Hypothalamic-Pituitary-Gonadal Axis Flashcards
What do we need to reproduce?
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 is the HPG axis the master controller of reproduction?
Gonadal function is controlled via feedback by:
- Hypothalamic & pituitary peptide hormones. - Gonadal steroid (and peptide) hormones.
What are the hormones of the HPG axis?
Hypothalamus , releasing hormones (RH)- Gonadotrophin Releasing Hormone (GnRH)and (kisspeptin) a pretty new hormone
Pituitary, stimulating hormones (SH)- Follicle Stimulating Hormone (FSH) and Luteinising Hormone (LH)
Gonad- (Female. ) Oestradiol (E2), Progesterone (P4), (M) Testosterone, (Inhibin and activin which are the peptide hormones but dw about those).
Can you give an overview of the HPG axis?
It all begins with a positive drive of GnRH from the hypothalamus
GnRH acts on the gonadotroph cells of the anterior pituitary
The gonadotroph cells go on to produce gonadotrophins, so LH and FSH so we have that as a positive drive
LH and FSH act on the cellular compartments of the gonads to produce oestrogen, progesterone and androgens such as testosterone
These steroid hormones act via feedback on different points of the anterior pituitary and the hypothalamus
This feedback is always negative feedback in males and primarily negative in females except for that one time during ovulation when it switches to positive feedback
This is all essential to coordinate gonadal function for viable gamete production (male), growth and development (both)
How does kisspeptin influence the HPG axis?
In response to kisspeptin, as mentioned before kisspeptin acts upstream of GnRH, so the same way you have GnRH neurons in the hypothalamus you also have kisspeptin neurons in the hypothalamus.
The kisspeptin neurons produce kisspeptin and in response to the kisspeptin, the GnRH neurons produce GnRH
GnRH makes it way through a network of blood vessels called the hypophyseal portal circulation, form the primary plexus to the secondary capillary plexus, until it makes it way to the anterior pituitary
And then GnRH acts on the anterior pituitary so that it produces LH and FSH which make their way into the circulation
What is kisspeptin and what does it do?
Role in reproduction recently discovered – 2001 - gatekeeper of puberty
Hypothalamic expression- ARC and AVPV
Upstream of GnRH
Kisspeptin neurons send projections to GnRH neurons, and binding to GPR54 (kisspeptin receptor) expressed on GnRH neurons
What is the structure of kisspeptin like?
Kisspeptin is initially synthesised as a prepro protein until it is proteolytically cleavage into kisspeptin 54 (old name is Metastin)
Kisspeptin 54 will undergo further proteolytic cleavage to produce Kp-14, Kp-13 or Kp-10
What is GnRH and its characteristics?
Synthesised and secreted from GnRH neurons
Secreted in a pulsatile fashion- pulse generator responsible is orchestrated
Hypothalamic expression- ARC (arcuate nucleus) and MPN (medial preoptic nucleus) (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 the structure of GnRH?
GnRH is also initially synthesised as a prepro protein before undergoing proteolytic cleavage
Then it is cleaved into its ten amino acid state
The reaction also produces a 56aa protein called GAP
Why is the pulsatility of GnRH secretion important?
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.
That does not mean the other completely stops being produced, it just means one is favoured.
Continuous release results in a cessation of response.
What are the therapeutic applications of GnRH?
Synthetic GnRH – same structure as endogenous GnRH
- pulsatile administration-> Stimulatory
GnRH analogues – modified GnRH peptide structure
- Single bolus, long half life, loss of pulsatility -> Inhibitory
- Agonists or antagonists
What are the characteristics of gonadotrophin hormones? And how does pulsatility of GnRH affect secretion?
Gonadotrophin hormones: LH, FSH (hCG)
• Heterodimeric peptides – consist of a common α-subunit and hormone-specific β-subunit
• N-linked carbohydrate side chains required for biological function
• Free subunits have no biological action, so the subunits on their own
• α-subunits are synthesized in excess with β-subunit limiting the hormone concentration
So the fast pulse favours the synthesis of LH beta subunit whereas the slow pulse favours the FSH beta subunit synthesis
Pulsatile secretion due to pulsatile GnRH release from hypothalamus but pulsatile secretion not necessary for biological activity
What are the functions of gonadotrophins on testes and ovaries?
Luteinising hormone • Testis: - stimulation of Leydig cell androgen synthesis • Ovary: - theca cell androgen synthesis - ovulation - progesterone production of corpus luteum Follicle-stimulating hormone • Testis: - regulation of Sertoli cell metabolism • Ovary: - follicular maturation - granulosa cell oestrogen synthesis
What are the functions of different 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
How does the female and male HPG axis differ?
In response to kisspeptin the GnRH neurons secrete GnRH which travels to the anterior pituitary to release FSH and LH
For females, LH acts on the theca cells to produce androgens
FSH acts on the granulosa cells to convert the androgens to oestrogens
In the luteal phase you have progesterone being produced
In men LH acts on the Leydig cells to produce testosterone
FSH acts on the Sertoli cells to convert testosterone to oestrogens? OR FSH acts on Sertoli cells to regulate spermatogenesis
