Dr. Bernard Reproductive system Flashcards
where are LH and FSH neurons secreting?
in median eminence in hypothalamus
what direct estradiol’s effect?
its interaction and affinity with receptors, not its circulating level
what happens during each phase of menstrual cycle?
Follicular phase: follicles grow
ovulation: egg release triggered by LH
luteal phase: corpus luteum grows and is maintained
menstruations: corpus luteum degenerates
what hormone is only present during pregnancy? what does it trigger?
HCG; thickens uterine, stimulates testosterone production
what is caused by a lack of GnRH?
no puberty, infertility
how long is GnRH precursor? how many cleavages for activation?
92 amino acids; 2 cleavages
where are GnRH cells located and where do they project? what’s a special feature?
in SON and MBH mediobasal hypothalamus;
project to median eminence;
dendron
what is HH and what causes it?
hypogonadotropic hypogonadism, cause by a 1 bp insertion in GnRH1 gene that keeps from producing GnRH
is HH dominant or recessive?
it is an autosomal recessive condition
what happens to hypogonadal mice reproductive organs?
super small
where and how is GnRH released?
in pulses in median eminence
what is kallman’s syndrome?
GnRH neurons fail to migrate in the brain (GnRH deficiency)
how are GnRH/LH pulses throughout the menstrual cycle?
follicular phase: more but smaller pulses
luteal phase: less but bigger pulses
where is the pulse generator?
in MBH mediobasal hypothalamus and arcuate nucleus
what happens to gonadotropins when arcuate nucleus is lesioned
no more LH or FSH secretion
what happens when GnRH is continuously secreted?
it downregulates LH and FSH
what are the KNDy neurons?
kisspeptin, dynorphin, and neurokinin neurons in the arcuate nucleus exhibiting pulsatile activity
what are dynorphin and neurokinin’s role?
dynorphin inhibits kisspeptin release, neurokinin stimulates kisspeptin release
what is GPR54 and where is it found?
kisspeptin (kiss1) g-protein-coupled receptor on hypothalamic GnRH neurons, in pituitary, placenta, pancreas, spinal cord
what happens to GPR54 KO mice?
inhibited kisspeptin secretion -> inhibited GnRH secretion but not production -> super small ovaries, no gonadotropins release
what are the 3 forms of kisspeptin?
where are they expressed?
kisspeptin-10, -13, -14;
placenta, testis, small intestine, brain (Arc)
what does kisspeptin do?
stimulates LH release in women
how does estradiol do negative feedback?
inhibits GPR54/kiss1 expression in GnRH arcuate nucleus neurons and inhibits KNDy neurons pulsatile activity (inhibits kisspeptin production and secretion)
what happens to ERalphaKO mice?
knocked out estradiol receptor suppresses the estradiol negative feedback = too much estradiol = infertility
what cells express ERalpha?
kisspeptin neurons
can you cancel the effect of ERalphaKO by giving estradiol?
no because the estradiol receptors still don’t work
what is the same between ovariectomized and ERalphaKO mice?
increased KNDy pulsatile activity leading to infertility. due to lack of estrogen feedback
how does estradiol positive feedback work?
estradiol activates AVPV ERalpha receptor -> stimulates kiss1 expression in AVPV anteroventral periventricular nucleus and in rostral periventricular area of 3rd ventricle -> stimulates POA GnRH neurons
How can estrogen stimulate Kiss1 in the AVPV/RP3V while at the same time inhibiting Kiss1 in the ARC?
ERalpha must bind to DNA to stimulate kiss1 in AVPV.
ERalpha inhibition on kiss1 in Arc is DNA-independent.
the promoters/enhancers are also different
what drive the GnRH/LH surge?
the stimulatory input from AVPV/RP3V kisspeptin neurons
the amplitude of LH and FSH release is mediated by what?
by the pituitary
in addition to the hypothalamus, estrogen has a negative and positive feedback effect where else? (on gonadotropins)
on pituitary
what effect does elevated estrogen levels have on the pituitary?
increases pituitary sensitivity to GnRH
what hormone acts the most to slow down LH pulses and regulates (amplifies) LH surge amplitude?
progesterone
what differs between LH and FSH?
the beta subunit
what is LH’s half life? what cells does it target? what phenomenons does it regulate?
