Hypothalamo-Pituitary-Gonadal 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: • 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 GnRH-associated 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 half-life (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 protein-coupled receptors. • Receptor binding activates phospholipase C. This leads to the activation of several second messenger molecules, the most important being diacylglycerol (DG) and inositol 1,4,5-trisphosphate (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 b 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, estrogen-dependent 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.