HPG Axis Flashcards
What do we need to reproduce?
- Correct process of sex determination and differentiation
- Sexual maturation (puberty)
- Production and storage of sufficient sperm and eggs
- Correct number of chromosomes in egg and sperm
- Actual sexual intercourse
- Nurture of baby until capable of independence
What are the hormones of the HPG axis?
- Hypothalamus - GnRH and kisspeptin
- Pituitary - FSH and LH
- Gonads - Inhibin and activin, Oestradiol, Progesterone/ testosterone
Brief HPG axis overview
Hypothalamus -> GnRH -> pituitary -> LH + FSH -> gonadal receptors -> Oestrogen, P and androgens
- Negative feedback onto axis from P and androgens
- Oestrogen usually has negative feedback, but when it reaches a critical level, and ovulation is imminent, there is positive feedback to give the surge in levels.
What is the pathway from the hypothalamus to the pituitary?
- Neural inputs (including kisspeptin) will cause the release of GnRH into the primary plexus
- ## It will then travel via the median eminence and hypophysial portal vessel to the anterior pituitary and bind to the gonadotroph cells
What is GnRH?
- Decapeptide (10aa) cleaved from larger prepropeptide
- Sythesised and secreted from GnRH neurones
- Secreted in a pulsatile fashion, orchestrated by a pulse generator that can change the pulse frequency
- Binds to the GnRHR on gonadotroph cells of the anterior pituitary to stimulate the synthesis and secretion of gonadotrophins (LH and FSH)
Pulsatile GnRH release
- Pulses every 30-120 mins
- A GnRH pulse stimulates a pulse of LH and FSH secretion from the pituitary
- Pulsatile GnRH secretion is vital for stimulation of LH/FSH secretion
- Slow frequency pulse favours FSH release, rapid pulse frequency favours LH - GnRH can regulate the two
- Continuous release results in cessation of response
- At the increase of the peak, oestradiol production increases, when the peak decreases, the P level increases
What are clinical applications of GnRH?
- Synthetic GnRH - same structure as native GnRH -> STIMULATORY
- GnRH analogues - modified GnRH peptide structure (AA substitutions), loss of pulsality -> INHIBITORY
What is the mechanism of action of synthetic GnRH?
- Binds to receptor
- Activates signalling
- Stimulates Gonadotrophin synthesis and secretion
- Dissociates from receptor
- GnRHR responsive to next GnRH pulse
What is the mechanism of action of GnRH analogues (agonists)?
- Binds to receptor
- Activates signalling
- Stimulates Gonadotrophin synthesis and secretion
- uncoupling of GnRHR from G-protein signallg (receptor still present, just uncoupled)
- GnRH non-responsive to GnRH
What is the mechanism of action of GnRH analogues (antagonists)?
- Binds to receptor
- Blocks receptor
- No downstream effects
What can GnRH analogues be used for clinically?
- Ovulation, induction and IVF
- GnRHR/GnRH + ovarian/endometrial cancers
- PCOS
- Oestrogen responsive breast cancer in premenopausal women
- Uterine fibroids
- Endometriosis
- Prostate cancer
What is the structure of gonadotrophins?
- Heterodimeric peptides - common alpha subunit and a hormone-specific beta subunit
- Different AA lengths and glycosylation patterns
- N-linked carbohydrate side chains (+O-linked in hCG) = microheterogeneity, required for biological production
- Free subunits have no biological action
- Alpha-subunits are synthesised in excess with beta-subunits limiting the hormone concentration
What is glycosylation?
- Enzymatic process to link saccharides together to form glycans
- FSH and LH require carbohydrates to be active
What is the difference in LH/FSH pulses in an underweight individual?
They have much lower levels of FSH
What is the function of LH?
Testis
- Stimulation of leydig cells to produce androgens
Ovary
- Theca cell androgen synthesis
- Ovulation
- Progesterone production of CL
