Does GLP-1 (Glucagon-Like Peptide-1) therapy improve fertility in women with Polycystic Ovary Syndrome (PCOS)?

GLP-1 Therapy and Fertility in PCOS

GLP-1 receptor agonists are not currently recommended as first-line fertility treatment for PCOS, but emerging evidence suggests they may improve fertility outcomes indirectly through weight loss and metabolic improvements when used as adjunctive therapy in overweight/obese women with PCOS. 1

Current Guideline-Recommended Fertility Treatment Algorithm

First-Line Approach: Lifestyle Modification

• Begin with weight control and regular exercise as the foundation of fertility treatment in all PCOS patients attempting to conceive 2
• Weight loss of just 5% of initial body weight significantly improves both ovulation and pregnancy rates 2, 3
• Target a 500-750 kcal/day reduction or 30% energy deficit 3
• Exercise programs show positive effects even without weight loss 2

Second-Line: Clomiphene Citrate

• After lifestyle modification, clomiphene citrate remains the ACOG-recommended first-line pharmacological treatment for ovulation induction 2, 3
• This recommendation is based on good and consistent scientific evidence, with approximately 80% of PCOS patients ovulating and 50% of those who ovulate conceiving 2, 3

Third-Line: Insulin-Sensitizing Agents

• Metformin improves ovulation frequency and appears safe during pregnancy, though effects on early pregnancy outcomes are not fully established 2, 3
• Metformin reduces insulin levels, which decreases ovarian androgen production 2

GLP-1 Receptor Agonists: Emerging Role

Regulatory Status and Current Recommendations

• GLP-1 receptor agonists are NOT FDA-approved for PCOS treatment or fertility enhancement 1
• The 2023 International Evidence-based Guideline states that anti-obesity medications, including GLP-1 RAs, could be considered for weight management in adult women with PCOS and BMI ≥30 kg/m², following general population obesity guidelines 1
• This is an off-label use that should be considered in addition to, not instead of, active lifestyle intervention 1

Evidence for Fertility Improvement

Mechanism of Action:

• GLP-1 RAs improve fertility indirectly through weight reduction, improved insulin sensitivity, and decreased androgen levels 4, 5, 6, 7
• Preliminary data suggest improved menstrual regularity and increased fertility rates in overweight/obese women with PCOS treated with GLP-1 RAs in the preconception period 5
• GLP-1 appears to have anti-inflammatory and anti-fibrotic effects in the gonads and endometrium affected by obesity and PCOS 5

Clinical Evidence:

• Liraglutide and semaglutide demonstrate superior clinical benefits compared to shorter-acting GLP-1 RAs like exenatide 1
• A 2024 systematic review found that GLP-1 RAs effectively reduce body weight and improve endocrine and metabolic parameters in PCOS 4
• Combined treatment with GLP-1 RA and metformin shows significant effects on weight loss and favorable results on endocrine and metabolic parameters 4

Critical Limitations of Current Evidence

• Most studies used suboptimal medication doses and short 12-week protocols, limiting the ability to demonstrate changes in fertility outcomes 1
• The 2023 International Evidence-based Guideline explicitly states that published data examining anti-obesity agents in women with PCOS are very limited, and further research is urgently needed 1
• Quality trials are inadequate given the prevalence and impact of PCOS 1

Practical Clinical Algorithm for PCOS Fertility Management

Step 1: All Patients

• Implement lifestyle modification targeting 5% weight loss through 500-750 kcal/day reduction and regular exercise 3
• Provide preconception counseling about increased pregnancy risks 3
• Screen for metabolic abnormalities: fasting glucose, 2-hour glucose tolerance test, and lipid profile 3

Step 2: Pharmacological Ovulation Induction

• Start clomiphene citrate as first-line medication 2, 3
• If clomiphene fails, use low-dose gonadotropin therapy 2

Step 3: Consider GLP-1 RA for Specific Patients

Appropriate candidates:

• BMI ≥30 kg/m² who meet general population obesity treatment criteria 1
• Patients with concurrent insulin resistance or prediabetes 1
• Those who have failed lifestyle modification alone and need additional weight loss support 1

Preferred agents:

• Liraglutide or semaglutide over shorter-acting agents like exenatide 1
• Exenatide twice daily did not confer significant benefits over metformin and was associated with more adverse events 1

Combination approach:

• Physical activity, specifically resistance training, should accompany GLP-1 RA treatment to preserve lean body mass 1
• Consider combining with metformin for enhanced metabolic and weight loss effects 4

Safety Considerations and Caveats

Adverse Events

• All GLP-1 RAs consistently result in greater adverse events than controls, including compared to metformin 1
• Use caution in patients with history of pancreatitis, as acute pancreatitis is a rare but documented adverse effect 1
• Avoid in patients with gastroparesis and consider dose reduction if symptomatic gastrointestinal side effects occur 1

Pregnancy Planning

• Engage in shared decision-making with patients, considering both potential benefits and adverse events 1
• Monitor closely throughout pregnancy once conception occurs: blood pressure, kidney function, and proteinuria 3
• Prescribe low-dose aspirin from week 12 to week 36 to reduce preeclampsia risk 3

Bottom Line for Clinical Practice

For PCOS patients seeking fertility, prioritize lifestyle modification and clomiphene citrate as guideline-recommended first-line treatments. 2, 3 GLP-1 receptor agonists may be considered as adjunctive therapy for weight management in obese patients (BMI ≥30 kg/m²) with PCOS, particularly those with insulin resistance, but should not replace established fertility treatments. 1 The fertility benefits appear to be mediated primarily through weight loss and metabolic improvement rather than direct reproductive effects. 4, 5, 7 Larger interventional studies are urgently needed to establish the role of preconception GLP-1 RA therapy in fertility outcomes. 1, 5