CHAPTER4

wPOTHALAMUS-PITUITARY
HYPOTHA

NTRODUCTION
&GONADAL
AXIS
me
hypothalamic-pituitary-gonadal
pituitary gland,
the hypothalamus, pituitary and
axis (HPG axis) refers
the connection between
to
the hyp gonads. The HPG axis
anism mainly involved in the regulation of the plays an important control
Ehctuations
animals.
in this axis cause development,
changes in the hormones reproduction and ageing in
have various
local and systemic effects on the produced by each gland and
body.
with other hypothalamic-pituitary related
As
axes, regulation
edhack loop. Regulation of the reproductive axis
is
through a negative
begins at the level of the
hypothalamus.
here neurosecretory cells synthesize and release a
hormone (GnRH) into the
decapeptide, gonadotropin-releasing
hypothalamic-hypophysial-portal circulation. In response. gonadotropes
the anterior pituitary synthesize and release the
in
gonadotropins follicle-stimulating hormone
-

(FSH) and luteinizing hormone (LH), both of which ultimately control gonadal function.

LOCATION AND REGULATION

The hypothalamus is located in the brain and secretes GnRH. When GnRH is released,
itravels along the hypophyseal portal system and binds to secretory cells ofthe anterior pituitary
adenohypophysis). In response to GnRH stimulation these cells procduce LH and FSH, which
are then secreted into the bloodstream. From here, LH and FSH go on to produce different
effects in both sexes, namely through the production of estrogen in females and testosterone in

males.
produce estrogen and inhidun and to
In females FSH and LH activate the ovaries to
forms a negative feedback loop by
cycle and ovarian cycle. Estrogen
Tgulate the menstrual
Inhibin acts to inhibit activin, which
DIting the production of GnRH in the hypothalamus. the interstitial cells located
cells. In males LH stimulates
Vely stimulates GnRH-producing FSH a role in spermatogenesis.
plays
Only small
to produce testosterone, and
e Lestis
aOunts of estrogen are secreted in males.
has nhibitory effets
effects and ghrelun
stimulatory
and insulin have hypothalamus. Kisspeptin
also
aadition, leptin from the
(GnRH) secretion
gonadotropP-Teleasing hormone
intluene
nfluences GnRH secretion.
YPOTHALAMIC-PITUITARY-OVARIAN AXIS follicle, takes
follicle to early tertiary
from primordial tertiary follicles,
ending
Thehe process of development
humans. The
final stages of
development
These change
nges are regulated by
approximately two 1
wo
months in 28 days.
approximately

with ovulation OCcur

occur oover of
v e r aa
course

h O n and FS
any
any GnRH, LH,
hormones including
 Physlology Controllng and Coordinatinat
158 Inetlng System
The hypothalamus prduces GnRU, a hormone that signals the anterior
anterior pituitar yland
FStH and LH. These
topratce the gonadtropins and travel
gonadtryins leave the pituitary through
the blondstream to the ovaries, where they bind to
the
moeptors on the granulosa and theca cells of
tollicles. FSH stimulates the tollicles to grow (hence Hypothalamus
its nane of follicle-stimulating hormone). The release OnRH
ofLH also stimulates the granulosa and theca cells
of the follicles to produce the sex steroid hormone Anterior
estradiol, a type of estrogen. pituitary
The more granulosa and theca cells a follicle
has (more developed), the more estrogen it will
produce in response to LH stimulation. As a result,
systemic plasma estrogen concentrations increase. Ovaries
Following a classic negative feedback loop, the high
concentrations of estrogen will stimulate the
hypothalamus and pituitary to reduce the production EstrogenProgesterone
of GnRH, LH, and FSH. Because the
large tertiary Fig.4.1 Hypothalamus.
folhicles require FSH to grow and survive at this Pituitary- Ovarian Axis
point,
this decline in FSH caused by negative feedback leads most of
them to die (atresia). Only one
follicle, now called the dominant follicle, will survive this reduction in
be the one that releases an
FSH, and this follicle will
oocyte. The factors that lead to a particular follicle becoming
dominant include the size, the number of
granulosa cells, and the number of FSH receptors
on
those granulosa cells.
When the only dominant follicle
OFollieuler phese
Ptultary hormone
remains in the ovary, it again begins to etect:LHseveral
and FSH
Secrete
stmulate GnRH
estrogen. It produces so much oclos to grow.
estrogen that the normal negative
feedback doesn't occur. Instead, these
extremely high concentrations of
systemic plasma estrogen trigger a
positive regulatory switch in the anterior FSH
pituitary that responds by secreting
amounts of LH large Estredio Overlen
and FSH into the hormone
bloodstream.The positive feedback Folcles efecte:
by which more estrogen loop Dominent oldle
of more LH and triggers release Droducos estedo,

