What do we need to reproduce?
- correct process of sexual differentiation
- correct number of chromosomes in eggs and sperm
- puberty
- sexual intercourse
- fertilisation and implantation
- correct placenta development
what is the hypothalamic pituitary gonadal axis?
hypothalamus -> pit -> gonad
gonadal hormones can feedback to the hypothalamus and pit in a positive or negative way
how do gonadal hormones usually feedback to the hyp and pit?
mostly negative feedback, only time its positive is in females during ovulation
-all of the events that coordinate ovulation require positive feedback to occur
what does the hypothalamus produce?
Gonadotrophin Releasing Hormone (GnRH)
what does the pituitary produce?
Follicle Stimulating Hormone (FSH) and Luteinising Hormone (LH)
what do the gonads produce?
-Oestradiol (E2)
-Progesterone (P4)
-(M) Testosterone
(Inhibin and activin)
explain how the axis all works
- kisspeptin binds to receptors on GnRH neurons
- Gnrh secreted into the primary plexus of the median eminence, travels via hypophysial portal vein to anterior pituitary where it binds to receptors on gonadotroph cells, coordinating synthesis and secretion of LH and FSH into circulation
- both bind to receptors on the gonads, coordinating synthesis and secretion of oestrogen, progesterone and androgens
- they all feedback in a primarily negative fashion to the hyp and pit
- oestrogen also positively feedbacks, coordinate ovulation
what is kiss peptin?
a peptide hormone cleaved from a much larger pre-pro structure into 4 different variants
where is kisspeptin expressed?
expressed within 2 different nuclei of the hypothalamus, the ARC and AVPV
ARC = Arcuate Nucleus
AVPV = Anteroventral Periventricular Nucleus
what does kisspeptin do?
regulates GnRH production
- kisspeptin neurons project to GnRH neurons
- kisspeptin neurons secrete kisspeptin to its receptor, which is localised to GnRH neurons
what is kisspeptin is cleaved into?
metastin - kisspeptin 54, tumour supressor
- proteolytic cleavage to become smaller variants, kisspeptin 13, 14 10
- kisspeptin 54 can be used for in-vitro studies because it can cross the blood brain barrier, and kisspeptin 10 is thought to not do that as well
how is GnRH secreted and why is this important?
secreted from GnRH neutrons in the hypothalamus in a pulsatile fashion
- pulsatile secretion is critical for its function
- pulsatility changes through the menstrual cycle, which is why we get differential secretion of LH and FSH
- specialised set of neurons called the pulse generator, orchestrate the change in GnRH pulsatility
after GnRH is secreted from the hypothalamus where does it go?
Binds to the GnRH receptor (GnRHR) on gonadotroph cells of the anterior pituitary to stimulate the synthesis and secretion of gonadotrophin hormones- LH and FSH.
what is GnRH co-secreted with?
GAP
GnRH associated peptide, a much larger peptide
GnRH structure
really small
-produced from a larger pre-pro protein, which is spliced into a decapeptide
what occurs when you don’t give GnRH in a pulsatile fashion, instead a continuous fashion?
- if you don’t give GnRH in a pulsatile fashion, you don’t get LH and FSH production
- giving GnRH continuously results in cessation and shutting down of the HPG axis
what does a slow frequency pulse favour?
FSH release
what does a rapid frequency pulse favour?
LH release
Therapeutic application of GnRH
Synthetic GnRH
GnRH analogues
Synthetic GnRH
- same structure as endogenous GnRH
- pulsatile administration, stimulatory
- allows people who lack GnRH to undergo normal puberty
GnRH analogues
- modified GnRH peptide structure
- single bolus, long half life, loss of pulsatility
- inhibitory
- sit on the GnRH receptor and cause it to downregulate, useful if we want to shut down the system
- agonists and antagonists
2 types of GnRH analogues and how they work
agonists and antagonists - both have the same end result of shutting down the HPG axis
- antagonists block the GnRHr and there are no further downstream effects
- agonists take longer to down regulate, binding of the agonist to the receptor causes gonadotrophin synthesis and secretion, but then GnRHr uncouples from g-protein signalling, so GnRHr is unresponsive to next pulse of GnRH
clinical uses of GnRH and GnRH analogues
cancer
- ovarian
- prostate, tends to be androgen dependent, so shutting down the HPG axis is really important for killing androgens present and restricting cancer growth
Gonadotrophin hormone (LH, FSH hCG) structure
- Heterodimeric peptides – common α-subunit and hormone-specific β-subunit
- N-linked carbohydrate side chains required for biological function
- Free subunits have no biological action
- α-subunits are synthesized in excess, β-subunit limits the hormone concentration
