HPG Axis 1 Flashcards
Gonadotrophin releasing hormone (GnRH)
A hypothalamic decapeptide hormone, released in a pulsatile fashion that controls the synthesis and secretion of luteinising hormone (LH) and follicle stimulating hormone (FSH) from the anterior pituitary.
Luteinsing hormone (LH):
a heterodimeric gonadotrophin hormone, comprised of a common alpha glycoprotein hormone subunit and hormone specific beta subunit.
LH is synthesised and secreted by the gonadotroph cells of the anterior pituitary. It is released into the portal circulation and binds to its receptor (LHR) on the theca cells of the ovary and Leydig cells of the testis. It is essential for androgen production, and progesterone production.
Follicle stimulating hormone (FSH)
a heterodimeric gonadotrophin hormone, comprised of a common alpha glycoprotein hormone subunit and hormone specific beta subunit. FSH is synthesised and secreted by the gonadotroph cells of the anterior pituitary. It is released into the portal circulation and binds to its receptor (FSHR) on the granulosa cells of the ovary and Sertoli cells of the testis. It is essential for oestrogen production.
Steroid hormones:
Derived from cholesterol, steroid hormones (androgens, oestrogens and progesterone) are produced by the theca and granulosa cells of the ovary and Leydig and Sertoli cells of the testes, by the actions of the gonadotrophin hormones.
Gonadal function is controlled via feedback by:
- Hypothalamic & pituitary peptide hormones.
* Gonadal steroid (and peptide) hormones.
HPG axis Hormones
• Hypothalamus (RH)- Gonadotrophin Releasing Hormone (GnRH),
(kisspeptin)
• Pituitary (SH)- Follicle Stimulating Hormone (FSH) and Luteinising
Hormone (LH)
• Gonad- (F) Oestradiol (E2), Progesterone (P4), (M) Testosterone, (Inhibin
and activin).
Hypothalamus: Kisspeptin (KISS1/kiss1)
- 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 expressed on GnRH neurons
Hypothalamus: 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.
It’s all about 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.
Therapeutic application 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
Mechanisms of action of synthetic GnRH and GnRH analogues
diagram
Clinical uses of GnRH and GnRH analogues
Ovulation induction and IVF Endometriosis GnRHR/GnRH + ovarian and endometrial cancers PCOS Uterine fibroids Prostate cancer ER+ breast cancer in pre-menopausal women
Gonadotrophin hormones: LH, FSH (hCG)
• Heterodimeric peptides – common α-subunit and hormone-specific β-subunit
• N-linked carbohydrate side chains required for biological function
• Free subunits have no biological action
• α-subunits are synthesized in excess with β-subunit limiting the hormone
concentration
• Pulsatile secretion due to pulsatile GnRH release from hypothalamus but pulsatile
secretion not necessary for biological activity
Functions of gonadotrophins
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 estrogen synthesis
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
