PCOS and Hirsuitism Flashcards
What are Virilisation and Hirsutism?
- Virilisation: Extreme manifestations of androgen exposure, e.g. temporal hair recession, clitoromegaly, increased muscle mass, breast atrophy, deepening of voice
- Hirsutism: Hair growth in areas usually associated with male sexual maturity, e.g. face, lower abdomen, anterior thigh, periareolar region
What factors make up Polycystic Ovarian Syndrome?
- Hyperandrogenism (e.g. acne and hirsutism)
- Anovulation (typically amen/oligomenorrhoea)
- Appearance of polycystic ovaries on ultrasound
What is the Epidemiology of PCOS?
- Affects 20% of Caucasian women, more common e.g. Hispanic Americans or UK Asians
- Considered to arise during puberty and associated with obesity in ~40% of cases
- Cost US Health Economy $4.4 billion in 2005 - 4 million women (6.6% of reproductive aged women, 1990 NIH criteria)
What are clinical features of PCOS?
- Oligo/Amenorrhoea (Anovulatory cycles, Dysfunctional uterine bleeding, Infertility)
- Androgenisation (Hirsutism, Acne, Male pattern hair loss)
- Acanthosis nigricans
- Obesity (30-75%)
- IGT (30-40%) and T2DM (10%)
- Hypertension/vascular dysfunction
- Obstructive sleep apnoea (44-70%)
What is the International evidence-based guideline for the asessment and mangement of PCOS?
- When irregular menstrual cycles are present a diagnosis of PCOS should be considered
- Calculated free testosterone, FAI or bioavailable testosterone should be used to assess biochemical hyperandrogenism
- LCMS or extraction/chromatography immunoassays, should be used for assessment of testosterone
- Consider androstenedione and DHEAS if normal total or free testosterone
- Where androgen levels are markedly elevated, other causes of biochemical hyperandrogenism need to be considered
What are the conditions with features overlapping PCOS?
Familial/Idiopathic Hirsutism: Non-androgenic pattern of hair growth
Pregnancy: Amenorrhoea, weight gain.
- Useful test: Urine/serum HCG is a test for differentiation
Hypothalamic Amenorrhoea: Amenorrhoea, low BMI, excessive exercise. Lack of clinical features of androgen excess, PCO sometimes present
- Useful test: LH, FSH, E2
Primary Ovarian Insufficiency: Amenorrhoea and Symptoms of oestrogen deficiency.
- Useful test: FSH, E2
History of drug therapy
Steroid pathway defects: Lower likelihood of anovulation and PCO prevalence (24%) than in PCOS (90%)
- Useful Test: Urine steroid metabolites, 17-OHP (basal + stimulated)
Prolactin excess
- Useful test: Prolactin (↑ in 10-25% of PCOS)
Thyroid disorders: ↑ ovarian volume and cystic changes reported in primary hypothyroidism
- Useful test: TFTs
Cushing’s syndrome: 70-80% menstrual abnormalities, 46% PCO. Prevalent hirsutism (100% low SHBG as cortisol-induced IR and hyperinsulinaemia,increasing FAI). Have Cushingnoid features
- Useful Test: Overnight DST, 24h urine free cortisol
Acromegaly: Oligomenorrhoea, 40-80% hirsutism. Skin changes, headaches, peripheral loss of vision, enlarged jaw/hands/feet.
- Useful Test: GH suppression test, IGF1, MRI pituitary
Adrenal and ovarian androgen-secreting tumours: Potentially life-threatening. Rapid virilization (clitoromegaly, vocal deepening, frontal balding, muscular hypertrophy). Extremely high androgen levels, e.g. testosterone levels >5 nmol/L
- Useful Tests: Testosterone (MS assay), DHEAS, Androstenedione, US ovaries, MRI adrenals
Ovarian hyperthecosis: Non-malignant luteinized thecal cells in the ovarian stroma secrete testosterone. Peri-menopausal. Serum testosterone higher than PCOS
Severe insulin resistance: Diabetes, Obesity, Hyperlipidaemia
- Useful Tests: HOMA-IR (insulin, glucose)
What are drugs causing PCOS type features?
Differentiating Features
- Hirsutism: steroids, androgens, progestogens,danazol
- Non-androgenic pattern hypertrichosis: valproate, phenytoin, minoxidil, ciclosporin
Suggestive Features
- Lower likelihood of anovulation and PCO prevalence (24%) than in PCOS (90%)
- Useful test: Urine steroid metabolites and 17-OHP (basal + stimulated)
What are differences between prolactin excess and PCOS?
Suggestive features
- Prevalence of PCO/PCOS and identification of underlying mechanisms with different causes of hyperprolactinaemia poorly evaluated
Useful Test: Prolactin (↑ in 10-25% of PCOS)
What is involved in the aetiology of PCOS?
- Hypothalamic
- Pituitary
- Ovarian
- Metabolic
- Sympathetic nervous system
- Genetic
What are the results of faulty regulation of GnRH pulse generator?
