HPG Axis

Question 1

What is the HPG axis?

Answer 1

Hypothalamus
Pituitary
Gonads

Question 2

Hypothalamus to pituitary

Answer 2

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Question 3

Kisspeptin background (4) 1996-2003

Answer 3

1996 Kiss1 gene discovered
2001 Peptide products (kisspeptins) identified
2001 GPR54 identified and deorphanised (named in numbers all order)
2003 Given role as gatekeeper of puberty

Question 4

Kisspeptin structure

Answer 4

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Question 5

Kisspeptin receptor + role + mutations (GPR54/KISS1R) (4)

Answer 5

• Expressed on GnRH neurons
• Kisspeptin/KISS1R system is a component trigger of puberty.
•Inactivating mutations of KISS1R and Kisspeptin = failure to undergo spontaneous puberty.
• Activating KISS1R mutations can lead to precocious puberty.

Question 6

How does KISS regulate GnRH secretion? - mice explants (4)

Answer 6

• Hypothalamic explants from mice shown kisspeptin administration stimulates GnRH synthesis and secretion.

• Kisspeptin neurons send projections to GnRH neurons, and binding to KISS1R expressed on GnRH neurons.

• A bolus of Kisspeptin correlates with a peak of LH secretion.

• Sexual dimorphic responses - cyclical differences.

Question 7

Kisspeptin-mediated regulation of GnRH

Answer 7

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Question 8

GnRH summarised (3)

Answer 8

• Synthesised and secreted from specialised neurons of hypothalamus-GnRH neurons.
• Secreted in a pulsatile fashion - pulse generator orchestrated.
• Stimulates the synthesis and secretion of pituitary gonadotrophin hormones - LH and FSH.

Question 9

GnRH structure

Answer 9

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Question 10

GnRH pulsatility

Answer 10

• 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 synthesis and secretion of LH/FSH

• Slow frequency pulse favours FSHb transcription and FSH release, rapid pulse frequency favours LHb transcription and LH release

• Continuous release results in cessation of response

Question 11

What is the GnRH pulse generator? (3)

Answer 11

Studies by Clarkson et al. (2017)

Provided evidence for identity of GnRH pulse generator in mice: ARNkiss (Arcuate Nucleus Kisspeptin Neurons)

ARNKISS were all found to exhibit intermittent periods of synchronized electrical activity which had a near perfect correlation with pulsatile LH secretion.

Inhibition of ARNKISS in the mid-caudal region of the arcuate nucleus suppressed pulsatile LH secretion

Question 12

Mode of GnRH action (3)

Answer 12

1)GnRH binding to GnRHR
2) signal transduction
3) gonadotropin gene expression, gonadotropin synthesis, gonadotropin secretion

Question 13

Gonadotropin hormones: LH, FSH, hCG (3)

Answer 13

Glycoprotein hormones
Heterodimeric
Pulsatile

Question 14

Structures on gonadotrophins

Answer 14

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Question 15

Structure of gonadotrophin receptors

Answer 15

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Question 16

Functions of gonadotrophins - (FsH/LH) - both men and women

Answer 16

Follicle-stimulating hormone (via FSHR)
• Testis:
- regulation of Sertoli cell metabolism
• Ovary:
- follicular maturation
- granulosa cell estrogen synthesis

Luteinising hormone (via LHR)
• Testis:
- stimulation of Leydig cell androgen synthesis
• Ovary:
- theca cell androgen synthesis
- ovulation
- progesterone production of corpus luteum

Supports germ cell growth, development and maturation to produce oocyte and sperm competent for fertilisation

Question 17

Steroid hormones (3)

Answer 17

• Progesterone
• Oestrogens: Oestradiol and also oestrone
• Androgens: Androstenedione, testosterone, dihydrotestosterone

Question 18

Male gonadal steroid production

Answer 18

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Question 19

Female gonadal steroid production

Answer 19

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Question 20

Inhibin (6)

Answer 20

• Peptide hormones
• Heterodimers
• 2 isoforms of inhibin: A and B.
• Inhibin = gonadal, inhibits FSH secretion via direct negative feedback to anterior pituitary.
• Males: Inhibin B
• Females: cyclical dependent