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

Richard S. Legro, Huiman X. Barnhart, William D. Schlaff, Bruce R. Carr, Michael Peter Diamond, Sandra A. Carson, Michael P. Steinkampf, Christos Coutifaris, Peter G. McGovern, Nicholas A. Cataldo, Gabriella G. Gosman, John E. Nestler, Linda C. Giudice, Kathryn G. Ewens, Richard S. Spielman, Phyllis C. Leppert, Evan R. Myers

Research output: Contribution to journalArticle

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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 ≥ 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.

Original languageEnglish (US)
Pages (from-to)792-800
Number of pages9
JournalJournal of Clinical Endocrinology and Metabolism
Volume93
Issue number3
DOIs
StatePublished - Jan 1 2008

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Polycystic Ovary Syndrome
Metformin
Polymorphism
Ovulation
Body Mass Index
Genes
Androgens
Confidence Intervals
Odds Ratio
Genotype
Liver
Therapeutics
Alleles
Clomiphene
Biometrics
Genetic Polymorphisms
Phosphotransferases
Nucleotides
Single Nucleotide Polymorphism
Molecular Biology

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

Cite this

Ovulatory response to treatment of polycystic ovary syndrome is associated with a polymorphism in the STK11 gene. / Legro, Richard S.; Barnhart, Huiman X.; Schlaff, William D.; Carr, Bruce R.; Diamond, Michael Peter; Carson, Sandra A.; Steinkampf, Michael P.; Coutifaris, Christos; McGovern, Peter G.; Cataldo, Nicholas A.; Gosman, Gabriella G.; Nestler, John E.; Giudice, Linda C.; Ewens, Kathryn G.; Spielman, Richard S.; Leppert, Phyllis C.; Myers, Evan R.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 93, No. 3, 01.01.2008, p. 792-800.

Research output: Contribution to journalArticle

Legro, RS, Barnhart, HX, Schlaff, WD, Carr, BR, Diamond, MP, Carson, SA, Steinkampf, MP, Coutifaris, C, McGovern, PG, Cataldo, NA, Gosman, GG, Nestler, JE, Giudice, LC, Ewens, KG, Spielman, RS, Leppert, PC & Myers, ER 2008, 'Ovulatory response to treatment of polycystic ovary syndrome is associated with a polymorphism in the STK11 gene', Journal of Clinical Endocrinology and Metabolism, vol. 93, no. 3, pp. 792-800. https://doi.org/10.1210/jc.2007-1736
Legro, Richard S. ; Barnhart, Huiman X. ; Schlaff, William D. ; Carr, Bruce R. ; Diamond, Michael Peter ; Carson, Sandra A. ; Steinkampf, Michael P. ; Coutifaris, Christos ; McGovern, Peter G. ; Cataldo, Nicholas A. ; Gosman, Gabriella G. ; Nestler, John E. ; Giudice, Linda C. ; Ewens, Kathryn G. ; Spielman, Richard S. ; Leppert, Phyllis C. ; Myers, Evan R. / Ovulatory response to treatment of polycystic ovary syndrome is associated with a polymorphism in the STK11 gene. In: Journal of Clinical Endocrinology and Metabolism. 2008 ; Vol. 93, No. 3. pp. 792-800.
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title = "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 ≥ 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.",
author = "Legro, {Richard S.} and Barnhart, {Huiman X.} and Schlaff, {William D.} and Carr, {Bruce R.} and Diamond, {Michael Peter} and Carson, {Sandra A.} and Steinkampf, {Michael P.} and Christos Coutifaris and McGovern, {Peter G.} and Cataldo, {Nicholas A.} and Gosman, {Gabriella G.} and Nestler, {John E.} and Giudice, {Linda C.} and Ewens, {Kathryn G.} and Spielman, {Richard S.} and Leppert, {Phyllis C.} and Myers, {Evan R.}",
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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 Peter

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.

PY - 2008/1/1

Y1 - 2008/1/1

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.

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