Lec6 Disorders of Fertilisation Flashcards
What are kisspeptin and KNDy neurons potent stimulators of?
GnRH
What are kisspeptin and KNDy neurons stimulated by?
Oestrogen
Kisspeptin and KNDy neurons cause:
Stimulation of GnRH to drive LH production
Kisspeptin, GnRH and LH are all what?
Pulsatile - every 60-90mins
Where does the first step in ovulation start?
In the Supra Chiasmic Nuclei in the hypothalamus
What is the function of the SCN?
Supra chiasmic nuclei govern the circadian clock that interacts with the kisspeptin neurons and KNDy neurons (neurokinin B and dynorphin)
Where are the kisspeptin neurons located?
The kisspeptin neurons are located in the arcuate nucleus (ARN) and anteroventral periventricular area (AVPV)
Where is GnRH synthesised?
GnRH is synthesised by neurons in the PreOptic Area (POA) which project into the median eminence where they release GnRH into the portal system every 60-90mins
What effect does release of GnRH have?
Anterior pituitary gonadotrophin cells secrete FSH
What effect does the FSH have?
Acts on Primary Follicle Granulosa Cells which produce oestrogen and inhibin
What other effect does FSH have?
Increases the LH receptors on the granulosa cells
What effect does the oestrogen and inhibin secreted by the PFGCs have on FSG
Suppresses FSH secretion - due to negative feedback
What happens when the oestrogen levels gets to a critically high point?
They stimulate Kisspeptin and KNDy neurons again to cause GnRH secretion
What happens this time following GnRH secretion?
LH is produced because of the increased frequency and amplitude of the pulse from GnRH
What is the effect of LH secretion?
LH triggers ovulation, resumption of oocyte meiosis and changes the granulosa cells into luteal cells
What is characteristic of the first half of menstrual cycle?
FSH falls as oestrogen and inhibin rise
at critical level oestrogen stimulates kisspeptin and KNDy neurons
Stimulates secretion of GnRH increased freq and increased amplitude
Increased pulsatile secretion = LH surge
What is characteristic of the second half of the menstrual cycle?
LH converts granulosa cells to luteal cells
Hormone production swaps from oestrogen to progesterone
Progesterone peaks at day 21/ seven days before period
Progesterone, oestrogen inhibin all inhibit FSH and LH
What is used to diagnose ovulation?
Progesterone blood test day 21/ 7 days before period
LH detection urinary kit - from day 10
Transvaginal pelvic ultrasound alternate days from day 10
Name three types of causes of ovulation problems
Hypothalamic
Pituitary
Ovary
Give 4 examples of Hypothalamic causes for ovulation problems
Lack of GnRH due to:
- Kiss1 gene deficiency - rare
- GnRH gene deficiency - rare
- Weight loss/ excessive exercise/ stress
- Anorexia/ bulimia
Give 2 examples of Pituitary causes for ovulation problems
- Pituitary tumour (prolactinoma or other tumour)
2. Post pituitary surgery/ radiation
Give 2 examples of Ovarian causes for ovulation problems:
- Premature Ovarian insufficiency
- Genetic/ developmental e.g. Turners Syndrome
- Autoimmune damage/ destruction of ovaries
- Cytotoxic/ radiotherapy
- Surgery - Polycystic Ovarian Syndrome - commonest cause
What is Hirsutism?
Androgen dependent hirsutism
excess body hair in a male distribution
What is the triad of symptoms usually used to diagnose PCOS?
Androgen excess
Oligomenorrhoea
Polycystic Ovaries
but only need 2 of these to diagnose PCOS
What are the clinical features of PCOS?
Androgen excess- hirsutism/acne
Oligomenorrhoea - less than 9 periods a year, subfertility
Obesity - but 25% are “lean”
Metabolic disturbances are often seen in these pts
What is the underlying problem in PCOS?
Insulin resistance
What is the effect of high insulin on granulosa cells?
High insulin and high androgens cause the granulosa cells to become less functional
- secrete less oestrogen
- follicle arrests
What is the effect of high insulin on theca cells?
High insulin causes increased LH secretion which causes theca cells to produce excess androgens
What are the hormonal abnormalities in PCOS?
Raised LH:FSH ratio - 3:1
Raised androgens and free testoserone
Reduced SHBG (SHBG is decreased by testosterone so increased levels of free testosterone = reduced SHBG)
Oestrogen usually low but could be normal
What is the relationship of PCOS and metabolic syndrome?
Reduced insulin sensitivity - increased insulin
causes:
Increased androgen production by theca cells
Reduced SHBG production by the liver
Increased risk of GDM and type 2 diabetes
Dyslipidaemia
Increased risk of CVD
What is the relationship between PCOS and endometrial cancer?
The risk of endometrial hyperplasia is increased in PCOS
Lack of progesterone on the endometrium
Endometrial cancer is associated with type 2 diabetes and obesity
What are treatment options for PCOS?
- COCP - increases SHBG therefore decreasing testosterone
- Anti Androgens +/- COCP
e.g. cyproterone acetate - stops testosterone and 5 alpha-DHT binding to androgen receptors
Spironolactone - antimineralocorticoid and anti androgen properties - Lifestyle factors e.g. lose weight, stop smoking, better diet and more exercise - improves SHBG conc, reducing free testosterone - improved fertility outcomes
- Targeting insulin resistance in PCOS - METFORMIN - biguanide - improve ovulation with CLOMIFENE
- Hair removal - photoepilation/ laser/ electrolysis/ eflorthinine inhibits orthinine decarboxylase
