Hypothalamic / pituitary / gonadal axis

Question 1

What do we need to reproduce?

Answer 1

• Correct process of sex determination + differentiation
• Sexual maturation - puberty
• Production and storage of sufficient supply of eggs + sperm
• Correct number of chromosomes in egg + sperm
• Actual sexual intercourse - egg + sperm transported + meet
• Fertilisation, implantation, embryonic + placental development
• Once delivered, to nurture individual until capabale of ‘independent’ life

Question 2

In the HPG axis, what type of hormones do the hypothalamus and pituitary release?

Answer 2

Peptide

Question 3

What type of hormones does the gonad release?

Answer 3

Steroidal mainly (some peptide)

Question 4

What is the ‘master controller of reproduction’ hormone released by the hypothalamus? What is this hormone controlled by?

Answer 4

Gonadotrophin Releasing Hormone (GnRH) - controlled by kisspeptin.

Question 5

Which hormones are released by the anterior pituitary?

Answer 5

FSH and LH

Question 6

What hormones does the gonad release (male and female)?

Answer 6

F - Oestradiol, Progresterone

M - Testosterone

Question 7

Which peptide hormones that are released from the gonad, directly regulate FSH production?

Answer 7

Inhibin + activin

Question 8

How does GnRH reach the anterior pituitary and what result does it exert?

Answer 8

• Various neural inputs (kisspeptin) stimulate GnRH neurones
• GnRH released into primary plexus
• Travel to anterior pituitary
• Bind to GnRH receptors on gonadotroph cells of anterior pituitary
• FSH and LH produced + secreted into circulation

Question 9

Describe the peptide structure of GnRH

Answer 9

Decapeptide (10 AA) -> quite tiny

Question 10

Where is GnRH released from?

Answer 10

The GnRH neurones, located in arcuate nucleus (of hypothalamus)

Question 11

What is meant by the ‘pulsatility’ within the HPG axis?

Answer 11

• GnRH secreted in a pulsatile fashion from hypothalamus - pulse generator orchestrated
• GnRH pulse stimulates pulse of secretion of LH and FSH from ant pit
• Pulsatile GnRH secretion = vital for stimulation of LH/FSH secretion
• Slow freq pulse favours FSH, rapid pulse freq favours LH
• Continuous release results in cessation of response

Question 12

What is the difference between gonadotrophs and gonadotrophins?

Answer 12

• Gonadotrophs – cells in anterior pituitary that synthesise and secrete LH and FSH in response to GnRH
• Gonadotrophins – LH and FSH stimulate the ovary and testis

Question 13

What is the difference between synthetic GnRH and GnRH analogues?

Answer 13

• Synthetic GnRH - same structure as native GnRH -> stimulatory
• GnRH analogues - modified GnRH peptide structure, loss of pulsatility -> inhibitory - they are either agonists or antagonists

Question 14

What is the mechanism of action of GnRH at the GnRH receptor?

Answer 14

• Binding to receptor
• Activation of signalling
• Stimulation of gonadotrophin synthesis + secretion
• Dissociation of GnRH from GnRHR
• GnRHR responsive to next GnRH pulse

Question 15

How is the mechanism of a GnRH agonist different to GnRH itself?

Answer 15

• Agonist binds to receptor in same way and does activation and stimulation of gonadotrophin synthesis + secretion too
• BUT then… uncoupling of GnRHR from G-protein
• leaves GnRHR non-responsive to GnRH

Question 16

How do GnRH antagonists act at the receptor?

Answer 16

• Bind to receptor
• Block receptor
• No downstream effects

Question 17

What are important clinical uses of GnRH analogues?

Answer 17

• Ovulation induction + IVF
• Prostate cancer
• Estrogen responsive breast cancer in pre-menopausal women
• Ovarian + endometrial cancers
• Gonadal protection (prior to chemo)
• Uterine fibroids
• Endometriosis
• PCOS

Question 18

What is the basic structure of the gonadotrophin hormones (LH, FSH, hCG)?

Answer 18

• Hereodimeric peptides
• Common alpha-subunit + hormone specific beta-subunit

Question 19

In gonadotrophin hormone structure, what determines biological function?

Answer 19

The microheterogeneity due to the N-linked carbohydrate side chains (+ O linked in hCG) - this is glycosylation which is necessary.

Question 20

Which of alpha or beta subunits are synthesised in excess in gonadotrophin hormones?

Answer 20

Alpha are in excess

Beta-subunits limit the hormone concentration

Question 21

Does biological activity depend on pulsatile secretion of gonadotrophins?

Answer 21

No, pulsatile secretion not necessary - eg doesn’t occur in IVF which works

Question 22

What link does nutritional status have with the HPG axis in terms of gonadotrophin concentrations?

Answer 22

In underweight paitents, the LH and FSH levels are dramatically decreased as well as frequency being decreasd.

Question 23

What is the function of LH in males?

Answer 23

Stimulation of Leydig cell in testes -> androgen synthesis

Question 24

What is the function of LH in females?

Answer 24

Act at ovary:

• > theca cell androgen synthesis
• > ovulation
• > progesterone production of corpus luteum

Question 25

What is the function of FSH in males?

Answer 25

Testis -> regulation of Sertoli cell metabolism (key for spermatogenesis)

Question 26

What is the function of FSH in females?

Answer 26

Ovary:

• > follicular maturation
• > granulosa cell oestrogen synthesis

Question 27

Summary of female and male HPG axis

Answer 27