GnRH Flashcards
GnRH roles
Master controller of reproduction
Gene on chromosome 8
23 isoforms in vertebrates
Most vertebrates- GnRH I (GnRH) and GnRH II
Roles include: Neuroendocrine - HPG Paracrine (placenta/gonads) Autocrine (prostate/breast cancer) Neurotransmitter (Regions of the brain)
GnRH structure
Pre-pro hormone
Cleavage steps-= Mature GnRH and GAP
Structure from left to right is:
Signal peptide, GnRH, GnRH associated peptide
GAP peptide- co-secreted with GnRH, unknown function
Migratory path for GnRH neurones
Embryonic period:
Originate outside CNS, in medial olfactory placode
Cells migrate
Nasal region brain medio-basal hypothalamus
Numerous genes involved
Regulatory gene mutations leading to hypogonadotrophic hypogonadism
Known mutations causing HH
KAL1, FGFR1, FGF8, PROK2, PROKR2, NELF, CHD7,
GNRH1, GNRHR, GPR54, TAC3, TAC3R, NKB/NK3R, WDR11
Kallman syndrome
Mutation in KAL-1 gene
Premature termination of migration
anosmia & hypogonadotrophic hypogonadism
GnRH release
GnRH is processed and packaged into storage granules that are transported down the axons to the external zone of the median eminence. GnRH released in synchronized pulses from the GnRH nerve endings into hypophyseal portal system.
Rhythmic pulses- every 30-120 minutes – “circhoral pulses”
GnRH Pulse generator
collection of hypothalamic neurons producing endogenous secretory rhythms
GnRH t1/2 2-4 minutes
GnRH stimulates synthesis and secretion of gonadotrophins.
Differential frequency and amplitude alter pattern of FSH and LH secretion, therefore impact gonadal response.
GnRH receptor
G-protein-coupled receptor (GPCR)
Two variants Type I and II GnRHR
Type 1- full length, Type 2 - missense truncation (humans)
Resistant to desensitisation (some exceptions)
Expressed on gonadotroph cells of anterior pituitary
How does GnRH regulate gonadotrophin production
Glycoproteins with α & β chains
α-chains identical in FSH & LH
β-chains unique & confer biological actions
Rhythm & pulsatility of GnRH
Relative rates of gene expression for α/β
Slow frequency or low amp GnRH pulse ⇒ ⇧FSHb gene expression
Fast frequency GnRH pulse ⇒ ⇧LHb transcription
Determines dimerisation of subunits
Determines glycosylation
Higher frequency GnRH pulse (every 30min) = favours LH secretion
Lower frequency/amplitude GnRH pulse (every 90-120min) = favours FSH synthesis and secretion
ERK signalling qs (refer to panopto bc you don’t get this)
Premise: ERK1/2 was thought to be the major pathway mediating GnRHR-dependent control of LHb and FSHb- is this the case?
Pituitary specific deletion of ERK1/2 to delete ERK1/2 from pituitary gonadotrophs and investigate reproductive consequence in male and female mice.
GnRH receptor signalling FSH vs LH
LH
GnRH binds receptor, activates G alpha q/11, activates PLC B, activates DAG, PKC, MEK 1/2, ERK 1/2, EGR
FSH
GnRH binds receptor, G alpha q/11, PLC B, DAG, PKC, MEK, ERK, difference here is ICER is activate along with CREB
What is the feedback from gonadal steroids
n FEMALES through most of menstrual cycle:
Progesterone & low plasma oestrogen negative feedback
Net effect = reduced LH & FSH
High sustained (48h) plasma [E2] = enhanced LH & FSH positive feedback
P4 ↓GnRH pulse freq
E2 ↓GnRH pulse amplitude
Positive feedback on days 12-14 of cycle
Where would the site of steroid feedback be and how would it work
Where it would act:
Either anterior pituitary or hypothalamus
Oestrogen & progesterone receptors on anterior pituitary and hypothalamus
Inhibin receptors found only in pituitary
How it would work:
In anterior pituitary by direct regulation of GnRHR
In hypothalamus by directly affecting GnRH neurones or indirectly by changing activity of other neural system that influence GnRH release
E2 must only be exerting negative feedback on the anterior pituitary as in rhesus monkeys, the hypothalamus was lesioned and this mechanism had no effect
What are the methods of feedback on the pituitary
Positive feedback
E2 induces & maintains GnRHR by increasing GnRHR mRNA in pre-ovulatory phase
E2 sensitises “self-priming” effect i.e. enhances interaction between GnRH & GnRHR
Negative feedback
E2 ??
Inhibin??
Progesterone ↓ GnRHR mRNA, also evidence of P4 response element in GnRHR gene
what are the methods of feedback on the hypothalamus
GnRH neurones only express ERβ Need ERα for positive feedback Erα is crucial for reproductive function Erα knock-out mice E2 must act on other afferents that project onto GnRH neurones
E2 indirectly stimulates GnRH neurones via other neuronal inputs:
Kisspeptin
Other hypothalamic neurotransmitters- e.g., GABAnergic neurons
