ( target organs) wh~:rc
they exert their action;;. They include the fo li o'' ing gland (figure I ).

PI N.EAL

4 PAQAT~YROIOS

------- - - - - - THYM US

-- ., --
....
'
2 SUPRAQ ENALS
CORr~XIl
MED UI.I.A

-- PANCQEAS
(lskcs o/
Lam_;frrhans)

2 TESTES in Male
/ ( 2 OVARIES in Fcemalcz.
' fplvs p/oca.·'l!o in
,/ \ ,crq9n oncyj)
I
,I
I '

w
Figure I : The human endocrine glands.
 Section 1- Chapter 1 Properties o(hormnnes

(I) Pituitary gland (the hypophysis).

(2) Thyroid gland.
(3) Parathyroid glands (usually 4 glands).
(4) Adrena l (or suprarenal ) glands (2 glands, each contains conex & ncdulla)
(5) Sex glands or gonads (2 testes in males unci 2 ovaries in females).
(6) Islets of Langcrhans (in the pancreas).
(7) Pineal gland (the epiphysis).
(8) Thymus gland (refer to blood).
:::_ All glands arc important for normal body function, but the anterior
pituitaty, adrenal cortex and parathyroid glands are essential to life.

I OTHER ENDOCRINE ORGANS I

In addi tion to the endocrine glands mentioned above, the following
organs also exert endocrine functions besides their original functions :
1. The kidn eys : These secrete (a) Renin (b) E'J'fll ropoietin
(c) 1,25 -dihydro.\)•c/wlecalciferol (the actil·e metoho!ite of vitamin DJ).
2. The heart : The atria secrete ANP (Atrial Natriuretic Peptide)
which causes natriuretic and hypotensive effects (refer to kidney).
3. T he hypotha lam us : This secretes (a ) The hypophysiotropic
hormones, which r!flect the activity <~!'the anterior pituitaJ:v gland (b)
A ntidiuretic hormone (or vasopressin) ami oxytocin, which are stored in
then releosed.fi'om the posterior pituitarv gland (rclcr to the pituitary gland).
4. T he placenta (page 139).
5. T he lungs (rdcr to rcspimtion).
6. The liver (refer to digestion).
Apart from these "gener al hormon es" secreted by the
endocrine glands and rhe other endocrine organs, there are also "local
hormones" that act at (or near) the sites of their secretion. These include
(a) The gastrointestinal hormones (e.g. gastrin , secreti n, CCK, etc.) (b)
The 11arious chemicaltransmillers released by nerve endings.

I PROPERTIES OF HORMONES I
1. They cxcr1 no tljfa'ti on the glands t!tat secrete them.
2. Some hormones affect cell activity all over the body (e.g. the growth
hormone) while others act only on specific lfll~~et cells (e.g. sex hormones)
3. In the target cells. they trigger (initiate) certain biochemical reac-
tions which often continue for sometime afte r disappearance of the hor-
mones from the bloodstream.
 J

Section 1- Chapter I Chemical structure of hormones

.t. Some hormotH.!S exert other eff(!C:ts in addi tion to thei r spec ifie
effects e.g. the main action of insulin is to decrease the blood glucose level
but. howe\'er. it also stimulates protein symhesis (chapter 7).
5. Stimuli that release a cenain honnonc inhibit the secretion of
other hormones that exert antagonistic effect.\ e.g. hyperglyccnua
stimulates insulin sccn.:t ton and inhibits the secretion of its antagonists
(e.g. the growth hormone and glucagon).
6. Normally, hormones are secreted in very small amounts that
maintain a basal quantity of each hormone in the bloodstream , and
the rate of secretion or a certain hom10ne depends on the needs of the
body to this hormone.
7. Many hormones sho" cyclic variations in their rate or secreti on over
the 24 hours(= diumal or circadian rhythm) e.g. ACTII and melatonin.
8. Hormones (in contrast to enzymes) arc continuously lost rrom
the bloodstream by either excretion or metabolic inactivation.
9. Some honnones arc secreted in rclati' el) inacti' c forms then they arc
com•erterl in the tissues to more actil'e hormones (e.g. testosterone and
thyrox ine).
10. Most hormones circulate in the bloodstrea m in 2 forms : A very
sma ll amount in the free form, and a much greMer amount bound to
plasma proteins. The free pan is the acti\ e part capable of cxening effects
on the target cells" hile the bound part acts as a rescn oir for the hom1one.

Lf:HEMICAL STRUCTURE OF HORMON;s j

Chemically, the hormones are cithl!r protein or .\teroitl in nature.

(1) PRO TEIN HORMONES : These arc classifi ed into 2 groups :

(A) ll onnoncs fhnned from on e amino acid : These include
(I) The thyroid horm ones i.e. tri-iodothyronine and tctra-iodothyronine
(T3 and T4 ) and catecholamines (epinephrine and norepinephrine). All
these honnones arc derh ed from the amino acid tyrO\ine.
(2) ~lela10nin. which is fonncd from the amino ac1d trypwpltan.
(B) I lom1ones fonned of long or short peptide chains
po(rpeptide hormone.\). fhesc include : ( I) All hormones of the amcrior
and posterior pitu itary glands (2) The parathyroid hormone (3) All panc-
reatic hormones (insulin. glucagon, somatostatin and thi! PP. chapter 7).
 Section 1- Chapter I Tlt e ltormonal receptor.,

(4) Calci ton in (5) ll ypophysiotrop ic hormom:s (6) Gastrointesti na l

hormones (7) Relaxin (8) lnhibin (9) Some placental hormones (e.g. hCG
and hCS) ( 10) Erythropoietin ( II ) Renin. The later 2. a well as TSII.
FSII, LH and hCG an! ~~rcop roteins (refer to pituitary gland and placenta).

-Fr r>/ ) I ) J[ ~-- These arc derived from cltolestero/,

and they include ( I) i\ II hormones of the adrenal cortex (2) The sex
hormones secreted by the male and female gonads (testes and O\ aries), the
adrenal cortex and tht.: placenta (estrogen and progesterone). (3) 1.25-
dihydroxycholeealcilcrol (the active metabolite of'vitnmin O,).

( iHE HORMONAL RECEPTORS

The honnonal receptors arc located either inside tlte target cells (in
the cytoplasm or in the nucleus) or on their m embranes. They arc
chemically protein in lltltllre. and they arc spedjic (i.e. each receptor is
specified to bind ton certain honnom:).

Regulation of llormonal receptors

The hormonal receptors arc 1101 sllllic cmiiJ>OII£'111\ of the cell. but the)
an: tZrllamic: structtm!.\ i.e. their numbers iJH:re.tse and decn:asc b) the
ctlcct or' arious ~timul1 as" ell a~ according to the hormonal blood le' cl. In
the lath.:r cnse, the regulatton of the hormonal receptors is 2 types :

l. Up regulation : A low blood level of a certain hormone leads to an

increase in the number of its active receptors.

2. Down regula eion : A high blood level or a certain hormone leads to a

decrease in the number of its acti\ c receptors. In case or cell membrane
rccepto~. this occur~ b) either (a) En docytoo.\ i.\ of the receptors (=
intemali:ation) or (h) De'iemiti:ation oftlte receptor~ (i.e. the receptors
arc dtemically modified 111 ways that make them Jc..,.., rcsponsi' c).

I MECHANISM OF ACTiON or- HORMoNEs]

l lormones arc chemical messengers(= li~wuf.\· ) that carry signals (or
messages) to the target cells to produce certain responses. The first event in
 5

Section 1- Chapter 1 Mec/umism o(action o{/wrmones

this process is binding of the hormones to their specific receptors in these

cel ls. Such binding produces conformational changes in the receptors, which
lead to their activation. This initiates a sequence of reactions in the cells that
finally cause the required response. This process is ca lled signa/transduction.

mRNA
Bonding to recaptor t
Protcon
loclttd in nucleus or
oncytoplum t
Response

F igure 2 : Mechan ism of action of steroid and thyroid honnoncs.

R = Receptor , H = l lormone.

Depending on the site of the hom1onal receptors, signal transduction

inside the target cells is produced by one of the following pathways :

I (I) A pathway initiated by activation of the intracellular receptors

The honnoncs that act through this pathway arc the fat-soluble
hormones (= lipopltilic hormones) that can cross the target cell membranes
and cnter inside these cells. These honnones includl! (a) The steroid
lwmumes, which combine to receptors located in the cytoplasm of the
tm-xet cells (b) The thyroid hormones (T-' and T-1 ), which combine to
receptors located in the nuclei oftlte target cells.
The acti vated receptors in both cases (i.e. the receptor-hormone com-
plexes) bind to DNA in the nuclei of the tnrget cells and this increases
transcription of specific mRNAs . These pass to the cytoplasm where they arc
 6

Section 1- Chapter I Mechanism o{action o{/wrmun es

translated in the ribosomes. leading to production of increased quantities of

regulatory proteins that alter the cell functions and, consequently, lead to the
required responses (figure 2).

HEAT SHOCK PROTEINS (HSP) OR STRESS PROTEINS

These arc cytoplasmic proteins that increase when the cells arc exposed to
heat and other stresses, and they help the cells to sur·vive in these conditions.
The receptors of the glucocorticoid hormones (= steroid
hormones secreted by the adrenal cortex and exerl pOII'el:ful amistress
effects) me bound to one of these proteins (HSP 90) and thi s protein covers
the DNA binding si tes in absence of the hormones. The secretion or these
hormon<.:s in<.:reases in <.:ases of stress, and when they bind to their receptors,
the liSP 90 is released. This exposes the DNA binding sites. which initiates
the requ ired anti stress responses (page 52). Other steroid hormone receptors
e.g. progesterone receptors are also bound to heat shock proteins (page 132).

[Jill: Pathways initiated by activation of cell membrane receptor~

The hormones that act through these pathways an.: the water-so lu ble
hormones (= ltydropltilic hormones) which include all protein hormones
except the thyroid hormones T3 & T-1 111hich are lipophilic (see above).
Act iva tion of the receptors or these horm ones cnn produ ce ce ll
responses by botlt direct all(/ indirect pathways (the later through activat-
ing certain proteins in the ce ll membranes ca lled G prot eins).

(A} The direct pathways that produce cell responses

I. Activation or inactivation of ion c:lumne/s (i.e. opening or clos ing

these cha nn els respectivt.:ly) e.g. a· and K chan ne ls. This affec ts the
rates of influx and efflux of these ions. which consequently alter the cell
funct ion. and leads to the required responses.
2. In creasing the activity of the ~wosine kinase ell':,y m e (which is
present in the cy toplasmic portion of the receptor). Thi s enzyme ca tal yzes
phusplunJiotion of certain C)'loplasmic proteins, whic h alters the ce ll
runction s and len ds to the req uired response. The main hormone that acts
by thi s mcc hnni sm is insulin.
3. Stimulation of tlte Guanylyl (= guanylate or guanyl) cyclase en:;yme
wlticlt converts GTP ( Gmmosine- Tri-PiwvJiwte) into c GTP (cyclic GTP).
 7

Section 1- Chapter I Mechanism o(action o(hormones

The latter acts as a second messenger that acti vates a speci fie cGTP-
dependent kinase em_.yme. This enzyme catalyzes phospho1:rlation of cerrain
cytoplasmic p roteins, which alter th e cell functions and lead to the required
response. The main honnonc that acts by this mechanism is ANP i. e. the
atrial natriuretic peptide (page 2).

THE G PROTEINS

The G proteins are regulatory proteins located in the cell membranes.

They are nucleotide-bimling proteins that bind GTP (so they arc ca lled GTP-
bincling proteins or simply G proteins) and they play an essential role in the
translation of signals to biologic effects inside the cells (sec below). They arc 2
types ; small and large, and either may be stimulatory ( Gs proteins) or
inhibitory (Gi proteins). Activation ofthe Gs proteins produces cell responses.
H'hile acrivation of the Gi proteins prevents rhese responses. The large G
proteins are made up of 3 subunits (alpha. beta etllll gamma) and are ca lled
lleterotrimeric G proteins (figures 3 and 4 ).

THE SERPENTINE RECEPTORS

All the heterolrimeric G protein-coupled receptors are proteins that spcm

over tile eel/membrane and cross it 7 times like a snake (figures 3 and 4 ), so
they are called seqJentine receptor!S (se1pent = snake).

Cytoplasm
ATP cAM P
l
Prote:n kinase A
l
Phosphoprote1ns
l
Physlolog1c effects

Figure 3 : Mechanism of action of hydrophilic hormones by fom1ation of

cAM P. Notice the structure or the serpentine receptors and adcnylyl cyclase.
 8

Section 1- Cltapter I Mechanism o(action o(ltormones

(B) The indirect pathways that produce cell responses

(through activating G proteins)

Most hydrophilic hormones produce cell responses by this mechanis111.

ln this case, the hormones act as first m essengers that activate their receptors.
The activated receptors then activate the mssociated Gs proteins, which induce
format ion or another intracellu lar chemical mediators (= second m essengers)
and these produce the requi red cel l responses. The commonest indirect path-
ways and their associated second messengers include the fo llow ing :

1. Cyclic AMP (cAMP) pathway

The activated Gs protein activates the Adenylyl (= adenyl or
adenylate) cyclase en zym e (a long po lypeptide that crosses th e ce ll
membrane 12 times) which catalyzes formation '~f cAMP fro m A TP
(figure 3). cAM P then activates a specific cAM P dependent kjnase enz-
yme (=protein kinase A) wh ich catalyzes phosphorylation of a certain
protein. This alters its conformation (configuration) & function. Conse-
quentl y the ce ll fun ctions arc changed, leading to the requ ired response.
_:: The hormones that act via increasing cycl ic AMP include ACTII,
calcitonin, glucagon, para/hormone, lipotropin, HtiiiUIII chorionic
gonadotropin (hCG), MSH, TSH, Vasopressin (at the V1 receptors), FSH
and LH, most hypophysiotropic hormones (e.g. Gn-RH and TRH) and
c:atecltolamines (at all beta receptors).
~ Some hormones act by decreasing cyclic AMP through stimu lation
of Gi protein s (fi gure 3) . These inc lude sollullostatin, cateclwlamines (at
the alpha 2 receptors) and dopamine (at the D z. J & -1 receptors).
:_: The activated Gs proteins can also stimulate the pltosplwdiesteruse
enzym e (PDE) . This enzyme catalyzes conversion of cyclic GJWP to 5'-
GMP , so the intracellular content of cyclic GMP decreases and this
initiates the cell response. The mai n receptors that act by this mcchani sm are
the photoreceptor.,· (rods and cones) in the ret ina (refer to specia l senses).

2. Calcium Calmodulin pathway

The activated Gs protein triggers open ing of various ion channels
in the ce ll membrane, pariicularl y Ca 2+ channe ls. 1\ccordingly, the Ca 2 +
influx into the cell s from the ext race ll ular fluid increases. This Ca 2+ also
stimulates Ca 2+ release from tlte endoplasmic reticulum, so the
cytop lasmic Ca 2+ content markedly increases. Ca 2+ acts as a secon d
messenger and combines with one of the Ca 2 + - binding proteins
particularly calmodulin.
 9

Section 1- Chapter I Medumism o(action o[/10rmones

The Ca 2+- calmodulin complex activatl:S specific protein kinase enzymes

which cata lyze phosphot:\·lation of certain proteins. This alters their
conformation and functions. Consequently the cell functions arc changed,
leadi ng to the required response. The o.\)'tocin hormone increases the
intracellul ar Ca 2+ content probably by this mechanism.

3. /nositolu tpho pi .ue (IP J) & Diacyl glyc rol (DAG),JJlhW1Y

Activation of Gs proteins activates the phospholipase C ew;,yme
which catalyzes formation of both lP3 and OAG by hydrolysis of phospha-
tidylinositol diphosphate (PIPJ). IP3 difTuses into the endoplasmic reticulum
and causes release orCa 2 ~ into the cytoplasm (figure 4) which produces ce ll
responses. On the other hand, DAG activates protein kinase C which alters
the cd l runcti ons and produces the required responses (as protein kinase A in
case or cyclic AMP).. Many hormones act by this mechanism including
norepinephrine (at the alpha 1 receptors), angiotensin 11 (increases DAG).
Vasopressin (at the V1 receptors) and probab~l' also oxytocin (the latter 2
act by increasi ng fonmltion of IP3 ).

4. Arucllidonic acid p:~thw,1y · Acti vation or Gs proteins leads to

activati on or the p/10spl10/ipase A 1 en-::J'IIIe, which cata lyzes conversion of
certain phospholi pids in the cell membrane into arachidonic acid. This acid
acts as a second messenger that leads to formation of many substances e.g.
prostaglandins. thromboxancs and lcukotricncs. which alter the cell func-
tions and produce the required responses.

Stimulatory

-~@PIPTDAG ~
l (l y
Gq, etc. IP3 Phosphoproteins

CaBP - Ca2· -
Cytoplasm

.J! I
J
PhyStOIOgtC effects
~R PhysiologiC
effects

Figure -": Mechanism of action of hydrophilic hormones by formation of

DAG and lP3. PLC = Phospholipase C. PKC = Protein kinase C. ER =
Endoplasmic reticulum, CaBP = Ca lcium binding protein.
 10

CHAPTER 2

I THE PITUITARY GLAND (THE HYPOPHYSIS) I

This is a ~mall gland. 0.5- 1 gm in weight. sinmted at the base of the
skull in a small cavity cal led the sella turcica (= hypophysial fossa),
and is att ached to the floor of the 3rd ventricle of the brain by a stalk (-
pituit{lf:J' stalk or inji111tlihulum ). It cons ists or 3 lobes (figure 5b) : A large
anterior lobe ca lled the adenohypophysis or anterior pituitary gland, a
small intermediate lobe (which is rudimemw:r in lwmcms) . and a large
posterior lobe ca lled the neurohypophysis or posterior pituitary gland.

Third ventrlcln

Posterior lobe

Rathke's pouch
Inter mediate lobe

Figure 5: Dcvt.:lopment of the pituitnry gland (a) and its lobes (b).
r.c. = "residual cleft.

The gla nd develops from 2 different structures ( ligure 5a) : An

upward ectodermal groll·th from the roof of the pharynx knO\\ n as the
Rathke's pouch, and a dollmmrd neural groll·th from th~ floor of the 3rd
ventric le of the brain. These meet in the sell a turcica. and the stalk of the
Rathke's pouch degenerates whil e that of the neural growth persists and
forms the pilllitaiJ' stalk.
The Rathke's pouch develops into 3 parts (1) Pars dista lis (= pars
glandu laris) which develops from the anteri or wall of the Ra thke's pouch (2)
Pars tuh cra lis which is an upward ex tens ion of the pars di stal is (3) Pars
inlcrmcdia which develops from the dorsa l half ofthe Rath ke's pouch. Bot h
th e pars distal is and the pars tuberalis rorm the anterior lobe or the gland
while the pars intermedin forms the intermediate lobe. The dO\vnward neural
 II

Section 1 - Chapter 2 Tlt e pituitarv gland (th e ltppopltpsis)

growth develops into the pat·s nervosa (formi ng the posterior lobe) to which
the intennediate lobe becomes closely adherent and is separated from the
anterior lobe by the remains of the Rathke's pouch known as the res idual
cleft (fi gure 5 b).

Hypotllllamus

Optic cho;n.,
~~. .- - -- Artery

Postttior - - -+-
piruotlfY gland
Anterior potu oUry gt1nd
V~m

Figure 6 : The hypothalamo-hypophysial porta l circulation.

HYPOTHALAMIC CONNECTIONS WITH THE PITUITARY GLAND

There arc 2 types of connections between the hypothalamus and the pit-
uitaJy gland (which form a li nk between the nervous system and the gland) :
1- A vascular connection between tlze ltypotlzalamu:s ami anterior lohe
in the form of a hypothalamo-hypophysia l porta l circulation (fi gure 6).
Arterial twigs from the carotid arteries form a primary capillary ple..'CuS in
the basal part of the hypothalamus known as the median eminence from
which blood is drained by p ortal hypophysial vessels down in the pi tuitary
stalk to a secondtll)' capillary plexus in the anterior lobe (which then drains
into the hypophysial vein)
2- A nervous connection between tlte hypothalamus and p osterior lohe
in the fo rm of a hypothala mo-hypophysial tract (figure 7).
THROUGH THESE CONNECTIONS THE HYPOTHALAMUS ACTS AS
A CONTROL CENTRE TO THE ENDOCRINE SYSTEM AS FOLLOWS :
(1) The hypothalamus secretes several hormones called ltypopltysiotropic
hormones (sec below) from an area ca lled the hypopltysiotropic area (which
includes the preoptic. arcuate and ventromedial nuclei). These honnoncs are
 12

Section 1- Chapter 2 Tlz e pituitary gland (lite lt!I[JO[Jitvsis)

then releasedfiwu tlte m edian eminence into lite portal vessel\· through whil:h
they reach the anterior pituitary gland where U1ey affect the secretion of its
hormones. In this way, the hypothalamus indirectly controls the activity a./most
of the endocrine :,ystem because the anterior pituitary gland secretes tropic
hormones that control most of the other endocrine glands (see below).
(2) The hypoth alamus also secretes tlte 2 lwrmoues of tlte posterior
pituitary glaml. which arc transported via the hypothalamo-hypophysialtract

P a~tncul .- ~:·
nucleon

' ' " ' " " ' ' "" " " - - { [ ) - - l\ntot 1or IJi tw r• rv

Figure 7 : The hypothalamo-hypophysialtract.

hy fLwma l flow to tlte posterior pituitary gland wltere they are stored tlten
released wlten required by signals discharged from the hypothalamus (sec
the posterior pituitary gland. page 27).
~ The hypothalamus is connected to almost all areas in the nervous
system. This explains why endocrinal disturbances frequent ly occur second-
ary to emotions. psychological disorders and other nervous diseases .
.::_ The hypothalamus contains osmoreceptors, thermoreceptor.,· am/
glucoreceptors \\ hich detect the plasma osmolality. body temperature and
blood glucose level respectively. It then corrects any detected disturbance by
changing the rate or secretion of its hormones according to the underlying
condition (refer to metabolism and kidney).

[ THE ANTERIOR PITUITARY GLAND (ADENOHYPOPHY ~

This gland secretes 7 protein ltormones, which arc classilied as follows :

(1) Polypeptide hormones ·These include the fo ll owing :

I. A drenocorticotropic !tormone ( = ACTH or corti cotropin).
2. Prolactin (- PRL,Mammotropin or Lactogenic hormone, LGII).
Section 1-C/ta[Jter 2 Th e pituitary gland (the hvpopltvsis)

3. Growth hormone(= Somatotropic hormone, STII or Somatotropin).

4. Beta lipotropin (8- LPH), a polypeptide that contains the am ino acid
sequences of endorphins and enkepha/ins.

(2) Glycoprotein hormones :These include the fo llowing hormones :

I. Thyroid stimulating hormone (TSH, thyrotropic hormone, thyrotropin).

2. Luteini:;ing hormone ( = LH) or interstitial-cell stimulating hormone.
3. Follicle stimulating hormone ( = FSH).
:.:_ Both FSH and LH control the gonads in the males and fema les.
so they are ca lled together the gonadotropic hormones ( = GTI Is).
** The anterior pituitary gland is frequently called the master
gland because it secretes tropic hormones that control most of the other
endocrine glands (ACTH controls the ad rena l cortex, TSH controls the
thyroid gland. while the GTHs control both male and female gonads).
** Tropic hormones stimulate secretion from other endocrine
glands except somatotropin (the growth hormone) because the latter is a
systemic hormone that is not tropic to any specifie endocrine gla nd.

CELL TYPES IN THE ADENOHYPOPHYSIS

The cells of the anterior lobe of tlte anterior pituit(lly gland are
trad itionally class ified on the basis of their staining reC'lctions into 2 types :

( 1) Chromophobe cells :
These cells do not stain with either acidic or basic dyes and they are
inactive secret01y cells that contain few secret01y granules.

(2) Chromophil cells :

These nrc granular secretory cells and they arc 2 types :
I. Acidophilic cells : These stain with C'lcidic dyes and they arc 2 types
a- Somatotropes which secrete somatotrop in (GI-l).
b- Mammotropes (or lactntropes) wh ich secrete prolactin.
2. Basophilic cells : These stain with basic dyes and they are 3 types :
a- Thyrotropes which secrete TSH.
b- Gouatlotropes which secrete the GTHs (LI I and FSH).
c- Corticotrnp es wh ich secrete J\CTH, beta Lipotropin (B-LP II) as
well as the opioid peptide beta emloqJhiu.
** The anterior pitui tary gland also contains folliculostel/ate cells \Vhich
secrete the cytokine iuterleukin 6 (but thei r phys iological role is unknown) .
 14

Section J-Chapter 2 The pituitarv gland (th e lt vpop/tJJsis)

THE INTERMEDIATE LOBE

This contains basophilic ce lls that synthesize a large precursor protein

called pro-opiomekmocortin (POMC). Thjs is hydrolyzed to gamma lipotropin
(unknown functions), 8 -em/orpltin as weiJ as a/pita & betamelanocyte-stimulatinJ.:
hormone~ ( = MSJl,·, melanotropin or intermedin). l11c MSIIs accelerate
melanin synthesis by the mdanocytcs. and trcatmem with these hormones in
humans produces detectable skin darkening in 2-1 hours. However, the
interm ediate lobe is rudimentary in humans. and it appears that both alplw
and beta-lVISHs are not secreted in adult humans.

~ ·n1e cor1icotropcs also synU1csize pro-opiomekmocortin (POMC) but 11 IS

hydrolyzed into A CTH , betalipotropin and a small amount ofB-emlotphin.
** The MSI/s and ACTH are srmctural~l ' inter-related because both are
derh·ed.fimn POMC. This. wgether with absence q(MSHs in humans and presence
q{melmwtropin receptOI:\· in the me/anoc..ytes that can bind ACTH led to the.f(tct
that the p(,;:menlaiJ• changes in several endocrine di'ieases are due pri11wri~l ' to
changes in the blood level ofACTH {which exerts a cnnsiderable MSII actil>iM
e.g. thc abnorma l pigmentation that occurs in Add ison's disensc is due to
increased ACTII secreti on (page 60) whi le the pa ll or obscrvcd rn
panhypopituitarism is due to deficient ACTII secretion (page 26).

REGULATION (CONTROL) OF ANTERIOR PITU ITARY SECRETION j

The secretion of the anterior pituitary hom10ncs is controlled by
the ltypotlllllamus as well11s by feedback m edumism s.

(A) HYPOTHALAMIC CONTROL

The hypothalamus controls the activity or the anterior pituitary gland

by releasing hormont.:s called th e hypophysiotropic hormone.,· that
reach the gland 'ia the hypotlwlamo-hypopltysial portal circulution. Th...:se
hypotha lamic hormones arc po~vpeptides that act mostly by increasing the
intracellular content of (l'Ciic A /liP and they either stimulate release(~(
the anterior pitui1m~1· hormones (= releas ing horm ones) or inhibit tlte
releose (?{these lwnnones (= release-inhibiting hormones).
Because of the numerous inter-connections between the hypothalamus
and otht.:r areas or the nervous system, the latter influences most of the end-
ocrine system through the neuroendocrine regulation of th e anterior pit-
uit((f:Y g land by tlte hypophysiotropic hormones.
 15

Section 1- Ch apter 2 Th e pituitan• gland (th e hreoph1•sis)

Hypothalamic hormones (hypophysiotropic hormones)

(1) Releasing hormones :

I. Corticotropin-releasing horm on e or CRII {stimulates ACTII secretion).

2. Thyrotropin-releasing hormone or TRH {stimulates TSI I secretion).
3 . Growtlt lwrmone-releasing hormone (G RH) .
.J. Gtmctdotropin-relea~inJ: hormone (GnR H).
5 .Prolactin-releasing hormon e or PRH (stimulates prolactin secretion).

(2) Release-inhibiting (or inhibiting) hormones :

I. GrowlIt hormone-inhibiting h orm one (Gill or som atostatin).

2. Prolactiu-inltibiting hormone (P IH, wltich ll'tts clt emicai~J·Jouml to he
dopamine). It exerts a tonic inhibi!Ot)' effect 011 the IIIWII/1/0tropes.
:::": The actil•ity ofthe a11terior pitui!OIJ' gland is lmge~\' controlled by the
h.l'lJOPh.niotropic hormo11es. All amerior pituitm:r hormo11e~ are controlled
lllltilt~l' hy their releasing hormone.\· except prolactin 11'/ticlt is controlled
11witt~\' /J.1' Pf/1 (.\·ee aluwe). This explains why section (~/the pituitw:r stalk
decreases secretion ofall a111erior pituitm:1· hormone.\ excepttlte secretio11 r?f'
prolactitt ll'hich temporari~r increases (page 147).

I
I
1 TRH

L Anttr~
\ ~P<IIJilary
1

:,' I
fr·t
) TSH
T1 d T.
\

'W,. . .
\

Figu rc H : Negati ve feedback mechanisms that control secretion or the

lhyroicl hormones. Dashed arrows indicate inhibition.
 1(,

Sec tion 1- Chapter 2 Tile pituitarv gland (tlte "''[JopiiFsis)

(B) FEEDBACK MECHANISMS

These constitute the relations between the blood levels of the

hormones and the secretory rate of their pituitary tropic hormones as wel l as
the hypothalamic hypophysiotropic hormones. Such relations arc 2 types :
I. Posith•e f eedback : This mechanism acts only in certain sinw-
tions. If thl: blood level of a certain hormone is increased. it stim ulates
the secretion of its corresponding pituitary tropic hormone or hypotha-
lamic releasing honnone. leading to a further increase in its blood le1•td.
2. Negatil'e feedbac/1 : Th is mechanism is ///Ore C0/1111/()1/, Ir the blood
leve l of' a certain hormone is increased, it wi ll be rapidly reduced to its nor-
mal kvcl, and vice ver. a. It is produced by a direct effect of the hormonal
blood level on the sec retory rate of eith er the pituitary tropic hormones,
the hypophys iotropic hormones or both together e.g. if' the blood levels
of the thyroid hormones increase, they will be reduced to thei r normal
leve ls through inhi biting the secretion ol'botb TSII and T RII (!igun.: 8).

[THE GROWTH HORMONE (GH) I

The human anterior pituhary gland secretes 2 biologically active types
t~l Glls, the lirst (about 75 %) is a protein hormone consisting of 191 amino
acids and has a molecular weight 22000, wh ile the other is smaller than the
first (it lacks 15 amino ac ids and has n molecular weight 20000). They
strru.:tural~v resemble prolactin and the placental gro ll'th hormones
(page 138). In normal adults. its daily output is 0.2- 1 mg and its basal
plasma level is 2-4 ng/ml (and 5-8 ng/ml in children). Th e monkey 's GH is
the on~r Gll from animals that can safely be gh•en to humtms.

[Efi=ECTS (ACTIONS) OF THE GROWTH HORMONE (GH) I

A . INDUCTION OF GROWTH I
Growth involves on increase in the boc(r 11wss. and the G II is th e
prin cipal g rmvth promoting factor in the body. It induces growth
through increasing the rate:; or both protein synthesis and ce ll di vision as
well as by exerting many metabolic eflects tsce below) that lead to
retention (~l all elements required for growth (inc luding am ino ac ids,
ca lcium , phosphates and other electrolytes). The GH causes the follow ing :
 17

Section 1- Chapter 2 Tlte pituitary gland (th e hvpophvsis)

1- Growth of almost all so ft tissues in the body including skeletal

muscles, skin and m m;t viscera . ll owever, it docs not affect the nervous
tissues and docs not produce tissue maturation (wh ich is main ly a func ti on
of the th yro id hormones) and it also increases the metabolic rate.
2- Ch ondrogenesis r- cartilage formation) ll'hich is .follo\\'ed by ossi-
jication and Krowrh o,(hones. In long bones, if the epiphyses arc not yet
fused to the bones (the case in children), as the cartilaginous epiphysial
plates \\'iden (figure 9), they lay down more bone matrix at the ends of
these bones, so their lengths increase leading to increase in the body stature.

Figure 9: Eflcct of Gil on growth of the epiphysial plate. Before giving the
horm one (left) and after giving the hormone (right).

B. METABOLIC EFFECTS I
I. Protein me ta bolism : The G il is a protein an abolic
hormone. It increases th e uptake or amino acids and protein sy nthesis
in the ti ssue ce ll s. Therefore. it produces a posirin! nitmgen balance to-
gether with a decrease in the blood levels of urea and amino acids.
2. Electrol yte meta bolism : The GH in creases the gastroint es tinal
absorption or Ca2-r and also produces a posirive plwsplwms balance. Tt
also decreases rile rare c~( urinm:r excre1ion of hmh Na and 1\ (so these
electrolytes arc diverted to the growing tissues).
3. Fa t metaboli sm : The GH mobili zes rat from adipose tissues and
stimulates lipolysis, so it decreases the body fat content and incrcrascs
th e blood leve l of the free fatty acids (FFAs) an d keton e bodies. The
FFAs pnJI•ide a ready source o,( energy for the rissi/(.!S, which spares
prote ins (thu s promo tin g protei n synthesis). Th is pmtein sparinK e.fl'e ct
of tlte Gil maintains it s gro\ovth eiTcct in hypoglycemia, fa sting and
stress. and is th e m ain {imction o[tlte ltorm on e in adults (in whom the
growth hormona l blood leve l is low but important, not fo r growth but
for ma intenance of the tissue mass by its prote in sparin g cf'f'ect).
 IH

Section 1- Chapter 2 Tlt e pituilarl' glan d (lit e lt vpop/tpsis)

-L Ca rboh ydrate metaboli sm : The growth hormone is diabeto-

genic (i.e. it incr~ases the blood glucose level) by (a) In creasing the hepatic
glucose output (b) Exerting an anti-insulin effect (decreasing glucose up-
take by the tissues specially skeletal muscles) through reducing the ability of
the ti ssues to bind insulin nnd also because FFAs arc readily available.
The G H also increases tlte sen sitivity of the pan creatic: insulin-
secretiiiJ: cells (th e 8 cells) ami their response to l'arious stimuli
(specia lly im;ulinogenic stimuli e.g. glucose and arginine). For this
reason. administration of GH may initial~)' cause temporcu:r hypo-
glycemia but it will eventual ly increase the blood glucose level. The
resulting hyperglycemia facilitates the release of insulin. •rhich is an
additional 1vay to prom ote growtlt (since insulin also exerts an anabolic
effect). ll owcver, prolonged secretion (or administration) of' the Gl I leads
to exhaustion (~/ th e 8 cells. and accordingl y insulin secretion will be decr-
eased resulting in frank diabetes called pituitmJ' (or hypophysial) diabetes.

I SOMATOMED1 NS I
These arc po~vpeptide growth fa ctors that arc secreted by the lil·er as
well as by cartilage and other organs. There arc a variety of' di f'fercn t
somatomedins, the principal of which in man are insulin-like growth
factor I ( = IGF-1 or somatom edin C) and IGF-11. The secretion <~[
IGF-1 is stimulated by the GH only after birth . On the other hand, the
secretion of /GF-1/ is large~\ ' independent of tile GH and it plays o role in
fetal grOII'th be/()J'e birth (however. the stimuli that cause its release arc
unknown, and in adu lts. it is synthesized only in the choroid plexus and
meninges). The structure of these factors is close~\' related to imwlin (hence
the name) and they exert the following actions :
I. They have a ll'eak insulin-like activi~l '·
2. They induce protein synthesis, groll'th and chondrogenesis.
3. They inhibit lipolysis.
~ The GH does not produce most of its effects by itse(l but through
IGF-1, the presence of which is essential e.g. protein synthesis and chondro-
genesis are persumably produced on~)' by !GF-1. However, it was suggested
that GH com bines with IGF-! in various proportions to produce its effects
and in case of chondrogenesis, it is believed that the GH ~tcts on cartilage to
convert its stem cells into cells that respond to IGF-1, then the locally-
produced and circulating lGF-1 make the cartilage grow.
** In add iti on to it s growth & metabolic actions, the Ci I I also ex ens a11
i11trinsic lactogenic aclil'i~l' due to its stmctural resemblance to prolacrin.
 19

Sec tion 1- Chapter 2 Th e pituitan• gla11d (the hrpoph!'Sis)

AntltiOI
potuot.Jry

l"'tr
(ond other
atgensl

Figure I 0 : Feedback cont rol of secretion of the growth hormone.

Dashed arrows indicate inhibition.

[g_oNTROL OF GROWTH HORMONE SECRETION I

The secretion of Gil is controlled by (n) Feedback mecltamisms
(b) 2 hypophysiotropic honnones. GRII a11d GJH (= somatostatin) (c) A
newly discovered 28 ami noac id polypeptide ca lled Ghrclin : This is secret-
ed from thl.! stomach and hypothalamus. and it cxcrts a marked Gil -
stimulating acth ity. The rate of Gil secretion undergoes marked lluctua-
Li ons in response to a variety of stimuli (specia lly in children and young
adults before it decl ines in old age) as follows :

(A) Stimuli tl1at increase GH secretion

I. Deficiency ol' the energy-producing subst rates (e.g. in hypoglyc-

em ia and lasting) or increased demand to them (t:.g. during exercise).
2. Increased blood le,·cls of ecnain amino acids (e.g. arginine). so a
rich -protein meal stimul a t e~ GH secretion.
3. Stressful stimul i e.g. ps) cho logie stresses .
.t. Going to sleep (atthc beginning ofnonnal non-REM slecp).
5. Ce rta in drugs and hormones e.g. glu cago n, noradrcna linc.
estrogens. androgens. 2-deoxyglucose, alpha receptor adrenergic
stimulating drugs, L-dopa and dopamine- receptor agonists (e.g.
apomorph inc).
Section 1- Chapter 2 Til e pituitarr r:land (tile llrpopltrsis)

(B) Stimuli that decrease GH secretion

I. Increased blood glucose kvel (i.e. hyperglycemia).

2. During REM sleep (refer to C.N.S.).
3. Increascd blood levels of certain hormones e.g. cortisol.
-t Increascd blood level of free fatty acids ( FF As), possibl) by
inhibiting release of the Ci II from the anterior pituitat') gland by a
negath·efeedhack meclwnism (sec below).
5. When the IGF-l blood lc'cl is increased ( b,rclllegatin!jeeJback
mechanism as described below).

FEEDBACK CONTROL OF GH SECRETION

The hypothalamic growth hormone-releasi ng hornwnc (GR II ) stimulates Gil

secretion from the anterior pituitary gland. Gil stimu lates release of IGF I
from many organs particular~\' the fi,·er (figure 10) and IGF I in tum inhibits
the release ofG H by (a) a direct action on the anterior pituitary gland and (b)
stimulating the release of somatostatin (S ) from the h) pothalamus.

15 4

I
203 I
I
I
I

r;
g ·~ 7
.."'
~

i 101
"'

figure J I : The rate of growth in boys and gi rls li·om birth to 20 years of ag~.:.
 21

Section J- Chapter 2 Tlt e pituitarv gland (the lqwophvsis)

PHYSIOLOGY OF GROWTH

I RATE OF GROWTH I
Fetal growth is independent of the fetal GH, and it depends only on
lctall Gf II (page 18). Aller birth, growth normally continues ti ll the age of
about 20 years in males and 18 years in fema les. The growth rate is high in
the first year then it declines at fir t rapidly then slowly till puberty at which
there is a spurt of growth (after wh ich it declines till it stops clue to fusion of
the epiphyses to the bones). Therefore. there arc 2 periods of rapid growtlt
the first in infancy and the second in late puberty (figure II). In fantile
growth after birth is partly a continuation of fetal growth (depending on
IGF II ) but the Gil and thyroid hormones soon contribute. and it is epi-
sodic (i .c. there are short periods of accelerated grO\:vth that arc separated
by long periods of non-detectable growth). On the other hand, pubertal
growth is produced by the comb ined effects of the GH and sex hormones.