20 min
theca/mural granulosa and Leydig cells.
regulates ovulation and androgens synthesis
what is FSH’s half life? what cells does it target? what phenomenons does it regulate?
3-4 hours
ovary granulosa and testis sertoli cells
regulates follicle development, estrogen synthesis, spermatogenesis
at what menstrual cycle stage are LH and FSH levels respectively higher?
FSH high during early follicular phase, both LH and FSH peak at ovulation
what cells produce LH and FSH? what stimulates those cells to secrete?
gonadotropes
GnRH
what does continuous GnRH secretion cause?
down-regulation of gonadotropin (LH, FSH) secretion
what pulse frequency favors each gonadotropin?
high GnRH pulse frequency favors LHbeta.
low GnRH pulse frequency favors FSHbeta.
what decodes the GnRH pulses?
gonadotropes (GnRH pulse frequency decodor)
so which gonadotropin is more sensitive to GnRH?
FSH
however, does GnRH pulse frequency mediate gonadotropins release through the cycle? how do we know?
no, pulse frequency doesn’t change during the follicular phase. It slows down during luteal phase only due to high estrogen negative feedback
when is each inhibin made during menstrual cycle?
Inhibin B is mainly secreted during follicular phase
Inhibin A is mainly secreted during luteal phase
where is each inhibin produced?
Inhibin B is a product from proliferating granulosa cells of growing follicles.
Inhibin A is a product of corpus luteum.
what is inhibin’s role?
inhibits only FSH secretion
what are inhibins and activins?
structurally related TGFbeta ligands with opposing effects on FSH
what are inhibin’s structure?
same alpha subunit + betaA or betaB subunit
what are activin’s structure?
combination of betaA and/or betaB subunits
how and where do activins work?
activins work on the pituitary to stimulate only FSH production
what’s different about inhibins in primates vs rodents?
in primates, corpus luteum makes inhibin A.
In rodents, preovulatory follicles make inhibin A
in rodents, what do the LH/FSH surges during proestrus do?
suppress ovarian inhibin A and B synthesis
what happens when you knock out even just type 2 activin receptor? what consequence does that have
can’t make FSG -> can’t make estrogen -> no estrogen feedback -> increase in LH
why are ovaries small in animals who can’t make FSH?
no FSH = no estrogen stimulation of endometrial cells in uterus
what is inhibin’s effect on activin? how does it affect activin receptor?
inhibins act as endogenous competitive receptor antagonist (alpha subunit binds to betaglycan co-receptor to block activin type 2 receptor)
what happens to inhibin A and B effect in mice that lack betaglycan and TGFBR3L co-receptor?
no more suppression of FSHbeta from inhibins
what do betaglycan and TGFBR3L bind to respectively?
betaglycan: inhibin A and B
TGFBR3L: inhibin B only
how are each inhibin’s level through menstrual cycle?
inhibin A increases during luteal phase.
inhibin B increases during follicular phase (cus follicles increase)
basically what 2 phenomenons stimulate FSH production right at the beginning of the follicular phase?
- loss of estrogen negative feedback on GnRH increases GnRH
- loss of inhibin A negative feedback increases activin
what does the increase of FSH at the beginning in follicular phase cause related to inhibins?
increase in inhibin B levels
why is there an FSH decrease during follicular phase? what does it cause?
because some follicles don’t have enough FSH to grow due to estrogen neg feedback -> causes a decrease in inhibin B
what cells have FSH receptors?
granulosa cells
what is recruitment? what controls it?
follicle growth: oocytes get bigger and pre-granulosa cells differentiate into granulosa cells.
don’t know what triggers!
when do follicle start responding to FSH?
when antrum (fluid-filled space) forms and granulosa cells start expressing FSHR
more specifically how does FSH work?
activates PKS -> triggers granulosa cell proliferation and differentiation, aromatase production, and LH receptor production
what are LH’s main effects?
androgen synthesis by theca cells,
support of dominant follicles,
ovulation
where is the LH receptor expressed?
in theca cells and mural granulosa cells of mature follicles
how is LH secretion during follicular phase?
constant pulses
on what cells does the LH surge act on? what does it trigger?
mural granulosa cells -> secrete epidermal growth factor EGF to cumulus cells -> myotic maturation
what is the main androgen made by theca cells?
androstenedione
how are androgens made?
communication of enzymes between theca and granulosa cells. needs both LH and FSH
what does the corpus luteum respond to? what does it secrete?
responds to LH, produces progesterone, estradiol, inhibin A
what happens to corpus luteum during pregnancy?
