Neuroendocrine Control of Fertility

GnRH neurons

• scattered throughout hypothalamic region

• axons project to median eminenece where GnRH is release into the hypophyseal portal circulation

• GnRH stimulates anterior pituitary to release LH and FSH which act on Gonads to regulated sex steroid production and gamete development

Hypophyseal portal system

• GnRH neurons release GnRH at the median eminence

• GnRH enter primary capillary network

• Portal vessels transport GnRH to the anterior pituitary

• Blood enters the 2nd capillary network

• GnRH stimulates pituitary gonadotrophs to release LH and FSH

this system is important because GnRH is released in small amount and this system delivers all the GnRH without diluting in

Negative and positive feedback in HPG axis

Negative

• in males and females

• when circulating sex steroid concentrations increase, signals to hypothalamus and pituitary reduces further sex steroid secretion to maintain homeostasis

Positive

• females: elevated oestradiol during appropriate stage of reproductive cycle can stimulate HPG axis to produce pre ovulatory LH surge triggering ovulation

What is the name of the kisspeptin receptor and its precursor

Term	Meaning
Kiss1	Gene encoding kisspeptin
Kisspeptin	Neuropeptide produced from the Kiss1 precursor
GPR54 / KISS1R	Receptor for kisspeptin
Kisspeptin-54	A 54-amino-acid form of kisspeptin
Kisspeptin-10	A shorter active form containing 10 amino acids

Different kisspeptin peptides share a common c terminal sequence important for receptor activation

What did increased kisspeptin do?

correlation between GnRH neurons and kisspeptin

• increasing doses of kisspeptin produced increased LH secretion

• When GnRH receptors blocked, LH release was blocked suggesting mechanism is kisspeptin administered, GnRH neuron stimulated, GnRH released and anterior pituitary LH released

• Kisspeptin causes rapid depolarization on GnRH neurons followed by a dramatic increase in AP firing

• 90% or more of GnRH neurons expressed kisspeptin receptor

What are the 2 locations/population of kisspeptin neurons

AVPV kisspeptin neurons in Rostral hypothalamus. Function: Positive oestrogen feedback and LH surge

Arcuate kisspeptin neurons in Caudal/basal hypothalamus. Function: Negative feedback and pulsatile GnRH release

Kisspeptin Projections to GnRH Neurons

Kisspeptin fibres observed close to GnRH neuronal cell bodies. described as close appositions (2 neuronal structures located close to one another)

Which 2 locations can kisspeptin stimulate neurons

Kisspeptin stimulates neurons at 2 locations:

• GnRH neuronal cell bodies and dendrites

• GnRH nerve terminal near median eminence, arcuate kisspeptin neurons project towards median eminence where GnRH terminals release hormone into portal blood

Kisspeptin expression when ovaries were removed and oestrogen drops then oestradiol replacement administered

• ovaries intact oestrogen level physiological, when ovaries removed oestrogen level low and when ovaries removed and oestradiol replacement was given levels increased

• When oestrogen levels fall, arcuate kisspeptin neurons increase kiss 1 expression stimulating GnRH LH pathways and when oestrogen levels rise, arcuate kiss1 expression suppressed. negative feedback

• In AVPV, ostegrogen stimulated Kiss 1 expression and when ovaries were removed kiss 1 expression decreased. positive feedback

What is observed when optogentically stimulating arcuate kisspeptin and AVPV kisspeptin neurons

• arcuate, pulses of LH

• avpv, large LH response similar to pre ovulatory LH surge

which receptors were detected in AVPV and ARC kisspeptin neuronal population

AVPV: Oestrogen receptor alpha (ERα) and oestrogen receptor beta (ERβ).

ARC: Oestrogen receptor alpha (ERα), Oestrogen receptor beta (ERβ), Androgen receptor (AR) and Progesterone receptor (PR).

these allow them to detect sex steroids

What 2 neuropeptides are expressed by ARC kisspeptin neurons and their mechanism

Neurokinin B (NKB) and dynorphin which are called KNDy neurons which comes from Kisspeptin + Neurokinin B + Dynorphin.

• NKB: help initiate and synchronize pulse

• Dynorphin: helps terminate a pulse

• Kisspeptin: stimulates GnRH neurons to produce GnRH release

Mechanism: NKB signaling increases activating and synchronizing KNDy neurons, kisspeptin released stimulating GnRH secretion, GnRH pulse to LH pulse generated, dynorphin signaling terminating the pulse

these provide mechanism for generating rhythmic kisspeptin signals that produce GnRH and LH pulses

What did the experiment examining if kisspeptin is critical for puberty find

• even when kisspeptin neurons were removed, normal reproductive maturation occurred in female mice

• kisspeptin theorized to be important for puberty so this maybe happened because maybe not all kisspeptin neurons were eliminated and possible compensation from other circuits

How does kisspeptin influence energy balance

• mice without kisspeptin receptor were infertile, increased fat mass was observed but when ovaries were removed increased fat mass was still obsered

• kisspeptin mice actually consumed less food but because mice without kisspeptin had lower energy expenditure there was increased fat accumulation even when they were eating less