ENDOCRINOLOGY.doc

7/27/2019 ENDOCRINOLOGY.doc

1/24

ENDOCRINOLOGY

Mark Johnson

Introduction

In this chapter the endocrine system will be introduced by describing mechanisms of

hormone action and hormones types. Six groups of hormones and/or endocrine system will

then be discussed: (! hypothalamus" pituitary and pineal glands" (#! reproduction (puberty"

menstrual cycle" pregnancy" lactation and menopause!" ($! growth" (%! metabolism and the

pancreas" (&! thyroid" ('! adrenal.

Mechanisms of hormone action and second messenger systems

ell surface receptors

)ormones may act in an autocrine (acts on the cells that produced it!" paracrine (acting on

neighbouring cells! or endocrine manner (acting on cells at a distant site ha*ing been

transported to that site in the blood or lymphatic system!. In the circulation" some hormones

such as steroids" insulin+related growth factors and thyroid hormones are bound to carrier

proteins. ,nly the free hormone" that fraction of the total hormone le*el which is unbound" is

acti*e and a*ailable to bind to specific receptors to induce its effects. -hese receptors may be

on the cell surface and ha*e associated secondary messenger systems or be in the nucleus and

ha*e effects directly on the 0 to alter messenger 10 (m10! expression. 0t eachreceptor a hormone may be an agonist" a partialagonist or an antagonist.

eurotransmitters and peptide hormones act predominantly through cell surface receptor.

-heses are di*ided into four main groups: (! se*en+transmembrane domain (2)" 3S)" -S)"

4+adrenergic" typically linked to 5+protein second messenger system!6 (#! single

transmembrane domain growth factor receptors (insulin" I53s" linked to tyrosine kinase

second messenger system!6 ($! cytokine receptors (cytokines" 5)" prolactin!6 (%! guanylyl

cyclase+linked receptors (natriuretic peptides related to guanyl cyclase second messenger

system!.

3igure . Se*en transmembrane receptor

3igure .# 5+protein receptor acti*ation represented by a 4+adrenagic receptor

-he se*en+transmembrane receptors" as their name implies" loop in and out of the cytoplasm

(fig .!. -he amino terminus has the hormone binding domain and the carboxy terminus the

5+protein transducer. -here are multiple types of 5+protein which are heterotrimers made up

of an 7" 4 and 8 subunit (fig .#!. 9ach type (determined by the 7+subunit! may relate to

different receptors and be linked to different second messenger systems. 3or example 4+

adrenergicsystemislinkedto 7s 5+protein" which in turn is linked to adenylyl cyclase. -hus 4+

adrenergic acti*ation is associated with an increase in intracellular c0M (3ig. .#! 9ach 5+

protein is made up of a 5+5- binding domain (the 7+subunit!" and a 4+and 8+subunit. Inthe absence of stimulation" the 5+protein is bound to 5. ;ith receptor acti*ation the 7+


2/24

subunit binds to the receptor and dissociates from the 5 and the 4 and 8 subunit. 5- then

binds to the receptor+linked 7+subunit initiating its dissociation from the hormone+receptor

complex. -he acti*ated 5+protein then acti*ates its second messenger system (e.g. adenylyl

cyclase!. -he deacti*ated 5+7+subunit complex re+associates with the 4+ and 8+subunit (fig

.#!. the 5+protein system can be manipulated experimentally by using agents such as

cholera toxin" which prolongs the acti*ity of the 7+subunit+5- complex or pertussis toxin"which uncouples the 5+protein system and inhibits its acti*ity.

0s described earlier" adenylyl cyclase acti*ation generates c0M whichacti*ates protein

kinase 0 (


3/24

includes oestrogen" retinoicacid and *itamin +receptor!. )owe*er" independent of their

location" when these hormones bind to their receptors. 0ll act in the nucleus to alter gene

expression. -he steroid family exists in the cytoplasm as a complex with heat shock protein

()S!. ;hen the ligand binds with the receptor" )S dissociates re*ealing a nuclear

translocation signal which initiates the transport of the hormone+receptor complex to the

nucleus where it binds to the hormone response element to exert its effect (fig. .$!. -he0 binding region has two Binc @fingersA6 between the two Binc molecules lies the amino

acid se>uence which binds to the 0. -he thyroid family exists in the nucleus and" with the

exception of the oestrogen receptor" do not associate with )S. -hey bind to 0 as

dimers6 for oestrogen this is a homodimer (i.e. two oestrogen receptor molecules! and for the

other members of the family" as heterodimers formed between the receptor molecule and a

retinoid C receptor.

Hormones types

eptide hormones

Most hormones are peptides. 0 peptide is made up of a chain of a *ariable number of amino

acids. -he precise se>uence is determined by the 0 coding for it. -he process of peptide

synthesis is initiated by the transcription of 0 into a specific m10. -his passes from the

nucleus into the cytoplasm" where it binds to ribosomes in the rough endoplasmic reticulum

(191! and is translated into the peptide se>uence (illustrated by insulin in 3ig. .%!. Dsually

this is in the form of a pre+pro+hormone which is then clea*ed to form first a pro+hormone

and then the hormone itself. Some peptides are secreted immediately while other are stored in

secretory granules.

3igure .$ uclear receptor acti*ation by ligand 5#which passes through the cell wall" binds

to its receptor in the cytoplasm before passing into the nucleus to bind to its response elementon 0.

3igure .%. Synthesis of insulin

Steroid hormones

In terms of reproduction this is the most important group of hormones. -hey are synthesiBed

from cholesterol and all ha*e the same basic ring structure of E carbon atoms with different

numbers of carbon atoms added. 5lucocorticoids (stress and metabolism!" aldosterone (fluid

balance! and progesterone (reproduction! ha*e # carbon atoms6 testosterone and other

androgens ha*e F carbon atoms while oestrogens ha*e G (fig. .&! -he synthetic pathwaysare the same in o*ary" testis and adrenal" but the dominant product *aries fromtissue to tissue

(3ig. .'!. -he pathway always starts from cholesterol which is deri*ed either from

circulating 22 or from intracellular cholesterol esters.

Ovary

,*arian steroid production *aries during the cycle. ,*erall" the o*ary is the main source of

circulating oestrogens" although peripheral con*ersion of androgens also makes a significant

contribution in some situations. uring the follicular phase of the cycle" the o*ary produces

oestrogens predominantly" and both oestrogen and progesterone in the luteal phase

ndrena!


4/24

-he adrenal cortex is di*ided into three Bones: (! the outer Bona glomerulosa" (#! the middle

Bona fasciculata" which consists of cells full of cholesterol and ($! the inner Bona reticularis.

-he first Bone is concerned with aldosterone secretion and is under the control of the renin+

angiotensin pathway and the lasttwo are controlled by adrenocorticotrophic hormone

(0-)-! and are concerned primarily with the secretin of cortisol and" to lesser extent"

adrenal androgens. More details will be gi*en about each in their rele*ant sections.

"estis

-he 2eydig cells of the testis produce testosterone in the response to luteiniBing hormone

(2)!. -his circulates predominantly bound (FEH! to sex hormone binding globulin (S)=5!

and to lesser extent to albumin. In some tissues testosterone is a acti*e" but in others it has to

be con*erted to dihydrotesterosterone ()-! by the enByme & 7+reductase. =oth testosterone

and )- bind to a cytoplasmic receptor before passing into the cell nucleus to bind to

specific areas of 0 to produce their effect.

3igure .& -he synthesis of the key reproducti*e steroids (highlighted!

3igure .'. Steroid hormone synthesis

3igure .E 3eto+placental oestogen production. -he fetus lacks sulphatases $4+

hydroxysteroid dehydrogenase ($4)S! and aromatase" and therefore produces

dehydroepiandrosterone sulphate ()90S!" which it exports to the placenta" which possesses

these enBymes and produces oestrone (9!" oestradiol (9#! and oestriol (9$!. hol" cholesterol6

progesterone" rg" pregnenolone

#!acenta

uring pregnancy" the placenta synthesiBes and releases large amounts of progesterone into

the maternal circulation. regnenolone is also released into the fetal circulation to be

con*erted by the fetal adrenal into androgens" which pass back to the placenta to be

aromatiBed to oestrogens and released into the maternal circulation (fig. .E!

$teroid %inding and meta%o!ism

In the circulation" all steroid hormones circulate bound to *arious proteins (table .!.