HCG acts through LHR to maintain corpus luteum when LH can’t anymore
what is LH and FSH’s effect in males
they both drive spermatogenesis.
only LH drives testosterone production
what inhibin do males have?
only inhibin B
where do steroidogenesis and spermatogenesis take place?
testis sertoli cells
what drives testosterone pulses?
LH pulses (driven by GnRH pulses)
what is the difference between testosterone and estrogen release?
testosterone is released in pulses, not estrogen
what brain region works as the pulse generator?
arcuate
what is affected in GnRH in Gpr54/kiss1 KO mice?
GnRH secretion! not it’s production
what is the effect of castration?
loss of T neg feedback = increased KNDy neurons activity, increased kiss1 expression in Arc
what is testosterone? what does it become
a prohormone.
5alpha-reductase transforms it into dihydrotestosterone DHT
aromatase transforms it into estradiol
what is DHT? what does it do?
an androgen.
downregulates kiss1 (less efficient than estradiol tho)
Gets converted to estrogen by aromatase.
where does inhibin B come from in males?
testis
where do inhibins work?
directly on pituitary
what happens to male LHbeta KO mice?
decreased testis weight
no mature sperm
decrease plasma and testicular T
infertility
what happens to male FSHbeta KO mice?
decreases testis weight
decreased sperm count (but they still have some, compared to LHbeta KO)
normal T level
fertile
what happens to people with LHbeta inactivation mutation?
low T, high FSH, undetectable LH.
caused by missense mutation blocking dimer assembly.
FSH can be stimulated by GnRH, not LH
how did we treat patient with LHbeta inactivation mutation?
intramuscular T: still small testis and no sperm
then, HCG treatment: increased testis volume and now made sperm
what happens to a patient with inactivating FSHbeta mutation?
infertile, normal T level, small testis, can’t make sperm (mice can make sperm without FSH, humans can’t).
caused by nonsense mutation preventing dimeric FSH production.
what is LH and FSH effect in males?
LH -> leydig cells -> testosterone production
FSH -> sertoli cells -> inhibin B and androgen binding protein ABP production
what are leydig and sertoli cell’s equivalent in females
leydig = theca cells
sertoli = granulosa cells
signalling cascade triggered by LH
LHR -> cAMP -> PKA phosphorylates StAR -> StAR brings cholesterol in mitochondria -> testosterone release
what is androgen binding protein ABP?
binds T to increase it’s concentration in testis
(necessary for spermatogenesis)
can testosterone be stored in cells?
no
where are sertoli cells?
seminiferous tubule
is T necessary for spermatogenesis and spermiation?
no
what happens to sertoli cell androgen receptor knockout mice?
slightly smaller testis,
spermatocytes can’t mature to spermatids
what is one thing that dictates how much sperm can be made?
amount of sertoli cells
do males have estradiol positive feedback?
no. males loose the AVPV/RP3V kiss1 expressing cells. estradiol only inhibits LH in males.
how is the brain feminized/masculanized?
increase of T production around birth defeminizes male brains
how can you reverse masculinization of the brain?
neonatal castration reverses kiss1 expression in AVPV/RP3V
how can you reverse feminization of the brain?
neonatal estrogen exposure reverses kiss1 expression in AVPV/RP3V
what does the high aromatase level in the placenta do?
converts systemic androgens into estrogen
what is the protein that protects female from defeminizing effects of estrogen?
alpha-fetoprotein. Necessary for LH surges
what drives the positive estrogen feedback in primates?
the pituitary. more than AVPV/RP3V kisspeptin expression (that’s more in rodents)