Estredlo whch:
FSH only occurs at Inhlbits GnAH, FS
this point in the cycle. and LH production
Causos
endometlum o
This large burst of LH (LH Endometrum thioken
surge) leads to ovulation of the dominant Fig.4.2 Hypothalamus -Pituitary-Ovarian AX
(Regulating follicular phase)
AaprodtvctiveS y s t m

159
LH surge
surge induces many
The

ticlehcke. dominant follicle, inchuding onteton

nsinthe
ohangesm the
resumption of meiosis of Pmry homene
the
FSH
ad
anPH
stimulating

oocyte to a secondary
ry
one oft
theprimary

triggers proteases
he It also gong ble
m c y t e

proteins) to break
mes
enzyes that cleave Arterlor
d o w n s t r u c
rural proteins in the ovary
t u r .
phultery Estrarle

wall on the
surface of the bulging
dominantfoll follicle. This degradation of the
with pressure from the
al. ombined results in the
efuid-filled antrum, Overe Overnt
ofthe oocyte surrounded by homone
pu/sion ec
nulosa cells into the peritoneal cavity. Growing tollcie
continuee to produce
ovulation. srdol, wmich:
release is
This Est Stimulntes GnRH,
The surge of LH also
stimulates terus FSH and
production
theca cells of the
thegranulosa and Endomtrhum surge
Ovulnton
ggers
follicle after ovulation, and
rema ining
into a new endocrine Fig.4.3 Hypothalamus -Pituitary
transforms it Ovarian Axis (Regulating ovulation)
structure called the corpus luteum.
and theca cells of the corpus luteum begin to produce large
Instead of estrogen, the granulosa
establishment and maintenance of
amounts of progesteronehormone, that is essential for the
feedback at the hypothalamus and pitutary.
now triggers negative
pregnancy. Progesterone develop at this
and FSH secretions low, so no new dominant follicles
which keeps GnRH, LH,
ime
luteum will stop seereting
to 12 days, the corpus
does not occur within 10
lf pregnancy albicans. During this period
of redhuced progesterone
progesterone and degrade into the corpus and the follicular phase begins again
with a
stimulated,
Secretion, FSH and LH are once again secrete estrogen.
beginning to grow and
follicles
ew cohort of
early tertiary
HPG Axis in Females (Function) of the menstrual
and
involved in the regulation
is mainly bloodstream, these
In females, the HPG axis and FSH into the
releases LH roles un the
Once the anterior pituitary which play important
Cycle. and inhibin, production
hormon Signal the ovaries to produce estrogen properties that can suppress the Inhibun
S inhibin possess tfeedback loop.
Teproductive Both estrogen and cycle. via a negative
production
of nRH. inhibits GnRH activn

Estroge directlycomplex
protein
inhibits GnRH production
by inhibiting the
h reproduction by
Reproductive Cycle functions of the
HPG axis is to regulate
of the
ovarian
follicle is

One Or
of the
the most
most important females
the preparation
Release of the
and LH.
COntrol cycles. In both estrogen
ng the
e uterine:and ovarian
uterine
that
involves
done ththro a
One
E
loop positive-feedback
 160 Physiology Controlling and Coordinating s
ovarian follicle leads to the production of progesterone from the ovary. Progesteron steme
hypothalamus and the anterior pituitary thus stopping the estrogen-LH positive fahibit
Ifconception occurs, the placenta will take over the secretion of progesterone: tho
e, therefore the
mother cannot ovulate again. If it does not occur, the level of progesterone
esterone in
in the
the h r e the
bloods
decreases and this decreases the negative-fecdback on the hypothalamus, which all
produce GnRH and thus stimulate the anterior pituitary to produce and release FSH
preparing the female for the preparation of the next ovarian follicle. In women, ovarian LH,
jan follicles
are stimulated by FSH to grow and
Luteel pheeo
mature; LH stimulates ovulation Ptutary hormone
and corpus luteum formation. nect: LHstimulatoss
ormaton of a copUs GnRH
utoum rom tollcular
Menstrual Cycle tlssue lott behind ator
ovulation.
The HPG axis is involved
in all three phases of the menstrual
cycle. The hormones of the HPG
FSH
axis also control the uterine
LH Progesterone Ovrien
(menstrual) cycle causing the
hormone
proliferation phase in preparation Corpuslutoum ect
The corpus
for ovulation, the secretory phase uteun secretes
progesteone, which:
after ovulation, and menstruation Progesterone hbs GnRH, FSH,
and LH producion
when conception does not occur. Malntans he
Endomeum endometrium; as the
Secondary Sex Characteristics copusuteum degrade
progosioone decines
Fig. 4.4 Hypothalamus - Pituitary niaing skoughing of
The hormones of the HPG h straum funcionals
Ovarian Axis (Regulating menstruation)
axis also contribute to the
secondary sex characteristics of females. These include, growth of breasts, erection of nipples,
growth of body hair, increasing width of hips, and increased muscle mass in the muscles posterior
to the femur.

