What are the primary treatment goals and options for a patient with Polycystic Ovary Syndrome (PCOS)?

Treatment of Polycystic Ovary Syndrome (PCOS)

All women with PCOS must begin with lifestyle modification targeting 5-10% weight loss through a 500-750 kcal/day energy deficit, followed by treatment selection based on whether they are seeking pregnancy: combined oral contraceptives for those not attempting conception, or clomiphene citrate/letrozole for ovulation induction in those desiring fertility. 1

Mandatory First-Line Foundation for All PCOS Patients

Lifestyle modification is non-negotiable regardless of reproductive goals or body weight. 1

• Target 5% weight loss of initial body weight, which improves metabolic, reproductive, and hormonal outcomes even in normal-weight patients 1
• Create an energy deficit of 500-750 kcal/day with total intake of 1,200-1,500 kcal/day adjusted for individual requirements 1
• Any balanced dietary approach creating an energy deficit is acceptable—no specific diet type has proven superior 1
• Prescribe at least 150 minutes/week of moderate-intensity exercise or 75 minutes/week of vigorous activity, plus muscle-strengthening activities on 2 non-consecutive days/week 1
• Exercise provides metabolic benefits even without weight loss 1

Treatment Algorithm Based on Reproductive Goals

For Women NOT Attempting to Conceive

Combined oral contraceptives (COCs) are the first-line pharmacological treatment. 1, 2

• COCs suppress ovarian androgen secretion, increase sex hormone-binding globulin, regulate menstrual cycles, prevent endometrial hyperplasia, and reduce hirsutism and acne 1
• COCs containing norgestimate (like Sprintec) are commonly recommended due to favorable side effect profiles 2
• Start within the first 5 days of menstrual bleeding (no backup contraception needed), or at any time if pregnancy is reasonably excluded (use backup contraception for 7 days) 2
• Standard regimens include 21-24 hormone pills followed by 4-7 placebo pills 2
• Baseline venous thromboembolism risk is 1 per 10,000 woman-years; COCs increase this three to fourfold 2

Alternative: Progestin-only therapy when COCs are contraindicated or not tolerated.

• Medroxyprogesterone acetate (MPA) 10 mg daily for 12-14 days per month is the only progestin with robust evidence for inducing secretory endometrium and providing endometrial protection 2
• MPA also suppresses circulating androgen levels and pituitary gonadotropin levels 2
• Oral micronized progesterone 200 mg daily for 12-14 days per month is an effective alternative with superior cardiovascular and thrombotic safety profile 2
• Regular monthly cycling (every 28 days) is recommended to maintain endometrial protection 2

For hirsutism specifically: Combine COC with spironolactone 50-200 mg daily, as this combination provides superior results compared to monotherapy. 1, 2

For Women Attempting to Conceive

After lifestyle modification, proceed directly to clomiphene citrate as first-line ovulation induction, with letrozole as an increasingly preferred alternative. 3

Clomiphene citrate dosing:

• Start at 50 mg daily for 5 days beginning on cycle day 5 3
• Escalate to 100 mg, then 150 mg in subsequent cycles if ovulation does not occur 3
• Approximately 80% of PCOS patients ovulate with clomiphene, and 50% of ovulators conceive 3, 4
• Limit to six total cycles maximum due to worsening endometrial receptivity with prolonged use 1, 4

Letrozole demonstrates superior outcomes compared to clomiphene citrate, with higher live birth rates and pregnancy rates. 3

Second-line for clomiphene/letrozole failure:

• Low-dose gonadotropin therapy is preferred over high-dose protocols due to higher monofollicular development rates and lower ovarian hyperstimulation syndrome (OHSS) risk 3, 2

Adjunctive metabolic management:

• Metformin 500-2000 mg daily improves ovulation frequency and should be used as adjunct to lifestyle modification and ovulation induction agents, not as primary fertility treatment 3, 1
• Metformin appears safe in pregnancy and may reduce miscarriage rates 3
• Metformin decreases circulating androgens and weight 2

Inositol offers distinct advantages including no risk of multiple pregnancy, no weight gain, and favorable safety profile compared to metformin, with pregnancy rates equivalent or superior to metformin. 3

Mandatory Metabolic Screening for ALL PCOS Patients

Screen all PCOS patients at diagnosis and at least annually, regardless of weight or reproductive goals. 1, 2

• Fasting glucose and 2-hour glucose tolerance test 1, 2
• Fasting lipid profile 1, 2
• BMI and waist-hip ratio calculation 1
• Use ethnic-specific BMI and waist circumference categories for Asian, Hispanic, and South Asian populations who are at higher cardiometabolic risk 1

Add metformin 500-2000 mg daily when insulin resistance or glucose intolerance is documented, lifestyle modifications alone are insufficient, or the patient has obesity or elevated cardiovascular risk factors. 1

Emerging Therapies

• GLP-1 receptor agonists show promise for weight reduction and metabolic improvement when combined with lifestyle interventions, and may be considered for patients with obesity or elevated cardiovascular risk factors when lifestyle and metformin are insufficient 3, 1
• Bariatric surgery is emerging as a potential adjunct therapy for PCOS patients with clinically severe obesity, with reported improvements in hirsutism, menstrual regularity, and fertility 1

Critical Pitfalls to Avoid

Do not use spironolactone in patients attempting to conceive—it is contraindicated in pregnancy. 3, 1

Do not delay lifestyle intervention—it must be the foundation of treatment before pharmacological therapy. 3, 1

Do not assume normal weight excludes metabolic dysfunction—screen all PCOS patients regardless of BMI. 1

Do not exceed clomiphene dosage and duration recommendations—limit to six total cycles due to worsening endometrial receptivity. 1, 4

Monitor for OHSS in patients on ovulation induction therapy, especially those with polycystic ovary syndrome who are unusually sensitive to gonadotropin and may have exaggerated response to usual clomiphene doses. 4

• Early warning signs include abdominal pain and distention, nausea, vomiting, diarrhea, and weight gain 4
• If ovarian enlargement occurs, discontinue clomiphene until ovaries return to pretreatment size 4

Discontinue clomiphene immediately if visual symptoms occur (blurring, scotomata, phosphenes) and perform complete ophthalmological evaluation. 4