Neuroendocrine control of the HPG axis

Integration of _____, _____, and ______ to impact the HPG axis

nutrient, endocrine, environmental signals

______ released from the testes and _______ released from the ovaries inhibit the hypothalamus

Androgens, estrogens

____ is the primary regulator of gonadotropin secretion

GnRH

GnRH is released into the ______

hypophyseal portal system

GnRH half life = _____

5mins

GnRH is a ______, _____ among mammal species

decapeptide, conserved

______ is central to GnRH regulation of ________

Pulsatile release, gonadotrope cells

Pulsatile release is coordinated by a _____ - ______

neural pacemaker, GnRH pulse generator

GnRH decapeptide forms a ______ to interact with its receptor

horseshoe-like shape

3 AAs involved in receptor binding and activation

pGlu, His, Trp

3 AAs involved in receptor binding only

Gly, Pro, Arg

D-AA substitution of _____ can make a GnRH agonist

Gly at position 6

Continuous GnRH causes ______ LH and FSH

decreased

GnRH pulses are ____ right before LH surge and _____ after ovulation

higher, lower

____ is a marker for GnRH because it is released in a ____ ratio

LH, 1:1

_____ pulse frequency favours LHB gene expression and ____ pulse frequency favours FSHB gene expression

rapid, slow

Change in ________ partially explains differences in pulse frequency LH/FSH stimulation

feedback

FSHB gene expression (7)

1. GnRH binds GPCR

2. At low frequency Gas activated

3. Adenylate cyclase activated

4. cAMP and PKA activated

5. CREB activated

6. CREB phosphorylated and enters nucleus

7. FSHB mRNA 

LHB gene expression

1. GnRH binds GPCR

2. At high frequency, Gaq activated

3. PLC activated, converts PIP2 to DAG and IP3

4. MEK activated

5. ERK1/2 phosphorylated

6. ELK activated

7. EGR1 activates SF1, PITX1, EGR1

8. LHB mRNA

IP3 binds IP3R receptors causing increased _____ release from endoplasmic reticulum and trigger release of ___

Ca2+, LH

GnRH → FSH → _________ → inhibin -| _____

granulosa/luteal cells/sertoli cells, inhibin

GnRH → _______ -| activin

follistatin

GnRH → LH → granulosa/luteal cells/leydig cells → ______ -| ____

progesterone, estrogens, testosterone, GnRH

During slow pulses ____ released from the pituitary can stimulate FSH secretion

activin

How does follistatin inhibit activin

Binds activin and prevents binding to its receptor

How does inhibin inhibit activin

Released from gonads and binds activin receptor without triggering intracellular signalling

Follistatin released from the _____, Inhibin released from the ____

anterior pituitary, gonads

______ stimulates GnRH release

Kisspeptin

GnRH neurons express ____

GPR54 (Kiss receptor)

LOF mutations in GPR54 lead to ________

hypogonadotropic hypogonadism

Levels of kisspeptin increase at ______

puberty

Kisspeptin is a ____ AA protein released by neurons in the _____/_____

54, hypothalamus/preoptic area

KISS1 neurons are found in the ______ in the hypothalamus; the site of ______ ()

Anteroventral-periventricular region (AVPV), positive feedback (25%)

KNDy neurons produce ____ and _____, found in the ____ in rodents (__)

neurokinin B, dynorphin, arcuate nucleus, 75%

KNDy neurons are the site of _____

negative feedback

Neurokinin B is a peptide part of the _____ family

tachykinin

Neurokinin B acts by binding _______ found on ___ neurons and ___ neurons

NK3 receptors, GnRH, KISS1

Neurokinin B stimulates ____ and ___ neuronal activity

GnRH, KISS1

LOF mutation of neurokinin B can cause ______

normosmic hypogonadotropic, hypogonadism

Dynorphin is an _______ derived from the precursor protein _____

endogenous opioid, prodynorphin

Dynorphin includes ____, ____, and _____

dynorphin A, dynorphin B, neo-endorphins

Dynorphin activates _____ found on ____ neurons and ___ neurons

K opioid receptors, GnRH, KISS1

Dynorphin inhibits ____ and ___ neuronal activity

GnRH, KISS1

_____ neurons are believed to be the ______

pulse generator

In adult males, GnRH pulses ~ ____

1-2hrs

Frequency and amplitude of GnRH pulses vary with ___

age

Effect of estradiol on KNDy neurons

negative feedback inhibits Kiss1 release, decreasing GnRH

Estradiol effect on Kiss1 neurons

Positive feedback increases Kiss1 release and GPR54, increasing GnRH

Why do females have estradiol-mediated positive feedback while males do not?