FACTORS THAT CONTROL GROWTH I

(A) Genetic fa cto rs : These dctcr111ine the rate and limit of growth.
(B) Extrins ic fa ctors : These include the following :
1. N utrition ( f ood supply) : This is the most important extrinsic
factor that aflccts growth. Diet should con tain adeq uate amounts of pro-
teins, vitamins and minerals as well as calories (in the form of carbo-
hydrates and fats). so that the proteins arc used only to promote grO\\ th.
2. Disease or injiiiJ' : These delay growth because they increase
protein catabolism. However. for unknown reasons, fo ll owing a period of
illness or starvat ion in children. there is a period of accelerated rate of
growth(- catclt up f.: rOIVtlt ) that continues until the norma l rate is reached
3. Stress and emotions : Certain stressfu l and emotional
conditions may be associated with retarded growth (see in the ca11se.\ (?/"
d~t •arflsm and short stature. page 23).
(C) Hormon es : Growth is affected not on ly by the GH but also by :
1. Thyroid hormones : These hormones arc essential for
normal gro wtlt . They contribute wi th the G il and somatomedins in
promotion ofgrO\rth in the earlyfew months ({/ier hirth,and after that
th eir action is permissive to tltat of the GH (possibly by potentiation of
 22

Section I- Chapter 2 The pituitar)! gland (lite lq!popltvsis)

the actions of somatomcdins).i.e. the GH cxa1s its actions only in pn:scncc of ~lCSC
hormones. They also stimulate Gl l secretion and an:: essential for ti'i.\ue maturation and bruin
derelopment. 1lley also have marked cfK:ct.s on ossification of cmtilagc, tcctl1 growtl1 , U1c
contours oftl1e face and the pn:>J:X>rtions of d1e body. so h)'IX)thyroid infants (who are called
cretim) are dwarfed mentally retarded, and have infantile features (page 44).
2. Glucocorticoid hormones : At normal secretory rates. these
hormones exert a permissil'e action on groll'th by maintaining constant
the l'arious body conditions specially the circulaticm am/ blood pressure.
However, excess glucocortico ids inhibit growth because of their direct
catabolic action on the cells (page 5 1).
3. Ins ulin : Diabetic animals fail to grow due to lack of the
anabolic action of insulin, and insulin causes growth in hypophysectomized
animals but only when great amounts of carbohydrate and protein arc
supp li ~.:d with insu lin (page 87) .
.J. Sex hormones : These hormones ca use a spurt of growth at
puberty by (a) Interaction with the CHand ICF I (they stimul ate secretion
of GH which increases IGF I that ca uses growth) (b) Producing a marked
anabolic e_ffect. particularly androgens (= male ex hormones), the
secretion of which increases i11 hoth sexes ot puberty. In males, androgens
arc secreted from both the testes and the adrena l co rtex, whi le in females
they arc secreted from th e adrena l cortex on ly. The female sex hormones
(= estrogens) exert similar (but weaker) effects as those of androgens.
Sex hormones initially stimulate growth, but th ey rapidly terminate
it, special(v estrogens (i.e. their action 0 11 growtlt is selj:limiting) by
causing fusion of the epiphyses to the long bones (so linear growth will
stop). This explains wlty (a) Pituitary dwarfs (sec be low) trea ted with
androgens grow first a few in ches then stop (b) Eunuch s (cas trated
male individua ls before puberty) tend to be tall (due to deficiency of
the sex horm ones) (c) Patients with sex ual precocity (early puberty) arc
liable to be dwarfs (due to the action of the sex hormones, which cause
early fusion of the epiphyses to the long bones).

[CAUSES OF DWARFISM {short stature or stunted growth} I

I. Deficient GH secretion : This may be due to ei ther a pituitary
di sease or deficient secretion of GRH from the hypothalamus. Isolated GH
deficiency leads to dwmfism , whi le its deficiency together with the GTI Is
leads to infantilism (sec below).
2. Cretinism(= llypotllyroidism in infants) (page 44).
 23

Section 1- Chapte r 2 Th e pituitarr gland (the hrpoph!•Sis)

3. Laron dwarfism (= growth hormone insensitivity) : Thi s is a

condition of stunted growth although the plas ma (i/1/e l'el is normal or
even eleva!ed. It occurs as a result of unres ponsiv eness of the Gi l
receptors to the growth hormone. which leads to dejicienc:r of rile
circulating somaromedins (resulting in stunted growth ).
.f. Precocious puberty (see above).
5. Certain bone and m etabolic diseases.
6. Genetic causes e.g. the dwarfism that occurs in achon droplasia
am/ African pygmies(= a dwarf race in equatorial africa).
7. Some chromosomal diseases e.g. Turner's syndrome (page I 00).
8. Constitutional delayed gro1vtlt (short stature wi th unknown causes).
9. Chronic abuse a11d 11eglect in children (= Psyclwsocia/ chtl(trjism
that is known as the Ka.,JJar Hauser ~:rmlrom e) .
~ PiluiiW)' dwcnfis m is better than borh il~/tmtilism and cre1i11ism bec-
ause the palient is only slwrt.ln the latter 2 conditions, the patient is short and
also has hypogonadism. In cretinism, there is, in addition, mental retardation.
~ Treatment c~f any rype ofdwmfism should begin he.fore puber1y.

[D ISEASES OF THE ANTERIOR PITUITARY GLAND]

[ (A) Excessive secretion of GH I
Thi s resu lts from au ac:idopltil somatotrop e cell t11111011r which secretes large
amount<; of Gi l. It causes Gigantism in children and Acrom ega~r in adults.

(1) Gigantism(= giantism)

This disease is due to excessive secretion of the Gil in children i. e.

before union of the epiphyses. It i characterized by the following :
I. Overgrow th or th t: skt:leton in normal proportions, so the stature
increases to 2 m eters or more (7 -H feet) and osteoarthriti s may occur.
2. Overgrowth of so ft tissues and viscera {=.']Jitmclllwme~aly).
3. Infantile gonads may be present due to pressure of the tumour on the
gonadotrope ('' hich lead to decrea ed secretion of the GTH s) .
.f. Diabetes m ellitus may de, clop due to the diabetogenic effect ofGH .
5. Signs due to local eff e cts of the tumour may appear (sec below).
 2-1

Sect ion 1- Chapter 2 Th e pituitarr gland (th e llrpopltrsis)

Eni••!IW hand'
~nd fetl

Figu rc 12 : Typical findings in acromegaly.

(2) AcroMegaly
This disease i~ due to excessive secretion of the Gil in adults i. e. aj;er
union of the epiphyses. It i~ characteri7cd by the following (figure 12) :
I. Thick bones, but there is no linear gro ll'tlt . The acral pan~
(specially the hands and feet) arc markedly enlarged (hence the name).
2. enlargement of the lo\\ cr jaw (the mandible) leading to fo rward
protrusion of the chin ( prognathism ). This together" ith O\ ergrowth
of the facial bones and enlargement of the supraorbital ridges. lips, cars
and nose produce coarse lttc1al features called the acromegalic faces.
3. Overgrowth of the vertehme leading to kyphosis (which commonly
predisposes to osteoartlt ritis ).
-'· 0\ crgrowth of' 1sccra ( sp/a n clmom ega~l') and other soft tissues.
·1he skin becomes coarse and thick. and that of the forehead and scalp is
thro'' n into '' rinkles ( lml/dog o;calp). The enlargement of the heart ma}
prcdi'>JXlSe to myomrdial i.,c:lwmia ami cardiou~ropatlty.
5. The body and limb hair is increased (- hirsutism) and the male sex
organs may enlarge bcl·ausc the Gil increases the actions of androgens.
6. In 25 % of patie nt s, tlh.: re arc s ig ns r~f' diabetes due to the
diabetogenic e.ffecr of the Gil.
 25

Sec tion 1- Chapter 2 Th e oituitarr gland (the ln'Poplt)lsis)

7. Gynecomastia (= enlargement of breasts in males) and lactation in

4 % o/ non-pregnam female patients (due to the lactogeni c effect of Gl 1).
8. Signs due to local eff ects of tile pituitary tumour . These include :
(a) Enlargement of !he sella turcica.
(b) Changes in the visua l fi e lds in th e form of bitemporal
hemianopia. due to pressure of the pituitary tumour on the central pari of
1he optic chiasma (refer to special senses).
(c) Headache, blurring of vision and vomiling (due to in crease of
the intracran ial pressure).
** Hypersecretion of the GH by a pituitary somatotrope tumour can
be treated by either {I) Surgical removal of the tumour {2) Destruct ion of
the tumour by irradiation (3) Drugs or hormones that inhibit the release of
the Gil (e.g. somatostatin).
~ Signs of adrenocorlical hyperfimction (knO\\ n as Cushing disease)
can be produced as a result of excess ACT! I secretion by ACTH-secreling
pituitCII')' tumours. Such tumours (and the ACTH-secreting tumours that
can develop in other tissues) are often diffi cult to detect (page 61 ).

I (B) Deficient secretion of GH I

GI-l deficiency in you ng individuals before pbert y causes dwarfism (or
infantilism if accompan ied by failu re of sexual development due to si mul-
taneous deficiency of the GTH s). In adults, GH deficien cy causes decr-
ease of tlte tissue mass (page 17). Pituitm:J' rlwmfism is characteri zed by :
1. Arrested skeletal growth (the patient's height is I00-120 em in adult
li fe ). Temporary little gro\\'th occurs at puberty (by androgens).
2. The stunted skeletal growth is symmetrical, so the body propor1ions
are like chi lds (but the head tends to be large relative to the body).
3. There is acceleration o_(1he aging process (because the GH hormone
exerts an anti-aging fiCtion ).
4. The mental development is normal, and the patients arc usually
intelligent but emotiona lly unstable.
5. There is nonnal sexual maturity (since there is only Gil deficiency).

I (C) Panhypopituitarism (Simmond's disease) I

Th is is generafi=ed failure of the anterior pituif{//J' gland d ue
to either damage by disease or necrosis in som e women wh o ha ve an
episode of shock fo llo u·ing severe pos tpartum hemorrhage (Sh eelum 's
symlrome). It is characterized by the foll owing man ifestations :
 26

Section I- Chapter 2 The pituitarv gland (the hvpoph)lsis)

. 1- Arrested gro.'~th in children and acceleration of aging in adults prod-

c-
ucmg premature scntl lty progeria).
2- Atrophy of (a) The thyroid gland (leading to cret inism in ch ildren
and myxedema in adults) (b) Some zones of the adrenal cortex (leading to
inability to resist stress conditi ons) {c) The gonads, leading to hJ;Jo-
gonadism which is manifested by impaim1ent of sex functions in males
(page 114) and stoppage or· the sex cycles in females (page 135).
3- flypog~)'cemia due to increased sensiti vity to insulin caused by de-
ficiency of the main insulin antagonists (i.e. the GH and glucocorticoids).
4- Severe pallor ,mainly due to lack ofACTH (page 14).
5- Mild loss of weight due to lack of the anabolic effects of the GH and
the androgens. llowcvcr. cachexia or emaciation (severe loss of weight) may
occur if there is fill orexia ner11osa ( = se1•ere loss (~! oppetite).
~ Damage of the posterior lobe leads to severe diuresis due to lack
or A DH (see posterior pituitary gland). However. damage of both lobes of
the pilllitm}' gland leads on~•· to mild duresis. This is due to reduction of the
osmotic load delivered to the renal tubules that is caused by decreased
secretion of both the glucocorticoids (which decrease protein catabolism) as
well as the thyroid hormones (whith decrcnses the metabolic rate).

FROHLICH'S SYNDROME

This disease is also known as the adiposo-genital syndrome

or hypothalamic eunuchism. It occu rs in children as o result (?!'damage of'
certain hypotlwlamic areas. cmcl is chnmcteri=ed hy (a) l1~{antile geniwl
organs due to decreased secretion of the vnR/1 (whi ch reduces GTII s
secretion from the adenohypophysis) (b) O••ereating and obesio· due to
disturbance of the appestat centre in the hypotlwlamus i.e. th e feeding
and satiety centres (refer to metabolism).

[ THE POSTERIOR PITUITARY GLAND (NEUROHYPOPHYSIS) J

This gland is made up of the following structues :

I. PituiCI'tes : These are modified astrocytcs (= supporting neuroglial cells).

2. No n-medullated 11en•e .fibres : fhcse originate at the su()raoptic
and panJ\ entricular nuclei of the hypothalamus and rcnch the gland in the
pituitnry stalk via the hypothalamo-ltypophysialtrac:t (figure 7).
3. //erring bodies : These are granules of stored hormones.
 '27

Section 1- Chapter 2 Tlt e pituita,.,, gland (lit e ft)lpopltvsis)

2 hormones arc released (not secreted) from the gland. These are
the antidiuretic lromwne (= ADH or vasopressin) and oxytocin. Both
hormones are polypep1ides (each containing 9 amino ac ids) which are
structurally simi lar except fo r 2 amino acids (i n ADH, phenylalanine and
arginine replace leucine and iso leucin e in th e oxytocin molecule). Since
1\D ll co ntain s arginin e, it was also ca ll ed arginine vasopressin (in
some animals, arginine is replaced by lysine forming ~~ ·sin e vasopressin).
The 2 hormones arc synthesized in the cell bodies or the magno-
cellular n eurons in botlt tire supraoptic and paraventricular nuclei of tire
llyporllalamus, but AOH mainly (more than 80 %) in the supraoptic
nucleus wh il e oxytocin mainly (a lso more than 80 %) in the para-
vcn tricu lar nuc lcus ). T he hormones are then 1ransportccl by axoplasmic .flo"'
clown the axons of' the mngnoccllular neurons to their endin gs in the
posterior pituitary gland where they arc stored as Herring hodies (t ill they
arc released in response to electrical activity in their endings). For this
reason. these hormones arc typical neural hormones (i.e. hormones
secreted into the ci rculation by nerve cells).
Both horm ones arc synthesized from large precurso r mol ecul es
ca ll ed neurop hvsi ns (neu rophys in 1 or O.':J'[Jitysin in case or oxytocin. and
neurophysin II or pressopltysin in case or ADll ). Cleavage of' these precursor
molecu les occurs during 1heir dOII'II tmnsport in 1he hypotlwlomo-
h.lpophysiol tract. and the storage granu les contain both the free hormones as
well as their corresponding ncurophysins.

MECHANISM OF RELEASE OF THE HORMONES

Stimulati on or the hypothalamic nuclei initi ates action potentials

in their neurons which. on reaching the nerve end ings. cause release of the
hormones {by Ca! depende111 exocytosis) together with Lhcir neurophysins.
and all are absorbed into the local blood ' esse b. from \\'hich the) reach the
gcnern l circulation.Thc fun cti ons of the hormones arc well kno'' n. but how-
ever. the functions or the neurophysins arc unknown.

I THE ANTIDIURETIC HORMONE ( ADH OR VASOPRESSIN) J

I Functions (effects or actions) of ADH I
(A) II ata n•temion (tilt tlllli-diuretic' t•/(t'l'f) /\011 increases !he
permeability (~l the distal segments o/the renal tuhules. main~\' the
colleuing ducts, thus promoting water reabsorption which results in water
retention in the body and production of concentrated urine.
 28

Section I- Chapter 2 Tlt e pituitarr gland (lll e !l)lpopll)lsis)

l\l cchunism : AD II binds to special receptors in the tubular cells called

1'1 receptors. Such binding leads to activation of the adcny/(l{e c.:rclase
en::yme and increased formation of cyclic AMP. which causes insertion of
protein water channels called aquaporins in the luminal borders of the
tubular cells . Thi s increases the permeability (~l these cells 10 water, and
consequent ly augments ll'ater reabsorption hy passil'e d([(usion under
il!/luence of t he ltyperosmolality of the reno/ medullary interstitium that is
produced by the countercurrent function of the loops of Henle (sec kidney).

(B) (,('Jtt>rali;.etl wt.\ocolt'itriction (I . C.) : In large doses only. ADH

ca uses di rect strong V.C. allover the body, which increases the arterial
blood pressure (so the hormone is also called vasopressin ).
Mechanism : 1\0H binds to special receptors in the arterioles called
V1••1 receptors which increase the cytoplasmic Ca 2• (through formation of ino-
sitollriplwsplwte, page 9) leading to smooth musc le contraction and V.C ..

:.:_ V1• 1 receptors are also found in the liver & hrain where AOi l sti mulates
glycogeno lysis in the former and acts as a neurotransmitter in the later.
::_:: There arc another type of V1 receptors ca lled VIIJ (or V3) receptors that
are located in the adenohypophysis, where they stimulate ACTI/ secretion.

I Factors that control the release of ADH I

I. Plasma os molalit y : Significant changes in AO II release occur
when the plasma osmolality is altered by as little as I %1, aiming at
maintaining it close to 285 mOsml litre. These changes are mediated
through affecting certain osm oreceptors located in tlte anterior ltypo-
tltalamus (these are located in the organum vasculosum (~(the lamina
1erminalis and are outside the blood brain barrier). Ri se of the plasma
osmotic pressure (e.g. due to dehydration) stimulates the osmorcceptors,
which discharge signals that stimulate the 1\DII -sccrcting neurons in the
hypotha lnmus. These neurons discharge impu lses, whi ch on reaching their
tem1inals in the neurohypophysis stimulate the release of ADII. This causes
water retention which decreases the plasma osmotic pressure back to its
nom1al lc\ el. Opposite dTccts occur if the plasma osmotic pressure falls
(e.g. due to overhydration).
2. l~ xtraccllular flu id volume : Changes in the ECF volume also
a ffcet 1\0 II secretion. This is mediated through affecting certain receplors
Section 1- Chapter 2 The pituitan• glan d (the lq'poph psis)

in the low and high-pressure portions ofthe I'OScular system.

The low pressure receptors arc located in the atria. great veins and
pulmoiWI)' l'essels. whi lc the high pressure receptOrs are those in the carotid
sinus and aortic arch {i. e. the arterial baroreceptors).
The lo11· pressure receptors monilor the .fit!lness of the vascular
::.:J'S/em and arc the primWJ mediators thai e./feel release r~{ A D/ 1. A
moderate decrease in the ECF volume (i.e. IIJJJOI'olemia ) stimulates these
receptors, which discharge signals that stimulate the hypothalamic A OH-
secreling neurons leading to ADH release from the neurohypophysis. This
causes water retention, which increases the ECF volume back to its nonnal
level. Hypovolem ia also leads to secretion of ren in from the kidneys and
this leads lo formation of' augiotensiu II, which also causes ADH re lease
by st imul ating the organum vascu losum or the lami na terminalis (sec
abo\ c). Opposite effects occur in hypen olemia.
1

The high pressure receptors act in a simil ar way as the low pressure
receptors, but they regulate release of AD II onzr if The changes in ECF
volume are great enough 10 affect the arterial hlood pressure.
ADH is a lso released 011 stan diug (because the blood pools in the
legs and the low pressure receptors monitor a decrease in the ECF vo lume).
llowe\Cr, hemorrhage is the must pute11t stimulusfor ADH release which
helps rise of the blood pressure (by its Y.C. and fluid retention ciTects).
3. Other factors : A wide \'aricty of conditions affect the release of ADH
e.g. it is released by pain, nausea, exercise. some emotions & surgical stress.
-t. Drugs :The re lease of AD II is affected by ce rta in drugs e.g. it is
stimulated by morphine and nicotine while it is inhibited by alcohol.

I DIABETES INSIPIDUS I
This is a disease caused by ADH dejic:ien q, as a result of damage
of the ADH- secreti11g hypothalamic nuclei by disease. The h()((l' of the
neurohypophysis is not essential for secrelion r?l ils hormones (opposite to
the adenohypophysis) and its removal produces on ly temporary symptoms
because the sectioned nerve fibres will recover and secrete ADll agai n.
Some cases are due to inability (?llhe kidne_,·s lo respond to .lDJ/
(- nephrogenic diabetes iusipidus) because of ei ther congenilol defects in
the V.! recepton; or mutaliom in the gene thai produces 1he aquaporim. The
main symptoms of the disease arc the following:
l. Polyurht : Thi s is excretion or large amounts of urine ( 15-20 litrcs
daily) that is almost colourless and much diluted (due to reabsorption
 30

Section 1- Chapter 2 Th e pituitarr gland (the hvpophrsis)

or so lutes) having a low specifi c gravity ( I002-1 006) and is often

accompani ed by loss of the water-soluble 1•iwmins.
2. Polydipsia: This is drinking oflargc amoun ts of water as a result of
an excessil•e sensaTion o.fthirst (caused by the dehydration due to
polyuria). The sensation oftltirst in tltis condition is l~fe-saving .

The main differences between diabetes insipidus and diabetes mellitus

are summarized in the following table (sec pages 9-i and 95) :

Diabetes insioidus Diabetes mellitus

Polyuria, polydipsia Severe Less severe
a nd thirst
Glucosuria Absent Present
Urine specific gr nvity Vcry low (I 002- 1006) lligh ( I030 or more)
Urine colour Colourless Lemon ye llow
Urine pH Almost neutral (due to Acidic (due to presence
excess water diuresis) of keto-acids.

Syndrome of inappropriate hypersecretion of ADA (SIADA) I

Hypersecretion of AD H sometimes occurs in patients having certain
cerehral diseases. It was al so encountered in certain pulmonm y diseases
particularly cancer of the lung. ln the latter cond ition, the syndrome may be
due to either excessive AO II secretion from the tum our, or interruption
of the afferent vagal nerve fibres from th e stretch receptors in the atria
and great veins that tran smit inhibitory signals for the secreti on of AOH.

Effects of SIADH

The main cl'fcct of S II\ DII is excessive water retention in the bot~~·
which leads to the following :
1. Signs of water intoxication (refer to blood).
2. A marked increase in the ECF volume. This resu lts in the following
a) Reduction ofNa - concentration and osmolality of the ECF.
b) Inhibition ol. secretion ol. lite aldosterone hormone. This leads to Na ~
loss in the urine (so the condition is sometimes called cerebral or pulm-
omii'J' salt '""sting). and the resulting hyponatremia further decreases
the plasma a• concentration (from 135-145 to 11 0-1 20 mEq I litre)
wh ich produces characteristic signs and symptoms (refer to kidney) and
frequently causes sudde11 death.
 31

Section 1- Chapter 2 Th e pituitarr gland (the ltypophvsis)

Treatment of SIADH

1. Treatment ofthc cause if detected. e.g. if the cause is an ADH - secreting

tumour, removal of the tumour would improve the condi tion.
2. Drugs that produce diuresis. induce pa1tial renal damage, inhibit ADH
secretion or reduce the renal response to ADI I e.g. (the antibiotic den1cc-
locyclinc).
3. Water restrict ion.

IOXYTOCIN I
This is a 9 amino acid po~vpeptide that is secreted mainly by the
paraventricular nucleus of th e hypothalamus (page 27) and is stored in the.:
neurohypophysis. Its action on the target cells is mediated by increasing the
intracellular Ca 2 ' content (page 9).

EFFECTS (FUNCTIONS OR ACTIONS ) OF OXYTOCIN

(1) MILK EJECTION : This is the most importantfimction t~f oxytocin in

mamma ls. The hormone causes contraction of special smooth muscle lib res
arou nd the ducts of the mammary glands known as the myoepithelial cells.
thus squeezing milk outwards through the nipples (page 146).

(2) CONTRACTION OF THE MYOMETRIUM ( =UTERINE MUSCLE) :

Oxytocin causes contraction or the myometrium or both the pregnaw
and IIOn-pregnalltlllems. During intercourse. oxytocin is released leading to
uterine contractions which produce the sensation of orgasm in the female
and help the transport of sperms upwards in the f emale genital tract. In the
pregnant uterus, oxytocin (wlticlt is also locally produced in tlte uterus)
plays an important ro le in labor (page 143).

(3) CONTRACTION OF SMOOTH MUSCLE IN THE MALE

INTERNAL GENITALIA : This causes discharge of sperms from the
seminiferous tubules and epidic(l'mis to the \'OS deferens and ji·01n the later
to the urethra. ll'ltich helps emission ofsemen.

(4) INVOLUTION (DEGENERATION) OF THE CORPUS LUTEUM :

In some domestic anima ls (a nd probab ly also in humans), this process (a lso
called luteolysis) is induced by prostaglandins form ed under i1~{luence of O.\)'-
tocin that is local~y-secreted by the coqm s luteum itse/f(page 120).
 32

Section 1- Chapter 2 Th e pituitarv gland (lite lt}lpopll)l.\'is)

I FACTORS AFFECTING OXYTOCIN SECRETION I

1. Tactile stimulation pftlle nipples and surrounding areas oftlte breast: This
occurs during suckling, and it stimulates o.\)'tocin and prolactin secretion in lact-
ating women which leads to both milk secretion & milk ejection (page 146).This
mechanism is a neuroendocrine refles ca lled the suckling reflex (figure 13).

2. Distension or stretch of the cervix of tlte utems : This occurs during labor,
and it leads to oxytocin secretion which causes uterine contractions, thus helping
delivery of the baby (page 143).

3. Stimulation oftlte genital organs: This occurs during sexual intercourse. and
it leads to oxytocin sccretion in hoth sexes. In females, it produces uterine contr-
actions that cause transport or the sperms up (thus helping the process of fertiliz-
ation), while in males ir helps emission of semen (sec above).

4. Otlter factors: The secretion of oxytocin is a lt ered by many emotio nal

and stressfu l stimuli , inhibited by alcohol and sti1nu latcd through condi-
tifmed reflexes e.g. it is secreted when a mother thinks in her baby or hears
him crying (page 146).

Figure 13: The suckl ing reflex.

Mechanism of oxytocin secretion in various conditions

Signals from the nipples (in case of suck ling). from the genita l
organs (during intercourse) and frorn the uterine cervix (during labour) arc
discharg~d to the sp inal cord f'rom which signa ls arc then transmitted
upwards to the hypothalamus, where they stimulate the paraventricular
nucleus leading to release of oxytocin from the neurohypophysis as
described above.
 33

CHAPTER3

THE THYROID GLAND

The thyroid gland is located in the front of the neck below the
larynx on either side of the trachea. It is fom1ed of 2 lobes connected by a
narrow isthmus, and sometimes there is a sma ll pyramidal lobe arising from
the isthmus (figure 14). Histo logical ly, the gland is made up of spherical
ac ini ca lled the thyroid follicles. Each follicle is lined by a single layer of
epithelial cells (wh ich arc cuboidal in the euthyroid state) and is surrounded
by a dense network of fenestrated capillaries. The lumens of the follicles are
fill ed with a protein material call ed colloid, and in between them there are
special ce ll s ca lled the clear (or C ) or parajollic:u/ar cells (figure 15).

Hyoid bone

Figure 14 :The human thyroid gland (anterior view).

When the gland is inacti ve, the co lloid is abundant, the folli cles are
large and the cel ls lining them are nat. On the other hand, when the gland is
active, the follicles arc small, the cells en large (becom ing columnar) and the
colloid is decreased and its edge becomes scalloped fom1ing many small re-
absorption lacunae (figure 15).
 Section I - Chapter 3 The thvroid gland

ReabsorP110n PiJrafolhcular
lac u n:l~ C4?11 s

Figure IS : Histology of the thyroid gland. Inactive (left) and active (right).
THE THYROID HORMONES I
I. Thyroxine (= Tetraiodothyronine or T4 ).
2. Triiodoth yronine (= T3 ) and a smal l amount of an inacti ve comp-
ound ca lled reverse triiodothyronine (RT3 ) . Under norma l condi tions
the gland sec retes dai~l' about 80 meg (micrograms) of To~ . 4 meg of'
T.1 ancl 2 meg of RT3.
3. Ca lcitonin (formerly thyrocalci!Onin) : This is a polypeptide hormone
that is secreted by the parafollicular cell\·. It is a calcium-lowering
hormon e that is discussed with the parathyroi d glands (chapter 6).

I IODINE METABOLISM]
Daily requirement and supply of iodine

The mini mal dail y requirement of iod ine which maintains a normal
thyroid fun ction is about ] meg I kg of hody lt·eight (abo ut ISO m eg dai~v) .
but the usua l intnkc is much greater (about 500 meg da ily). Iodine is rich in
areas near the sea. and it enters the body with rood and water. Subjects who
live i11 areas away from seas (eg. the oases ami centra l Europe) are protected
fro m iodine lack by adding sodium iodide to table salt (iodi=ed table sal!) .

Fate of iodine

The ingested iodine is converted to iodide then it is absorbed rrom the

small intestine. When 500 meg arc ingested. the thyroid gland takes up only
120 111cg (a t the norma l rate of fun cti on) whi le 380 meg remain in the
plasma. The gland secretes 80 meg in the form ofT3 and T4 , while 40 meg
 35

Section I - Chapter 3 Til e tflwoirl gland

r in diet

It 120JJgr~ -

40)Jg 1- Thyroid

BO)lg in
ECF T3,T4

Liver
60)Jgi" and other
tissues

I I Bile
l l
4BOJJg r 20)Jgl-
in uri ne ln stool

Figure 16 : Iodine metabol ism.

diffuse into the plasma . The secreted hormones arc mclaboli zed in the liver
(und other ti ssues) and their iod ide conten t is released. About 60 meg enter
the plasma while 20 meg are excreted in bile and lost in feces. The iodide in
the plasma will be, therefore. 480 meg (380 + 40 + 60). and this wi ll be
ex creted in urine (figure 16).

Synthesis and secretion of thyroid hormones

I. Iodide trappi11K (= iodide pump) : This is an act ive process by

wh ich iodide is taken by the thyroid gland cells from the plasma, and is
the firs/ s1ep in symflesis of 1he 1hyroid hormones . Iodide is transported
into the thyroid follicular ce lls with Na • by a secondcn:\' acfil·e fransport
mechanism using a ca rri er ca ll ed NIS (Na+- r Symport) and the energy is
provided by Na +_K ' ATPase acti vity. Iodide then moves into the co ll oid by
diffusion (possibl y along I" chan nels). This symport can produce intra-
cellu lar I" concentrations that arc 20-..fO times as great as the concentration
in th e plasma and still iodide is active ly transported !'rom th e serum into
th e thyroid ce lls aga inst both the concentration and electrica l grad ients for r
2, Oxidation of iodide to iodine : After iodide trapping, it is oxidi zed
in the coll oid to iodine by activity of the thyroid peroxidase en::yme.
3. Binding l~( iodine to tyrosine: Iodine is th en bound to tyrosine
forming mono-iodo1yrosine (i\1/17) . which is fun her iodinated forming
di-iodo(vrosine (DIT). and both MIT and DIT are biologically inactive.
 Section I - Cltnpter 3 Til e tltrroid gland

Such ioditwlion reaclion.\ arc also cataly/cd by the thyroid pcro:\idasc

c•vymc and they occur in the colloid by combination of' 1· with the tyro~ine
rc~iducs that arc part of a large glycoprotein moh.:culc (m.w. 660000) called
tllyroglobulin ( ligure 17). Both the thyroid pero:\idasc enzyme as well as
thyroglobulin arc synthesi7cd by the follicular ce lls then secreted into the
colloid by exon·wsis.

Plf•S' \A lilY AI) I COLLO 0

C[Ll ............--,

""0'"•
I
((If
~
fo 'v

I
.. ..
I I I od I ._

uoQc. ,
I
l Tyr 1

I
~H
...::t
<
()
I

1 ~"n• H IIIUiutyrH\IIIf' tM I 1) b
01
c

Qo,
~

I ':
H
,..m
.. n
c
~

l l ,f> I )f1 0ll<IIV1"'""' lfll ll '"

I I

- () 0 I

Ml • 1 11 ,..I I ,,,,,,.,a , "' • l 1J 1 "'""o1hv1 •lilt• 11 11

Figure 17 : Synthcsis of the thyroid hormones .

.f. Condensation (coup/in~) of M IT and DIT : '> DIT molecules

undergo an oxidative condensation forming T 1· T, is f(mncd by condensation
or to. liT" ith 1)11. nnd a small amount of RT, is abo f'onned. Such coupling
reactions arc probably also catal}/ed b) the thyroid peroxidase cJvyme.
5. Secretion of tile thyroid lwrmo1tes : The hormones rem a in bound
to th~ roglobulin till they arc secreted. When the gland secretes. the follicular
cdb ingest the colloid hy cndocytosi..,. producing the reahsorptionlac11mte
 37

Section I - Chapter 3 The th yroid gland

(figure 15). In the lysosomcs, the peptide bonds between the iodinated com-
pounds and thyroglobulin nrc broken by protease en:ymes leading to release
ofthcsc compounds into the cytoplasm. The iodinated tyrosincs (MIT and
DIT) arc dciodinated by the iodotyrosine deiodinase en:yme and the iodide
liberated is re-used in honnonal synthesis. However, this enzyme does not
attack the iodinated thyronine.\· (T1 and To~), which wi ll puss into the blood-
stream. In normal conditions, small amounts of the colloid and thyroglob-
ulin also enter the bloodstream. but their functions in the body arc unknown.

::_ The thyroid cells exert 3 function s : (1) They collect and transport
iodide (2) They synt hesize thyroglobulin then secrete it (with the thyroid
peroxidase enzyme) in the colloid (3) They ingest the thyroglobulin,
separate the hormones and then secrete them into the bloodstream.

:2 The sali vary glands, gastric mucosa, placenta, ci liary body, choroid
plexus (in the brain) and the mammary glands also transport iodide against a
concentration gradient. The mammary glands also bind iodine, and DIT is
formed but T3 and T4 arc not. ll owever, unlike the thyroid gland, such
processes in these organs arc not stimulated by TS I I.

I Transport and concentration of the thyroid hormones

The normal tota l plasma T4 level is about 8 meg 1111 and that or T3 is
about 0.15 meg IJ-u (while the normal inorganic iodide plasma level
a\ cragcs 0.3 meg ~ ~~;. Both hormones arc present in 2 forms. the majority is
bound to plasma proteins, while a vel)' smrJJI.fi"action is presenrJi·ee.
The plasma prote ins that bi nd the hormones arc mostly albumin, a
prealbumin called trcmstllyretin and a thyroxine-binding globulin. The
free hormones are the physiologically active hormones. and constitute the
fraction capable to inhibi L TSII secretion. The protein-hound fraction acts
as a store (or resen •oir) for the hormones, and is norma lly in equilibrium
with the free fi·ac tion (aiming at maintaining the level of' the free hormones
constant). The amounts of the protein-bound and free fractions of the
thyroid hormones arc as fo llows :
1. T4 : /\bout 99.98% is bound and 0.02% is free.
2. TJ : About 99.80% is bound and 0.20% is free.
It is clear that T1 is less bound. thus it has a shorter half-life, its biolog-
ical activity is 3-5 times greater and its action is much more rapid than T4 . It
is believed that T.1 is changed to T3 in the C:l'loplasm o.lrhe target cells.
 3R

Section I - Chapter 3 Th e tlt vroid gland

I Mechanism of action & metabolism of the thyroid hormones I

The thyroid hormones bind to spec(fic nuclear receptors in the
target cells and exert their effects by increasin g transcription of mRNAs
(figure 2). They arc then inactivated in the fo llowing ways :
I. Deiodination (by 3 different deiodinase en::ymes). : This occurs
in the liver, kidneys and many other tissues. Normally about J/3 ofT4 is
converted to T3 (see above) and 45 % is converted to RT3 (most of the
circulating T 3 and RT 3 arc formed by deiodination of T4). T 3 and RT 3 arc
then further deiodinatcd and bro~en down to tyrosine and iodide (which is
re-used by the thyroid gland in the synthesis of thyroid hormones).
2. Conjugation : In the li ver, T., and T3 arc conjugated to form su lph-
atcs and g lucuroniclcs, which arc then excreted in the bile. Ln the intes-
tine, the thyroid conjugates arc hydrolyzed, and some of the hormones
are reabsorbed while some are excreted in the stool.

I Actions (functions or effects) of the thyroid hormones

I . Caluri~cnk cfTcct : The thyroid hormones increase the 111etoholic
rore and 0 ! consumption in al l tissues (except tbe adult brain. testes, uterus,
lymph nodes. spleen and anterior pihtitaJy gland). This eflect increases heat
production and body temJ:x:mnu'C, and is prutly due to incte<lscd metabolism of fatty acids
(since tl1e honnones stimulate lipolysis in adipose tissue) ~mel (mly due to inct~ activity ol'
1 1
tl1e membrane bound Na - K ATPasc.
2. Effects on the h t•art : The thyro id hormones increase the myocard-
ial CO/l!mctility (by stimulating formation of alpha myosin heavy chains
which have hi gh Na 1 - K+ ATPase activity). They also increme the 1111mber of
heta adrenergic receptors and enhance the re:sponses to calecholamines.
Accordingly, the heart rate. stroke volume. cardiac output and systolic B.P.
are increased. Such effects lead to increase of the pulse pressure.
shorteni11g of rhe circulation time and liabiliry to develop arrhythmias e.g.
exrrmystoles and atrial.fibrillation (due to increased cardiac excitability).
3. Effects nn the nervous system : The thyroid horm ones are essential
for the normal development of the nervous system (so in hypothyroid
in [ants the synapses develop abnormally, myelin ation is defective, the ref-
lex reacti on time is prolonged, and mental development is retarded).
-L EfTl•t.:ts on ~rowth : The thyro id horm ones pro mote bone growth &
ske letal development early in life (with othe r hormones) and are also ess-
ential for growth afterwards by exerting a permissi\1e action to the growth
 39

Section I - Chapter 3 Tlt e th yroid gland

hormone 1l1C)' also aflix:t la."th g.tuwth , the contOUIS of the face and the J11U!XX1ions of the
body (page 22). They also exert a direct effect 011 tissue maturatio11 e.g.
tadpoles treated with th yroid hormones metamorphose early into dwarf
frogs, whi le those deprived from these hormones never become frogs.
5. Efft•cl'> ou n·.,pirator~ function., : The thyroid hormones help 0 2
dissociation l"rom haemoglobin by increasing the amou nt of 2. 3 diphospho-
g lyceratc (D PG) in the R.£3. C.s. (refer to respiration).
6. Lfl~ch uti '>1.'\ tunctinn., : Sex functions arc stimul ated by th e
th yroid hormones . They are essential for n orma/ m enstrual c:J•cles and
spermatogen esis, and also i11crease milk secretio11 in lactating women.
i. ( unH·r.,ion or carott•nc to 'ita min A in th~ lh er : If the thyroid
hormo nes are deficient, caroten emia results. This causes yellowish
colouration of the skin, but unlike jaundice the colour of the sd cru is not
altered.
X. Lftcch on protein ml'talwlbm and .,l,t•lt·tal mmclc' : The thyro id
honnoncs cause protein catabolism and -vc nitrogen balance. so in hyper-
thyroidi sm, bone demineralization. osteoporosis & muscle weakness occur.
9. EITcch on carhuhydratt• nwtaholbm : The thyroid hormones inc-
reast.: the rate of carbohydrate absorpt ion from th e G.LT., thus tlte h/ood
g lucose /e11el increases ajier a carbohydrute meal I Iowcver, it normally
fa lls again rapidl y because glucose utilizati on in the ti ssues also increases .
10. I· tfcd~ot on lipid and choleM erol ml'taholism : The thyroid
hom1ones lower tlte blood ch olesterolle••el by increasing formation of low-
density lipoprotein (LDL) receptors in the li ver. which fav our hepatic remova l
of cholestero l from the blood. They also lower the blood level or lipids
(although they stimulate lipolysis in adipose tissue) bacausc they sim ultane-
ously increase the metabolism o f the fatty acids (sec above).

Relation between the thyroid hormones and catecholamines

The actions of thl: thyroid hom1oncs and those or catecholamines
arc ·' )'llergistic am/ close~l' i11terrelated . Like thyrox ine, epinephrine
increases the metaboli c rat~.: (calorigeni c action), stimulates the nervous
system and produces simi lar cardiac effects (but for a shor1cr duration).
According ly, the tox icity of catccho lamines is markedly increased in rats
treated with T..~ . Many of the effects produced by the thyro id hormones
seem to be mediated through i11creasi11g the tissue respo11Sil'e11ess to
c:atec/1()/amilles special~l ' stimu/atio11 of tlte 11eri'Ot1S !))'Stem ami tlte
cardiac eff ects This is proved by the fact that in hyperthyroidism. many of
the symptoms arc improved after sympathectomy. The cardiac effects arc also
improved by beta adrene1~~ic: blocker dmgs e.g. propranolol.
 40

Section I - Chapter 3 The thwoid gland

I Control (regulation) of thyroid gland activities I

The synthesis and secreti on of the thyroid hom1ones is control led by the
thyroid stimulating hormone (TSH) as well ashy the dietary iodine intake

I (A) TSH ( or thyrotropin) I

This hormone {which is secreted by the thyrotropc cells or the adeno-
hypophysis) is a g~vcvprotein that entire~\' controls the activity of lhe
thyroid gland by increas ing the intracellular content of cyclic AMP (so after
hypophysectomy, the thyroid gland mrophics). Its normal pl asma leve l avera-
ges 2 microunits I ml and it exerts a generali7cd stimulating effect on the
thyroid g land lead ing to :
( l) A marked increase in (a) The si7c of the fol licular cells
(becoming columnar) (b) The vasculari ty and acti\ ity of the gland (so the
rates of iodide pump and iodine binding. synthesis and secretion of thyroglo-
bulin as well as the release of the hormones arc all increased).
(2) Generali zed enlargement of the gland(= goiter).
:::._: In addition to the TS I I receptors, the thyroid cells also contain receptors
for IGF I which promotes their growth.

