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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
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