Hypothalamo-Pituitary-Gonadal Axis

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Hypothalamo-Pituitary-Gonadal Axis

• Dr. D. Johnson
• Assoc. Professor
• UNECOM

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PARENT Easiest Job in the World to GetHardest
Job in the World to do Right
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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

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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.

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Hypothalamic GnRH

• The decapeptide GnRH is derived from
  posttranslation processing of a 92amino 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.

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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 acidsreferred 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.

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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).

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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.

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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.

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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.

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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 1980s
  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.

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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 its 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.

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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.

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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.

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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.