G6. Stein-Leventhal Syndrome / Polycystic Ovary Syndrome (PCOS)

I. Definition and Pathophysiology

Definition

• Polycystic ovary syndrome (PCOS): common endocrine-metabolic disorder of reproductive-age women.
• Stein-Leventhal syndrome: older name for classic PCOS with hyperandrogenism, chronic anovulation and polycystic ovaries.
• Frequency: about 6-10% of reproductive-age women.
• Clinical importance: common cause of hirsutism, oligomenorrhea/amenorrhea and anovulatory infertility.

Pathomechanism

• Complex origin: genetic susceptibility + environmental/metabolic factors.
• Altered GnRH pulsatility → relative LH hypersecretion → ovarian theca cells produce excess androgens.
• Relative low/insufficient FSH effect → impaired follicle maturation → chronic anovulation.
• Androgens → peripheral aromatization to estrogens, especially in adipose tissue → unopposed estrogen effect without cyclic progesterone.
• Insulin resistance → hyperinsulinemia:
  • Insulin stimulates theca-cell androgen production.
  • Insulin decreases hepatic SHBG → more free testosterone.
  • Result: hyperandrogenism worsens → anovulation continues.
• Chronic anovulation → continuous estrogen stimulation of endometrium → endometrial hyperplasia/cancer risk.

II. Clinical Features and Risks

Reproductive Features

• Menstrual dysfunction: oligomenorrhea, amenorrhea, irregular bleeding.
• Chronic anovulation: infertility, subfertility, increased miscarriage risk.
• Abnormal uterine bleeding: often due to anovulation and endometrial overgrowth.

Hyperandrogenic Features

• Hirsutism: terminal hair in male-pattern distribution.
• Acne, seborrhea, androgenic alopecia.
• Virilization: clitoromegaly, deep voice, rapidly progressive severe hirsutism → think androgen-secreting tumor rather than typical PCOS.

Metabolic and Long-Term Risks

• Insulin resistance: may occur independent of body weight.
• Central obesity, acanthosis nigricans, impaired glucose tolerance, type 2 diabetes risk.
• Metabolic syndrome: abdominal obesity, hypertension, dyslipidemia, impaired fasting glucose / impaired glucose tolerance.
• Other associations: obstructive sleep apnea, nonalcoholic fatty liver disease, hidradenitis suppurativa, depression/anxiety, eating disorders.
• Cancer risk: increased risk of endometrial hyperplasia and endometrial carcinoma; no clear routine exam association with ovarian or breast cancer.

III. Diagnosis and Differential Diagnosis

Rotterdam Criteria

• Diagnosis: 2 of 3 criteria, after exclusion of mimicking disorders.

1. Oligo-ovulation or anovulation: oligomenorrhea, amenorrhea, infertility.
2. Clinical or biochemical hyperandrogenism: hirsutism, acne, androgenic alopecia, increased testosterone/free androgen index.
3. Polycystic ovarian morphology on ultrasound.

Investigations

• Pregnancy test: exclude pregnancy in amenorrhea.
• Hormones to exclude mimics: TSH, prolactin, FSH/LH, estradiol.
• Androgen profile: total/free testosterone, SHBG/free androgen index; DHEA-S if adrenal source suspected.
• 17-OH-progesterone: exclude nonclassic congenital adrenal hyperplasia when indicated.
• Pelvic ultrasound: ovarian morphology and endometrial thickness; polycystic ovaries alone do not equal PCOS.
• Metabolic evaluation: BMI/waist, blood pressure, fasting lipids, HbA1c or oral glucose tolerance test.

Differential Diagnosis

• Pregnancy: always first in amenorrhea.
• Thyroid disease and hyperprolactinemia: irregular cycles and anovulation.
• Nonclassic congenital adrenal hyperplasia: hyperandrogenism + cycle disorder.
• Cushing syndrome: obesity, hypertension, striae, hyperandrogenism.
• Androgen-secreting tumor: rapid onset virilization or very high testosterone/DHEA-S.
• Primary ovarian insufficiency: high FSH + low estradiol.
• Functional hypothalamic amenorrhea: low energy/stress + low estradiol, usually no hyperandrogenism.

IV. Treatment

General Goals

• Regulate bleeding and protect endometrium.
• Treat hyperandrogenic symptoms.
• Improve metabolic risk: diabetes, dyslipidemia, hypertension, cardiovascular risk.
• Induce ovulation if pregnancy is desired.
• Provide contraception if pregnancy is not desired.

Not Currently Seeking Pregnancy

• Lifestyle: weight reduction if overweight, regular exercise, diet, smoking cessation; even modest weight loss may restore ovulation.
• Combined oral contraceptive pill: first-line for irregular bleeding, contraception and hyperandrogenic symptoms.
• Progestin therapy: cyclic or continuous progestin if estrogen-containing contraception is contraindicated → endometrial protection.
• Antiandrogens: spironolactone, cyproterone acetate, finasteride.
  • Use with reliable contraception because of fetal antiandrogenic risk.
  • Consider if hirsutism/acne persist after several months of combined oral contraceptive pill.
• Acne/hair symptoms: topical acne therapy, dermatology care, cosmetic hair removal/laser when needed.

Metabolic Treatment

• Metformin: useful for insulin resistance, impaired glucose tolerance/type 2 diabetes risk, and may improve cycle regularity.
• Dyslipidemia / hypertension / diabetes: treat according to general cardiovascular-risk guidelines.
• Screen and manage: obstructive sleep apnea, mood disorders, eating disorders, fatty liver disease when suspected.

Seeking Pregnancy

• Preconception: weight/lifestyle optimization, folic acid, exclude other infertility factors when indicated.
• First-line ovulation induction: letrozole in current guidelines for anovulatory infertility without other infertility factors.
• Classic exam alternative: clomiphene citrate.
  • Mechanism: blocks hypothalamic estrogen receptors → decreased negative feedback → increased GnRH/FSH/LH → follicle maturation and ovulation.
• Other options: metformin adjunct, gonadotropins with monitoring, IVF if other methods fail or other infertility factors exist.
• Laparoscopic ovarian drilling: second-line option in clomiphene-resistant anovulation; destroys part of androgen-producing ovarian stroma.