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Science of reproduction > HPG axis > Flashcards

HPG axis Flashcards

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1
Q

What is key in the HPG axis?

A
  • Negative and positive feedback
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2
Q

Give a brief summary of feedback in the HPG

A
  • Hypothalamus releases GNRH
  • that affects gonadotroph cells which release FSH and LH
  • They act on the gonads and then release steroid hormones (progesterone, oesterone, tostesterone)
  • The hormones feedback to the pituitary and hypothalamus
  • In men feedback is always negative, in women it’s mostly negative except for when there’s a LH surge
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3
Q

Where are the GnRH neurones in the hypothalamus expressed?

A

GnRH neurones in the hypothalamus are expressed in 2 locations:

  • arcuate nucleus
  • the medial preoptic nucleus
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4
Q

What is the hypophyseal portal system?

A
  • Network of blood vessels that connect the hypothalamus and the anterior pituitary.
  • It allows GnRH to move to the gonadotroph cells in the anterior pituitary
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5
Q

What happens after GnRH is made in the hypothalamus?

A
  • The neurones synthesis and secrete GnRH

- It makes it way from the medial eminence to the anterior pituitary by hypophyseal portal system

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6
Q

What is kisspeptin?

A
  • ‘gatekeeper of puberty’
  • Controls synthesis and secretion of GnRH in GnRH neurons.
  • Upstream of GnRH.
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7
Q

Where is kisspeptin expressed?

A

In the hypothalamus in:

  • The arcuate nucleus (ARC)
  • The anteroventral periventricular nucleus (AVPV)
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8
Q

What is the kisspeptin gene?

A

Kiss1

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9
Q

What is the kisspeptin receptor?

A

GPR54/KISS1R

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10
Q

What is kisspeptin expression regulated by?

A

Gonadal steroids - oestrogen and progesterone

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11
Q

What is kisspeptin initially synthesised as?

A

A prepro-protein

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12
Q

How is the original prepro-protein modified to become kisspeptin?

A
  • It undergoes proteolytic cleavage (makes kisspeptin 54)

- cthen undergoes more cleavage to be made into different types of kisspeptin (kp-14, kp-15, kp-10)

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13
Q

Which kisspeptin is used in in-vivo studies?

A
  • Kp-54

- crosses the blood brain barrier easily

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14
Q

Which kisspeptin is used in in-vitro studies?

A

Kp-10

  • very active ligand of the GPR54 receptor
  • cheaper to make
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15
Q

Where is the kisspeptin receptor expressed?

A

On GnRH neurones

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16
Q

What can inactivating mutations of KISS1R and Kisspeptin do?

A

Lead to failure to undergo spontaneous puberty

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17
Q

What does early activation of KISS1R lead to?

A

precocious puberty

18
Q

How does KISS1 regulate GnRH secretion?

A
  • 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.
  • May be differences due to the fact mice are a different species
19
Q

How is GnRH mediated by sex steroids?

A
  • Sex steroids made the by the gonads
  • Sex steroids mediate their negative feedback via the kisspeptin neurones on the arcuate nucleus
  • This cases GnRH to be downregulated and the expression of LH and FSH is also downregulated
20
Q

What does the LH surge do?

A
  • Switch the negative feedback to positive
  • The positive feedback is mediated via the kisspeptin neurones in the AVPV
  • This leads to the upregulation of GnRH
21
Q

Where is GnRH synthesised and secreted from?

A
  • Synthesised and secreted from specialised neurons of hypothalamus- GnRH neurons.
  • Secreted in a pulsatile fashion - pulse generator orchestrated.
22
Q

What does GnRH do?

A
  • It stimulates the synthesis and secretion of pituitary gonadotrophin hormones (LH and FSH) from the pituitary
23
Q

What is the structure of GnRH?

A
  • Initially synthesised as a prepro-protein

- It’s then cleaved into a 10 amino acid protein and GAP (GnRH associated protein)

24
Q

How is GnRH secreted?

A

In pulses from hypothalamus every 30 - 120 mins

25
Q

What do slow pulses of GnRH do?

A

Slow pulses favour FSH-beta transcription and FSH release

26
Q

What do fast pulses of GnRH do?

A

Fast pulses favour LH-beta transcription and LH release

27
Q

What does continuous release of of GnRH do?

A

Leads to cessation of response - HPG axis shuts down

28
Q

What is the GnRH pulse generator?

A
  • A sub-population of Arcuate Nucleus Kisspeptin Neurons (ARNKISS)
  • ARNKISS 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
  • However this study was done in mice
29
Q

What is the mode of GnRH action?

A
  • GnRH binds to its receptor
  • That leads to signal transduction
  • That leads to expression of LH and FSH beta genes and the production of FSH and LH
30
Q

What are the gonadotrophin hormones?

A

LH, FSH and hCG

31
Q

What is the structure of FSH and LH?

A
  • They are both glycoprotein hormones and have a sugar residue attached
  • They are heterodimeric: made of an alpha and a beta sub-unit held together by a disulphide bond
  • FSH and LH have the same alpha subunit but the beta subunit is different gives them their distinct properties and function
  • The type of glycosylation also gives them their unique properties
32
Q

What is the structure of gonadotrophin receptors?

A
  • Characterised by their large extracellular region with the amide part: this is where FSH and LH bind
  • Are transmembrane
  • Have an intracellular part which contains the -COOH tail
33
Q

Where does FSH act?

A
  • On the testis: regulates the Sertoli cell metabolism

- On the ovaries: matures follicles and acts on the granulosa cells for oestrogen synthesis

34
Q

Where does LH act?

A
  • On the testis: stimulates androgen synthesis in the Leydig cells
  • On the ovaries: stimulates androgen synthesis in theca cells
  • causes ovulation
  • causes progesterone production of the corpus luteum
35
Q

What are steroid hormones?

A
  • Progesterone
  • Oestrogens: Oestradiol and oestrone
  • Androgens: Androstenedione, testosterone and dihydrotestosterone
36
Q

Describe male gonadal steroid production.

A
  • In the region between tubules (the interstitial region) the Leydig cells express LH receptor.
  • Through this receptor LH modulates the production of androgens (DHEA, testosterone etc)
  • Inside the tubules are Sertoli cells. Sertoli cells have FSH receptors
  • FSH modulates Sertoli cell metabolism which is crucial for spermatogenesis. It is also needed for concentration of testosterone turning into DHT
37
Q

Describe female gonadal steroid production

A
  • Theca cells are on the lining of the mature antral follicle and they express LH receptors
  • LH binding to the LHr produces testosterone/androstenedione.
  • Cells that surround the oocyte are granulosa cells and they express FSH receptors
  • FSH/FSHr binding modulates the conversion of the androgens made in the theca cells into oestrogens through the help of aromatase
38
Q

What does the corpus luteum express and produce in the luteal phase?

A
  • Expressed both LH and FSH in the luteal phase

- Produces both progesterone and oestrogen

39
Q

What is inhibin?

A
  • A peptide hormone
  • A heterodimer
  • Has 2 isoforms: A and B
  • Made in the gonads
40
Q

What does inhibin do?

A

It inhibits FSH secretion via direct negative feedback to the anterior pituitary

41
Q

What isoform of inhibin do men and women produce?

A
  • Males only make inhibin B

- With females the inhibin depends on the menstrual cycle

Science of reproduction (32 decks)

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