L6 Disorders of Ovulation Flashcards
What stimulates GnRH?
Kisspeptin
KNDy neurones
What are kisspeptin and KNDy neurones stimulated by?
High oestrogen
What do kisspeptin and KNDy neurones drive the production of?
LH production through stimulation of GnRH
Pulsatility of kisspeptin/GnRH/LH
60-90 minutes
Normal process of ovulation
GnRH stimulates FSH which acts on the primary follicle granulosa cells which start producing oestrogen and inhibin
FSH also increases the LH receptors in the grannulosa cells
These hormones in turn inhibit FSH (negative feedback)
HOWEVER when oestrogen levels get to a critical high level they positively act on the Kisspeptin and KNDy neurones which stimulate the production of GnRH which in turn produces LH (due to increased frequency and amplitude of the pulse from GnRH)
LH triggers ovulation, resumption of oocyte meiosis and changes the granulosa cells into luteal cells
First half of menstrual cycle
FSH falls as oestrogen and inhibin rise
At a critical level, oestrogen positively feeds back to Kisspeptin and in turn causes an increase in frequency and amplitude of GnRH which causes the LH surge
Second half of menstrual cycle
As LH now converts the granulosa cells to luteal cells, hormone production swaps from oestrogen to progesterone.
Progesterone peaks at Day 21 (7days before period).
Progesterone, oestrogen and inhibit inhibit FSH and LH
Diagnosis of ovulation: clinical
Clinical: Take a history from the woman
Regular menstruation usually 28 days (check not on hormonal contraception)
Mid cycle pain at ovulation
Vaginal discharge alters (increased mucus post ovulation)
Diagnosis of ovulation: biochemistry
Day 21 progesterone blood test (7 days before start of next menstrual period)
LH detection kits:
urinary kits bought over the counter
Diagnosis of ovulation: transvaginal pelvic ultrasound
Done from day 10, alternate days to demonstrate the developing follicle size and Corpus Luteum
NOT basal body temp, cervical mucus change, vaginal epithelium changes nor endometrial biopsies
Causes of ovulation problems: hypothalamus
Lack of GnRH
Kiss1 gene deficiency - rare
GnRH gene deficiency - rare
Weight loss/ stress related/ excessive exercise
Anorexia/bulimia
Causes of ovulation problems: pituitary
Lack of FSH and LH
Pituitary tumours (prolactinoma/ other tumours)
Post pituitary surgery/radiotherapy
Causes of ovulation problems: ovary
Lack of oestrogen/progesterone
Premature ovarian insufficiency
- Developmental or genetic causes e.g. Turner’s syndrome
- Autoimmune damage and destruction of ovaries
- Cytotoxic and radiotherapy
- Surgery
Causes of ovulation problems: commonest cause
Polycystic Ovarian Syndrome
Define amenorrhoea
Lack of a period for more than 6 months
Primary amenorrhoea - never had a period (never went through menarche)
Secondary amenorrhoea - has menstruated before
Define oligomenorrhoea
Irregular periods
Usually occurring more than 6 weeks apart
Define polymenorrhoea
Periods occurring less than 3 weeks apart
Define hirsutism
‘Androgen dependent’ hirsutism
-excess body hair in a male distribution
NOT
- androgen-independent hair growth = hypertrichosis
- familial/racial hair growth
Clinical features of PCOS
Hyperandrogenism
-Hirsutism, acne
Chronic oligomenorrhoea/amenorrhoea
- = 9 periods/year
- subfertility
Obesity (but 25% of women with PCOS are lean)
Elements in the diagnosis of PCOS
Polycystic ovaries
Androgen excess
Oligo-anovulation
PCOS and the metabolic syndrome
Insulin resistance with increased insulin
- increased androgen production by ovarian theca cells
- decreased SHBG production by the liver
Impaired glucose tolerance
-increased risk of gestational DM and T2 DM
Dyslipidaemia
Vascular dysfunction
? Increased risk of cardiovascular disease ?
