S4: Hypothalamic/Pituitary/Gonadal Axis Flashcards
Describe the hypothalamic/pituitary/gonadal axis
- Hypothalamus - releasing hormone. Gonadotrophin releasing hormone (GnRH) influenced by kisspeptin.
- Pituitary - stimulating hormone. Follicle stimulating hormone (FSH) and Luteinising hormone (LH). These are glycoprotein hormones known collectively as gonadotrophins.
- Gonads - sex steroids. Estradiol (E2) and Progesterone (P4 is made by the ovarian follicle) and are sex steroids. In males, the main sex steroid is Testosterone, though all 3 steroids are produced in both sexes.
Describe history of kisspeptin
The gene for Kisspeptin was isolated from a cancer cell around 1996 in a laboratory located in Hershey, Pennsylvania which is the home of Hershey’s Kisses chocolate factory. Kisspeptin was found to play a role in hypogonadotropic hypogonadism around 2003 and its involvement in the hypothalamic pituitary axis and sexual maturation + puberty was uncovered.
Describe structure of hypothalamic kisspeptin
- Hypothalamic expression in the arcuate nucleus (ARC) & anteroventral periventricular nucleus (AVPV).
- Kisspeptin neurons send projections to GnRH neurons where the kisspeptin receptor is localised causing synthesis and release of GnRH.
- Translated as biologically inactive intermediate prepropeptide of 145aa, which cleaved to four biologically active peptides distinguished on the basis of their number of amino acids.
- All kisspeptin have a C-terminal region that contains an Arg–Phe–NH2 motif characteristic of the RF-amide peptide family, which allows them to fully activate KISS1 receptor.
Hormones anterior lobe of pituitary gland release
- Follicle stimulating hormone FSH and Luteinising Hormone LH
- Thyroid stimulating hormone TSH
- Adrenocorticotropic hormone ACTH
- Growth Hormone GH
- Prolactin PRL
Hormones posterior lobe of pituitary gland release
- Oxytocin OT
- Antidiuretic Hormone ADH
Describe mechanism of kisspeptin on pituitary
- Kisspeptin neurons send projections to GnRH neurons where the kisspeptin receptor is localised causing synthesis and release of GnRH.
- The GnRH neurones (neurosecretory hormones) release GNRH into the median eminence.
- GnRH travels via the hypophysial portal vessel into the anterior pituitary and binds to its receptor on the gonadotroph cells which produce the gonadotrophin hormones LH and FSH.
- LH and FSH are secreted into the blood stream.
Describe GnRH structure
- GnRH secreted as a much larger peptide.
- Co-secreted with the GnRH associated peptide (GAP) 56 amino acids long. Its function is unknown, suggestion of an involvement in prolactin secretion but studies ongoing.
- The signal peptide co-ordinates its release from the golgi apparatus and secretion from the cell.
- The active peptide is only 10 amino acids (decapeptide). In other words, this 10aa GnRH section is the active part of the molecule.
- Endopeptidases cleave at processing site P.
What is the importance of pulsatile GnRH secretion?
- GnRH secreted in pulses from hypothalamus every 30-120min.
- There is a pulsatile signal in the brain that directs the GnRH neurones to secrete - normal of pulses of GnRH releases high levels of gonadotrophin hormones (LH and FSH).
- Slow frequency pulse favours FSH release.
- Rapid pulse frequency favours LH.
- Pulse frequency changes with day and night and phases of the menstrual cycle.
- Pulsatile GnRH secretion is vital, continuous release results in cessation of response.
Describe role and mechanism of synthetic GnRH
Synthetic GnRH has the same structure as native GnRH and the same stimulatory role if given as a pulsatile fashion in the form of a timed pump.
- Given in a nasal inhaler to regulate axis.
- GnRH agonist, if given continuously have the effect of downregulating the GnRH pituitary response as they decouple the G protein coupled receptor from second messenger systems.
Describe role and mechanism of modified analogues
Modified analogues function as antagonists and block the receptor without stimulating a response.
List clinical uses of GnRH analogues
- Ovulation induction and IVF
- ER receptor positive breast cancer in pre-menopausal women
- Endometriosis
- Uterine fibroids
- Prostate cancer
- Gonadal protection prior to chemotherapy
Describe structure of gonadotrophins
- Gonadotrophins are glycoproteins that are dimers with alpha and beta subunit. Heterodimeric peptides have a common a-subunit and a specific b-subunit.
- All gonadotrophs have the same A subunit.
- B subunit is the only difference between LH and FSH.
- There is different glycosylation between the different gonadotrophs that are N-linked carbohydrate side chains in LH and FSH, O linked in hCG. These are required for biological function and may vary through the menstrual cycle.
- Free subunits have no biological action.
- α-subunits are synthesized in excess with β-subunit limiting the hormone concentration.
What produces gonadotrophins?
- LH and FSH produced by anterior lobe of the pituitary gland.
- hCG produced by the embryo.
They all have effects on ovaries or testes (gonads).
How is gonadotrophins released?
Pulsatile secretion due to pulsatile GnRH release from hypothalamus but pulsatile secretion not necessary for biological activity unlike with GnRH.
Describe role of gonadotrophins in ovary
- FSH and LH stimulate growth of ovarian follicle which then responds by making steroids.
- Theca cells on the outside of the granule respond to LH and produces androgens.
- Granulosa cell produces oestrogen from androgens by the enzyme aromatase in reponse to FSH. Follicle therefore produces oestrogen until it hits a critical level causing the pituitary to release a big spike of LH causing ovulation.
- The corpus luteum left behind produces progesterone in response to LH for 2 weeks and then breaks down. However, if the women is pregnant, the corpus luteum will not break down as it is rescued by hCG (produced by embryo).