Steroid hormone metabolism occurs in the li*er. 3or example oestradiol is con*erted tooestrone" which may re+enter the circulation" be further metaboliBed to catechol oestrogens or

con?ugated to form oestrone sulphate" and excreted.

rogesterone is con*erted to pregnanediol and con?ugated to glucuronic acid" and excreted as

pregnanediol glucuronide. 0ndrogens are metaboliBed and excreted predominantly as E+

oxossteroids (which used to be measured to assess androgen synthesis!. ortisol is mainly

con?ugated to glucuronide and excreted. Its metabolites can be measured in the urine in the

form of E+oxogenic steroids (not to be confused with the androgen metabolites" E+

oxosteroids!" but this is rarely measured now" as cortisol can be measured in the urine

directly.

0mino acid hormones


5/24

Se*eral hormones" thyroid (tyrosine!" catecholamines (tyrosine! and melatonin (tryptophan!

are deri*ed from amino acids. -hese hormones are stored in granules.

-heir acti*ities are regulated by their release and by the expression of the enBymes necessary

for their synthesis

rostaglandins and leukotrienes

ollecti*ely known as the eicosanoids" these hormones are deri*ed from arachidonic acid.

Synthesis occurs in the cell wall and the hormones pass either into the cell cytoplasm or out

of the cell (fig. .G!

-able . Steroid binding profiles

3igure .G rostaglandin and leukotriene synthesis form arachidonic acid. (1eproduced with

permission from greenspan 3S" Strewler 5? FFE =asic and clinical endocrinology. &th edn

0ppleton and 2ange" 2ondon!

Hypotha!amus and #ituitary

-he hypothalamus is at the centre of the different endocrine autonomic and homeostatic

mechanisms which maintain the body and allows it to reproduce. It directly control the

pituitary" which in turn controls the reproducti*e axis" lactation" growth" the thyroid and

adrenal glands.

9mbryology

-he thalamus and the hypothalamus de*elop from the diencephalon" which with thetelencephalon (which forms the cerebral hemispheres! forms the pro+ecephalon. =oth the

thalamus and the hypothalamus de*elop in the lateral walls of the diencephalon" the ca*ity

that becomes the third *entricle (figure .F!

-he pituitary de*elops in close association with the hypothalamus and is made up of two

parts: (! the anterior or adenohypophysis and (#! the posterior or neurohypophysis. -he

anterior pituitary is formed from the *entral ridges of the primiti*e neural tube" which are

pushed forward by the de*eloping 1athkeAs pouch (3ig. .!. =y E weeks" the sella floor

has formed and the pituitary start to de*elop under the influence of the hypothalamus.-he

posterior pituitaryis formed by a downward e*agination of the diencephalon called the

infundibulum. -hus" the neurophypophysis is in direct contact with the phypothalamus" whilethe anterior pituitary is connected to the phypothalamus *ia a rich *ascular network called the

portal system. -he portal system carries all of the hypothalamic hormones which regulate the

function of the anterior pituitary (3ig. .!. 0 small part of the anterior pituitary

immediately opposed to the neurohypophysis becomes the intermediate lobe (3ig. .#!

3igure .F 9mbryonic de*elopment of the hypothalamus. (1eproduced with permission

form Moore


6/24

3igure .# 1elations of the pituitary

0natomy

&oundaries

-he thalamus lies superior lies superior to the hypothalamus" separated from it by the

hypothalamic sulcus. Medially the third *entricle" superiorly the thalamus and inferiorly the

pituitary stalk pro*ide anatomical limits for the hypothalamus6 anteriorly" posteriorly and

laterally the hypothalamus is without distinct boundaries.

-he pituitary lies within the sella turcica (the -urkish saddle!6 anteriorly and inferiorly lies

the sphenoid sinus" laterally the ca*ernous sinus (containing internal carotid arteries" and

sixth cranial ner*e!" posteriorly the clinoid processes of the sphenoid bone (often eroded on

skull C+rays in the presence of a pituitary tumour!" and superiorly the pituitary stalk which

merges into the hypothalamus (3ig. .#!. 0nterior to the pituitary stalk lies the optic

chiasma" which may be compressed by an expanding pituitary tumours" gi*ing the typicalpresentation of bi+temporal haemianopia

&!ood supp!y

-he hypothalamus" pituitary stalk and the pituitary are supplied by carotid arteries bia the

superior and inferior hypophyseal arteries (fig. .!. -he superior hypophyseal arteries

form a primary plexus in the base of the hypotalamus in a region called the median eminence.

-he flexus forms into the portal *essels which pass on either side of the pituitary stalk to the

anterior pituitary" where they form a secondary plexus. -he ner*es from the hypothalamic

nuclei which regulate anterior pituitary function end close to primary plexus and release their

regulatory hormones which are taken up and are carried *ia the portal *essels to the anteriorpituitary. -he posterior pituitary is supplied by the inferior hypophyseal artery.

$tructure

-he hypothalamus is made up of a series of nuclei arranged around the third *entricle. -he

nuclei consist of the cell bodies of the neurones. In the case of the nuclei which regulate the

anterior pituitary" the axons pass to the area of the median eminance (see earlier!. -he axons

of the para*entricular (situated in the lateral wall of the third *entricle! and the supraoptic

nuclei (situated abo*e the optic tract! pass down the pituitary stalk to the posterior pituitary.

=oth synthesiBe and release oxytocin and *asopressin (fig .$!

0s described earlier" the pituitary de*elops from two pats. -he anterior pituitary is made up

of a mixture of cells with different secretory properties. -hey are de*ided into three groups

on the basis of their staining with haematoxyclin and eosin. -he chromophobes (which do not

stain! are thought to be resting cells" but chromophobe adenomas ha*e been shown to secrete

gonadrophin subunits. -he acidophils synthesiBe prolactin and growth hormone and the

basophils" which secrete the gonadotrophins" thyroid+stimulating hormones (-S)! and

0-). -he posterior pituitary is pale and consists of the ner*e rerminals of the

para*entricular and the supraoptic nuclei. -he axons are surrounded by glial cells called

pituicytes" which regulate the rate of transmission and the cross+talk between neurones.

)ypothalamic products


7/24

-able .# summariBes the hormones produced by the hypothalamus which regulate anterior

pituitary function. 3urther details are gi*en in the rele*ant sections later in the chapter.

ituitary gland products

-able .$0 0"= summariBes the hormones produced by the anterior and posterior parts ofthe pituitary gland" respecti*ely. 3urther details are gi*en in the rele*ant sections later in this

chapter

#inea! g!and

-he pineal gland lies the roof of the third *entricle at the posterior end. Its role in the human

is uncertain.

3igure .$ iagrammatic representation of the hypothalamus and pituitary. -he

connections of the posterior lobe of the gland with the hypothalamus are indicated" (3ig.

.+.$! courtesy of passmore 1" -obson J (eds!. ompanionto medicalstudies.=lackwell Scientific. ,xford!

-able .# 1egulators of anterior pituitary function

It producesmelatonin" which may ha*e a role in the regulation of the @body clockA and

puberty. -umours of the pineal gland are associated with the usual symptoms and signs of a

space+occupying lesion and a deficiency of hypothalamic hormones or occasionally with

precocious puberty. ;ith age" the pineal gland calcifies and may be seen on a skull C+ray

Reproductive hormones

-he reproducti*eaxisis made up of the hypothalamus" pituitary and gonads. -he embryology

and anatomy of the reproducti*e tract are discussed elsewhere and in this chapter only the

endocrine aspects will be re*iewed.

3unction

5onadotrophin+releasing hormone (5n1)! is synthesiBed in the pre+optic area of the

hypothalamus and passes *ia the median eminence and the portal *essel to the anterior

pituitary" where it stimulate the gonadotrophs to synthesiBe and release 2) and follicle

stimulating hormone (3S)!. It is released in pulses" controlled by the pulse generator in the

arcuate nucleus. In the female" the pulse fre>uency *aries with the phase of the cycle" duringthe follicular phase e*ery ' min and during the luteal phase e*ery F min. -he release of

5n1) is modulated by opioid and catecholamine inputs. 5n1) is synthesiBed firn a F#+

aminoacid pro+hormone" which is split into 5n1) and a &'+amino+acid 5n1)+associated

peptide (5!. -he physiological role of 50 is unknown" but it has been shown to inhibit

prolactin secretion.

