Hypothalamic-Pituitary-Gonadal Axis Flashcards
The HPG axis is the axis along which the sex steroids are secreted
Describe the HPG axis
Kisspeptin acts on the hypothalamus, stimulating release of GnRH, a 10 amino acid peptide
The sex steroids negatively feedback into the anterior pituitary and hypothalamus. BUT sustained, high oestrogen levels can cause positive feedback, increasing sex steroid release- occurs in ovulation
What is hypothalamic Kisspeptin?
what is it isolated from, 2 places its expressed, where do its neurones project, how does the GNRH released travel
Kisspeptin gene was isolated from a cancer cell + is expressed in the arcuate + AVPV nucleus
Kisspeptin neurones project to GnRH receptors within the hypothalamus, causing GnRH synthesis and release.
GnRH travels via hypophysial portal vessel –> anterior pit and binds to gonadotroph cell receptor –> prod. LH & FSH
structure of Kisspeptin:
what is it translated as initially + then cleaved into?
what is characteristic of all Kisspeptin Peptides + why is this useful?
Kisspeptin is translated as a biologically inactive intermediate of 145 amino acids, which is cleaved to 4 biologically active peptides
All Kisspeptin peptides has a C-terminal region containing an Arh-Phe-NH2 motif from the RF-amide peptide family
This allows them to fully activate the KISS1 receptor on GnRH neurones
Describe the srtucture of GnRH: how is it secreted, what coordinates its release
What is the structure of the remaining peptide?
GnRH is secreted as a larger peptide, despite the active peptide being just 10 aa long
The signal peptide coordinates GnRH release from Golgi ap. and its secretion from the cell
The remaining peptide= GAP (GnRH Associated Peptide), which is 56 aa long. GAP’s function= maybe prolactin secretion??
Endopeptidases cleave the active 10 amino acid peptide from GAP at the P (processing) site
How is GnRH secreted and what is the importance of this?
How does GnRH release affect LH and FSH release?
GnRH secreted in pulses from hypothalamus every 30-120min
GnRH stimulates pulses of LH and FSH secretion from the anterior pituitary
A slow Hz pulse favours FSH release, fast Hz pulse favours LH release (memory aid- slower to say FSH than LH)
Pulsatile GnRH secretion is vital bc continuous release causes cessation of the response!
What is the effect of synthetic GnRH?
How are they used as agonists or antagonists + why does this work?
Synthetic GnRH also stimulates HPGA if given pulsatile + timed.
GnRH will dissociate from the receptor, & waits for the next GnRH pulse
GnRH analogues (agonist or antagonist) inhibit HPGA: when given continuously (usually as a nasal spray) they downregulate the GnRH pituitary response as they decouple the GPCR from its 2nd messenger system
Antagonists bind to the GnRH receptor and block receptor activation (competitive inhibitors)
Clinical uses of GnRH analogues?
Ovulation induction, IVF
Gonadal protection prior to chemotherapy
Prostate cancer: GnRH analogues suppress testosterone, which slows cancer cell growth
Endometriosis, uterine fibroids,
Oestrogen receptor positive breast cancer in pre-menopausal women: GnRH analogues shut down the HPGA and oestrogen production to help with all of these
Describe the structure of gonadotrophins
2 units they consist of, side chains, secretion
Gonadotrophins= heterodimeric peptides, consist of a common a-subunit and a hormone-specific beta subunit
Alpha subunits are synthesised in excess, w beta subunit production limiting the hormone conc
They have N-linked carbohydrate side chains (O-linked in hCG).
Pulsatile secretion due to pulsatile GnRH release, tho pulsatile secretion not essential for gonadotrophin function
How do gonadotrophins act in the ovary?
FSH promotes follicular maturation.
LH binds to its receptor on theca cells–> androgen synthesis.
FSH binds to its receptor on granulosa cells and induces aromatase, converting androgens to estrogen here.
LH surge caused by sustained high level of oestrogen triggers ovulation. Upon ovulation, the follicle undergoes remodelling forming the CL
CL produces progesterone in response to LH, hCG sustains the CL in pregnancy.
How do gonadotrophins act in the testes?
LH -> Leydig cells - converts progestogens -> testosterone
testosterone stimulate spermatogenesis in Sertoli cells
FSH binds to FSHr on Sertoli cells -> induces aromatase, converting androgens to oestrogen
FSH establishes a quantitatively normal Sertoli cell population, whilst testosterone initiates and maintains spermatogenesis
Compare how gonadotrophins act in the testes vs ovaries
Describe the sex steroids
Estrogen and Progesterone produced by the ovarian follicle
Testosterone produced by testicular Leydig cells
All 3 sex steroids are produced in both sexes and usually provide negative feedback along the HPG axis
EXCEPTION: - Maintained high oestrogen causes positive feedback–> LH surge, which causes ovulation
Gonadal, adrenal and thyroid axes?
