HPG Axis - SOM Lecture

what is the HPG axis?

hypothalamic-pituitary-gonadal axis:

- hypothalamus contains GNRH neurons which releases GNRH into portal vasculature, from where it is carried to anterior pituitary

- anterior pituitary releases LH/FSH which then acts on the gonads

- gonads release sex steroids and can act in feedback loops back to hypothalamus to regulate this axis and keep it maintained in homeostatic balance

female gonads mainly release which sex steroids

estrogen, progesterone

male gonads mainly release which sex steroids

testosterone

what is GNRH?

gonadotropin releasing hormone; this is a decapeptide! (linking of 10 amino acids)

where is GNRH secreted from and is carried where?

secreted from hypothalamus (specifically, the median eminence) —> released into hypophyseal portal system/vasculature, which carries it directly to anterior pituitary

what does GNRH do (and what does it cause)

1) acts on G protein coupled receptors on pituitary gonadotropes —> activates various secondary messenger pathways

2) as a result, it induces synthesis & secretion of LH/FSH from anterior pituitary —> act on gonads to produce sex hormones and gamete production

how does GNRH change its signal?

GNRH neurons secrete GNRH in a pulsatile fashion! GNRH changes its signal based on pulse frequency, not "more vs. less" secretion

does simply more secretion of GNRH cause more reaction?

no!!

what is the hypothalamus pituitary portal system?

aka hypothalamo-hypophyseal portal system: specialized network of blood vessels that directly connects hypothalamus to anterior pituitary

the hypothalamus pituitary portal system allows for what?

1) allows hypothalamus hormones like GNRH to reach anterior pituitary quickly and in high concentration, without being diluted in systemic bloodstream

2) keeps hypothalamic hormones undiluted, allows pulsatile signaling, allows tighter control of anterior pituitary

describe the pathway of the hypothalamus pituitary portal system

this is a 2 capillary bed vascular system:

1) first capillary bed is in median eminence of hypothalamus: hypothalamic neurons release their hormones into this capillary bed

2) portal veins then carry this blood directly to anterior pituitary

3) hypothalamic hormones exit the blood at the second capillary bed in the anterior pituitary —> acts on pituitary cells

what is one cause of hypogonadism, and what would a patient often also have if they have this form of hypogonadism

1) absence of GNRH neurons

2) often also have anosmia - inability to smell

what happens if there is continuous (not pulsatile) GNRH stimulation to the pituitary cells?

continuous exposure of the gonadotropes to GNRH downregulates GNRH receptors in pituitary and stops gonadotropin secretion!!

pulses are ____________ to sustain LH and FSH secretion from anterior pituitary

required!!!!

how can GNRH agonists be used to stop LH and FSH secretion?

because continuous exposure of the gonadotropes to GNRH causes the anterior pituitary to become desensitized and stop responding, GNRH analogues (agonists and antagonists) are used therapeutically to turn off gonadotropin secretion, if necessary! (ex to stop precocious puberty or slow the progression of prostate cancer)

what is a glycoprotein hormone

a protein hormone that has a carbohydrate (sugar) groups attached; these hormones are typically secreted by anterior pituitary or placenta

glycoprotein hormones are composed of 2 subunits; what are they?

1) a common alpha subunit - identical among all glycoprotein hormones

2) a distinct beta subunit - unique to each hormone; gives biological specificity/activity of the glycoprotein hormones

because glycoproteins all have the same alpha subunit, they can sometimes get "confused" in the body, meaning?

too much of one can stimulate the target of the other! for example, too much hCG can stimulate the thyroid

which hormones are glycoproteins?

LH, FSH, TSH, hCG (LH, FSH, hCG are gonadotropins)

the beta subunits of which 2 gonadotropins are very similar (but not identical) to one another

LH and hCG!

