6. Disorders of ovulation Flashcards
What regulates GnRH release?
Kisspeptin and the KNDy neurones are potent stimulators of GnRH
They are stimulated by high oestrogen and they drive LH production through stimulation of GnRH
Note: Kisspeptin / GnRH/ LH all pulsatile (60-90 minutes)
How does GnRH act?
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 granulosa 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)
What does LH do?
LH triggers ovulation, resumption of oocyte meiosis and changes the granulosa cells into luteal cells
Describe the first half of the cycle
First half of cycle: FSH falls as oestrogen and inhibin rises. At a critical level oestrogen positively feeds back to Kisspeptin and in turn causes an increase in freq and amplitude of GnRH which causes the LH surge.
Describe the second half of the cycle
Second half of cycle: As LH now converts the granulosa cells to luteal cells hormone production swaps from oestrogen to progesterone. Progesterone peaks at Day 21 ( 7 days before the period). Progesterone, oestrogen and inhibin inhibit FSH and LH.
Diagnosis of ovulation
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)
History: regular 28 days between the first day of every period. Ovulation pain (leakage of follicle fluid at the time of ovulation irritates the peritoneum and causes pain.
Biochemistry: Day 21 progesterone blood test
(7 days before start of next menstrual period)
LH detection kits:
urinary kits bought over the counter
Transvaginal pelvic ultrasound done from Day 10, alternate days
to demonstrate the developing follicle size and Corpus Luteum
not Basal Body Temperature, 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 Pituitary (lack of FSH and LH) pituitary tumours (prolactinoma/other tumours) post pituitary surgery /radiotherapy
Ovary (lack of oestrogen/progesterone)
Premature ovarian insufficiency
Developmental or genetic causes eg Turner’s syndrome
Autoimmune damage and destruction of ovaries
Cytotoxic and radiotherapy
Surgery
Polycystic Ovarian Syndrome: commonest cause
Menstrual patterns (terminology)
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
Oligomenorrhoea - irregular periods
usually occurring more than 6 weeks apart
Polymenorrhoea - periods occurring less than 3 weeks apart
Hirsutism
‘Androgen-dependent’ hirsutism
Excess body hair in a male distribution
NOT:
Androgen-independent hair growth
Hypertrichosis
Familial / racial hair growth
Clinical features of hirsutism
Hyperandrogenism Hirsutism, acne Chronic oligomenorrhoea / amenorrhoea < 9 periods / year Subfertility Obesity (but 25% of women with PCOS are “lean”)
Elements in diagnosis of PCOS
Polycystic ovaries
oligo/anovulation
androgen excess
Insulin and PCOS
Insulin resistance is the underlying problem ( genetic factors also important). High levels of Insulin and androgens cause granulosa cells to become less functional ( less oestrogen) and the follicle to arrest, also causes increased LH levels which drives thecal cells to increase androgens.
USS appearance of polycystic ovary syndrome
> 10 subcapsular follicules 2-8 mm in diameter,
arranged around a thickened ovarian stroma
not all women with PCOS will have USS appearance
USS appearance of polycystic ovary syndrome
> 10 subcapsular follicules 2-8 mm 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 Sex Hormone Binding Globin (SHBG)
Oestrogen usually low but can be normal
Sex hormone binding globulin
Produced by the liver
Binds testosterone and oestradiol
If testosterone bound - not converted to active component dihydrotestosterone ie not “free”
SHBG increased by oestrogens
SHBG 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 of ovulation
80% of lack of ovulation due to PCOS
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 & obesity
Life-style modifications to treat PCOS
Diet & exercise Stop smoking RESULTS: Decreased insulin resistance Increased [SHBG] Decreased [free testo] 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!
Combined oral contraceptives in PCOS
increases SHBG and thus decreases free testosterone
decreases FSH & LH and therefore ovarian stimulation
regulates cycle & decreases endometrial hyperplasia
BUT may cause weight gain, venous thrombosis, adverse effects on metabolic risk factors
Anti-androgens in PCOS treatment
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
Hair removal in PCOS
Photoepilation (laser) / electrolysis etc
Eflornithine cream (non-NHS) Inhibits ornithine decarboxylase enzyme in hair follicles
Targeting insulin resistance in PCOS
Metformin (biguanide)
Decreasesinsulin 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 & oligomenorrhoea, but may be an option for obese PCOS women
Primary ovarian insufficiency
Presentation: Primary or secondary amenorrhoea Secondary amenorrhoea may be associated with hot flushes & sweats Other terms used: Premature ovarian failure Premature menopause Aetiology: 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
premature ovarian failure
Investigations: history / examination Increase LH and FSH ? Karyotype Consider pelvic USS Consider screening for other autoimmune endocrine disease Thyroid function tests, glucose, cortisol Management: 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 short stature in childhood
May present with primary / secondary amenorrhoea
Associated problems with Turner Syndrome
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 polycystic ovarian syndrome:
5-10% women!
When to worry
Sudden onset of severe symptoms Virilisation Frontal balding Deepening of voice Male-type muscle mass Clitoromegaly Possible Cushing’s syndrome
Congenital adrenal hyperplasia (CAH)
disorders of cortisol biosynthesis Carrier frequency 1 : 60 Most patients are compound heterozygotes 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-hydroxylase deficiency
Defect in cortisol biosynthesis -> raised CRH / ACTH (lack of negative feedback) -> drives excess adrenal androgen production
Diagnosis: high concentrations of 17-hydroxyprogesterone
Can confirm with Synacthen test
CAH presentation
CHILDHOOD
‘Classic’ / ‘severe’
Salt-losing (2/3rd)
Non-salt losing (1/3rd)
Simple virilising
Salt wasting Hypovolaemia, shock Virilisation Ambiguous genitalia in girls Early virilisation in boys Precocious puberty Abnormal growth Accelerated early Premature fusion
ADULTHOOD
‘Non-classic’ / ‘mild’
‘late-onset’
Adulthood (mild): Hirsutism Oligo / amenorrhoea Acne Subfertility
Similar to ‘PCOS’ presentation
CAH treatment
Glucorticoid & mineralocorticoid replacement
Hydrocortisone & fludrocortisone
Additional salt in infancy
Glucocorticoids suppress CRH / ACTH
Supraphysiological 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 +/- anti-androgen
