Transcript Hypothalamo-Pituitary-Adrenal Axis

Hypothalamo-PituitaryGonadal Axis
Dr. D. Johnson
Assoc. Professor
UNECOM
PARENT: Easiest Job in the World to
Get…Hardest Job in the World to do Right
The HPG Axis

The HPG axis in the female.

Important to recognize that
reproductive problems in
male or female usually occur
at one of 3 levels:
1.
2.
3.
Hypothalamic
Pituitary
Gonad
Hypothalamo-Pituitary
Connections

Arcuate, medial preoptic, and
paraventricular hypothalamic
neurons send projections to the
median emminence, which in turn
drains into the hypophysial portal
veins.

These nuclei release GnRH into the
median emminence in pulses, where
it is then shunted directly to the
anterior pituitary via the
hypophysial portal veins.

In the anterior pituitary, GnRH binds
surface receptors on cells which
produce and release the
gonadotrophins FSH and LH. Thus,
it is a neurohormone.
Hypothalamic GnRH
 The decapeptide GnRH is derived from posttranslation
processing of a 92–amino acid (AA) pre-pro-GnRH. The first 23
AA is a signal peptide and the last 56 AA is known as GnRHassociated protein (GAP).
 GnRH is encoded from a single gene located on the short arm of
chromosome 8.
 Serum levels of GnRH are difficult to obtain due to its short halflife (2-4 min) and nearly complete confinement to the
hypophyseal-portal blood supply.
More on GnRH..
 So far, three types of GnRH have been isolated in
humans: GnRH type I, GnRH type II and GnRH
type III.
 GnRH type I (10 amino acids…referred to from
hereon simply as ‘GnRH’) is the classical
hypothalamic reproductive neuroendocrine factor
that works in the anterior pituitary.
 The physiological meaning of the multiple
isoforms of GnRH in humans has not been well
elucidated.
GnRH Receptor

A single GnRH receptor has been
identified in humans, which binds with
GnRH.

GnRH binds with high affinity to these
receptors, which are located on the cell
surface of anterior pituitary
gonadotrophs. GnRH receptors are 7
transmembrane cell surface G proteincoupled receptors.

Receptor binding activates
phospholipase C. This leads to the
activation of several second messenger
molecules, the most important being
diacylglycerol (DG) and inositol 1,4,5trisphosphate (IP3).
Gonadotrophin INHIBITORY
Hormone (GnIH)
 Researchers at the University of California,
Berkeley reported in the February 14, 2006
Proceedings of the National Academy of Sciences
(vol. 103, no. 7, pp. 2410-2415) that they have
discovered a GnIH peptide in mammals (rats mice,
and hamsters).
 If the new finding is mirrored in humans, it would
offer physicians another means of tweaking the
reproductive system to fix problems ranging from
infertility to precocious puberty.
Pituitary FSH / LH
 Both FSH and LH are composed of
polypeptide chain subunits. These subunits,
termed  and  are coded for by separate
genes.
 They differ only in the composition of the 
subunit.
Pituitary FSH / LH
 Both FSH and LH are glycoslyated with
various sugar residues (oligosaccharides
with sialic acid residues).
 FSH has more associated sugars, it is
cleared more slowly from the serum than
LH.
Circhoral Oscillator
 It is now a well-established fact
that GnRH is released into the
hypophysial portal blood in
pulses, typically one pulse every
30 to 60 minutes.
 Surgical techniques perfected in
the 1980’s allowed cannulation
of the hypophysial portal blood
in primates, and measurement
of GnRH levels.
 However, it is not well known
which parts of the brain are
responsible for causing the
pulsatile release of GnRH from
hypothalamic nuclei.
Clinical Importance of
Pulsatility
 Pulsatile release of GnRH
results in pulsatile release of
stored FSH / LH first, then
newly synthesized FSH and
LH.
 If GnRH binds it’s receptor
on pituitary gonadotrophs
chronically instead of in
pulses, secondary
messengers are uncoupled,
receptors involute, and both
synthesis and release of FSH
and LH is halted.
GnRH Analogues
 GnRH agonists were initially designed to provide agents with
more potent stimulatory action than native GnRH. Their
prolonged administration, however, is used clinically to take
advantage of the fact that shutting down FSH and LH release
can lead to decreased production of gonadal steroids (ie,
‘chemical castration’).
 This is useful in the treatment of several sex steroid-dependent
conditions (androgen-dependent prostate cancers, estrogendependent breast cancers, endometriosis).
 More recently, GnRH antagonists inducing immediate reduction
of gonadotrophin levels have been introduced in clinical
practice.
CNS Disease / Injuries and
Reproduction
 GnRH is considered the most important
final common mediator on all influences
on reproduction conveyed through the
brain.
 Therefore, disorders of the brain can
often lead to infertility problems.
The Gonads
 We have now seen the importance of the
hypothalamo-pituitary axis in initiating the
process of reproduction by releasing the
gonadotrophins.
 The next step is to investigate the action of
the gonadatrophins at the level of the female
(ovary) and male (testis) gonad itself.