Polycystic Ovary Syndrome
Conditions
Keywords
PCOS
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.
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.
Interventions
DRUGMetformin 500 mg tablet
Metformin 500 mg tablets; two tablets every 12 hours for 9 months
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Virginia Commonwealth University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 45 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Responders/Non-responders for Each STK11 rs8111699 Genotype (C/G, C/C, G/G) | 9 months | Responders were defined as those that had a doubling of baseline ovulation rate estimated by self-report of menstrual history. |
| Ovulation Rate Over Study Duration for STK11 Genotypes CC, CG and GG | 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
| Measure | Time frame | Description |
|---|---|---|
| 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. | 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) |
Countries
United States
Participant flow
Pre-assignment details
55 subjects were enrolled, however some subjects failed to meet eligibility criteria resulting in 26 subjects initiating and completing all study phases.
Participants by arm
| Arm | Count |
|---|---|
| Metformin Metformin tablet, 500 mg/tablet, 2 tablets every twelve hours, 9 months duration
Metformin 500 mg tablet: Metformin 500 mg tablets; two tablets every 12 hours for 9 months | 26 |
| Total | 26 |
Baseline characteristics
| Characteristic | Metformin |
|---|---|
| Age, Continuous | 27.9 years STANDARD_DEVIATION 4.2 |
| BMI | 35.0 kg/m^2 STANDARD_DEVIATION 7.6 |
| Sex: Female, Male Female | 26 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 1 / 26 |
| serious Total, serious adverse events | 0 / 26 |
Outcome results
Primary
Number of Responders/Non-responders for Each STK11 rs8111699 Genotype (C/G, C/C, G/G)
Responders were defined as those that had a doubling of baseline ovulation rate estimated by self-report of menstrual history.
Time frame: 9 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| G/G Genotype | Number of Responders/Non-responders for Each STK11 rs8111699 Genotype (C/G, C/C, G/G) | responders | 6 participants |
| G/G Genotype | Number of Responders/Non-responders for Each STK11 rs8111699 Genotype (C/G, C/C, G/G) | non-responders | 3 participants |
| C/G Genotype | Number of Responders/Non-responders for Each STK11 rs8111699 Genotype (C/G, C/C, G/G) | responders | 7 participants |
| C/G Genotype | Number of Responders/Non-responders for Each STK11 rs8111699 Genotype (C/G, C/C, G/G) | non-responders | 4 participants |
| C/C Genotype | Number of Responders/Non-responders for Each STK11 rs8111699 Genotype (C/G, C/C, G/G) | responders | 5 participants |
| C/C Genotype | Number of Responders/Non-responders for Each STK11 rs8111699 Genotype (C/G, C/C, G/G) | non-responders | 1 participants |
Primary
Ovulation Rate Over Study Duration for STK11 Genotypes CC, CG and GG
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.
Time frame: 9 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G/G Genotype | Ovulation Rate Over Study Duration for STK11 Genotypes CC, CG and GG | 0.47 ovulations/month | Standard Deviation 0.31 |
| C/G Genotype | Ovulation Rate Over Study Duration for STK11 Genotypes CC, CG and GG | 0.36 ovulations/month | Standard Deviation 0.396 |
| C/C Genotype | Ovulation Rate Over Study Duration for STK11 Genotypes CC, CG and GG | 0.34 ovulations/month | Standard Deviation 0.336 |
Secondary
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.
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)
Time frame: 9 months
Population: Individuals that were lost to follow up had missing data on testosterone and OGTT (oral glucose tolerance testing) for Matsuda index.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| G/G Genotype | 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. | Ovulation rate vs Testosterone post treatment | 0.138956 Correlation coefficient (r^2) |
| G/G Genotype | 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. | Ovulation rate vs Matsuda Index post treatment | 0.27144 Correlation coefficient (r^2) |
| C/G Genotype | 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. | Ovulation rate vs Testosterone post treatment | 0.035449 Correlation coefficient (r^2) |
| C/G Genotype | 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. | Ovulation rate vs Matsuda Index post treatment | 0.01918 Correlation coefficient (r^2) |
| C/C Genotype | 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. | Ovulation rate vs Testosterone post treatment | 0.049263 Correlation coefficient (r^2) |
| C/C Genotype | 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. | Ovulation rate vs Matsuda Index post treatment | 0.132059 Correlation coefficient (r^2) |
p-value: 0.0234Regression, Linear
p-value: 0.074Regression, Linear
p-value: 0.4698Regression, Linear
p-value: 0.118Regression, Linear
p-value: 0.0311Regression, Linear
p-value: 0.1586Regression, Linear