Affecting up to 10% of women of reproductive age, the polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility in the U.S. and is often characterized by insulin resistance and compensatory hyperinsulinemia, which play a key role in the pathogenesis of the anovulation and hyperandrogenism. Several studies have demonstrated an increase in ovulation frequency in women with PCOS receiving the insulin-sensitizing drug metformin, which was confirmed by a rigorous meta-analysis. As a result, metformin is widely used to treat infertility in PCOS. However, not all women with PCOS benefit from the administration of metformin, and no validated predictors of response have been identified. A substudy of the recent PPCOS Trial evaluated single nucleotide polymorphisms (SNPs) in candidate genes, including the STK11 gene, with respect to ovulation. LKB1 kinase, which is the protein product of the STK11 gene, is the key target of metformin action, and the presence of LKB1 is required for metformin efficacy. The substudy analyzed 311 women with PCOS who were treated with metformin or clomiphene for 6 months. SNP_rs8111699 is located in the first intron of the STK11 gene in a region of linkage disequilibrium that extends to the STK11 promoter. Women with the C/C and C/G genotypes were less likely to ovulate than women with the G/G genotype after treatment with metformin. Thus, the """"""""C"""""""" allele appears to be associated with reduced responsiveness to metformin in terms of ovulation. These results are the first evidence that genetic variation in a metformin response gene may be associated with altered efficacy. The proposed investigation will examine the ability of STK11 genotyping, as well as genotypes of other metformin pathway and PCOS candidate genes, to identify women with PCOS who would respond to metformin in terms of increased frequency of ovulation. We will prospectively test the hypothesis that women with PCOS who have the G/G genotype of rs8111699 in STK11 will exhibit a significantly greater response to metformin, in terms of ovulation, compared with women with either the C/G or C/C genotype. Specifically, we anticipate the frequency of ovulation (defined by number of ovulations/9 months/subject) to be at least 2-fold higher in women with the G/G STK11 genotype compared with women with either the C/G or C/C genotype. To test this hypothesis, we will obtain DNA for STK11 genotyping in 152 women with PCOS who are treated with metformin and carefully monitored for ovulation for 9 months. STK11 genotype status will be determined at end-of-study, and at that time the ovulation rates in the G/G, G/C and C/C genotype groups will be compared with one another. Metformin is widely used in clinical practice to treat infertility, but not all women respond. Knowing that a specific STK11 genotype predicts the effect of metformin on ovulation would facilitate more efficient and effective treatment of infertility in PCOS.
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