Factors that control TSH secretion

I . Thyrotropin-re leasin g ho rm o ne (TRH) : Th is is one o r the

hypophysiotropic hormones secreted by the hypothalamus. Like TSI I, it
acts through increasi ng the C:l'c/ic AMP content of the thyrotropes lending
to secre ti on of TSH . It is liberated in certain conditions e.g. exposure to
cold (specia ll y in in fants).
2. Feedback co ntrol : There is a negative feedback relation
between the plasma level of the .fi"ee part f~( the thyroid hormones and
the releose o{ TSH i.e. when the free blood hormona l leve l increases
(spec ia ll y T1), the release of TS H decreases and vi ce versa. Thi s
mechani sm mai ntains a constant hormonal blood level, and it acts at both
the hypothalamic as well as the pi tuitary levels (figure 8).
3.0thcr factor s :
(a) Dopamine. somatostatin and glucocorticoids inhibit TSII secretion.
(b) The sec retion of' TS II shows a circadian rhythm . it s mea n
outpu t starts to ri se at about 9 PM , peaks at midni ght. then
dec lin es durin g the clay.
(c) During pregnancy, the placental hormone hCG (page 137) activates
 41

Section I - Chapter 3 Tlt e t!tvroid gland

the thyroid receptors leading to mild hyperthyroidism and enlargement of the

thyroid gland (goiter). In this case, the secretion of the pituitary TSH may be
depressed. ll was reported that the placenta also secretes a thyroid stimulator
other than hCG, and it was caUed human chorionic thyrotropin (page 140).

I (B) Dietary iodine intake I

An adequate di etary iodine intake is essenti al for normal thyroid
function. Wh en the intake falls belo w 50 meg/day, th e sy nth es is a nd
secretion of the thyroid hormones are decreased and as a result, the secretion
of TS H in creases leading to thyroid enl arge ment (go iter). Such iodine-
deficiencv goiter can be corrected by iodine admini stration in diet.
On the other hand, when iodides arc present in the blood in high conc-
entrations, the vascul arity and all acti vities or the thyroid gland are decreased
and consequently, the release of the th yroid hormones is also decreased.
This effect is known as the Woljf-Chaikoff effect, and it occurs because the
excess iodide (a) Decreases the organi c binding or iodine in the thyroid
gland (b) Reduces the effect ofTS H by reduc in g the cyc li c AM P response
to thi s hornwne (c) Inhibits proteo lysis of thyroglobulin.
** Th e Wo(ff-Ciwikojf e.ffect is greater and more prolonged when
the iodide transport is increased. This is why pati ents with hyperthyroidi sm
arc more responsive to iodi de than nom1al individuals. and before the
operation or thyroidectomy, these patients arc treated with iodide salt s to
decrease the size and vascul arit y or th e gland , thus the surgery becomes
easier and the blood loss is minimized.

I Antithyroid substances and drugs I

I. Excess iotlide salts : These depress the acti vity or the thyroid gland,
so when given to hyperth yro id patients, temporary improvement occurs.
2. Perclllorate and cltlorate anions : These and certain oth er mono-
valent anions (e.g. pertechnetate, nitrate, peri odate and biiodate anions)
decrease iodide trapping in the thyroid gland by competitive inhibition
(they compete with iodide .for transport into the g land via theNa- -r
symport) . Thiocyanate (a nother monova lent anion) also inhibits iodide
transport but it is not concentrated in the gland (so percltlomte is about 10
times more active than thiocyanate).
3. Tlziolll:ylenes : Th ese arc a group or co mpounds re lated to thi o-
urea (e.g. propylthiouracil and metlzima:;o/e). Th ese drugs (a) Inhibit
organic binding of iodide because they compete with tyrosine for iodine
 -12

Section I - Chapter 3 Tire tlr }Jroid gland

and become iodinated instead (b) Block the coupling reactions that l'o rm T1
and T4 . Propylthi oura cil also inhib its conversion or T.1 into T 3 in ex tra -
thyroidal tissues (by blocking the deiodinase enzyme). In hyperthyroi dism,
these drugs may also improve the symptoms by inhibiting the immune sys-
tem, which decreases the formation of stimulatory antibodies (sec below).
4. Na turally-occurring goitrogenic su bstan ces (go itrogen .\) : Certa in
,·egewhles (specia ll y cahhage and rumips) contain antithyroid substances
ca ll ed goitrogens (beca use th ey decrease the thyroidal hormonal blood
level, so TSII is excessively secreted leading to goiter). These vegetab les
contain an inactil'e go itrogen called progoitrin. and an acril ·ator that
col1\ert progoitrin to active goitrin. This activator is heat-labile, but when
destroyed by cooki ng, goitrin is still formed because th ere arc other
acti\'ators in the intestine (probab ly of bacterial ori gin). On normal
mixed diets, the goi trin intake is usually not enough to produce goiter, but
in vegetari ans "cabbage goiters" do occur. Other plant goitrogens probably
exist and may be responsible for the small goiter epidemics that arc repOiied
every now and th~..:n from various parts of the world.

!GOITER I
Go iter is a thy roid enlargem ent that is n on-iJ~flammatory ami
non-malignant (i.e. not due to tumours). It is 3 types :

(A) Simple goiter

Thi s is assoc iated with normal rhyroidJimction (euthyroidism)
and histological srructure. lt occurs due to either mild iodine deficiency or
normally during puberty (in which there is increased need for iodine)
produc ing physiological goiter. In such cases. the blood level of the thyroid
hormones is initially decreased. so excessive TSH is secreted leading to
thyroid enlargement. Simple goi ter may also occur du r ing pregna ncy (. cc
above).

(B) Co/lotd goiter

This is associated with hyp othyroidism and the follicles are
enlarged and lined by .flea cells (figure 15). The conditi on resu lts from
severe iodine de.ficien(l'. and its mechanism is si mi lar \o that or simpl e
goiter, cxc.:cpt that TSH stimu lates the thyroid cel ls to secrete larg~..: amounts
or col loid, bur the synrhesis and secretion (~(the rhyruid lwmwnes do nul
increase due to lack (?/iodi11e, resulting in goiter together with symptoms of
hypothyroidism (= iodine deficien cy goiter).
 -13

Section J - Chapter 3 Th e th yroid gland

::::_ In the areas that are deficient in iodine e.g. central Europe
(which is far from seas) and the area around the great. lakes in USA (in
which the soil is deficient in iodine by the effect of rain), iodine deficiency
goiter prcvai led in the past (before using iodi:ed table salt) and was thus
called endemic goiter.

(C) Toxic goiter

This is associated with hyperthyroidism, and the follicular cells
become columnar while the follicular lumens are decreased in size and
contain small er amounts of colloid than normal (figure 15). lt is due to
excessive stimulation of the thyroid glan d and is known as Graves' disease
(page 46).

IDISORDERS (DISEASES) OF THE THYROID GLAND I

[I] Hypothyroidism (myxedema and cretinism)

(A) Myxedema(= hypothyroidism in adults)

The common causes of myxedema include the following :
l. Damage of the thyroid gland as a result of di sease e.g. cancer {=
primaiJI hypothyroidism) .
2. Deficient TSH secretion due to either pituitary or hypothalamic
d iscase (= secondmJ' hypothyroidism).

Manifestations (symptoms) of myxedema

(1) S kin changes : The sk in beco mes dtJ', scaly and yellowish (due
to carotenemia) and hair falls (becoming coarse and scanty). There is
genera li zed nonpitting edema but specially in the face, producing charac-
teristic puffiness (figure 18). This is due to subcutaneous accumu lation of a
waxy-like myxematous tissue (w hich is formed of proteins , polysaccha-
rides, hyaluroni c acid , chondroitin sulphuric acid and wa ter).
(2) The basal metabolic rate {B.M. R.) is decreased, and the patient
cannot tolemte cold weather. The decreased B.M.R. together with the
myxematous tissue lead to an increa!.ie in tlte body weight although there is
decreased appetite and food intake.
(3) The muscles becom e weak ami easi~v f atigued and thl:rc is a lso
muscle cramps and st iffncss.
(4) Nervous !>Jllll]Jfoms : Mental functions arc depressed, so the patient's
thinking becomes slow and his memory poor. Somnolence is marked and
Section [ - Cltapter 3 Tlte tl11woid gland

facial expression become~ dull, so the patient looks apathetic. In som<.:

patients, there are scv<.:re mcntal symptoms(= myxedema madness).
(5) The patient's 11oice becom es husky llll(/ slow (so myxedema is
probably the only disease that can be diagnosed m•er the telephon e).
(6) The blood cholesterol lc\ el ( normall y 150-250 mg 0 -'o ) is increased
( hyperch olesterolemia ) and this predisposl!s to atltero.,c:lerosis.
(7) Depression of., ex function., (so spennatogenesis is depressed in male
patients and amenorrhea may occur in female pntients).
(8) There may also be hypochromic microcytic: anaemia (due to depre-
ss ion of the metabolic processes in the bone man·ow).

Figure 18: The face in case of myxedema (note punine~s and falling ofhair).

(B) Cretinism (= hypothyroidism in youngs)

Children'' ho an.: h:ypothyrotd fTom binh arl! <.:alkd cretins (ligure 19).
The condition is usually due to either :
1. Maternal causes. w mmonly maternal iodine ddi<.:iency or matemal
antithyroid anti bodi~:s that cross the placenta and dmnagc the fl:talthyroid gland.
2. Fetal causes e.g. Ictal thyro id gland maldcvclopment, fetal hypopitui-
tarism or inborn error~ or thyroid honnonc S) nthesis.

Manifestations (svmotoms) of cretinsim

( l ) Delayed ph y~ i cal gnm th : During infnrlC). all li.:atures of gro\\ th
arl! delayed (e.g. tccth eruption. sitting. walking and closurl! of the skull
f(mtanclles}. Latcr, there is failure of proliferat ion of epiphyseal cartilages.
so the cr etin is(/ d11'l11f having a height not <.:xceeding one meter (fig. 19).
(2) Mental reta rdation : The cretin may be a complete idiot. There are
also speech defects as wd l as urine and feces incontinence.
(3) low B.M.R. (so the cretin camwt tolerate cold ll'eatller}.
Section I - Chapter 3 Th e th vroid gland

(4) T he skin is thick a nd dry, the huir is coa r se :tnd scanty, and the
na ils are brittle. Skin thickening is due to subcutaneous overgrowth of soft
tissue, and it gives the pa ti ent an obese appea rance.
(5) Sexual retardation : Sexual development and puberty arc delayed
(page I02) and sexual maturation may be completely arTcsted (leading to
impotence in males and amenorrhea in females).
(6) General features : In the face, the eyelids arc swollen 1rith
narrowing of the palpebral fissure. the nose is depressed with wide nostrils.
and the tongue is enlarged and protn1des between thick lips. There is also
bulging abdomen and frequent ly umbilica l hcmia (figure 19).

Treatment of myxedema and cretinsim

Myxedema is treated by thyroid hormones. l lowcvcr, TS II is useful
in cases due to pituitary disease while TRH is useful in cases secondary to hypo-
thalamic disorders. On the other hand, in cao;cs of cretinism. unless the mother
was severely hypothyroid, all symptoms can be prevented by giving thyroid
hormones. provided that the treatment is started soon ajier birth (but once the
typical picture has developed, it is usually too late for the treatment to be
cncctivc, particularly in preventing mental retardation which is in-eversible).

Figure 19 : A cretin (note dwarfism, bulging abdomen and facia l changes).

 -l6

Section I - Chapter 3 Tile thyroid gland

[II] Hyperthyroidism (thyrotoxicosis) & Graves' disease

I fyperfunction of the thyroid gland may occur as a result of tumours
in the gland itself or TSH-sccreting pituitary tumours. However, the most
common cause of thyroid overactivity (60-80 % of cases) is Gral'es'
llypertllyroidism or disease (or exoplttltalmic ~-:oiler). This is an
autoimmune disease in "hich abnormal antibodies arc formed. Opposite
to may be expected, these antibodies stimulate tlte TS H receptors in the
thyroid gland. They were ca lled thyroid-stimulating immunoglobulins
(TSI) or long-acting thyroid stimulators (LATS) but now they are called
TSH receptor-stimulating antibodies (TSH-R-stim-Ab).

Figure 20 : The face in Graves' disease (note the goiter and exophthalmos).

Manifestations (symptoms) of Graves' disease

( I ) The thyroid gland is diffusely en larged, and since there is also
exophtha lmos. the disease is ca lled exop hthalmic goit er (ligure 20).
(2) Increased B.:\I.R. (from ~I 0 % up to + I 00 °'o) so there is
exccssi vc sweating (to increase the heat loss) and the patient's skin is
always moist, warm am/ flushed (i.e. red) due to V.D. This is associated
\\ ith /t eat intolerance.
(3) Cardiovasc ular sy mptoms : These include tachycardia and palp-
itation, increased cardiac output and systolic B.P., extra.\)'SIOies and mriol
jihrillatio11 in some cases. The diastolic B.P. is not cha nged or decreased
 ..n

Section I- Chapter 3 Th e th vroid gland

(due to the cu taneous V.D.) so the pulse pressure increases leading to

water hammer (collapsing) pulse. The cardiac musc le may also suffe r
relative ischemia due to its increased demand of blood supply. Jn some
cases, the cardiac output is increased but is still inadequate to ma intain tissue
perfus ion due to the increased B.M. R., lead ing to "a high output.failure".
(4) Ner vous symptoms : There is increased excitability of the nervous
system (probabl y as a resul t of increased responsive11ess of the reticular
formation to catecholamines). This is shown by nervousness, irri tab ility,
anxiety, restlessness, insomnia and fine tremors o.ftlte outstretched.fingers.
(5) Metabolic changes : Hyperglycem ia (and may be glucosuria) and a
decrease in the serum cholesterol level (below 120 mg %).
(6) Increased food intake (= hyperphagia) associa ted with we ight loss
due to the excessive metabolism.
(7) Increased intesti nal movements and may he diarrhea.
(8) Incr eased protein catabolism : In bones, thi s leads to demineraliz-
ation and osteoporosis associated with hypercalcemia and hypercalcuria.
The ske leta l musc les become weak & easily fatigued (thyrotoxic myopathy)
due to loss of creatine, which is excreted in urine resulting in creatinuria.
(9) Ex oplultalmos : This is forward protrusion of the eyeballs and is
usua lly associated with eye lid retraction. It is an ea rl y sign or the disease
and it occurs in 50 %of cases. lt is due to swelling of the orbital tissues
(the connective tissue and extraocu lar muscles) wh ich pushes the eyeballs
forward. It is be lieved that fibrob lasts that conta in TSH receptor protein
develop in the orbits and these cel ls arc stimu lated by the TSH-R-stim-Ab
and in response they re lease certa in q tokines that promote in fla mmati on
and edema of the orbital tissues, leading to forward eyeball protrusion.

Treatment of Graves' disease

I. Giving antithyroid drugs e.g. propylth iouracil (page 4 I).
2. Givin g radioactive iodine ( 123 1) in cert ain doses that damage
some of the overactive thyroid cells.
3. Surg ica l remova l of a part of the thyroid gland (=s ubtotal
thy roidectomy).

THE THYROID FUNCTION TESTS

[A] SPECIFIC TESTS

(1) Meas uremen t of P BJ (Protein -Bound Iod ine) : The normal

va lue of PBI is 4- 8 meg% . It increases in hyperthyroidism and decrea-
ses in hypothyroidism. However, it is not co nclusive in the diagnosis of
 48

Section I- Chapter 3 The thyroid gland

thyroid diseases because the amounts of the thyroid bind ing proteins vary
normal ly by various factors. and consequently hi gh or low values of PBI
may be found in individuals with euthyroid (= normal thyroid) activity.
(2) Measu rem ent of th e total thyro id hormonal blood level : ln
spite of the hi gher va lues than normal found in thyrotoxicosis and the low-
er va lues found in myxedema, yet as the PBI , it is also not conclusive in the
diagnosis since high or low values may be found in normal indi vidua ls.
(3) Es timation of r adioactive iod in e up take by the thyroid
gla nd : The iod ine uptake by the th yroid gland is a good index of its
131 123
function. A tracer dose of a radioactive iodine e.g. 1 (or bet1er 1) that has
no damaging effects on the gland is adm ini stered and the thyroid uptake is
determined. In hyperthyroidism, the iod ine uptake is more than nom1al ,
whi le in hypothyroidism it is less than nom1al.
(4) TS H s timulnlion test : T hi s test differentiates between prinuu:l'
and secoll(/atJ' hypothyroidism. A test dose of TSH is injected, then 1he
thyroid hormoncil blood level is measured. It increases in cases of secon da-
ry hypothyroidism and not affected in case s of primary hypothyroidism.
(5) TRH stimu lati on t est : Thi s test differe n tiates between
pituitary aut! ltypotltalamic lesions in cases of secon dary !typo -
tltyroidism A test dose of TR H is injected, then lite plasma TSJ/Ievel is
measured. It increases in cases due to hypothalamic lesion s but it is not
affected in cases due to pituitary lesions.
(6) Estim a tion of th e plas ma fr ee T 3 & T~ a nd TSH leve ls : Th is is
accurately done now (by r ad ioi m mun oassay), and is th e most reliable
method for assessing thyroid jimction. Th e ji-ee !/tyroid lwrmo1wl blood
le1•ef is decreased in hypothyroidis m and increased in hyperlltyroidism. On
the other hand , !he TSJI level is increased in hypothy roidis m and
decreas ed in ltypenltyroidism (if th e disease is due to a thyroid disorde1J

[ B ] NONSPECIFIC TESTS

( I ) Determination of the basal metabolic rate (B.M.R.): Normally, it

averages 40 ± 15% kilocalories/ sq.m/ hour in adult males (refer to meta-
bolism). [t increases in hyperthyroidism and decreases in hypothyroidism.
(2) Determin ation of t he serum chol esterol level (normal ly about
200 mg %). It increases in hypothyroidism and decreases in hyperthyr-
oidism (however both B. M. R. and serum cholesterol are qfTected by ma11y
other/actors. so they are not specijic in diagnosis a./thyroid disorders) .
CHAPTER 4

I THE ADRENAL (SUPRARENAL) CORTEX I

There arc 2 adrena l glands (each weighing 4-5 gm in adults), one at
the su perior pole of each kidney (figure I). Each gland consists of 2
separate endocrine ti ssues that arc difTerent stntcturally and developmentally
as well as functionally. The inner part is the adrenal medulla (abou t 28 °o of
the mass of the gland), '' hile the outer part is the adrenal corte:-. (abou t n
%of the mass of the gland) which is essential to life (page 2).

Figure 21 : Strm:ture of the adrena l cortex.

Functional histology of the adrenal cortex

The adrenal corte\ is formed of 3 dil>tinct zones (figure 21) :
I. Zona glom erulo.\ il : This is the outer ;one and it constitu-
tes about 15 °o of the mass nf the gland. The cells of this tone arc ahle to
form ne11 cl!/1:, I hal reg<'nerate the other :one'.
2. Zona fasciculata (fasc:ic: ulosa) : Thi s is tht.: middl e w nt.:. It is tht.:
ltugcst zone since it const itutes about 50 % or the mass of th e gland.
3. Zmw reticularis : This is the inner zone. It is the sma llest zone
since it constitutes only about 7 1Yo of the mass o r the gland.
 50

Section 1- Cltapter 4 Tlt e adrenal (suprarenal) cortex

The ce ll s or the adrenal cortex are ri ch in clwlesterol (from which its

hormones arc synthesized) and contain large amounts of smooth
endoplasmic reticulum fmd mitochondria (in wh ich synthesis of the
hormones takes place).
/\ II adrenocortical hormones contain a steroid ring (so they arc called
corticosteroid hormones). They arc 2 types : C2 1 steroids and C 19 steroids.
Both mineralocorti co ids and glucocorti co ids are C21 steroids (sec below)
whil e Cr9 steroids ha ve an androgenic activity and most of them include a
keto group at position 17 (so they are also ca lled 1 7- ketosteroid\·).

Rate of secretion of the corticosteroids

Corticosterone is synthesized in the 3 zones of the gland, a nd is the
prec ursor of all secreted hormones which include the fo llowing:

(1) From zona glomerulosa : 2 mineralocorticoid hormones :

a. Aldosterone (formed ji·om corticosterone at about 0.15 mg per day).
b. Deoxycorticosterone (DOC) (about 0. 2 mg p er cla_1 ).

(2) From both zonae fasciculata and r eticularis :

A. 2 glucocorticoid h ormones (mainlyji·om :::onafascuculata)
1- Cortisol (aboutlO mg per day )
2- Corticosterone (about 3 mg p er day).
B. Se..v: hormo11es (main~)' fro m :::ona reticularis) : These arc mainly
androgens (about 20 mg per day) which arc mostly tleltydroepi-
androsterone (DH EA) and androstenedio11e (some of the latter is conver-
ted to estrogen in the circulation and certain tissues).

Plasma content and transport of the corticosteroids

The average plasma cortisol level is about 13.9 meg %. llowcvcr, it
shows diurnal variation (being highest in the morning and lowest at ni ght).
A very small part of the plasma cortisol is free while the majority is bound
to plasma proteins [mosll y to an alpha g lobulin call ed corticosteroid-
bindillg globulin (CBG) or transcorti11 and a minority to albumin].
The average plasma concentration of corti costerone is about 0.4 meg %
and simi tar to cort iso l, it is mostly bound to plasma protein s.
T he average plas ma leve l of each or the mincralocorti co ids is about
0.006 m eg %, while that of each or the and rogens is 175 m eg %.
 51

cction 1- Chapter 4 Til e adrenal (mprarena/) cortex

Mechanism of action & metabolism of corticosteroids

These hormones bind to spcci fie cytoplasmic receptors in the target

cells and exert their effects by increasing transcription of mRNAs (figure 2)
then they nrc inactivated mainly in the liver by the following ways :
I . Most cortisol is reduced to dihydrocorti.wlthen to tetmhydrocorti-
wl "hich is conjugated to glucuronic acid amlthe conjugates an: e~creted
in the urine. Some cortisol is c:onl'erted to cortisone" hich is also reduc-
ed. conjugated and excreted in urine. Cortisone is an acth•e .\ teroid
JVII en gi ven as a treatment since it is converted to cortisol in tile hotly.
2. Most aldosterone is also convened to tetraltydroaldosterone
Jflucuronide (which is also excreted in the urine).
3 . The adrenal androgens and about 10 uo or cortisol arc
excreted in urine as 17- k etosteroids. Testosterone{\\ hich is secreted
from the testes) is abo corn cncd to 17- ketosteroid and e\crcted in
the urine. The normal urin:tr) excretion of 17- kctostcroids in adult
females i., about 10 mg/day. ami in adult males 15 mg/rlay. In females.
all arc or an adrenal origin only, while in males abou t 2/3 (I 0 mg) is of
an ndrcnal origin while about I /3 (5 mg) is of' a testi<.:u lar origin.

Functions (actions or effects) of glucocorticoids

Glucocorticoids incluck mainly cortisol ami corticosterone. They

arc scerctcdfi·om both =mwefasciculma allCI reticulari.\ {specially the
former) and they exert the folio\\ ing actions or cffccts (figure ::!2) :

(1) Metabolic effects

a. Prot e in rn ctaholi sm : C:Jiucoconicoids cause protein (.'Otaho/ism

(increasing the amino acid It,:, el in the blood). In the liH:r the) increase the
uptake of amino acids and their conversion into carbohydrates
(f.:ltu·oneoeenesis). Protein catabolism in bones is due to increasing the
ostcodasti<.: activity and it results in (a) Osteoporosis or osteopenia (b)
Increased C(/1- mobi/i:_(ltion from bones and its e\crction in the urine.
b. Carbohyd r ate meta bolism : Gluco<.:orticotds stimulate ~lunmeo­
.l!LIIt "·' rn the li' cr. and tht., rncrca c both ghcogcllt'\1\ in the lin•r and
also the hepatic glucow output. At the tissues. they decrease glucose
upl:lke (a n ami-im ulin action ) except 111 the brain and heart. Such
effects lend to hyperglycemia and n u~v cw1.w: diabetes mellitus (steroid
or adrenal diabetes) or ll'onen the diabetes i/it is a/reac(t• present.
 52

Section 1- Chapter -1 Th e adrenal (5 uprarenal) cortex

c. Fat meta bolism : Glm:oconicoids mohili::e.farfrom adipose lissue

and decrease hepatic lipogenesis. thus increasing the plasma level of free
fatty acids (FFAs). which are a good source of energy. The hormones also
a./feet 1he distribution oJfat in the body (sec adrenocortical hypcrfunction,
page 61).
(2) Permissive action · The presence of glucocorticoids is important
for some other hormones to exert their effects, specially for calecholamines
and glucagon to produce their calorigenic effects, and for colecltnlamines
to produce 1heir bronchodilator, lipo~vtic and pressor ejfects (the latter
effect of glucocorticoids is due to increasing tile vascular reactivity to
catecllolamines).
(3) Effects on water & electrolyte metabolism : Glucocor1icoids
promote water excretion in the urine as a result of inhibiting secretion of
ADfl am/ increasing tile glom erular filtration rate. They also stimulate
secretion of ANP which helps urinary excretion of excess salt loads. lt is to
be noted that glucoconicoids also exert a mineralocorticoid effect (helping
Na_,. retention) but such eiTect is weak in the normal conditions.
(4) Effects on blood cells and lymphatic organs : Glucocorticoids
decrease the number eosinophil.\·. basophil.\· & ~\ 'lllplwLytes. and increase the
number of neutrophils. plaielets & red blood cells. Lymphopenia is due to
inhibition of lymphocyte proliferation in the lymph nodes and thymus
(which leads to reduction of their sizes) as a result of inhibiting production
of intcrleukin-2 by the T lymphocytes (refer to blood).
(5) Effects on nervous functions : Glucocor1icoids innuence the
nervous system as cv idcncccl by appearance or certain nervous symptoms in
patients with adrena l insufficiency that arc reversed on ly by glucocorticoids
e.g. changes in the electroencephalogram and personality, irritability,
apprehension and inability to concentrate.
(6) Resistance to stress : Stressful stimuli (page 55) arc defined
as the noxious (or injurious) stimuli that increase secretion nf' ACT! I
(through CRII secretion) leadi ng to a rise in the plasma glucocorti coid
level. This rise is essen tial for su rvival in these cond itions by an unknown
mechanism. llowever, the role of glucocorticoids in stress may be through
(a) Providing substrates for extra-supply of energy specially FFAs (b)
Their permissive action to mtecholamines (sec above), the liberat ion of
"hich is stimulated by most stressfu l stimuli.
(7) Anti-inflammatory effects : Glut:ocorticoicls suppress the infl-
ammatory reactions by (a) Inhibitin g release of the lysosomal enzymes
(b) Formation of leukotri cnes and interleuk ins (c) Decreasing the capillary
 53

Section 1- Chapter 4 Tlt e adrenal (m prarena/) cortex

pcrmcability. They al so inhibit fibrobl astic activity. which would prevent

loca liza tion or the infection (helping its spread to the ncighbouring areas)
but however. it prevents development of adhesions during healing.
('J) ~nti-alleraic eftecr . Glucocorticoids suppress all manifesta-
tions of nllergy by pret•enting release of histamine from lite mast cells.

SlW!tMENAL GLAND

,..--- -+--- POTAUIUH

SY5TEHIC BLOOD VESSEL

WATU

WA1111 fXC.nlOH INCUASIO]

POTAUIUH VCCUTlON INCUAKD
CAlCI"" EXC.ETION ...aEARD

Figu rc 22 : Functions of glucocnrt icoids

 5-1

Section 1- Chapter 4 The adrenal (f;upraren a/) cortex

::_ Both 7 and 8 arc produced on~)! by large (pharmacologic)

doses of glu cocorticoid.~. These hormones arc also emperically given in
other diseases e.g. autoimmune and neopla sti c di seases as well as in
ca es of shock and brain edema. Doses exceeding 20 mg dai ly gi,·en for
more th an 3 weeks cause persistent inhibition of the hypothalamic-
pituitary axi, by a negative feed back mechanism. so the secretion of both
CRII and ACTII is severely decreased and the ad renal cortex becomes
functionless. In such cases, sudden wi thdrawal of the exogenous hormones
leads to signs of adrenocortica I insu ffic iency (cor/ isol ll'i thdrall'af
syndrome) . To avoid these effects. the hormones are preferably given in
srnall doses an d every ot her day. and their witltdmwnl should be gradual
over several months (= tapering of glucocorticoid treatmen t) becnusc
complete recovery or the hypothalamic-pituitary axis and the adrenal
cortex requires 2 months up to one year after withdrawal of the hormones.

(9) Effects on other hormones : G lucoco rti co ids decrease t!t e

secretion of both tlt e grmt•tlt h orm on e (page 20) and TS/1 (page 40).
(10) Effects on the respiratory system : During feta l lire, the
glucocort icoids accelerate tlt e fo rmation ojslllfactant in tlte lung'i.

Regulation (control) of glucocorticoid secretion

Glucocorti coid secretion is stimulated mainly by the adrenocortico-

tropic hormone (ACTH) which is secreted by the corlicolrope cells (~/ the
anlerior pituilm:l ' gland. ACTH is a single-chain po lypeptide (contnining
39 amino acids) that maintains the structure, size and vascularity of the
adrenal cortex. l t stimulates glucocorticoid and androgen secretion from
b01h ::onaefasciculata and relicularis (but its effect on zona glomerulosa
is minimal) and it also exerts a considerable MSH acti vi~J' (page 14 ).

Mechanism of action of ACTH and control of its secretion

In the adrenal cortex. ACTH acts by increasing the intracell ular cyclic
AMP content in the target cells. Tts secretion is controlled by 2 factors :
I. Co rticotropin-releasing hormone (C RH) : This is secreted from the
hypo thulumus (ligurc23) and it promotes ACTH synthscsis & release l'rom
the corticotropcs (by increasi ng the cyclic AMP content in these cells).
2. Feed back control : A negati ve feedback relati on exists between the
free plasma glucocorticoid level and the secretion of ACTH. Such effect is
produced at both the pituitary and hypoth alami c levels (figure 23).
 Section 1- Chapter 4 Til e adrenal Gmprarena/) cortex

ACTH response to stress

Many stressful stimuli lead to secretion of ACT! I (through stimu lating
CR II secretion from the hypothalamus) e.g. trauma or injury, acute
hypoglycemia, anxiety. fear and other emotional stresses. Such timuli
excite many parts of the brain (specially the limhic S\ '\'tem) which in turn
stimulate CRH secretion from the hypothalamus.

Diurnal (circadian) rhythm of ACTH secretion

Normall y, ACTII is secreted irregularl y throughout the 2-1 hours and
in response. the plasma glucocorticoid level tends to rise and fall. In
humans, the peak ol A CT/1 secretion occurs in the eor~\' 1110mi11g and is
lowest in the evening. This phenomenon is known as the diurnal or
circadian rhythm and it is due to a diurnal 1'ariatio11 in CRJ I secretion.
Tile biologic clock responsible for the diurnal ACT! I rhythm is located in
the .m pracllias matic nuclei of tile hypothalamus.

flllO\IlH1 VI1J
svilrm
lunt.t~c

Ttaum• v11
sp uiOi h dlilm•c
p•rhw•v•
Alftrtn u lrom,
nucltu• o t lhr '
ttl tu\ loOIII.tt n

CR H

I <b
' A lrr or
,' , I ) , . •..
1 I
II
Cotl•lol \ \ ACTH

* A .hrn•lCO fl ~ '

Figure 23 : Control of secretion of glucocorticoids.

Functions (effects or actions) of mineralocorticoids
Mincralocorticoids include mainly aldosterone om/ deo.\) ·corticosterone
(DOC). Both arc secreted on ly from the ::mw glomemlosa in almost equal
omo11111s but DOC ltas oii~JI 3 % t~j'aldosterone activity. They arc important f'or
regulating Na+ and K+ meta bolism and extracellular fluid (ECF) volume. The
IUJI'IIWI serum Na +level is 135- 145 mEq/litrc, IV!Ii/e that of K is 3.5-5 m Eq/litre.
 56

Section 1- Chapter -1 Th e adrenal (\ltprarena/) cortex

Mincralocorticoids increase Nr/ c:on centratitm in the £CF

(ami consequently th~.: l:CF vo lume) by the folio'' ing ml.!chanisms :
I. Actions on the kidn eys : The kidneys arc th e major site of
action of these hormones. \\'here they act mainl) at the distal
convoluted tubules am/ the collecting ducts , increasing Na +
reabsorption in e.n:lumge ll'ith secretion of either JC or II
(according to the bod~ conditions).
2. Actions out side the kidn eys : Mincralocorllcoid!:> increase
Na absorption from other body nuids than the urine (e.g. Sll'eat and
.wlim) as 1re// as.from the CIT mucosa (special~\' ot the colon).

Mechanism of action of aldosterone

Na absorption i.., promoted by aldosterone through binding to

speci ric cytopla.,mic receptor.\ in the target cells '' hich incrl.!ase
transcripton of mRNAo; resulting in production of certain protei11s
ilwt alta the cell (lmcttnm. These protein.\ im:rea.\ e the ac:til·i~l' of
Na ~ c:/umm!ls 1111tl also stimulate tlteir ·':l'ntltesis at the luminal
border:- of the tubular cdb. They also in crease the ac:til•io• of the
m embrane N a• - K'" exc:IUIIIJ.:ers special(r A TPase (refer to kidn~.:y).

~
JuxiOCJ rul4r
lnctea d teNI artrr al
__ meo.n fllt'UUic dtertas.!'d
~ ~ - - -- - - - dtehaooolr Nl ntrns

//If\___ \
1\•llJ•Otensrnogon
/"'"
!--
Augll leru n I
lutr..: llular
laud :;olumtl

!- I
Figur~ 2-t : Th~.: fe~.:d back mechanism that rcgulatl!s secretion or '
rcnrn and aldosterone (the dashed arTO\\' indicatl!s inhibition).
 57

Section 1- Chapter 4 Th e adrenal (suprarenal) cortex

I Factors that regulate (control) aldosterone secretion I

J. Angiotensin I I : This stimulates com •ersion of corticosterone to
alrlosterone in the zona g lomerulosa cells aml secretion of aldosterone
from these cells. It is formed through the renin -a ngiotensin system which
regulates aldosterone secretion by a feedback m echanism as fo ll ows : A
decrease in th e ECF vo lume leads to renal ischemia and also incrcnscs the
sympathetic activity. Both effects stimulate renin secretion from the j uxta-
glom erular cells of the k idney and renin. in turn , leads to formati on or
angiotensins I, II & III (refer to circulatimr). The latter 2 stimulate aldost-
erone secrelion which ca uses Na + and water retenti on. This increases
the ECF vo lume, wh ich. in turn , inhibits renin secret ion (ligurc 24).
2. ACTH : This hormone sti mulates secretion of mincralocorticoids.
ll owever, aldosterone secretion is reduced within few days because
the resulting hypervolemia inhibits renin secretion which decreases form-
ati on or angiotensin II. hut the secretion of deo.\yco rtic:osterone (DOC)
remains elel'llted because its secretion is controlled on~r by A CTII and is not
qffected ~~~·the le1·e/ ofangiotensin /1.
:::..: A pituittu:J' hormone oth er than A CTH hel ps to maintain the integrity
and responsiveness of the zona glomerulosa to angiotensin II. Therefore,
immediately after hypophysectomy. both zonae l'asciculata and reticularis
begin to degenerate but the zona glomcru losa persists for sometime (because
it sti II responds to angiotensin II). llowcvcr, it degenerates in long standing
cases because of absence of this pituitary hormone .

3. Nu+ and K + serum levels : Aldosteronc secretion varies inversely

with serum Na- level and directly with serum K" level but it is more
sensitive to changes in K than to ch anges in Nc/ (the a • level must
drop about 20 mEq/litrc to stimulnte aldosterone secretion whil e such effect
can be produced by an increase inK level of only I mEqllitrc}.

4. Other factors :

(a) The atrial natriuretic peptide (ANP) inhibits renin secretion and decrea-
ses the responsiveness of' the zona glomcru losa cel ls to angiotensin fl.
(b) The rate of aldosterone secretion shows a circadian rltythm being highest
in the early morning before awakening and lowest in the cvening.
(c) /\ ldostcronc secretion is increased together witlt tile glucoc:ortit:oitls in
stress conditions.
 Section I- Chapter 4 The adrenal (mprarena/) cortex

.::: The high se rum K' level direct ly stimul ates the i'Ona glomentlosa cells
to secrete aldosterone. On the other hand, the. low serum Na + level stimu lates
these cells through formation of angiotensin 11. because it leads to hypo-
volemia which stimu lates renin secretion by the resulting renal ischemia and
increased discharge of the renal sympathetic nerves (sec next).
~ Renin secretion in creases by renal ischemia or increased discharge
in the renal symp. nen·es (or both togetiJe1) in the foll owing co nditions :
I . Hyponatremia (sec above) and hypotension.
2. Constriction ofthe renal arteiJ' or the aorta.
3. Drop in the ECF volume i.e. hypovolemia (e.g. due to hemorTbage
or dehydration) or the intra-arterial vascular volume (e.g. due to
prolonged standing or constriction of the thoracic inferior \'ena cava).
4. Som e cases ofc.:ongesth·e heart failure, nephrosis and liver cirrhosis
(= secontlar) hyperaldosteronism).
5. A ctivation oftlte .\ ympathetic ~ystem : Sympmhetic stimulation
and catecholamine.,· increase renin secretion by actii'Oting the
beta 1 adrenergic receptors at the juxtaglomemlor cells (?/the kidneys.

ALDOSTERONE ESCAPE
High doses or aldosterone ca use sodi um nnd water retention and
increase the ECF volume. llo\\'ever. afterfell' days this ejJect di:wppears and
the kidneys escape j/'om tlte eff ect of aldosterone. so the excretion of sodium
and water increases again although the aldosternc blood level is maintained
high. Such phenomenon explains ll'hy on(\' .\light edema ocmrs in hyper-
aldosreronism, and it is due to tlte increase oft/It! /:: CF wllume itse({which
leads to (a) Rise or the arterial B.P., and this leads to pressure diuresis (b)
Secretion of ANP, which causes both natriuresis as well as water diuresis.

THE ADRENAL SEX HORMONES

The adrl.!nal androgens DIIEA ami andmstenedione arc the main

sex hom1oncs sccn.:tcd by the adrena l cortex. Very small amounts of estrogen
and progesterone are also secreted.
Androgens an.: honnoncs that produce mascu/ini:)ng effects (i.e. male
characteristics) and also promote protein anabolism and growth. Thl.!ir secretion
ti·om the adrcnnl cortex sta1 ts in I he young age, peaks ar pubt•rl)• then Iails to very
lm\ 'alues in old age. rhcy arc secreted equally in /writ Se'l.:es and their plasma
levels is the sa me in both mules and lcmales. llowcvcr, when secreh.xl in normal
amounts, they exert minor c.:ffects on reproduction ancllull'e l'el)' lillie mascu-
lini:ing effects as they exert only 20% ol' the activity of testosterone (page I09).
 59

Section J- Chapter 4 Tlt e adrenal (suprarenal) corte.\·

Functions : Androgens help early sexual maturation in males while in f emales

they cause growth of axil/my and pubic ltair at puberty. Their secretion is
controlled by A CTH and possibly also by a specific pituitary adrenal
androgen-stimulating hormone (but not by the gonadotropic hormones).

I Disorders (diseases) of the adrenal cortex I

[A] Addison's disease (= Adrenocortical hypofunction}

Thi s is primary adrena l insuffi ciency (hypocorticism) i.e. du e

to damage of tlte adrenal cortex itself It is usually clue to an auto-
immune disease but, however, some cases arc.: due to destruction or the
glands by other diseases speciall y tuberculosis and eel/leer. Secondary
adrenal insufficiency due to deficient ACTH secretion and ter tiary
adrenal in sufficiency due to deficient CRH secretion may also occur.

Manifestations (symptoms) ofAddison's disease

A- Aldosterone deficiency leads to :

I. Hyponatremia due to excessive Na.,. loss in the urine. It leads

to hypovolemia and hypotension due to simu ltaneous water loss.
2. Small heart size because hypotension decreases the heart work
3. Metabolic acid os is due to H-t retent ion (s ince 11 · secretion in the
kidneys is coupled witl1 Na' t\!absoiption, which is deficient in tl1is disease).
4. Hyperkalemia due to deficient K+ secretion. This causes muscle
1reaknes·s. tiredness c111d c/wracteristic changes in the ECG (r~fer to CVS).
B- Glucocorticoid defici ency leads to :

1. Hypoglycemia between meals (fasting leads to fatal hypoglycem ia).

2. Fatigue and general weakness due to lack of mobilization of sub-
strates that suppl y energy specially Ff As .
3. Gastrointestinal symptoms e.g. anorex ia( = loss of appetite). nausea.
and vom iting. These e ffects lead to loss of weight.
4. Lia bili ty to watct· intoxication (in ~1Jite of water loss in tile urine
with Ntt) : This is clue to inabi li ty to el iminate excess water loads from the
body and is helped by the plasmalrypotouicity (due to hyponatremia) which
favours di ffusion of water into the cells.
 60

Section 1- Chapter 4 Tile adrenal (mprarena/) cortex

5. Decreased res ista nce to s tress Stress cond itions aggravate the
disease leading to severe collapse and may cause fatal shock (a condition
known as Addisonian crisis).
6. Certain nervous ma nifestations (page 52).
7. Dark pigmentation of the skin and mucous membranes e.g. the gum.
This is due to excessive deposition ofmelanin caused hy increased
ACTH level in the blood. ACTH exerts 11 MSH-activity (page 14) and
its s~.:c rction is stimulated by a negative feedback mechanism due to
reduction of the plasma glucocorticoid concentration. Skin pigmentation
particularly occurs at the pressure points. palmar creases, the light exposed
areas (e.g. the face and front of the neck), areola of nipples and recent scars.