- GnRH pulse generator resists negative feedback of progesterone (mediated by androgen excess)
- Resulting high GnRH pulse frequencies favours production of LH versus FSH beta-subunits
- Relative LH excess drives ovarian steroidogenesis (increased androgen synthesis)
- Excess androgens interfere with normal follicular development
- Anovulation leads to low progesterone levels, limiting negative feedback on GnRH pulse generator
How is PCOS investigated?
Clinical evaluation
- Physical examination, history
Radiological
- Ultrasound scan of ovaries
Biochemical
What is the scoring system for PCOS?
Ferriman-Gallwey scoring system
What does a typical ovarian ultrasound show?
- Thickened capsule
- Multiple 3-5 mm cysts
- Hyperechogenic stroma
- May also reveal virilizing ovarian tumours
How PCOS biochemically investigated?
- Gonadotrophins + E2 (increased LH:FSH with low E2 is classic but not often seen)
- Prolactin (mild hyperprolactinaemia common)
- Testosterone (MS assay) + SHBG
- Androstenedione + DHEAS: Frequently slightly elevated (higher levels seen in CAH and virilizing tumours)
- 17-OHP: Elevated in late-onset CAH (may require ACTH stimulation test)
- Anti-mullerian hormone
How is Testosterone tested for and interperated in PCOS?
- Total testosterone often elevated (higher levels seen in virilizing tumours)
- Patients with hirsutism and normal testosterone frequently have low SHBG
- Free androgen index = 100 x (Testo/SHBG)
- Normal range not well evaluated, <4.5% generally used
What are the features of androstenedione that make it clinically significant?
AD predicts metabolic risk
- Strong negative association between AD and insulin sensitivity
- Incidence of dysglycaemia increased with severity of androgen phenotype
AD is a sensitive indicator of androgen excess
- PCOS had higher levels than controls
- All 56 subjects with ↑T also had ↑AD
- 20 had ↑AD with normal T
Hyperandrogenemia predicts metabolic phenotype in polycystic ovary syndrome: the utility of serum androstenedione
What is Anti-Mullerian Hormone?
- Glycoprotein produced by granulosa cells of the ovary in folliculogenesis
- Small antral follicles make highest levels
- Development switches to FSH-dependent after selection of dominant follicle
- Regulates follicular growth initiation
How does AMH regulate follicle growth initiation?
- Inhibits early follicular recruitment preventing premature exhaustion of oocyte pool
- Inhibits cyclic follicular recruitment by reducing sensitivity to FSH
- Inhibits FSH-induced pre antral follicle growth
- Reduces the number of LH receptors in granulosa cells induced by FSH
- Inhibits FSH-induced CYP19a1 expression leading to reduced E2 levels (E2 inhibits AMH expression)
How does Follicular arrest happen in PCOS?
- FSH stimulates AMH and E2 in granulosa cells of small and large antral follicles
- In small follicles, AMH inhibits aromatase, impairing E2 production
- When E2 reaches a threshold in large antral follicles, AMH is inhibited through ERβ receptors, overcoming FSH and switching from AMH to E2 tone
- In large follicles from PCO, the lack of FSH-induced E2 production and the high level of AMH impair the shift from the AMH to the E2 tone, causing follicular arrest
What is the significance of Anti-Mullerian Hormone in PCOS?
- High AMH levels in PCOS (multiple small follicles – surrogate marker for AFC)
- Correlates with ovarian dysfunction, androgenaemia and clinical signs
- High diagnostic specificity and sensitivity
- High levels predictive of more challenging therapeutic management
What are drawbacks of using AMH in PCOS?
No universal diagnostic threshold at present
- Highly variable ultrasound inclusion criteria for PCOS in clinical studies
- Awaiting international standard for serum AMH assay
What are therapeutic options for PCOS?
Weight loss (Only if overweight)
- ↓ Androgens but uncertain effect on hirsutism
- Improved cardiovascular risk
- May improve ovulation + endometrial protection
Mechanical hair removal
- ↓ Hirsutism
Combined OCP
- ↓ Androgens but uncertain effect on hirsutism
- Suppression of ovulation and Endometrial protection
- 1st line for menstrual abnormalities and hirsutism/acne, 6 months to see improvement
Cyproterone acetate
- ↓ Clinical androgenisation
- Anti-androgen (use with OCP)
Spironolactone
- ↓ Clinical androgenisation
- Anti-androgen (use with OCP)
- Pregnancy must be avoided, Electrolyte effects (diuretic)
Metformin
- ↓ Androgens but uncertain effect on hirsutism
- May improve ovulation + endometrial protection
- ↓ Metabolic/glycaemic abnormalities
- Improving menstrual irregularities, but it has limited or no benefit in treating hirsutism, acne, or infertility
Clomiphene citrate
- Ovulation induction
- 1st line for fertility
Ovarian drilling
- Ovulation induction
- 2nd line for fertility
CVD monitoring also required
