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

Abstract

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/G 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>or=10], and a shorter duration of attempting conception [adjusted OR of 1.63 (95% CI 1.20, 2.21) for<1.5 vs.>or=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 metformin alone in a prospective randomized trial. The interaction with the effects of changes in modifiable factors (e.g. BMI or FAI) requires further study.

Trial registration: ClinicalTrials.gov NCT00068861.

Figure 1

Study flow chart.

Figure 2

Proportion of ovulated cycles for patients in the metformin group (each dot represents a subject) by genotype at STK11_rs8111699. The mean (sd, no.) proportion of ovulated cycles is 0.26 (0.35, 21), 0.31 (0.30, 48), and 0.46 (0.34, 19) for C/C, C/G, and G/G groups, respectively. Mean proportion is indicated by a diamond with line.