Hypothalamo-Pituitary-Gonadal Axis

Hypothalamo-Pituitary-Gonadal Axis

Dr. D. JohnsonAssoc. Professor

UNECOM

Dr. D. JohnsonAssoc. Professor

UNECOM

PARENT: Easiest Job in the World to Get…Hardest Job in the World to do Right

PARENT: Easiest Job in the World to Get…Hardest Job in the World to do Right

The HPG AxisThe HPG Axis

The HPG axis in the female.The HPG axis in the female.

Important to recognize that Important to recognize that reproductive problems in reproductive problems in male or female usually occur male or female usually occur at one of 3 levels:at one of 3 levels:

1.1. HypothalamicHypothalamic

2.2. PituitaryPituitary

3.3. GonadGonad

The HPG axis in the female.The HPG axis in the female.

Important to recognize that Important to recognize that reproductive problems in reproductive problems in male or female usually occur male or female usually occur at one of 3 levels:at one of 3 levels:

1.1. HypothalamicHypothalamic

2.2. PituitaryPituitary

3.3. GonadGonad

Hypothalamo-Pituitary Connections

Hypothalamo-Pituitary Connections

Arcuate, medial preoptic, and Arcuate, medial preoptic, and paraventricular hypothalamic paraventricular hypothalamic neurons send projections to the neurons send projections to the median emminence, which in median emminence, which in turn drains into the hypophysial turn drains into the hypophysial portal veins.portal veins.

These nuclei release GnRH into These nuclei release GnRH into the median emminence in the median emminence in pulses, where it is then shunted pulses, where it is then shunted directly to the anterior pituitary directly to the anterior pituitary via the hypophysial portal veins.via the hypophysial portal veins.

In the anterior pituitary, GnRH In the anterior pituitary, GnRH binds surface receptors on cells binds surface receptors on cells which produce and release the which produce and release the gonadotrophins FSH and LH. gonadotrophins FSH and LH. Thus, it is a neurohormone.Thus, it is a neurohormone.

Arcuate, medial preoptic, and Arcuate, medial preoptic, and paraventricular hypothalamic paraventricular hypothalamic neurons send projections to the neurons send projections to the median emminence, which in median emminence, which in turn drains into the hypophysial turn drains into the hypophysial portal veins.portal veins.

These nuclei release GnRH into These nuclei release GnRH into the median emminence in the median emminence in pulses, where it is then shunted pulses, where it is then shunted directly to the anterior pituitary directly to the anterior pituitary via the hypophysial portal veins.via the hypophysial portal veins.

In the anterior pituitary, GnRH In the anterior pituitary, GnRH binds surface receptors on cells binds surface receptors on cells which produce and release the which produce and release the gonadotrophins FSH and LH. gonadotrophins FSH and LH. Thus, it is a neurohormone.Thus, it is a neurohormone.

Hypothalamic GnRHHypothalamic 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.

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..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.

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 ReceptorGnRH Receptor A single GnRH receptor has been A single GnRH receptor has been

identified in humans, which binds with identified in humans, which binds with GnRH.GnRH.

GnRH binds with high affinity to these GnRH binds with high affinity to these receptors, which are located on the cell receptors, which are located on the cell surface of anterior pituitary surface of anterior pituitary gonadotrophs. GnRH receptors are 7 gonadotrophs. GnRH receptors are 7 transmembrane cell surface G protein-transmembrane cell surface G protein-coupled receptors.coupled receptors.

Receptor binding activates Receptor binding activates phospholipase C. This leads to the phospholipase C. This leads to the activation of several second messenger activation of several second messenger molecules, the most important being molecules, the most important being diacylglycerol (DG) and inositol 1,4,5-diacylglycerol (DG) and inositol 1,4,5-trisphosphate (IP3). trisphosphate (IP3).

A single GnRH receptor has been A single GnRH receptor has been identified in humans, which binds with identified in humans, which binds with GnRH.GnRH.

GnRH binds with high affinity to these GnRH binds with high affinity to these receptors, which are located on the cell receptors, which are located on the cell surface of anterior pituitary surface of anterior pituitary gonadotrophs. GnRH receptors are 7 gonadotrophs. GnRH receptors are 7 transmembrane cell surface G protein-transmembrane cell surface G protein-coupled receptors.coupled receptors.

Receptor binding activates Receptor binding activates phospholipase C. This leads to the phospholipase C. This leads to the activation of several second messenger activation of several second messenger molecules, the most important being molecules, the most important being diacylglycerol (DG) and inositol 1,4,5-diacylglycerol (DG) and inositol 1,4,5-trisphosphate (IP3). trisphosphate (IP3).