~ In secondary and tertiary adrena l insufficiency, the symptoms arc mild

because the electrolyte met11bolism is less affected. In addition, there is 110
pig mentation because the blood ACTH level is low in these conditions.
1
:!:_ Patients arc adviced to take foods rich in Na nnd poor in K •. However,
tre11tment with both mineralo and gluco-corticoid lwrmones is essential.

figure 25 : Typical findings in Cushing's syndrome

 61

Section I- Chapter 4 The adrenal (mprareual) corte..\:

[B] Adrenocortical hyperfunction (hypercorticism)

This includes 3 syndromes, each of \\'hich is characterized by

ovcractivity of a panicular zone of the gland.

( I ) Cushmg's syndrome (disease)

This is due to ovcractivity of the zona fasciculata (which leads

to excessive secretion of glucocorticoids and to a little extent. also
androgens). Lt occurs as a result of either (a) An adrenocort ical tumour
{= Primary hypercorticism nr Cushing 's syndrome). This type is
ACT/1-indepem/ent and is also produced b) prolonged administration
of exogenous glucoconicoids (b) Excessive secretion or ACTH by
t. : ithcr a pituitary tumour or due to oversecrction of CR II r-Secondary
hypcrcorticism or Cushing's disease). This type is A CTH-depe11dent
and is also produced by ACTTI-secreting tumours in other organs,
usually the lungs (= ectopic A CTH syndrom e). However. it is often
clifricult to detect the site orlhese ACTH-scc rctin g tumours.

Manifestations (symotoms) of Cushing's syndrome

(1) lncr·eased protein catabolism : This leads to :
a. Poorly-developed muscles resu lting in muscle weakness.
h. Thin skin and subcutaneous tissues. Wounds hertl poorly
and minor injuries cause bmiscs (figure 25) .
.c. Bone resorption leading to osteop enia (o r osteoporosi.,~. This leads
to collapse of the vertebral bodies (and other frac tures) resulting in
kyphosis , which increases the buffalo hump appearance (sec below).

(2) Central (o r trunk) ohesity : Body lltt is redistribuwd. Fat collects

mainly in the face. abdominal wall. suprac lavicular n.:gion and upp~.:r part or
the back (producing a bufftdo hump ), but no/ in tire /imh.\ wlriclr become
1hi11 and weak. As the thin abdominal skin is stretched, the subdermal
tissues rupture producing reddislt-purple striae.

(3) llypertcn sion: This m:curs in 85 %or patients as u result of (a)

due to increased Na and water retention. which is produced
I Zl'fH! rvo/emia
by the excess glucocorticoids and increased secretion of'minernlocorticoicls
and may be also angiotensinogcn (b) V. C. produced hy the glucocorticoids
directly and by increas ing the vascul<t r reactiv ity to catccho lamincs.
 62

Section I- Chapter 4 The adrenal (suprarenal) cortex

_::: There may be significant K+ depletion, which adds to the state of geneml
weakness.
_::: Salt and water retention plus the facial obesity cause a characteristic pleth-
oric and rounded face in this disease that is described as moon face.

(4) Impaired glucose tolerance :The increased gluconeogenesis pro-

duced by the glucocorticoids leads to hyperglycemia and glucosuria. This
together with the decreased peripheral utilization of glucose may prod-
uce a type of secondary diabetes called steroid or adrenal diabetes in the
patients who are genetically predisposed to diabetes (page 94).

(5) Nervous symptoms : The excess glucocorticoids accelerate the

basic EEG rhythms and produce mental abnormalities (e.g. irritability, an-
xiety, insomnia, emotional disturbances, depression and toxic psychoses)
which are more severe than those occurring in Addison's disease (page 52).

(6) Androgenic manifestations :These appear in females due to more

secretion of the adre11al a11drogens (e.g. hirsutism and acne).

(7) Blood changes : Mild polycythemia and lymphopenia often occur.

(8) Increased susceptibility to infections as a result of depression of

tire immune system (due to lymphopenia).

_::: In cases that are ACTH-dependent i.e. Cushing's disease or secondary

hypercorticism (see above), there is also skin pigmentation and more
secretion of the mineralocorticoid deoxycorticosterone and the adrenal
androgens. It is to be noted that ACTH secretion is decreased in primary
hypercorticism (i.e. Cushing's syndrome) by negative feedback.

_::: The disease can be promptly treated by surgical removal of the tumours
whether in the adrenal cortex or in the adenohypophysis. Drugs that inhibit
cortisol secretion or functions can also be used, but surgery is the basic
treatment. It was noticed that following removal of an adrenocortical tumour,
many patients develop a syndrome called Nelson's syndrome. This is
characterized by hyperpigmentation of the skin and signs of increased
intracranial tension that occur due to development of rapidly growing
ACTH-secreting tumours (which may be malignant) in the adenohypophysis.
Section 1- Chapter 4 Tile adrenal (supraren al) cortex

( II ) The adrenogenital syndrome

Th is is due to excessive secretion of ad renal a ndrogens. In

adults, it is often due to tumours in the zona reticu lar-is, but in ch ildren, it
is usual ly due to exposure or the fetus to excess androgens during the period
beflveen tlte 8'" ami 13'" weeks ofpregnancy. Th is can be produced by
androgens transmitted from the mother but more common ly, it is the result
of congenital adrenal hyperplasia which occurs due to congenital
deficiency of certain enzymes specially the 11 and 21 beta hydroxylase
enzymes. In this condition. glucocorticoid synthesis is inhibited. and the
metabolic pathways in the adrenal cortex arc shunted to the production of
excess and rogens. The low plasma glucocorti coid level stimulates release of
ACTII by negative feedback which causes adrena l hyperplasia and further
increases the synthesis and secretion of androgens.

• Baldntu
"Rtcrdonq hairhnt

Hoovy arms
and lt<Js

Enlargfd
CfllOtll

Figure 26: The adrenogenital syndrome (viril ism) in an adult woman.

 64

Section 1- Chapter 4 Tire adrenal (mprarena/) cortex

Manifestations (symptoms)

(A) In females

Ad ult fema les show signs of masculinization ( = Virilism or Virilh.-

atiou ). On the other hand, if the disease occurs in a fema le fetus, it
ca uses female pseudoltermap!troditism (i.e. the patient is born with
the ge11etic constitution and gonads offemales but ll'it/J the external
genitalia o.lma/es) and signs of virilism develop later in life.
VI. L.IS1vt · This is development of male secondary sex
charac-teristics in fema les. The size of skeletal muscles in creases together
wit h hirsutism, bitemporal recession of the ji-ontal scalp hairline am/
may he baldness. appeara11ce o.t beard and moustache (figure 26). deep
coarse voice (d ue to laryngeal growth), male escutcheon (hair growth in the
midline between the umbilicus and pubic area) and suppression of the
efTecLs or estrogen (resul ting in amenorrhea and infertility, atrophy of the
breasts and external genitalia except the clitoris which is enlarged).

(B) In males

A male fetus havi ng excessive secreti on of adrenal androgens is

born normal. but he will show precocious pseudopuberty i.e. early de-
velopment of secondary sex characteri stics with out test icul ar growth.
However, if the excess androgen secretion occurs during adult li lc, onl y th e
already ex isting mal e characteri stics wi ll be intensi1iccl , and since there is
no comp launt by the patient, the cond ition usually passes unnoticed.

( Ill ) Conn's syndrome (primary hyperaldosteronism)

Th is is due to ovcractivity of the zona glomerulosa as a result of'
tumours, which leads to excessive secretion of the rnincralocort icoids.

Manifestations (symptoms)
1. Na + retention : This is associated with equivalent water retention, so
there will be 110 llypematremia. It results in e.\]Ja11sio11 oftlte ECF volume,
lt.J'{JerwJ!emia and hypertension. llowever. these effects arc moderate am/
n o (or slight) edema occurs because of the phenomenon of aldosterone
escape (page 58). Metabolic alkalosis may develop due to excess H+ sec-
retion in the renal tubules in exchange with the increased a+ reabsorption.
 65

Section 1- Chapter 4 Tile adrenal (mprarena/) cortex

2. K+ depletion : This kads to hypokalemia, which leads to :severe

muscle weakness, renal damage (= !typokalemic nep!tropathy) as well as
many cardiac effects (refer to CVS).

:::_ Treatment of Conn's syndrome can be achieved by surgical remova l

of the causing tumour and administration of aldostertone antagonistic drugs.

I THE ADRENOCORTICAL FUNCTION TESTS I

( I) Measurem ent o.ftlw serum levels of N(/ am/ K, cortisol, DHEA,
aldosterone am/ ACT/I as well as tlte plasma p/1 give good indication
about the functions of the adrenal cortex and nature ol' its disorders.

(2) Determination of tlte steroid metabolites in urine : The common ly

measured metabolite is the 17-ketosteroids. which increase in Cushing's
disease and the adrenogeni tal syndrome. and decrease in Addison's
di sease.

(3) ACTH test : A test dose of ACT! I is injected i. v. and the plasma
corti sol level is measured after one hour. lt increases in norma l subjects
and in cases of secondary and terti ary adrenocortical insufficiency but not
in the primary type (so this test can be used to differentiate between the
primary and the other cau~es of adrenal insufficiency).

(.t) Saline suppression test: An isotonic saJ ine solution is given i. v. for 4
hours at a rate of 400 ml I hour then the plasma level of aldosterone is measured.
It decreases in normal subjects but is not affected in Conn's syndrome (so it is
helpful in the diagnosis of this disease).

(5) Salt deprivation test : A salt-free diet is given lor 3 days then the aCl
content in the urine is measured. Nonnally, the urinary aCl content should be
markedly decreased (and may be absent), but in adrenocortical insu fficicncy
the urinary NaCl excretion is not afTected.
CHAPTER 5

[n!E:AURENAL(SUPRARENAL)MEDULCAJ
The 2 adrenal (or suprarenal) medullae secrete 3 catecholamincs
/adrenaline (or epinep hrine), noradrenaline (or norepinephrine) ami
dopamine I. In addit ion, they also secrete small amounts of upioid peptides
(spcc:ia ll y mt;tenkephalin) and adrenomedullin (a vasodepressor poly-
peptide), the functions of which are unknown.

Histological structure and innervation

The adrenal medullae are mod(fied ·':J'mpathctic gang lia in which the
postganglionic neurons become secretory cell s, and glucocorticoid,· ore
11ecessm:\' .fiJr their normal del'elopment. The secretory cells arc called
chromaffin cells and they arc 2 types : 90 % epinephrine-secreting cells
and I 0 % norepinephrine-secreting cells (the cells that secrete dopaminc arc
unknown). and they arc innervated by sympathetic c:lwliner~-:ic pre~-:rmg/io­
nic neurm1sji·om the greater .\ planclmic nerves.

Catecholamines' concentrations in the plasma

Nonna ll y, about 80 % of the catecho lam ines ou tpu t from the

adrenal medullae is epinephrine wh ilc on~r 20 1!o is f/Orepinephrine.
(hO\\ e\ cr, the Iauer is also added to the blood from the noradrcnt;rgic
sympatheti c ncn cs). Abou t 70% of these hormones arc conjugated in the
blood to sulphate. The normal free plasma norepin ephrine level is about
300 pg/ml. "hilc that of epinephrine is about 30 pg/ml (pg = picogram).
J/2. of the plasma dopamine comes from the adrenal medullae while the
other I/2. comes from the sympathetic ganglia and other componcn\'i of the
au tonomic nervous system (a nd its free plasma level is about 35 pg/rnl).

Mechanism of action of catecholamines

The effects of catecho lamines arc produced through acting on 5 types of

receptors in the effector organs : The alpha l & 2 and beta l, 2 & 3
receptors. At al l beta receptors, the honnones act by increasing the
intracellular cyclic-AMP co ntent. On the other hand, at the alpha 1
receptors. the hormones act by increasing DAG and I P3 (w hich increases
the intrace llular Ca 21 content) \\bi le at the alpha 2 receptors, they act by
decreasillf: the intrace ll ular cyc lic-AM P content (pages g and 9).
Section I - Chapter 5 The adrenal (suprarenal) medulla

Effects (actions) of catecholamines

The adrenal medullae operate with the sympathetic nervous system as

one system (= sympathoadrenal system ). Th is system acts during
emergencies to prepare the individual for tight or night when threatened.
This was call ed by Cannon " the emergency jim ction of the sympatlw-
adrena/ ::,)'stem", and it is produced through exerting widespread effects on
almost all systems of the body as fo ll ows
1. The cardiovascular system
Catccholamincs directly increase the heart rate and myocardial
contractility. However, norepin ephrine a lso prod uces V.C. in most organs,
and this causes marked increase in both the systolic and diastolic B.P.
Accordingly, the arterial baroreccptors arc stimu lated thus leading to reflex
bradycardia, which overcomes the direct effect of the hormone on the hear1,
resulting in decrease of the cardiac outplll.
On the other hand. epinephrine produces V.O. in the skeletal muscles
which overcomes its V.C. effect elsewhere. This decreases the peripheral
resistance (so the diastolic B.P. is not changed or it may slightly decrease). At
the same time, the systolic B.P. is increased (as a result of the direct effect
of the hormone on the heart) and accordingly, the pulse pressure is
increased. However. the mean arterial B.P. increases only slightly and the
baroreceptor mechani sm does not produce bradycard ia, thus under tlte
effect of epinephrine, the cardiac ourput is increased.
2. Skeletal muscles
Catecholamincs (particul arly epinephrine) strengthen skeletal n1usclc
contraction and delay the onset of its fatigue because they (a) Stimulate
glycogenolysis and li po lysis (wbich supply glucose and free fatty acids i.e.
more energy) (b) Produce loca l V.D. in the muscles (which provides more
blood supply).
3. Nervous system
Catccholamines excite the nervous system. and increase the mental
activity and alertness through stimulating the reticular activating system.
4. Respiration
Catecholamincs increase the rate and depth of respiration by (a) Direct
excitation of the rcspinllory centre as a part of their excitatory effect on the
nervous system (b) l'ncrcasing the metabolic rate.
Section I - Chapter 5 Tlte adrenal (mprarena/) medulla
5. Blood glucose level
Catecholamines (~pccially epinephrine) stimulate glycogenolysis
in the li ve r, resu lt ing in ltyperglyc:emia (which may lead to glucosuria ).
f Metabolic rate (calorigenic action)
Catccho lamines increase the mctabol ic rate and 0 1 consumpt ion
(thus increasing heat production). The initial rise in the metabolic rate is
/iver-imlepemielll and may be clue to either (a) The cu taneous V.C. effect
(which decreases heat loss. leading to rise of the body temperature) or (b)
The increase in muscular activity. However. the delayed rise is due to
oxidation of lactate in the liver (since it is abolished after hepatectomy).
7
• Adipose tissue
Catccholamincs mobili;.c free 1~ttty acids (FFAs) from adipose
tissue which leads to in crease of the plasma FFAs level.
8. Smooth muscles
The effects or cnt~.:cholamines nn smooth muscles arc similar to
those produced by sympathetic stimulation (refer to autonomic N.S.).
9. Kidneys
Catecholamines cause oligu ria (= decreased urine 'olumc) due to
V.C. of the renal blood vessels. Such ciTect is beneficial in certain
emergencies e.g. the hypovolemic shock caused by severe hemotThag~.:.
10. Blood
Catccholamines cause co ntraction of th e spl enic caps ule \\ hich
adds about 200 ml blood to the general circulation (thus increasing th e
blood volu me, red cell count. Hb co ntent and hemutocrit value). They
a lso shorten the clottin g time because they stimulate synthesis or fib-
rinogen and prothrombin and increase the activity or clotting factor 5 .
11. Elcccrolyres
Catecholamines cause an initial rise in the plasma K- level (due to K -
release from the liver) followed by its fall (due to K· en tty into the skeletal
muscles. Therefore, catccholamines may play a role in regulating the ratio
hetll'een t!te extracellular ami intracellular/( .
1L Vicion
Catccholamines increase the visual fields by producing pupillo-
di latation. exophtha lmos and widening of the palpebral fissure.
Section I - Chapter 5 The adrenal (mprarena/) medulla

Rol -~ r~t~rhnl~minPc: =~ '""rir· '"' mProPncies

Catecholamines arc essential for an efficient body performance
during various emergencies as shown in the folio'" ing conditions :
1. Muscu lar exercise : They help skcletnl muscles to perform
extrawork through increasing (a) Their blood supply (by increasing the
cardiac output and causing local V.D. in the muscles) (b) The energy
supply (glucose and l~llly acids) (c) The blood O>-)gen content, by
increasing both the blood volume (due to splenic contraction) and
pulmonary ventilation (by producing bronchodilatation).
2. Hemorrhage : They prevent development of hypovolemic
shock through producing (a) V.C. in the cu tan eous and splanchni c
vessels (h) I !cart acceleration (c) lncrcasc ol' the blood volume (d)
Bronchodilatation (\\ hich aids better \Cntilation) (c) Shortening of the
clotting time(\\ hieh helps hemostasis).
3. Hypoglycemia : The) increase the blood glucose level through
stimulating the process of'g(l'Cogeno/ysis in tile liver.
4. Exposure to cold : They help to maintain a constant body
temperature through preventing h efll loss (by causing V.C. in the
cutaneous blood vessels) and increasing the heat production (by tlu:ir
calorigenic action).

:.!: When the adrenal medullary secretion is increased. the ratio l?/
norepinephrine to epim!phrine is generalz\· unclumged.
According!}. there is 110 selectil·e secretion of catecholamim'\
according to the IW/ttre l?/ emergency as sho" n e.g. in case of hemorrhage.
in which epinephrine is still predominantly sccn~ted although norepineph-
rine is more useful because of its potent V.C. effect.
However, it wns found thai more norepinephrine is secreted in
emotional stresses ll'ith ll'hich the indil'idual is /iuniliar. ll'hereas 11/0rC!
epinephrine is sec:n.!ted in c{/.\es in H•hich the! inclil·idual does not knoll'
ll'hat to expect.

Effects of dopamine

The physiologtc functions of the circulating dopamine arc

unknown. However, an injected dose of dopamine produces V.C.
(probably by releasing norepinephrine) except in the mescntery and
kidneys where it produces V.D. {probably by ncting on certain
specific dopamincrgic rcc<.:ptors). Dopamine also exerts
 70

Section I - Chapter 5 The adrenal (mprarena/) medulla

a fve inotropic ej]'ect on tlte !teart so the net ciTcct is an increase in

tlte systolic blood pressure ami no cltange in tlte diastolic blood
pressure. Because of these actions. dopamine can be used in the
treatment of traumatic am/ cardiogenic sltock. Dopamine also
causes natriuresis probably b) inhibiting the renal Na -K ATPasc.

S(.laG! tro n o f the SUPRARENAL MEDULLA is under

;~~n t ro l o f th-;5Ytv1PAfHETIC NER.VOUS SYSTEM
-
/r; rtmrts ot/ \
51 :<ESS f
,.~ ( J.IYPOTIIALA M US
,.• 'R I
, , ... ~ t
__./ Cr:~ntrrz
m
MEDULLA
OBLONGA TA
~
:;qn.:ls ??::: :ls rz s a/ong
S}:m,Ja fhrNtC Nrzrvrz s
( Gr~atrzr Spianch mc )
wh1c h cause
ftbrzratton of A dr~~nalmrz
by ~:..,.~J_rar<Z/Jal Medu!/a,z
tnto
Blood S trea m

Figu re 27: Regulation (control) ofadrenomedullary secretion.

Regulation (control) of adrenomedullary secretion

The secretion or catecholamincs from the adrenal medullae is little
during rest and is further decreased during sleep. It is controlled b) ib
:-.) rnpathetic suppl) and it markedly increases in case. of emergeiiC.:r am/
during tlte alarm response as a part of the diffuse sympathetic activity in
these condi1ions (in order 10 amplify and prolong the sympathclic cffi:cls).
l'he 'asoeonstric10r cenlre (V.C.C.) in lhc medulla oblongala is conm:ctcd
10 1he origin of 1he greater spla nchn ic nerve via the r·cticulospin al tract
 71

Section I - Chapter 5 The adrenal (liuprarenal) m edulla

(li gure 27). When this centre is stimulated. the neural di scharge to the
adrena l medullae increases leading to an increase in catecholamines
secretion and vice versa. The activity of this centre is affected by
impulses discharged from the following sites :
I. The hypoth alamus : This is stimu lated in various emergency
conditions (e.g. hypoglycemia, exposure to cold. stress and emotions). and
subsequently it sends stimu/arm:r signals ro the V.C.C. which lends to
an increase in the secretion of catccholamines.
2. Arterial baroreceptors (in th e ca r oti d sinus & aortic a rch) :
When these receptors are stimul ated (by a rise of the arterial B.P.).
they send inhibitory s ignals to the V .C.C. which leads to a decrease
in 1he secretion of ca techolamines. and vice versa (refer to circu lation).
3. Pe riph eral chemorccept ors (in th e ca rotid and aortic bodi es) :
When these rece ptors arc stimulated (e.g. in cases of hypoxia and
asphyxia). they send stimulatory signal s to the V. C.C. which leads to
an in crease in the secreti on of catccholam incs.
~. Volume rece ptors in the right atrium :
When these receptors arc stimulated (by an increase in th e central
venous pressure). they send inhibitory signal s to the V.C.C. which leads
to a decrease in the secretion or cntceholamines, and vice versa.

Mechanism of release (secretion) of catecho/amines

The sympatlwtic signa ls to the gland lead to release of acetylcholine
at the preganglioni c nerve endings, which causes opening of Ca~· channels
in the membranes or the secreting cells (SO Ca 2; eli ffusc from the ECF into
these cells). In the secretory cells. the hormones arc stored in granules
bound to A TP and a protein ca lled cltromo~::raniu A . and Ca 2+ lead to
ex trusion of the sec retory granul es by exocytosis so that the hormones.
ATP and chrornogranin A arc all rclenscd together into the bloodstream.

Pheochromocytoma
This is a tumour oftlte adrenal medulla. Its main symptom is
sustained ltypertensiou because most tumours secrete excess norepi-
llephrille only or together with lilfle epinephrine. However, some
ttmw urs secrete epinephrine Olt ~r. and in 15 <yo of these cases, the
hormone is secreted episodically producing i11termiflent bouts ofsevere
systolic llyperrensio11. palpitaliolls and headache as 1rell as glucosuria.
CHAPTER 6

HE PARAT YRO!D G DS • •
CALCIUM METABOLISM

In humans, there arc usually 4 parath) roid glands that arc

embedded in the po~tcrior -.url~1cc of the th) roid gland (figure 28). The)
sccn:te a polypeptide hormone (containing 84 amino acids) called the
parathyroid hormone or paratlwrmone (PTH) . The primaty function or
this hormone is regulation of the Ca 2+ concentration in the extracellular
lluid, and for this reason il is csscnlial to life (page 2).
The normal plasma level or PTH is I 0-55 pgl ml and it is inactivated
mamly in the liver b) the Kuplrer cells and to a lesser extent in the kidneys.

Figure 28 : The human parathyroid glands.

I ACTIONS OF THE PARATHORMONE I

The parathonnonc ( PTH ) is a major regulating factor for borh calcium
(Ca' ) a11el inor~anic pho.,l'hare (PO./) concemrations in the boc~r jluick
Norma lly, the plasma J>o..·· concentration is in versely related to the Ca 2'
concentration, so the product of Ca 1... x PO./ i., alll'ays constant (\\ hich
I'> 1-no\\ n as the soluhilit) product). The main full(:tion of PT/1 is to
increase the plasma C nH level ami decrease the plasma PO/ level (so
a., to maintain the so lubility product constant).
 73

Section I - Cllaoter 6 Tile paratlqwoid glands

PARATHOPMONE; d cis o n KIDNE Y TUBU LES, BO'if:. a n d on GUJ. to m ai nta i n

BLOOD CALCIUM l~tv~ l 8t ll mgfiOO ml PLASMA

BO N E~
••

Figure 29 : t\cuon~ of the pnrathnnnone.

(A) Mechamsms o creasing thP l~sma Ca 2 + l~v~l

The P'lll increases the plnsmn Ca~ bel b) .3 mechanism!. (figure 29) :
I. Increasing Caz.t mohili ~:at i on from hones : PTII acts directly on
bone incl"'!:tsing the fom1ntion and ,tcti\ it) of the tH teoclast~ ( bone eati ng
cells) '' hich destro) the bone b) rdeasing II and protease ent) rnes. n:sult-
ing in bone resorption and Ca:!• mobili7ation to the bloodstream.
2. In creas ing CaH reabsorption in th e distal convoluted tubules of
th e kidneys.
3. l ~crc:t'ling nbsorpt ion of Ca 2 fro m th e int estine indinxt ly
through in crca~i ng formation and activity of I, 25- l)ihydroxycholccalcili.:rol (=
OHCC or calcit•;ot). "hich i5 the acti\e metabolite or 'itamin 0 \ (page~ I ).
d:;l 9
1
The PTII decreases the PO 1 plasma level by cxe11ing a plw.\ plwturic
action (i.e. incrca~ing Po,'· excretion in the urin~.:) through inhibiting PO./
reabsorption in tile proximal com •oluted tubules oftlte kidney.\·.
 74

Section I - Chapter 6 The parathyroid glands

Mechanism of action of the parathormone

The PTH acts mai nly through acti vating the adcnylyl cyclase
enzyme and increasing th e cyclic: AMP content in the target cells (page 8).

I Regulation (control) of parathormone secretion 1

The main regulating factor for PTII secretion is the plasma ion ized
calcium (Ca 2) level 'vvhich directly controls the parathyroid glands by a ne-
gative feedback m echanism . When the plasma Ca2+ level is high. the
secret ion of the hormone is inhibited and ca lci um is depos ited in bones. On
the other hand, when the plasma Ca2 ' is low. the sec ret ion of the hormone is
increased and calcium is mobilized from bones. Mg2+ generally exerts
Mi.,.
similar cfTccts as Ca2.... In addition. is required to maintain normal para-
lhyroid secretory responses. and this explains why hypocalcemia may occur in
Mg:!- deficiency. PTH secretion is also affected by the following factors :
1. Ca lcitriol: Its increase inhibits PTH secreti on (page 83) and vice versa
2. J> lasma PO/· leve l : Its in crease s timulates PTH secre ti on by low-
21
ering the plasma Ca level and inhibiting formation ofcalc itriol (page 82).
3. Nervous facto rs : PTH is increased by beta-receptor stimulating drugs.

I HYPOPARATHYROIDISM I
In man, hypoparathyroidism occurs when at least 3 parathyroid glands
arc damaged. This may occur as a result of autoimmunity or accidently
during thyroid surgery. It leads to h ~ poc:tkc m ia i.e. reduction of' th.e
plasma Ca 2• level (normal value 9 - 11 mg %) and h~pcq>hll.,phatcnua
i.e. increase of the plasma Po} · lcvt::l (norma l value 2.5- 4.5 mg %).
_ Pseudohypoparathyroldrsm :Signs of the disease may occur
with normal or elevated plasma levels of PTII. These cases arc call ed
pseudo-hypoparathyroidism and are due to unresponsiveness or the tissues
to the hormone as a result or congen ital receptor disorders.
Hypocalcemia occurs as a result of depression of the osteoclastic
activity and bone resorption as well as decrea ed formation or I ,25- DIICC
and reabsorption of Ca~· in the distal tubules or the kidneys. It cause
numbness and tingling sensations. muscle weakness, cardiac arrhythmias and
GIT disorders. It also increases the excilabiliZI' o./ lhe nervous system and the
neuromuscularjunclions leading to tNarn which is the m ain character-
istic feature of hypoparat!tymidism .
 75

Section I - Chapter 6 Tile paratflt,roid glands

Definition of tetany
Tetany is a state of spastic contraction of the skeletal mu scles
due to a n increase in the neuromu scular exc it abilit y that occu rs as n
1
resu lt of a decrease in the ionized plasma Ca · level.

Causes of tetany

The causes of tctan) arc those that cause hypocalcemia. the most
important of'' hich include the following :
(l) ll ypoparathyroidism (see above).
(2) Rena l failure (due to decreased formation of 1.25-01-ICC as well ns
ca lcium reabsorption in the distal convoluted tubules).
(3) Alkalemia (which promotes precipitation of calcium phosphate. so
the plasma ioni;;ed Ca:! lc\ el is decreased).
(-t) Vi tamin D deficiency (decreases Ca~- absorption from the inte. tine).
(5) Low calcium content in the diet. or diets that combine with ca lcium
and form unabsorbable ca lcium compounds.
(6) Steatorrhea(= fatty diarrhea). which decreases calcium absorption.

Types and manifestations (symptoms) of tetany

Depending on the plasma Ca2.. level, there arc 2 main types of tetany
(A) Manifest tetany

This occurs when the plasma Ca2 + lel•t!l drops below - m,r: 0 o.
There is stiffness of the skeletal muscles intem~pted by attacks of spa modic
contractions caused by spontaneous discharge of action potentials at th e
motor end plates. In the hands and feet. a characteristic pnttcrn of spasm
known as carpopedal spasm may occur. In th e cm·pn l spasm (figure 30).
the hands adopt the obstetric position ( = accouclu.'/11' hand). in which the
"ri!>t and metacarpophalangeal joints are fle~cd while the interphalangeal
joints are extended and the thumb is adducted into the palm. In the pedal
spasm, the feet and toes arc plantar flexed (but the ankle joints may be
dorsincxed). In severe conditions. generalized convu lsions may occur.
Spasmod ic contraction or the laryngeal musc les leads to respira-
tory distress and cyanosis. nnd if severe or prolonged. the glottis may be
completely closed leading ro death as a rcsulr of asphyxia (a condition called
lriiJ'II!feal stritlor).
 76

Section I - Chapter 6 The parath!lroitl glands

Figure 30: The obstetric hand( - accoucheur hand) seen in manifl:st tetnny.

(B) Latent tetany

This occurs when the drop in the plasma Ca 1+ level does n ot reach
7 mg %. Tetany appears only in conditions that increase the neuromuscular
exci tab ility e.g. emot ions, hyperventilation (due to the tendency to develop
alkalos is}, prcgnam:y and lactation. It can be diagnosed hy m easuring the
ioni:ed plasma Ca 2+ level or by the folio\\ ing tests( = pro vocation tests) :
(I) I rous\t :w •, tc't : The cuff of a ~phygmo n1 anometer is wrapped
around the arm and the pressure is rai sed above th e systolic B.P. fo r 3
minutes (to occlude the circulati on). In case or latent tetany, carpal spasm
appears because the \.!!Teets of hypocalcemia arc potent iated by ischemia.
(2) ( h' "'' ·I ' tl '' : Tnpping over the facial ncn c (by a hammer )
in fro nt of the car (at the angle of the ja'') causes quick comractions of the
ipsilateral facial muscles specia ll y those or the upper lip.
(3) l.rb 's tt· ~o,t : Stimulation of a superfi cial motor nerve by a
weak Ga lva nic current which normally produces no effect, causes a prolon-
ged spasmodic contraction or the muscles supplied by the stimulatl!d nerve.

Treatment of tet"'ny
l. lntr~\\ cnousinjection or a soluble calcium sa lt (e.g. calcium gluconnte or
chloride) during the cu:w e allacks.
2. Giving diets rich in ca l<.:ium and vitamin D (and vitam in D by injection).
3. Diltydrotacltysterol (= A. T. I 0) : This is a synthetic steroid which pro-
duces similar effec ts us PTII. However. it is preferred bccausl! no anti-
bodies arc form ed against it (the naturo!/JTf l is not used because it
leads to formation<~( antihormones. and in addition, it acts )or a
shorter durarion and is much more expensh·e) .
 77

Section I - Chapter 6 Th e parathvroid glands

I HYPERPARATHYROIDISM I
This condition occurs primarily as a result of parathyroid tumours.
and is associated with excessive bone res orption that leave multiple cysts
in the bones (so the condition is also called osteitis f ibrosa cystica).
Accordingly, bones become weak and liab le to sJumtan eous .fractures
21
(which may be the presenting symptom). The excessive Ca mobilization
to the bloodstream leads to 1 ( l'Lr: I '111 which causes the following
1. Depression of the neuromuscular cxcitabiliry which causes m uscle
weakness, decrease of th e muscle lon e (= jlaccidiry) and constipation .
2
2. Hypcrcalcurin in spite of the increased Ca reabsorption by the eff-
+

2
ect of PTII (bccausL: of the excessive Ca +- filtration in the rena l glomeru li).
This leads to (a) Polyuria and polydipsia (b) Recurrent formation of
t·cnal ston es (which IIW)' also be the presenting .\:wnptom) (c) Nephro-
calcinosis that may tenninate by renal failure.
J. In severe cases. metastatic calcification may occur in other tissues
e.g. the cornea, lungs and arterial wa lls(= parath yroid poisoning).
4. Card iac arrhythmias.

" * Seconddry hyperpatathyroidism : In cases assoc iated

with chronic decrease of the plasma Ca 2+ level (e.g. rickets and chronic
renal disease) there is feedback stimulation of the parathyroid glands
resulting in compen.\·at01:1' parathyroid hypertrophy which is known as
secondary hyperparathyroidism.

The parathyroid hormone related protein (PTHrP)

A protein with PTH activity is produced by many tissues e.g. the

breasts (and is discharged with milk ), smooth muscle , brain and teeth
(where it is important for reeth eruption). It is fomted of 1-10 amino acids.
and is ca lled parathyroid horm on e related protein (PTIIrP). It is a tissue
factor that acts where it is produced. lt stimu lates growth (~{cartilage in the
fetus and is also involved in Ca!+ transporl in the placema.
'!:..::.. f (vpercalcemia is commonly present in cancer patients. About 80
% of these patients have elevated blood levels of PTHrP secreted by the
tumour (specially cancers of the breast, kidney, ovary and skin). In the
remaining 20% of cases, the hypercalcemia is due to erosion or bones by
mctastascs of the tumour, probably by certain prostaglandin s (s uch as
PGE) that are re leased from the tumour ce ll s.
 7X

Section I - Cltapter 6 Calcium metabolism

I CALCIUM METABOLISM

Ca lcium is an essential element and its chi ef sources arc milk

'
cheese, eggs and green vegetables. It is absorbed in the sma ll intestine
mainly by an active process , and its absorpt ion is stimul ated by I ,25-
DI ICC (= calcitriol. page 8 1) and undergoes adaptation (i.e. it is
increased when the calcium intake is low and decreased "hen the
calcium intake is high) also secondary to changes in 1,25-DHCC
plasma level (page 82). Calciw11 pcrfom1s the following functions :
J. It maintains the nonnal excitability c~/nerves am/muscles.
2. It is important in neuromusc11lar trcmsmission.
3. ll is essentia l for IIJuscle contraction.
4. It is a second messenger in many hormonal actions (page 8).
5. It maintains normal pem1eability of eel/membranes and capillaries.
6. It is essential for acrimrion ofmcmy en=_ymes.
7. It is essential for thc.formation ofnormal bones amlreeth.
H. It is essential for IJ/oud coagulation.
9. It is essentialjhr the release f?/lllostneurotransmilfers.

CALCIUM HOMEOSTASIS AND TURNOVER

In normal adult individuals. tlte dai~l' calcium requirement is about

600 mg. However, the intestine receives about 1500 mg of calcium dai~l'
(I 000 mg from diet and 500 mg fi·om the digest ive juices), 900 mg of wh ich
arc lost in the feces and GOO mg are absorbed, wi th a net ga in or I 00 mg.
These enter the calcium pool in the plasma and ECF which is in a continu-
ous turnover (i.e. constantly exchanging) in (a) The intestine (where
calcium is secreted then reabsorbed) (b) The kidneys (where calcium is
filtered then reabsorbed) (c) The intracellular fluid (d) The bones.
Normal calcium balance is maintained largely by calcium excretion in
thc f eces ami urine. Fecal excretion is about 900 mg dail y (sec above). On
the other hand, the kidneys filter about 10 gm calcium daily, or wh ich 99 %
is reabsorbed while I 1Vo (100 mg) is excreted in the urine. In this way, the
daily calcium intake and output are eq ual (about I 000 mg each).

CALCIUM CONTENT AND DISTRIBUTION IN THE BODY

The adu lt human body contains about 1100 gm of calciu m , 99 % or

which is present in the bones (skeleton) wh ile the rema ining part is present
in the intracellular and extracellular fluids.
 79

Section I - Chapter 6 Calcium m etabolism

Calcium in the plasma

Th!! normal plasma calcium level averages 10 mg ryo (range 9- 1I mg
%). It is present in the fo llowing fonns :
(1) Nondiffusible (bound to albumin and globulin, specia ll y albumin).
This is about 4.5 mg% and is biologically inactive.
(2) Diffusible : This is about 5.5 mg% and is 2 types :
a. N on -ioni:;ed (form ing complexes with bicarbona te and citrate). It
is about 0.5 mg %.
b. !oni-;.ed (Ca1+) : This is about 5 mg %. It is the hiologically acth•e
f raction that is necessary for most of the fu nctions of calc ium and
therefore, it is under strict control to be maintained constant.
.:.:..:: Most methods used for estimating the plasma cal cium level measure
the totaltJiasma calcium level and not the biologically nctive ionized plasma
Ca:!' level, because measurement of the latter alone is difficult (but it can
sti ll be done by usc of a ca lcium-sensitive electrode). These me thods would
give fa lse eva luati on of the plasma Ca2- level because the amount of ca lcium
bound to the plasma proteins vari es proporti onately with the leve l of these
proteins. Since calcium is bound mostly to albumi n, it is necessary when
evaluating the plasma Ca2 ' level to m easure the plasma a/humin level also
then correcting the result accordinK to this level.

Calcium in the bones

Bones contain about 1000 gm of calcium, which is 2 types:
I. 99.5 °/c, is present as sta ble salts that arc l"el)' sl011"~1' exclwllg-
eoble \l'ith the plasma calcium.
2. 0.5% (about 5 gm) is readi~)' excltangeable. It constitutes n rcsen'-
oir that is in equi librium with the plasma calc ium and keeps it constant at 7
mg % in absence of the PTH (!Ire main regulator q(calcium/wmeostasi.s ).

PHOSPHORUS
This is an importa nt constituent in many vi tal substances e.g. 1\ TP,
cAMP. 2,3-D PG and others. In additi on, protein phosphorylation is essential
for honnonal action (chapter I). The body contains 500-800 gm most of
which is in the bones. main ly as hydroxyapatitcs. The total plasma
phosphorus is about 12 mg % , one third of which (average 4 mg %) is in
the inorganic forms : POo~ J., HPO/· a nd H2 PO~-.
Inorganic phosphate is absorbed in the duodenum and small intestine t111cl
like calcium is stimulated by 1,25 Dl-ICC (but un like calcium, it undergoes
n o adaptation). It is fi ltered in the renal glomerul i then reabsorbed in the
prox imal convo luted tubul es (but this is powe1jr tl~v inhihitecl by the PT!f) .
 80

Section I - Chapter 6 Calcium m etabolism

I HORMONAL CONTROL OF CALCIUM METABOLIS~

3 main hormon es affect calcium metabo li sm. These hormones may be
called calcitropic hormones, and include • l , c.tldl lllin and' il. mi 1 >.
In addition, certai n other hormones also play a role. PTII has already been
discussed and th e role or the other hormones is di scussed below.

I CALCITONIN I
This is a l'alcium-lowcring poh JH'ptilk hormnn(' (containing 32
amino acids) that is secreted by the parafolli cular cell s of the thyroid
gla nd (so it is also called thyrocalcitonin). It was also found in certain other
tissues (so total thyroidectomy docs not reduce the calcitonin circulating level to
zero). The actions of ca lcitonin are mediated by stimulating the adenylyl cydase
enzyme and increasing the intracellular content of cyclic AMP (page 8).