2) and 3S) are glycoptoteins from the family which includes -S) and human chorionic

ganadotrophin (h5!. -hese hormones consist of a common 7+subunit and specific4+subunit.

0ll are glycosylate" which determines their bioacti*ity and half+life. =oth 2) and 3S) act on

the gonads to stimulate gametogenesis and hormone synthesis (see later!. -he le*els of the

gonadotrophins *ary with age. =efore puberty they are low6 they rise at puberty" initially at


8/24

night in both sexes" then continuously in the male and cyclically in the female. ;ith the

menopause" the le*els of both rise markedly.

-able .$0 0nterior pituitary hormones

-able .$= posterior pituitary hormones

-able .% -he properties of oestrogen

uring the follicular phase" 3S) and 2) stimulate oestrogen synthesis by the de*eloping

follicle. -his initially feeds back to the le*el of the hypothalamus and possibly to the pituitary

to inhibit 3S) and 2) release. egati*e feedback occurs in a short and ultrashort manner

too" in that 2) and 3S) feed back to the hypothalamus to reduce further 5n1)6 5n1) also

feeds back to inhibit its own release.

ositi*e feedback also occurs at mid+cycle. ,estrogens rise to such a point that their usual

negati*e feed back is re*ersed and a marked positi*e effect occurs. 5n1) release increasesand results in a 2)" and to a lesser extent 3S)" peak. -he former" but not the latter" is

responsible for o*ulation and initiation of luteiniBation of the follicle.

Oestrogen and progestoren

,estrogens ha*e a number of important general effects (table .%! but during the menstrual

cycle their most important role is to stimulate endometrial growth. 3ollowing o*ulation" the

corpus luteum continues to synthesiBe and release oestrogens and progesterone. -heir

production peaks E days after o*ulation and thereafter declines unless conception and

implantation occur" when the de*elopingembryo releases h5 into maternal circulation

which maintains corpus luteum function. rogesterone also has se*eral effects (table .&!but during the luteal phase it regulates endometrial recepti*ity.

ndrogens

In the female" androgens are synthesiBes in both the o*ary and adrenal glands. ,f the

circulating testosterone" #&H is formed directly in the o*ary. -he remainder is deri*ed either

directly from the adrenal (#&H! or indirectly through the peripheral con*ersion

predominantly of androstenedione (&H from the o*ary and &H from the adrenal! and to a

much lesser extent of dihydroepiandrostenedione (&H form the o*ary and &H from the

adrenal ! and to a much lesser extent of dihydroepiandrostenedione ()90" deri*ed mainly

from the adrenal glands!. In the female" androgens are probably responsible for themaintenance of pubic and axillary hair and also control libido.

Sex differentiation in utero

In the absence of any stimulation" the default phenotype is female. -he male phenotype is

determined by one key gene called the sex determining region (S1! gene. -his is

expressed by the support cells of the embryonic testis" which de*elop into Sertoli cells. It also

stimulates the germ cells to become spermatogonia" the steroid secreting cells to become

2eydig cells and the connecti*e tissue cells to be peritubular cells. In the absence of S1" the

four cell lineages de*elop into the granulosa cells" oogonia" thecal cells and stromal cells of

the o*ary.


9/24

-he ;olffian and Mullerian systems initially de*eloping parearel. -he secretion of Mullerian

inhibitory substance (MIS! by the Sertoli cells causes regression of the Mullerian system. -he

secretion of MIS is controlled by S1 and epidermal growth factor (953! 3urther sex

differentiation occurs with secretion of testosterone by the testis. -estosterone promotes

de*elopment of the ;olffian ducts into *as deferens" seminal *esicles and epididymis. In

order for some structure to de*elop (penis" scrotum and prostate! testosterone has to becon*erted to dehydrotestosterone by the enByme &7+reductase. In the absence of testosterone

(and thus of dehydrotestosterone! the embryo willde*elop into a phenotypic female" at least

in terms of the external genitalia.

-able .& -he properties o progesterone

-able .' Stages of breast growth

#u%erty

3emale

-here is *ariation in the timing and order of the e*ents of puberty. Dsually breast growth and

the growth spurt occur fist" followed by the appearance of public" then axillary hair" and then

menstruation (table .'" .E!. Increase in height prior to puberty is about & cm per year

uring the growth spurt (lasting #+$ years!" this increases to G+F cm per year. eak growth

*elocity usually occurs at around # years. =reast growthusually begins between F and $

years.-hea*erage time to de*elop from tage II to K (table .'! is % years (range .&+F years!6for pubic hair the a*erage $ years (range #+& years!. -he first menstrualperiod usually occurs

at the age of $ years (range +& years!. In affluent societies" better nutrition and health

mean that the age of menarche is decreasing.

Structurally" the reproducti*e organs change mark+edly with puberty. -he o*aries elongate

and become o*al in shape due to follicular de*elopment and an increase in stroma. =efore

puberty" the cer*ix makes up two+thirds of the uterus6 with puberty this changes" so that at

menarche it makes up half and within # years only one+third" -his is due to the increase in

siBe of the body of the uterus. -he *agina changes fromha*ing a thinepihelium" to a thicker

stratified multi+layered s>uamous epithelium" rich in glycogen.

-able .E Stages of pubic hair de*elopment

Ma!e

-he firs sign of puberty in boys is an increase in the siBe of the testis secondary to an 3S)+

induced increase in the seminiferous tubules -his is defined as stage II. 0t stage III" the

scrotum reddens and the penis starts to increase in length. 0t stage IK the process continues

with a more marked increase in the siBe of the penis" testes and scrotum. Stage K is reached

when the testes are approximately & cm in length" the scrotum is pigmented and thickened

and the penis is of adult siBe and proportions. ubic hair starts to appear at stage III and is of

an adult pattern at stage K. -he growth spurt stars # months after the increase in testicular*olume is noted.


10/24

9ndocrinology of puberty

-he factors controlling the time of onset of puberty are uncertain. It is thought that the

hypothalamus in childhood is highly sensiti*e to sex steroid inhibition of 5n1) secretion and

that" as puberty approaches " thisinhibition reduces resulting in increased secretion of 5n1)

and conse>uently of the gonadotrophins. )owe*er" in children without gonads" there is stillinhibition of gonatrophin secretion" implying the existence of another mechanism. -his may

in*ol*e leptin (see later!" the hormone produced by fat tissue. ,nce the hypoghalamic

inhibitionis o*ercome" and/or the inhibition from other factors is released" then" in females"

the initial endocrine change is an increase in the nocturnal pulse fre>uency of 5n1). -his

stimulates 3S) secretion and results in a multicystic appearance in the o*aries (also seen in

the reco*ery phase of anorexia ner*osa or exercise+induced amenorrhea and in oestrogen

secretion. 2aterin puberty" the le*els of 2) also increase. 0s puberty ad*ances" the peaks in

gonadotrophins occur during the day as well as at night" and finally in late puberty the

secretionof gonadotrophins loses its diurnal pattern and the le*els remain ele*ated. -he next

step is the onset of positi*e feed back of oestrogen on 5n1) release" resulting in the 2)

surge"o*ulation and menstruation (see later!. ,fthe initial cycles.FH are ano*ulatory. ;ithtime the number falls. So that %+& years after menarche" less than #H of cycles are

ano*ulatory. -he increasing le*els of oestrogen stimulate the maturation of the female genital

tract" breasts" the initial growth spurt followed by fusion of the epiphyses and the

redistribution of the body fat. 3usion of the epiphyses limits growth. -herefore" high le*els of

oestrogen (endogenous or exogenous! in early life are one cause of stunted growth (see later!.

Independent of the changes in gonadotrophins and oestrogen" the adrenal gland is

increasingly acti*e early in puberty" as shown by the higher circulating le*els of

dihydroepiandrostenedione sulphate ()90S!. -he factors controlling the onset of adrenal

acti*ity (adrenarche! are uncertain.

Leptin

2eptinis the 'E+amino+acid product of the ob+gene in white fat cells. It is a helicalmolecule

and a member of the tumour necrosis factor group of cytokines. It was disco*ered in the

ob/ob mouse" where a mutation of the ob+gene results in obesity and hypogonadotrophic

infertility" 1eplacement with leptin results in weight loss and the restoration of fertility"

probably by increasing 5n1h le*els. 2eptin expression is increasedby insulin"

glucocorticoids" noradreanaline and food. irculating le*els are reduced in weight+related

amenorrhoea.2eptin is the probable link between body weight and menstruation.

