Official Title: “Pharmacogenetics of Metformin Action in PCOS”

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.

Study Type: Interventional

Study Design: Treatment, Non-Randomized, Open Label, Single Group Assignment, Pharmacokinetics/Dynamics Study

Study Primary Completion Date: March 2013

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 152 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.

Intervention(s) in this Clinical Trial

• Drug: Metformin
  • Metformin 500 mg tablets; two tablets every 12 hours for 9 months

Primary Measures

• Determine if ovulations/9months/woman is greater in women with the G/G genotype of STK11 rs8111699 compared with women with the C/G and C/C genotypes.
  • Time Frame: 9 months
    Safety Issue?: No

Secondary Measures

• Determine in which genotype(s) frequency of ovulation correlates with improvement in insulin sensitivity and/or reduction in total testosterone.
  • Time Frame: 9 months
    Safety Issue?: No

Inclusion Criteria:

• Premenopausal women between 18-40 years of age and BMI less than 40
• Diagnosed with PCOS as defined by chronic oligo-or amenorrhea (less than 8 menstrual periods annually); biochemical hyperandrogenemia (elevated total or free testosterone); 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
• seeking pregnancy; 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.

Gender Eligibility for this Clinical Trial: Female

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 40 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: Accepts Healthy Volunteers

Lead Sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Overall Clinical Trial Officials and Contacts

John E. Nestler, M.D. Principal Investigator Virginia Commonwealth University  

Overall Contact: Manar T. Nazmy 804-827-0171 mtnazmy@vcu.edu

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00703508

Study ID Number: VCU IRB HM11153

ClinicalTrials.gov Identifier: NCT00703508

Health Authority: United States: Federal Government