HPG axis Flashcards
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
causes of hypothalamic amenorrhoea
functional: weight loss, exercise, stress
GnRH deficiency: Kallman’s syndrome, idiopathic
Tx of hypothalamic amenorrhoea
pulsatile GnRH
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
where is testosterone produced
males: leydig cells of testis
females: ovary and adrenal cortex
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
where is progesterone produced
corpus luteum + placenta
functions of progesterone
maintenance of endometrium, implantation and maintenance of pregnancy
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
where are oestrogens produced
ovary, growing follicles, corpus luteum, adipose tissue, placenta
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
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
functions of FSH (F: 2 / M: 1)
females: conversion of androgens to oestrogens by granulosa cells
follicular maturation
males: sertoli cell metabolism
what receptor does kisspeptin bind to
GPR54, found on GnRH neurons
how is oestrogen -ve/+ve feedback mediated (in rodents)
low levels: arcuate nucleus (-ve)
high levels: kisspeptin neurones in AVPV (+ve)
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
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
- chromosomal
- gonadal
- hormonal
- phenotypic
- behavioural
sexual differences in HPG axis (5)
- larger anteroventral periventricular nucleus in females (as needed for GnRH/LH surge)
- M always respond to kisspeptin / women most sensitive to kisspeptin during preovulatory phase
- AVPV kisspeptin neurones in F only, ARC kisspeptin in both
- organisational effect (neuro-anatomical difference) - oestrogen/testosterone in utero in F -> fewer AVPV
castration in M -> development of AVPV kisspeptin neurones - in F high E2 in preovulatory phase -> increased sensitivity to GnRH - activational effect (reversible)
- may be difference in neurokinin B but currently unclear
effects of: 1. ghrelin 2. PYY 3. leptin on reproductive activity
- ghrelin suppresses
- PYY enhances
- 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
- Primary structure: 10 amino acids
- Horseshoe structure
- Synthesised as pre-prohormone: signal peptide, GnRH decapeptide, link and GAP peptide
GnRH and GAP co-secreted; function of GAP unknown - N-terminus: receptor binding and activation
- C terminus: receptor binding only
- Central arginine often modified to give agonistic/antagonistic effects
- L to D-amino acid (resistant to proteolytic degradation) substitutions → long half-life in blood
