Polycystic Ovary Syndrome

Robert L. Barbieri, M.D.
Harvard Medical School

Definition/Key Clinical Features
Differential Diagnosis
Best Tests
Best Therapy
Best References

Definition/Key Clinical Features

• Hyperandrogenism and oligo-ovulation (menstrual cycle > 35 days long)
• Hirsutism, acne, male-pattern hair loss
• Irregular and infrequent menstrual cycles
• Anovulatory infertility
• Insulin resistance, obesity, increased risk of type 2 diabetes
• Endometrial hyperplasia/cancer
• Associated with metabolic syndrome, cardiovascular disease, nonalcoholic steatohepatitis, sleep apnea

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Differential Diagnosis

• Idiopathic hirsutism
• Nonclassic 21-hydroxylase deficiency
• Androgen-secreting tumor, ovarian or adrenal
• Virilization syndromes
• Ovarian hyperthecosis
• Cushing syndrome
• Valproic acid side effect
• Exposure to exogenous androgens

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Best Tests

• History
  • Onset of oligomenorrhea, hirsutism, acne in perimenarchal years
  • Irregular menstrual cycles starting at menarche
  • Slowly progressing hirsutism
  • Family history of PCOS and/or type 2 diabetes
  • Long-term use of valproate
  • Smoking
• Physical exam
  • Assess hirsutism
  • Assess insulin resistance
    • BMI > 25
    • Waist-to-hip ratio > 0.85
    • Waist circumference > 89 cm
    • Acanthosis nigricans or achrochordons (skin tags)
  • Assess for metabolic syndrome
    • Waist circumference > 35 in
    • BP > 130/85 mm Hg
    • Fasting blood sugar > 100 mg/dl
    • Triglycerides > 150 mg/dl
    • HDL-C < 50 mg/dl
  • Signs of virilization indicate androgen-secreting tumor
• Laboratory tests
  • Total serum testosterone (normal range, 0.60–0.80 ng/ml); > 2 ng/ml indicates ovarian stromal hyperthecosis or tumor
  • 17-Hydroxyprogesterone > 2 ng/ml at 8 A.M. indicates probable nonclassic adrenal hyperplasia; confirm by ACTH stimulation test
  • Dehydroepiandrosterone sulfate (DHEAS) > 10.7 µg/dl suggests adrenal tumor (normal range 0.12–5.35 µg/dl)
  • Serum prolactin to rule out pituitary tumor
  • Serum TSH
  • LH:FSH ratio more informative than single serum LH measurement
  • Antimüllerian hormone level elevated in PCOS
  • Screen for diabetes mellitus, fasting glucose
• Pelvic ultrasound if ovaries palpable and enlarged or if total testosterone > 2.0 ng/ml

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Best Therapy

• Cyclic estrogen-progestin contraceptive
• Any agent except androgenic progestin (e.g., norgestrel)
• Long-cycle regimens may work better than standard cycle regimens
• Twofold greater risk for coronary vascular disease in PCOS
• Metformin
• Cyclic progestin (e.g., medroxyprogesterone acetate, 10 mg daily for 14 days each mo)

• Cyclic estrogen-progestin oral contraceptive, alone or with an antiandrogen (e.g., spironolactone, 100 mg/day)
• Shaving, electrolysis, laser treatment
• Topical eflornithine
• Avoid glucocorticoids

• Weight loss of ≥ 10% if BMI > 27
• Drug therapy
• Clomiphene citrate
• Dose: 50 or 100 mg/day for maximum 5 days per cycle
• Cost/mo: $28
• After spontaneous menses or induction of menses with progestin withdrawal maneuver (medroxyprogesterone acetate, 10 mg p.o. daily for 5 days), start clomiphene, 50 mg/day, for 5 days on cycle day 3, 4, or 5; 50% of patients will ovulate
• By increasing dose to 100 mg/day, another 25% of patients will ovulate
• Some patients require 150 mg/day for 5 days
• Determine ovulation by basal body temperature, ultrasound, luteal-phase progesterone measurements, or endometrial biopsy (when conception is not attempted)
• Risk of multiple pregnancy
• Spontaneous abortion rate ~ 15%
• Vasomotor symptoms, adnexal tenderness, nausea, headache, blurring of vision or scotomata
• Metformin: alternate choice
• Dose: 1,500 mg in divided doses with meals; start with 500 mg/day for first week, then 500 mg b.i.d. for second week, then 500 mg t.i.d.; extended release: 1/day with dinner
• Cost/mo: $51
• Side effects: GI disturbances
• Before starting, confirm that serum creatinine < 1.4 mg/dl
• Metformin + clomiphene
• Effective if clomiphene alone does not produce ovulation after 5–10 wk
• Clomiphene + glucocorticoid
• If clomiphene alone does not produce ovulation, short course of dexamethasone followed by clomiphene may be tried
• Gonadotropin induction
• FSH, 75 U/day s.c. for 14 days; increase by 37.5 units q. 7 days until follicular ripening complete
• Can be used with clomiphene or metformin
• Can cause ovarian hyperstimulation syndrome
• Abdominal pain, distention
• Nausea, vomiting, diarrhea, dyspnea
• Weight gain, ovarian enlargement, ascites, pleural effusion, hemoconcentration, electrolyte imbalances, renal dysfunction, thrombosis
• Multiple pregnancy rate ~ 15%
• In vitro fertilization with embryo transfer
• Ovarian surgery
• Laparoscopic drilling of ovary: pregnancy rate ~ 50% at 12 mo and 70% at 24 mo
• Surgery to reduce androgen-secreting tissue: only if standard approaches fail to induce ovulation

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Best References

Elnashar A: Human Reprod 21:1805, 2006 [PMID 16543255]

Farquhar C: Cochrane Database Syst Rev (4):CD000194, 2003 [PMID 14583916]

Grundy SM: Circulation 112:2735, 2005 [PMID 16157765]

Hughes E: Cochrane Database Syst Rev (2):CD00056, 2000 [PMID 10908458]

Lord JM: Cochrane Database Syst Rev (3):CD003053, 2003 [PMID 12917943]

February 2007