Hypothalamic Pituitary Gonadal Axis: 1 Flashcards
Why do we need the HPG Axis?
We need the HPA Axis in order to reproduce
How do we get reproduction?
- Correct process of sex determination (genotypic sex) and differentiation (phenotypic sex).
- Sexual maturation- Puberty
- Production and storage of enough supply of eggs & sperm.
- Correct number of chromosomes in egg and sperm
- Actual sexual intercourse! Egg & sperm have to be transported and meet
- Fertilisation, implantation, embryonic and placental development
- Once delivered, to nurture individual until capable of “independent” life
What controls gonadal function?
Gonadal function is controlled via feedback by:
• Hypothalamic & pituitary peptide hormones.
• Gonadal steroid (and peptide) hormones.
What hormones are released from the hypothalamus?
• Hypothalamus (RH)- Gonadotrophin Releasing Hormone (GnRH), (kisspeptin)
What hormones are released from the pituitary gland?
• Pituitary (SH)- Follicle Stimulating Hormone (FSH) and Luteinising Hormone (LH)
What hormone is released from the gonads?
• Gonad- (F) Oestradiol (E2), Progesterone (P4), (M) Testosterone, (Inhibin and activin).
Give an overview of the HPA axis
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Always negative in males, only positive in females during ovulation.
Needed for gamete production.
Kisspeptin acts upstream of GnRH.
Label the Hypothalamic-hypophyseal portal system
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How are LH and FSH released from the anterior pituitary?
- Kisspeptin neurones secrete kisspeptin. This causes GnRH neurones to produce GnRH.
- This then passes through a network of blood vessels till the anterior pituitary to produce FSH and LH which make there way to the circulation
When we’re talking about the hypothalamus, we’re talking about specialised neurons within the brain that secrete hormones. The hypothalamus is composed of various nuclei that not only coordinate reproduction but other functions as well such as spermiogenesis, regulation of appetite etc. In terms of reproduction we’re talking about GnRH and Kisspeptin which are localised there.
Where are the kisspeptin neurones expressed?
- ARC = Arcuate Nucleus
2. AVPV = Anteroventral Periventricular Nucleus
Describe the binding of kisspeptin to cause the release of GnRH
• Kisspeptin neurons send projections to GnRH neurons, and binding to GPR54 expressed on GnRH neurons
How is kisspeptin synthesised?
What kisspeptin-54 used for?
What is Kisspeptin-10 used for?
- Kisspeptin is initially synthesised as a preproprotein. It then undergoes proteolytic cleavage t kisspeptin 54
- This undergoes further cleavage to form other forms.
Kisspeptin-54 - for in vivo clinical studies - can cross the blood-brain barrier
Kisspeptin - 10 - used in cell culture studies, cheaper to produce a 10 amino acid protein, it has a high biological activity
Where is GnRH synthesised?
How and where is it secreted?
• Synthesised and secreted from GnRH neurons
- Secreted in a pulsatile fashion-pulse generator orchestrated
- Hypothalamic expression- ARC and MPN (Parvocellular system)
- ARC = Arcuate Nucleus
- MPN = Medial preoptic nucleus
What does GnRH bind to?
• 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.
How is GnRH synthesised?
- GnRH is initially synthesised as a preproprotein before it undergoes proteolytic cleavage
- GAP has similar functions to GnRH
In what fashion is GnRH released?
What does slow and rapid pulse impact?
What does continuous impact the axis?
- GnRH is secreted in pulses from hypothalamus every 30-120min.
- A GnRH pulse stimulates a pulse of LH and FSH secretion from the pituitary.
- Pulsatile GnRH secretion is vital for stimulation of LH/FSH secretion.
- Slow frequency pulse favours FSH release, rapid pulse frequency favours LH.
- Continuous release results in cessation of response.
Why do we have a pulsatile secretion of GnRH?
Need for LH surge during the menstrual cycle and progesterone during the luteal phase. It drives reproductive function via pulsatility
What are the therapeutic applications of GnRH?
Synthetic GnRH – same structure as endogenous GnRH
• pulsatile administration - >Stimulatory
GnRH analogues – modified GnRH peptide structure
• Single bolus, long half life, loss of pulsatility -> Inhibitory
• Agonists or antagonists
Therapeutically, this property (pulsatility) has been harnessed to look at different things.
Describe the mechanism of action synthetic GnRH and GnRH analogues
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What are the clinical uses of GnRH and GnRH analogues?
Ovulation and IVF - 2 billion dollar industry - GnRH analogues are used to shut down the HPG Axis so you can administer LH to stimulate the growth of as many follicles
Treatment of Prostate cancer - cancer is androgen dependant so shutting down the HPG axis reduces androgen secretion
ER and breast cancer
Ovarian and endometrial cancers
Endometriosis
PCOS
Uterine fibroids
What type of peptides are LH and FSH (hCG)?
What side chains do they have?
How are the alpha and beta subunits synthesised?
• 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 with β-subunit limiting the hormone concentration. Alpha are synthesised by a central pathway, coded for by genes. Beta is dependant on GnRH, beta production is dependant on GnRH activity.
What affects the expression of the beta subunit of LH and FSH?
What is crucial for reproduction and what is not?
- Pulsatile secretion of LH and FSH due to pulsatile GnRH release from hypothalamus but pulsatile secretion not necessary for biological activity. The fast pulse of GnRH favours increased expression of the beta subunit of LH, slow pulse of GnRH favours FSH beta. Alpha are unaffected.
- The pulsatile secretion of GnRH is crucial for reproduction, however secretion of LH and FSH is not. GnRH requires pulsatile to function.
Describe the structure of gonadotrophins
- All the alpha subunits are the same
- Beta subunits are off different length, and off different sequence
- They are dimerized, they become active when they come together
- They Y structures are the carbohydrate side chains, that are needed for the biological activity of the gonadotrophin hormones
Describe the study where they looked into the pulsatile activity of GnRH during the follicular phase
- In this study they looked at the pulsatile activity of GnRH during the follicular phase, they drew blood at 20mins, measuring the LH and FSH levels. They saw a constant pulsatile effect across a time period. Showed effect of pulsatile effect of GnRH on the pulsatile secretion of LH and FSH.
- Blood drawn every 20 mins
- The most important hormones from the anterior pituitary that stimulates the gonads are – LH/FSH/hCG
What is Glycosylation?
What does Beta-hCG from developing blastocyst do?
- Glycosylation – enzymatic process to link saccharides together to form glycans. FSH and LH require carbohydrates (CHOs) to be active. In fact, when first tried to make synthetic FSH, couldn’t get it to work because it wasn’t glycosylated.
- Beta-hCG from developing blastocyst – it maintains Corpus Luteum
What does LH do in the gonads?
• Testis:
- stimulation of Leydig cell androgen synthesis
• Ovary:
- theca cell androgen synthesis
- ovulation
- progesterone production of corpus luteum
What does FSH do in the gonads?
• Testis: BIND TO FSH receptors - regulation of Sertoli cell metabolism • Ovary: - follicular maturation - granulosa cell estrogen synthesis
Identify the Leydig cells and Sertoli cells
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Identify the theca cells, granulosa cells and corpus luteum
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Describe the functions of the gonadal steroid hormones
Oestrogens
Oestradiol and also oestrone
Folliculogenesis
Positive feedback triggers ovulation
Androgens
Androstenedione, testosterone, dihydrotestosterone
Spermatogenesis
Progesterone
Prepares the uterus for implantation
Maintains conditions required for the early stages of pregnancy
Describe the female and male HPG axis
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