Life cycle
The activation and deactivation of the HPG axis also helps to regulate life cycles. At
birth FSH and LH levels are elevated, and females also have a lifetime supply of
0ocytes. These levels remain low through childhood. During puberty the HPG axis is activated
primary
by the secretions of estrogen from the ovaries. This activation of estrogen causes physioog al
and psychological changes. The HPG axis becomes
deregulated in women, eaus
menopause. This deregulation is caused ma inly by the lack of oocytes that normally prou
estrogen to create the positive feedback loop.

(HYPOTHALAMIC-PITUITARY-TESTICULAR AXIS
The hypothalamus synthesize gonadotropin-releasing hormone (GnR) a
into the
hypothalamo-hypophyseal portal blood. After reaching the anterior pituitary,
binds to the pituaLCSH
GnRH

gonadotropes and stimulates the release of the gonadotropins, FSH and L

 ctive System
Rgproductiv

aeneral circulation. Secretions of

into the general

intoregulated by feedback mechanisms. LHthese

hmones are regulate 161
bythe Leydig cells and this promotes the
is CNS
enU jon of testosterone
up

(androgens). In turn,synthesis
taken

andse
kvels
stosterone inhibit the elevated
secretion of LH from
rior ituitary through a direct the
action on the
jalsoexert an inhibitory effect at the pituitary
inhibiting the release of GnRH.
hypothalamic level
hv
Hypothalamus
Roth the hypothalamus and the
pituitary have
Androgen and estrogen receptors. However, the GnRH
inhibitory effect of androgen on the hypothalamus major
to be mediated principally by estradiol that
appears Anterior
aly through the aromatization of testosterone. be
may derived pituitary
FSH binds
ta SDecific receptors in the Sertoli
cells and stimulates LH
the FSH
production of androgen binding protein (ABP). ABP binding
with androgen initiates spermatogenesis. FSH Testis
secretion is
inhibited by the hormone inhibin, which is also TLeydig cll
Inhibin
the Sertoli cells of the seminiferous produced by Testosterone
Sertoli
Cell
tubules. Inhibin is
probably a physiologic regulator of pituitary FSH secretion,
possibly together with the gonadal steroids. Vinilizing efects Spermatogenesis
HPG Axis in Males
(Function) Fig. 4.5 Hypothalamus
Pituitary Testicular Axis
Both components of the
testis, the Leydig cells and the seminiferous tubules, are
nterrelated and require the presence of
of their hypothalamic-pituitary axis for initiation and maintenance
function. In males, the HPG axis is involved in the regulation of the of production
LSErone and the process of spermatogenesis. LH is involved in the synthesis of testosterone
Leydig cells of the testis while FSH is involved in production of spermatoz0a
LOgenesis). Development and maintenance of genital ducts and glands, and the secondary
aracteristics in males is mediated by testosterone secreted by the Leydig celsunderthe
is also called as
of
Ce luteinizing hormone (LH) from anterior pituitary. LH in males
nterstitial cell stimulating hormone (ICSH).

Spermatogenesis and FSH are similar, but the effects are

males, the production of GnRH, LH, to the Sertoli cells. These cells
nt. bloodstream, it binds
Once FSH is released into the LH cause interstitial
release
release which promotes
t e s t o s t e r o n e binding.
the
rogen-binding protein, spermatogenesis and inhibits
cells toto sec
ells s Testosterone
stimulate
responsible for the initiation of
testosterone. is mainly
hypothalamus
speri Olicular
stimulating
hormone (FSH)

the spermatozoa
require both,
FSH and testosterone.
inhibits the
esis, while full maturation of
through inactivating activin,
Inhibin produced by
Dy the
spermatogenic
cells, which,
remain
relatively
constant.

hypothalamus. After puberty these

hormones
levels
 162
Physiology-Controlling and Coordinating Systems
Secondary Sex Characteristics
The hormones produced by the HPG axis also contribute to secondary sex characteristics
in males. These include body hair growth, facial hair growth, increased muscle mass, deepened
voice, and greater shoulder width.
Life cycle

During puberty the HPG axis is activated by the secretions of testosterone from

physiological
the testis. This activation of testosterone causes and
psychological changes. Once
activated, the HPG axis continues to function in men for the rest of their life

Although males remain fertile until death, the activity of the HPG axis decreases. As
a condition known as post-
males age, the testis begin to produce less testosterone, leading to
results in progressive muscle mass
pubertal hypogonadism. Post-pubertal hypogonadism
increased risk of fractures, and abnormal
decrease, increase in visceral fat mass, loss of libido,
sperm production.
EXERCISE