Gonadotrophin INHIBITORY Hormone (GnIH)

Gonadotrophin INHIBITORY Hormone (GnIH)

Researchers at the University of California, Berkeley Researchers at the University of California, Berkeley reported in the February 14, 2006 Proceedings of the reported in the February 14, 2006 Proceedings of the National Academy of Sciences (vol. 103, no. 7, pp. National Academy of Sciences (vol. 103, no. 7, pp. 2410-2415) that they have discovered a GnIH 2410-2415) that they have discovered a GnIH peptide in mammals (rats mice, and hamsters). peptide in mammals (rats mice, and hamsters).

If the new finding is mirrored in humans, it would If the new finding is mirrored in humans, it would offer physicians another means of tweaking the offer physicians another means of tweaking the reproductive system to fix problems ranging from reproductive system to fix problems ranging from infertility to precocious puberty.infertility to precocious puberty.

Researchers at the University of California, Berkeley Researchers at the University of California, Berkeley reported in the February 14, 2006 Proceedings of the reported in the February 14, 2006 Proceedings of the National Academy of Sciences (vol. 103, no. 7, pp. National Academy of Sciences (vol. 103, no. 7, pp. 2410-2415) that they have discovered a GnIH 2410-2415) that they have discovered a GnIH peptide in mammals (rats mice, and hamsters). peptide in mammals (rats mice, and hamsters).

If the new finding is mirrored in humans, it would If the new finding is mirrored in humans, it would offer physicians another means of tweaking the offer physicians another means of tweaking the reproductive system to fix problems ranging from reproductive system to fix problems ranging from infertility to precocious puberty.infertility to precocious puberty.

Pituitary FSH / LHPituitary FSH / LH

Both FSH and LH are composed of Both FSH and LH are composed of polypeptide chain subunits. These subunits, polypeptide chain subunits. These subunits, termed termed and and are coded for by separate are coded for by separate genes. genes.

They differ only in the composition of They differ only in the composition of thethe subunit. subunit.

Both FSH and LH are composed of Both FSH and LH are composed of polypeptide chain subunits. These subunits, polypeptide chain subunits. These subunits, termed termed and and are coded for by separate are coded for by separate genes. genes.

They differ only in the composition of They differ only in the composition of thethe subunit. subunit.

Pituitary FSH / LHPituitary FSH / LH

Both FSH and LH are glycoslyated with Both FSH and LH are glycoslyated with various sugar residues (oligosaccharides various sugar residues (oligosaccharides with sialic acid residues). with sialic acid residues).

FSH has more associated sugars, it is FSH has more associated sugars, it is cleared more slowly from the serum than cleared more slowly from the serum than LH. LH.

Both FSH and LH are glycoslyated with Both FSH and LH are glycoslyated with various sugar residues (oligosaccharides various sugar residues (oligosaccharides with sialic acid residues). with sialic acid residues).

FSH has more associated sugars, it is FSH has more associated sugars, it is cleared more slowly from the serum than cleared more slowly from the serum than LH. LH.

Circhoral OscillatorCirchoral Oscillator It is now a well-established fact It is now a well-established fact

that GnRH is released into the that GnRH is released into the hypophysial portal blood in hypophysial portal blood in pulses, typically one pulse pulses, typically one pulse every 30 to 60 minutes.every 30 to 60 minutes.

Surgical techniques perfected Surgical techniques perfected in the 1980’s allowed in the 1980’s allowed cannulation of the hypophysial cannulation of the hypophysial portal blood in primates, and portal blood in primates, and measurement of GnRH levels.measurement of GnRH levels.

However, it is not well known However, it is not well known which parts of the brain are which parts of the brain are responsible for causing the responsible for causing the pulsatile release of GnRH from pulsatile release of GnRH from hypothalamic nuclei.hypothalamic nuclei.

It is now a well-established fact It is now a well-established fact that GnRH is released into the that GnRH is released into the hypophysial portal blood in hypophysial portal blood in pulses, typically one pulse pulses, typically one pulse every 30 to 60 minutes.every 30 to 60 minutes.

Surgical techniques perfected Surgical techniques perfected in the 1980’s allowed in the 1980’s allowed cannulation of the hypophysial cannulation of the hypophysial portal blood in primates, and portal blood in primates, and measurement of GnRH levels.measurement of GnRH levels.

However, it is not well known However, it is not well known which parts of the brain are which parts of the brain are responsible for causing the responsible for causing the pulsatile release of GnRH from pulsatile release of GnRH from hypothalamic nuclei.hypothalamic nuclei.

Clinical Importance of Pulsatility

Clinical Importance of Pulsatility

Pulsatile release of GnRH Pulsatile release of GnRH results in pulsatile release results in pulsatile release of stored FSH / LH first, of stored FSH / LH first, then newly synthesized then newly synthesized FSH and LH.FSH and LH.

