november 6 lecture

name of lecture

Neuroendocrine control of the HPG axis

Core principles of this lecture (7)

• Pulsatile release of GnRH is critical for its function

• Pulse frequency differentially regulates LH and FSH production and secretion

• Normal pulsatile and surge patterns of GnRH release — essential for reproductive function — require kisspeptin signaling

• Kiss neurosecretory cells mediate positive feedback effects of estradiol on GnRH secretion

• KNDy neurons regulate negative feedback to GnRH neurosecretory cells

• The induction of puberty in humans is poorly understood but requires a reduction in the expression of MKRN3

• Stress and low body weight reduce GnRH release and reduce fertility

Reproduction occurs only if sufficient — are present

resources

Primary regulator of gonadotropin secretion is

GNRH

half life of gnrh

under 5 mins

how many peptides in GNRH?

10 (decapeptide)

is gnrh conserved in mammalian species?

yes

— is central to Gnrh’s regulation of the gonadotrope cells

Pulsatile release

Pulsatile release of gnrh is coordinated by —

a neural pacemaker – GnRH pulse generator

GnRH decapeptide forms a —-like shape to interact with its receptor

horseshoe

what happens when gnrh is continuous?

lh and fsh levels drop

GnRH pulse — and — change during the menstrual cycle

frequency and amplitude

t or f

GnRH is not measurable in the systemic circulation

t

how do we measure gnrh?

each pulse in GnRH evokes a pulse of LH; thus, LH pulsatility is often used as an indicator of GnRH pulsatility

when are gnrh pulses the most freqeunt?

right around ovulation

—- pulse frequency of gnrh favors LH Beta gene expression

rAPID

— pulse frequency of gnrh favors FSH Beta gene expression

slow

when grnh pulse is low, when gnrh binds to its receptor, which signalling pathway is set off?

G alpha-s pathway

what does the G alpha-s pathway entail?

• adenylate cyclase

• cAMP

• PKA

• CREB

• creb TF for FSH

when gnrh pulse is high, and gnrh binds to receptor, what pathway gets set off?

G alpha-q pathway

what happens in the Gaq pathway?

• PLC

• PIP2 makes (DAG+IP3) and PKC

• IP3 releases calcium from ER

• PKC induces MEK

• MEK induces ERK ½

• turns on ELK1

• transcribes ERG1

• ERG1 increases LH transcription

where is Gnrh released?

the hypothalamic hypophyseal portal system

most amino acids in nature are L or D?

L

when the GNRH molecule is in the horseshoe shape to bind with its receptor, what would happen if you did D-amino acid substitution for all the L-amino acids?

• stabilizes the horseshoe conformation

• increases binding affinity

• enhance the activity of GNRH

why would it be important to know about this D-amino acid substitution?

because that’s one way you can make an agonist drug, it makes it stronger

what are 2 reasons we cant measure GNRH in the blood?

• it never gets into full circulation, it only goes through hypophyseal portal system

• half life is less than 5 mins

in the follicular phase describe the appearance of LH peaks (whihc are a proxy for GNRH pulses)

relatively low amplitude but frequent

near ovulation describe the appearance of LH peaks (whihc are a proxy for GNRH pulses)

largest amplittude and frequency

in the luteal phase describe the appearance of LH peaks (whihc are a proxy for GNRH pulses)

• high amplitude but lower frequency

Two components can change LH/FSH ratio

• amplitude of pulse

• frequency of pulse

where is activin released from?

cells in the pituitary

is activin a protein?

yes

where does activin bind to?

receptors on the gonadotrope cells

when activin binds to the receptor on the gonadotrope cell membrane, what happens?

apparently it triggers FSh and GNRH secretion??? idk how it can trigger GNRH release?

okay I think her main point is that it locally triggers FSH release

When you have rapid pulses, you also get the production of a locally produced protein called —

follistatin

both— and — block the activity of activin in different ways

inhibin and follistatin

where does inhibin come from?

released by sertoli/granulosa cells following FSh stimulation

how does follistatin inhibit activin?

it acts like a fake receptor kind of, it just like envelops activin and stops it from binding to its receptor

how does inhibin inhibit activin?

it binds to the type 2 receptor for activin but does not activate it, so the receptor is clogged up and then activin cant bind

Which statement correctly describes the role of follistatin in regulating FSH secretion?

A. Follistatin binds to GnRH and prevents its release from the hypothalamus.

B. Follistatin binds to activin and prevents it from binding to its receptor.

C. Follistatin stimulates activin to enhance FSH secretion during slow GnRH pulses.

D. Follistatin acts as an activin receptor antagonist by triggering intracellular signaling.

B. Follistatin binds to activin and prevents it from binding to its receptor.

whats the name of the kiss peptin receptor

GPR54

where is the kiss receptor expressed?

GNRH neurons

LOF mutations in GPR54 lead to —

hypogonadotropic hypogonadism

what is hypogonadotropic hypogonadism

the pituitary gland or hypothalamus fails to produce enough gonadotropins (LH & FSH), leading to low sex hormone (testosterone/estrogen) production by the gonads (testes/ovaries), resulting in delayed puberty, infertility, low libido