USS appearance of polycystic ovaries
> /= sub capsular follicules 2-8mm in diameter
arranged around a thickened ovarian stroma
not all women with PCOS will have USS appearance
Hormonal abnormalities in PCOS
Raised baseline LH and normal FSH levels. Ratio LH:FSH 3:1
Raised androgens and free testosterone
Reduced SHBG
Oestrogen usually low but can be normal
Sex Hormone Binding Globulin: synthesis, role, what happens when testosterone bound and what it is increased/decreased by
Produced by the liver
Binds testosterone and oestradiol
If testosterone bound - not converted to active component dihydrotestosterone i.e. not ‘free’
Increased by oestrogens
Decreased by testosterone thus releasing more free testosterone
Reproductive effects of PCOS
PCOS is maybe associated with varying degrees of infertility
- 15% of all causes of infertility is lack f ovulation
- 80% of lack of ovulation due to POS
Associated with increased miscarriages
Increased risk of Gestational Diabetes
PCOS and endometrial cancer
Increased endometrial hyperplasia and cancer
Lack of progesterone on the endometrium
Endometrial cancer associated with type 2 diabetes and obesity
Treatment of PCOS: life -style modifications
Diet and exercise
Stop smoking
Results:
- decreased insulin resistance
- increased SHBG
- improved fertility/pregnancy outcomes
- improve metabolic syndrome risk factors
High frequency eating disorders
-Bulimia associated with PCOS
Lean women with PCOS should try not to get fat
Treatment of PCOS: combined oral contraceptives
Increases SHBG and thus decreases free testosterone
Decreased FSH and LH and therefore ovarian stimulation
Regulates cycle and decreases endometrial hyperplasia
BUT may cause weight gain, venous thrombosis, adverse effects on metabolic risk factors
Treatment of PCOS: anti-androgens
With COCP/other form of secure contraception
Cyproterone acetate (oral tablet) -inhibits binding of testosterone & 5 alpha dihydrotestosterone to androgen receptors
Spironolactone (oral tablet)
-anti mineralocorticoid and anti androgen properties
Treatment of PCOS: hair removal
Photoepilation (laser)/electrolysis etc
Elflornithine cream (non-NHS) -inhibits ornithine decarboxylase enzyme in hair follicles
Targeting insulin resistance in PCOS
Metformin (biguanide)
- decreases insulin resistance, decreases insulin levels, decreases ovarian androgen production
- may help with weight loss/diabetes prevention
- may increase ovulation (with clomifene), safe in pregnancy
- less helpful for hirsutism and oligomenorrhoea but may be an option for obese PCOS women
Presentation of primary ovarian insufficiency
Primary or secondary amenorrhoea
-secondary amenorrhoea may be associated with hot flushes & sweats
Other terms used for primary ovarian insufficiency
Premature ovarian failure
Premature menopause
Aetiology of primary ovarian failure
Autoimmunity
-may be associated with other autoimmune endocrine conditions
X chromosomal abnormalities
- Turner syndrome
- Fragile X associated
Genetic predisposition
-Premature menopause
Iatrogenic
-Surgery, radiotherapy or chemotherapy
Investigations for premature ovarian failure
History/examination
Increased LH/FSH
? Karyotype
Consider pelvic USS
Consider screening for other autoimmune endocrine disease
-thyroid function tests, glucose, cortisol
Management of premature ovarian failure
Psychological support
HRT
-continue till 52
Monitor bone density
-DEXA scan
Fertility
-IVF with donor egg
Turner syndrome
Complete/partial X monosomy in some/ all cells
- 50%of cases will be XO
- Rest:partial absence of X or mosaicism
1:2000 - 1:2500 live-born girls
Presentation
- may be diagnosed in the neonate
- may present with primary/secondary amenorrhoea
Turner syndrome: associated problems
Short stature
-consider GH treatment
CV system
- coarctation of aorta
- bicuspid aortic valve
- aortic dissection
- hypertension (adults)
Renal
-congenital abnormalities
Metabolic syndrome
Hypothyroidism
Ears/hearing problems
Osteoporosis (lack HRT)
Differential diagnosis of hirsutism
95% PCOS or ‘idiopathic hirsutism’
1% non-classical congenital adrenal hyperplasia (CAH)
<1% Cushing’s syndrome
<1% adrenal/ovarian tumour
Prevalence of PCOS: 5-10% of women
When to worry about Turner’s syndrome
Sudden onset of severe symptoms
Virilisation
- frontal balding
- deepening of voice
- male-type muscle mass
- clitoromegaly
Possible Cushing’s syndrome
What are adrenal steroids synthesised by?
cholesterol
via progesterone/DHEA
Congenital adrenal hyperplasia
Disorders of cortisol biosynthesis
- carrier frequency 1:60
- most patients are compound heterozygotes i.e. different mutations on two alleles
95% CAH cases caused by 21-hydroxylase deficiency
- cortisol deficiency
- may have aldosterone deficiency
- androgen excess
- depends on degree of enzyme deficiency
21-dehydroxylase deficiency
Defect in cortisol biosynthesis => raised CRH/ACTH (lack of negative feedback) => drives excess adrenal androgen production
CAH presentation
Childhood
- ‘classic’/’severe’
- salt-losing (2/3rd)
- non-salt losing (1/3rd)
- simple virilising
Adulthood
- ‘non-classic’/’mild’
- ‘late-onset’
CAH presentation in childhood (detailed)
Salt wasting
-hypovolaemia, shock
Virilisation
- ambiguous genitalia in girls
- early virilisation in boys
Precocious puberty
Abnormal growth
- accelerated early
- premature fusion
CAH presentation in adults (detailed)
Hirsutism
Oligo/amenorrhoea
Acne
Sub fertility
Similar to PCOS presentation
CAH treatment
Glucocorticoid and mineralocorticoid replacement
- hydrocortisone & fludrocortisone
- additional salt in infancy
Glucocorticoids suppress CRH/ACTH
Supra physiological glucocorticoid doses may be needed to suppress adrenal androgen production
- monitor [17-OH-P]/androstenedione
- monitor growth in childhood -excess glucocorticoid treatment may inhibit growth
Surgical management for ambiguous genitalia
Non-classical CAH in adult women (mild)
-can treat as for PCOS with COCP and anti-androgen