- note that the beta subunit of hCG has additional moieties on the molecule that allow it to last much longer in the blood; half life of hCG is considerably longer than half life of LH

which "gonadotropin" hormones are released from the pituitary

LH and FSH

where does LH act (what are their targets) in females, and what does it do at these targets

1) ovaries - theca cells: stimulates androgen/testosterone production

2) later in the cycle, LH surge triggers ovulation

3) transforms ruptured follicle into corpus luteum after ovulation

4) under LH stimulation, corpus luteum secretes progesterone

where does LH act (what are their targets) in males, and what does it do at these targets

testes - leydig cells: stimulates testosterone production

where does FSH act (what are their targets) in females, and what does it do at these targets

ovaries - granulosa cells: promotes synthesis and secretion of estradiol

where does FSH act (what are their targets) in males, and what does it do at these targets

testes - sertoli cells: stimulates spermatogenesis, inhibin production

hCG is released by ?

after fertilization, the trophoblast of the implanting embryo (zygote/blastocyst stage) begins producing hCG, and eventually the placenta!!!

where does hCG act (what are their targets) in both males and females, and what does it do at these targets

1) corpus luteum: stimulates production of estrogen and progesterone —> sustains early pregnancy

2) fetal testes: stimulates production of testosterone

how are GNRH neurons unusual from most hypothalamic neurons?

most hypothalamic neurons that control releasing hormones are all regulated directly by the target gland's hormone - like T4 and TRH, for instance. however, GNRH neurons are unusual in that they cannot sense testosterone directly!

what is the intervening neuron in the central nervous system (in the hypothalamus) that responds to testosterone levels and then regulates the GNRH neuron?

KNDy neurons - these are located in the arcuate nucleus of the hypothalamus. testosterone binds to androgen receptors on KNDy neurons, not on GNRH neurons —> KNDy neurons release kisspeptin, a potent stimulator of GNRH neurons --> regulates pulsatile GNRH secretion

how does the male HPG axis work?

1) KNDy neurons interact w GNRH neurons; responsible for driving pulsatile GNRH secretion

2) pulsatile GNRH secretion drives LH and FSH secretion from anterior pituitary, which in turn drives testicular function

3) LH —> leydig cells —> testosterone production

4) FSH —> sertoli cells —> spermatogenesis & inhibin production

GNRH release is regulated indirectly by testosterone via ?

KNDy neurons (kisspeptin)

testosterone also has a mild effect to inhibit the pituitary production of gonadotropins directly. how?

inhibin produced by the sertoli cells will act directly on pituitary gland to inhibit production of FSH

how does the female HPG axis work?

1) KNDy neurons —> GNRH neurons —> pulsatile secretion of GNRH —> pituitary responds by producing LH & FSH

2) FSH —> granulosa cells —> folliculogenesis & estradiol production

3) LH —> theca cells —> androgen production (testosterone) & stimulates corpus luteum to secrete progesterone

recall: androgens produced by the theca cells in response to LH diffuse into the granulosa cells, where what happens?

androgens are converted into estradiol (FSH stimulates aromatase in the granulosa cells which converts the androgens into estradiol; so FSH = estradiol)

estradiol and progesterone also act on which neurons to alter the secretion of GNRH

KNDy neurons to alter secretion of kisspeptin —> alters secretion of GNRH

which hormone produced by which female cells also acts on the pituitary to specifically inhibit the production and release of FSH

inhibin from the granulosa cells

KNDy neurons function as the ___________ to control the GNRH pulses

pacemaker

the sex steroids do not act directly on the GNRH neurons, they act on ?

KNDy neurons, which control the GNRH neurons

sometimes, the KNDy neurons are simply called ?

Kiss1 neurons

what is the function of kisspeptin, the neuropeptide produced by KNDy neurons

stimulates release of GNRH

quick summary of LH and FSH roles in females

1) LH in follicular phase (pre-surge) —> theca cells —> androgens

2) FSH in follicular phase —> granulosa cells —> estradiol (granulosa cells + FSH convert these androgens from theca cells into estradiol)

3) estradiol high = positive feedback = LH surge

4) LH surge —> granulosa & theca cells —> ovulation (rupture of follicle) + luteinization (transformation of ruptured follicle into corpus luteum) —> progesterone