TY - JOUR
T1 - Ovulatory response to treatment of polycystic ovary syndrome is associated with a polymorphism in the STK11 gene
AU - Legro, Richard S.
AU - Barnhart, Huiman X.
AU - Schlaff, William D.
AU - Carr, Bruce R.
AU - Diamond, Michael P.
AU - Carson, Sandra A.
AU - Steinkampf, Michael P.
AU - Coutifaris, Christos
AU - McGovern, Peter G.
AU - Cataldo, Nicholas A.
AU - Gosman, Gabriella G.
AU - Nestler, John E.
AU - Giudice, Linda C.
AU - Ewens, Kathryn G.
AU - Spielman, Richard S.
AU - Leppert, Phyllis C.
AU - Myers, Evan R.
N1 - Funding Information:
Disclosure Summary: R.S.L. has served as a consultant to GlaxoSmithKline and Ferring, and has had lecture fees paid by Serono, meeting support from Abbott, and grant support from Pfizer. J.E.N. has equity ownership/stock options in Bristol Myers Squibb. P.C.L., E.R.M., and H.X.B. had grant support from Tap, H.X.B. also had grant support from Ortho Biotech, and E.R.M. has received research support from Merck and is also a consultant. W.D.S. has grant support from Organon and Wyeth. N.A.C. consults for Organon. P.G.M. has grant support from Ferring and Serono. M.P.D. has grant support from Serono, Tap, Glaxo Smith Klein, and Merck, and has served as a consultant for Tap and Serono. S.A.C., C.C., K.G.E., R.S.S., L.C.G., M.P.S., G.G.G., and B.R.C. have no disclosures.
Funding Information:
This work was supported by National Institutes of Health/National Institute of Child Health and Human Development Grants U10 HD27049 (to C.C.), U01 HD38997 (to E.R.M.), U10 HD39005 (to M.P.D.), U10 HD27011 (to S.A.C.), U10 HD33172 (to M.P.S.), U10 HD38988 (to B.R.C.), U10 HD38992 (to R.S.L.), U10 HD38998 (to W.D.S.), U10 HD38999 (to P.G.M.), U54 HD34449 National Cooperative Program in Infertility Research (to R.S.S.), U54-HD29834 University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core, GCRC Grant MO1RR00056 to the University of Pittsburgh, and MO1RR10732, and construction grant C06 RR016499 to Pennsylvania State University. Glucophage XR and matching placebo were provided by Bristol-Myers Squibb.
PY - 2008/3
Y1 - 2008/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=40849126625&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=40849126625&partnerID=8YFLogxK
U2 - 10.1210/jc.2007-1736
DO - 10.1210/jc.2007-1736
M3 - Article
C2 - 18000088
AN - SCOPUS:40849126625
SN - 0021-972X
VL - 93
SP - 792
EP - 800
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 3
ER -
