Reproduction: Hypothalamic/Pituitary/Gonadal Axis I Flashcards
What are some of the things that the HPG axis is responsible for/needed for?
- Correct process of sex determination sexual and differentiation
- Sexual maturation - Puberty
- Production and storage of sufficient supply of eggs & sperm
- Produce correct number of chromosomes in egg and sperm
In the HPG axis what hormones are secreted by the hypothalamus?
- Gonadotrophin releasing hormone (GnRH)
- Kisspeptin (newly discovered)
In the HPG axis what hormones are released by the anterior pituitary?
- Follicle stimulating hormone (FSH)
- Luteinising hormone (LH)
In the HPG axis what hormones are secreted by the gonads?
- Ovaries - Oestradiol (E2), Progesterone (P4)
- Testes - Testosterone
Breifly explain how the HPG axis works
- Hypothalamus releases GnRH which binds to the GnRH receptor on the anterior pituitary
- This causes the Gonadtroph cells of the anterior pituitary to produce and then secrete LH and FSH
- LH and FSH then bind to their receptors on the gonads
- This causes the gonads to release Oestrogens, Progesterone and Androgens, e.g. testosterone.
- These hormones then bind to either the hypothalamus or anterior pituitary resulting in negative feedback
What is the one instance in which a hormone released by the gonads leads to positive feedback rather than negative feedback?
During ovulation in females Oestrogen is able to produce positive feedback by causing a surge in LH production by the anterior pituitary
Describe how the Hypothalamic-hypophyseal portal system transports GnRH from the hypothalamus to the anterior pituitary
- GnRH is produced and then released by GnRH neurons in the hypothalamus
- The GnRH then travels from those GnRH neurons to the primary capillary plexus of the hypophyseal portal system
- GnRH travels in the circulation from the primary capillary plexus to the secondary capillary plexus
- Once in the secondary capillary plexus GnRH is able to bind to the GnRH receptors on the anterior pituitary
What is the role of kisspeptin within the HPG axis?
Kisspeptin stimulates the release of GnRH form GnRH neurons in the hypothalamus
How does Kisspeptin stimulate GnRH release from the GnRH neurons?
- Kisspeptin neurons send signals to GnRH neurons
- This reults in the kisspeptin neurons releasing kisspeptin which then binds to kisspeptin receptor (KISS1) on the GnRH neurons
- This results in the activation of the GnRH neurons which eventually leads to the secrtetion of GnRH
In what regions of the hypothalamus is Kisspeptin expressed?
- Arcuate Nucleus (ARC)
- Anteroventral Periventricular Nucleus (AVPV)
Originally kisspeptin is synthesised as prepro-kisspeptin that then undergoes proteolytic cleavage to form Kissppetin. Explain this protelytic cleavage process
- Prepro-kisspeptin is cleaved between amino acid 68 and amino acid 121 to form Kisspeptin-54
- Kisspeptin-54 can be further processed to form Kisspeptin-14; Kisspeptin-13 or Kisspeptin-10.
In what region/s of the hypothalamus are the GnRH neurons located?
- Located mainly in Arcuate nucleus (ARC)
GnRH is also synthesised as a prepro-protein. Explain the catalytic cleaving process for GnRH
- Prepro-GnRH is cleaved to form GnRH which is a decapeptide (10 amino acid peptide)
- Associated with GnRH is a protein called GAP (GnRH-associated protein)
In what way is GnRH released from the GnRH neurons in the hypothalamus?
GnRH is released in a pulsate manner every 30-120 minutes
How does the frequency of pulsatile secretion of GnRH affect LH and FSH secretion?
- Pulsatile GnRH release from hypothalamus stimulates a pulse of LH and FSH secretion from the anterior pituitary
- A slow frequency pulse of GnRH favours FSH secretion
- A rapid frequency pulse of GnRH favours LH secretion
Why is the pulsatile release of GnRH important?
- If GnRH is released continuously it will eventually lead to the cessation of the secretion of FSH and LH from the anterior pituitary
- This is because continous release results in the saturation of the GnRH receptors (GnRHR) on the anterior pituitary which results in gonadatroph cells to stop producing LH and FSH
- Pulsatile relase of GnRH also important because it helps to induce the LH surge from anterior pituitary during ovulation
What are the 2 types of GnRH that are used in therapeutics?
- Synthetic GnRH - same structure as endogenous GnRH
- GnRH analogues - modified GnRH (can be an agonist or an antagonist)
What modifications are done to GnRH to produce GnRH analogues?
- Modified so that GnRH analogues have a much longer half-life than normal GnRH
- Also modified so GnRH analogues have much greater receptor affinity
What is the difference in the way synthetic GnRH and GnRH analogus are administered? What is the reason for this difference
- Syntheric GnRH administered in pulses
- GnRH analogues administered in a single bolus
- This is because GnRH analogues have a much higher receptor affinity than synthetic GnRH so not as much needs to be administered to have the same effect
Both agonist and antagonist GnRH analogues result in the inhibition of GnRH release from the hypothalamus. How do both types of GnRH analogue do this?
- Agonist GnRH analogue binds to GnRH receptor on gonadtroph cells
- This causes them to synthesise and secrete LH and FSH
- Because of the longer half-life the agonist GnRH analouge stays bound to the GnRH receptor
- This eventually causes the receptor to become uncoupled from the rest of the G protein signalling pathway
- This leads to the receptor becoming unresponsive to GnRH
- Antagonist GnRH bins to GnRH receptor on gonadatroph cells
- This binding blocks the GnRH recptor preventing any downstream effects from happening
What are some clinical uses of Synthetic GnRH and GnRH analogues?
- Ovulation induction and IVF
- Control of prostate cancer
- Control of ovarian and endometrial cancers
- Control of breast cancer in pre-menopausal women
What are some characteristics of the Gonadtrophin hormones LH and FSH?
- Heterodimeric peptides – common α-subunit and hormone-specific β-subunit
- Contain N-linked carbohydrate side chains which are required for biological function
- α and β-subunits need to be together to produce biological effects
- α-subunits are synthesized in excess while β-subunit synthesis dependent on GnRH secretion
How is β-subunit synthesis of the Gonadotrophin hormones dependent on GnRH secretion?
- Slow pulsatile release of GnRH results in the synthesis of the FSH β-subunit so FSH is synthesised
- Rapid pulsatile release of GnRH results in synthesis of the LH β-subunit so LH is produced
Is the pulsatile release of FSH and LH important for their biological activity?
- No pulsatile release of LH and FSH not important for biological activity
- This is in contrast to pulsatile release of GnRH which is VERY important for its biological activity
What are the functions of LH in both the testis and the ovaries?
- Testis - LH stimulates androgen synthesis, e.g. testosterone, in the Leydig cells
- Ovaries - Theca cell androgen synthesis
- Ovulation
- Causes remodelling of ovulated follicle into corpus luteum
What are the functions of FSH in both the testis and ovaries?
- Testis - Regulation of spermatogenesis in the sertoli cells as well as regulation of sertoli cell metabolism
- Ovaries - Follicular maturation
- Induces Granulosa cell oestrogen synthesis
In the ovaries what happens to the androgens produced by Theca cells?
- Androgens (mainly testosterone) produced by Theca cells travel to the Granulosa cells
- In the Granulosa cells the Androgens are then converted in Oestrogens via the enzyme Aromatase
In the testis what happens to the Androgens (testosterone) produced by the Leydig cells?
- Androgens produced by the Leydig cells travel to the Sertoli cells
- Once in the Sertoli cells the Androgens get converted into Oestrogens via the Aromatatse enzyme
