W4 - Hypothalamic Pituitary Gonadal Axis Flashcards
What are the master controllers of reproduction?
Gonadal function is controlled via feedback.
Starts with positive drive of hormones produced by hypothalamus acting on the anterior pituitary gland. In response, the anterior pituitary gland releases peptide hormones that goes on to act on gonads. Gonads also produce steroid/peptide hormones.
These hormones act at various points on the pituitary or hypothalamus via feedback.
Feedback is always negative in males. Primarily negative in females except during ovulation.
What does the Hypothalamus release? (Releasing hormones)
Gonadotropin Releasing Hormone (GnRH) and kisspeptin.
What does the pituitary gland release?
Follicle Stimulating Hormone (FSH) and Luteinising Hormone (LH)
These are gonadotropins. Name derives from the fact that the Gonadotrophin Releasing Hormone stimulates the pituitary to release those.
What does the Gonads release?
Oesteadiol (F)
Progesterone (P4)
Testosterone (M)
What are the elements required for reproduction?
• Correct process of sex determination (genotypic sex) and differentiation (phenotypic sex)
• Sexual maturation- Puberty
• Production and storage of sufficient supply of eggs & sperm
• Correct number of chromosomes in egg and sperm
• Actual sexual intercourse! Egg & sperm have to be transported and meet
• Fertilisation, implantation, embryonic and placental development
• Once delivered, to nurture individual until capable of “independent” life
How do signals travel from the Hypothalamus to the Pituitary gland?
Kisspeptin neurons produce kisspeptin.
And in response, GnRH neurones produce GnRH.
GnRH makes it way through a network of blood vessels to the anterior pituitary.
This produces FSH and LH, which makes it’s way into the circulation.
What is Kisspeptin (KISS1/kiss1) in the Hypothalamus?
• Role in reproduction recently discovered – 2001 - gatekeeper of puberty (genome sequencing showed that individuals with pubertal problems had mutations in kisspeptin. Mice without did not undergo puberty).
• Hypothalamic expression- ARC and AVPV
• Upstream of GnRH
• Kisspeptin neurons send projections to GnRH neurons, and binding to GPR54 expressed on GnRH neurons
Former name of Kisspeptin was Metastin - it is able to stop the metastatic growth of tumours.
Kisspeptin-54 is the best at crossing the blood brain barrier.
What is GnRH?
• Synthesised and secreted from GnRH neurons
• Secreted in a pulsatile fashion-pulse generator orchestrated
• Hypothalamic expression- ARC and MPN (Parvocellular system)
• 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 pulsatility?
• GnRH is secreted in pulses from hypothalamus every 30-120min.
• 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.
• Continuous release results in cessation of response.
What is the importance of pulsatile GnRH secretion?
When they did a test on animals where they exposed GnRH for prolonged periods. They were able to mimic the menstrual cycle.
What are the therapeutic application of GnRH?
• Synthetic GnRH – same structure as endogenous GnRH:
• pulsatile administration -> Stimulatory
This is where people with mutations for instance have a pump that administers the GnRH.
• GnRH analogues – modified GnRH peptide structure:
• Single bolus, long half life, loss of pulsatility Inhibitory
• Agonists or antagonists
These analogues are used in IVF treatment where the [APG axis] (?) shuts down so we can control the axis and administer doses of FSH for follicle growth. They are also used on hormone dependent cancers.
What are the mechanisms of action of the synthetic GnRH and GnRH analogues?
GnRH binds to GnRHR and activates signalling. This leads to the stimulation of Gonadotrophin synthesis and secretion. This has a short half life, so it then dissociates from GnRHR. This receptor is then responsive to more GnRHR.
If an agonist binds to the receptor instead, it would still reach the stage where gonadotrophin synthesis and secretions are made. But due to the longer half life, it uncouples the GnRHR from G protein signalling. Now it is unresponsive to GnRH.
If an agonist binds, it blocks the receptor so there is no downstream effects. So both the agonist and the antagonist eventually prevents GnRH from binding to the receptor.
What are the clinical uses of GnRH and GnRH analogues?
- Ovulation induction and IVF
- Prostate cancer
- GnRHR/GnRH and ovarian and endometrial cancers
- ER and breast cancer in pre-menopausal women
- Endometriosis
-PCOS - Uterine Fibroids
How does the signal go from the Pituitary to the Gonads?
Ultimate coordination of gonadal function to facilitate viable gamete production (male), growth and development.
What role does Gonadotrophin hormones (LH, FSH) play?
• Heterodimeric peptides – common α-subunit and hormone-specific β-subunit which varies on LG, FSH and hCG
• N-linked carbohydrate side chains required for biological function
• Free subunits have no biological action. They need to be glycosilated. They need to be dimerised and come together to be biologically active.
• α-subunits are synthesize d in excess with β-subunit (dependent on GnRH activity) limiting the hormone concentration
• Pulsatile secretion due to pulsatile GnRH release from hypothalamus but pulsatile
secretion not necessary for biological activity
What does LH do?
• Testis:
- stimulation of Leydig cell androgen synthesis
• Ovary:
- theca cell androgen synthesis
- ovulation
- progesterone production of corpus luteum
What does FSH do?
• Testis:
- regulation of Sertoli cell metabolism
• Ovary:
- follicular maturation
- granulosa cell estrogen synthesis
What is the significance of Male gonadal steroid production?
If you look at mammalian testes, and look at the spaces between the testes, they have Leydig cells present. They express androgen production like testosterone. There are also Sertoli cells that presents FSHR expressing Sertoli cell metabolism. It regulates Spermatogenesis.
What is the significance of Female gonadal steroid production?
There would be a mature follicle with an oocyte inside it. The lining of cells surrounding that white structure is called Theca cells, which represents the LH receptors, which presents Androgens. These Androgens make their way further into the cell called Granulosa cells acts on FSH receptors and they stimulate oestrogen. The enzyme Aromatase catalysed this conversion.
After ovulation, the corpus luteum presents LH receptor (and FSH receptor) and able to present Progesterone and oestrogen.
What are Gonadal steroid hormones?
Oestrogens
• Oestradiol and also oestrone
• Folliculogenesis
• Positive feedback triggers ovulation
Androgens
• Androstenedione, testosterone, dihydrotestosterone
• Spermatogenesis
Progesterone
• Prepares the uterus for implantation
• Maintains conditions required for the early stages of pregnancy
