Hypothalamic-Pituitary-Gonadal Axis

Question 1

What characteristics are required for reproduction?

Answer 1

• correct sex determination
• sexual maturation (puberty)
• production + storage of gametes
• correct chromosome no.
• sexual intercourse

Question 2

How is gonadal function regulated?

Answer 2

Via negative feedback from hypothalamic an dpituitary hormones on the HPG axis
- gonadal steroids too

Question 3

Name the hypothalamic (releasing hormones)

Answer 3

GnRH: Gonadotrophin releasing hormone

Kisspeptin

Question 4

Name the peptide hormones of the anterior pituitary

Answer 4

FSH: follicle-stimulating hormone
LH: Lutenising hormone

Question 5

What are the steroid gonadal hormones ?

Answer 5

E2 - oestradiol
P4 - progesterone

Testosterone, Inhibn and activin

Question 6

Outline the mechanisms of the HPG axis

Answer 6

1. +ve drive for GnRH from hypothalamus
2. GnRH acts on gonadotroph cells of anterior pituitary
3. Gonadotroph cells synthesis LH and FSH
4. LH & FSH bind + act on gonadal receptors
5. Gonads secrete E2, P and androgens which -vely feedback to anterior pituitary and hypothalamus

Question 7

When does +ve feedback occur on the HPG axis?

Answer 7

Positive feedback occurs during ovulation in females due to oestrogen triggering an LH surge

Question 8

How do hypothalamic hormones reach the anterior pituitary?

Answer 8

via the hypothalamic-hypophyseal portal system

Question 9

How many neurons does the hypothalamus contain?

Answer 9

The hypothalamus has many functions ∴ has many different neurons secreting various hormones

Question 10

What produces GnRH?

Answer 10

Within the hypothalamus there are a series of GnRH neurons that produce and secrete GnRH into the hypothalamic-hypophyseal circulation

Question 11

What is the hypothalamic-hypophyseal portal system ?

Answer 11

Network of blood vessels transporting GnRH from hypothalamus to anterior pituitary

Question 12

Describe the route of GnRH across hypophyseal circulation

Answer 12

Crosses primary plexus first
Moves to secondary capillary complex where it comes into contact with gonadotroph cells in anterior pituitary

Once GnRH binds to its receptors in anterior pituitary, LH and FSH can be synthesised

Question 13

When was kisspeptin discovered?

Answer 13

Recently discovered- 2001- gatekeeper of puberty

Question 14

Where is kisspeptin expressed?

Answer 14

Hypothalamic expression - ARC and AVPV nuclei

Upstream of GnRH

Question 15

What is the role of kisspeptin neurons?

Answer 15

Kisspeptin neurons send projections to GnRH neurons, and binding to GPR54 / KISS1 receptor (kisspeptin receptor) expressed on GnRH neurons

Question 16

Describe the post-traslational modifications that kisspeptin undergoes

Answer 16

1. Kisspeptin expressed as a preproprotein
2. Undergoes proteolytic cleavage into Kisspeptin-54
   - (Metastin as its a tumour suppressor)
3. Kisspeptin-54 further cleaved into kisspeptin 14, 13 & 10

Question 17

Describe the secretion of kisspeptin

Answer 17

Secreted in a pulsatile fashion every - pulse generator orchestrated

Question 18

What is the role of kisspeptin?

Answer 18

Binds to GnRHr on gonadotroph cells of ant.pit.

Stimulates synthesis + secretion of LH + FSH.

Question 19

How is GnRH modified?

Answer 19

GnRH also synthesised as a preproprotein and cleaved into a simple decapeptide.

Also secreted along with a GnRH Associated Protein (GAP)

Question 20

Describe the pulsatility of GnRH

Answer 20

Secreted in pulses from hypothalamus every 30-120min

- stimulates pulsatile LH/FSH release from ant.pit.

Question 21

What is the significance of pulsatile GnRH release?

Answer 21

Pulsatile GnRH secretion is vital for stimulation of LH/FSH secretion
Continuous release results in cessation of response

Question 22

How odes the pulsatile frequency affect gonadotropin release?

Answer 22

Slow frequency pulse favours FSH release

Rapid pulse frequency favours LH

Question 23

Describe the structure of synthetic GnRH

Answer 23

same structure as endogenous GnRH

Question 24

What is the use of synthetic GnRH?

Answer 24

pulsatile administration through pump 🡪 Stimulatory for patients undergone pubertic delay or with GnRH mutations

Question 25

What are GnRH analogues?

Answer 25

More common – modified GnRH peptide structure

Question 26

Why may a GnRH analogue be administered as a single bolus?

