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Submitted on August 3, 2007
Accepted on November 7, 2007
Department of Obstetrics and Gynecology, Pennsylvania State University, Hershey, PA (R.S.L); Department of Obstetrics and Gynecology and Duke Clinical Research Institute, Duke University Medical Center, Durham, NC (H.Y., E.R.M.); University of Colorado, Denver, CO (W.D.S.); University of Texas Southwestern Medical Center, Dallas, TX (B.R.C.); Departments of Obstetrics and Gynecology, Wayne State University, Detroit, MI (M.P.D.); Baylor College of Medicine, Houston, TX (S.A.C.); University of Alabama, Birmingham, AL (M.P.S.); University of Pennsylvania School of Medicine, Philadelphia, PA (C.C., K.G.E., R.S.S.); University of Medicine and Dentistry of New Jersey, Newark, NJ (P.G.M.); Stanford University, Stanford, CA (N.A.C.); University of Pittsburgh, Pittsburgh, PA (G.C.); Department of Medicine, Virginia Commonwealth University School of Medicine (J.E.N.); Department of Obstetrics and Gynecology, University of California at San Francisco, San Francisco, CA (L.C.G.), and the Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC (formerly Reproductive Sciences Branch, National Institute of Child Health and Human Development, Bethesda, MD) (P.C.L.)
* To whom correspondence should be addressed. 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: To identify predictive genetic polymorphisms and other determinants of ovulatory response.
Design: Substudy of a multicenter randomized clinical trial
Setting: Academic medical centers and their affiliates
Participants: 312 women with PCOS
Main Outcome Measures: Historical, biometric, biochemical, and genetic parameters.
Results: We found that the C allele of a SNP 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 analysis of ovulation per cycle, the adjusted odds ratio (OR) comparing the C/C genotype to the G/G genotype was 0.30 (95% CI [0.14, 0.66]) and the OR for the C/G genotype versus the G/G genotype was also 0.30 (95% CI [0.14, 0.66]). In analysis of metformin-treated subjects, we found that the percent of women who ovulated increased with number of G alleles present: 48% (10/21) of CC women, 67% (32/48) of CG women, and 79% (15/19) of GG women ovulated. We also found that increased frequency of ovulation was associated with lower body mass index (adjusted OR of 2.36 [1.65,3.36] and 2.05 [1.46,2.88], respectively, for comparisons of BMI < 30 versus BMI 
35, BMI 30–34 versus BMI 35, in the analysis of ovulation per cycle), a lower free androgen index (FAI) (adjusted OR of 1.59 [1.17,2.18] for FAI < 10 versus FAI 10), and a shorter duration of attempting conception (adjusted OR of 1.63 [1.20,2.21] for < 1.5 yrs versus 1.5 yrs).
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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