Medications for Polycystic Ovary Syndrome (PCOS)
Treatment Strategy Based on Primary Goal
The medication choice for PCOS depends entirely on whether the patient desires pregnancy: combined oral contraceptives are first-line for women NOT seeking pregnancy, while clomiphene citrate or letrozole are first-line for women seeking conception. 1, 2
For Women NOT Seeking Pregnancy
First-Line: Combined Oral Contraceptives
- Combined oral contraceptives suppress ovarian androgen secretion, provide endometrial protection against cancer risk, and reduce hyperandrogenism manifestations like hirsutism and acne. 2, 3
- These agents regulate menstrual cyclicity and protect the endometrium against dysplasia and carcinoma in oligomenorrheic women 4
- For women with contraindications to estrogen, progestin-only contraceptives are recommended as an alternative 3
Adjunctive Metabolic Management
- Metformin (1,000-2,000 mg daily in divided doses) should be added for overweight patients with cardiometabolic risk factors, insulin resistance, or dysglycemia. 5, 3, 6
- The American Diabetes Association recommends metformin as the cornerstone medication for improving insulin sensitivity and reducing testosterone levels 2
- Metformin improves menstrual regularity and has positive effects on insulin resistance, though it is NOT first-line for fertility 4, 6
For Severe Hirsutism
- Add antiandrogens (spironolactone, cyproterone acetate, flutamide, or finasteride) to estrogen-progestin therapy for severe hirsutism. 7, 8, 6
- Critical pitfall: Never use spironolactone as monotherapy in women of childbearing age due to contraindication in pregnancy. 1
- Topical eflornithine can be added to pharmacological treatment for cosmetic improvement 3, 6
For Women Seeking Pregnancy
Foundation: Lifestyle Modification FIRST
- Target 5-10% weight loss through a 500-750 kcal/day energy deficit before or concurrent with pharmacotherapy. 1, 2
- Prescribe at least 250 minutes/week of moderate-intensity exercise, which benefits PCOS even without weight loss 1
- Weight loss improves ovulation, pregnancy rates, and decreases androgen levels 1
First-Line Ovulation Induction
- Letrozole is the preferred first-line agent, demonstrating superior live birth rates and pregnancy rates compared to clomiphene citrate. 1
- Clomiphene citrate remains an acceptable first-line alternative, achieving approximately 80% ovulation rates with 50% conception rates among ovulators. 1, 2, 5
- Start clomiphene citrate at 50 mg daily for 5 days, escalating to 100 mg then 150 mg in subsequent cycles if ovulation does not occur 1
- Critical pitfall: Do not exceed clomiphene dosage/duration recommendations due to worsening endometrial receptivity. 1
- Visual symptoms warning: Patients developing visual blurring, scotomata, or phosphenes must discontinue clomiphene immediately and undergo complete ophthalmological evaluation. 9
PCOS-Specific Caution with Clomiphene
- Women with polycystic ovary syndrome are unusually sensitive to gonadotropins and may have exaggerated responses to usual clomiphene doses, requiring the lowest recommended dose and shortest treatment duration for the first course. 9
- If ovarian enlargement occurs, do not give additional clomiphene until ovaries return to pretreatment size 9
Metformin Role in Fertility Treatment
- The American College of Obstetricians and Gynecologists explicitly states that metformin should NOT be used as first-line therapy for ovulation induction, as clomiphene citrate or letrozole are significantly more effective. 5
- Metformin should be used as adjunct to lifestyle modification and ovulation induction agents, not as primary fertility treatment 1
- Women demonstrating insulin resistance or metabolic syndrome features may benefit from metformin addition 5
- Metformin appears safe in pregnancy and may reduce miscarriage rates, though it readily crosses the placenta. 1, 5
Critical Metformin Safety Concerns in Pregnancy
- Follow-up studies show concerning metabolic effects in children exposed to metformin in utero, including higher BMI, increased waist circumference, and increased obesity risk at ages 4-10 years. 5
- Do NOT use metformin in pregnant women with hypertension, preeclampsia, or those at risk for intrauterine growth restriction due to potential for growth restriction or acidosis. 5
- Provide preconception counseling, as metformin may restore ovulation and lead to unintended pregnancy 5
Second-Line for Clomiphene/Letrozole Failure
- Low-dose gonadotropin therapy (preferably recombinant FSH) is preferred over high-dose protocols due to higher monofollicular development rates and lower ovarian hyperstimulation syndrome (OHSS) risk. 1, 7
- Laparoscopic ovarian diathermy is an alternative for clomiphene-resistant patients 7
Ovarian Hyperstimulation Syndrome (OHSS) Warning
- OHSS can progress rapidly within 24 hours to several days and become a serious medical disorder with potential for death due to hypovolemic shock, hemoconcentration, or thromboembolism. 9
- Early warning signs include abdominal pain and distention, nausea, vomiting, diarrhea, and weight gain 9
- Severe cases manifest with gross ovarian enlargement, ascites, dyspnea, oliguria, pleural effusion, and potentially renal failure or pulmonary edema 9
- Use the lowest dose consistent with expected clinical results to minimize risk 9
Mandatory Metabolic Screening
- All PCOS patients require metabolic surveillance regardless of weight or testosterone levels, including screening for glucose intolerance and obtaining fasting lipid profile. 1
- This addresses the increased risk of diabetes, systemic hypertension, and dyslipidemia in PCOS patients 3
Agents NOT Recommended as Primary Treatment
- Berberine is NOT FDA-approved for PCOS and is not mentioned in American College of Obstetricians and Gynecologists, Endocrine Society, or other major PCOS guidelines. 2
- Berberine should not be used as monotherapy for ovulation induction or endometrial protection 2
- GLP-1 agonists show promise for weight reduction when combined with lifestyle interventions but are not yet guideline-recommended 1