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.
• Clinical importance: common cause of hirsutism, oligomenorrhea/amenorrhea and anovulatory infertility.

Pathomechanism

• Altered GnRH pulsatility → relative LH hypersecretion → ovarian theca cells produce excess androgens.
• Relative low/insufficient FSH effect → impaired follicle maturation → chronic anovulation.
• Androgens → aromatization to estrogens in granulosa cells/adipose tissue → inhibits FSH → persistent anovulation.
• Insulin resistance → hyperinsulinemia:
  • Insulin stimulates theca-cell androgen production.
  • Insulin decreases hepatic SHBG → more free testosterone.
• Chronic anovulation → continuous estrogen stimulation of endometrium → endometrial hyperplasia/cancer risk.

II. Clinical Features and Risks

Reproductive Features

• Oligomenorrhea, amenorrhea or irregular bleeding.
• Chronic anovulation → infertility/subfertility.

Hyperandrogenic Features

• Hirsutism: terminal hair in male-pattern distribution.
• Acne, seborrhea, androgenic alopecia.
• Rapid virilization/clitoromegaly/deep voice → think androgen-secreting tumor, not typical PCOS.

Metabolic and Long-Term Risks

• Central obesity, insulin resistance, acanthosis nigricans, impaired glucose tolerance/type 2 DM risk.
• Metabolic syndrome: abdominal obesity, hypertension, dyslipidemia, impaired fasting glucose / impaired glucose tolerance.
• Unopposed estrogen → increased risk of endometrial hyperplasia and endometrial carcinoma.

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 or 17-OH-progesterone if adrenal/CAH cause suspected.
• 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, hyperprolactinemia, nonclassic congenital adrenal hyperplasia and Cushing syndrome.
• Androgen-secreting tumor: rapid onset virilization or very high testosterone/DHEA-S.
• Primary ovarian insufficiency: high FSH + low estradiol.

IV. Treatment

General Goals

• Regulate bleeding and protect endometrium.
• Treat hyperandrogenic symptoms.
• Improve metabolic risk: obesity, insulin resistance/DM, dyslipidemia and HT.
• Induce ovulation if pregnancy is 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.

Metabolic Treatment

• Metformin: useful for insulin resistance, impaired glucose tolerance/type 2 diabetes risk, and may improve cycle regularity.
• Dyslipidemia, hypertension and diabetes: screen and treat according to general risk.

Seeking Pregnancy

• Preconception: weight/lifestyle optimization, folic acid, exclude other infertility factors when indicated.
• Ovulation induction: letrozole is current first-line; clomiphene citrate is the classic exam drug.
  • Clomiphene mechanism: blocks hypothalamic estrogen receptors → ↓ negative feedback → ↑ GnRH/FSH/LH → ovulation.
  • Letrozole: aromatase inhibitor → ↓ estrogen synthesis → ↑ FSH.
• Alternatives: metformin adjunct, gonadotropins, IVF.
• Laparoscopic ovarian drilling: option in clomiphene-resistant anovulation; destroys part of androgen-producing ovarian stroma.