What pharmacologic and lifestyle treatments should be offered to a reproductive‑age woman with polycystic ovary syndrome?

Treatment of Polycystic Ovary Syndrome (PCOS)

For a reproductive-age woman with PCOS, begin with lifestyle modification targeting 5-10% weight loss through diet and exercise, then add metformin 1.5-2g daily for metabolic management, and use combined oral contraceptives as first-line hormonal therapy if she is not attempting pregnancy. 1, 2

Initial Management: Lifestyle Modification (Mandatory First-Line for All Patients)

• Target a 500-750 kcal/day energy deficit with total intake of 1,200-1,500 kcal/day, adjusted for individual energy requirements and activity levels 2
• Prescribe at least 250 minutes/week of moderate-intensity exercise (or 150 minutes/week vigorous activity) plus muscle-strengthening activities on 2 non-consecutive days per week for weight loss 2
• Even 5% weight loss significantly improves metabolic and reproductive abnormalities in PCOS, including ovulation rates and pregnancy outcomes 3, 2
• Any balanced dietary approach creating an energy deficit is acceptable—no specific diet type has proven superior in PCOS 2

Pharmacologic Management Based on Clinical Goals

For Women NOT Attempting Pregnancy

Combined oral contraceptives are first-line hormonal therapy because they: 3, 2, 4

• Suppress ovarian androgen secretion and increase sex hormone-binding globulin 2
• Regulate menstrual cycles and prevent endometrial hyperplasia 2, 4
• Improve hirsutism and acne 3, 4

Add metformin 1.5-2g daily when: 1, 2

• Insulin resistance or glucose intolerance is documented 2
• Lifestyle modifications alone are insufficient for metabolic control 2
• The patient has obesity or elevated cardiovascular risk factors 2

Metformin provides multiple benefits even with normal HbA1c: 1

• Improves or maintains glucose tolerance over time 1
• Decreases LDL cholesterol and triglyceride levels 1
• May normalize ovulatory abnormalities 1
• Causes weight loss or maintains stable weight (unlike thiazolidinediones) 1

For hirsutism refractory to oral contraceptives, add antiandrogen therapy: 3, 5

• Spironolactone (competitive androgen receptor antagonist) 3, 5
• Finasteride (5α-reductase inhibitor) 3, 5

For Women Attempting Pregnancy

Clomiphene citrate is first-line ovulation induction therapy because approximately 80% of patients ovulate and 50% conceive 3, 2

If clomiphene fails, use low-dose gonadotropin therapy rather than high-dose protocols to reduce ovarian hyperstimulation risk 3

Metformin 1.5-2g daily improves ovulation frequency and can be used as adjunct therapy, though clomiphene remains first-line 3, 1

Consider letrozole as an alternative ovulation induction agent based on recent evidence 6

Emerging Therapies: GLP-1 Receptor Agonists

GLP-1 agonists (semaglutide, liraglutide, exenatide) show superior weight reduction compared to placebo when combined with lifestyle interventions 3, 2

• These agents provide additional metabolic benefits beyond metformin alone 3
• Evidence quality is limited but promising for anthropometric and metabolic outcomes 3, 2
• Consider when lifestyle plus metformin are insufficient for weight management 2

Adjunctive Therapy: Inositol Supplementation

Myo-inositol 2000mg twice daily plus folic acid 200mcg twice daily can be added as adjunct to lifestyle modification 7

• 68% of patients restore menstrual regularity within 6 months 7
• 70% achieve restored ovulation with myo-inositol therapy 7
• Pregnancy rate of 15.1% achieved with this combination 7
• Better tolerability than metformin with equivalent or superior pregnancy rates 7
• Use physiological 40:1 ratio of myo-inositol to D-chiro-inositol 7

Mandatory Metabolic Screening and Monitoring

Screen all PCOS patients regardless of weight for: 2, 4

• Type 2 diabetes (fasting glucose, HbA1c, or oral glucose tolerance test) 2, 4
• Fasting lipid profile 2, 4
• Blood pressure 2
• BMI and waist-hip ratio using ethnic-specific cutoffs 2

Repeat metabolic screening at least annually because PCOS patients are four times more likely to develop type 2 diabetes than the general population 4

Screen for mental health disorders including depression, anxiety, and eating disorders, which occur more frequently in PCOS 2, 6

Critical Contraindications and Precautions

Metformin is contraindicated in: 1

• Impaired renal function 1
• Known hepatic disease 1
• Hypoxemic conditions 1
• Severe infections or alcohol abuse 1
• Temporarily discontinue during acute illness with dehydration or hypoxemia 1
• Discontinue with radiocontrast material administration 1

Before prescribing oral contraceptives, document risk factors: 8

• Age, smoking status, obesity 8
• Any degree of glucose intolerance including prediabetes 8
• Hypertension, dyslipidemia 8
• Thrombophilia or personal/family history of venous thromboembolism 8

Thiazolidinediones should be avoided due to weight gain and hepatotoxicity concerns (troglitazone was removed from market) 3

Special Considerations for Pregnancy Planning

Discontinue these medications before or upon pregnancy confirmation: 2

• Thiazolidinediones (insufficient safety data) 2
• Clomiphene citrate (no benefit after conception) 2
• Oral contraceptives 2

Metformin is considered safe during pregnancy per ACOG guidelines, though routine use solely for preventing gestational diabetes is not supported 2

Provide preconception counseling about increased risk of unplanned pregnancy when metformin improves ovulation 1

Evaluate blood pressure, renal function, and thyroid function before conception to identify modifiable risk factors 2

Common Pitfalls to Avoid

• Do not delay metabolic screening in normal-weight PCOS patients—insulin resistance affects 50-70% of all women with PCOS regardless of BMI 4, 6
• Do not exceed recommended clomiphene dosage and duration to minimize ovarian hyperstimulation risk 2
• Do not use metformin as monotherapy for ovulation induction—clomiphene remains first-line 3, 2
• Do not neglect endometrial protection—cycles >35 days increase risk of endometrial hyperplasia and cancer 5
• Do not prescribe oral contraceptives without baseline cardiovascular risk assessment in obese patients with severe insulin resistance 8