13.10.07 PCOS

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