Answer 26

Single bolus as it has a longer half life so binds to the receptor longer

Question 27

Why are GnRH analogues modified to have longer half lives?

Answer 27

Endogenous half life is ~2-4 mins | Alter GnRH analogues to extend half life - gives higher receptor affinity

Question 28

Why may GnRH analogues be used to shut down the HPG axis?

Answer 28

Loss of pulsatility: - shuts down HPG axis - good as prevents production of hormones aiding proliferation of cancer and IVF stimulation protocols 🡪 Inhibitory

Question 29

What is the use of GnRH agonists?

Answer 29

GnRH agonists bind to GnRHr causing initial flare of GnRH activity, increasing release of LH/FSH HPG axis shuts down shortly afterwards

Question 30

What is the effect of using GnRH antagonists?

Answer 30

bind to receptor and block the receptor ∴no activity

Question 31

What is a common clinical use of GnRH Analogues?

Answer 31

Ovulation induction and IVF

Question 32

How are GnRH analogues used for IVF?

Answer 32

GnRH and GnRH analogues shutdown HPG axis so menstrual cycle can be manipulated without interference from HPG axis Exogenous FSH then administered to stimulate follicle growth

Question 33

How are GnRH analogues used in prostate cancer?

Answer 33

Androgen dependent - involves shutting down HPG axis to deal with cancers

Question 34

What other treatments involve GnRH analogues?

Answer 34

ER+ breast cancer in pre-menopausal women | GnRHR/GnRH + ovarian and endometrial cancers

Question 35

What are newer hormone pathologies that could use GnRH analogues?

Answer 35

Endometriosis PCOS Uterine fibroids

Question 36

Describe the structure of gonadotrophins

Answer 36

LH FSH and hCG contain α-subunits and β-subunits dimerised together to form the hormones Also have N-linked carb side chains and free subunits

Question 37

Describe the heterodimeric structure of LH/FSH/hCG

Answer 37

Heterodimeric peptides – common α-subunit and hormone-specific β-subunit

Question 38

What provides the unique functions of the gonadotropins?

Answer 38

The unique properties are provided by the specific β-subunits which is GnRH dependent The α-subunits is thought to be produced via constitutive pathway

Question 39

What is the role of the N-linked Carbohydrate side chain of th eognadotropins??

Answer 39

N-linked carbohydrate side chains required for biological function Deglycosylating FSH/LH will cause them to cease to be active

Question 40

What is the role of the free subunits on LH/FSH/hCG?

Answer 40

Free subunits have no biological action: α-subunit and β-subunits have no function on their own - have to be dimersied together

Question 41

Describe the rate of production of the gonadotropin subunits

Answer 41

α-subunits synthesized in excess | β-subunit limits [hormone] as its GnRH dependent

Question 42

What is glycosylation?

Answer 42

The enzymatic process to link saccharides together to form glycans

Question 43

What are the functions of LH in the testis?

Answer 43

Stimulates Leydig cell androgen synthesis and secretion Leydig cells have LHr allowing LH binding = secrete androgens specifically testosterone

Question 44

What is the role of LH in the ovary?

Answer 44

Theca cells are analogues to leydig cells also enabling androgen synthesis and secretion via LH receptors Ovulation: LH surge due to oestrogen positive feedback Progesterone production of corpus luteum: remodelling of ovulated follicle into corpus luteum during luteal phase

Question 45

Describe the role of FSH in the testis

Answer 45

Regulation of Sertoli cell metabolism and spermatogenesis through FSH receptor binding

Question 46

What is the role of FSH on the ovary?

Answer 46

Follicular maturation: via granulosa cell oestrogen synthesis (androgens) testosterone from theca cells cross over into GC where they’re converted into oestrogens

Question 47

What are the seminiferous tubules?

Answer 47

Seminiferous tubules are the site of germination, maturation, and transportation of sperm cells within male testes

Question 48

Describe the structure of seminiferous tubules

Answer 48

Made of columnar Sertoli cells (FSHr) surrounded by spermatogenic cells on epithelial interior and stem cells exteriorly

Question 49

Where do leydig cells reside in the testis?

Answer 49

Interstitial spaces of Seminiferous tubules is where leydig cells are found (LHr)

Question 50

Where on the ovary are theca cells found?

Answer 50

Theca cells line follicle and possess LHr secreting androgens

Question 51

How do androgens move to the egg?

Answer 51

Androgens cross into granulosa cells directly lining the egg

Question 52

How are androgens converted to oestrigens?

Answer 52

Androgens converted into oestrogen via aromatase enzyme