Regul tion (control) of c., lei onin secrttion

Ca lcitonin secretion is regulated by the following factors :
21
1. Plasma CaH level : Calcitonin is secreted when the plasma Ca
level exceeds 9.5 mg (Yt1.
2. Gastr ointest inal hormon es : Several GIT hormones (e.g. gastrin,
secretin, and CCK) stimulate secretion of calcitonin.
3. Ca lcitonin secretion is also stimulated by dopamine,. beta adrenergic
stimulating drugs and estrogens.
Ac io s OT c ci .lr ir
Ca lcitonin decreases the plasma Ca 2• level through acting on the bones
and kidneys where it exerts the following efTccts :
1. Bones : Ca lci tonin inhibits bone reso11Jtion by reducing the acth·ity
of the osteoclasis (thus it helps Ca~ deposition in bones).
2. Kidneys: Ca lcitonin increases the urimuy excretion ofCa2• by inhibit-
ing its reabsoq Jtion ji·o/JI the rena/tubules.
Importance of ... , lctlonin
l . lts release followin g meals (by the gastrin hom1one) helps prel'ention of
postprandial hypercalcemia.
2. Its plasma level increases during pregnane:!' and in lactating ~mmen. This
protects the mothds bones from excessive loss of calcium.
3. Its plasma level is more in children than in adults. which helps bone
grow th and dcvclopmenr of the skeleton.
4. lt is used in the trcattnent of a serious bone disease called Paget's disease
which is characterized by excessive osteoclastic activity.
 HI

Section I - Clwpter 6 Culcimn metabolism

VITAMIN D

The term "vitamin D'' refers to a group of sterols that arc formed by the
action of ultraviolet rays on certain provitamins. Vita min 0 3 (= chole-
calciferol) is important in man because its provitamin is 7-dchydro-
cholcsterol, and this is present in the skin of man (so vitamin D3 is some-
times called I he skin hormo ne). Vitamin 0 3 is one of the fa r-soluble vil a-
mim that is also naturally present in certain foods specially fish li\'cr oils.
Whether ingested in diet or fom1cd in the skin by the action of sun-
light on ?-dehydrocholesterol. vitamin D3 is not active by itself. It is trans-
ported in the plasma bound to a spcci fie globulin ca lled l'itamin D binding
protein (DBP) and is activated as follows (figure 31) :
(I) In the liver, vitamin D:l is converted by activity or the 25 - hydroxy-
lase enzyme to anoth er inactive metabolite called 25-hydro.\y-
cholccalci lcrol (= 25-IICC or cakidinl ).
(2) In the pro xima l convoluted tubules of the kidneys, calcidiol is
converted by activity of the I a/pita hydroxylase en zyme to the active
metabolite I ,25-clihyclroxycholcealciferol (= 1,25-DIH '('or calcitrinl ) and
ihc latter enters the blood (in which the ca lcitriol level is about 0.03 ngm/
ml). Since ca lcitrio l is transported by the bloodstream from th\! kidneys to
distant target organs (the intestine, bone and teeth), it is co nsid ered to he a
steroid hormone (and similar to these hormones, it also acts on intracel lular
receptors that induce transcription of mR J\).

Sunligh l

7 Odlydrocholultrol---....~--- Pre-itamon o, - - - - -- Vot.tmin O,

(chol..:.l~olttoll
SKIN

LIVER ~25 Hydroxylase)

Other
mtt~bololll - -- - 25 llydroxycholtcaltolcool

24 ,25 ·0ohydroxycholculcoferol

Figure 3 1: Activa tion ofvitam in 0 3 to 1,25 dihydroxycholccalcifcrol.

ACTIONS Or CALCITRIOL {1 ,25 DHCC)
21
l. It increases Cu (and PO}-) absorption rrom lhc intesti ne by (a)
Stimul ating synthesis of a protein called calbindin-D that l~1cilitalea Ca 2 '
transpor1 across the intestinal epithelium (b) Increasing the Ca2' - f-t ATPasc
in the intestinal cel ls which is needed to pump Ca 2 ~ into the ECf.
 82

Section I - Chapter 6 Calcium metabolism

2. It faci litates Ca2t reabsorption in the dista l tubu les of the kidneys.
3. It is necessary for the development of bone (by increasing activity of
the ostoblasts), as well as the calcification of bone matrix. However, in higlt
concentrations, it mobilizes Ca2+ and PO/ · .fi'om bone (by second{uy
increase in tile activity ofosteoclasts) .
4. It stimulates ditTcrentiation of the immune cell s (the lymphocytes)
which helps production of appropriate immune responses. For this reason,
vitamin D deficiency increases the incidence of infections.
5. Jt stimulates differentiation of keratinocytes in the skin. So vitamin D
is useful in the treatment of certain skin diseases.
6. It may be involved in growth regulation & production of growth factors.

PTH..._ - - - - - --Co 2 ~

25·0HD3
~
C::.~
!
. ., f. ---TT:._..__ ___./
,,.
1.25·{0Hl 2D 3 ~ and
ontestme

I
\ _ - - - - - - - - P 0 43 -

Figure 32 : Control of calcitriol synthesis. Dashed arrows arc inhibitory.

REGULATION (CONTROL) OF CALCITRIOL SYNTHESIS

The acti vity of 1 alpha Hydroxyla se enzyme (I alpha H) is the

main factor in the regu lati on of calcitriol synthes is. Factors that stimulate
thi s enzyme increase ca leitriol synthes is, and vice versa. These facto rs
include the follow ing (figure 32) :
1. PTH : Thi s stimulates the ( I alpha H) thus increasing calcitriol synthesis.
2
2. Plasma Ca 2+ level : When the plasma Ca + level is high, the secretion of
PTH decreases and little calcitri ol is synthesized. The opposite occurs when
the plasma Ca21 level is low. In the form er condition, the kidneys fo rm the
relatively inactive merabolite 24,25 DHCC instead ofcalcirriol. Th e adapta-
tion of intestinal calcium absorption (page 78) occurs by this mechanism.
3. Plasma PO.t level : As in case ofplasma Ca2+ , calcitriol synthesis is
stimu lated by a low and inhi bited by a high plasma PO.. 3 - leve l (but by a
direct e.ffect on the activity (~/the I alpha H in rhis case).
-t Hormones : Prolactin, ca lcitonin , hCS and growth hormone stimulate
ca lcitriol synthes is. Estrogen increases the total circulating <.:a lcitriollcvc l
probably due to increasing the amount of its binding protein.
5. Metabolic acidosis : This depresses calcitriol synthesis .
6. Hyperth yroidism decreases calcitriol synthesis (due to hypercalcem ia).
 ))3

Section 1 - Chapter 6 Calcium metabolism

7. T he calcitriol plnsma level : Its excess ive increase leads to (a) Feed-
back inhibition of the (I alpha II ) as well as inhibition of PTII secretion
(page 74) (b) S£imulation of formation of the relatively inactivt:: metaboli£e
24,25-DHCC (figure 32).
HYPOVITAMINOSIS D :This decreases intestinal calcium absorption
resulting in hypocalcemia. The latter leads to excessive secreti on or PTH
which increases the blood Ca 2 level, but it also causes bone deminer-
alization. This results in rickets in children, and osteoma lacia in adults.
Rickets is characterized by soft bones (which are easi ly bent leading
to bone deformities) and dental caries (and tetany when the calcium
stores arc exhausted). It occu rs due to either (a) Deficient intake of
vitam in 0 3 in the diet or absorption in the intestine e.g. in cases or obstrud ive
jaundi ce (b) Inadequate exposure to sun light (c) Severe re1wl disease (=
renal rickets) in 1vhich the kidneys foil to produce 1. 25-D/-/CC (d)
Congenital de.flcienc:l' of the 1-alpha hydrwylase en:::y me ( ~J'fJC! I vitam in D
resistant rickets) (e) Congenital defect in the target cell receptors that bind
1.25- DHCC (O'Pe ll viwmi11 D resista/11 rickets ).
On the other hand, osteomalacia is less sel'ere than rickets, and it
common ly occurs in women during pregnn ncy or lactation. It dirTers from
os teopo rosis or ostcopenia. In the latter conditions, the prote in matrix of
bones is deficient leading to bone thinning, while in osteomalacia the protein
matrix is normal but poorly calcified.
HYPERVITAMINOSIS D :This produces effects resembling those of hyper-
puruthyroidism although PTH secretion is inhibited.The osteoclastic activity
increases leading to bone resorption and osteoporosis. Plasma Ca~ and PO/
levels increase. leading to polyuria & polydipsia (due to excessive excretion
in urine) and deposition of calcium salts in so n tissues e.g. the lungs. blood
vesse ls and kidneys (so rena l failure and hypertension commonl y occur) .
Other hormones that affect calcium metabolism
I. Cl ucoco rticoids lower the plasma C:a~~ lc,•cl b) inhibiting
formation & activity or ostcoclasts and cxcning anti-vitamin D actions. I low-
ever, prolonged adm inistrntion stimulates the ostcoc lasts causing osteoporosis.
2 Growth ho r mon e increases Ca1 • excretion in the urine and Ca 2-
absorption from the intestine. ll owever, the latter effect predominates lead-
ing to an increase in the plasma Ca 2+ level.
21
3. T hvroid hormones increase Ca mobi lizat ion !"rom bone. So
their excess inc~cascs the plasma Ca :l• level and may cause osteoporosis.
4. Estrogens hl.!lp bone developme nt by stimulating ostcoblasts and
inhibiting osteoclasis (indirectly through stimu lating secretion or calcitonin).
5. Insulin stimulates bone gro,Hh b) its anabolic effect (sec chapter 7).
 84

CHAPTER 7

ENDOCRINE FUNCTIONS OF THE PANCREAS

(THE ISLETS OF LANGERHANS)

The pancreas is a glnnd that consists of 2 di ffcrcnt types or tissues :

(A) Th e pancreatic acini : These arc exocrine glands that secrete the
pancreatic juice into the small intestine (refer to digestion).
(B) The islets of Langerhans : These are 1-2 million in number and
arc endocrine glands that make up 1-2 % of the pancreatic mass. They
arc more plentifu l in the tail of pancreas and receive both sympathetic and
vaga l nerve supply. They contain the following 4 types or cell s (figure 33):
I. A (a lpha) ce lls (20 %) : These secrete tlw glu cagon hormone.
2. B (beta) cells (60-75 %) : These secrete the insulin hormon e.
3. D (delta) cells (8 %) : These secrete so matostatin.
4. F cells : These secrete the pancreatic po lypeptide (PP).

hlol o f l,Jtngs ham

Delta
cell

ell't c ,.

Figure 33 : llistological structure of the pancreas.

I INSULIN I
Insulin is a ~fucose-lowering po~J'peptide h ormon e. its mole-
cular "eight is 580R and its molecule consists of 2 chains of amino
acids (A and 8) linked by 2 disulphide bridges (figure 34). The A chain
contains 21 amino acids while the B chain contains 30 amino acids. It is
synthcsi%ed in the endoplasmic reticulum of the B cells from a large
proins ulin molecule which consists of 3 parts (the A and B chn ins, and a
connecting peptide called C peptide which contnins 3 I amino acids).
 Section 1- Chapter 7 Endocri11e {im ctio11s o(tlle pancreas

Before secretion, proinsulin is changed to in~ulin by acti\ it) of

certain converting cn7ymes, which separate the C peptidcs, and both
insulin as well as the C pcptides normally enter the bloodstream (for this
n.:ason. measuremem of the C peptide plasma fe,·el is usefid as an index
./(Jr the 8 cell jimctio11 in patients receil•ing ewgc.'IIOII\ ill'iulin).
The half-life of insulin in the circulation is 5 minutes. and alter bind-
ing to its receptors and performing its l'uncttons. the 111sulin-rcccptor
comple\es aggregate into patcht.:s that arc taken into the cell by endocytosis
(a process called internaliza tion ). In the lysosomcs, insulin is destroyed by
protease enzymes \\'hilc the receptors are broken do" nor recycled.

En.topbvmc netoculum

Secret<on Gro nul~

Figure 34 : Synthesis of insulin from proinsulin.

Mechanism of action of insulin (the insulin receptorc)

Th.: tnsulin receptors arc complc\ proteins (each ha\ tng molecular
\\eight about 340000) that arc present in the membranes oftlte target cells.
l:.ach is made up of 2 alpha and 2 bcra gl) coprotcin subunits. The alpha
subunits arc cxtraccllular and bind insulin. \\'hilc the beta subunits span
O\ cr the cel l membrane and thetr imraccllular porttons ha\ e t ) r os in e
kinase activit y (page 6). Binding nf insulin tri ggers the tyrosine kinase
activity resul ting in au tophosphory lation of the beta subunits and th is
lea ds to phos phorylation or some cytop lasmic proteins and dcphosphoryl-
ntio n or oth ers, which prod uce the va rious effects or in su lin (sec be low).
Section 1- Chapter 7 Endocrine (unctions o(the pancreas
Glucose transport across cell membranes
The glucose transporters (GLUTs)

Glucose enters the cells by facilitated diffusion i.e. a carrier protein

(now called glucose transporter or GLUD mon!s glucose down its conc-
entration gradient from the ECF into the c<.:lls 11'ithout need to energl'. These
GLUTs arc d(Uerelll .fi'mn 1he soditmt-depemlent xlucose Jr(msporter.\
(SGLTs I and 2) that arc r<.:sponsiblc for glucose entrance from the intes-
tinnl and renal tubular fluids into their cells by secondary active transport.
7 types of GLUTs were discovered and were numbered from I to 7.
The GLUT 4 is the only one that is stimulated by insulin, and is kept in
vesicles in the cytoplasm of insulin sensitive cells (see be/o n~. The other
GLUTs are present everywhere in the body but they nrc insulin-indepen-
dent. The liver cells contain GLUTs 2 and 7. GI.UT 2 is also presem in the
8 cells ofThe pancreatic islet.\, as ll'ell a.\ in the inteHinal and renal wbular
cells. H·here i1 1ranspons glucose owsicle these cells to the ECF (refer 10
glucose absmyJiion in the GIT and kidney).

ACTIONS (EFFECTS) OF INSULIN

Insulin is the main h) poglyccmic horm one in the body. It also
affects the serum K• level and is an anabolic hormo ne that promotes
growth by increasing the storage of glycogen, fat and protein (so it is also
called the hormone ofabumlan ce).
(1) Effects on carbohydr "'tc metabolism :
Insulin decreases the blood glucose level by the following mechanisms :
n. Enhancing facilitated diffu sion of glucose into the cells of the
insulin-sensitive tissues (which are rich in GLUT 4). These tissues include
all t)'lJC.'S of muscles, adipose tissue. hone. skin and other/issues (e.g. mam-
mw:l' glands) . Binding of in sulin to its r<.:c<.:ptors in these tissues moves tlw
GLUT 4-containing vesic les to th<.: cell membranes. so the number of these
transponers increases. "hich t~n ours glucose diffusion into the cells.
b. Enhancing glucose entry into the liver cells. Insulin stimulates the
glucokinase ew:;yme which catalyLes glucose phosphorylation to glucose-6-
phosphate. Accordingly. the intracellular free glucose concentration is decr-
eased. This helps glucose diffusion imo the Ji,cr cells aided by GLUT 2.
c. In creasing glycoge n sy nth esis in the musc les und li ver by acti\-
<Hing the glycogen synthase cn1.yme & inhibiting the phosph01ylase enzyme.
d. Decreasing glucose output from the liver by increasing glyco-
Section 1- Chapter 7 Endocrine (unctions o(llte pancreas

genesis and inhibiting bot h gluconeogenesis and glycogenolysis (by inhibit-

in~ the gluconeogen ic and the glucose-6-phosphatasc enzymes).
(2) Effects on fat metabolism :
a. In sulin stimulates lipogenesis in tlte liver & adipose tissue
as follows : Under the effect of in su lin. the excess gluco:.e in the li' er
undergoes glycolysis and is transformed into fall) acids. "hich arc
released into the circulatton as lipoproteins. In the adipose tissue.
in:.ulin actimtes the lipoprotein lipase en=yme which releases fall) acids
from the lipoproteins. These acids enter the fat cells (adipocytcs) where
they arc cstrified with glycerol phosphate (which is formed as a result of
metabolism of the glucose that enters the fat cells by the effect of
in sulin) forming triglycericks which arc stored.
h. Insu lin prevent.\' lipolysis in tlte fa t cells by inhibiting the
illlracellular lwrmone-.wmitil·e lipase en=.\'IIU! .
c. Insulin decreases ketogenesis in tlte lil•er and increase:. the uptake
of ketone bodies by the skeletal muscles.
(3) Effects on protein metabolism :
Insulin exerts an anabolic effect by in creasi ng th e prote in
co nt ent in the musc les and liver through the fqllowi ng effects :
a. Insulin increases the uptake (transport) of amino acids into the
muscle cells and the synthesis of proteins in the ribosomes. It also decrea-
ses protein catabolism and the release of gluconeogenic amino acids.
h. ln-.ulin increases protein ~)nthesis in the li,er as a result of suppre-
ssion of gluconeogenesis.
** Insu lin prO\ ides an adequate suppl) of intracellular glucose
a\ ailable for oxidation and production of energy. In this "ay, fats are
stored in considerable a mounts a nd proteins a rc spa red to promote
growth (=sparing action of in sulin ).

(4) Effect on growth ·

Because of its protein anabolic effect. insulin(\\ ith the gro" th horm-
one) is essential for normal cellular growth (page 22).
(5) Effect on plasma KT level :
Insulin decreases the plasma K+ level by increasing ~ entry into
tlte cells of musc:les ami adipose tissue through actil'flling tlte Na ' -
K' ATPase en zym e. For this reason, high doses of insulin (e.g. for treat-
ment or diabetic ketoacidosis) may lead to hypoka lem ia. On the other
hand, insu lin is helpful in treating cases of hyperka lemia.
 xs

Sectio n 1- Chapter 7 Endocrine {unctions o{tlte pancrea.,

rht.: principa l ac ti ons of insulin in va ri ous tissues arc as fol lows :

(A ) In mu scles : ( I) lm:rcas ing glucose entry, upta ke or amino ac ids. K' &
kctorH.: bod ies, gly<.:ogcncs is and prote in synthes is (2) Decreasing protei n
catabolism as well as the release of gluconeogcnic amino acids.
(B) In th e li\'c r : (I) Decreasing both glucose output and ketogenesis (2)
Incr~a-;rng glycogenesis and protein and lipid S) nthC'>I'> (lipoproteins).
(C) In adipo'lc t i'l~ u c : ( I) Increasing glucose entr) . K uptake. l~llt) acrd
& gl) c.:erol phosphate s) nthesis. and triglycemlc deposit ron (i.e. incr~a ... ~d
lipogcncsrs) (2) Acm ation of the lipoprotein hpa'>l.! l.!ll/}me (3) lnhrbiuon
ofthc hormone sensiti\e lipase enzyme.
~ The most rapid actions arc the increase in th<.: transport of glucose,
amino acids and K into thl! <.:el ls. while li pogenesis is a delayed effect.
~ 'I he nom1a l H1sting plasma insulin level is 0-70 microU nits/ml, and the
amount secreted in a normal human is about-tO Units/day.
~ The secretion of insulin increases by factors that increase cyc:lic AMP
1
111 the 13 cel ls. probabl} b) increasing the intracellular Ca content.

Figure 35 : Mc<.:hanism of insulin secretion from the pancreatic islet 13 cl!!ls.

h.~~;;;~UiaLIUrl \\;Ufl{, ...,.) ..,, ,,..,.ul,, ..,."',..., ..... I ......
(A) F--~ rr- '11"'' r-ljtJJ(JJ-~-. i'1Cfl/i" corr~tion

I. Glu cose : ll yperglyccmia stimulates insulin sccretion as f'ollo" s :

(a) Gluc.:osc enters the B cells helped by GLUT 2 (b) Glucose is
mctaboli/Cd, gcncrating . JTP by oxidati' e phosphor) lation (c) ATP
closes thc t\ '1P-scnsiLiH.: K channels. \\ hich n.:duccs K efflux (d) nus
dcpolari/cs the B cells. '' hich activates (opcns) 'oltagc-galcd Ca '
channels (c) This causcs Ca ~ in nux from thc I:CF, "hich causes insulm
secretion by t.:xocytosis or the secreto ry granules (ligurc 35).
 X9

Section 1- Chapter 7 Endocrine {imctions o{the pancreas

2. Amino acid s : Certain amino acids (e.g. arg inine and leucine)
stimu late insulin secretion like glucose i.e. by generating ATP when
metabolized (sec above). In addition, arginine is the precursor of N O.
which also stimulates insu lin secretion.
3. K etone bodi es : The beta keto acids (e.g. acetoacetic ac id) also sti-
mulate insulin secretion like glucose(by generating ATP when metabolized).
4. Parasympathetic stimulation : Stimulation of the right vagus nerve
(which innervates the pancreatic islets) increases insulin secretion through
releasing acetylcholine whi ch nets by stimu lat ing certain muscarinic recep-
tors (M4 ) at the 8 cells.
5. G.I.T. horm ones : Many GIT hormones stimulate insulin secretion
e.g. secretin. gastrin. CCK and GIP (gastri c inhibit ory peptide). The latter
(Gl P) is the most po.velf ul, and it seems that its main .function is stim-
ulation of imwlin secretion and not inhibition of the g astric activities.
~ Recenf~l'. a more pOII'el[ul insulinorropic gut .facror than GlP was
identified. It was found to be a glucagon-like polypeptide (G LP). There arc
receptors for both GfP and GLP on the 8 cells, and both act by increasi ng the
21
Ca innux into these ce ll s via voltage-gated Ca2' channels.
6. Glucagon : This hormone stimu lates insulin secretion by increasing
the cyclic AMP in the 8 cell s, and also by caus ing hyperglycem ia.
7. Drugs : The sulphonylurca group of drugs stimulate insulin secretion
by the same mechanism of glucose i.e. by inducing ATP fonnation in the 8
cells (sec above). Other drugs that stimulate insulin secretion act by increas-
ing the cyclic AMP in the 8 cells e.g. the beta-adrenergic stimu lating
dru gs and theophylline (the latter inhibits the phosphodiesterase enzyme. thus
preserving cAM P).
(B) Factors that inhibit insulin secretion
I. Som a tostatin.
2. K+ dep letion. so conditions of hypokalemia (e.g. due to Conn's
syndrome or prolonged use ofthia/ide diu~tics) decn.--asc glucose tolc.::mnce.
3. 2-deoxyglu cose a nd ma nnohcptu lose : These substances prevent
glucose metabolism in tbe B ce lls, leading to inhibition or insulin secretion.
4. Ex ogenou s insulin : This inhibits panc reatic sec retion of insu lin
through a negative feedback mechanism and also by causing hypoglycemia.
5. Allox an : This substance select ively destroys the 13 ce lls lead ing
to decreased insulin secretion and diabetes( = alloxan diabetes ).
6. Dr ugs e.g. the thia7ide diuretics, diazoxicle, phenytoin. alph a-
adrenergic receptor stim ulators am/ beta adrenergic receptor blockers.
7. Sympathetic stimulation (St.~ next).
 90

Section 1- Chapter 7 Endocrine {imctions u[the pancreas

~The islet 8 cells contain both alpha 1 and beta 1 adrenergic receptors.
The a lph a receptors arc inhibitory for insulin secretion (because they
decrease the intracellular cyclic AMP content) while the beta receptors arc
sti mulatory (because they increase the intracellular cyclic AMP content).
However, the alpha receptors IIOI'IIWI~F predomi11ate, so the net result of
·':vmpathetic stimulatio11 is i11hibitio11 of insulin secretio11 .
~ A polypeptide cal led ga lanin is found in some or the auton·omic
nenes that supply the islets of Langcrhans. It inhibits insulin secre-
tion by actiwtting (open ing) the It' chann els (sec abo,·c).

I GLU CAGQfi]

Glucagon is a polypeptid e hormon e (consisting or 29 amino acids

and having 111.\\'. 3485), that is sccrdcd by the A (alpha) cells of the
pancreatic islets. Its half life is 5-10 minutes and it acts mainly by increas-
ing formation of cyclic Al\lP in the target cells (page 8).

Actions (effects) of glucagon

I. It is a hyp erg~vcemic homtoue (i.c. it incrcast.:s the blood glucose
level) by increasing glucose outpu1 from tlte liver (through stimulating
both g~rcogeno lys is a11d gluco11eogenesis).
2. It i11 creases lipo~rsis in adipose tissue which leads to increa-
st.:d formation or kctont.: bod ies in the liver (so it is lipolytic (Ill(/ ketogenic).
3. It elevates the metabolic rate(- calorigenic action) probably due to
the increased hepatic dcamination or amino acids.
-L It exerts a positive inotropic effect on tlte !teart (without increas-
ing the myocardial excitability).
5. It st imulates secre ti on of the gro\\'th hormone (page 19). insulin
(page 89) and the pancreatic somatostatin.
6. It produces so m ~.:: eiTccts on the GIT e.g. it inhibits gastrit.: sccrt.:tion.
** The main funct ion or glucagon in physiologica l doses is its
hyperglycemic efTcct, which supplies energy substrate to the tissues (so it is
an energy releasing ltormone). Its other functions require much higher doses,
specially its lipolytic. kl!logcnic and cardiac effects (sec above).

Regulation (control} of glucagon secretion

(A) Factors that stimulate glucagon secretion
I. Decreased blood glucose level (hypoglycemia).
2. Amino acids, specia ll y th e glucoge11ic ones eg ala nine. glycine.
 91

Section 1- Chapter 7 Endocrine {unctions o(tlte pancreas

serine and cysteine (which arc converted to glucose by effect of glucagon).

3. Certa in GIT. hormones. specially CC K and gastrin.
4. Cortisol (the major glucocorticoid).
5. Exercise, infections and other stresses (e.g. starvation) probabl y
due to increased .\)'lllpatheric srimularion (sec below).
6. Acetylcholin e (so vagal stimulation increases glucagon sccrclion ).
7. Drugs e.g. theophylline and beta-adrenergic receptor stimulators
(see below).

(B) Factors that inhibit gl ucagon secretion

1. increased blood gl ucose leve l. due to release of GA BA from the

beta cells (together with insu lin) which inhibits the alpha cells.
2. Somatostatin and insulin.
3. Certain G.I.T. hormones. speciall) secreti n.
.t. Increased plasma level of free fatty acids (FF As) or ketone bodies.
However, this is not ohmys rhe case e.g. in diaberic ketoacidosis. g lucagon
secretion is not inhihited and its plasma level is high (page 94 ).
5. Drugs e.g. phenytoin and alpha-adrenergic receptor stimulators .

. ::_ Like the 8 cells , the islet A cel ls also contain both alpha 2 and
beta 2 adrenergic receptors, and the alpha receptors arc inhibitory for
glucagon secretion "'hilc the beta receptors are stimulatory. However. unlike
the 8 cells. the beta receptors normally predominate. so th e uet resulr of
sympathetic stimulation (or adreualiue) is glucagon secretion .
Accordingly, stimulation of both parasympathetic and sympa th etic
nerves increase sec ret ion of glu cagon.

SOMATOSTATIN
This hormone ex~;rts only inhibitory effects at the sites or it s
release which include (a) The pancreas, where it inhibits the release or the
other pancrl!atic hormom:~ (i nsu lin, glucagon and the PP) (b) The G IT.
where it inhibits its motili ty and secretion (sec last page in digestion) (c)
The hypothalamus, where it inhibits growth hormone secretion (page 15).

THE PANCREATIC POLYPEPTIDE (PP)

Thi s consists or 36 amino acids. and its sec retion is stimulated by a
high protein meal. cxcn.:isc. fasting and hypoglycemia as well as by
parasympathetic stimulation. It slows food absorption in the GIT, but its
exact physiologica l sign ilicance is unknown.
Section 1- Chapter 7 Endocrine {imctions o(llte pancreas

REGULATION OF THE BLOOD GLUCOSE LEVEL

(GLUCOSE HOMEOSTASIS)

The blood glu cose content is normally variable, depending on the

balance between the amount or glucose entering the bloodstrea m and the
amou nt leavi ng it. However, such variabi lity is norma lly limited by certain
regulatory mechanisms which prevent its rise more than 150 ml/dL arter
ca rbohyd rate-rich mea ls and its fall below 60 mg/dL arter prolonged
starvation (d L = I 00 ml). In the postabsorptive state ( 12 hours afrer the last
meal ), the blood glucose level in peripheral venous blood averages 90
mg/dL, ranging from 70 to 110 mg/dL. and it is normally higher by 15- 30
mgldL in arterial blood. This is ca lled fasting blood glu cose, and it is
frequent ly measured for detection of disorders in carbohydrate metaboli sm.
The organs that add glucose to the blood besides the G IT arc (1)
The liver (through glycogenolysis and gluconeogenesi.\) (2) Tile kidneys
(which are reported to be capable a./gluconeogenesis, but only in cases of
prolonged starvation).
On the other hand , the orga ns that remove glucose from t he blood
include (I) The liver am/ skeletal lllllscles, through glucose uptake and
glycogenesis (2) A dipose tissue, through glucose uptake and lipogenesis (3)
The kidneys, through excreting glucose in the urine [fits blood level exceeds
a certain threshold known as the renal threshold for glucose (abo ut I 80
mgldL) (4) Other tissues particu larly the blood cells and brain (in whiclt the
fu el that can be used is tJ/1~}' glucose). After a carbo hydrntc-rich meal, 5- 10
(Yo or the ingested glucose is changed into glycogen in the liver (wh ich
contains abou t I 00 gm glycogen), 30-40 % is converted into fa t in adipose
tissue, 30-40 % enters the muscles (to be stored in the form or glycogen)
whi le the remainder is metabolized in other tissues.

THE GLUCOSE REGULATORY MECHANISMS

(1) HEPATIC REGULATION

The liver acts as a glucostat by (a) Removing excess glucose from the
blood when its level increases after meals and converting it into glycogen (=
glycogenesis) (b) Addition or glucose to the blood when its level decreases
between meal s, lirst through glycogeno lysis then through glu co neo-
genes is c!fier exhaustion (~/'the lit·er g~rcogen (the liver sto res about I 00
gm glycogen that supplies glucose jiH only 6-8 hours).
Such glucostatic funct ions of the liver are controlled by numerous
hormones (sec next), a lthough they are induced to a li ttle extent cliret:t ly by
 93

Section 1- Chapter 7 Endocrine [unctions o[the pancreas

the changes in the blood glucose level independent or tile hormones (=

autoregulation by the hlood g lucose level).

(2) HO'?MONAL REGULATION

T he glucoregulatory hormon es inc lud e the fo ll owing :
1- Insul in : This is almost the only glucose-loll'ering horm one in the
body. I I is secreted if the blood glucose level incrca~cs in order to
prevent hyperglycemia through (a) Increasing glucose uptake by the
tissues (b ) Decreasing glucose output from the liver (page S6).
2- Anti-insulin hormones : These are the growth hormone (page I R).
co rtisol (page 5 1), catecholami nes (page 68) and glucagon (page 90). The
actions or these hormones arc opposite to those of insulin. They arc !f/ucnse-
misinx lwrmnm!s. and they arc secreted if the blood glucose level
decreases in order to prevent hypoglycemia through (a) Stimulating
release of glucose from th e liver into the bloodstream (b) Dl!crcasing
glucose uptake by the tissues.
(3) RLNA kF;;ULA TION
The kidneys act only in certain situiations. Their abilit y or gluconeo-
genesis and addition of glucose to the blood is signilicant only in cases ol·
prolonged starvation. On the other hand, they can remove glucose !'rom the
blood in cases of hyperglycemia and its excretion in the urine only if the
blood glucose level exceeds the renal threshold of I RO mg /elL (sec above).

(4) Nt:.Uf?AL PECUL4 T/0"'1

Sympathetic stimulation increases glycogenolysis in the Ii' cr which
increases the hepatic glucose output. resulting in eleva tion of the blood
glucose level. It is doubtful whether parasympathetic stimulation produces an
opposite effect.
The cfTcct of sympathetic stimulation is important in cases of hypo-
glycemia. In such cases. certain glucoreccptors in the hypothalamus arc
stimulated. resulting in activation of the sympathetic ~ystem as wdl as re-
lease or catccholamines from the adrenal medullae (page 71) \\ hich increase
the blood glucose level. In addition. excitation or thl! sympatho-adrenal
system stimulates secretion ofglucagon and inhibits W!Cretion of i11sulin (sec
nbo,·c), and these effects also help elevation of the blood glucm.c lc\ d

DIABETES MELLITUS ( DM )

OM results from decreased actions of insu li n. This rarely occurs

due to genetic defects in the insu li n molecule itself, the insu lin receptors or
 94

Section 1- Chapter 7 Endocrine [unctions o(lhe pancreas

the GLUT 4. OM may also occur secondary to excessive secretion of the

anti-insulin hormones e.g. in Cushing 's syndrome and acro11wga~)' (=
seco nd ary DM). However, most cases belong to one of the following types:
1. 1)1pe I or insulin-dependent DM: This type is also cal led .Juv enile
DM because it occurs in young ages. ll is a T fvmphocy te - mediated (or
awoimmtme) disease in which antibodies against the B cells arc formed
leading to their destructi on. with eventual absence of insu lin in the blood.
2. Type 11 or nonimmlin-depemlent DM : This type is also ca lled i\ lat-
urity-onset DM because it usually occurs a Ocr the age of 40 yea rs, and is
almost always associated with obesity. The patients usua ll y have normal B
cel ls morphology and their plasma insulin levels are normal or elevated
(except in long-standing cases). ll owever, the defect lies in presen ce of
insulin resistance i.e. decreased sensitivity of the tissues to insulin.
Lack of insulin act ivi ty leads to ( I) Decreased entry of ami no acids
imo the musc les (2) Increased lipolysis in adipose tissue (3) Reduced entry
of glucose into the cells and increased hepatic glucose outpu t (= gluco-
genesis) resulting in hyperglycemi a. Glucagon is also usutt/~1 · increased
which increases the hyperglycemia by .inducing gluconeogenesis. Other anti -
insulin hormones also contribute when the stress of illness is severe. Accord-
ingly, there wi ll be starvation in the midst of plenty (i.e. intracellular
glucose deficiency with extracellular glucose excess), and the fasting blood
glucose level is elevated usua ll y more than 1-10 mg/d L. and frequently it may
exceed its renal threshold ( 180 mg/dL) resulting in glu cos uria .
LEPTIN AND THE OTHER ADIPOKINES
It was suggested that a chemical signal from the ad ipose ti ssue increases
insulin resistance because of the common observa ti on that weig h t reduction
freq uently improves DM. This seems to be true. si nce recently several sub-
stances that are secreted by the fat cells and a./feet insulin resistance were
idemi fi t.:d. They arc ca ll ed adipokin es e.g. leptin a nd resistin (the former
decreases insulin res ista nce while the latter increases it). Lcptin is n sa tiety-
producing protein hormone, consisting of 16 7 amino acids, and it decrea-
ses the food intake and also increases the energy consumption.

SYMPTOMS (MANIFESTATIONS) OF OM

I. Po lyuria : Th is occurs due to glucosuria which produces osmotic

diuresis (sec table in page 30). It causes loss of Nn+. K · and watcr-so luble
vitamins in the urine, and mttscle cramps mc~v occur due to hyponatremia. Severe
cases also lead to dehydration. hypovolemia and hypotension.
2. Polyd ipsia (= excess ive drinking of water) due to an increased
semation o/thirst that results f'rom (a) Reduction of the ECF I'Oiume sccon-
 95

Section I- Chapter 7 Endocrine functions ofthe pancreas

dary to polyuria (b) Plasma hyperosmolality produced as a result of

hyperglycemia (refer to the mechanisms of thirst in blood and kidney).
3. Hyperphagia or polyphagia(= increased appetite & food intake)
due to deficient glucose utilization in the cells of the satiety centre in the
hypothalamus secondary to insulin deficiency (which decreases the activity of
this centre, so the feeding centre opemtes unopposed resulting in polyphagia).
4. Muscle wasting and rapid fatiguability : Muscle wasting
occurs secondary to protein depletion caused by the increased protein cata-
bolism. This, together with inability of the muscles to utilize glucose due to
insulin deficiency, render the patient to be tired and rapidly fatigued.
5. Loss ofweight due to both muscle wasting and depletion of the fat depot
stores in the body (see below).
6. Decreased resistance to bacterial infections :The patient is sus-
ceptible to infections (specially in the skin and external genitalia) due to
both the protein deficiency and the hyperglycemia (the sugar-rich body
fluids are good media for bacterial activity).
7. Visual manifestations : Hyperglycemia causes visual disturbances
which vary from just changing the refractive power of the various optic media
(which decreases the visual acuity) to microva'lcular changes in the retina which
may lead to its scarring (diabetic retinopathy) resulting in blindness.
8. Increased lipolysis : This leads to depletion of the fat stores and
causes (a) Lipemia (increased blood levels of FFAs and triglycerides) ,
which predisposes to fatty liver degeneration (b) Increased plasma clw-
lesterollevel which predisposes to atherosclerosis in long-standing cases
(c) Increased blood level of ketone bodies (=ketosis or ketonemia) which
are organic acids (= ketoacids) that cause acidosis. They include aceto-
acetic acid and its derivatives (beta hydroxybutyric acid and acetone). They
are formed in the liver as a result of FF As catabolism to acetyl-CoA and
when they exceed a certain blood level, they are excreted in the urine (=
ketomtria). These effects are so prominent that diabetes is sometimes
described to be "more a disease of lipid than ofcarbohydrate metabolism".
9. Acidosis : This occurs in severe cases due to excess ketosis and
the blood pH may be lowered (= acidemia}, although the buffering mecha-
nisms are acting (refer to kidney). In addition, lactic acid is liberated in
excess from the tissues as a result of their hypoxia (due to dehydration)
leading to lactic acidosis (which worsens the acidemia due to ketosis).
10. Coma : The plasma hyperosmolality due to hyperglycemia causes
dizziness and even unconsciousness or coma due to dehydration of the brain
cells (hyperosmolar coma). However, in the terminal stage of the disease
coma (which is often fatal) occurs because of the combined effects of
acidosis, dehydration and plasma hyperosmolality on the nervous system.
 96

CHAPTER 8

I THE PINEAL GLAND (THE EPIPHYSIS) I

The pi neal gland arises from the roof of the 3rd ventricle of the
bra in and it was believed to be the seat of the soul. It is innervated by
sympath etic postgan glionic fibres (= ner vi conarii) that arise from the
superior cervical g anglia (refer to autonomi c N.S.). It is large in youngs,
bu t it begins to invo lute before puberty with deposition or ca/ciulll salts
(which appear in X-ray as pin eal sand) and its secretion declines gradual~v
with age. Hi sto logically, it consists o[ neurogl ia and parenchyma l secretory
cells call ed pinealocytes which secrete a hormone ca lled melatonin.

MELATONIN (N -Acetyi·S·mcthoxytryptami ne)

Thi s is a hormone that lightens the skin of tadpol es (by an action

on melanophores) but not mammals, and is synthes ized fi·om serotonin. It is
secreted by the pinea l gland and, to a little extent, also by certa in other
organ s. The extra-p inea l melatonin is tonica{~,, secreted to maintain a
constant bl ood level, but in contrast to the pinl:a l me lat onin, it is not
affected by li ght, age or nervous stimulation (sec below).
Qegulat/On of melatonin secretion . The secretion of pineal melatonin is
increased by sympa thetic stimulation (via beta adrenergic receptors in the
gland). and shows a characteristic light-da r k circadi an r·hythm. It increa-
ses on exposure to darkness a nd decreases d uring day- li ght hours. This
occurs through il!fluellcing the .\ympathetic discharge to the gla11d as ro ll -
ows : Signa ls discharged via rctino-hypotltalamic nerve fi bres affect the
activity of the hypothala mic suprachiasmatic nuclei (lite biologic clock in
tlte body), which control the sympathetic activity to th e gland via
hypothalamo-spinal fibres that terminate at the latera l hom cells in the
upper thoracic segments or the spina l cord, from wbich preganglionic fibres
arise and reach the superior cervica l gangl ia (the ori gin of the nervi conarii).
Functions of melatonin : There arc no es tablished fun ctions for mcla·
tonin in mamm als. T he diurnal variation in melatonin secretion probably
func tions as a timing device that keeps in ternal events synchronized with
the light-dark cycle in the environment. It is also reported that it (a)
Inhibits gonadal fun ctions and LH secretion (b) Delays the onset of
pu bc1·ty, because pineal damage (e.g. by tiiii/OIIr.\·) is sometimes associated
ll'ith se.rual precocity. ll owever. this was round to occur only when such
ti/1/IOIII·s cause hypothalamic damage as ll'ell (page I02). In addition. it
induces sleep and produces a sense of well-being (so it is sometimes used
in the treatment of certain cases of depress ion).
SECTION II

REPRODUCTION
 97

CHAPTER 1

I SEXUAL DEVELOPMENT AND PUBERTY I

The sex orga ns inc lude the gonads or primary sex organs (wh ich
arc 2 resres il1 males and 2 OI'Ciries in females) as well as the other sex
organs (= secondary or accessory sex orga ns). The gonads arc con-
trolled by the go nadotrop ic hormones and they perform 2 functions :
l. Ga metogenes is i.e. production of ga metes(= germ cells) : This
includes spermatogenesis in the males (= production of sperm s) and
oogenes is in the.females (=production of ova).
2. Secretion of sex hormon es (so the gonads arc endocrine glands).

