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Ovulatory Response to Treatment of Polycystic Ovary Syndrome Is Associated with a Polymorphism in the STK11 Gene

Department of Obstetrics and Gynecology (R.S.L.), Pennsylvania State University, Hershey, Pennsylvania 17033; Department of Obstetrics and Gynecology and Duke Clinical Research Institute (H.X.B., E.R.M.), Duke University Medical Center, Durham, North Carolina; University of Colorado (W.D.S.), Denver, Colorado; University of Texas Southwestern Medical Center (B.R.C.), Dallas, Texas; Departments of Obstetrics and Gynecology (M.P.D.), Wayne State University, Detroit, Michigan; Baylor College of Medicine (S.A.C.), Houston, Texas; University of Alabama (M.P.S.), Birmingham, Alabama; University of Pennsylvania School of Medicine (C.C., K.G.E., R.S.S.), Philadelphia, Pennsylvania; University of Medicine and Dentistry of New Jersey (P.G.M.), Newark, New Jersey; Stanford University (N.A.C.), Stanford, California; University of Pittsburgh (G.G.G.), Pittsburgh, Pennsylvania; Department of Medicine (J.E.N.), Virginia Commonwealth University School of Medicine, Richmond, Virginia; Department of Obstetrics and Gynecology (L.C.G.), University of California at San Francisco, San Francisco, California; and Reproductive Sciences Branch (P.C.L.), National Institute of Child Health and Human Development, Bethesda, Maryland

Address all correspondence and requests for reprints to: Richard S. Legro, M.D., Department of Obstetrics and Gynecology, Pennsylvania State College of Medicine, M.S. Hershey Medical Center, 500 University Drive, H103, Hershey, Pennsylvania 17033. E-mail: RSL1{at}psu.edu.

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 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 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.

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				S. Palomba, A. Falbo, F. Zullo, and F. Orio Jr. Evidence-Based and Potential Benefits of Metformin in the Polycystic Ovary Syndrome: A Comprehensive Review Endocr. Rev., February 1, 2009; 30(1): 1 - 50. [Abstract] [Full Text] [PDF]