REPRO: Hypothalamic/Pituitary/Gonadal Axis I Flashcards
Practically, 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 and sperm
- sexual intercourse, where the egg and sperm have to be transported and meet
- fertilisation, implantation, then embryonic and placental development
- once delivered, we need to nurture the individual until it is capable of ‘independent’ life
The HPG axis is known as the master controller of reproduction.
How does it control it?
Gonadal function is controlled by feedback by:
- the hypothalamic and pituitary peptide hormones
- the gonadal steroid (and peptide) hormones
The hypothalamus releases hormones that positively affect the pituitary, which then releases hormones that positively affect the gonads. The gonads then release hormones that, mostly negatively, affect the hypothalamus and pituitary. Thus, their function is controlled.
What are the hormones of the HPG axis?
HYPOTHALAMUS (RH):
- gonadotrophin-releasing hormones (GnRH)
- kisspeptin
PITUITARY (SH):
- follicle-stimulating hormone (FSH)
- luteinising hormone (LH)
GONADS:
- [F] oestradiol (E2)
- [F] progesterone (P4)
- [M] testosterone
- inhibin
- activin
Give a brief overview of the hormones in play in the HPG axis.
The hypothalamus releases GnRH, which acts on the pituitary to coordinate the synthesis and release of LH and FSH. These, in turn, coordinate the secretion of oestrogen, progesterone, and androgens.
These feedback, mostly in a negative manner, back to the hypothalamus and pituitary.
Describe kisspeptin.
- it was recently discovered in 2001
- it’s expressed in two different nuclei in the hypothalamus - ARC and AVPV
- it’s upstream of GnRH (ie. it regulates GnRH production) [paracrine regulation]
- the kisspeptin neurons send projections to GnRH neurons, and bind to GPR54 expressed on GnRH neurons
Describe GnRH.
- it’s synthesised and secreted from GnRH neurons
- it’s secreted in a pulsatile fashion - orchestrated by pulse generators (a special set of neurons)
- it 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
Expand on the importance of pulsatility with LH and FSH release.
- GnRH is secreted in pulses from the hypothalamus 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 pulses favour FSH release, while rapid frequency pulses favour LH release [this occurs via differential pathway activation]
- continuous release results in the cessation of response
Explain the therapeutic exploitation of GnRH.
- SYNTHETIC GNRH - has the same structure as endogenous GnRH
- its pulsatile administration is stimulatory (for fertility)
- allows people who, essentially, haven’t undergone puberty to be able to
- GNRH ANALOGUES - modified GnRH peptide
- has a single bolus, long half-life
- the loss of pulsatility is inhibitory
- can be agonists or antagonists
Describe the mechanism of action of GnRH.
WITH GNRH:
- It binds to the receptor, GnRHR
- It activates the signaling pathway
- It stimulates gonadotrophin synthesis and secretion
- There is then the dissociation of GnRH from the GnRHR
- The GnRHR is responsive to the next GnRH pulse
Describe the mechanism of action of synthetic GnRH and GnRH analogues, as agonists.
WITH AGONISTS:
- It binds to the receptor, GnRHR
- It activates the signaling pathway
- It stimulates gonadotrophin synthesis and secretion
- There is then the uncoupling of GnRHR from G-protein signaling
- GnRHR is now non-responsive to GnRH
Describe the mechanism of action of GnRH analogues, as antagonists.
WITH ANTAGONISTS:
- It binds to the receptor, GnRHR
- It blocks the receptor
- There are no downstream effects
List some clinical uses of GnRH analogues.
- ovulation induction and IVF
- prostate cancer
- GnRHR/GnRH and ovarian and endometrial cancers
- ER+ breast cancer in pre-menopausal women
- endometriosis
- uterine fibroids
- PCOS
Describe the structure of gonadotrophin hormones.
- they’re heterodimeric peptides - with a common α subunit and hormone-specific β subunit
- they are glycoprotein hormones, so the N-linked carbohydrate side chains are required for biological function [free subunits have no biological action]
- α subunits are synthesised in excess with the β limiting the hormone concentration
- pulsatile secretion is due to pulsatile GnRH release from the hypothalamus, but the pulsatile secretion is not necessary for biological activity
What are the functions of LH in the gonads?
In the testis:
- stimulation of Leydig cell androgen synthesis
In the ovary:
- theca cell androgen synthesis
- ovulation
- progesterone production of corpus luteum
What are the functions of FSH in the gonads?
In the testis:
- regulation of Sertoli cell metabolism
In the ovary:
- follicular maturation
- granulosa cell oesterogen synthesis
