Definition - Anovulation
- Resulting in irregular menstruation, amenorrhea, ovulation-related infertility
- Androgen excess
- Resulting in acne and hirsutism
- Insulin resistance
- Often associated with obesity, Type 2 diabetes, and high cholesterol levels
Risk factors - FHx (autosomal dominant)
- Obesity
- Epilepsy
- Use of anti-seizure medications
Differential diagnosis - Ovarian hyperthecosis
- Congenital adrenal hyperplasia (late-onset)
- Drugs (eg, danazol, androgenic progestins)
- Hypothyroidism
- Patients with menstrual disturbances and signs of hyperandrogenism
- Idiopathic hirsutism
- Familial hirsutism
- Masculinizing tumors of the adrenal gland or ovary (rapid onset of signs of virilization)
- Cushing syndrome
- Hyperprolactinemia
- Exogenous anabolic steroid use
- Stromal hyperthecosis (valproic acid)
- 3-Beta-Hydroxysteroid Dehydrogenase Deficiency
- Acromegaly
- Amenorrhea
- Ovarian Tumors
Epidemiology - One of the most common endocrine disorders of reproductive-age women, with a prevalence of 4-12%
- A great deal of ethnic variability in hirsutism is observed
- Asian (East and Southeast Asia) women have less hirsutism than white women given the same serum androgen values
- PCOS affects premenopausal women, and the age of onset is most often perimenarchal (before bone age reaches 16 y)
- However, clinical recognition of the syndrome may be delayed
- Irregular menses, hirsutism, other PCOS findings may overlap with normal physiologic maturation during the 2 years after menarche
- In lean women with a genetic predisposition to PCOS, the syndrome may be unmasked when they subsequently gain weigh
Aetiology / Pathophysiology - Abnormalities in the metabolism of androgens and estrogen and in the control of androgen production
- Peripheral insulin resistance and hyperinsulinemia
- Secondary to a postbinding defect in insulin receptor signaling pathways
- Hyperinsulinemia => Suppression of hepatic generation of sex hormone–binding globulin (SHBG) => Androgenicity
- Insulin resistance in PCOS has been associated with high adiponectin levels
- Proposed mechanism for anovulation and elevated androgen levels:
- Excess LH secreted by the anterior pituitary
- => Stimulation of ovarian theca cells is increased
- => Increased androgen production
- Decreased FSH levels => Ovarian granulosa cells cannot aromatize the androgens to oestrogens
- => Decreased estrogen levels and consequent anovulation
- Growth hormone (GH) and insulin-like growth factor–1 (IGF-1) may also augment the effect on ovarian function
- Hyperinsulinemia => Dyslipidemia => Elevated plasminogen activator inhibitor-1 (PAI-1) => Intravascular thrombosis
Cinical features
- FHx
- Menstrual disorders
- Adrenal enzyme deficiencies
- Hirsutism
- Infertility
- Obesity and metabolic syndrome
- Diabetes
- Menstrual abnormalities
- Abnormal menstruation patterns (attributed to chronic anovulation)
- Oligomennorhoea
- Secondary amenorrhea
- Dysfunctional uterine bleeding
- Infertility
- Hyperandrogenism
- Excess terminal body hair in a male distribution pattern
- Hair is commonly seen on the upper lip, on the chin, around the nipples, and along the linea alba of the lower abdomen
- Some patients have acne and/or male-pattern hair loss (androgenic alopecia)
- The modified Ferriman-Gallwey (mFG) score grades 11 body areas from 0 (no hair) to 4 (frankly virile)
- A total score of 8 or more is considered abnormal for an adult white woman; a score of 44 is the most severe
- Other signs of hyperandrogenism are more characteristic of hyperthecosis
- E.g. clitoromegaly, increased muscle mass, voice deepening
- Could also be consistent with androgen-producing tumors, exogenous androgen administration, or virilizing congenital adrenal hyperplasia
- Premature adrenarche
- Infertility
- A subset of women with PCOS is infertile
- Most women with PCOS ovulate intermittently
- Conception may take longer than in other women, or women with PCOS may have fewer children than they had planned
- In addition, the rate of miscarriage is also higher in affected women
- Obesity and metabolic syndrome
- Nearly half of all women with PCOS are clinically obese
- Many patients with PCOS have characteristics of metabolic syndrome
- Abdominal obesity (waist circumference >35 in)
- Dyslipidemia (triglyceride level >150 mg/dL, high-density lipoprotein cholesterol [HDL-C] level < 50 mg/dL)
- Elevated blood pressure
- Proinflammatory state characterized by an elevated C-reactive protein level
- Prothrombotic state characterized by elevated plasminogen activator inhibitor-1 (PAI-1) and fibrinogen levels
- Increased prevalence of coronary artery calcification and thickened carotid intima media, which may be responsible for subclinical atherosclerosis
- Diabetes mellitus
- Approximately 10% of women with PCOS have type 2 diabetes mellitus by 40 years of age
- 30-40% of women with PCOS have impaired glucose tolerance by 40 years of age
- Sleep apnea
- Many women with PCOS have obstructive sleep apnea syndrome (OSAS), which is an independent risk factor for cardiovascular disease
- Acanthosis nigricans
- Diffuse, velvety thickening and hyperpigmentation of the skin, thought to be the result of insulin resistance
- May be present at the nape of the neck, axillae, area beneath the breasts, intertriginous areas, and exposed areas (eg, elbows, knuckles)
- NB Acanthosis nigricans can also be a cutaneous marker of malignancy
- Hypertension
Investigations- Bloods
- TFTs
- Prolactin
- Total and free testosterone
- Free androgen index
- Serum hCG level
- Cosyntropin stimulation test
- Serum 17-hydroxyprogesterone (17-OHPG) level
- Urinary free cortisol (UFC) and creatinine levels
- Low-dose dexamethasone suppression test
- Serum insulinlike growth factor (IGF)–1 level
- Others
- Androstenedione level
- FSH and LH levels
- GnRH stimulation testing
- Glucose level
- Insulin level
- Lipid panel
- Imaging
- Ovarian ultrasonography, preferably using transvaginal approach
- Pelvic CT scan or MRI to visualize the adrenals and ovaries
Management - Lifestyle changes
- Diet + exercise
- Comparable to or better than treatment with medication
- Medical
- Metformin
- Combination low-dose oral contraceptive (reduce testosterone, LH, FSH)
- Clomiphene citrate
- Exogenous gonadotropins
- Antiandrogens (spironolactone, leuprolide, finasteride) - NB Contraindicated in pregnancy
- Topical eflornithine (for hirsutism)
- Topical acne agents
- Surgical
- Laparoscopic ovarian drilling
Prognosis - Women with polycystic ovarian syndrome (PCOS) may be at increased risk for cardiovascular and cerebrovascular disease
- Women with hyperandrogenism have elevated serum lipoprotein levels similar to those of men
- Approximately 40% of patients with PCOS have insulin resistance that is independent of body weight
- These women are at increased risk for type 2 diabetes mellitus and consequent cardiovascular complications
- Patients with PCOS should be periodically reassessed for diabetes/IFG throughout their lifetime
- Patients with PCOS are also at an increased risk for endometrial hyperplasia and carcinoma
- Due to the chronic anovulation in PCOS leading to constant endometrial stimulation with oestrogen without progesterone
- RCOG recommends induction of withdrawal bleeding with progestogens a minimum of every 3-4 months
- No known association with breast or ovarian cancer has been found; thus, no additional surveillance is needed
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