HPG Axis Flashcards
What do we need to reproduce?
- Correct process of sex determination and differentiation
- Sexual maturation (puberty)
- Production and storage of sufficient supply of eggs and sperm Correct number of chromosomes in egg and sperm
- Actual sexual intercourse/ IVF
- Fertilisation, implantation, embryonic and placental development
What controls gonadal function?
It is controlled via feedback by:
- Hypothalamic and pituitary peptide hormones
- Gonadal steroid (and peptide) hormones
! Only on one occasion there is positive feedback which is in females during ovulation.
What does the hypothalamus release?
It releases Gonadotrophin releasing hormone (GnRH), (kisspeptin).
What does the pituitary release?
Follicle Stimulating Hormone (FSH) and Luteinising Hormone (LH)
What do the gonads releases?
Female: Oestradiol (E2), Progesterone (P4)
Male: Testosterone (M), Inhibin and activin.
Describe the release of hormones from the HPG axis.
- Series of GnRH neurons will produce and secrete GnRH
- GnRH will be secreted into the hypophyseal portal circulation (primary plexus to secondary capillary plexus)
- GnRH will bind to GnRH receptors on gonadotroph cells in the anterior pituitary to produce FSH and LH
- FSH and LH bind to FSH/LH receptors on the gonads
Gonads secrete oestrogen, progesterone and androgens which will feedback to anterior pituitary and hypothalamus through neg. feedback
What is kisspeptin upstream to?
What does it regulate?
How does it do this?
Kisspeptin is upstream to GnRH and regulates GnRH production
It does this because kisspeptin neurons will send projections to GnRH neurons and bind to KISS1R expressed on GnRH neurons
Where is kisspeptin expressed in the hypothalamus?
In the arcuate nucleus and the anteroventral periventricular nucleus
What is kisspeptin upstream to?
GnRH
What is the structure of kisspeptin?
Expressed as a prepro protein which is cleaved into different types of kisspeptin
The most common is kisspeptin 54 (metastin) and kisspeptin 10
What does GnRH do?
It binds to the GnRH receptor on gonadotroph cells of the anterior pituitary to stimulate the synthesis and secretion of gonadotrophin hormones - LH and FSH.
What is the structure of GnRH?
10 amino acids long
When is GnRH secreted from the hypothalamus (minutes)?
Every 30-120 mins
What does the GnRH pulse stimulate?
It stimulates a pulse of LH and FSH secretion from the pituitary.
What do slow and rapid pulse frequency of GnRH favour?
Slow - FSH release Rapid - LH release
What happens when there is continuous release of GnRH?
Results in cessation of response
How is synthetic GnRH administered and what does it stimulate?
- Synthetic GnRH: same structure as endogenous GnRH -> pulsatile administration - stimulatory effect of fertillity e.g ovulation
What are GnRH analogues?
How are they administered?
What are they used for?
What two forms do they exist in?
- Modified GnRH structure
- Single bolus administration = loss of pulsabillity
- Inhibition of HPG axis
- Exists in two forms agonist and antagonist
Describe the mechanism of action of a synthetic GnRH agonist
- Bind to receptor
- Activation of signalling
- Stimulation of gonadotrophin synthesis and secretion
- Uncoupling of GnRHR from G protein signalling
- GnRHR non-responsive to GnRH
Describe the mechanism of action of a normal GnRH signalling profile
- Bind to Receptor 2. Activation of signalling 3. Stimulation of gonadotrophin secretion and secretion 4. Dissociation of GnRH from GnRHR 5. GnRHR responsive to next GnRH pulse
Describe the mechanism of action of a GnRH antagonist
- Bind to receptor 2. Blockage of receptor 3. No downstream effects
What are the clinical uses of GnRH and GnRH analogues?
- Ovulation induction and IVF (shuts down menstrual cycle so it can be manipulated)
- Prostate cancer
- Endometriosis -
- PCOS
- Uterine fibroids
What is the structure of gonadotrophins?
- Heterodimeric peptide
- Common alpha subunit
- Hormone specific beta subunit
- LHbeta, FSHbeta, hCGbeta
- N-linked carbohydrated side - required for biological function
What are the most important hormones from the anterior pituitary?
LH, FSH and hCG
What action do the free subunits have in gonadotrophic hormones?
The free subunits have no biological function
How are the alpha and beta subunits synthesised of gonadotrophic hormones?
he alpha subunits are synthesised in excess with beta subunits limiting the hormone concentration
What is the function of LH in ovulation?
Maintains progesterone production of the corpus luteum
Why is the beta subunit of gonadotrophins released in a limited fashion?
The beta subunit is secreted in a limited fashion because it is dependant on GnRH
- A slow pulse of GnRH = transcription of FSH beta
- A fast pulse of GnRH = transcription of LH beta
What is the function of LH in testis?
Stimulation of leydig cell androgen synthesis
What is the function of LH in the ovary?
Theca cell androgen synthesis Ovulation Progesterone production of corpus luteum
What is the function of FSH in the testis?
Regulation of Sertoli cell metabolism
What is the function of FSH in the ovary?
Follicular maturation Granulosa cell estrogen synthesis
What do the leydig cells do?
They express LHR to produce androgens such as testosterone
What do the sertoli cells do?
They express FSHR that is important for sertoli cell metabolism for spermatogenesis.
What do the theca cells do?
They have LHR which produces androgens