HPG axis 1

Question 1

What do we need to reproduce?

Answer 1

• correct process of sexual differentiation
• correct number of chromosomes in eggs and sperm
• puberty
• sexual intercourse
• fertilisation and implantation
• correct placenta development

Question 2

what is the hypothalamic pituitary gonadal axis?

Answer 2

hypothalamus -> pit -> gonad

gonadal hormones can feedback to the hypothalamus and pit in a positive or negative way

Question 3

how do gonadal hormones usually feedback to the hyp and pit?

Answer 3

mostly negative feedback, only time its positive is in females during ovulation
-all of the events that coordinate ovulation require positive feedback to occur

Question 4

what does the hypothalamus produce?

Answer 4

Gonadotrophin Releasing Hormone (GnRH)

Question 5

what does the pituitary produce?

Answer 5

Follicle Stimulating Hormone (FSH) and Luteinising Hormone (LH)

Question 6

what do the gonads produce?

Answer 6

-Oestradiol (E2)
-Progesterone (P4)
-(M) Testosterone
(Inhibin and activin)

Question 7

explain how the axis all works

Answer 7

• kisspeptin binds to receptors on GnRH neurons
• Gnrh secreted into the primary plexus of the median eminence, travels via hypophysial portal vein to anterior pituitary where it binds to receptors on gonadotroph cells, coordinating synthesis and secretion of LH and FSH into circulation
• both bind to receptors on the gonads, coordinating synthesis and secretion of oestrogen, progesterone and androgens
• they all feedback in a primarily negative fashion to the hyp and pit
• oestrogen also positively feedbacks, coordinate ovulation

Question 8

what is kiss peptin?

Answer 8

a peptide hormone cleaved from a much larger pre-pro structure into 4 different variants

Question 9

where is kisspeptin expressed?

Answer 9

expressed within 2 different nuclei of the hypothalamus, the ARC and AVPV
ARC = Arcuate Nucleus
AVPV = Anteroventral Periventricular Nucleus

Question 10

what does kisspeptin do?

Answer 10

regulates GnRH production

• kisspeptin neurons project to GnRH neurons
• kisspeptin neurons secrete kisspeptin to its receptor, which is localised to GnRH neurons

Question 11

what is kisspeptin is cleaved into?

Answer 11

metastin - kisspeptin 54, tumour supressor

• proteolytic cleavage to become smaller variants, kisspeptin 13, 14 10
• kisspeptin 54 can be used for in-vitro studies because it can cross the blood brain barrier, and kisspeptin 10 is thought to not do that as well

Question 12

how is GnRH secreted and why is this important?

Answer 12

secreted from GnRH neutrons in the hypothalamus in a pulsatile fashion

• pulsatile secretion is critical for its function
• pulsatility changes through the menstrual cycle, which is why we get differential secretion of LH and FSH
• specialised set of neurons called the pulse generator, orchestrate the change in GnRH pulsatility

Question 13

after GnRH is secreted from the hypothalamus where does it go?

Answer 13

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.

Question 14

what is GnRH co-secreted with?

Answer 14

GAP

GnRH associated peptide, a much larger peptide

Question 15

GnRH structure

Answer 15

really small

-produced from a larger pre-pro protein, which is spliced into a decapeptide

Question 16

what occurs when you don’t give GnRH in a pulsatile fashion, instead a continuous fashion?

Answer 16

• if you don’t give GnRH in a pulsatile fashion, you don’t get LH and FSH production
• giving GnRH continuously results in cessation and shutting down of the HPG axis

Question 17

what does a slow frequency pulse favour?

Answer 17

FSH release

Question 18

what does a rapid frequency pulse favour?

Answer 18

LH release

Question 19

Therapeutic application of GnRH

Answer 19

Synthetic GnRH

GnRH analogues

Question 20

Synthetic GnRH

Answer 20

• same structure as endogenous GnRH
• pulsatile administration, stimulatory
• allows people who lack GnRH to undergo normal puberty

Question 21

GnRH analogues

Answer 21

• modified GnRH peptide structure
• single bolus, long half life, loss of pulsatility
• inhibitory
• sit on the GnRH receptor and cause it to downregulate, useful if we want to shut down the system
• agonists and antagonists

Question 22

2 types of GnRH analogues and how they work

Answer 22

agonists and antagonists - both have the same end result of shutting down the HPG axis

• antagonists block the GnRHr and there are no further downstream effects
• agonists take longer to down regulate, binding of the agonist to the receptor causes gonadotrophin synthesis and secretion, but then GnRHr uncouples from g-protein signalling, so GnRHr is unresponsive to next pulse of GnRH

Question 23

clinical uses of GnRH and GnRH analogues

Answer 23

cancer

• ovarian
• prostate, tends to be androgen dependent, so shutting down the HPG axis is really important for killing androgens present and restricting cancer growth

Question 24

Gonadotrophin hormone (LH, FSH hCG) structure

Answer 24

• 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, β-subunit limits the hormone concentration

Question 25

the beta subunits are regulated by?

Answer 25

GnRH production

Question 26

which subunit is common to all 3 hormones?

Answer 26

alpha

Question 27

what do the beta subunits undergo?

Answer 27

differential glycosylation

-enzymatic process to link saccharides together to form glycans

Question 28

function of LH in testis and ovary?

Answer 28

• Testis:
- stimulation of Leydig cell androgen synthesis
• Ovary:
- theca cell androgen synthesis
- ovulation
- progesterone production of corpus luteum

Question 29

function of FSH in testis and ovary?

Answer 29

• Testis:
	- regulation of Sertoli cell metabolism
• Ovary: 
	- follicular maturation
	- granulosa cell estrogen synthesis

(the actions of FSH and FSH receptor actually regulate the transcription and translation of aromatase)