Menstrua! cyc!e

0t the time of puberty the o*ary contains between $ and ' primordial follicles.

-hese consist of an oocyte (L#&m! and its associated granulosa cells. Maturation from a

primordial follicle is independent of gonadotrophins until the follicle reaches secondary

follicle stage" when furthermaturation is dependent of 3S) (fig" .%!. -he tertiary follicle

contains a steroid+rich" fluid+filled antrum and rapidly grows to become a pre+o*ulatory"

orgraafianfollicle (#.+#.& cm! In each cycle" around secondary follicles are recruited.

9*entually one becomes the dominant follicle and the remainder become atretic. 3ollowing

o*ulation" the granulosa cells luteiniBe and *essels form the theca in*ade as the remnant of

the follicle becomes the corpus luteum.


11/24

3igure .% 3ollicular maturation form (0! ,to (=! #,to the mature $, (! graafian follicle

(1eproduced with permission from Johnston M) FGG 9ssential reproduction" $rd =lackwell

Scientifics" ,xford.!

,estrogen synthesis by the de*eloping follicle is controlled by 3S)" which stimulates the

production of aromatase by the granulosa cells. 0ndrogens. SyntesiBed by thecal cells inresponse to 2)" pass across the basement membranes to granulosa cells to be con*erted by

aromatase to oestrogens. -his thw Ntwo cellO theory of oestrogen synthesis" de*eloped from

obser*ations that granulosa cells do not possess the enBymes to be able to synthesiBe

oestrogen from pregnenolone and progesterone themsel*es. )owe*er" thecal cells can also

produce oestrogens and it has been suggested that the thecal cell oestrogen production

determines the circulating le*el of oestradiol" while the follicular fluid oestrogen is granulosa

cell deri*ed. irculating oestrogen le*els rise through the follicular phase of the cycle"

peaking between days # and % (fig .&!. -he increasing le*els trigger the 2) surge"

which stimulates o*ulation. rogesterone le*els increase slightly towards the end of the

follicular phase and may also play a role in the 2) surge.

0fter o*ulation" the follicle remnant becomes the corpus luteum and produces oestrogen and

progesterone. It also produces relaxin" inhibin+0 and inhibin+=. -he role of relaxin in

uncertain" during both the menstrual cycle and pregnancy. Inhibin hs been suggested to feed

back to the pituitary to inhibit 3S) release in both the male and female (see below!. If

pregnancy occurs" increasing le*els of h5 maintain the corpus luteum and its production of

oestrogen and progesterone until G+F weeks of pregnancy. -hereafter" the placenta becomes

the main source of oestrogen and progesterone. -he corpus luteum continues to produce

relaxin throughout pregnancy.

3igure .&. iagrammatic representation of changes in hormones le*els during hte

mensturla cycle. -he 2) peak is left open because it is sub?ect to great *ariation.

3igure .'.-he subunitsforming acti*in and inhibin

Inhi%in and activin

Inhibin and acti*in belong to the same family. Inhibinis a heterodimer made up of an 7 and 4

subunit. -here are two 4+subunits+ 0 and = P thus inhibin may exist as either inhibin P0 or

inhibin+=. 0cti*in is a homodimer of the 4+subunit" and thus may exist as acti*in+0" acti*in+

= or acti*in P0= (figure .'!. uring the menstrual cycle" acti*in is notdetectable oris

found at *ery low le*els. Inhibin 0 and = are present in the circulation and are deri*ed from

the o*ary. Inhibinis known to inhibit 3S) release while acti*in stimulates it" but as bothinhibin and actibin are synthesiBed in the pituitary" they may actin a paracrine manner

toinhibit or stimulate 3S) synthesis and release. uring pregancy" circulating le*els of

inhibin P0 and acti*in P0 are deri*ed from the fetoplacental unit. irculating le*els of

inhibin+0 peak in early pregnancy and rise again at the end. -hose of acti*in increase

gradually with gestation. 0 further marked increase in acti*in +0 le*els occurs with the onset

of labour and in pregnancies complicated by preeclampsia. o changes habe been reported in

the circulating lebels of inhibin+0 with the onset of labour" but marked increases habe also

been reported inpregnanciescomplicated by pre+eclampsia. -he role of either acti*in or

inhibin during pregnancy is unknown.

#regnancy


12/24

-he placenta becomes the dominant source of circulating oestrogen and progesterone from G+

F weeks of gestation. In addition" the placenta produces se*eral peptides (h5" human

placental lactogen Q)2R! ans *irtually all of the hypothalamic+releasing hormones. h5 is

structurally similar to 2) but has an additional $ amino acids. It is detectable in the

maternal circulation approximately days after o*ulation. -he le*el rises and peaks at +#

weeks @gestation (3ig. .E!. h5 pre*ents corpus luteum in*olution. It may also stimulatethe maternal thyroid and be responsible for hyperemesis gra*idarium. It is produced in

excessi*e amounts by placental tumours and may be used as a marker of therapeutic

response.

uring pregnancy" progesterone acts to maintain myometrial >uiescence. Its importance is

confirmed by the efficacy of progesterone antagonists in the induction of abortion in early

pregnancy or labour in late pregnancy. In addition" it inhibits other smooth muscles of the

body (the 5I tract and urinary tract!6 it stimulates the appetite" fat storage and the respiratory

centres (-able .&!. -he role of the three dominant oestrogens" oestrone Q9R"

oestradiolQ9#R" and oestriolQ9$R" during pregnancy is less clear. -hey may promote uriterine

blood flow" myometrial growth" stimulate breast growth and at term promote cer*icalsoftening and the expression of myometrial oxytocin receptors (table .%!.

)2 is a member of the 5)+prolactin family. It antagoniBes the effect of insulin and so

promotes lipolysis" reduces glucose utiliBation and enhances amino acid transfer across the

placenta. -hese effects may be designed to increase nutrient supply to the fetus. rolactin

le*els rise through pregnancy probably from both pituitary and decidual sources. It promoted

breast de*elopment" regulates fat metabolism and may contribute to the maternal immune

suppression.

3igure .E. 2e*els of human chorionic gonadotrophin during pregnancy

=iochemistry of human labour

uring pregnancy" the uterus expands to accommodate the growing fetus and placenta"

without increasing contractility" while the cer*ix remains firm and closes" throughout

pregnancy @pro+pregnancyA factors operate to inhibit myometrial contractility and allow

myometrial hypertrophy until" near to term" @pro+labourA factors begin to operate to mediate

remodeling of the cer*ix. -hese factors allow the cer*ix to efface and dilate" and stimulate

the uterus to begin coordinated contractions. 2abour is the result of the acti*ation of a

@cassette of contraction+associated proteinsA which act to con*ert the myometrium from a

state of >uiescence to a state of contractility. -hese include gap ?unction proteins" oxytocin

and prostaglandin receptors" enBymes for the synthesis of prostaglandins or cytokines" andalso components of cell+signaling mechanisms" which affect the way in which the uterus

responds o receptor acti*ation. It is likely that the factors which control the acti*ation of the

N cassette of contraction+associated proteinsA also acti*ate factors in the fetal membranes that

lead to the production of prostaglandins and cytokines associated with labour" and factors

within the cer*ix which lead to cer*ical remodeling and ripening.

regnancy can be di*ided into four parturitional phases. -he first phase" during the first and

second trimesters" is dominated by @pro+pregnancy factorsA and is the period of myometrial

growth and >uiescence.

-he second phase" during the early and mid+third trimester" is also a phase ofmyometrial>uiescence" but during which preparation for labour is made by upregulation of


13/24

myometrial" cer*ical and fetal membrane proteins which will be needed for labour. -he third

phase is the phase of labour itself and has the character of an inflammatory reaction. uring

this third phase of pregnancy" the @brakeA on myometrial contractility caused by @pro+

pregnancyA factors is released and the spontaneous contractility of the uterus is augmented by

oxytocic compounds such as prostaglandins and possibly oxytocin itself. -he fourth

parturitional phase represents the state of the intrauterine tissues after the process of labour.

#ro'pregnancy factors

rogesterone is the principal pro+preganncy factor. It has a negati*e regulatory effect upon

many of the @contraction+associated proteinsA associated with the formation of myometrial

gap ?unctions (connexins!" and the modulation of cer*ical ripening (interleukin+G!. It also

decreases uterine sensiti*ity to oxytocin. In many species" a withdrawal of progesterone

immediately precede the onset of labour either through regression of the corpus luteum (e.g.

in rodents! or through changes in placental steroidogenesis (e.g. in sheep!. -here is no

ob*ious systemic withdrawal of progesterone prior to labour in the human or other primates.

