What is the treatment for patients with Polycystic Ovary Syndrome (PCOS) and insulin resistance?

Treatment of PCOS with Insulin Resistance

Multicomponent lifestyle intervention—combining diet, exercise, and behavioral strategies—is the mandatory first-line treatment for all patients with PCOS and insulin resistance, regardless of body weight, because insulin resistance is present irrespective of BMI and affects both lean and overweight women. 1, 2

Understanding the Critical Pathophysiology

Insulin resistance is fundamental to PCOS pathophysiology and occurs independent of weight status. 2 The resulting hyperinsulinemia drives hyperandrogenism through direct effects on the pituitary, liver, and ovaries in all women with PCOS, creating a vicious metabolic cycle that worsens all PCOS symptoms. 2 This means even normal-weight women require aggressive insulin resistance management—do not dismiss lifestyle intervention in lean PCOS patients simply because they have normal BMI. 2

First-Line Treatment: Structured Lifestyle Intervention

Dietary Management

• Target a 500-750 kcal/day energy deficit (total intake 1,200-1,500 kcal/day) adjusted for individual energy requirements, body weight, and physical activity levels. 1, 3
• Any balanced dietary approach that creates an energy deficit is acceptable—no specific diet type (low-carb, DASH, high-protein) has proven superior in PCOS. 1, 3
• Follow general healthy eating principles tailored to food preferences while avoiding overly restrictive or nutritionally unbalanced diets. 1, 3
• Even modest weight loss of 5-10% yields significant clinical improvements in metabolic and reproductive outcomes. 2, 3

Exercise Prescription

• For weight maintenance and health: Perform at least 150 minutes/week of moderate-intensity activity OR 75 minutes/week of vigorous-intensity activity, plus muscle-strengthening activities on 2 non-consecutive days/week. 2, 3
• For weight loss and prevention of regain: Increase to at least 250 minutes/week of moderate-intensity activity OR 150 minutes/week of vigorous-intensity activity, plus muscle strengthening on 2 non-consecutive days/week. 2, 3
• Both aerobic and resistance exercises improve insulin sensitivity in PCOS, with benefits occurring even without significant weight loss. 2, 4
• Activity should be performed in at least 10-minute bouts, aiming for at least 30 minutes daily on most days. 2

Behavioral Strategies

• Implement SMART (specific, measurable, achievable, realistic, timely) goal setting and self-monitoring. 2, 3
• Include stimulus control, problem-solving, assertiveness training, slower eating, reinforcement of changes, and relapse prevention. 2, 3
• Address psychological factors including anxiety, depression, body image concerns, and disordered eating, as these require active management to optimize engagement with treatment. 2, 3

Second-Line Treatment: Pharmacological Management

Metformin for Insulin Resistance

Add metformin (500-2000 mg daily) when: 1, 5, 6

• Insulin resistance or glucose intolerance is documented on screening
• Lifestyle modifications alone are insufficient for metabolic control
• Patient has obesity or elevated cardiovascular risk factors

Metformin improves insulin sensitivity and reduces circulating androgen levels, with better glucose tolerance maintained over time. 1, 7 While metformin improves insulin resistance, randomized controlled trials show it does not significantly affect body mass index, fasting glucose, or lipid levels as monotherapy. 7 Metformin appears safe during pregnancy and may reduce miscarriage risk in PCOS. 5

Combined Oral Contraceptives (COCs)

For women not attempting to conceive, COCs are first-line hormonal therapy. 1, 3, 5 They suppress ovarian androgen secretion, increase sex hormone-binding globulin, regulate menstrual cycles, prevent endometrial hyperplasia, and reduce hirsutism and acne. 1, 3, 5 Low-dose oral contraception does not appear to cause clinically significant metabolic dysfunction. 7

Emerging Anti-Obesity Agents

The 2024 international evidence-based guideline systematic review found that GLP-1 receptor agonists (liraglutide, semaglutide, exenatide) and orlistat show promise for weight reduction and metabolic improvement when combined with lifestyle interventions. 1, 3 However, published data remain very limited—only 11 trials with 996 participants were identified, and most agents improved anthropometric outcomes descriptively. 1 Liraglutide, semaglutide, and orlistat appeared superior to placebo for anthropometric outcomes. 1 Meta-analysis showed no differences between exenatide versus metformin for most outcomes except slightly lower fasting glucose with metformin. 1

Mandatory Metabolic Screening

All patients with PCOS require comprehensive metabolic surveillance regardless of weight: 1, 3

• Screen for type 2 diabetes with fasting glucose followed by 2-hour oral glucose tolerance test (75-gram glucose load). 1, 5
• Obtain fasting lipid profile including total cholesterol, LDL, HDL, and triglycerides. 1, 3
• Calculate BMI and waist-hip ratio using ethnic-specific cutoffs (Asian, Hispanic, South Asian populations require lower thresholds). 2, 3
• Repeat screening at least annually, with weight and waist circumference monitored every 6-12 months. 1

Special Considerations for Fertility

If pregnancy is desired: 3, 5

• Continue lifestyle modifications and metabolic management as foundation
• Clomiphene citrate is first-line ovulation induction (approximately 80% ovulate, 50% conceive). 1, 3
• Consider low-dose gonadotropin therapy if clomiphene fails. 3
• Do not use spironolactone as monotherapy in patients attempting to conceive—use clomiphene citrate instead. 5
• Do not use thiazolidinediones in pregnancy—their effects on early pregnancy are poorly documented compared to metformin. 5

Critical Pitfalls to Avoid

• Do not assume normal weight excludes metabolic dysfunction—insulin resistance requires management regardless of BMI. 2, 5
• Do not delay lifestyle intervention—it must be the foundation, not an afterthought. 5
• Do not exceed recommended clomiphene dosage and duration. 3, 5
• Do not neglect metabolic screening even in normal-weight PCOS patients. 3
• Ensure health professional interactions are respectful and patient-centered, avoiding weight-related stigma. 2, 3

Ethnic and Cultural Considerations

Ethnic groups with PCOS who are at high cardiometabolic risk (Asian, Hispanic, South Asian) require greater consideration for lifestyle intervention intensity. 2, 3 East Asian women with PCOS have the highest prevalence of metabolic syndrome despite lower BMI and less hyperandrogenic features. 1 Use ethnic-specific BMI and waist circumference categories to guide treatment decisions. 2, 3