HPG axis Flashcards by nam u

LH/FSH structure

α subunit common to all glycoprotein hormones
β subunits differ and confer specificity and biological activity
subunits have no biological activity when separate

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causes of hypothalamic amenorrhoea

functional: weight loss, exercise, stress

GnRH deficiency: Kallman’s syndrome, idiopathic

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Tx of hypothalamic amenorrhoea

pulsatile GnRH

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inhibin A vs inhibin B

males/female production, function

males: no inhibin A, inhibin B produced by sertoli cells and inhibits FSH secretion (negative feedback)
females: produced by granulosa cells, inhibin B rises in early follicular phase, inhibin A (more dominant) in mid-late follicular phase and peaks at mid-luteal phase

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where is testosterone produced

males: leydig cells of testis
females: ovary and adrenal cortex

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functions of testosterone (in males and females)

males: spermatogenesis, development of secondary sexual characteristics (facial hair, muscle mass, change in voice etc.)
females: biosynthesis of oestrogens

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where is progesterone produced

corpus luteum + placenta

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functions of progesterone

maintenance of endometrium, implantation and maintenance of pregnancy

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different types of oestrogens (3)

E1: oestrone, main oestrogen of menopause
E2: oestradiol, most bioactive, preparation of uterus + reproductive tract for conception + pregnancy
E3: oestriol, main oestrogen of feto-placental unit

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where are oestrogens produced

ovary, growing follicles, corpus luteum, adipose tissue, placenta

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function of kisspeptin

controls GnRH synthesis and secretion
central and peripheral administration increases LH, FSH and testosterone (dose-dependent)
studies showed that kisspeptin increased number of LH pulses and pulse amplitude

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functions of LH (F: 4 / M: 1)

females: androgen production by thecal cells
remodelling of follicle to remnant corpus luteum
corpus luteum progesterone production
ovulation
males: testosterone production by leydig cells

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functions of FSH (F: 2 / M: 1)

females: conversion of androgens to oestrogens by granulosa cells
follicular maturation
males: sertoli cell metabolism

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what receptor does kisspeptin bind to

GPR54, found on GnRH neurons

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how is oestrogen -ve/+ve feedback mediated (in rodents)

low levels: arcuate nucleus (-ve)

high levels: kisspeptin neurones in AVPV (+ve)

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GnRH pulse freq and amplitude in males vs females

males: constant freq every 2hrs
females: high freq (every 30min) -> LH
low freq and amplitude (every 90-120min) -> FSH

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GnRH pulses during menstrual cycle

early follicular phase: slow pulses -> FSH
mid-late follicular phase: increased freq -> LH
after ovulation: pulses decrease -> FSH production
end of luteal phase: pulses increase -> FSH secretion

GnRH intracellular signalling

binds to GnRHR (GPCR) -> Gαs and q -> cAMP -> MAPK -> LHβ and FSHβ genes -> GnRH transcription, translation & secretion via exocytosis

FSH intracellular signalling

FSH binds to FSHR -> exchange of GDP for GTP -> dissociation of Gα from βγ -> adenylate cyclase -> cAMP -> PKA -> downstream phosphorylation, further kinase activation -> cellular responses

regulation of FSH receptor signalling

receptor activation -> activation of G-protein regulatory kinases -> phosphorylation of residues on intracellular loops -> βarrestin targets receptors for endocytosis in clathrin-coated pits -> dynamin pinches off endocytotic vesicles -> receptor undergoes lysosomal degradation or recycling to membrane

inhibin: produced where? function?

produced by sertoli cells

decreases FSH secretion from pituitary

activin: produced where? function?

produced by sertoli cells

increases FSH secretion from pituitary

cause of familial hypogonadotrophic hypogonadism

GnRH frameshift mutation

Kallman syndrome: pathophysiology -> presentation

failure of migration of hypothalamic neurones from medial olfactory placode to medio-basal hypothalamus -> loss of hypothalamic GnRH secretion
HH + anosmia + delayed/no puberty

LHbeta mutation -> ? in females vs males

females: anovulatory infertility males: loss of testosterone -> impaired sexual maturation

FSH receptor mutation -> ? in females vs males

females: arrested follicular maturation males: reduced fertility, poor sperm quality

differences in LH KO in mice and humans

KO of pituitary LH in humans → hCG still produced which can bind to LHR → testosterone → male differentiation KO of LHR -> loss of LH and hCG effects KO of pituitary LH in mice -> compensation by paracrine factors

evidence for kisspeptin action being mediated via GnRH

kisspeptin causes depolarisation of GnRH neurones in vitro | kisspeptin stimulated LH secretion dependently from hypothalamic explants

what gene and receptor for neurokinin B

TAC3 | NK3R

where are neurokinin B neurones found

hypothalamus (particularly arcuate nucleus), basal forebrain

neurokinin B action

NK binds to NK3R on kisspeptin neurones (project to GnRH neurones) -> kisspeptin release -> GPR54 on GnRH neurone -> augments GnRH synthesis and/or release

evidence for kisspeptin effects on LH

anti-kisspeptin Ab -> loss of LH surge in rats

Jost paradigm

1. chromosomal 2. gonadal 3. hormonal 4. phenotypic 5. behavioural

sexual differences in HPG axis (5)

1. larger anteroventral periventricular nucleus in females (as needed for GnRH/LH surge) 2. M always respond to kisspeptin / women most sensitive to kisspeptin during preovulatory phase 3. AVPV kisspeptin neurones in F only, ARC kisspeptin in both - organisational effect (neuro-anatomical difference) 4. oestrogen/testosterone in utero in F -> fewer AVPV castration in M -> development of AVPV kisspeptin neurones 5. in F high E2 in preovulatory phase -> increased sensitivity to GnRH - activational effect (reversible) 5. may be difference in neurokinin B but currently unclear

``` effects of: 1. ghrelin 2. PYY 3. leptin on reproductive activity ```

1. ghrelin suppresses 2. PYY enhances 3. leptin enhances

mechanism of leptin enhancement of HPA

leptin activates GnRH neurones via kisspeptin or via glutamate (in ventral premamillary nucleus) therefore puberty can occur even w leptin KO

hormonal changes at puberty

LH + FSH -> testes development, follicle development, menarche oestrogen -> female secondary sex characteristics testosterone -> male secondary sex characteristics DHEAS -> pubic and axillary hair growth inhibin produced from sertoli / granulosa cells GH -> growth spurt prolactin -> breast development

mechanism for increased FSH during and after menopause

decreased ovarian reserve of follicles -> decreased E2 and increased FSH -> multiple antral follicles / follicular cysts -> E2 -> FSH suppression after menopause too few follicles to respond to FSH

causes of decreased fertility w age (4)

occurs 10 years before menopause decreased ovarian reserve (by ovulation and attrition) increased chromosomal abnormalities hypothalamus less sensitive to E2 decreased coital freq -> oocyte spends more time in repro tract

causes of secondary amenorrhoea (2)

PCOS | hypothalamic hypogonadism: functional, Kallman's, prolactinoma or other pituitary tumour

GnRH structure (7) essay topic

1. Primary structure: 10 amino acids 2. Horseshoe structure 3. Synthesised as pre-prohormone: signal peptide, GnRH decapeptide, link and GAP peptide GnRH and GAP co-secreted; function of GAP unknown 4. N-terminus: receptor binding and activation 5. C terminus: receptor binding only 6. Central arginine often modified to give agonistic/antagonistic effects 7. L to D-amino acid (resistant to proteolytic degradation) substitutions → long half-life in blood