)owe*er" inhibition of progesterone" using mifepristone (1D%G'!" causes cer*ical ripeningand increases myometrial contractility. It is possible that in human there is no actual or

functional withdrawal of progesterone prior to labour" rather its @pro+pregnancyA action is

simply o*erwhelmed by Npro labourO factors. 0lternati*e hypotheses are that there is a

reduction in free" acti*e progesterone" that progesterone withdrawal is a local e*ent seen only

within the fetal membranes" or that functional progesterone withdrawal occurs because of a

switch from expression of the type to the type # progesterone receptor within the uterus

near to term. It has also been suggested that functional progesterone withdrawal may occur as

a result of competition between progesterone and increased concentrations of cortisol which

compete for binding to the same receptor.

In some species" for example the rabbit" nitric oxide synthesis in the endometrium alsomediates myometrial >uiescence and there is abrupt withdrawal ?ust before labour. -his is not

seen in primates. 0lthough the human uterus will relax if exposed to high concentrations of

nitric oxide" there is no e*idence for any physiological role for nitric oxide in human labour.

#!acenta! c!oc(

-he timing of human labouris probably controlled by increased placental release of

corticotrophin+releasing hormone (1)!" oestrogens" or a combination of both. -he

concentration of 1) in maternal plasma rises about F days prior to the onset of labor while

binding protein falls. 1) acts to increase prostaglandin synthesis and may also directly

stimulate myometrial contractility. 0lthough maternal oestrogen concentrations do not rise

acutely before human labour" as they do in sheep" there is a gradual rise in both oestriol and

oestradiol concentrations during the third trimester" reaching a plateau at about $G weeks.

,estradiolupregulates oxytocin receptors and oxytocin synthesis within the uterus.

-he role of oxytocin probably berries form species to species. In the monkey"

increasedoxytocin release is associated with the switch from prpe+labour contractures to

labour contractions. In the human" there are no changes in oxytocin concentrations before or

during labour" and" although the density of myometrial oxytocin receptors does increase

toward term" oxytocin is not thought to signal the onset of human labour.

La%our) an inf!ammatory reaction


14/24

2abour is associated with increased prostaglandin synthesis within the uterus" especially

within the fetal membranes. -his increase is associated with increased acti*ity of the pro+

inflammatory prostaglandin synthetic enByme cyclooxygenase type #. rostaglandins mediate

cer*ical ripening and stimulate uterine contractions. -hey also act indirectly to increased

fundally dominant myometrial contractility" by upregulation of oxytocin receptors and

synchroniBation of contractions. -here is also an increase in the production of inflammatorycytokines such as interleukin +4 and of chemokinessuch as interkeukin+G. -hese are

in*ol*ed in complex feed+forward and feed+back mechanisms" which further increase

cytokine and prostaglandin synthesis" 0t term" near to labour" the collagen of the cer*ix

changes" undergoing collagenolyisis" -he fibrils become dissociated from their tightly

organiBed amount of ground substance6 there is also a loosening of the collagen bundles in

the cer*ical stroma. -here is an accumulation of neutrophils which release collagenase into

the cer*ix. er*ical ripening therefore resembles an inflammatory reaction. It is currently

thought that neutrophils are attracted into the cer*ix at term by the combinationof increased

prostaglandin synthesis and the @neutrophil attractant peptideA interleukin+G.

unified hypothesis of the onset of !a%our in humans

)ow each of these *arious factors that are associated with the control of the length of human

pregnancy and the onset of labour are linked is currently far from understood. 0 current

hypothesis is that during the first parturational phase the uterus is under strong progesterone

repression. uring the second phase" rising oestrogen and 1) concentrations acti*ate

proteins such as cell surface receptors and gap ?unctions" which will be needed for labour

itself. 1) also increases the expression of inflammatory cytokines and of type #

cyclooxygenase.

2abour itself arises because a relati*ely rapid increase in synthesis of inflammatory mediators

and the influx of inflammatory cells leads to cer*ical ripening and uterine contractions. It isprobable that the transition from parturitionalphase two to phase three occurs one a certain

threshold or 1)" or of cytokines stimulated by 1)" is reached. In addition" the fetus may

signal its maturity" either through increased cortisol release" which stimulates placental 1)

synthesis" and/or through release of platelet acti*ating factor form the lungs" which also

stimulates prostaglanding and and cytokine synthesis. ,nce phase three is entered" there are

multiple positi*e feedback mechanisms which accelerate the processed of labour" which only

stops once deli*ery is complete.

2actation

uring pregnancy" se*eral hormones stimulate breast growth (oestrogen" progesterone" )2

prolactin" cortisol and insulin!. )owe*er" the high concentrations of oestrogens inhibit

lactation. 0fter deli*ery" with the fall in oestrogen le*els" lactation is initiated by the

continuing prolactin stimulation. rolactin is released from the anterior pituitary under the

control of dopamine (inhibitory! and -1) (stimulatory!. rolactin continues to be released in

response to suckling and promotes milk formation. -he milk let+downreflexin*ol*es the

release of oxytocin from the posterior pituitary" which stimulates the smooth muscle

surrounding the acini to contract and cause milk e?ection.

Menopause


15/24

-he menopause is a retrospecti*e diagnosis made after the absence of periods for year. -he

a*erage age in the D< is & years. It occurs because the o*ary has run out of recruitable

follicles. In utero" the peak number of oocytes is E million. =y the time of puberty only $+

' remain. -he factors which determine the initial number of oocytes and their rate of

loss are unknown" but a premature menopause is associated with deletions of C chromosome"

smoking and galactosaemia. In the absence of sex steroids and probably of inhibin"gonadotrophin le*els rise and remain ele*ated for years or more. -he o*aries become

atrophic" as does the uterus (which re*ert to a : ration of body to cer*ix! and the *agina.

-he lack of oestrogenincuces a series of *asomotor changes which include hot flushes" night

sweats and palpitations. epression os also more common and all these symptoms may be

helped by hormone replacement theraph ()1-!. ,ther structurally important changes occur

in the the heart" which becomes more susceptible to ischaemic heart disease (probably due to

changes in the structure of the *essel wall and reductions in )2 and increases in 22

le*els!" and in the bones where bone restoration increases and formation reduces" together

resulting in oesteroporosis.

Gro*th

5rowth in uteroseems to be determined prim airily by the maternal en*ironment rather than

any genetic influence. =y the current siBe and the childAs final height. ;hether a child will

fulfil its genetic potential or not will depend on nutrition" health and the expression of the

correct growth hormones. 5rowth is at its most rapid in utero and immediately after birth6

thereafter a second peak occurs before puberty" but during puberty itself the increased le*els

of oestrogen and testosterone result in epiphyseal fusion and the cessation of longitudinal

growth.

hysiology

5rowth hormone (5)! is a F+mino+acid peptide secreted from the somatotrophs of the

anterior pituitary. It has some homology with prolactin and human placental lactogen ()2!

and its synthesis is increased in resposne to the growth hormone releasing hormones (5)1)!

and reduced by somatostatin. =oth 5)1) and somatostatin are synthesiBed in the

hypothalamus and carried to the anterior pituitary in the portal blood system. 5) stimulates

the synthesis of the insulin+related growth factors (53+I and I53+II! predominantly in the

li*er" but also in the chondrocytes" fat and muscle. It promotes lipolisys in fat and

gluconeogenesis in the muscle. lasma le*els of the I53s are highest in childhood" and fall

with age. -hey act in both a paracrine and endocrine manner to promote bone growth" protein

synthesis in muscle and lipolysis in fat cells. 5) release is also stimulated by exercise and

hypogycaemia.

