Hypothalamic/Pituitary/Gonadal Axis I Flashcards
What are the requirements needed for successful reproduction to occur?
- Correct process of sex determination (genotypic sex) and
differentiation (phenotypic sex) - Sexual maturation - Puberty
- Production and storage of sufficient supply of eggs &
sperm - Correct no. of chromosomes in egg and sperm
- Actual sexual intercourse!
- Fertilisation, implantation, embryonic and placental
development - Once delivered, to nurture individual until capable of
“independent” life
Why is sexual intercourse required for fertilisation?
Egg & sperm have to be transported and meet
How can fertilisation occur without intercourse?
Fertilisation can occur without sexual intercourse (e.g. IVF and other assistive reproductive treatments)
What is the master controller of Reproduction?
Master Controller of Reproduction
What hormones control gonadal function?
Gonadal function is controlled by negative feedback by:
- Hypothalamic & pituitary peptide hormones
- Gonadal steroid (and peptide) hormones
What are the hormones of the HPG axis originating in the hypothalamus?
Hypothalamus (RH) (hypothalamic hormones)
- Gonadotrophin Releasing Hormone (GnRH) and
(kisspeptin)
What are the pituitary hormones involved in the HPG axis?
Anterior Pituitary (SH) (peptide hormones)
- Follicle Stimulating Hormone (FSH) and Luteinising
Hormone (LH)
What gonadal hormones take part in the reproductive HPG axis?
Gonad (steroid hormones)
- (F) Oestradiol (E2), Progesterone (P4), (M) Testosterone,
(Inhibin and activin)
Outline how the reproductive hormones of the HPG axis aid reproduction?
- Positive drive for GnRH from hypothalamus
- GnRH acts on gonadotroph cells of anterior pituitary
- Gonadotroph cells synthesis LH and FSH
- LH & FSH bind and act on their gonadal receptors
- Gonads secrete oestrogen, progesterone and
androgens which feedback to the anterior pituitary and
hypothalamus in a negative fashion
When does positive feedback occur in the reproductive HPG Axis?
Positive feedback occurs during ovulation in females due to oestrogen triggering an LH surge
What is the significance of the reproductive HPG Axis?
Ultimate coordination of gonadal function to facilitate viable gamete production (male), growth and development
What is the hypothalamic-hypophyseal portal system?
This is a network of blood vessels transporting GnRH from hypothalamus to anterior pituitary `
Why is there such a large number of neurons in the hypothalamus?
The hypothalamus has many functions ∴ has many different neurons secreting various hormones
How is GnRH found in the hypothalamus?
Within the hypothalamus there are a series of GnRH neurons that produce and secrete GnRH into the hypothalamic-hypophyseal circulation
How does GnRH move along the HPG axis?
GnRH crosses the primary plexus first and moves to the secondary capillary complex where it comes into contact with the gonadotroph cells in the anterior pituitary
What is the effects of GnRH binding to its receptor?
Once GnRh binds to the GnRH receptors in the anterior pituitary, LH and FSH can be synthesised
What is kisspeptin?
Kisspeptin is a G-protein coupled receptor ligand for GPR54
Where is kisspeptin expressed?
Hypothalamic expression - ARC and AVPV nuclei
Upstream of GnRH
What is the role of kisspeptin in HPG axis?
Kisspeptin neurons send projections to GnRH neurons, and bind to GPR54 / KISS1 receptor (kisspeptin receptor) expressed on GnRH neurons
Describe the structure of kisspeptin
Kisspeptin is expressed as a preproprotein that undergoes proteolytic cleavage into Kisspeptin-54 (Metastin as its a tumour suppressor)
Kisspeptin-54 undergoes further cleavage into kisspeptin 14, 13 & 10
Where is GnRH secreted form?
Synthesised and secreted from ~1000 GnRH neurons primarily in the arcuate nucleus
How is GnRH secreted in the hypothalamus?
Secreted in a pulsatile fashion - pulse generator orchestrated
What is the role of GnRH in the reproductive HPG Axis?
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
Describe the structure of GnRH?
GnRH is also synthesised as a preproprotein and then cleaved into a simple decapeptide.
It’s also secreted along with a GnRH Associated Protein (GAP)
How often is GnRH secreted form the hypothalamus?
GnRH is secreted in pulses from hypothalamus every 30-120min
What does a GnRH pulse stimulate?
A GnRH pulse stimulates a pulse of LH and FSH secretion from the anterior pituitary
Pulsatile GnRH secretion is vital for stimulation of LH/FSH secretion
What effect does GnRH pulsatile frequency have on the HPG axis?
Slow frequency pulse favours FSH release, rapid pulse frequency favours LH
Continuous release results in cessation of response
How do we exploit GnRH therapeutically?
take advantage of the pulsatile nature
What is the structure of synthetic GnRH?
same structure as endogenous GnRH
How is synthetic GnRH administered in patients?
pulsatile administration through a pump for a stimulatory effect
Which patients are given synthetic GnRH?
Stimulatory for patients undergone pubertic delay or with GnRH mutations
What are the therapeutic uses of GnRH?
Synthetic GnRH GnRH analogues (more common)
What is the structure of GnRH analogues?
modified GnRH peptide structure
What does single bolus dose mean?
A bolus is a single, large dose of medicine
How are GnRH analogues administered?
