Hypothalamic-Pituitary-Gonadal Axis Flashcards
What characteristics are required for reproduction?
- correct sex determination
- sexual maturation (puberty)
- production + storage of gametes
- correct chromosome no.
- sexual intercourse
How is gonadal function regulated?
Via negative feedback from hypothalamic an dpituitary hormones on the HPG axis
- gonadal steroids too
Name the hypothalamic (releasing hormones)
GnRH: Gonadotrophin releasing hormone
Kisspeptin
Name the peptide hormones of the anterior pituitary
FSH: follicle-stimulating hormone
LH: Lutenising hormone
What are the steroid gonadal hormones ?
E2 - oestradiol
P4 - progesterone
Testosterone, Inhibn and activin
Outline the mechanisms of the HPG axis
- +ve drive for GnRH from hypothalamus
- GnRH acts on gonadotroph cells of anterior pituitary
- Gonadotroph cells synthesis LH and FSH
- LH & FSH bind + act on gonadal receptors
- Gonads secrete E2, P and androgens which -vely feedback to anterior pituitary and hypothalamus
When does +ve feedback occur on the HPG axis?
Positive feedback occurs during ovulation in females due to oestrogen triggering an LH surge
How do hypothalamic hormones reach the anterior pituitary?
via the hypothalamic-hypophyseal portal system
How many neurons does the hypothalamus contain?
The hypothalamus has many functions ∴ has many different neurons secreting various hormones
What produces GnRH?
Within the hypothalamus there are a series of GnRH neurons that produce and secrete GnRH into the hypothalamic-hypophyseal circulation
What is the hypothalamic-hypophyseal portal system ?
Network of blood vessels transporting GnRH from hypothalamus to anterior pituitary
Describe the route of GnRH across hypophyseal circulation
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
When was kisspeptin discovered?
Recently discovered- 2001- gatekeeper of puberty
Where is kisspeptin expressed?
Hypothalamic expression - ARC and AVPV nuclei
Upstream of GnRH
What is the role of kisspeptin neurons?
Kisspeptin neurons send projections to GnRH neurons, and binding to GPR54 / KISS1 receptor (kisspeptin receptor) expressed on GnRH neurons
Describe the post-traslational modifications that kisspeptin undergoes
- Kisspeptin expressed as a preproprotein
- Undergoes proteolytic cleavage into Kisspeptin-54
- (Metastin as its a tumour suppressor) - Kisspeptin-54 further cleaved into kisspeptin 14, 13 & 10
Describe the secretion of kisspeptin
Secreted in a pulsatile fashion every - pulse generator orchestrated
What is the role of kisspeptin?
Binds to GnRHr on gonadotroph cells of ant.pit.
Stimulates synthesis + secretion of LH + FSH.
How is GnRH modified?
GnRH also synthesised as a preproprotein and cleaved into a simple decapeptide.
Also secreted along with a GnRH Associated Protein (GAP)
Describe the pulsatility of GnRH
Secreted in pulses from hypothalamus every 30-120min
- stimulates pulsatile LH/FSH release from ant.pit.
What is the significance of pulsatile GnRH release?
Pulsatile GnRH secretion is vital for stimulation of LH/FSH secretion
Continuous release results in cessation of response
How odes the pulsatile frequency affect gonadotropin release?
Slow frequency pulse favours FSH release
Rapid pulse frequency favours LH
Describe the structure of synthetic GnRH
same structure as endogenous GnRH
What is the use of synthetic GnRH?
pulsatile administration through pump 🡪 Stimulatory for patients undergone pubertic delay or with GnRH mutations
What are GnRH analogues?
More common – modified GnRH peptide structure
Why may a GnRH analogue be administered as a single bolus?
Single bolus as it has a longer half life so binds to the receptor longer
Why are GnRH analogues modified to have longer half lives?
Endogenous half life is ~2-4 mins
Alter GnRH analogues to extend half life - gives higher receptor affinity
Why may GnRH analogues be used to shut down the HPG axis?
Loss of pulsatility:
- shuts down HPG axis
- good as prevents production of hormones aiding proliferation of cancer and IVF stimulation protocols 🡪 Inhibitory
What is the use of GnRH agonists?
GnRH agonists bind to GnRHr causing initial flare of GnRH activity, increasing release of LH/FSH
HPG axis shuts down shortly afterwards
What is the effect of using GnRH antagonists?
bind to receptor and block the receptor ∴no activity
What is a common clinical use of GnRH Analogues?
Ovulation induction and IVF
How are GnRH analogues used for IVF?
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
How are GnRH analogues used in prostate cancer?
Androgen dependent - involves shutting down HPG axis to deal with cancers
What other treatments involve GnRH analogues?
ER+ breast cancer in pre-menopausal women
GnRHR/GnRH + ovarian and endometrial cancers
What are newer hormone pathologies that could use GnRH analogues?
Endometriosis
PCOS
Uterine fibroids
Describe the structure of gonadotrophins
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
Describe the heterodimeric structure of LH/FSH/hCG
Heterodimeric peptides – common α-subunit and hormone-specific β-subunit
What provides the unique functions of the gonadotropins?
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
What is the role of the N-linked Carbohydrate side chain of th eognadotropins??
N-linked carbohydrate side chains required for biological function
Deglycosylating FSH/LH will cause them to cease to be active
What is the role of the free subunits on LH/FSH/hCG?
Free subunits have no biological action: α-subunit and β-subunits have no function on their own - have to be dimersied together
Describe the rate of production of the gonadotropin subunits
α-subunits synthesized in excess
β-subunit limits [hormone] as its GnRH dependent
What is glycosylation?
The enzymatic process to link saccharides together to form glycans
What are the functions of LH in the testis?
Stimulates Leydig cell androgen synthesis and secretion
Leydig cells have LHr allowing LH binding = secrete androgens specifically testosterone
What is the role of LH in the ovary?
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
Describe the role of FSH in the testis
Regulation of Sertoli cell metabolism and spermatogenesis through FSH receptor binding
What is the role of FSH on the ovary?
Follicular maturation: via granulosa cell oestrogen synthesis
(androgens) testosterone from theca cells cross over into GC where they’re converted into oestrogens
What are the seminiferous tubules?
Seminiferous tubules are the site of germination, maturation, and transportation of sperm cells within male testes
Describe the structure of seminiferous tubules
Made of columnar Sertoli cells (FSHr) surrounded by spermatogenic cells on epithelial interior and stem cells exteriorly
Where do leydig cells reside in the testis?
Interstitial spaces of Seminiferous tubules is where leydig cells are found (LHr)
Where on the ovary are theca cells found?
Theca cells line follicle and possess LHr secreting androgens
How do androgens move to the egg?
Androgens cross into granulosa cells directly lining the egg
How are androgens converted to oestrigens?
Androgens converted into oestrogen via aromatase enzyme