,ther hormones are important in growth. -hese include those that: (! control the a*ailability

of materials for growth" such as parathyroid hormone (calcium! and insulin (fats"

carbohydrates and amino acids!6 (#! inhibit 5) release such as cortisol6 and ($! ha*e effects

on cell growth and differentiation themsel*es such as insulin" thyroid hormones and

oestrogen and progesterone.

ysfunction

eficiency in 5) leads to dwarfism in children and weight loss" lethargy and impaired

physical performance in adults. 9xcess 5) leads to gigantism in children and acromegaly in


16/24

adults. -he latter is characteriBed by excessi*e of soft tissues (tongue" li*er" heath! and of

bones (hand" feet and ?aw!6 diabetes mellitus and hypertension

#ancreas

-he seat of control of blood glucose le*el is the pancreas" working in concert with the li*er"which acts as a store. 5lucose is the principal energy source of the body and so its le*el has

to be tightly controlled. 9xcess glucoses is stored in the liber and muscle as glycogen and in

adipose tissue as fat. 0t times of fasting" these stores are broken down to pro*ide glucose and

fatty acids as sources of energy. ,nly one hormone" insulin" controls the reduction in blood

glucose le*els. Se*eral other hormones act to increase blood glucose6 these include glucagon"

adrenaline" growth hormone and cortisol. =oth insulin and glucagon are synthesiBed and

released in the islet cells of the pancreas.

9mbryology

-he pancreas de*elops between the layers of *entral mesentery from endodermal buds(*entral and dorsal! which originate from the caudal part of the foregut. -he *entral bud

forms the uncinate process and some of the head of the pancreas but the ma?ority of the

pancreas is deri*ed from the dorsal bud. -he main pancreatic duct is deri*ed from the *entral

bud6 this usually fuses with the dorsal bud duct" but occasionally the dorsal bud duct persists

and opens into the doudenum independently.

0natomy

-he pancreas weighs approximately G g and is di*ided into the head (including the uncinate

process!" neck" body and tail It is retroperitoneal" the head lying within the cur*e of the

duodenum and the neck" body and tail extending in front of the *ena ca*a and aorta to thespleen. -he stomach lies anterior to the body and tail. -he pancreas is made up of glandular

acini (which secrete enBymes and bicarbonate! and the islets of 2angerhans (+#H of the

pancreas! which synthesiBe glucagon (7+cells! insulin (4+cell!" somatostatin ( cells! and

pancreatic polypeptide (!.

3unction

Insulin (mol. wt &E$%" & amino acids! is made up of two chains (0 and =!. It is synthesiBed

as pre+pro+hormone and clea*ed to pro+insulin and finally to insulin and +peptide which are

released in e>ual amounts (3ig. . %!. Its release is stimulated by glucose (oral stimulus is

greater than intra *enous due to the in*ol*ement of the intestinal hormones!" basic aminoacids" ketones and free fatty acids. Insulin release is further potentiated by glucagon" 5) and

gut hormones" and inhibited by hypocalcaemia" adrenaline and somatostatin. -he release

profile of insulin is di*ided in to two phases6 the first is a burst lasting L min" and the second

is more prolonged" persisting as long as does the stimulus to insulin secretion. Insulin

promotes the transport of glucose and amino acids across the cell membrane in muscle and

adipose tissues. In adipose tissue it inhibits lipolysis" and in the li*er it increases glucose

uptake and glycogen formation. Insulin is metaboliBed by the li*er and kidney and has a half+

life of approximately +&min.

5lucagon (mol.wt $%G&" #F amino acids! is released in response to hypoglycaemia" basic

amino acids" gut hormones" exercise and adrenaline. Its release is inhibited by increasing

blood glucose" ketones" free fatty acids" insulin and somatostatin. It generally inhibits the


17/24

uptake of glucose and amino acids" promotes lipolysis and hepatic glycogenolysis"

gluconeogenesis and ketone generation.

ancreatic somatostatin regulates stomach motility and the secretion of gut hormone and

pancreatic polypeptide may ha*e a role in the regulation of digestion.

ysfunction

Insulin deficiency results in hyperglycaemia. -he effects of hyperglycaemia are salt and

water depletion due to an osmotic diuresis" weight loss" tiredness" *omiting" hypotension"

infections" hyper*entilation (due to ketoacidosis! and impaired conscious le*el and coma.

hronic hyperglycaemia results in microangiopathy (affecting the kidney" ner*es and retina!

and macroangiopathy causing peripheral" coronary and cerebral *ascular disease.

)ypoglycaemia (defined as a blood sugar of L#.& mmol/2! is usually a complication of

insulin treatment and rarely the presenting symptom of li*er disease" hypoadrenalism or

insulinoma. In the early stages of hypoglycaemia" patients are pale" sweaty and tachycardic6they may complain of hunger and palpitations" and later may be confused" in a coma or e*en

con*ulsing.

"hyroid

9mbryology

-he thyroid is the first endocrine gland to appear" beginning de*elopment oat #% days after

fertiliBation and becoming acti*e in terms of thyroid hormone secretion at about weeks of

pregnancy. It is deri*ed from the floor of the primiti*e pharynx in the form of the @thyroid

di*erticulumA. 0s the embryo grows" the thyroid descends to lie below the hyoid bone infront of the de*eloping tracheal rings. uring de*elopment the thyroid is connected to the

tongue *ia thethyroglossal duct" a remnant of which may gi*e rise to a thyroglossal cyst. -he

thyroid di*erticulum di*ides into the left and right lobes and is connected by the isthmus (fig.

.G!

0natomy

-he thyroid weighs about # g and each lateral lobe is about % cm long. Its blood supply is

from the superior thyroid artery (external carotid! and the inferior thyroid artery (subcla*ian

artery!" and the superior and middle thyroid *eins grain into the internal ?ugular and the

inferior into the brachiocephalic *ein (fig. .G!.

-he four parathyroid glands lie on its posterior aspect. Microscopically" the thyroid is seen to

consist of million or more follicles. 9ach has a layer of follicular cells surrounding a central

colloid. -he follicular cells secrete thyroBine (-%! and tri+iodothyronine (-$!into the colloid

which are then stored" bound to thyroglobulin. arafollicular cells (+cells! synthesiBe and

secrete calcitonin.

-hyroid hormone synthesis

-he thyroid hormones are iodinated metabolites of tyrosine (-$! has three iodine molecules

and (-%! four! -heprocess of thyroid hormone synthesis (fig. .G! is split into se*eral steps:(! iodide is acti*ely taken up into the follicular cells by the iodide pump against the


18/24

concentration gradient (iodide trapping!6 (#! it is con*erted to iodine (iodide oxidation!6 ($!

tyrosine is incorporated to form pre+thyroglobulin6 (%! which is iodinated to form

iodoprethyroglobulin (contains $% tyrosine residues" of which only #&+$ can be iodinated

and '+G coupled into hormone residues! (3ig. .#!6 (&! coupling of -and -# to form-$and

of -# and -# to form -%" both of which are stored in the colloid in the form of

iodothyroglobulin6 ('! iodothyroglobulin is taken up by the follicular cells and broken downinto free -$and -%" which diffuse into the blood. ,nce in the circulation thyroid hormones are

bound (-%FF.F'H and -$" FF.%H! either to thyroxine binding globulin (-=5!" pre+albumin or

albumin (table .G!6 only the free portion is acti*e. -he circulating le*els of - %are higher

than -$as the thyroid secretes more -%than -$and -%has longer half+life. howe*er -% is less

acti*e than -$and acts more as a storage form6 it is also con*erted peripherally and within

cells to -$. -%con be con*erted to -$and to r-$an inacti*e form!. -he relati*e balance in this

con*ersion *aries and more -%is con*erted to r-$ during illness. 0lso during illness" the

feedback effects of thyroid hormones seem to be lost" so that" although the peripheral

concentrations are low" the pituitary response seems to be reduced and -S) le*els are not

ele*ated" gi*ing rise to the @sick euthyroidA picture. -$is inacti*ated by further deiodinationor

con?ugation on the li*er. -he fetus and neonate also ha*e relati*ely high le*els of r- $.

3igure .G. -he *ascular supply of the thyroid gland

-abel .G.1elati*e binding of -%and -$to plasma proteins and its effect on their acti*ity.

3igure .F.-he synthesis" storage and release of thyroid hormones (1eproduced with

permission from 5reenpan 3S" Strewlwe 5J FFE =asic and clinical endocrinology.

&thedn.0ppleton and 2ange. 2ondon!

3igure .#. -he structure of monoiodotyrosine and diiodotyrosine

-he recommended daily intake of iodine id & mg6 it is found in meat and *egetables.

-hyroid uptake of iodine id enhanced by -S) and iodine deficiency" but reduced by an

excess of iodine and digoxin. Most iodine is excreted *ia the kidneys (3ig. .#!