If GnRH binds it’s receptor If GnRH binds it’s receptor on pituitary gonadotrophs on pituitary gonadotrophs chronically instead of in chronically instead of in pulses, secondary pulses, secondary messengers are messengers are uncoupled, receptors uncoupled, receptors involute, and both involute, and both synthesis and release of synthesis and release of FSH and LH is halted.FSH and LH is halted.

Pulsatile release of GnRH Pulsatile release of GnRH results in pulsatile release results in pulsatile release of stored FSH / LH first, of stored FSH / LH first, then newly synthesized then newly synthesized FSH and LH.FSH and LH.

If GnRH binds it’s receptor If GnRH binds it’s receptor on pituitary gonadotrophs on pituitary gonadotrophs chronically instead of in chronically instead of in pulses, secondary pulses, secondary messengers are messengers are uncoupled, receptors uncoupled, receptors involute, and both involute, and both synthesis and release of synthesis and release of FSH and LH is halted.FSH and LH is halted.

GnRH AnaloguesGnRH Analogues

GnRH agonists were initially designed to provide agents with GnRH agonists were initially designed to provide agents with more potent stimulatory action than native GnRH. Their more potent stimulatory action than native GnRH. Their prolonged administration, however, is used clinically to take prolonged administration, however, is used clinically to take advantage of the fact that shutting down FSH and LH release advantage of the fact that shutting down FSH and LH release can lead to decreased production of gonadal steroids (ie, can lead to decreased production of gonadal steroids (ie, ‘‘chemical castrationchemical castration’’).).

This is useful in the treatment of several sex steroid-dependent This is useful in the treatment of several sex steroid-dependent conditions (androgen-dependent prostate cancers, estrogen-conditions (androgen-dependent prostate cancers, estrogen-dependent breast cancers, endometriosis). dependent breast cancers, endometriosis).

More recently, GnRH antagonists inducing immediate reduction More recently, GnRH antagonists inducing immediate reduction of gonadotrophin levels have been introduced in clinical of gonadotrophin levels have been introduced in clinical practice.practice.

GnRH agonists were initially designed to provide agents with GnRH agonists were initially designed to provide agents with more potent stimulatory action than native GnRH. Their more potent stimulatory action than native GnRH. Their prolonged administration, however, is used clinically to take prolonged administration, however, is used clinically to take advantage of the fact that shutting down FSH and LH release advantage of the fact that shutting down FSH and LH release can lead to decreased production of gonadal steroids (ie, can lead to decreased production of gonadal steroids (ie, ‘‘chemical castrationchemical castration’’).).

This is useful in the treatment of several sex steroid-dependent This is useful in the treatment of several sex steroid-dependent conditions (androgen-dependent prostate cancers, estrogen-conditions (androgen-dependent prostate cancers, estrogen-dependent breast cancers, endometriosis). dependent breast cancers, endometriosis).

More recently, GnRH antagonists inducing immediate reduction More recently, GnRH antagonists inducing immediate reduction of gonadotrophin levels have been introduced in clinical of gonadotrophin levels have been introduced in clinical practice.practice.

CNS Disease / Injuries and Reproduction

CNS Disease / Injuries and Reproduction

GnRH is considered the most GnRH is considered the most important final common mediator important final common mediator on all influences on reproduction on all influences on reproduction conveyed through the brain.conveyed through the brain.

Therefore, disorders of the brain Therefore, disorders of the brain can often lead to infertility can often lead to infertility problems.problems.

GnRH is considered the most GnRH is considered the most important final common mediator important final common mediator on all influences on reproduction on all influences on reproduction conveyed through the brain.conveyed through the brain.

Therefore, disorders of the brain Therefore, disorders of the brain can often lead to infertility can often lead to infertility problems.problems.

The GonadsThe Gonads

We have now seen the importance of We have now seen the importance of the hypothalamo-pituitary axis in the hypothalamo-pituitary axis in initiating the process of reproduction by initiating the process of reproduction by releasing the gonadotrophins.releasing the gonadotrophins.

The next step is to investigate the The next step is to investigate the action of the gonadatrophins at the action of the gonadatrophins at the level of the female (ovary) and male level of the female (ovary) and male (testis) gonad itself.(testis) gonad itself.

We have now seen the importance of We have now seen the importance of the hypothalamo-pituitary axis in the hypothalamo-pituitary axis in initiating the process of reproduction by initiating the process of reproduction by releasing the gonadotrophins.releasing the gonadotrophins.

The next step is to investigate the The next step is to investigate the action of the gonadatrophins at the action of the gonadatrophins at the level of the female (ovary) and male level of the female (ovary) and male (testis) gonad itself.(testis) gonad itself.