• Females have more Kiss1 neurons in AVPV

• Amount triggers positive feedback

• Treating with androgen decreases number

Steroids present for short window in development responsible for this difference

GnIH mediates _______ induced inhibition of ____

chronic stress, GnRH

GABA _____ GnRH

inhibits

Epinephrine _____ GnRH

activates

____ activates B-End, _____GnRH

CRH, inhibiting

NO ____ GnRH neurons

activates

Glutamic acid _____ norepinephrine, _____ NO to stimulate vesicle release

activates

Neuropeptide Y ______ GnRH neurons

inhibits

What occurs at puberty

• Acquisition of secondary sex characteristics

• Maturation of gonads

  • Formation of BTB and spermatogenesis

  • Ovarian follicles progress beyond stage 5

• Reproductive capacity

Puberty begins with __________ + maturation of _____

increased pulsatile release of GnRH, neurons

Balance of _____ and ____ of GnRH determines the timing of puberty

negative, positive regulators

Positive regulators of GnRH (LOF leads to __________)

• Kisspeptide

• Neurokinin B

• Glutamate

Hypogonadotropic hypogonadism

_______ is expressed in the arcuate nucleus of the hypothalamus

Makorin ring finger protein 3 (MKRN 3)

MKRN3 inhibits _____ acting as a ________ and _______

GnRH, E3 ubiquitin ligase, transcription repressor

Expression of hypothalamic MKRN3 ______ just prior to puberty initiation possibly via _____

decreases, expression of miRNA

Mutation of MKRN3 leads to ________

early onset puberty

MKRN3 prevents expression of ___, ____, and ____

KISS, TAC3, GnRH

Stress causes release of ____, ____ and thus _____ from the adrenal cortex

CRH, ACTH, glucocorticoids

Stress causes release of _____ from the adrenal medulla

epinephrine

Chronic stress causes elevated ______

glucocorticoids

Inhibition via cortisol release

• Hypothalamus

• Pituitary

• Locus ceruleus

_______ is an endorphin activated by ____ and inhibits GnRH

Proopiomelanocortin (POMC), CRH

Cortisol release inhibits _____ and ______

LH/FSH, target tissues

_____ inhibit every level of the reproductive axis

Glucocorticoids

Glucocorticoids inhibit ____ by preventing ____

LHB mRNA, EGR1 expression

_____ is correlated with reduced fertility and poorer outcomes for infertility treatments

obesity

Essential processes

• Cell maintenance

• Circulation

• Neural activity

Reducible processes

• Thermoregulation

• Locomotion

• Growth

Expendable processes

• Fat storage

• Reproduction

Electrical stimulation orexigenic neurons stimulates ____

appetite

Electrical stimulation of anorexigenic neurons _____ feeding

suppresses

Orexigenic neurons = ______ neurons

Neuropeptide Y (NPY)/Agouti-related peptide (AgRP)

Anorexigenic neurons = ____

a-MSH neurons

Orexigenic neurons are more active in _______, increasing ___ and decreasing ____

low body weight, food intake, energy expenditure

Anorexigenic are more active in _______, increasing ____ and decreasing _____

high body weight, energy expenditure, food intake

Ablation of orexigenic neurons causes ____

starvation

Ablation of anorexigenic neurons leads to _____

obesity

Orexigenic neurons inhibit ____ and ____, anorexigenic neurons activate them

Kiss and GnRH neurons

Leptin in the product of the _____ gene

Obese (OB)

Leptin is a ___ kDa protein, secreted by ______

16, mature adipocytes

Leptin is a ____ factor

satiety

Ob/Ob mice have a defect in _____, and Db/Db mice have a defect in _____/ Both are ____

leptin production, receptor for leptin, infertile

Treatment of Ob/Ob mice with _____ restores reproductive function, improving _____, _____, ____, and _____

leptin; follicle diameter, ovarian volume, number of dominant follicles, endometrial thickness

Leptin is necessary for ______ pulsatility

GnRH/LH

Leptin primarily acts indirectly via ______ on GnRH to have a _____ effect

a-MSH neurons, permissive

Leptin inhibits ______ and activates ____, ____ and ___

NPY/AgRP neurons, a-MSH, GnRH, Kiss neurons

Environmental causes of hypogonadotropic hypogonadism

• Stress

• Nutrition

• Disease

Hypothalamus causes of hypogonadotropic hypogonadism

GnRH (can be genetic)

Pituitary causes of hypogonadotropic hypogonadism

• LH

• FSH

Ovary causes of hypergonadotropic hypogonadism

Steroidogenesis

Uterus causes of hypergonadotropic hypogonadism

• Presence

• Outflow

Hypergonadotropic hypogonadism

• Increased GnRH, LH, and FSH if there is issue with steroidogenesis

• Lack of negative feedback