3igure .#. Iodine metabolism

3unction

-hyroid stimulating hormone (-)" molecular weight #G" #% amino acids! is released

from the anterior pituitary in response to -1)" dipeptide synthesiBed in the supraoptic and

supra*entricular nuclei. -S) has a number of effects on the thyroid: it increases its siBe"*ascularity" iodine uptake" protein synthesis" storage of colloid and the secretion of - $and -%.

-hyroid hormones feed back to both the hypothalamus and pituitary.

-here are se*eral thyroid receptors which bind to the thyroid hormone response element on

0. -he transcriptional effects of -$ take hours or days to occur (such as tissue growth"

brain maturation!. ,ther non+genomic effects are more immediate6 these include an increase

in glucose and amino acid transport. -%and -$are essential for normal fetal de*elopment. In

their absence" brain de*elopment and musculoskeletal maturation are markedly impaired

resulting in @cretinismA. -hyroid hormones maintain the normal hypoxic and hypercapnic

dri*es to the respiratory entre and this may account for the occasional need to *entilate

patients with se*ere hypothyroidism. Metabolically" -%and -$stimulate lipolysis" glycolysis"gluconeogenesis" the absorption of glucose and the metabolism of insulin and cortisol.


19/24

In excess" thyroid hormones increase ,#consumption and heat production onby stimulation of

aT+uestion of thyrotoxicosis. 0lso" during pregnancy" maternal thyroid disease can

affect the fetus in two ways: (! the maternal antibodies causing thyrotoxicosis or

hypothyroidism may cross the placenta and cause a similar self+limiting problem in the fetus

and (#! the therapy used in the treatment of thyrotoxicosis may cross the placenta and causefetal hypothyroidism.

-able .F -he effects of thyroid excess and deficiency

ysfunction

-he effects of thyroid hormones deficiency and excess are shown in table .F

-herapy of thyroid disease

-he management of thyrotoxicosis due to 5ra*esA disease is usually with antithyroid drugs"the most common of which are carbimaBole and propylthiouracil (-D!. =oth act to inhibit

the con*ersion of iodide to iodine" the iodination of tyrosine and the release of both - %and

-$6 propylthiouracil in addition pre*ent the deiodination of - %. 5i*ing iodine also suppresses

the thyroid gland *ia an uncertain mechanism. -he dose of antithyroid drugs used during

pregnancy should be determined by the maternal free thyroxine and -S) le*els. 0s these

drugs readily cross the placenta while a relati*ely smaller proportion of the maternal thyroid

hormones cross the placenta" a block and replace approach is not appropriate. 0lthough both

drugs are present in breast milk" the amount of propylthiouracil is relati*ely less.

In hypothyroid women the replacement dosage of thyroxine should also be titrated to the

-S) and for maternal free thyroxine le*els using normal ranges for pregnancy.

drena! G!and

9mbryology

-he cortex of the adrenal gland de*elops from mesoderm (the mesothelium of the posterior

abdominal wall!" the medulla from neural cress cells. -he latter is essential part of the

sympathetic ner*ous system. ifferentiation of the cortex begins in late fetal life" but the

Bonareticularis is not recogniBable until $ years of age. 0t birth" the adrenal cortex is large

due to the presence of the fetal cortex (which produces )90S as a substrate for placental

oestrogen synthesis! -his regresses o*er the first year of life.


20/24

0natomy

-he adrenal gland weigh approximately %+& g" are retroperitoneal and lie on top of the

kidneys. -he yellowish cortex accounts for FH of the gland weight and the medulla" the

remainder. -he adrenals are supplied with blood by branches of the aorta" renal and inferior

phrenic arteries. 9ach gland has onUe *ein which drains on the right into the inferior *enaca*a and on the left into the renal *ein.

-he cortex is di*ided into three layers. -he outer" Bonaglomerulosa" produces aldosterone (it

lacks E7+hydroxylase and so cannot produce cortisol or androgens!. -he middle" Bona

produces androgens and cortisol. =oth of the inner Bones are controlled by

adrenocorticotrophic hormone (0-)!

0drenal cortisol synthesis

0-) controls the synthesis of cortisol (and androgens! by the Bonafasciculata and

reticularis. 0-) is itself controlled by the hypothalamic hormones 1) and *asopressin.0-) stimulation of the adrenal results in an immediate increase in the circulating le*els of

cortisol6 it also increases the a*ailability of cholesterol.

0-) is released in a circadian rhythm" so that cortisol is lowest in the e*ening and highest

in the early hours of the morning. -his pattern is lost during illness" stress" ushingAs

syndrome and alcoholism. 0n acute stress" physical or otherwise" results in an increase in

0-) and cortisol le*els. ortisol feeds back at the le*el of the hypothalamus and the

pituitary. 0t the le*el of the pituitary" cortisol reduces 0-) release acutely within minutes"

and chronically by reducing synthesis of its precursor" pro+opiomelanocortin.

,nce released" F&H of cortisol circulates bound to cortisol binding protein (GH! andalbumin (&H!. Most is metaboliBed in the li*er and a small amount I excreted unchanged in

the urine (#%+h urine collection and cortisol measurement is used as an initial estimation of

cortisol production!.

3unction

ortisol. 2ike the other steroid hormones" enters the cell" binds to its receptor and then

directly interacts with a response element on 0 to alter gene expression. It is important

metabolically and in the management of @stressO

Meta%o!ism

ortisol stimulates gluconeogenesis and lipolysis (increasing glycerol and free fatty acid

le*els!" but inhibits peripheral glucose usage. ,*erall effect is to maintain glucose le*els.

Connective tissue

3ibroblast are inhibited and collagen lost" resulting in thin skin with bruising and poor wound

healing. =one resorptionis enhanced and formation inhibited resulting in bone loss" both by a

direct effect on bone and indirectly by (! enhancing the acti*ity of parathyroid hormone and

*itamin " and (#! increasing urinary calcium excretion and reducing calcium absorption in

the gut. In the adult" this results in bone loss" and in children this may contribute to the

obser*ed reduction in growth.


21/24

Haemato!ogy and immuno!ogy

ortisol has little effect on haematopoiesis" but it does increase the circulating neutrophil

count by increasing their production and half+life" and reducing their mo*ement out of the

circulation. irculating numbers of lymphocytes" eosinophils and monocytes are reduced by

increasing their mo*ement out of the circulation. 5lucocorticoid steroids are generally

immunosuppressi*e.

Cardiovascu!ar and rena! effects

ardiac output is increased as is peripheral resistance. -he combination results in an increase

in blood pressure. -his effect is augmented by salt and water retention (potassium excretion!"

which is induced by stimulation of the mineralocorticoid receptors.

Misce!!aneous effects

orticosteroids may cause a change in affect resulting in euphoria6 other psychiatric states

may also be obser*ed. 5onadal function may be suppressed.

ysfunction

-he typical pictures of ushingAs syndrome (cortisol excess! and 0ddisonAs disease (cortisol

deficiency! are shown in table ..

-able . 3eatures of cortisol excess and deficiency

drena! androgens

0drenal androgen synthesis occurs predominantly in the Bonareticularis" is controlled by

0-) and starts between E and F years of age (adrenarche!. )90 and androstenedione"

and to a lesser extent testosterone" are synthesiBed and coconut for &H of testosterone in the

female and &H in the male. 9xcessi*e secretion results in hirtutism and *irilism in the female.

dena! medu!!a

-he adrenal medulla is essentially part of the sympathetic ner*ous system from which it

recei*es a rich ner*e supply. Sympathetic stimulation results in the release of adrenaline and

noradrenaline (both synthesiBed from the amino acid tyrosine! into the blood" where they

circulate bound to albumin until metaboliBed in the li*er (b catecholamine+,+methyltransferase and monoamine oxidase into *anillylmandelic acid" KM0!. -he effects of

adrenaline and noradrealine are mediated through 5+protein+linked surface receptors which

are classified generally into 7 and 4. -heir acti*ation produces the typical @flight or fight

responseA (-able .!.

In excess" as seen in a phaeochromocytoma" adrenalinecause marked hypertension and

anxiety. It may also be associated with sweating" pallor and tremor as expected from its

effects listed in table .. It is possible to measure the circulating le*els of catecholamines

to make the diagnosis of a phaeochromocytoma" but many units still use #%+h urinary

excretion of KM0. If either is ele*ated" further in*estigation in*ol*es *isualiBation of the

adrenals.


