GnRH

Question 1

Which gene codes for GnRH

Answer 1

chromosome 8

Question 2

GnRH roles generally speaking (4)

Answer 2

• Neuroendocrine - HPG
• Paracrine (placenta/gonads)
• Autocrine (prostate/breast cancer)
• Neurotransmitter (Regions of the brain)

Question 3

GnRH do not actually originate from hypothalamus but from the..

Answer 3

Olfactory region

Originate outside CNS, in medial olfactory placode

Question 4

Cells migrate from this
Nasal olfactory region to..

Answer 4

brain (specifically medio-basal hypothalamus) whilst responding to a series of genetic cues

Question 5

Issues with cell migration can cause..

Answer 5

hypogonadotrophic hypogonadism

Question 6

From the known mutations causing hypogonadotrophic hypogonadism

Kallmann Syndrome:
1- Mutation in which gene?
2- What happens in terms of migration?
3- What can it cause?

Answer 6

1 - Mutation in KAL-1 gene
2 - Premature termination of migration
3 - Anosmia & Hypogonadotrophic Hypogonadism

Question 7

Anosmia

Answer 7

partial or full loss of smell

Question 8

Hypogonadotrophic Hypogonadism

Answer 8

Hypothalamus or the pituitary gland do not produce the hormones that signal to the testes (in males) or the ovaries (in females) to produce sex hormones.

Question 9

How is GnRH is processed and packaged and where is it transported down?

Answer 9

GnRH is processed and packaged into storage granules that are transported down the axons to the external zone of the median eminence.

Question 10

How is GnRH released?

Answer 10

It is released in synchronized pulses from the GnRH nerve endings into hypophyseal portal system.

Question 11

The GnRH receptor is of two types:

Answer 11

Type 1- full length, Type 2 - missense truncation (humans)

Question 12

what is meant by missense truncation?

(relating to type 2 of the GnRH receptor)

Answer 12

We know that the type II mRNA is expressed, protein and receptor is not translated/expressed.

Question 13

GnRH receptor is resistant

Answer 13

..Resistant to desensitisation

Question 14

GnRH receptor is expressed on..

Answer 14

Expressed on gonadotroph cells of anterior pituitary

Question 15

How does GnRH regulate transcription of FSH and LH

MOST AGREED MODEL

Answer 15

GnRH bind to GnRHR then..

studies showed that if you were to block the ERK1/2 pathway, it is accompanied by LHB transcription and translation

EGR1 is early growth restriction factor

Question 16

High GnRH pulse impact on LH

Answer 16

Upregulation of EGR1 binds to promoter of LHB

Transcripton and Translation of LHB

Question 17

High GnRH pulse impact on FSH

Answer 17

SAME BUT ICER instead of EGR1

ICER (inhibitor) binds to promoter prevents upregulation of FSH.

ICER inhibits activity of CREB - no expression of FSH

Question 18

low GnRH pulse impact on LH

Answer 18

Question 19

low GnRH pulse impact on FSH

Answer 19

Creb is successfully able to bind to the FSHBeta gene promoter. NO icer, creb upregulates FSHBeta transcription

Question 20

♀ GnRH pulses change frequency during menstrual cycle

Answer 20

(1) Early Follicular phase – pulses slow (every 90-120mins) »FSH

(2) Mid-late F phase – pulse freq increases (every hr.) »LH

(3) After ovulation – pulses slow (every 3-5h) »FSH production

(4) End of luteal phase – increase in GnRH pulse secretion » FSH release

Question 21

In MALES:
Testosterone from Leydig cells reduces.. (Rhesus monkey experiments)

Answer 21

reduces LH secretion

Question 22

Inhibin decreases what from the pituitary?

Answer 22

Inhibin decreases FSH secretion from pituitary

Question 23

Activin increases what from the pituitary

Answer 23

Activin FSH secretion from pituitary

Question 24

In FEMALES through most of menstrual cycle:
Progesterone & low plasma oestrogen cause a what?

Answer 24

negative feedback which in turn cause a net effect of reduced LH & FSH

Question 25

High sustained (48h) plasma [E2] =

Answer 25

enhanced LH & FSH positive feedback

Question 26

Progesterone decreases..

Answer 26

↓GnRH pulse freq

Question 27

Oestrogen decreases..

Answer 27

↓GnRH pulse amplitude

Question 28

Where would the site of steroid feedback be?

Answer 28

• Either anterior pituitary or hypothalamus
• Oestrogen & progesterone receptors on anterior pituitary and hypothalamus
• Inhibin receptors found only in pituitary

Question 29

How would this occur? (steroid feedback)

Answer 29

• In anterior pituitary by direct regulation of GnRHR
• In hypothalamus by directly affecting GnRH neurones or indirectly by changing activity of other neural system that influence GnRH release

Question 30

Mechanisms of feedback - Pituitary

Positive feedback?

Answer 30

• E2 induces & maintains GnRHR by increasing GnRHR mRNA in pre-ovulatory phase
• E2 sensitises “self-priming” effect i.e. enhances interaction between GnRH & GnRHR

Question 31

Mechanisms of feedback - Pituitary

Negative feedback?

Answer 31

E2 ??
Inhibin??
- Progesterone ↓ GnRHR mRNA, also evidence of P4 response element in GnRHR gene

Question 32

Mechanisms of feedback - Hypothalamus

Answer 32

• GnRH neurones only express ERβ
• Need ERα for positive feedback
• Erα is crucial for reproductive function
• E2 must act on other afferents that project onto GnRH neurones

Question 33

E2 indirectly stimulates GnRH neurones via other neuronal inputs:

Answer 33

• Kisspeptin
• Other hypothalamic neurotransmitters- e.g.,
• GABAnergic neurons