GAMETOGENESIS

The sperms and ova are formed from primitive gcnn eelIs present in
the gonads ca lled spermatogonia in the testes and oogonia in the ovaries.
These ce ll s, like the somatic cells in the body, conta in a diploid 1111mber
of cl11·omoso11te.'i (46 chromosomes) which inc lu de 44 somatic chromo-
somes (= a11/osomes) and 2 <~/th e sex chromosomes (the X and Y chromo-
somes). Spermatogonia conta in one X and one Y chromosome (XY pattern)
whereas the oogon ia contain 2 X chromosomes (XX pattern).

SPERMATOGENESIS

The spermatogonia proliferate then grow into prirnmy spermatoc.:vtes

which contain the diploid number of chromosomes i.e. 46 chromosomes
(44 autosomes, and one X and one Y chromosome). The primary
spermatocytes then mature through meiosis (= reduction division) then
mitos is as follows : Each primary spermatocyte undergoes mei ot ic
di vision producing 2 secondmy sperma/ocytes (each containing onl y a
lwploid 1111111her ~f chromosomes i.e. 23 chrom osomes, 22 autosomcs and
one sex chromosome, the X or the Y), then by mitotic di vision. each
secondary spermatocyte di vides into 2 spermatids (tbat also conta in a
hapl oid number of chromosomes) and these are then transformed into
mature spermato::oa by a process known as spermiogenesis. Therefore,
.fi'om each primm)' spermatoc.:vre. 4 spermato::oa are fo rmed ( ligurc 36 ).
Through proliferation of the spermatogonia, it was estimated that 5 12
spermatids are fo rmed from a si11gle spermatogonium.
:::::._ The control of the 4 stages of spermatogenesis (the prol[lerative.
growth, maturation and transformation stages) will be discussed in the male
reproductive system.
 9X

Section II- Clu1pter 1 Sexual development and pubertF

S i" ·rtn :tl n>:on imn

Oogoni u m
<Oro wlh
P r lmu ry
S t)(•rma to<·yll· l'rim ury
00l'.)'ll:
.\l :t tura t ilJn

St·<'0111111 r y
::.ltw r ma l u<"y iP
:o;I'I'Oildll l'.)'
Oikyl t·

.·" Oiit.ltl

(() \' lllll )

l 'o lnr Hotl i!•;;

Figure 36 : Spermatogenesis (left) and oogenesis (right). R = reduction

division (meiosis). M =m itotic division.

OOGENESIS

The oogonia grow into primmy oocyres wh ich conwin the diploid
number or chromosomes i.e. 46 chromosomes (44 autosomes and 2 X
chromosomes) then through meiosis. each primary oocyte divides producing
a secondm)· oocyte and the .first polar boc6' (each containing onl y a haploid
number of chromosomes i.e. 23 chromosomes (22 autosomes and one X
chromosome). The first po lar body degenerates wh ile the secondary oocyte
by a mitotic division, produces em notid containing a haploid number of
chromosomes (whi ch develops into the mature ovum) and the second polar
boc~r (which also degenerates) . In this way, each primary oocyte produces
only o11e mature 01'11111 (figure 36).
When th e ov um is fe rtilized by a sperm, a ce ll with a diploid
number or chromosomes is fom1ed (= zygote) and sex is then determ-
in ed by presence or absence of the Y chromosome (sec nex t). I r the
sperm was containing a Y chromosome, an XY pattern results and the
zygote develops into a male. ·wh ile if it was containing an X chromosome,
an XX pattern results and the zygote develops into a female.
 9l)

Section II- Chapter 1 Sexual developmellf and puberf!'

Until the 6'11 week of pregnancy , the primitive fct<tl gonads (which
arc f01111cd ncar the adrenal glands) are identical in both sexes and arc bi-
potcntia l i.e. they can be differentiated into either testes or ovaries. Each of
these gonads is fom1ed of a cortex a nd a medulla. In genetic males. the
medulla develops into a testis and the cortex regresses. '' hilc in genetic
females. the cortex dc\elops into an ovary and the medulla regresses.
Gomulnl differentiation occurs during the 1" and 8'" ll'eeks, and at this
time. the embryo also forms both male and female primordinl genital
ducts. The female genital ducts are called Mulleri an ducts while the male
genital ducts arc cal led Wolffia n ducts, and both open externa ll y together
with the urchra at the urogenital slit. Sex determination depends 0 11 the
presence or absence of the Y ch romosome as follows :
( I) In presence of the Y chromosome (i.e. in genetic malt.:s), the
testes arc formed because the Y chromosome causes testicular di ffcrcntia-
tion from the medulla of the primitive gonads (sec above). and the product
or the tcstes-detcnnining gene is called SRY (=Sex-determining Region of
theY chromosorne). The embryoni c testes secrete (a) Mullerian inh ibiting
su bstnncc (MIS) uy the Scrtoli cells (page I05), which causes regression
of the Mullerian ducts by apoptosis (= programmed cell death) so female
genital organs do not develop (b) Testostreroue by the Leydig cells (page
I04) under influence of a hormone called human chorionic gonadotropin
(rage 137). Testosterone causes the following : (a) Development of the
Wolnian ducts which consequently develop into the male intemal genital
organ\ (epididymis. vas deferens and seminal vesicles) (h) Closu re of the
urogenital slit and formation of the male extemal genital organs (by its
metabolite called c!ihydrotestosterone. pagelll) (c) Dcvelopmt.:nt of the
brain, and such early exposure of the brain to testosterone may be the cause
t~f tile male fUll/em of se.:nwl behavior at pub er~! '.
(2) In absence of the Y chromosome (i.e. in genetic lcmnles). no
testes arc formed and instead, the ovaries develop from the cortex of the
primitive gonads (sec above) but they do not secrete hormones. Due to
absence of MI S, the Mullerian ducts develop and form the lema it.: internal
gen ital orgnns (u terus and fallopian tubes) as well as the upper part or the
vagina, while the Wolflian ducts regress due to absence or testosterone.
The urogenital slit remains open and th e fcma le externa l genital organs
(vulva and labia majora and minora) as well as the lower part of the vagina
will subsequently be rom1ed.
~ Since development of the external gen ital organs in both sexes
occurs al"tcr gonndal differentiation, these organs also remain bi-potcntial
until the R' 11 week of development. after which they arc dificrcntiatcd.
 100

Section ll- Chapter I Sexu al development and puberty

:::: The human Y c/11·omo.\·ome is smaller than the X chromosornc, so the

sperms having Y chromosomes are li ghter and swim faster in the femal e
genita I tract than those having X chromosorncs, and thus can reach the ova
more rapidly. This may e..:'<plain wlty tlte number of bom males is normally
sliglttly greater titan tlte number of f emales.

I ABNORMAL SEXUAL DIFFERENTIATION I

(A) Chromosomal abnormalities
(1) Nondisjunction
This is a defect in gametogcncsts rn which the pair of sex
chromosomes fail to sepamte during m eiosis. so that both go to one of the
daughter cell s whil e the other cell wi ll contain 0 (zero) sex chromosome.
Therefore, in the process of ferti lization. zygotes having abnonnal
chromosomal pattcms wi ll be produced e.g. during oogenesis, ifsome of the
OI'CI contain the 2 X chromosomes while others contain 0 sex chromosome,
thefollowing almormalities IIU~I' he produced Oll.fertili:::ation :
l. XXV patter n : This occ urs as a res ult of fertilization or an ovu m
containing 2 X chromosomes by a sperm containing a Y chromosome. It is
the commonest disord er and is ca ll ed KJinefelter syndrome. The patient
has the genita lia of a norma l ma le (and develops male characters) but his
seminiferous tubules arc abnonmrl (so the conditi on is ca lled semin iferous
tubu le dysgenesis) and there is also mental retardati on.
2. XXX pattern : Th is occurs as a res ult o f' fertilization of an ov um
containin g 2 X ch romosomes by a sperm co ntaining an X chrom osome.
Such case is ca lled superfemalc and is not assoc iated with any character-
istic abnormalities (so it usually passes unnoticed).
3. XO pattern : This occu rs as a res ult or fertili zation of an ovum
containin g 0 sex chromoso me by H sperm conta ining an X chromoso me.
Such case is called Tu rner synd rome, ova ri an agenesis or gonadal dys-
genesis. The gonads (ovaries) arc rudimentary, stature is short, other conge-
nital abnormali ties arc often present, and puberty is delayed or absent.
4. YO pattern : Thi s occurs as a result of fe rtili zation of an ovum
con taining 0 sex ch romosome by a sperm contHining a Y chromosome.
Such conditi on is lethal (= fatal) due to lack of lite X cftromo.\·ome (whic h
carries essenti al genetic in fo rmations lor the normal fetal development).

(2) Mosaicism
Th is is a pathological conditi on that results from faulty mitoses
in the early =_,·gcJie. producing an individual wit h 1 or more d({ferent
 101

Section II - Chapter 1 Sexual development and pubertv

chromosomal fWflems. Such individual is ca lled a mosa ic e.g. XX/XY

mosaicism (which may be associated with true hermaphrod itism i.e. an
individual that has both types of gonads).

(B) Hormonal abnormalities

The commonest hormonal sexua l abnormality is pse udo herma-

phrodi tism. This is a condition in which an indi' idual has the genetic
constitution and gonads of one sex bwtlte external genitalia oftlte otlter.
There arc 2 types of this condition :
1. Female pseud ohermaphroditism : This is development of male
external geni talia in females. It occurs when a female fetus is exposed to
excess androgens during the gth -13 1h weeks of pregnancy. common ly due to
a COIIf:enitaf ,•irili-;.illg adrenal tumour (page 64) or as a result or cxccss-
ive doses of androgens given to the mother.
.::_ A/fer the 13'" week o_fpregnancy, the genitalia are almost
complele~\ ' /(mnecl and exposure of the female fetus lo androgens can
c:tmse on~\' hypertrophy of 1he cliforis .
2. Ma le pscudohcrnulphruditism : Thi s is deve lopment of female
extern al gen italia in males. It occurs when development or the embryo-
nic te.,·tes is defective or if there is a11drogen resistance {= a con-
diti on in which testosterone is secreted from the testes, but it is unable to
exert its effects). Such res istance is usually du e to either absent or abno-
rmal and rogen receptors, but dejicieii(.JI f~lthe 5 alpha - reductase
en zym e (which converts testosterone to another important active form
called dilzydrotestosterone) may also be a cause (page 11 2).

I PUBERTY !
The gonads remain quiescent (= silent) until adolescence. and at that
time they become activated by the GT II s. Puherty is the lime 11'/ten lire
endocrine and gwne10genic jimc1ions (~/' 1he go11ads are de1·e/oped
enough so lfw1 reproduction becomes possible. The normal range of age at
which puberty occurs (in USA) is 8-13 years in girls and 9-14 y ears in boys.

MECHANISM (CONTROL) OF ONSET OF PUBERTY

In child ren, the anterior pituitary gland contains GTHs. but they arc
not secreted although the hypothalamus contains GnRl l. It seems that a
neural mechanism prel'ents the release of GuRH. and puberty sets in when
 tO:!

Sect ion II - Chapter I Sexual de1•elopmeut aud pubert1•

sm:h mechanism fail!.. II O\\ ever, the nature of this medwnism and the cause
of its failure me unknown.
1 1 ( ll ( 1 If IJ i ( £'1c. _ 1·ic •Y 1 r-l' i1 h r 1 n }
It was recently reported that a critical body" eight must be reached for
puberty to occur. It nppears that lcptin (page 94) rna) be the link bet\\'een
the hod) \\eight and pubcrt) sin<.:e obese mice that lack kptlll arc infertile
and lcpun treatml.!nt induces precocious pubcrt) 111 111111l.llure female mtce.

ABNORMAL PUBERTY
(AJ PrP"'""ic ·~1"'1~, fM.,,_, --;:c, ;~., · This is 2 types :
1. Prc coc iou~ pseuclopnhcrty : This is an l.!arl) development of" the
secondar) sex characteristics and accessory sex organs but ll'itllout uamet-
o~-:euesis (i.e. there is no spermatogenesis or oogenes is). It occurs as a
result of an abnormal Ol'er.\ecretion of androgens in immature males or
e.\lrogens iu immature females. In males. the condition ma) be due to
e11hcr an wtdrvxen-\ecreting 11/mour of the adrenal correx (page 64). or a
twnm11· in the l.eydi}!. cell' <?/the testis (whi ch secretes excess testo-
sterone) . On th e other hand. in fcrnales. the condition may result from
either m1 estrop,eii-.H'crelillg tt1111011r of the or/renal cortex. oro gra11ulosa
cell tumour (~/ th e ovw:l' (which secretes excess estrogens).

2. True precociou s pubert y : This is a true premature puberty (i.e.

accompanied by both SC\U<d de' clopmcnt and gametogenesis) that occurs in
}Oung ages as a n~s ult of carl~ sec retion of G TII~ . In some ca~cs. it is
con.\ titllfional in nature, but m most ca~cs it is due to hypothalamic
di.\Order., that are tts.mc:iated with increased secretion of GnR/1 (e.g.
tumours or infections). Some cases are not initiated by Gn RII secretion
( gonadotrop in -independ ent precocity). Tumours of the pineal gland
arc sometimes also assm:iated '' ith sex ual precoc ity. but thi s was found to
occur only when there i~ secondary damage of the hypothalam us (page 96).

(B) '( ( f 11 ~ 1 t
Puberty is considered to be pathological ly delayed in females when
the nu!nw·cllf.! ( first menstruation) does not occur hy the age f?l 17 years.
and in mnles ll'hen testicular del'e/opment fails to occur hy t!te age f~/ 20
yc·w·s. The conditi on may occur a~ a result of panh ypopituitarism. Tu rner
sy ndrom e (page I 00) or cretinism (page 45). but however. in some
indi viduals puberty is de layed " 'itlwut w1 apparent couse. Such cases arc
ca ll ed eunuchoidism in mal es and primary amenorrhea in females.
 103

CHAPTER 2

I THE MALE REPRODUCTIVE SYSTEM I

The ma le organs of reproduction include the following (figure 37) :
(1) The testes (male gonads) : These constitute the primary sex
organs, and arc concerned with !:tperm atogen esis and secreti on of 3 horm-
ones (a) Testosterone (b) lnhibin (c) Small amounts of estrogen (sec below)

(2) The accessory (or secondary) sex organs : These include :

a. T he epidid ymes : Each ep ididymi s is a single long coiled tub-
ule in which the sperms arc stored and become more mature.
b. The vasa deferens : Each vas is a long muscular duct that cond-
ucts the sperms from the epididymcs to the urethra by perista ltic movements.
c. T he semina l vesicles : Eac h vesicle is a glnnd that secretes visci d
fluid ri ch in fructose, prostaglandins, ascorbic ac id and flavins. Their ducts
join the ends of the vasa deferens f01ming the ejacu/atOIJ' ducts which pass
through the prostate and open into the prostatic portion or the urethra.
d. T he prosta te : Thi s is a ICirgc gland that surrounds the upper part
of the urethra. It secretes an alkal ine flu id during intercourse that contains
citric acid, Ca 2~ and proteo lytic enzymes.
e. The bulbouret hra l (Cowper 's) glands : These secrete mucus
during intercourse which neutralizes the acidity inside the urethra and lubri-
cates the sexual movements.
f- T he penis : This is fo rmed o:£ erectile tissue that can accomo-
dat c a great amount of blood by V.O. resulting in its erecti on (which is esse-
ntia l fo r introd uction of the semi nal nuid deep into the fema le genital tract).

Prostdll'

Figure 37 : The male reproductive system.

 I 0-1

Sect ion II - Chapter 2 The male reproductive spstem

STRUCTURE AND FUNCTIONS OF THE TESTES

Each testis is made up of 2 specialized types of tissues (figure 38) :
( \)Seminiferous tubules : These arc conc~.:rm:d '' ith formation of
spcrmatoLoa (i.e. spcrma10gcncsis) and they contain 2 ope.\ of cells :
I. Th e cells concerned ll'ith .\permatogenesi., (spermatogonia, primary
and secondary spcrmatocytcs and spermatids).
2. The Sertoli cells : These arc large ce lls located between the germ
cell s and they arc rich in glycogen which is used ror nutrition of the sperms.
They arc stimulated by FSII, and pcrfom1 several functions (sec next page).
( B l Interstitial cells of Leydig : These cells arc located between the scmi-
nill:rous tubules, and their function is the synthesi.\ aml .\ecretion oftlte testi-
cular androgen (- te.\10.\feronel

1"\lf"t\tllt.l
J,
((> \

"n 1 Lr,

....

...

Figure 38: (A) Cross-section in a seminiferous tubule. (B) F01mation

or spcnnai0/0<1 by the germinal epit helium.
 lOS

Section II - Chapter 2 Th e male reproductive Sl'Stem

Functions of the Sertoli cells

I. Nutri tion and maturation of the spermatids in deep folds in their
cytoplasm and their transfomuttion into spcnnatozoa (=spermiogenesis).

2. They secrete the following substances :

a. Androgen-bimling protein (A BP) : This maintains a high
concentration of androgen (testosterone) in the seminiferous tubular fluid.
which is essential in the process of spermatogenesis (sec below).
b. fnltibin (a honnone that inhibits FSH secretion from the antetior
pituitary gland) and a sma ll amount of estrogens (androgens diffuse from the
Leydig cells to the Scrtol i ce lls which contain the aromatase enzyme that
crmverts androgens to estrogens).
c. M ullerian-inhibiting substance or MIS (page 99) which causes
regression of the Mullerian ducts in males during fetal life (so it is
also ca ll ed Mullerian regression factor or MRF).The MJS also induces
descent of the testes to the inguinal region (page I07).

3. The tight junctions between adjacent Serto li cells ncar the basal
lamina form a blood-testis barrier which prevents :
a. Many large molecules to pass from the interstitial tissue to the
tubular lumen (thus protecting the germ cells from many noxious agents).
b. Antigenic products or germ ce ll division from en tering the cir-
culation (t hus protecting against development <?/autoimmune re.\ponses).

s,rn 50 prn 5pm

Jj
End p tecc PunctpHI ptecc Mtdd!C ptCCC Head

Fil!urc 39 : A human sperma tozoon.

 106

Section II - Chapter 2 Th e male reproductive S}'Stem

The spermatozoa (or sperms)

In humans, it takes about 74 days to./(mu a mature sperm. The human
sperm is a single motile ce ll formed of a head and a long tail (figure 39).
The head is composed mainl y of a nucl eus made up mostl y of chromosomal
materi al (DNA). and its anterior part is co,·crcd by a lysosomc-lik\.!
organelle ca ll ed acrosome (wh ich contai ns a number of pmteolytic en:ymes
that help tire sperm to penetrate andfertili:e the 01'11111. page 135).
Spermatozoa leaving the testes arc not fully motile. and they conti nue
maturity and acquire motility in the epididymis. Their progressive motili~l' is
produced by movement of their tails and in volves activation of a special
protein localized there called Ca tsper. Normal sperms move at a speed of
about 3 mm/minutc in the fe male genit al tract. Tlu:y reach the uterine tL1bcs
30-60 minutes after ejaculation and remain actil•e for aholll 48 hours
(however, they cnn live lor much longer times in l'ifl·o if they wen.: kept at
lower temperatures than 3 7 11C e.g. in seme/1 hanks).
~prrm l':tJ>.tc'tadf,n : This is a process of further maturation of the
sperms that occurs in the fcmak genital tract after ejacu lation. It takes 2-8
hours and involves a marked im:reasc or both the sperms' motility and their
ability for fertilization (by jitcilitating the acrosomal reaction. page 135 ).

I Factors that control (affect) spermatogenesis I

In addition to healthy testicula r germ inal epithelium a nd the role
played by the Scrtoli cells. the following l~tctors affect spcnnatog..::ncsis :

(I) HORMONES

(AI \II ll'lllpitu ' taa \ ~0 1 Hill '"IIJI•' lwrmulll:'i ,.' Til
l. FSH : Thi s acts on the Sertoli cells to f~tci Iitatc the last stages of
spermatid maturat ion (spermiogenesis). It also ma int ain s a high concent-
ration of testosterone in the seminiferous tubular fluid {which is essential
for normal spermatogenesis) by (a) Promoting secretion of the ABP rrom the
Sertoli cells (b) Sen.siti::ation q( the l..£.'_1'digce/Lno the action qj' L/1 (':IX next).
2. LH : This stimulates testosTerone secretion from the interstitial cells
of Leydig (so it is called the.: interstitial cell-stimulating lwrmcm e or ICS/1 ).
(B) ll-.IO,ll·ruu · : This hom10nc is secreted rrom the kydig cells under
the efTcct or LH. and it reaches the sem iniferous tubules directly where it is
maintained at a high concentra tion by the effect of the A Bl) (sec above). It is
essential for the maturation phase of spermatogenesis particularly spcm1atid
maturation in the Sertoli cell .
 107

Section II - Chapter 2 Tlze male reproductive svstem

.:::_ The blood in the spermatic vessels nows in a countercurrent system

(as in the loops of ll en le in the kidneys). Such arrangement al lows passage
of testosterone from tlze spermatic veins to the spermatic arteries (wh ich
contributes in maintaining a high testosterone concentration in the testes).

(( ') Othl'r hnrmmH·:o. : Estrogens and inhibin depress spermatogenesis by

inhibiting PSI-I secretion. On the other hand , thyroxine stimulates spermat-
ogenesis (page 39) , so it is depressed in cases of myxedema (page 44).
:::._ Administration of exogenous androgens in large doses inhibits
LH secretion, so the secret ion of endogenous androgen by the Leydig cells
is decreased. This decreases the loca l androgen concentration in the testes
resulting in depression or spermatogenes is, so treatment wi th exogenous
androgens can be used as a method of contraception in males (page 128).

(2) TEMPERATURE

Spermatogenesis requires a lower temperature than that of the body

(optimally 32-33 °C). Ri se of the testicular temperature e.g. due to CI)I[Jtm·-
chidism (see below), fevers or continuous wearing of tight rants, damages
the germina l epithelium (thus inhibiting spermatogenesis) and may kill any
preformed sperms resu lting in infc1iility (sterility). Tt also increases genetic
mutations during cell division, which would produce abnormal fetuses.
Therefore, for normal sperm format ion. it is essential/or the testes (11·hich
de1·e/op in the abdominal cal'ity ll'here the !emperature is high) to descend
10 the inguinal cwwls (which depends on the MIS. page 105). then 10 the
scrotum, in whi ch they arc cooled by the following mechanisms :
a. The sc rotal skin is thin (as it contains little fat) and is rich in sweat
glands. These favour heat loss (specially in presence of air currents).
b. Heat loss is a lso favoured by the countercurrent system or the
testicular vessels. ll allows heat transfe r from the spermatic arteries to the
spermatic ve ins (wh ich decreases the temperature in the scrotum).
c. The scrotal muscle (= Dartos muscle) relaxes in hot weather, wh ich

0
=
draws the testes fu rther away from the high temperature of the abdomen.
Spermatogenesis is also depressed at lowe•· temperatur es than 32
C. For this reason, the dartos musc le contracts in cold weather 10 draw the
testes upwards (in order lObe warmed by the abdominal temperature).

Cryptorchidism (undescended testes)

This is a congenital abnom1ali ty in which one or both testes fail to

descend into the scrotum (whi ch normally occurs during the 7'11 - 8' 11 month
 lOX

Section II - Chapter 2 Til e male reproductive system

of pregnanl:y). The high abdominal temperature damages the germina l

epithelium, so a:oospermia (= absence of sperms in semen) may occur
resulting in sterility. ll owevcr, the interstitia l cells of Leydig arc not
affected by high tempera tures, so they secrete testosterone normally (thus
the male secondary sex characteristics will appea r normally at puber1y).
Testicular descent occurs spontaneously in most cases. However, iritis
delayed. it can be induced by CTHs (but ir such treatment fai ls, surgical
inte rference will bl! ncces ary). Treatment shou ld be started before pu berty
as early as possible (a) To avo id excessive da mage o f the germ ce ll s
whi ch is irreversi ble (b) Becaus e the undescended testes are more
liable to ma lignant tumours.
(3) DIET
A ba lanced di et containing adequate amoun ts of proteins and vitamins
(specially vitamins A, E, C and B) is necessary for normal spermatogenesis.
In prolonged starvation or malnutrition. spermatogenesis is depressed and
may stop due to de ficient secretion of the pituitary GTHs. Vitamin A
deficiency causes keratinizati on and atrophy or the germinal epithelium.
whi le vitamin E dclk icncy ca uses degeneration or the seminiferous tubules
i11 rats (but this wns not proved in humans). Vitamin C and the various
members o f vitamin 8 catalyze the metabo lic processes in the germ cell s
(so the ir de fi ciency is also associated with depress ion of spermatogenesis).
(4) OTHER FACTORS
Prolonged ex posure to various types or radiations (x-ray, atomic or
nuclear radiations), prolonged hypoxia. certain tox ins and in fec ti ons (e.g.
mumps) all damage the seminiferous tubules and depress spermatogenes is.

ENDOCRINE FUNCTION OF THE TESTES

The testes secrete 3 hormones (testosterone, inh ibin and estrogens).

lnhibin

lnhi bin is a polypeptide hormone secreted by the Sertoli cells in

males and the granulosa cells of the ovarian follicles in females.Th crc
nrc 2 types(/\ and 13), and both inh ibit FS H secretion by a di rect negati ve
feedback action on the anteri or pitu itary gland (spec ially type B). Such cft(;ct
autorcgulatcs the rate or FSH secretion and its blood level.
It can be used as a method of con traception in males (page 128)
since it depresses spermatogenesis secondary to inhi bition of FSH secreti on.
 109

Section 11 - Chapter 2 Tlt e male reproductive S)'Stem

:::, From the inhibin precursors, other polypeptides that stimulate

FSH secretion arc also fanned. and arc called activins (however, their
exact role in reproduction is unsettled). Inhibins and activins arc a lso
found in the brain and many other tiss ues e.g. the placenta (page 139).
In the bone marrow, activins arc involved in development of the white blood
cells. and in embryonic life they arc in vo lved in the formation of mcsodem1.

Estrogens in males

About 80-90 % of estrogens in the plasma of adu lt men is formed by

aromati:;atiou of tlte circulatiug testoteroue & androstenedioue (probably
in adipose tissue), and the remainder is sccn:ted by the testes. main(\' by the
Scmoli cells (page I 05) and a I'C'I)' small WIWII/It by the Leydig cells. The
estrogen production in men is about 50 microgm I day (and it increases
with advancing age) and its plasma level ranges from 20 to 50 fJg!ml.

I TESTOSTERONE I
This is a C19 steroid that is synthesized from cholesterol. In males,
it is secreted mainl y by th e testicu lar interstitial ce lls or Leydi g under
influ ence of LH (at a rate of 4- 9 mg /day) while in females, a very sma ll
amount is secreted from the ovaries. The adrenal cortex probably al so
secretes very small amounts in both sexes under innucncc of ACTII.
Androgens arc masculinizing hormones (= honnoncs that produce
male sex characteristics), and testosterone is t!te most potent mulro~en .
The main androgens secreted by the adrenal cortex arc de!tydroepirmdr-
osterone (DHEA} and an drostenedione. and their potency is on ly abou t
20 °o that of testosterone {page 58).

Mechanism of action of testosterone

Like other steroid hormones, testosterone binds to cytoplasm ic receptors
in the target cells, resulting in increased transcription of mR NAs which
stimulate synthesis or proteins that alter the cell function (page 5).

Testosterone transport and concentration in the plasma

About 98 %, of the plasma fcsfos tcrone is hound to prot eins : 33 1X1
to album in and 65 % to a beta globulin called gonadal steroid-biuding
globulin (CBC). The plasma testosterone leve l (free and bound) is about
300-1 000 ng/dL in adult men (and it declines somewhat with age) nnd 30-70
ng/dL in adu lt women (dL = dec i-litre = 1/10 litre= 100 ml or em\
 110

Section I I - Chapter 2 Th e male reproductive srstem

Met boli!:»m of tt:s o l "ron

A sma ll amount of testosterone is converted into estrogen (sec above).
I lowever, most testosterone is converted into 17-kctosteroids which arc
excreted in the urine. In males, about I/3 of the urinary I 7-ketosteroids are
of testicular origin while the remaining 2/3 arc of adrenal origin {page 5 I).
Most I 7-kelosteroids (but not all) arc weak androgens (having only about
20 '% of' the potency of testosterone).

-- .,. ...__
..--- -'""'
L ... ,_ \ I
I• .

_...,
-1
...... .,

II

( . .,
~\
-... -- I
't'-

(,_ "' / I I1 (, {,
\!'
l_. ' t~,l; 1
,..,
~
)
'--\
/ {
'

\
Figure 40 : Frontal sca lp hairline in children and adult men and women.

ACTIONS OF TESTOSTERONE

(I) Testosterone secreted during intrauterine life by the embryonic testes is

responsible for maturation of the \\Olfflan ducts that consequently develop
into the male internal genital organs (page 99).
(2) Testosterone is essential for normal spermatogenesis (page I06).
(3) Appearance of male changes at puberty (virilization ) wh ich inc lude :
A. Rapid growth of the ncccssory sex organs (page I03 ).
B. Appearance of the seconda ry sex cha rac teri stics which include :
a. Hair growth : The body hair increases particularly in the face
(so the beard appears), chest. limbs. axillae and around the anus. The
pubic hair grows in the form of a triangle with its apex up ( = mal e
esc ut cheon). However, the scalp lwirfalls with bilateral temporal recess-
ion of the frontal scalp hairline (figure 40), and boldnc.•ss is accelerated.
h. C han ges in the qualit y of voice : The larynx cnlargcs and th e
voca l cords increase in length and thi ckness (so tlte voice becomes deeper).
c. Psycho logical changes : At puberty, boys become aggressive and
their interest in sex devclors with increased libido (sexua l desire).
 Ill

Section H - Chapter 2 The male reproductive spstem

d. Changes in hocly co nformation : The shou lders broaden and

the muscles enlarge due to the annbolic effect of testosterone (sec below).
c. Ski n changes : The secretion of tbe sebaceous glands increases
and thickens (which predisposes to the development of acne).

(4} METABOLIC ACTIONS OF TFSTOSTf:RONt:

J. Anaboli c action : Testos terone increases the synthesis and
decreases the break do" n of protein, leading to an increase in the growth rate.
2. Moderate retention of Na+, K+, water, Ca l+, SO~ 2• and PO/-
(secondary to the anabo lic action) and an increase in the si:e of the kidneys.
3. Increase of both the iodide uptake by the thyroid gland and the
secreti on of the thyroid hormones wh ich in creases tlt e m etabolic rate .
..t. Fusion of the epiphyses of th e long hon es to their shafts
('' hich limits the initi al spurt of gro" th that occu r at puberty).
5. Stimulation of secretion of the eryth ropoietin hormone. thus
increasing the rate of red blood cell fonnation (refer to blood).
6. Insulin-li ke act ion (testosterone directly increases glucose uptake
by the tissues and also their scnsiti\ ity to insul in).

D1hydrotestosterone (DHT)
Testosterone is convened to DHT in some target cells by activity
of an enzyme ca lled 5 alpha-reductase (sec brlow). The plasma level of
OIIT is about I0 % that of testosterone and it binds to the same receptors of
testosterone. I lowe\ cr, the /)//T- receptor complexes are more stah/e than
the testosterone-receptor complexes, thus DIIT formation is a way of amp-
lification of the actions of testostetoue. This i~ required in the target tissues
where it is formed (sec next).

THE 5 ALPHA REDUCTASE ENZYME & FUNCTIONS OF DHT

There arc 2 types of the 5 alpha-reductase enzyme. Type I is present
in the skin throughout the body nnd is specia ll y rich in the sca lp, while type
II is present in the genital skin and the prostate as well as in some other
genital tissues. Consequently, DIIT is formed in these tissues in considerable
amounts, and performs the following fun ctions (rather than testosterone) :
l. In the fe tus, it induces development or the prostnte and ex ternal
geni tal organs (page 99).
2. At puberty, it ca uses (a) Enlargement or the prostate (and also
the external genita lia i.e. penis and scrotum together with testosterone) (b)
Hair growth allover the body specially fac ial hair (c) Fa ll of the scalp hair
and bi lateral tempora l recession of the frontal sca lp hairline (d) lncreascd
secretion of the sebaceous glands and development or acne.
 11 2

Section II - Chapter 2 The male reproductive .w stem

:::_ Since DHT causes prostati c enlargement, 5 alplw-reductase inhibiting

dmgs (which decrease DHT .\ )ln/hesis) are no 11· used in the treatment <l
benign prostatic hype11Jiasia.
:_: After iden tification of DI IT actions, the main actions that arc produced
directly by testosterone are (a) Development or the intemal genitalia in
the fetus (page tOO ) (b) En largement of the external gen ita lia at puberty
with Df/T(c) Increase of the musc le and bone mass (d) Increase of' libido.
5 ALPHA -REDUCTASE DEFICIENCY
Deficiency of the 5-alpha reductase enzyme is often due to congenital
disorders. Ho~,ovcvcr, its effects usually appear at puberty and include (a) Less
enlargement of the prostate and penis than normal (b) No or lillie hair growth
on the body (c) Dense scalp hair without temporal recess ion of the fron tal
sca lp hairline (d) Decreased secretion of the sebaceous glands.
In rare cases, type ll of this enzyme is mutated and not acting. This
leads to failure of development of the male external genital ia (althoug h
there ore testes and male internal genitalia) and appearance of female
extcmal genitalia instead i.e. male pseudohermaplmulitism (page I 0 I), so
th e newl y born baby is considered a fema le. ll owever, at pubert y and
under the effect of Lll, excessive amoun ts of testosterone arc secreted
from the testes whi ch causes male body co ntours and male libido as well
as marked enlargement of the clitoris like a penis. At this time, these indi -
viduals usually change their gender identities and become ma les.
ANDROGEN RESISTANCE
This is a cond ition in which testosterone is secreted from the testes,
but it is unable to exert its effects due to either absen t or abnormal
androgen recepto rs. or inability to chan ge to DHT due to lack of the 5
alpha-reductase enzym e (page I0 I). In mild cases. the male character-
istics do not develop at puberty, and there will be inlcrtility with or
without gynecomastia (breast en largement). However. complete loss of
receptor fi.mction results in a condition called the testicular feminini:zing (or
complete androgen resistance) syndrome, which is a type of male pseurlo-
ltermapltrorlitism . ln this syndrome, MIS is secreted by the embryon ic testes
with testosterone. so female interna l genitali a do not develop but there will
be female ex ternal genita lia due to lack or response to (or absence of)
DIIT (sec above). The indi vidual is thus considered a female (bu t the l'ag-
ina ends blind~v due to absence (?( the female imernal genitalia). l lowever,
the condition is diagnosed when the individual complains lack of menstruation.
 II\

ection II- Chapter 2 Tile male reproduc:til•e svstem

Hypo1h111mua

I
,,
I
I
I
I
I
I
I
I
I
I
I
I ,
,-.&.-_ .,_.
I I
I I
tn!.Ostero
( .hbn
I
I
I
I

,..
\
And•ogtnoc
1nd an1b0hc
olfett<
' ~,

Figure -tl : Endocrine control of testicular function.

CONTQOL OF TESTOSTERON SECRETION
Testosterone is secreted b) the cmbr) onic teste\ and 11 induces
de\ clopment of the genital organs. It is secreted under cl'lcct of the human
chorionic gonadotrop in hormone which is secn~ ted by the syncytio-
trophob last (page 137) and pro bably also by the fct~t l li ver and lddn cy.
During the first year of life, there is a temporary increase in testosterone
st:cretion, \\ hich is necessary for brain th.:vclopment. after which the testes
remain quiescent till puberty. ~ l n~imum secretion of ll.:'itostcrone occurs at
pubert) under cfTcct of LII. and 1s maintained alien\ ard'i 1111 the age of male
climacteric (\\ hich is about 60 )Cars) alkr '' hich at declmc'i gradually.
In adults, the fun<.:tions of the testes nrc normally completely
controlled by the CTHs (f H and LH), the secretion of'' hich is stimulated
by the GnRII released from the h) pothalamus (figure -t I). Due to such hypo-
thalami c control, testosterone sccrction is altcn:d in emotions and many
psyd10logical disorders. Its secretion nl-;o shows a diurnal rhythm (being
highest during night at pubert). and in the carl) morning in adults).
L/1 is tropic: to tlte interstitial cells of Leydig (stimulating testo-
sterone secretion) '' hilc FS/1 ;, tropic to the Sertoli cells (stimulating
st:cri!IIOn of inhibin and estrogens) nnd the hom1onal blood Je, els control the
activity of the pituitary hypothalamic axis by feedback mechanisms.
r\ high tcstostt:ronc blood lc\ cl feeds bacl- to inhibit Lll
'iccrcuon al both th e h) pothalamic and p11ui ta1y lc' l:l" (figure 41 ), and
vice versa. On the other hand , a high inhibin blood leve l l<.:eds back to inhibit
FSI I secretion from the anterior pituitary glnnd. and 'icc , ·cr...n.
 Il-l

Section II - Chapter 2 The male reproductive S!IStem

MALE HYPOGONADISM
This results from failure of testicular functio n, and it is 2 types :
(A) Primary h)'pogonadi s rn : T hi s occurs as a r es ult of a tes ticular
disease and it may be complete (i.e. all testicular functions arc lost) or
partial (e.g. in cryptorch idi sm in which only spermatogenesis is lost).

(ll) Secondary hypogon adism : This occu rs due to eith er pituitary or

hypothalamic disease (Kallmann 's !J)'mlrome), and is mmal~l' complete.
The clinical picture in caSI:!S of complete hypogonadism depends on
wltether the condition develop.<;· before or after puberty :

II) Pn·-puht.•rtal h~ pngnnacfi,rn : This condition is called etmuch-

oidism since its manifestati ons (whi ch appear in adulthood) are similar to
those occurring in emtuchs (= indil'iduals subjected to hi/alent! castration
during childhood). In addition to sterility, it is characterized by :
I. Infanti le sex organs and loss of libido (sexual desire).
2. A tall er stature than norma l (d ue to delayed fus ion of the epi-
physes to long bones) and may be a greater spa11 (=distance between the
full extended anns) than the body height (nonnally both arc nearly equal).
3. Absence of male sec:om!fuy sex characteristics : The body config-
urat ion resembles that of fema les (narrow shoulders, small muscles and
femini ne fat distribution in the hips and lower abdomen). The voice is high-
pit ched and the frontal sca lp hClirl inc does not recede. Pubic and axillary
hair appear (by the adrenocortica l androgens) but the hair is sparse. and in
the pubic region. it is triangular with the hase up (as in females).

(2) Po,t-pulwrtal h~ pogunadism . This cond ition occu rs CIS a result

of testicular, pituitary or hypothalamic disease. It also normal~!' occurs in
old age (and is called male climacteric) at about the age of 60 years (but it
varies greatly, and there is no tmdropause similar to the menopause that
occurs in women). It is characteri;cd by the following :
I. Depressed sexua l functions and libido. in addition to sterility.
2. Wasting and osteoporosis due lo loss of the androgen anabolic effect.
3. The secondary sex characteristics and accessory sex organs arc
almost not affected (s ince they need \cry Iittlc androgen for maintenance).
so the vo it:c remains deep and the body hair and pl!ni s nre not afTcctecl.
-'· The pntienh occasionally ha' e symptoms lik e those occurring in
menopausal women {e.g. hot flushes, s weating and palpitation ).
5. Psycltological disturbances : The pati ents common ly beco me
more irritable. passi' e and depr<:!sscd.
 115

Section II - Chapter 2 The male re[Jroductive svstem

The testicular function tests (fertility tests)

1. Measurement of th e CTHs level in the urin e : These are increased
in primary hypogonadism and decreased in secondary hypogonadism (so this
test is used to di fferentiate between the 2 conditions).
2. Estim ation of th e 17-kctosteroid s leve l in th e u r ine : T hese
nrc decreased in testi cular diseases since they a re the mai n metabo lites of
testosterone (page II 0). It is noted that the urinary excretion of the 17-
kctosteroids is also altered in diseases of the adrenal cortex (page 65).
3. Testicular biopsy(= microscopic examination of a sa mp le from
the testi s).
4. Semen anal ys is : Se men is the nuid cj ac ul atccl at orgasm (
end o f inlcrcourse). It cont ains the s perma tozoa sus pended in the
seminal plasnw (- sec reti ons of the seminal vesicles, prostate and
Cowper's glands).

