Ovulatory response to treatment of polycystic ovary syndrome is associated with a polymorphism in the STK11 gene

Context: Clomiphene and insulin sensitizers such as metformin are used to induce ovulation in polycystic ovary syndrome ( PCOS), but the ovulatory response is variable, and the causes of this variation are poorly understood. Objective: Our objective was to identify predictive genetic polymorphisms and other determinants of ovulatory response. Design: This was a substudy of a multicenter randomized clinical trial. Setting: This study was performed at academic medical centers and their affiliates. Participants: A total of 312 women with PCOS were included in the study. Main Outcome Measures: Historical, biometric, biochemical, and genetic parameters were performed. Results: We found that the C allele of a single nucleotide polymorphism in the STK11 gene ( expressed in liver; also known as LKB1) was associated with a significantly decreased chance of ovulation in PCOS women treated with metformin. In an analysis of ovulation per cycle, the adjusted odds ratio ( OR) comparing the C/C genotype to the G/G genotype was 0.30[95% confidence interval (CI) 0.14, 0.66], and the OR for the C/C genotype vs. the G/G genotype was also 0.30 ( 95% CI 0.14, 0.66). In an analysis of metformin-treated subjects, we found that the percentage of women who ovulated increased with the number of G alleles present: 48% ( 10 of 21) of C/C women, 67% ( 32 of 48) of C/G women, and 79% ( 15 of 19) of G/G women ovulated. We also found that increased frequency of ovulation was associated with lower body mass index (BMI) [adjusted OR of 2.36(95% CI 1.65, 3.36) and 2.05 ( 95% CI 1.46, 2.88), respectively, for comparisons of BMI less than 30 vs. BMI equal to or more than 35, BMI 30-34 vs. BMI equal to or more than 35, in the analysis of ovulation per cycle], a lower free androgen index (FAI) [adjusted OR of 1.59 ( 95% CI 1.17, 2.18) for FAI < 10 vs. FAI >= 10], and a shorter duration of attempting conception [adjusted OR of 1.63 ( 95% CI 1.20, 2.21) for < 1.5 vs. >= 1.5 yr]. Conclusions: We have demonstrated that a polymorphism in STK11, a kinase gene expressed in liver and implicated in metformin action, is associated with ovulatory response to treatment with met formin alone in a prospective randomized trial. The interaction with the effects of changes in modifiable factors (e. g. BMI or FAI) requires further study.