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Pharmacogenetics of Metformin Action in PCOS

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ClinicalTrials.gov Identifier: NCT00703508
Recruitment Status : Completed
First Posted : June 23, 2008
Results First Posted : April 25, 2017
Last Update Posted : June 14, 2017
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
Virginia Commonwealth University

Brief Summary:
  1. The polycystic ovary syndrome is the major cause of infertility in the United States. Metformin has been shown to increase frequency of ovulations in PCOS, and is used in clinical practice to treat infertility, but some women with PCOS do not respond to metformin treatment.
  2. Knowing that a specific gene predicts the effect of metformin on ovulation would facilitate more efficient and effective treatment of infertility in PCOS.

Condition or disease Intervention/treatment Phase
Polycystic Ovary Syndrome Drug: Metformin 500 mg tablet Not Applicable

Detailed Description:

The polycystic ovary syndrome (PCOS) affects approximately 6-10% of women of childbearing age, i.e., 3.5-5.5 million women in the United States. PCOS is the most common endocrine disturbance of young women and the major cause (75%) of anovulatory infertility in the United States. We hypothesize that women with the polycystic ovary syndrome (PCOS) who have the G/G genotype of single nucleotide polymorphism (SNP)_ 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 36 women with PCOS who are treated with metformin and carefully monitored for ovulation for 9 months. STK11 genotype status will be determined, and the ovulation rates in the G/G, G/C and C/C genotype groups will be compared with one another. Our goal is to identify the genes that predict or modify response to commonly prescribed medications that will allow physicians to better choose among existing therapies and individualize treatment. While metformin has been shown to increase ovulatory frequency in PCOS and is widely used in clinical practice to treat infertility, a substantial number of women either do not respond or are slow to respond to metformin treatment.

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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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 55 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pharmacogenetics of Metformin Action in PCOS
Study Start Date : July 2008
Actual Primary Completion Date : September 2013
Actual Study Completion Date : March 2014

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Metformin
Metformin tablet, 500 mg/tablet, 2 tablets every twelve hours, 9 months duration
Drug: Metformin 500 mg tablet
Metformin 500 mg tablets; two tablets every 12 hours for 9 months
Other Name: Glucophage

Primary Outcome Measures :
  1. Number of Responders/Non-responders for Each STK11 rs8111699 Genotype (C/G, C/C, G/G) [ Time Frame: 9 months ]
    Responders were defined as those that had a doubling of baseline ovulation rate estimated by self-report of menstrual history.

  2. Ovulation Rate Over Study Duration for STK11 Genotypes CC, CG and GG [ Time Frame: 9 months ]
    Ovulations were determined by measurement of daily urine pregnanediol-3-glucuronide or weekly progesterone levels over 6-9 months of study duration for each participant. The ovulation rate was calculated as the number of confirmed ovulation events per months of study participation.

Secondary Outcome Measures :
  1. Determine in Which Genotype(s) Frequency of Ovulation Correlates With Improvement in Reduction in Total Testosterone and Insulin Sensitivity as Measured by the Matsuda Index. [ Time Frame: 9 months ]
    Bivariate fit (RSquare with P values) of ovulation rate post treatment by change in total testosterone and Matsuda Index for each of the 3 genotypes (G/G, C/G, C/C)

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Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Premenopausal women between 18-45 years of age and BMI less than 42
  • Diagnosed with PCOS as defined by the Rotterdam criteria, which is a combination of any two of the following three criteria: 1) chronic oligo- or amenorrhea (<8 menstrual periods annually); 2) biochemical or clinical androgen excess; and 3) polycystic ovaries on ultrasonography -Normal thyroid function tests and serum prolactin; and exclusion of 21 alpha hydroxylase deficiency by a fasting 17 alpha hydroxyprogesterone less than 200 ng/dl -In acceptable health on the basis of interview, medical history, physical examination, and laboratory tests (CBC, SMA20,urinanalysis) -Able to provide signed, witnessed informed consent -Able to comply with study requirements

Exclusion Criteria:

-Diabetes mellitus by fasting glucose or OGTT, or clinically significant pulmonary, cardiac,renal,hepatic,neurologic,psychiatric,infectious,neoplastic and malignant disease (other than non-melanoma skin cancer) -Current use of oral contraceptives; use of fertility drugs within 6 months of study -Current or recent use (within 3 months prior to study entry) of metformin -Documented or suspected recent (within one year)history of drug abuse or alcoholism -Ingestion of any investigational drug within two months prior to study onset.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00703508

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United States, Virginia
University Of Virginia General Clinical Research Center
Charlottesville, Virginia, United States, 22908
Virginia Commonwealth University
Richmond, Virginia, United States, 23298
Sponsors and Collaborators
Virginia Commonwealth University
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
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Principal Investigator: John E. Nestler, M.D. Virginia Commonwealth University
Additional Information:
Publications of Results:
Cheang KI, Bhavi Modi, Maria Shulleeta, William S. Evans, Lubna Pal, Jerome F. Strauss and John E. Nestler: Genetic Polymorphisms and Ovulatory Responsiveness to Metformin in Women with Polycystic Ovary Syndrome. Endo Reviews 36 (2): Supplement THR-109, Apr. 2015.

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Responsible Party: Virginia Commonwealth University
ClinicalTrials.gov Identifier: NCT00703508    
Other Study ID Numbers: HM11153
2U54HD034449 ( U.S. NIH Grant/Contract )
First Posted: June 23, 2008    Key Record Dates
Results First Posted: April 25, 2017
Last Update Posted: June 14, 2017
Last Verified: June 2017
Keywords provided by Virginia Commonwealth University:
Additional relevant MeSH terms:
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Polycystic Ovary Syndrome
Ovarian Cysts
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Female Urogenital Diseases
Female Urogenital Diseases and Pregnancy Complications
Urogenital Diseases
Genital Diseases
Gonadal Disorders
Endocrine System Diseases
Hypoglycemic Agents
Physiological Effects of Drugs