NORMALSEMrN
Thi s is a whitish, opalescent, viscous and alka line nuid (hav ing a
spccili c gra vity I028 and pit 7.35-7.5 ). It s normal average vo lu me per
ejacu late is 2.5- 3.5 m / and th e norma l count or sperms averages /(){}
mil/io11 I ml with less than 20 % abnorma l a nd immotilc forms.
The secretion of the seminal \'csicles fonm about 60 ° ·o of the total
vo lume of semen, and it contninsji·uctose (whic h is the mai n nutrient
fo r th e s perms}, as we ll as fl av ins, ascorbi c acid and prostaglandins.
The prostatic secretion is alk aline unci fo rms abo ut 30 %, o f the total
vo lume of semen. It con tains t:itric acid. calcium and acid phospha tase a~
well as proreo~\'flc en:::ymes a11d orher elemenrs.

Causes of reduced male fertility

A snmpk or semen can be obtained by prostatic massage (ma nua lly
through the rectum). The fe rt ility power of semen is red uced when :
1. lts viscos ity is abnormall y high (which prec ludes the motility or the
sperms in the female genital tract).
2. Its volume per ejaculate is less than 2 mi.
3. Its spcnn content is bclo\\ normal ( oligos permia ) or it contain~ no
sperms at a ll ( azoo s permia ). A sperm count below 50 million ' m l
or semen is considered subfert ilc (50% ormen with sper111 counts o f 20-40
million I ml and all men having counts below 20 mil lion I ml arc sterile).
4. Its fructose conten t is grea tl y red uced.
5. Tts content of abnormal or imrnotilc sperms exceeds 25 %.
CHAPTER 3

I THE FEMALE REPRODUCTIVE SYSTEM I

The female organs of reproduct ion include the fo llowing (figure 42) :
(I) Them :u·it•s (= fcmah.· go n ad~) : These consti tute tlte primaJJ' sex
organs in females, and they perform the following functions :
a. An exoc rine fun ction (production and extrusion of ova).
b. An e ndocrin e fun ction (secreti on o l' estrogens, progester-
one and inltibin, as well as relaxin and a small amount oftestosterone).

(2) The accessory (secondar·y) SC"\. or·gans : These include :

a. The vagina : This is a distensible muscular tube that leads
f'rom the external genitalia (the vulva) to the uterus. The protruding part of'
the uterus into the upper part of' the vagina is ca lled the uterine cervix.
b. The ute ru s (the muscular organ in wh ich the fetus develops).
c. The 2 uterin e tubes ( fallopi a n tubes or oviducts) : These
arc muscular tu bes through which the ova discharged from the ovaries pass
to the uterine cavit y. At their end s, there arc .fimbria e which encroac h
upon the ovaries (fac ilitating en try or the ova into the utcrin<: tubes).

Figure 42 : The female reproductive system.

 11 7

Section 2- Chapter 3 Tlte (emale reproductive s rstem

Gametogenic function of the ovary(= oogenesis)

Unlike spermatogenesis. the proliferation or the primitive germ ce ll s
in the ovaries (tlte oogonia) occurs on(r during embryonic life, so 110 nell'
ova are formed after birth. The oogon ia grow into primary oocytes each
of which is surrounded by a single layer of flat epithelial ce lls cnllcd the
g ranulosa cells, fanning a primordial follicle (figure -D). At the 6' 11
month or embryonic development, there arc 7 million or these fo llicles in
both ovaries. but many undergo atresia (= degeneration) so tho1 a1 the
time of birth, 1here are 011/y aboul one million normal follicles. Meiosis
starts in the prirnary oocytes but it is arrested in the prophase stage. and
they remain in this condition till puberty. Follicu lar atresia then con tinues,
so their number in both ovaries nt puberty becomes on ly about 300000.
The ova ri an functions start at puberty (average 12 years) and stop
at tlte menopause (average 50 years). During the period between these 2
events (wh ich is the reproductive life span of tlte woman ). only one ovum
(sometimes more) is discharged from the ovaries approximately every month
(probah(r alternate~)'). Therefore. during a normal female reproductive li fc
span, only about 500 ova are discharged from the ova ries (aiming to form
a fetus) whi le the rema ining ova degenerate.
Ju st before ovu lati on, th e meiotic divisio n is comp leted forming
the secondary oocyte while the first polar body (figure 36) degenerates.
Accordingly, the released ovum is in the stage of secondary oocyte and it
immediately begins to divide. but such division stops at the metaphase and
is comp leted only wh en the ovum is fertilized. At that time, the second
polar body is cxpdled and the fcrtiliLed ovum proceeds to form a Ictus.

I THE SEX CYCLES IN FEMALES I

These arc regu lar cyc lic changes that occur in the adult females spec-
iall y in the rcprodm:tive system . They start at puberty and conlinue till
the menopause, ,\ lopping 01r~r duriiiJ!. pregnanc:1· or by disease. The O\ arian
and uterine cycles constitute periodic preparations for pregnam:r, and the
latter is cha racterized by vaginal bleeding( = menstruation or menses).
The duration of a single cycle is not constant in all women. but on the
average. it is 28 days from lire sfw·f (~/one menstrual period 10 lire s/orl (~(
the next. The .first day of menses is considered as the jirs1 cla.1· o{ tlw (rcle
am/1he days (~/file (\'cle ore identified by 1rwnbers startingji-om thi.\ day.
The first event at puberty in girls is deve lopment of the breasts(= the-
larche) followed by appearance of the axi llary and pubic hair c-
puiJ-
archc) then by menstruation (the first men ses is called menarche).
 I I:\

Section 2- Chapter 3 Th e female reproductil•e S!'Siem

= ---Cl>IIIUI
CoqHJI twlnurthl)(JICum
1lh ,\n·

G -ONI•ted
oocv••

Regrr11ong M; nm Young AtretiC

COI'J)UIIUitum COf!>IJI nJitum COrpuslult u m fol cl'

figure -B : D1agram of a mammalian O\ ar) slto\\ ing de' clopmcm of a

graalian l()llicle and formationnfthc corpus lutcum.
r
L I lit; u QIIQII "Y"'~ I

The O\'arian cydc consists of3 phases : ( I ) Follicular phase (2)

Q, ulation phase (3) Lut ea l phao,e.

(1) The follicular pllase

This phase ~tarts "ith the tirst day of mcn.,truation and ends "ith
O\ulation. Its duration is not constant due to \anabilit~ of the time of
ovulation. llowcvcr, si nce ovulation often occu rs in the 14 111 day of the cyc le.
this phase usually C\tcnds from the first da~ to the 1-t'" day of th e cycle.
l:arl) in tillS pha.,t..:, st..:\ t..:ra l primordial fnllt~.:lcs (6-::!0) start to gnm
under intluclll.:c of FSII. \\ hich acts on the granulosa cdls (CCs) b)
h1nding to specific FSII receptors (so FS/1 ;, re'JUm\ib/e for the earZr
gro11'th of the follicle' ). I SH causes h) pertroph) ,tnd h) pcrplasia ( = pro-
ltlcration) of the GCs. ,\lld stunulates them to sel:n:tc (a) A fluid rich in
protein. pol) saccharide.., and clcctrolytcs ( folli cu lar fluid or liquor follic-
uli ) 11110 a ca' it) that forms around the O\ um (= antrum ). "hich graduall)
lllcreascs in si;e caustng tllsplat:ement or the mum to one sidc or the rollick
(h) An estrogen (estradiol) in the follicular fluid (c) i\ mucopolysacchnriclc
substance cal led the :~ona pellucida which surrounds the ovum directly.
 119

Section 2- Chapter 3 The female reproductive srstem

** FS E-1 stimulates synthesis (and secretion) of estradiol in tlte GCs

by increasing tlte activity of tlte aromatase en:;yme (which converts
and rogens into estrogens), and androgens are provider/to tlte GCs cells
ji-om the theca intema cells. In turn, estradiol in duces follicular growth
and maturation by increasing th e number of FSH receptors 011 tlte GCs
(which augments the growth promoting effects of FSH).
The growing fol licles also aqu irc 2 layers from the ovarian stromal tissue
that surround the GCs. These arc (a) An inner rich ly-vascu lari zed cellular
layer called the theca interna (b) An outer poorly-vascularized fib rous layer
called the theca cxtc rna .
On about the 61h day of the cyc le, only one follicle in one ovary sta rts
to grow rapidly, becoming a dominant (or graafian ) follicle (figu re 43)
whi lc the others becoml! atretic (i.e. regress then degenerate). The selection
of the dominant jhllicle is related to the ability (~/ its GC:v to secre1e estra-
diol, which is required for ils maturation (see above). The atresia or the other
growing fo llicles occurs due to insujjicient FSH receptors i11 som e follicles
and inadequate secretion of estradiol in the others.
Under il~flu en ce of FS fl, tlte mature GCs also aquire LH receptors.
This is important because Lll (a) Stimulat es estradio l sec reti on by the
GCs (so both FS/1 and L/1 are responsible for the final maturation of the
graajianfollicle) (b) Plnys an essential role in the processes of ovulation
and form ation of the corpus luteum (see next).

(2) The ovulation plla se

Ovu lation is the process of expulsion of the ovum from the
graafiall follicle . It occurs in the midcycle, usua lly on the 14 111 day (but it
may occur slightly earlier or later than this day). The mature graafian folli-
cle is pushed towards the periphcty of the ovary and protrudes against its
wall. It then ruptures, and the ovum (surrounded by the zona pcllucida and
a single layer or epi theli al cell s) is ex truded into thc abdomina l cavity in the
secondary ooqte stage (page 117) together'' ith some follicular fluid . The
ovum is then picked up by the fimbriated end or the fa llopi an tube and is
transported to the uterus where it is fixed (if fenili/.cd) or lost out through
the vagina during menstruation.
Rupture or the graafian follicle occurs as a result t~f a burst of L/1
secretion called the Lll !I urge (page 124 ). Lll is thu~ the lwrmone of
ovulation, and it produces this function b) (a) lm:reasing the secretio11 of
the follicular fluid which increases the intra follicular pressure and comp-
resses the ovum towards the follicular wall (b) Stimu lating the follicular cells
to secrete pmteo~)'lic en-;;.rm es tltat break down tlte rwaritm wall.
 1211

Section 2- Chapter 3 The female reproductive srstem

(3) The luteal phase

The duration of' this phase is n.:markably constant at 14 days,
usually from the 15111 to the 28'" days of the cycle. The ruptured follick is
filled with blood f{)rming a corpus hemorrhagicum (figure -B). The blood
is gradually absorbed and the follicu lar cells hypertrophy and proliferate.
and a }CliO\\ ish lipid material appears in their C) topla-.m. These cells arc
called the luteal cell!<., and "ithin I to 2 days. the luteal cell mass de,dups
into an endocrine organ called the corpus lutcum ( y elloll' body ). The
formation of the corpus luteum depends on L/1 (page 12~) as well as on
development of an adequate blood supply, which is produced by a vascular
endothelial groll'th jiu:tor (JIEG F).
Under inlllll.:nce of Lll , the corpus lutcum continues to grow and
secrete hormones (estrogen and progesterone) l(>r about I0 days. reaching
full maturation on about the 2-t'" day of the cycle. Ir pregnancy occurs. it
persists and grows fimher (and is called the corpus lutetun ofpregnanc:y ) by
the effect or a hormone called human chorionic gonadotropin (page 13 7).
On the other hand . if pregnancy docs not occur. the corpus
luteum (\\ hich is no" called the corpus luteum of me11struatio11 ) begins to
degenerate ( lutc(l l) sb) and" ithin about 2 months. it is replaced b) scar
tissue forming a corpus a lhican s (- white bot~l '). The procc~s of
lutcolys is is produced by the combined actions of (a) Certain
prostaglandi11s, which ma) be formed by local~r-produced o..\]'tocin from
tlte corpus luteum (page J I) (b) ET-1 ( Endothel in - I ).

l;l ,o. K:J S S PIIl Al 8AS A.L CL .O.., O!;

Alnt~IES ;o.r T£ Ri l S

Figure -t4 : Blood suppl) of the endometrium.

 I~ I

Section 2- Chapter 3 Tlte fem ale reproducth•e srstem

I The uterine (or menstrual ) cycle I

T his cycle occur s scco nda t·y to the ovarian cycle and consists pf
the cyclic changes that occur in the mucosal (ilme1) layer of tlte uterus
called the endom etrium. This layer is formed mainly of connective tissue
stroma that contains tubular glands, and is divided into 2 main parts :
I. A fu nction al (s uperficial) part : This is co\·crcd by a single layer of
columnar epithelial cell s and it form about 2/3 of the endometrial
thickness. It is supplied by long coiled spiral arteries (figure 4-l) and is
destro_ved and sloughed (sited off) during m enstruation.
2. A ba sal (deep) pa rt : This forms about 1/3 of the endometrial thi ck-
ness and is supplied by sltort straight basal arteries (figu re 44). It is kept
intact durint: menstruation then it regen emtes t!t e f unctional layer.

Phases of the uterine cycle

T he uter in e cycle co nsists of 3 phases (1) Bleed ing phase (2)

Proliferative phase (3) Secreto ry phase.

(1) The bleeding phase(= destructive or menstrual phase)

This phase lasts 3-5 days, and it coincides with the.first 3-5 days f?(
the follicular phase of the omrian cycle. lt occu rs as fo ll ows : The corpus
luteum of the preceding cycle starts to degenerate on about the 24'" day of
tlte cycle (page 120), so the blood levels of bl)th estradiol and progcsh:ronc
are decreased. This leads to sh edding of tlte functional layer ol' the
endometrium and menstruation occurs about ~ days later as a result of
"ithdrawal of the hormonal support for the endometrium (so this type
of bleeding is called 111itltdrawal bleeding ).
The endometrium is thinned out ami scverc spasm and necrosis (
death) occur ill the '"ails of the spiml arteries. This results ill i.H·hemia
and necrosis (d' the supe1.Jicial layers of the endometrium together 11 1ith
spotty hemorrhages. The latter coa lesce lead ing to bleeding, and the blood
together with the sloughed (shed out) necroscd endometrial tissue form the
menstrual now. Vascular spasm is produced by loca lly-fom1cd prosta-
glandins from the cellular phospholipids by acti\'ity of the lysosomal
enzymes (which arc released from the necrotic cell s).
T he amount of blood loss during men struation varies fi·om slight
spotting up to 80 ml (average 30 ml) and 75 %, of it is arterial blood whi le
25 % is o.l venous origin. Normally, thi s blood does not clot beca use it
contains f ibrinolysin (which is produced by the endometrial tissue).
Section 2- Chapter 3 Tlze female repruductille S)IStem

Follicular Ovulation ' Luteal phase

phase (Day 14)

Days 0 5 10 15 20 25 28
Menstrual Proliferative Secretory
phase phase phase

Figure 45: Phases or the uteri ne (menstrual) cyc le. The upper line shows the
phases or the ovarian cyc le.

(2) The proliferative (or preovulatory) phase

This phase starts after the end of menstruation and if coincides ll'ith !lze
follicular phase of the ovarian (\'Cie except the firs! 3-5 clc~\'S (during which
menstm atio11 occurs). Therefore. it terminates when ovulation occurs.
Its durat ion averages 9 days, but it is variable depend ing on the duration
or the menstrua l flow and the time or ovu lation (so variations in the length (?(
the (1'Cie are most~\' due to change.\' in the dumtion of this phase).
During this phase, the damaged superficia l pan or the endometrium after
menstruation is regenerated from the basal layer. Thi occurs by the action of
estmdiol secreted by the theca interna cells l~( the g raajian follicle (under
influen ce of UI) as fol lows : (a) The deep pits or the endometrial glands
(\\h i<.:h remain intact al'tcr menstruation) start new ep ithelial growth wh ich
covers the inner surface of the uterus (b) The glands grow and increase in length
but they do not secrete (c) The blood vcsscls grow and become spiral (cl) The
endometrium increases in th ickness (becoming 3-4 mm thi ck) due to proli fer-
ation or its stroma l cell .
 123

Section 2- Chapter 3 The female reproductive svstem

(3) The secretory (or postovulatory) phase

This phase fol lows the proliferative phase and it coincides with the luteal
phase of the ovarian cycle, thus it starts after ovulation and its duration is
remarkably consta nt at 14 days after \\'hich menstruation occurs (in other
words, m enstruation IIOI'IIUtl~)~ o<:c11rs almost e.xact~v 14 days t~fier ovulation).
During thi s phase, the endometrium is prepared for implantation of the ovum (if
fertilized) by the e.f/'ecl of estrogen and progesterone that are secreted hy the
corpus luteum (particularly progesterone) through the following changes :
a. Further thickening of the endomctri um (reaching about 6 mm thick), so
it becomes real(rfor implantation oftlte fertili';.ed 01111111.
b. Deposition of large quantities of fat, protein and g(l'cogen in the endo-
metrial cells (which will be cal led decidual cells if pregnancy occurs).
c. The e11dometrium becomes more vascularized and the spiral arteries
reach the endometrial surface.
d. The endometrial glands become tortuous (= coiled) and secrete a
clear fluid, so the endometrium becomes sligltt(v edematous.

F UI\'( ' I'IONS OF 1.11 : ( I) Fi11almaturation t~j'tlt e gNu~fian follide by

stimulating (with FSII) estradiol secretion by the granulosa cells (page 119) (2)
Stimulation of estradiol secretion by tlte theca intema cells which di ffuscs into
the bloodstream and produces the prol[f'erath·e phase (~{the werine cycle (page
122) (3) Ovulation, t!trouglt tlte LH surge (page 124) (4) Formation and
maturation of the corpus luteum ( 124) (5) Stimulation of the corpus luteurn to
secrete progesterone and estrogen which produce the secretOI)' phase of tile
u1erine C:I'Ci e (see above).
H It is noted that t!te bleeding and prol~ferative phases of tlte
uterine cycle occur during the follicular pltase of lite ovarian cycle wh ile the
secretOJT plwse occurs during tlte luteal pltase oftlte ovarian cycle.

[ HORMONAL REGULATION OF THE MENSTRUAL CYCL£j

t. During the first 3-5 clays of the foll icular phase of the ovarian cycle
(which coincides with the bleeding phase of the menstrual cycle), the blood
levels of the ovarian hormones (estrogen and progesterone as well as inhibin)
arc low (figure 46). This stimulates secretion of the piuitary GTI-ls by a
negative feedback mechanism. FSH produces tlte ear(l' grmvtlt oftlte grnajian
follicle ll'ltile botlt FSH ami Lll induce itsfinalmaturation (page I 19).
The theca interna has many LH receptors and U I stimulates estradiol
secretion )i'om the theca interna ce!/s (by converting cltolesterol to androgen
wlticlt is then con verted to estradiol). Estradiol then diffuses into the blood-
stream cmd produces the prolifcnHive phase of the uterine cycle (page 122).
Section 2- Cha[Jter 3 Th e female reproductive Sl'Siem

r OlltC.ul.u
phase

200

ng/m L 100
______ ,..
0

50

40

30
IU
/mL
20

10 .,.--- ... . . __ ..
!":"!' r s~·_:.., .....:-:. •
o~~~~-~~~~~~~~~~~~~
1511 1 3 5 7 9 11 13 15 17 19 2 1 23 25 11 I 3 5
0 nl(' v do

Figure 46 : The plasma concentrations of the 0' :man hormones and G rJ Is

(FS II and Lll) during a normal mcnstma l cy<.:le {~ 1 mcnstmation).
2. The rising blood lc\ els or estradiol (secreted 1>1 the thl..'ca intema cell'
u11der e.ffect of LH) and inhibin (secreted by 1he GO under e./feet of FSI I)
limit the secretion of FS II by a llt!J.:ative Jeer/hack medumism . LH secretion is
also held in check by th~.: m:gati' e feedback effect of the rising plasma estradiol
lc\ el. l lowcver. the blood FS II and Ll I levels remain high enough to maintain
follicular growth and its secretor) functions.
3. At about the I0111 da) of the cycle. tht: estradiol sccrctcd by th~.: theca
intcrna cells is marked I) increased. and at about the 12111 da) (i.e. 36-t8 hour
before o' ulation) the cxccssi' cl) high blood estradiol Jc,cl, through a positil·e
feedback m echanism. trix;.:ers a considerable bur.\1 of L/1 .\ ecretirm called L/1
.Hm:e (figure 46) together ll'ith a .\mtrller FS II surge (in spitc of the high blood
k\el of inhibin). This cffcct of cstradiol i:, attributt.:d to augmcntation of thl!
rcspons ivencss of the pitu itary gonadotropcs to GnRII. Lll induces o1•ulation
about 9 !tours after the LH p eak tlten luteini';.ation of the f ollicular cells.
formation of the corp/1\ luteum and its stimulation to \ ecrete lwmwnes
(e.\ tro~en am/ pro;.:estemne).
 125

Section 2- Cltapter 3 Tlt e female reproductive srstem

llypolhalamu s

I
,,
,'
I
I

I
I
I
I
I
I
I ,......._., _,a.o
I ,
I I
I I
Estrogen (
I
I

' ..
\

f igu re 47 : llormonal interacti on in the control of O\ arian functions. Th~.: dashed

arrows indicate inhibitory effects.
4. After ovu lation, the estrogen blood k\cl temporaril y drops, but however. it
increases again together with progesterone, since they arc secreted by the corpus
lu teum under effect of LH (figure 46). The blood levels of both hormones thus
markedly incrcast:, and they produce the secreto ry phase of the uterin e cycle,
specially progesteron e (page 123).
5. The im.:n:ascd estrogen and progestcrom: blood levels inhibit secretion or
the GTHs by a negative feedback action, so their blood levels decrease (figure
..J6). I lowe\ cr. once the corpus lutcum is formed. its acti\ ity is maintained
independent of the GTHs for I0 days (till the 24 111 day of the cycle). after'' hich
luteolysis occurs. This is foll owed about 4 days later by menstruation du e to
fall of the estroge n and progesterone hlnod levels after regression of th e
corpus luteum (page I 21 ).
6. The decreased estrogen and progesterone blood levels also lead to secre-
tion of GTH s rrom the anteri or pitu itary by n nega tive feedback mechani sm,
whid1 start a new cycle by inducing fo rmation or a new graafian follicle.
~ Til e granulosa cells of the o11arian follicles are controlled by
botlt FSH anti L/1 . fhc forml.!r stimulates secretion of inhibin and eo,tr:t diol
\\ hilc the Iauer stimulates secretion of l.!stradiol only. and tile \ecreted estradiol
enters tlte follicular fluid. On the other hand, I he theca in terna cells pro\'idc
a ndrogen to th e GCs (to synthesize est rad iol) a nd arc controlled hy LH
only, which stimulates th em to secrete estradiol that enters the circulation
(figurl.! 47).
Section 2- Chapter 3 The female reprot!ucth•e s pstem

~cl ic changes in the vagina and uterine cervixJ

Th e vaginal epithelium and the mucus in th e uterin e cer-vix

undergo changes secondm:r to the m·arian c:,·c/e as follows :
(I) In the follicular phase. estroge n secreted by the graafian follicle
makes the cervical mucus elastic, thinner and more alkalin e (\\ hich
promotes the survi\'al and transport or sperm.). and "hen spread on a
slide, it dries in an arbori:ing [em-like pattern (fern is a feathery plant).
On the other hand. the vaginal epithelium becomes comijied.
(2) In th e luteal phase. progesterone secreted by the corpus lutcum
makes the cervical mucus thick, tenacious and cellular bu t it rai ls to ronn
a fern-l ike pattern when dried. On the other hand. the l'(tginal epithelium
prol(lerates allCI is il!flltratecl ll'ith /eukoc:rtes.
~ There arc oth er cyclic cha nges in adult females which include :
1- The basal metabolic rate increases by 5-10 % and the basal body
temperature rises by about 0.5 nc after ovulation (figure 46) due to the
thermogenic e.ffect of progesterone (page 133 ), and they rem a in high ti II
the end or the cycle then they return back to their normal levels.
2- Under the effect of' progesterone, the blood flow in thi.! mammary
glands increases. This leads to edema in the interstitial ti ssw.: of the breasts,
so they swell and become tender and painfu l during the last I0 days or the
cycle. ll owevcr, such effects di sappear with the onset of menstruation.
3- Under the effect of estrogen and progesterone (as" ell as aldosterone)
some sa lt and water retention (and weight gain) occur in females during the
few days that precede menstntation (= premenstrual tension ). llowever.
such effect disappears with the onset or menstruation.
4- Libido (sexual desire) is said to increase from the midcyck onwards
(being highest towards the end or the cycle).

Reflex ovulation

Certain female animals oYulate only after copulation. This occurs

reflexly through afferent impulses arising from the genita lia (in addition ro
visual, auditory and olfactory impulses) U1at converge on the hypothalamus
(inducing release of GnRII , which produces ovula ti on by libcrn ting LH
from the anterior pi tuitary gland).
:,:: Re tlt:x ovulat ion docs not occur in human fema les. ll owcver, the
menstrual cycle in women is frequent ly disturbed in the sa me way (i.e.
through the hypothalamic control on the secretion of GnR H and GTHs) e.g.
during em otions and stressful conditions.
 ] _,
"-

Section 2- Chapter 3 Th e female reproductive S!'Stem

[A NOVULATORY(= NONOVULA TORY) CYCLES ]

These are menstrual cycles without ovul ation. They arc normally
common in the first 12-1 R months after menarche. before the menopause and
alter stopping lactation (page 146). In the e cycles. graafian follicles arc formed
and they secrete estradiol in amounts that produce endometrial gro'' th but fail
to stimul ate the Lll surge. Accordingly, ovulation docs not occur. the
corp us 1utcum is no t formed and the secretory phase of the menstrual cycle
disappears. However. estrogen continues stimulating proliferation of the
endometrium. then sloughing and bleeding occur as a re ult of either rcgre ion of
the graafian follicle ( o sloughing occur., due to estrogen witlulrml'lll). or
thic:kl'ning of the endometrium to the extent thnt induces its breakdown. The
ti me it takes fo r bleedi ng to occur and its amou nt an.: vari ab le in the anovul a-
tory cyc les. However, the duration of th ese cyc les is generally shorter th:m
the duration of norma l cycles (i.e. less than 28 days) in most cases.
ko~ can ovulario b,:l -Jet cted ? (hdic?tors of ovularion)
Ovulation can be detected b) the folio\\ ing methods :
I. Ex a mination of an endom etrial biopsy in the second half of th e
cycle : The presence of features of the secre tor) phase indicates ovulation.
2. Measurement of th e ha sa l bod y temp e r at ure (in the mo rning
bcl'ore getting out or bed). Its rise by about 0.5 ° ( at about the midd le of the
cycle (in absence of disease) is indicative of ovulat ion (pnge 126).
3. Exa min ation of a vagin a l s mea r a nd mu cus fr om the ute r ine
ce n h : The presence or the characteristic changes produced b] progesterone
(page 126) indicate O\ ulation.
-t Estimation of th e blood GTHs levels : A sudden increase just before
the midcycle (specially Lll ) suggests ovulation but is not conclusive.
5. Es timatio n of pro geste ron e leve l in th e plasma (o r pregnan ediol
in urine) : Their increase in the second ha lfol'the cycle suggests ovulation.
6. Obse rvation of a n ec tin g lowe r a bdom in al pain at th e middl e of
the C)cle : The presence or such pain (in absence of disease) often indicates
O\ ulation. It is due to p eritoneal irritation that occurs as a result of minor
bleeding in the abdominal ca' ity after rupture of the graalian follicle.
7. Obse rvatio n of mid cyc li c b leedin g : This may occ ur due to drop
in the blood estradiol le' el after rupture of the graafian follicle.
8. Detection of ovarian therma l changes : The ovarian temperature can be
detected by a simple thermosensi tive device. Its rise in one of the ovaries often
indicates ovulation (such rise is due to hyperemia produced by the LH surge).
 128

Section 2- Chapter 3 Th e [emale reproductive S!IStem

IContraception (prevention of pregnancy)

(A) Methods of contraception in females

1- Contraceptive pills : Most contracepti ve pil ls contain relative ly

large doses of both estrogen and progesterone or estrogen alone. whi ch
inhibit the release of GTI/s by a negativt.: feedback mechani sm, thus
preventing fo llicular growth and ovu lat ion. Progesterone also makes the
cervical mucus thick which precludes sperm migration.
_:: Synthetic progesterone preparations (:;::: progestins) alone (without
estrogen) can also be used as contracepti ves. They arc avail able in the form
or tablets, intramuscular injections (given once cvcty 3 months) and as
subcutaneous implants (which can prevent pregnancy for up to 5 years).
_::: Large doses or estrogen taken by the woman after coitus for 4-6
days can prevent pregnam:y by interference with implantation of the fertili-
zed O\ tun. This is kno'"n as postcoital (or moming ajfer) contraception .
2. Placing intra-ute rin e devices (I UDs) e.g. copper or plastic
loops: These devices were th ought to inletfere with ovum implattlfltion
by distutrbing the normal endomelrial cyd ic changes (which h.:ad to
failure or development or the progestationa l changes necessary for implan-
tation). ll owcver, it is now believed that they prevent sperms from ferti-
lizing ova. In addition. the devices that conta in copper appear also to exert a
spermatocidal effect.
3. Placin g spermatocida l foam s in th e vagina : These roams either
ki ll thl! sperms or precludt.: the ir motility (according to the type of foam).
-t Placing di ap hragm s in the vagina : These arc intended to cover
thl! uterine cervix. thus preventing the sperms from getting into the uterus.
5. T ubal ligation : This i~ ligation of the 2 fallopian tubes. ~o fertiliza-
tion ca nnot occur. ll owever, this method produces permanent steri lity.
~ I n lactating women, breast feeding can be used as a mcthocl of eont-
r:lcel)l ion because the lactation process prevents ovulation (page 146).

The rhythm method of contraception (Safe Period)

Si nee the Ol'(t are l'iahle for ferril i:;otionj(Jr Oll~l' about 2./ hour~
ci/ler O\'llllllion (al!lwugh !Ill!\' 11/C~\' sun·il·e .for 72 hours) am/the SfJt>l'll/,,
sun·il·e in the .female geniwl tract .fhr about -18 hours (and jiJr longer
limes in some instcmc:e.\'). the effective fertile period is about 72 hours
(..tH hours before and 2..t hours after ovulation) and the rhythm m ethod of
ctmtrac:eption depends 011 m•oidance of intercourse at that period. Dur-
ing the periods before th~ 9'11 thl) and after tht: 20'11 day of the C) cle. thl.!rt:
Section 2- Chapter 3 The female reproductive s rstem

is little chance lo r prcgnnncy to occur. and arc thus called the safe period .
I lowcvcr, th is meth od is not absolute~!' st~j'e bccaust: th t: tim e of ovula-
ti on is variab le and some ova and sperms may survive fo r longer times
than usual i.e. no day in the cycle is qui te sa fe, and pregnancy was repor-
ted to occur as a result of isolated coitus on l! l'l!IJ ' day oftlte c.:J'cle.
(B) Mett .ods or contraception 1n males
I. Coitus interruptus : Th is is rapid wi thdrawa l of the pt:nis j ust bcl(m:
ejacu lation so that semen is ejected outside the female genital tract.
2. Taking a hot bath 30 minutes before coitus : This ma) be ust:ful
since heat depresses spermatogenesis and kill s the stored sperms (page f07).
3. Usc of condoms : Condoms arc thin rubber sacs that arc applied to tht:
penis SO that they tightf ) CO\er lh glans. J\ t the end or a se:....uaf intercourse.
the ejaculated semen "ill be collected in these sacs and thus prevented to
enter the female genital tract.
~. Giving exogenous testosterone : Gi' ing moderate dail) doses of
testosterone depresses spcnnatogenesis (page I07).
5. Giving GnRII -reccpt or blockers : These dnags inhibit the secn:tion
of'GTII s \\'hich suppresses spermatogenesis. lnh ihin also dt:crea:.e~ the s~:cr­
~:t ion of FS II and is tried to be used us a contraccpt i' e drug (page I 01) ).
6. Vasectomy: This is bila teral ligation of the \as delerens. It is an cnici-
ent method of contraception , but it leaves the indi vidual permanently sterile.
THF MENOPAUSE
lenopause is the cessataon (stoppage) of the '>C:\ C) des in ti:malcs.
\lcnstrumion u.uall) becomes arregular then cease" hct,,een the age'> nr -t5
and 55 year:, (common I) at 50-52 yea rs). 'I hi:. occur.. due to (a) Decline in
the number of primordia/follicles (b) Lnre.,pomin'lle\.\ (?/the omrie\ to
the GTI is. although their secretion is increased by a neguti\ c feedback
mcchnnism due to the decrea~cd estrogen and progeslt:rone blood Jc,els.
l he dccn:asc in the marian hormonal blood lc\cls (spe<.:tall) estrogen)
leads to the following <.:hangcs :
1. O steoporosis (due to loss of the anaboltc effect or estrogens).
2. Regre sion of the eco nd a ry se:\ cha r ac tcri\t ics.
3 . .-\ trophy of th e a ccessor) se'\ or·gan s.
~. P ) Chic manifcstat itHl ' (irritabilll). an:....tet\. \\Cakness. l~tigue.
headache. dt//tness and lll:t) be true psydlOiogac,tl depress ton)
5.\'asom otor disturban ces : There 1s common!) a sen~ation or hnt
11ushcs assoc iated \\ ith sweating (probably due to an e\ent that occurs
in the b) pothalamus). Th ese .\ ymptoms ca n he re/i(!l'e d by da ily adm -
ini\lration of w w/1 doH!.\ of e\ troxen.
 IJO

Section 2- Chapter 3 Th e female reproductive srstem

I THE OVARIAN HORMONES I

I [A] ESTROGENS I
These arc C1x steroid hormones of which there are 3 types: estradiol
(the most potent). estrone and estriol (the least potent). In females. estrogens
in the circulation arc secreted from ( I) The ova ri es (by the cells of the
th eca interna of the graftian follicles and the cell s of' the corpus luteum) (2)
The placenta (page 139) (3) The adrenal cortex (very small amounts).
Plasma concentration and transport of estrogens
Only 2% of the circulating estradiol is f'rec while the remainder is bound
to protein. 60% to albumin and 3S cyo to gonadal steroid-binding globulin (GBG).
The secretion of estrogens is continuous throughout the menstrual cycle,
but it shows 2 peaks (figure 46) :
I. A maximal peak iust befo re ovu lation (380 microgm I day) due to
excessive secretion from the graalian follicle to initiate the LH surge.
2. A sma ller peak in the mid lu teal phase (250 microgm I day) due to
secretion from thecorpus luteum.
Mechanism of action and metabolism of estrogens
Like other steroid honnones. estrogens act through increasing
transcription of mRNAs in the target cells after binding to speci fie
cytoplasmic receptors (page 6). then they arc converted to glucuronide and
sulphate conjugates in the li ver, which arc cxcrcf'cd in the urine. Some
estrogens arc also excreted in the bile.

ACTIONS OF ESTROGENS

Estrogens initiate and maintain all changes that occur in females at

puberty. They nlso perform metabolic functions and special actions during
pregnancy. These multiple actions are produced through their effects on :
(1) The primary sex organs (t he ovaries) : They induce growth
and maturation of the graafian follicles. and arc essential for f01mation of the
corpus luteum by stimulating the LH surge (page 124).
(2) The accessory (seco ndary) sex organs :
a. Th e uterus : Estrogens stimulate growth of the myometrium and
the endometrial epithelium and glands, and increase the uterine blood flO\\.
They produce the proliferative phase of th e m enstrual cycle. They also
in crease the amount of uterine muscle in pregnancy, its activity and
excitability and make the uterus more sensitive to oxytocin (page 142).
 131

Section 2- Cllapter 3 Tile female reprod11ctive svstem

b. The ovid11cts (= uteri11e or Fa//opoia11 t11bes) : Estrogens stimulate

growth of their mucosal and muscular layers and increase their motility.
c. Tlte 11teri11e cervix : Estrogens make the cervical mucus thin and
alkaline which promotes the survival and transport of sperms (page 126).
d. The vagi11a : Estrogens cause thickening of the vaginal epithelial
lining and cornification of its superficial layers (page 126).
e. The external ge11italia : Estrogens are responsible for growth of the
vestibular(= Bartholin's) glands and the vulva (the labia majora and minora).
(3) The female secondary sex characteristics : Estrogens are the
feminizing hormones that produce the following changes in girls at puberty
a. Changes in the body configuration e.g. narrow shoulders, broad hips,
convergence of the thighs and divergence of the arms (wide carrying angle.'i).
b. Characteristic fat distribution: Fat is deposited in the breasts, butt-
ocks and lower abdomen (producing the characteristic feminine contours).
c. The larynx is not enlarged by estrogens, so the female's voice
remains high-pitched as in children (due to absence of androgens).
d. Less body hair and more scalp hair without frontal recession. An-
drogens from the adrenal cortex cause growth of the pubic & axillmJ' hair.
The pubic hair is triangular with its base up (=female e.'lclltclteoll).
(4) The mammary glands : Estrogens increase fat deposition and
blood flow and maturation of the duct system leading to breast enlarge-
ment. They also induce growth of the nipples and darkening of the areolas.
Such effects are intensified during pregnancy (page 144).
(5) Estrogens are also responsible for the psychological and behavioural
changes that occur in girls at puberty. They also increase libido(= sexual
desire) by a direct effect on certain neurons in the anterior hypothalamus.
(6) Interrelation between estrogens and other hormones :
a. The actions of estrogens on the endometrium and mammary
glands are 11ecessary for progestero11e to exert its actions.
b. Estrogen.'! control tlte secretion of GTHs as follows : A moderate
constant increase in the plasma estrogen level inhibits secretion of the
GTHs by a negative feedback effect, while a sudden increase in its
plasma level stimulates secretion of GTHs by a positive feedback effect.
The latter effect is manifested by the LH and FSH surges (page 124) and
is prevented if the plasma progesterone level is increased (as occurs in
the luteal phase of the ovarian cycle).
c.Estrogens stimulate prolactin secretion during pregnancy but prevent its
milk secretory' action by blocking its receptors in the brea.'lts (page 145).
d. Estrogens cause ACTH secretion and enlargement of the adrenal cortex.
e. Estrogens sensitize the myometrium to oxytocin action (page 142).
 132

Section 2- Chapter 3 Tlte (emale reproductil'l! spsl em

(7) Meta b o li c actio ns or es trogens :

a. Estrogens ~xert a protein anabolic e./feet and accelemte.fusion of
the epiphyses (so the body swturc is usual ly shorter in girls than in boys).
b. Estrogens have a sign ificam clwlesterol-/mvering action. This
may be the cause of the low incidence of atherosclerosis in women.
c. Estrogens cause salt and II'CI/er retention. This may cause premens-
tmaltension in some women before menstruation (page 126).
d. Estrogens render the secr etion (~/ th e sebaceous gland.\ more
Jlu id. H'hich pre1•ents formation of blackheads· (= comedones) and acne.
e. Estrogens increase the secretion of angiotcnsinogen by the liver.
f. Estrogens increase the formation of tiH.: thyroid-binding globulin.

I [B) PROGESTERONE I
Progesterone is a C21 steroid hormone that is secreted main ly by the
co r pus lut cum a nd placenta , and in very sma ll amounts by the ovarian
fol licles (granulosa cells). the testes (Leydig cells) and adrenal cortex.

Plasma conc<?ntration and transport of progesterone

During the prco\'l.tlatory (prolifcrati\e) phase of thl.! menstrual
cycle, the plasma progesterone level is about 0.9 ng /mi. Such val ue
increases 20 fold (becoming 18 ng /ml) during the postovulalory (secretory)
phase due to excessive secreti on from the corpus luteum. Similar to
estrogen~. 2 °o is free in the plasma \\'hile 9R 0 o is bound to protein. 80
0
o to albu min and 18 °fu to thr..: co11 icostcroid binding globu lin (CBG).

Mechanism of action and metabolism of progesterone

Like other steroid hormones. the effects or progesterone on its target
cells arc produced by increasing tNmscriptirm of mR1\'As after binding to
specific ( l'toplos/J/ic receptor.\. \l'hich are bound to a heat shoe/, protein
(page 6). Progesterone is then converted in the liver mainly to preg-
mmedio/, which is conju gated tn glucuroni c acid and excreted in the urine.

