Prepregnancy Insulin Resistance and Fertility in PCOS
Polycystic ovarian syndrome, or PCOS, is one of the most common hormone-related conditions affecting women of reproductive age. It often causes irregular ovulation, difficulty getting pregnant, and a higher risk of pregnancy complications. Many women with PCOS also have insulin resistance, meaning the body does not respond to insulin as efficiently as it should. As a result, the pancreas has to produce more insulin to keep blood sugar under control.
This study examined whether insulin resistance before pregnancy, and whether improvement in insulin resistance during ovulation induction treatment, were linked to fertility outcomes and pregnancy complications in women with PCOS.
Study Design
This was a secondary analysis of PPCOS II, a large multicenter randomized clinical trial. The original trial enrolled women aged 18 to 40 years with PCOS who were trying to conceive and were treated with either clomiphene citrate or letrozole to stimulate ovulation.
Researchers assessed insulin resistance at two time points: at screening before treatment and again at the end of treatment. They used three commonly accepted measures:
1. Homeostatic Model Assessment of Insulin Resistance, or HOMA-IR
2. Quantitative Insulin Sensitivity Check Index
3. Glucose-to-insulin ratio
The main outcome was clinical pregnancy, which means a pregnancy confirmed by ultrasound or other clinical evidence. Secondary outcomes included gestational diabetes mellitus, preeclampsia, and preterm birth.
Key Findings
Among 746 women included in the analysis, those with higher prepregnancy HOMA-IR levels had worse reproductive outcomes overall. Women in the highest insulin resistance groups were less likely to ovulate, took longer to ovulate for the first time, and had lower rates of clinical pregnancy and live birth.
Ovulation rates decreased across rising HOMA-IR quartiles, from 93.5% in the lowest group to 73.8% in the highest group. Clinical pregnancy rates also declined, from 36% to 26.5%, and live-birth rates dropped from 35.5% to 18.2%. At the same time, the risk of gestational diabetes rose sharply, from 13.8% in the lowest quartile to 45.7% in the highest.
Women with the highest insulin resistance also experienced more obstetric complications overall, with gestational diabetes being the most prominent. The findings suggest that insulin resistance is not only a metabolic problem but also an important predictor of reproductive success and pregnancy safety in women with PCOS.
Improvement in Insulin Resistance During Treatment
An especially important part of the study was the observation that improvement in HOMA-IR during ovulation induction was associated with better outcomes. Women whose insulin resistance improved were more likely to achieve clinical pregnancy and had a lower risk of preeclampsia.
This suggests that metabolic health may influence fertility even over a relatively short treatment period. In practical terms, improving insulin sensitivity may help the ovaries respond better to ovulation-induction medications and may also lower the chance of some pregnancy-related complications.
Why Insulin Resistance Matters in PCOS
Insulin resistance can worsen PCOS symptoms by increasing ovarian androgen production, disrupting follicle development, and interfering with regular ovulation. Higher insulin levels may also contribute to weight gain and make it harder to improve metabolic health, creating a cycle that affects both fertility and pregnancy.
During pregnancy, insulin resistance naturally increases, so women who already have significant insulin resistance before conception may be more vulnerable to gestational diabetes and related complications. This study adds strong evidence that the metabolic state before pregnancy matters.
Clinical Implications
The results support a more comprehensive approach to fertility care in women with PCOS. Rather than focusing only on ovulation induction, clinicians should also assess insulin resistance and consider strategies to improve it before conception.
Common approaches may include lifestyle changes such as dietary improvement, regular physical activity, weight management when appropriate, and, in selected patients, medications that improve insulin sensitivity. Metformin is often used in PCOS for metabolic support, although treatment decisions should be individualized based on symptoms, body weight, glucose status, fertility goals, and overall health. Letrozole and clomiphene citrate remain standard medications for ovulation induction, but their effectiveness may be influenced by the underlying metabolic environment.
Importantly, these findings do not mean that every woman with PCOS and insulin resistance will have infertility or pregnancy complications. However, the study indicates that higher insulin resistance increases risk on average and that reducing it may improve chances of conception and reduce some obstetric risks.
What Patients Should Take Away
For women with PCOS who are planning pregnancy, this study reinforces the value of preconception care. Checking blood sugar, insulin-related markers, body weight, and other metabolic factors before starting fertility treatment may help doctors identify women at higher risk.
If insulin resistance is present, improving it before or during fertility treatment may support ovulation, increase the chance of pregnancy, and lower the risk of gestational diabetes and preeclampsia. Even modest improvements in metabolic health can matter.
Patients should discuss the best plan with their obstetrician-gynecologist or endocrinologist. Because PCOS varies widely from person to person, treatment should be personalized. Some women may need only lifestyle counseling, while others may benefit from medication and closer pregnancy monitoring.
Study Limitations
As a secondary analysis, this research was not originally designed specifically to test every question about insulin resistance. Also, the study population included women receiving fertility treatment in a clinical trial, so the results may not apply equally to all women with PCOS.
In addition, insulin resistance was measured using surrogate indices rather than direct testing. Even so, the findings were consistent across several measures and are biologically plausible, making the conclusions clinically meaningful.
Conclusion
Prepregnancy insulin resistance is associated with poorer fertility outcomes and a higher risk of pregnancy complications in women with PCOS. Women with the highest insulin resistance were less likely to ovulate, less likely to achieve clinical pregnancy and live birth, and more likely to develop gestational diabetes.
Encouragingly, improvement in insulin resistance during treatment was linked to better pregnancy success and less preeclampsia. These results support routine assessment of metabolic health before conception and strengthen the case for early intervention to improve insulin sensitivity in women with PCOS.
For patients and clinicians alike, the message is clear: in PCOS, reproductive health and metabolic health are closely connected, and addressing insulin resistance before pregnancy may improve both fertility and maternal outcomes.
Reference
Yun BH, Seo SK, Maher JY, Dowlut-McElroy T, Gomez-Lobo V. Prepregnancy Insulin Resistance and Fertility and Pregnancy Outcomes in Women With Polycystic Ovarian Syndrome. Obstetrics and Gynecology. 2026-05-22. PMID: 42166772. ClinicalTrials.gov registration: NCT00719186.