Single bolus as it has a longer half life so binds to the receptor longer
What is the advanatge of having a longer GnRH half life
Endogenous half life is ~2-4 mins
Alter GnRH analogues to extend half life - gives higher receptor affinity
What are the effects of GnRH analogues?
loss of pulsatility
What effect does a loss of pulsatility have on the HPG axis?
shuts down HPG axis (good as prevents production of hormones aiding proliferation of cancer and IVF stimulation protocols) 🡪 Inhibitory
What is the function of GnRH agaonists?
GnRH agonists bind to GnRH receptor causing an initial flare of GnRH activity, increasing release of LH/FSH
HPG axis suits down shortly afterwards
What are the effects of GnRH antagonists?
Bind to receptor and block the receptor ∴no activity
Outline the normal GnRH response in the HPG axis
- Binding to GnRH receptors
- Activation of signalling (FSH & LH)
- Stimulation of gonadotrophin synthesis and secretion
- Dissociation of GnRH from GnRHR
- GnRHR responsive to next GnRH pulse
Describe the step by step activity of a GnRH agonist in the HPG axis
- Binding to GnRH receptors
- Activation of signalling (FSH & LH)
- Stimulation of gonadotrophin synthesis and secretion
- Uncoupling of GnRHR from G protein signalling
- GnRHR non-responsive to GnRH
Outline the effect on the step by step effect on HPG axis of a GnRH antagonist
- Binding to GnRH receptors
- Blockage of receptor
- No downstream effects
What are the clinical areas GnRH is used?
- Ovulation induction and IVF
- Prostate cancer
- ER+ breast cancer in pre-menopausal women
- GnRHR/GnRH + ovarian and endometrial cancers
How is GnRH therapeutics used in IVF and ovulation induction?
Very lucrative industry: 2 billion USD
Use GnRH and GnRH analogues to shutdown HPG axis so menstrual cycle can be manipulated without interference from the HPG axis
Patient initially given doses of GnRH analogues - shutting down HPG axis, uncoupling it from the gonads. Exogenous FSH then administered to stimulate follicle growth
How is Prostate Cancer treated using GnRH therapeutics?
Androgen dependent - involves shutting down HPG axis to deal with cancers
What are the newer hormone related pathologies treated using GnRH?
Endometriosis
PCOS
Uterine fibroids
Outline the effects of GnRH at the pituitary
- Extra hypothalamic input
- Hypothalamic neurotransmitters activated
- GnRH neurons excited
- GnRH synthesised and released
- Extra pituitary input
- Increases gene transcription of α and β-subunits of LH
and FSH - Pulsatile release of FSH and LH
Which subunits form the Gonadotrophin hormones?
LH FSH and hCG contain α-subunits and β-subunits dimerised together to form the hormones
What are the heterodimeric gonadotrophin peptides composed of?
common α-subunit and hormone-specific β-subunit
The α-subunits are the same sequence in FSH, hCG and TSH produced via constitutive pathway
The unique properties are provided by specific β-subunits which is GnRH dependent
What is the role of the N-linked carbohydrate side chains?
N-linked carbohydrate side chains required for biological function
Deglycosylating FSH/LH will cause them to cease to be active
What are the functions of the heterodimeric subunits on their own?
Free subunits have no biological action: α-subunit and β-subunits have no function on their own - have to be dimersied together
How is gonadotrophin hormone production regulated?
α-subunits are synthesized in excess with β-subunit limiting the hormone concentration as its GnRH dependent
What causes the pulsatile release of FSH and LH?
Pulsatile secretion due to pulsatile GnRH release from the hypothalamus but pulsatile secretion not necessary for biological activity
Describe the structure of gonadotrophins
α-subunit is the same and hormone-specific β-subunits have different lengths and sequences
The Y structures are the carbohydrate side chains important for biological activity
What is glycosylation?
The enzymatic process to link saccharides together to form glycans
What is the role of LH in the Testis?
- stimulation of Leydig cell androgen synthesis and
secretion - Leydig cells have LH receptors allowing LH binding to
secrete androgens specifically testosterone
What is LH?
Luteinising hormone
What are the effects of LH in the ovaries?
- theca cells are analogues to the 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 the luteal
phase
Describe the effects of FSH in the testes
Regulation of Sertoli cell metabolism and spermatogenesis through FSH receptor binding
What are the effects of FSH in the ovaries
- follicular maturation: via granulosa cell oestrogen
synthesis - (androgens) testosterone from theca cells cross over into
the granulosa cells where they’re converted into
oestrogens
What are seminiferous tubules?
Seminiferous tubules are the site of germination, maturation, and transportation of sperm cells within the male testes
Describe the structure of seminiferous tubules
Seminiferous tubules are made up of columnar Sertoli cells (FSH receptors) surrounded by spermatogenic cells on the epithelial interior and stem cells exteriorly
Where are leydig cells located in the male gonads?
Interstitial spaces of Seminiferous tubules is where leydig cells are found (LH receptors)
Where are theca cells located in the female gonadal system?
Theca cells line follicle and possess LH receptor secreting androgens
Where are granulosa cells found in the female gonads?
Androgens cross into granulosa cells directly lining the egg
What occurs in the granulosa cells?
Androgens converted into oestrogen via aromatase enzyme