22/24

-able . 9ffect of sympathetic acti*ation

3igure .##.alcium: secretion into an excretion from the blood to the gastrointestinal tract"

bone and kidney. -he influences of *itamin " parathyroid hormone and calcitonin

Ca!cium homeostasis

alcium is essential for many of the bodyAs processes. It is a key intracellular messenger

necessary for the maintenance of cell membrane potential in excitable cells (ner*e" cardiac!"

muscle contraction" enByme action and inhibition" and hormone release6 it also is important in

bone formation and clotting factor acti*ity. It is not surprising" therefore" that there is a

complex mechanism to ensure that its le*els are tightly regulated. -he key components are

parathyroid hormone (-)! *itamin and calcitonin" which act on the bone (which contains

most of the bodyAs calcium!" kidney and gut (fig. .##!. -he calcium concentration in

plasma is #.& mmol/26 approximately %&H is protein bound (albumin! and the remainder is

either free (%EH! and therefore acti*e" or complexed with other compounds.

arathyroid hormone (-)!

#"H anatomy and em%ryo!ogy

-here are four parathyroid glands which de*elop from the pharyngeal punches6 the superior

glands from the dorsal portion of the third pouch and the inferior glands from the superior

portion of the fourth pouch. -hey are o*al shaped" about .& cm n siBe" % g in weight and

embedded beneath the capsule in the posterior aspect of the thyroid gland. -heir blood supply

is deri*ed from the thyroid arteries. -hey contain two sorts of cell6 the chief cell which

synthesiBe " store and secrete -)" and the oxyphil cells of unknown function.

#"H synthesis

-he gene for -) is located on chromosome . It is synthesiBed as a pre+pro+hormone6 the

signal peptide is remo*ed to form pro+-)" which is con*erted to -) by the remo*al of the

pro+se>uence in the 5olgi apparatus prior to storages in the cell cytoplasm. It is an G%+amino+

acid peptide with a molecular weight of F$. 2ow plasma calcium le*els e*oke its release"

which is suppressed by increased plasma calcium le*els.

#"H function

-) acts *ia 3+protein+linked cell surface receptors in bone and kidney. In the kidney" it acts

on the renal tubule to enhance phosphate and bicarbonate excretion (proximal!" and calcium

and hydrogen ion reabsorption (distal!6 it also enhances the renal 7+hydroxylation of *itamin

" increasing *itamin acti*ity. -) acts indirectly on the gut through increased *itamin

acti*ity to enhance calcium and phosphate absorption. In the bone" -) reduces osteoblast

collagen synthesis and enhances osteoclast acti*ity" which results in increased osteolysis and

release of collagenase and hydrogenions6 the last two enhance bone resorption. -he o*erall

effect of -) is to increase circulating calcium and phoshate.

#"H dysfunction

0 deficiency of -) result in hypocalcaemia and the clinical picture of risk reflexes+

h*ostekAsign. (tapping o*er the facial ner*e causes a facial twitch!" numbness and

paraesthesia" tetany carpopedal spasm (-rousseauAs sign" induced by inflating a blood


23/24

pressure cuff!" and a prolonged V- inter*al on 95. 0n excess causes hypercalcaemia and

the clinical picture of @bones" stones" moans and groansA:

. Bonesare painful and fragile due to excessi*e resorption.

#. 1enal stones are due to increased urinary calcium le*els and ectopic calcification

secondary to hypercalcaemia in the heart" pancreas" uterus and li*er

$. Groans include headache" abdominal pain" anorexia andconstipation%. Moans include weakness and tiredness. 1eflexes are sluggish" there is polyuria"

dehydration and renal failure" confusion and coma. ,n 95" the V- inter*al is short

and cardiac arrhythmias

Kitamin

+itamin D synthesis

Kitamin is a sterol hormone (synthesiBed from cholesterol!. It is either synthesiBed in the

skin by photoisomeriBation (FH" action of DK light! or absorbed n the diet (H" fish and

eggs!. It is acti*ated in the li*er and kidney. In the li*er" *itamin is #&+hyfroxylated andthen stored in body fat. It is transported to the kidney where it is +hydroxylation is

controlled by -) (see earlier!" calcium and phosphate le*els" growth hormone" cortisol"

oestrogens and prolactin.

+itamin D function

Kitamin promotes calcium absorption at *arious sites (gut" kidney and bone!. It does this

by binding toa nuclear receptor (K1! which has a 0 binding domain. ,nce *itamin

has bound" the complex (*itamin +K1! has to bind with retinoic acid receptor to form a

heterodimer in order to be able to bind to 0 and to exert its genomic effects. In the gut"

*itamin increases calcium and phosphate absorption in the ?e?unum and ileum. -he are

se*eral possible mechanism: (! opening of calcium channels" (#! the increased synthesis oftwo calcium binding proteins (calbindins! which promote the passage of calcium across the

cell di*ision and growth. In the bone" it increases calcium and phosphate release by

enhancing osteoclast acti*ity6 this effect is indirect as osteroclasts lack K1. In addition"

osteoblast synthesis of osteocalcinis increased -hus" in the bone" *itamin has effects

which promote formation and resorption and >uite what its o*erall effect is

remainsuncertain (see later! In the kidney" *itamin increases tubular calcium and

phosphate reabsorption.

+itamin D dysfunction

0defiance of *itamin has *arying effects depending on the age of the sub?ect. In children"deficiency results in rickets with bowed legs" chest deformity and hypocalcaemia. In adults"

deficiency results inosteomalacia with bone pain" fractures" hypocalcaemia and on C+ray

pseudofractures are seen (2ooserABones!. -he effects of *itamin deficiency relate to

impaired gut absorption of calcium" which results in hypocalcaemia. -his increases serum

-) which stimulates bone resorption and causes the picture of bone demineraliBation.

Kitamin +resistant rickets rarely occurs and is an C+linked dominant condition" which is

rhe result of an abnormal *itamin receptor. Kitamin excess results in hypercalcaemia"

the features of which ha*e been described earlier in thesection on -).

Kitamin deficiency may arise in a *ariety of ways: (! dietary deficiency6 (#!

malabsorption due either to obstruction of the bile duct or bowel disease as seen in coeliac


24/24

or rohnAs disease6 ($! li*er disease that may result in redued #&+hydroxylation6 and (%!

renal disease that may result in reduced 7+hydroxylation.

Ca!citonin

alcitonin is synthesiBed by the parafollicular +cells of the thyroid -hese areneuroendocrine cells deri*ed from the neural crest" which make up less than .H of the

mass of the thyroid.

Ca!citoninsynthesis

alcitonin is $# amino acids in length and its synthesis is regulated by circulatingcalcium

le*els" increasing when the le*els are higher and reducing when the are lower.-he gene

encodes two different peptides which are formed by alternati*e splicing. -he first is

calcitonin and the second calcitonin gene+related peptide (51!. 51 is a $E+amino+

acid peptide with potent *asodilator properties which is thought to be at least in part

responsible for the marked *asodilatation of pregnancy.

Ca!citonin function

alcitonin acts *ia a 5+protein+linked receptor which is linked toadenyl cyclase. Its primary

site of actionis the bone where it reduces osteoclast acti*ity" although it also acts in the renal

tubule to reduce phosphate reabsorption and to a lesser extent calcium. -he importance of

calcitonin in calcium homeostasis is uncertain (see later!

Ca!citonin dysfunction

Medullary tumours of the thyroid secrete calcitonin and result in high circulating le*els.

espite this" calcium le*els are unaltered. or are calcium le*els altered by a total

thyroidectomy" which remo*es the only source of calcitonin" -hus" in the human it isuncertain whether calcitonin has any role in calcium homeostasis. e*ertheless"

therapeutically" calcitonin is useful for the treatment of agetAs disease of bone and as an

inhibitor of osteoclast acti*ity.

,steoporosis

In contrast to osteomalacia" osteoporosis occurs when there is insufficient protein synthesis"

i.e. a deficiency of bone trophic hormones" but mineraliBation is normal.

-he most common example is in postmenopausal women" although hypogonadal men ha*e

the same problem. eak bone mass is typically reached at #&+$ years and thereafter declinesat an annual rate of #+&H in women and .$+.&H in men. =one loss may be pre*ented or

reduced by a number of approaches: (! hormone replacement therapy" (#! calcium

supplements in combinations with *itamin 6 ($! calcitonin (inhibitors of osteoclast acti*ity

such as the bisphosphonate!" and (%! weight+bearing exercises

Documents

ENDOCRINOLOGY.doc