Flashcards in GnRH Deck (25):
Give a brief description of the history of GnRH.
- Master controller of reproduction.
- Characterised in 1971.
- R Guillemin and A Schally, Nobel prize in physiology and Medicine 1977.)
Which chromosome is the gene for GnRH on?
How many GnRH isoforms are there in vertebrates?
Outline the neuroendocrine role of the HPG axis.
Paracrine - placenta/gonads
Autocrine - prostate/breast
Neurotransmitter - regions of the brain.
Outline GnRH structure.
Preprohormone - cleaved and consecrated as mature GnRH (decapeptide) and GAP (GnRH associated protein.) May stimulate and increase increase prolactin secretion.
Where do GnRH neurones cells originate from?
Embryonic period - Originate outside the CNS in the medial olfactory placode. (area of thickening of the embryonic epithelial later from which the organ/structure later develops)
Cells migrate - via cribiform plate to olfactory bulb to medio-basal hypothalamus. (Numerous genes involved, e.g KAL1, FGFR1, FGF8, PROK2, PROKR2, CHD7, NELF.)
Name the genes responsible for homeostasis and GnRH secretion.
DAX1, PC1, LEPR, LEP, KISS1R, FGFR1, PROKR2, PROK2, TACR3, TAC3, GNRH1.
Outline an in vitro experiment to demonstrate GnRH neurone migration.
In vitro culture explants from fetal monkey placed.
Migration of GnRH neurones out of explant.
Name the syndrome associated with unsuccessful GnRH neurone migration.
Kallman's syndrome. KAL1 gene. Premature termination of migration. Associated with anosmia (indicative of malformation of the olfactory bulb and tract.) Leads to hypogonadotrophic hypogonadism.
Which system contains GnRH neurones.
Parvocellular system containing medial pre optic and arcuate nucleus.
What is the importance of the hypothalamus in GnRH neurone production.
Hypothalamus has both neural and vascular connections within the pituitary. Magnocellular neurones arise from paraventricular nucleus and supraoptic nucleus. These project to the posterior pituitary. Oxytocin and ADH made here and stored in Post Pit. Hypothal and ant pit - hypophyseal portal circulation.
Outline GnRH release.
- Processed and packaged into storage granules.
- Transported down axons to the external zone of the median eminence.
- GnRH released in synchonised pulses from GnRH neurone endings into hypophyseal portal system.
- Circhoral pulses (every 30-120m)
What is the GnRH Pulse Generator
Collection of hypothalamic neurones producing endogenous secretory rhythms. Occurs in the mediobasal hypothalamus.
What is the half life of GnRH?
What is the function of GnRH?
Stimulates synthesis and secretion of gonadotrophins.
Between which 2 hormones is there a close temporal relationship?
GnRH and LH. Been found in monkeys, ewes and humans.
Describe the structure of the GnRHR.
- 7 transmembrane domain structure.
- No carboxyl terminal chain.
- Type 1 - full length
- Type 2 - missense truncation.
-Resistance to desensitisation.
- Expressed on gonadotroph cells of AP.
Why are there GNRHRs in different tissues, e.g, breast, ovarian, placenta.
It is thought that in evolutionary terms maybe there was a direct regulation of the gonads as an early function and then the neuroendocrinological role in regulating the pituitary came as a later evolutionary development.
Name the different tumour cell lines of GnRHR?
Breast tumor cell lines (MCF-7 and MDA-MB 468) and prostate tumor cell lines (PC-3 and LNCaP).
Describe how GnRH pulsatility regulates gonadotrophin production.
- Slow frequency/low amplitude GnRH (120m) = FSHB gene expression.
- Fast frequency (30m) = LHB transcription.
- Wildt L et al 1981.
- Determines dimerisation and glycosylation of subunits.
JC Marshall on rats, proved glycosylation was needed for hormones to work.
Describe how GnRH pulsatility varies over the menstrual cycle.
(1) Early Follicular phase – pulses slow (every 90-120mins) »FSH
(2) Mid-late F phase – pulse freq increases (every hr.) »LH
(3) After ovulation – pulses slow (every 3-5h) »FSH production
(4) End of luteal phase – increase in GnRH pulse secretion » FSH release
- Marshall JC 1991.
Outline the feedback in males.
LH stimulates Leydig cells to produce Testosterone
FSH stimulates Sertoli cells to produce inhibin B, activin, ABP & transferrin & spermatogenesis
Testosterone from Leydig cells reduces LH secretion (Rhesus monkey experiments)
Mainly Inhibin that↓FSH secretion from pituitary
Activin ↑FSH secretion from pituitary
Where are the speculated sites of steroid feedback?
- Either anterior pituitary or hypothalamus
- Oestrogen & progesterone receptors on anterior pituitary and hypothalamus
- Inhibin receptors found only in pituitary
How does feedback of steroids occur?
-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