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