ACTIONS OF PROGESTERONE
Progesterone is essential for occurrence and maintenance of pregnancy
(so it i~ the hnrmonc of preg nan cy). It perform~ the folio\\ ing actions:
(1) On th e uterus
a. It produces the progeslarional changes in the endomelriu111 during
the secretory pltase oftlte menstma/ cycle \\'hich are essential fo r embedding
and implantation or the tet1ilized O\ um and f'onnation of the placenta.
 lJ3

Section 2- Chapter 3 Tlt e female reproductive Sl'Stem

h. It decreases 1he exciwbilily of the myometrium (h.'' increosing its

resling membrane polential and decreasing ils frequeiiC.'' ofsponlaneous
electrical activity). It decreases tlte myometrial sensitivity to oxytocin
(wltich is essential for tlte maintenance of pregnancy) and also the
1111111her of estrogen receptors in the endometrium.
(2) On the uteri ne ccrY ix a nd vagi na : Progesterone prod-
uces characteristic changes in the cervical mucus and vagina l epithelium
during the luteal phase of the menstrual cycle (page 126).
(3) On th e ma mmary glands : Progesterone stimulates develop-
ment of the lobules and secretory alveoli of these glands. and full matura-
tion occurs during pregnancy (page 145).
(.t) O n the a nterior pituitary gland & hypo tha lamu s :Progesterone
inhibits Ll I secretion by a -vc feedback mechanism at both levels (and also
potentiates the inhibitory effect of estrogen) so it prevents ovu lati on.
:::, Accordingly, large doses of progesterone or one of the .\ yntltetic
progestins are used as contracepti ve drugs (page 128).
(5) O n metabolism :
a. Progesterone has no sign(f/cant anabolic efTecr.
b. La rge doses of progesterone produce 11atriuresis probably by blo-
cking the action of aldosterone on the kidneys. lt also causes conslipation.
(6) O n body temp erature : Progesterone is thermogenic and it pro-
bably causes rise of the basal body temp. if ovulation occurs (page 126).
(7) O n resp iration : Progesterone stimu lates respiration, leading to a
decrease in the alveolar C0 2 tension in women during the luteal phase or the
menstrual cycle as wel l as during pregnancy.

I [C) RELAXIN I
Th is is a pn~vpeptide hormone (which structurally rese mbles the
human insulin and IGFs). During pregnancy. it is markedly secreted in the
first trimester by the placenta and the corpus luteum c~ltJregnall(\ ' under
effect c~l hCG (page 13 7), and it is also found in !he mammw:1· g./alllls.
It relaxes the symphysis pubis and olher peiFic joill(s. and sc~jiens and
dilales !he ulerine cen ,ix. thus facilitating delivery. It nl so inhihirs 11terine
contmctions and may help development of the mm11mm:l' gland. In non-
pregnant women. it is round in the corpus luteum and endomelrit1111 (during
the secretory phase) but its functions arc unknown. In men. relaxin is
produced by !he proswte gland and is frnmd in til e semen (in which it may
play a role in maintaining the sperm's motility and its ab ility to penetrate
the ovum).
 13-1

Section 2- Chapter 3 The (emale reproducti11e srstem

@ ONTROL OF SECRETION OF THE OVARIAN HORMONES

The secretion of the ovarian hormones is contro lled primarily by the

hypothalamic-pituitary axis (figu re 4 7). The hypothalamus secretes the
GnRII which stimulates secretion of the GTIIs (FSH and Lll) from the
anterior pituitary gland, and these in tum control secretion of the ovnrian
hormones.The GnR II is 11ormal~1' secreted in episodic bursts the lh:quency
of which (and consequently the rate of secretion of the GT!Is) is adjusted
by the blood le\ els of the O\'arian hormones through the folio" ing
feedback mechanisms :
1- FS II stmu lates the gra nulosn cells to secrete inhibin wh ich inhi bits
secret ion or FSH from the anterior pituitary by a rH.:gntivc feedback action.
2- Lll stimulates synthesis or estrogen ill the theca inlemo cell\ from
androgens (spt:cially androstenedione), which is then secreted into the blood
stream and produces the proli lcrativc phase of the uterine cycle (page In).
Accordingly. the estrogen blood level moderately increases and this inhibits
secretion of the GTII s by a negative feedback mechanism paricularly at llw
pituitary level. The the('(/ intema cells also prm·itle androgens w the gmnul-
osa cells /tJI' synthe~is of estrogen thm d[[/il.\es i1110 thej(JIIicularJiuid.
3- When the estrogen blood level is excessively increased late in thc
follicular phase of the on1rian cycle. it stimulates secretion or GTils by a
positi ve feedback action (LH and FSH surges, page 12.4). This effect
occurs because the high estrogen blood level i11creascs the Ji·eqtwllc_:r of the
GnR/1 hur.\ts am/the respomil·eness ofthe gonoclotmpes to tlti.\ hormone.
4- I II stimulates thl.! 111ature gro11ulo:w cells to secrete estrogen 11-hich is
imporwnt.fin'jii/1 moturotion <?l the gmqjiolljh!licle ll'ilh FS/1 (page I 19).
LH also induces o\'11/ation and formation or the corpus luteum after ovu-
lation. and its stimulation to secrete progesterone and estrogen (page 124 ).
5- The increased progesterone blood lc\ cl (potentiated by estrogen)
inhibits the release or Lll by a negative feedback mechanism (particularly at
the hypothalamic level by decreasing lhc l'rcqucncy of' the Ci nR II bursts)
which results in reduction or the blood levels of these hormones.
6- During the first 6-8 weeks or pregnancy. a special hormone called
hum an chorionic go nadotrop in (hCG) stimulates the corpus luteum to
secrete estrogen and progesterone (page 137).

Abnormalities of ovarian function

These occur as a result of either ovarian disorders, or hypothalamic or
pituitary diseases. The commonest abnormalities include the following :
( 1) \nm ulaton cyde., (page 127) (2 ) l\1en'itt ual ahnormalitil~., (sec next).
 135

Section 2- Chapter 3 The [emale reproductive svstem

n. Amenorrhea ( absence of menstruation) : This may be prim ary

(if the menstruation has never occurred) or seco ndary (if it occurs in a
woman with previously normal periods).Thc Iauer may be due to disease
or normally durin g pregnancy (page I-ll).
b. Oligomenorrhea: This is scanty (little) menstrual now.
c. Menorrhagia: This is profuse (excess) menstrual llow.
d. M etrorrhagia :This is uterine bleeding between the periods.
(3) II~ pu o\ urianbm (lunak In poguuadi,m)
The manifestations of this condition depend 011 the age of onset :
a. Bl'l"un~ puhl'rl~ [e.g. due to congenital absence or mal-
development of the O\aril:s). there will be primal)' amenorrhea. sterility,
no develop-ment of the secondary sex characteristics. and the accessory
sex orgnns remain infantik. In addition, the patient is taller than 1wrmul
due to delayed fusion or the epiphyses to the long bones.
h. \ltu puhcrt~ (e.g. due to a se' en: O\ arian disease). there will
be secondary amen orrhea, sterility, regression of the sex organs. •vasting,
osteoporosis. and the pubic hnir decreases and becomes thinner. II is noted
that such manifestations occur normally f~jier the m enopause (page 129).
(-t) (harian tumour-.;
The ovarian tumours arc general ly rare. Androgen-secreting tumours
can cause masculini::ation. \\bile estrogen-secreting tumours can cause (a)
Precocio us sexual development if they occur during childhood (b)
Irregular uterine bleeding if they occur in adult life. Uterine bleeding (!fter
the IIU!Ilopm1se is f~/ic!ll the./irst indication c~f'an Ol'arian 1111110111'.
[PREGNANCY (GESTATION OR CONCEPTIO]fl

FERTILIZATION AND IMPLANTATION

::.::_ When ovu lation occurs , the ovum is expelled into the
peritoncnl cavity then it enters the fimbriated end of the ut erine tube. and
fcrti l i~ation usua lly takes plncc in the !atcml part (ampulla) of this tube.
~ Sperms require H rcw hours in the fe male gen ital tract in order to
become more capab le lor tertilization ( SJH~•m rapacitation, page 106)
and ferti lization is favoured by chemo-allmction (~/the sper111 to the ovum
by substnnccs produced by the ovum.
::Although millions of spenns arc deposited in the vagina at the end
of intercourse, only 50 - I00 reach the ovum. and only about I0 of these
adhere to the ;ona pellucida (ZP) at spec{/ic sperm receptors coiled ZP3 .
This is fo ll owed by the :u.T o,umal n'al:lion i.e.brcakdown of the acrosome
at the sperm head (page I06) and release of various enzymes including a
tl:lpSill-!ike protease called acrosin which fl1cilitates penetration or the
spcm1 through the ZP.
 136

Section 2- Chapter 3 The [emale reproductive svstem

::..2 After penetration of the Z P, the sperm head adheres to the cell
membrane of the ovum. This is fol lowed by breakclwon of the area of
fusion and and release of the sperm nucleus into the cytoplasm of the
ovum. Fusion of the sperm to the ovum membrane is med iated by fertilin
(protein on the surface of the sperm head). The fusion causes red uction in
the membrane potential of the ovum fo llowed by a structural change in the
ZP, and these events prevent polyspermy (= penetmtion of the ovum by
more !han one sperm} which leads to failure of fertili zation .
'!:!._ The fusion of the sperm to the ovum provides the signal that
initiates dev.elopment.The result of such fusion is the zygote, whi ch after
about I day, starts to divide mitotically to form a mor ula. This moves
slowly down the uterin e tube (by the movement of cil in and al so peristaltic
contractions) and reaches the utems within 3-4 days r!fier.ferlili:::.ation.
::.::_ The morula then deve lops into a bl astocyst, whi ch becomes
sunounded by the t ropho blast (which consists of 2 la yers : an outer
layer called syn cytio-trophoblast and an inner layer called cytotropho-
blast). On about !he 6111 day afier ferlili:::.alion, the ZP disapp ears and !he
lrophoblasl adheres to the endometrium .
.:..::. The process of implantation sta rts on the 6th- 7t11 day after ferti -
lization and is completed on the gth - 9th day. The sy ncyt io-trophoblast
erodes the endometrium and the blastocyst burrows into it til l it becomes
implanted. Th is usually occurs at the posterior or dorsa/ wall of th e uterus
(figure 48), and is fo llowed by development of the placenta.
-::._ It is noted that implantation of the ovum starts about I week af1er
its ferti lization. This deh~v is important because the endomelmlln is prepared
during this period.for imp/all/a/ion b,l' the hormones f~/the co1ynts luteum.

I The corpus luteum of pregnancy I

Progesterone is essential to ma in ta in pregnancy (so it should be ava il-
ab le throughout pregnancy) because it reduces the excitability l~( the uterine
muscle to o.\yfocin (thus uterine contractions and abortion arc prevented).
In ordina1y (nonfertile) menstrual cycles, the increased blood levels of
estrogen and progesterone secreted by the corpus luteum inhibit GTIIs secretion
and the corpus Iuteum degenerates on about the 24th day of the cycle (page 120).
However. if fertilization of the ovum occur~, the coq)us lutcum docs not
degenerate but, instead, it markedly enlarges and is ca lled the corpus luteum of
pregnancy (page 120). Such enlargement. in spite of inhibition of secretion of
the pitui tary GTHs. is caused by a hormone ca lled the hum an chor ionic
go nadotropin (hCG) or the placental gon adotropin (see next page).
 137

Section 2- Chapter 3 The {emale reprodu ctive svstem

Human chorionic gonadotropin (hCG)

This is a glycoprotein secreted by the syncytiotrophoblast then the

chorionic villi of the placenta Q1ence the name). It is primarily 1//leinizing and
luteotropic (like the pituitaty LH) i. e. it induces g rowth of the co1p11s luteum
and stimulates it to secrete estrogen, progesterone and relaxin fo r the li rst
6-8 weeks of pregnancy (therefore, ovariectomy before rhe 6th 1mek of
pregnancy leads to abortion). The secretion of hCG is not subjected to a negarive
feedback inhibition by the high plasma levels of estrogen and progesterone, but
after about the 8th week of pregnancy, its secretOI)' rate progressively
decreases (reaching a ve1y low level by the end of the first trimeste1) .
ca using regression of the cm p us luteum. Ho wever, secretion of estrogen and
progesterone will be maintained n·om the placenta till the end of pregnancy
(page 139). hCG also exerts a TS H actvity (page 40), and in a male fetus,
it stimulates testosterone secretion by the Leydig cells of the embryonic
testes (pages 99 and 113). In addition, it probably participates in develop-
ment of the breasts during pregnancy (page 145).

Placental ~iUi

• the decidua
cetpsulari~~o ccrm:rttler~

Figure 48 : The placenta and fetal membranes.

Section 2- Cltapter 3 Tlt e [emale reproductive svstem

I EARLy PREGNANCY TESTS I

Pregnancy is suspected when amenorrhea occurs in a nonnal married
woman. In thi s case. early diagnosis of pregnancy can be achieved by detection or
hCG in either the blood or urine of the woman since this hormone is secreted by
the developing emb1yo (the syncyti o-trophoblast of' the blastocyst). I lowever. the
detection of hCG does not always indicate pregnancy because it is ulm secreted by
certain tumours. hCG can be detected in the \\'Oman's blood as early as 6 days ajier
conception and in her urine /.J days after conceprion. hCG can be measured by
radioimmunoassay. llowcvcr, the fo llowing tests for the early diagnosis of
pregnancy can also be used, and they dt.•pencl on cll·ll:c lwn ol h( (. in thl
'"'man'' 111 inl' :
1- Jmmunologicn l tests : These tests depend on tlte interaction between
lt CG (as an antigen) and its antibodies. In the agglutination test (the
commonest used immuno logica l test). the woman's urine is mixed with a solu-
tion that contains gmnules of certain substances (e.g. late.:<) coated with ltCG
antibodies. Agglutination of the substance indicates pregnancy, and vice versa.
2- C hemical tests : The woman's utinc is added to a solution of an indicator
substance that clumges its colour on contacting II CG. Thus a change in the
colour or the substance aflcr addition of urine indicates pregnancy and vice versa.
~ These tests arc useful on~r in rhe.flrsltrimesrer ofpregnancy, since the
hCG concentration in urine decreases to very low levels after this period.
_:::: In the past :mimal tests that also depend on presence of hCG in the urine wen:
uSt.'Cl for the e<1rly detection of prcgmmcy. In these tests, the woman's urine was injected into
an animal (e.g. mice in A'iChicm-Zondek test and rabbits in Friedman's test), and aller a
cctiain peticx:L tl1e animal's ovmics were examined. Pregnancy was diagnosed ir there wen::
signs of ovulation and COipus luteum fom1ation, and vice versa.

[ fUNCTIONS OFTHE PLACENTA

After implantation of the fcttilized ovum, the placenta is formed from the
trophoblast and endometrial cells (which arc now called the decidual cells, page
123). Its size increases progressively throughout the whole period of pregnancy.
although it become functionally efficient for the developing ferus after about 8
weeks through perrorming the following functions :
( I) '\utritiunal fllnrliun
The placenta supplies all nutritional clements to the fetus from the
materna l blood. Some clements arc transponed by simple dirfusion (e.g. fatty
1
acids, most vitamins, Na and K+ salts) whi le others arc transported by
facilitated diffusion (e.g. glucose) and still others are transpotted by active
transport (e.g. amino acids. Ca 2+. PO./ and Mg 2 "~ salts).
Section 2- Chapter 3 The female reproductil•e srstem

(2) lh·,piratur~ tunctic111

The placenta acts as a fetal lung. f=etal deoxygenated blood enters the
chorionic villi via branches of the umbilical arteries where gas exchange occurs
(C02 is eliminated to the maternal blood and 0 2 diffuses from the matemal to
the fetal blood) then the umbilical vein carries oxygenated blood to the .fetus. 0 2
deli very to the fet us is nwou red b) the high di fference in PO! between the
maternal and fe tal blood. the high concentration of fe tal hemoglobin (Hb I ) as
well as its high affinity to 0 2 specially after un loading C02 (which causes shift
of the 0 2 dissociation curve to the left ).
(J) ...,tur:tgc fum·tion
Earl y in pregnancy, considerable amounts of glycoge n, protein and
so me clemen ts (e.g. ca lcium and iron) arc stored in the pl acenta to b<.: used
later by the growing fetus.
H> I \lTl'ton l'unctiou
In the pl acenta, the fetal metabolic waste products (e.g. urea, and
creati nine) are excreted into the materna l blood by passive di iTusion.
(5 I 1 ll'C 1\ l' functio 1
The placema is an efjicielll harrier against passage of most bacterin
and toxi ns from the maternal blood to the Ic tus. It is also permeable to most
antitoxins and anribodies (particu larly immunoglobulin G). On the other hand .
most viruses and drugs can cross the placenta. For th is reason. viral in fec tions
and most drugs should be avoided during pregnancy (~'fJ ecial~,~ in the first
trimester) since certain viruses (e.g. those producing german measles) and some
drugs may cause serious feta l malfom1ations.
(6) nclm·rint· unrliun
The placenta secretes the follow ing hormones :
I. Human chorionic gonadot ropin (hCG ) : Sec page 137.
2. Relaxin : See page 133.
3. Estrogens : These promote (a) Enlargement of the uterus and increase
of its blood suppl y (b) Growth of the mammary glands nnd development or their
duct system (c) Enlargement of the external genitalia (d) Relaxation of the pchic
liga-mentsandjoints(likereltL\·in) (c) Sensitization of the myometrium to the action
of oxytocin. Their secretion markedly increases ncar fu ll term. and through their
actions on the myometrium and peh ic joints. the) faci/itare delh•ery of the baby.
l:..strogcns are synthcsi1cd through an imeraction l>etu een the placellla and /i!tal
adrenal glands. ll'hich is lmmm a\ the fctoplaccntal unit (page 14 1). and the main
secreted estrogen is estriol.
.t. Progesterone : This is essential for ma intenance of pregnane) by
(a) Maintaining and increasing the progestational changes in the endometrium
(b) Decreasing the sensitivity of the myometrium to oxytocin (thus preventing
uterine contractions that would lead to abortion). It also promotes maturati on of
 140

Section 2- Chapter 3 Tlt e female reproductive srstem

the mammary gland.., and (lc\ clopmem of their secretory ah coli. In addition,
the high blood levels or both progesterone and estrogen during pregnancy
inhibit GTHs secretion from the anteri or pituitary gland by a negative feedback
action (thus preventing tlte ovarian cycle and m enstruation during pregnancy).
, lfier regression ol tlte COI]JIIS lweum ofpregnancy on the 6th - ~~~ week (page
137). the placelila becomes the on~r source of estrogens. progesterone and
rL'Ia nn .
.... lluman dwriunk \lllllatomamnwtrupin (hC'\) · This is a protem
hormone that is secreted by the !JJ'n Cytiotropltoblast (like hCG). It is also
called cltorionic gro11•tlt h orm on e-prolactin (CGP) and ltuman placental
lru:to~-:en {ltPL) because it exerts (a) Mammotropin (prolactin)- li ke action i.e. it
stimulates milk secretion from the mammary glands (b) Somatotropin-like action
i.e. it exerts most actions or .w mwtotropin (lite pituitary gro111tlt horm one) hut
less ejjic:ieni~J' e.g. retention or the clements required for gro'>vth, increas ing
lipolysis and antagonizing im.ulin action (which increases the blood glucose level
tlw~ pro' iding more glucose to the fetus). The amoun t of hCS in the maternal
blood is proportionate to tlte si:e of placenta (which normally weighs about
1/(> or the fetal weight), and its decrease is a sign of placental insufficiency.
6. Other placenta l ho rm ones : These include a growth promoting ractor
<.:ai led va r ia nt g r owth hormo ne, hC th yrotr opin (page 41 ), CR H, MS H, Lcptin
(page 94). B-endorpltin am/ pro-renin . Variant forms of p ro lactirr as wel l as
G nRH and inhi bin arc also secreted. The Iauer 2 act locally for regulati on of
hCCi secreti on (G nRH increases while inhibin decreases hCG secretion).

Placent•

Choltl terol

~
Prc'9ntnotone OHEAS
~

I
Progt'1ttronc
160HDHEAS

Con.sol.
cor t•cos ~tront

Ei!r••llol OHEAS
Eurool 16 OHDH EAS

Figure 49 : The fetoplacental unit.

 1-t I

Section 2- Chapter 3 Tlte female reproductive S)•stem

I THE FETOPLACENTAL UNIT]

This term refers to the interaction between the placenta and fetal
adrenal cortex in the production of the placental estrogens as well as some
adrenal corticosteroids. Such interaction occurs as follows (figure 49) :
1- The placenta synthesizes pregnenolone and progesterone from cholesterol
2- Some progesterone enters the fe tal circulation and on reaching the fetal
adrenal glands, it leads to formation of cortiso l and corticosterone.
3- Some pregnenolone enters the fetal ci rculation and, with pregnenolone
synthesized by the fetal liver, they lead to formation of both dehydroepi-
androsteronc sulphate (OIIEAS) and 16-hydroxy-dchydrocpianclrostcrone
cpinndrostcrone sulphate (16-011-DH EAS) in the fetal adrena l cortex.
4. Both DHEAS and 16-011-D II EAS nrc then transported back to the
pl acenta in which tlte former forms estradiol wltile tlte later forms estriol.
_:: Since the main esrrogen formed is esrriol (see abo\ e). the urinary estriol
excretion of the mother can be taken a an index of the Ictal state (it shou ld
increase steadil y throughout pregnancy if the fetal grO\\ th ''as nom1al ).
Manifestations of normal pregnancy

1- Amenorrhea (t he first sign) occu rs due to feedback inhibition of release

or the pituitary GTII s by the high blood levels of estrogen and progesterone.
2- i\lorn ing sickness (malaise&vomiting) often occurs in the first trimester
,probably due to oversecretion or thyroxi ne by the hCG and hC thyrotropin.
3- Acromegalic appearance of the face (probab ly by the cfTect of hC ).
4- Enlargement of int ernal and external sex organs and the breasts.
5- Increase of the basal metabolic rate (due to excessive secretion of thyr-
oxine and glucocorticoids, and the high blood levels of the sex hormones).
6- In crease in th e blood volume, venou s return and card iac outp ut.
7- Mild increase in the urine volume und frequency of micturition.
8- The immune system may be inhibited which decreases the body resist-
ance against infections.
9- Ankle edema of a va rying severity oflen occurs late in pregnancy due to
obstruction ofblood flow from the lower limbs by the enlarged uterus.
10- Weight gain (due to weight of fetus. its membranes. the amniotic fluid.
the placenta, the enlarged uten•s & breasts and the increased blood 'olume).
It - In crease of the a ppetite and food intake (which supplie · the increased
nutritional demand of the pregnant woman for her grow ing fetus).
12- Increased pulmonary ventilation, which supplies extra 0 2 that is need-
eel by the fetus and the mother (because of the increased metabolic rate).
 142

Section 2- Chapter 3 The [emale reproductive svstem

13- Endocrinal changes

(a) The anterior pituitary gla nd is enla rged and secretes more ACTH
probably by effect of the placental CRH (page 140). Prolactin secretion is
also progressively increased during pregnancy by the effect of estrogen.
ll owever. the secretion ofsome hormones is inhibited by a feedback action
including GTHs (by the increased blood levels of both estrogen ami
progesterone), the growth hormone (by the effect of hCS which is called
the maternal growth lwmume of pregnancy) and frequently also TSJI (by
the effect of hCG and hC thyrotropin).
(b) T he adrenal co rtex secretes excessive amounts of glucocorticoids
(which increases the levels of amino acids, glucose and fatty acids in the
maternal blood, thus promoting their supply to the fetus) and ald osterone
(which leads to sodium and water retention in the mother's body).
(c) T he parathyroid glands are enla rged and secrete more pnrathor-
mon e specially if the mother~,. diet was poor in calcium. The hormone mob-
ilizes calcium from the mother's bones which is then delivered to the fetus.
(d) The thyroid gla nd secretes more thyroid hormones under effect of
hCG & hC thyrotropin (which increase the metabolic rate) and also calci-
tonin (page 80) which limits Ca 21 mobilization from the mother's bones.

I PARTURITION (DELIVERY OR LABOR)

The duration of norma I pregnancy in humans averages 270 days from

the date of fertilization (abour 38 weeks). I lowcvcr, it is usually counted
from the first day of th e last menstrual cycle. From this day. the normal
duration of pregnancy is therefore about 28-t days (which roughly equals
about 40 weeks, I 0 lunar months or 9 calendar months). During pregnancy.
there are irregular episodic uterine contractions which are probably produced
by the circulating oxytocin. ll owever, at full term (= end of pregnancy) the
delivery of the baby occurs by the following mechanism :
( I ) \ o, a pn•parn lion for lahm in the lao,l lllllnth . the frequency and
strength of uterine contractions markedly increase as a result of 2 factors :
(A) Increased synthesis of estrogens from DHEAS (sec above) with
marked increase i11 their blood levels. Estrogens increase (a) The myo-
metrial excitability and its sensitivity to oxytocin (pages 130 and I 31) (b)
The munher of oxytocin receptors in both the myometrium and the decidua
(= endometrium (?/pregnane:\'). wh ich increase more than I 00 fold during
early labor (c) The formation or certain pm:stag/(lfu/ins which stimulate
uterine contractions. The first 2 effects of estrogens cause the myometrium
to respond to the nom1al circulating oxytocin blood level (25 pg/ml) as well
as to the focally-produced o.\Tiocin in the uterus (page 31 ).
 14.1

Section 2- Chapter 3 The /'e11wle re(Jmductive srstem

( B) Uterine distension : The distended uterus increases tlte 1111111ber t~j'

o.\:ytocin receptors (together 111itlt estrogen ) and may also evoke spi11al
rejle:!<es that cause contraction or the myometrium.
~ It was believed that the progesterone blood ll:vcl drops in early labor
together with the rise in the estrogen blood level. llowcn~r. this docs not
occur in primates (thus the increase in the e.\troge~t-pro~:esterolt e ratio that
occurs in early labor is due 111t1il1~l' to tlte im:reased e.\ tro~:en blood level).
(l) t ft II tl 1 na , the uterine contractions become stronger, more
frequent, spasmodic and painful (so they arc called labor pains). The uterine
cervix is softened and dilated by the effects or relari11. estrogen 011d uterine
contrac-rions.Such contractions push the baby down resulting in stretch of
tlte cervix. This initiates rclkx release of oxytocin from the neurohypophy-
sis, which potentiates the uterine contractions, denoting tlte onset oflahor.
(.") >Ill l.•h•" ' .11 '' ·it proceeds by pn\IIIH ll'l h.ll'k ~·\dl'' that lead
to progressively stronger uterine contractions as folio" s : As the bab) is
forced down. it leads to stretch of the uterine ccn i\ and distension of the
\ agina. This sets up signals in afTerent nen•cs that arc transmiucd via asc-
ending tracts in the spinal cord to the hypothalamus. "hich stimulates oxyto-
cin secretion from the neurohypophysis. Accordingly, the plasma oxytocin
level rises and leads to more stronger uterine contractions which push the
baby further down, resulting in more stretch of the birth canal, and a posith•e
feedback loop is ti111S establislted which results in deli,cry of the bnby
(figure 50). Oxytocin ctwses uterine con traction.\ hy a direct effect on tlte
myom etrium and by forming prostaglandin.\ 11'/tic:lt directly cause uterine
ctmtractions and al.\o enlumce lite o.\)'tocin -im lucetl ctmtrm:tions.
~ During labor. reflex and 'oluntal) contraction of the abdommal
muscles (bearing doll'n ) also aid delivery. llowc,er, these actions (as ''ell as
reflex stimulation of oxytocin secretion) arc not es.'iential for labor, since
paraplegic women (in whom the spinal cord is sectioned) can sti ll deliver.
(3) The process of lubor is termina ted by delivery of th e baby. The
positive feedback cycles stop because the birth canal becomes no longer
stretched. I lowevcr. weak uterine contractions often continue spontaneously
afier delivery of the bab}. and these (aided by external massage to the uterus)
usuall) lead after I 0-45 minutes ro expulsion of the placc:nta and other
products of conception . Placental separation from the uterine "all leads to
n1pturc of most uterine hlood 'esscls. llo" e' cr. the resulting bleedmg
normally stops rapidly (so that the dangerous postpa rtum hemor rhage
wo uld be prevent ed ) because (a) The contracting uterine muscle fibres
compress the blood vessels (b) V.C. occurs by ef'!Cct of ccr1ain prosta-
glandins that are released at the time of placental separation
Section 2- Cltapter 3 Tlte female reproductive srstem

!
hn1 • ov" J to noolltoO
•n .,.. to noo ln~ll to

!
A'Y\~) rno1~ dum.;2
&>n1('0V bn'

l
no• J'!1.1'11 btU,.,1)rt l
•v•o I~
Figure 50 : Role of oxytocin in parturition.
~ The uterine contractions arc essential for delivery and also prevent
postpartum hemorrhage. Ito" c\ cr, if they arc cxccssh e or prolonged (e.g.
when giving oxytocin for induction or labor) they become dangerous, since
they mt~\ ' occlude the placenlal blood l'essels to the extent that leads to
placental ischemia and death of the fet us.
~ After delivery, the uterus involutes gradually. reaching its pre-
pregnancy weight after about 5 week . and breast f eeding ltastens in volution
because it stimulates prolactin secretion. which inh ibits the release of Gn RII
and GTI Is as well as the effects of the latter on the O\ aries (page 146).
I THE MAMMARY GLANDS AND LACTATION ]
The mammary glands arc modified sweat glands that develop at puberty.
During childhood, the mammary glands arc mdimentary (consisting of a few
ducts lined with nat epithelial cells surrounded by a small amount of connective
tissue). Their development & groll'tlt are comrolled by tlte following ltormnnes
(1) Estrogens These induce de,clopmcnt of the mammary
glands at puberty and also produce all its manifestations (page 13 1).
Other hom1ones arc also necessary as permissil·e factors for mammary
de' elopment. namel) glucoc:orticoids, ilzsttlin, gro111l1 hormone and prolactin.
During pregnancy. estrogens cause (a) deposition of more fill in the brcastc; (so
they are markedly enlarged) (b) enlargement of the nipples {c) more darkening of
the areola and appearance of a secondary arcola.
(2) Progesterone : This causes development and growth of the
·ecretory alveoli (acini) provided the gland is primed (i.c.prcparcd) by esu·ogcns
(page 131 ). Ho\\'evcr. this effect is apparent only during pregnancy
Section 2- Chapter 3 Tlt e [emale reproductive srstem

because it n:qutrcs a relattn:ly high concentration of progesterone. During

pregmuur. full de1•elopment of t!te breasts occurs b) the c!Tect of the high
blood levels of estrogen, progesterone, prolactin, ltCS ami possihly also !tCG'
(page 137).
(3) Prolactin · This stimulates milk secretion from the mammary
glands that an: fJrimed (prep{/r£'d) h_r estrogen & progesterone. During pn:g-
nanc). it i::. secreted in stcadily incrca&ing amounts from thc 51h month till
full term under effect of rite !ti;:lt estrogen blood lel'£'1 (which directly
stimu late the mammotropcs). ll owevcr. estroge11 also blm.:/;s t!te prolactin
receptors i11 t!te ma111111m:1' gla11ds, titus preventing its milk secretio11
eff ect. Prolactin is also sccn~tcd as a result of suckling (sec hel<)\\ ).
~ Rccausc of the action of estrogen on the prolactin receptors in the
mammary glands. women ll'lto do 110t ll'islt to nurse tlteir babies are gh•en
regular doses t~f"estroge" to stop lactation.
(4) hCS : Thi s is sec reted by the placenta (page 140). and its secre-
tion increases steadily from the 5111 month till full term (l ike prolactin).
rTowever. it is a weaker stimulant for milk secretion than prolactin.
(5) Oxytocin : This causes milk eJection by stimu lating contraction
of the myoepithelial cells (pag~ 31) that line the walls or the mammmy ducts
('' hich squci.!/CS the prei(Hmed milk outwards through the nipples). Oxytm:in
secretion is produced as a result of the suckling rcllcx as wel l :1!> in responsl.! to
manv emotional stimuli and conditioned rellexes (sec below).
• (6) Other hormones · The giucocorticoids. gro" th hormone and
thyroxine arc req uired to maintain the mammary functions produced by the
other speci fir hormones discw,scd above.

INITIATION AND MAINTENANCE OF LACTATION

AFTER LABOR

Absence of lactation during pregnancy is due to inhibition of the action

of prolactin b) the high blood estrogen lc'd (sec abo\'e). 11<)\\C\Cr. after
delive1J' of tit<.' baby and expulsion of the placenta, the sharp drop in the
c:irculatin~ estroJ:en blood level initiates lactation .
Immed iately after labor, the mammary glands secret<.: on ly a few ml
of a fluid called colostrum (\\ hich contains a gr..:ater amount or proteins. but
smaller amounts of lactose and n1ts than thosc present in milk). and it takes
1-3 days for the milk to "co me in " instead ol\:olostrum.
After delivery. prolactin secretion is decreased clue to drop or the
plasma est roge n leve l, so it s plasma level dec reases to the nonp regnant
level in about 8 days. I Jowevcr. in lactating women the plasma prolac-
tin level increases again because its secretion "ill be stimu lated as a result
 t-16

Section 2- Cltapter 3 Tlte female reproducth•e s rstem

of th~: 'IHI.:Iding rcll c\ (ligurc 13). This n.:lkx is init iated by suckling and is
esst.!ntial j()r maintenaJH:t.! of the process or lactation (i.e. mi lk scc rdion
and ejection) because it results in inc:reasinx tlte ~ec:retion ofbotlt prolactin
and oxytocin (page 32) by the following mechanisms :
1- Impu lses initiated by touching the nipple are transmitted by
a rrercnt ncn e fibres lo the spinal cord then up to the h) pothalamus
where they inhibit the release of Pill (the pro lactin inhibiting hormone).
Thi s stimulates secretion of prolactin from the ant eri or pituitary g land
whi~.:h indu~.:cs milk secretion ( mill. 'l'l'rction n·fln).
2- Impulses initiated by touching the nipple are similar!) trans-
mittt.:d by a ffe rent ncrv t.! fib res to the hypothalamus \\here they stim ulate
certain hypoth alami c nu ~.: l c i (parti~.:ularly the para ••entric:u/ar ll tl(:/eus).
Signa ls from these nuclei arc then transm itted 'ia the ltypotlwlam o-
ltypopltysialtract to tht.! llCUrohypoJ1hysis leading lO release of OX) toe in
which causes milk ejecti on( = milk ejection or ~t-Iling rl'fll'\ ).
-,.,* The ef(ecth·ene\'S
.. of
. these reflexes declines afier
. 3 /110/l{hs or lactution.
which leads 10 drop or the prolactin blood level. ll <mever. milk secretion
will still occ ur with pla sma prolactin levels that arc in the norma l range.
~ Milk cjcct ion can also occur ns a result or l:tln<lit iun cd rl'fll·\l'' e.g.
''hen a mother hears hcr bab) crying (or e\cn just thinks nt him). milk
ejection mny spontaneously occur as a result of o:\ylocin release from the
posterior pituitary gland.
~ The hypothalamic comrol on the release of hoth rro lactin and o,,ytocin
explains tlte lactation disturbances tltat mig ltt oc.Tur in emotions am/
the 1•arious P·':J'c/10/ogica/ and stressjitl conditions.

Effect of lactation on the menstrual cycles

In non-lactating \\omen. nwnstruation usuallr 1'1.!/llrns 6 ,,·eeks ofier

deiii'C'I:r. II <)\\ C\ cr. lactation pre,·enl.\ tlte m e nstrual <.:rcle., durin~: tlte
.first 6 - 7 IIW ntlts t~fter delil'et:r (and 50% of la ctating \\omen do not
ovulate as long as they arc nurs ing their babies) because lactation
stimulates pmlactin secretion wlticli {a) inhibits release of tile GnRH
and its effects on tlt e anterior pituitliiT gland (h) Antagoni-;,e.\ tlte
actions oftlte GTHs on tlte o11aries. For this reason . lactation can be used
as n method of contraception (page.: 12!<) bu t it is not a rcllahlc method
due to drop or the prolac tin blood lc\ cl after continuous lactation for about
3 months (sec above). Also about SO'Yt, of the sex cyc les in lh e lirst 6
mont hs a ft er retur n or menses arc norma lly anovula tory (page 127).
 n
J ..

Section 2- Clta[Jter 3 Th e {emale re[Jroductive srstem

I PROLACTIN I
Prolactin (-= mammotropin or lactogen ic hormone) is secreted by the
IIIC/1111/IOtrope (lacfofrope) eel/!; of the anterior p.ituitm)' gland. It is a poly-
pep! ide (consisling of 190 amino acids) \\ hit:h is structumlly similar to the
groll'th hormone uml hCS. and its normal plasmn concentration i~ about 5
ng /ml in males and 8 ng , ml in lcmaks. Stmctural~r similar pm/actin.,· are
also secreted by the placenta and endometrium.

Functions (actions) of prolactin

1- Togc lher with other hormones (spet:ially estrogens), il shares in the

de•'elopment of IIU/1/tllllii:J' glands (I( puherzr ami during pregnflll£:1'.
2- After labor. it initiates lac:togenesi!; (secretion of milk from the ma-
mmar) glands that arc primed (prepared) by estrogen and progesterone).
Lactogenesis is inhibited during pregnane) b) the high blood estrogen bel
3. Its fum:tion in mnlcs is unknown. llowcver. hypcrpro lactin cmia in
males causes h ypo~o nadi s m ancl impotence probabl y because prolaclin
inhibits secretion of the GnR II (page 146).
4. It prcn~ nl!. O\ uhltion and produ ces amenorrhea e.g. during
lactation (page 146) so cases of hypcrprolactinemia in wom en arc
characterized b~ ga la ctorrhea (= in creased milk sec retion) that is ass-
ociated with am enorrhea .

Regulation (control) of prolactin secretion

(1) Hypo thalami c contro l : The secretion of prolactin is controlled

by the foliO\\ ing 3 ltypopltysiotropic hormones that arc secreted by the
hypothalamus :
a. A prolactin-releasing hormone ( PRJI ).
b. A pro lact in-inhibiting hormone (Pill ).
c. TRII (which stimulates secretion of both TS ll and prolactin, and
some authors believe that TR H is itself the PRH ).
In normal cond iti ons, the inherelll acti vity ol' thc mammotropc
ce lls (which secrete prolactin) is tonically inhibited. \\'hich indicates that
the effect of Pill 11omwl~r m·erbala11ce'i the eff ects of PRII a11d TR/1 .
For this reason. it was found that scel ion or the pituitary slalk leads to
temporary clcvalion of thc blood prolactin level (page 15).
 148

Section 2- Chapter 3 The female reproductive svstem

~ The relation between the prolactin blood level and the hypo-
thalamic hormones which aiTect its secretion is controlled by a negntivc
feedbnck mechanism that aims at keeping the prolactin blood level
constant. It occurs as follows : Rise of the prolactin blood level stimulates
secretion of PIH, which inhibits prolactin secretion. thus its blood level
decreases. An opposite effect occurs if the prolactin blood level falls.

(2) Effect of drugs : It was found that the PIH is chemicnlly

dopnmine. Accordingly, the drugs that mimic dopamine (e.g. L-Dopa) or
stimulate the dopamine receptors (e.g. bromocriptine and apomorphine)
decrease prolactin secretion. whereas those which block the dopamine
receptors (as phenothiazines e.g. chlorpromazine) increase prolactin
secretion.
~ Like most hormones, the secretion of prolactin shows a circndian
rhythm, being highest in the early morning and lowest in the evening.

(3) Effect of pregnancy : Prolactin secretion is progressively

im:rem;ec/ cluring pregnancy, starting from the 5111 month and reaching a
peak at full term. This effect is produced by the high blood estrogen
lew/ although this also blocks the effect of prolactin on the mammary
glands (page 145).

(4) Effect of sleep : The plasma prolactin level rises after the onset
tJf sleep and persists tltrouglwut the ~·/eep peritJd. The significance of this
rise of the prolactin level during sleep and its mechanism arc unknown.

(5) Effects of other factors : In humans. prolactin secretion is stim-

ulated during exercise and on exposure to surgical and psychologic
stresses (the significance of which is unknown). as well as by tactile
stimulation of the nipples (page 32) through the suckling reflex (figure 13).

Pnnted en Egypt by ~' Commou:tal Prcns -KatyotJtt • Egyp1

 I AUTHOR'S AVAILABLE BOOKS
1- Human physiology for medical students : Endocrine glands and repro-
duction

2- Human physiology for medical students : Special senses

3- Human physiology for medical students : T he cell Autonorn1c ne1vous

I

system and Nerve & Muscle

4- Human physiology for medical students : Blood and body flu1ds

5- Human physiology for medical students : K1dney Electrolyte and Acid-

I

Base balance

6- Human physiology for medical students : Central nervous system (CNS)

7- Human physiology for medical students : Circulation

8- Human physiology for medical students : Respiration

9- Human physiology for medical students Digest ion

10- Human physiology for medical students :Energy metabolism

11-0 ral and written questions and answers ( 2 volumes )

12-M.C.Q.s and answers ( 2 volumes )

I.S.B.N. 977-203- 236- 8 u-1_,.1.11 ~jill

UNIVERSITY BOOK CENTRE

8, Soliman El Halaby Str., Cairo
Tel. 5774881 - 3957807
Fax: 5897635- Mobile 0123698600