Polycystic Ovary Syndrome
Conditions
Keywords
Polycystic Ovary Syndrome
Brief summary
The purpose of this study is to determine the efficacy of Lipitor (Atorvastatin) for the treatment of PCOS with elevated LDL cholesterol.
Detailed description
The investigators hypothesize that improving the lipid profile with atorvastatin will improve vascular function, increase the frequency of ovulation, decrease androgen levels, improve insulin sensitivity, and improve the lipid profile more efficiently than placebo.
Interventions
DRUGLipitor
40mg caplets per day for six weeks
DRUGPlacebo
1 placebo caplet per day for six weeks.
Sponsors
Milton S. Hershey Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 40 Years
Healthy volunteers
No
Inclusion criteria
Women with PCOS * 8 or fewer menstrual periods per year * elevated serum total testosterone * elevated LDL cholesterol
Exclusion criteria
* current pregnancy or breastfeeding * current use of oral contraceptives, progestins * insulin sensitizing medications * thyroid disease, hyperprolactinemia, active liver disease, type 1 or type 2 diabetes
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Brachial Artery Flow-mediated Dilation (FMD) | baseline and 6 weeks | Brachial artery FMD, the percent change in brachial artery diameter following release of transient occlusion, was selected as the primary outcome because it is the most widely used research tool for evaluating the effects of interventions on endothelial function. FMD has been shown to predict longterm cardiovascular events, even in patients with no apparent heart disease. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Peak Brachial Artery Conductance (BAC) | baseline and 6 weeks | Pneumatic cuffs were positioned on the upper arm and wrist of the experimental arm. The brachial artery was imaged using an ATL Doppler ultrasound probe (5-12MHz linear array scanhead, HDI 5000, Advanced Technology Laboratories, Bothell, WA). Mean blood flow velocity (MBV) and brachial artery diameter (BAD) were recorded at baseline. Then the wrist cuff was inflated to 200-250 mmHg. After a minute, with the wrist cuff still inflated, the arm cuff was inflated to 200-250 mmHg. After 10 minutes the arm cuff was released to induce reactive hyperemia in the brachial artery. Upon release of the arm cuff, we continuously measured blood pressure (BP), heart rate (HR), and MBV, and intermittently measured BAD in the experimental arm. Brachial artery conductance (BAC)was calculated as MBV/MAP and FMD was calculated as percent change in BAD from baseline. |
| Total Cholesterol | baseline and 6 weeks | — |
| LDL Cholesterol | baseline and 6 weeks | — |
| HDL Cholesterol | baseline and 6 weeks | — |
| Triglycerides | baseline and 6 weeks | — |
| Fasting Glucose | baseline and 6 weeks | — |
| Area Under the Curve (AUC) for Glucose During OGTT | baseline and 6 weeks | A 75 gram oral glucose tolerance test (OGTT) was performed with blood draws at 0, 30, 60, 90 and 120 minutes. |
| AUC for Insulin | baseline and 6 weeks | Area under the curve for insulin during OGTT: A 75 gram oral glucose tolerance test was performed with blood draws at 0, 30, 60, 90 and 120 minutes. |
| Total Testosterone | baseline and 6 weeks | — |
| Androstenedione | baseline and 6 weeks | — |
| DHEAS | baseline and 6 weeks | Dehydroepiandrosterone sulfate |
| Fasting Insulin | baseline and 6 weeks | — |
Other
| Measure | Time frame | Description |
|---|---|---|
| High-sensitivity C-reactive Protein (hsCRP) | baseline and 6 weeks | high sensitive C-reactive protein as a measure of inflammation |
Countries
United States
Participant flow
Recruitment details
Participants were recruited through the clinics of the Departments of Medicine and Obstetrics and Gynecology at Penn State Hershey Medical Center from October 20, 2006 to September 8, 2008.
Participants by arm
| Arm | Count |
|---|---|
| Atorvastatin Atorvastatin, 40 mg qd | 9 |
| Placebo Placebo qd | 11 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Atorvastatin | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants | 11 Participants | 20 Participants |
| Region of Enrollment United States | 9 participants | 11 participants | 20 participants |
| Sex: Female, Male Female | 9 Participants | 11 Participants | 20 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 9 | 2 / 11 |
| serious Total, serious adverse events | 1 / 9 | 0 / 11 |
Outcome results
Primary
Brachial Artery Flow-mediated Dilation (FMD)
Brachial artery FMD, the percent change in brachial artery diameter following release of transient occlusion, was selected as the primary outcome because it is the most widely used research tool for evaluating the effects of interventions on endothelial function. FMD has been shown to predict longterm cardiovascular events, even in patients with no apparent heart disease.
Time frame: baseline and 6 weeks
Population: All analyses were performed by intention-to-treat.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atorvastatin | Brachial Artery Flow-mediated Dilation (FMD) | Before treatment | 12.0 % change in brachial artery diameter | Standard Deviation 7.3 |
| Atorvastatin | Brachial Artery Flow-mediated Dilation (FMD) | After treatment | 10.4 % change in brachial artery diameter | Standard Deviation 4.6 |
| Placebo | Brachial Artery Flow-mediated Dilation (FMD) | Before treatment | 9.8 % change in brachial artery diameter | Standard Deviation 5.8 |
| Placebo | Brachial Artery Flow-mediated Dilation (FMD) | After treatment | 10.2 % change in brachial artery diameter | Standard Deviation 2.9 |
Comparison: This study was initiated as a pilot study with the goal of enrolling 19 women in each group, which we hypothesized would provide 80% power to detect an absolute difference in the change in FMD from baseline between the two groups (Atorvastatin vs. Placebo) of 3.75%, assuming a common standard deviation (SD) of 4%, using a two-sided, two-sample t-test with α=0.05. Recruitment was slow due to strict inclusion/ exclusion criteria so we analyzed our data after the first 20 women completed the study.p-value: 0.5895% CI: [-9.3, 5.3]Linear mixed-effects models
Secondary
Androstenedione
Time frame: baseline and 6 weeks
Population: All analyses were performed by intention-to-treat.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atorvastatin | Androstenedione | Before treatment | 3.4 ng/ml | Standard Deviation 0.8 |
| Atorvastatin | Androstenedione | After treatment | 2.5 ng/ml | Standard Deviation 0.9 |
| Placebo | Androstenedione | Before treatment | 3.8 ng/ml | Standard Deviation 1.2 |
| Placebo | Androstenedione | After treatment | 4.1 ng/ml | Standard Deviation 1.2 |
Comparison: What is being compared for this analysis is the change from baseline for Atorvastatin to the change from baseline for Placebo.p-value: <0.00195% CI: [-1.6, -0.5]Linear mixed-effects models
Secondary
Area Under the Curve (AUC) for Glucose During OGTT
A 75 gram oral glucose tolerance test (OGTT) was performed with blood draws at 0, 30, 60, 90 and 120 minutes.
Time frame: baseline and 6 weeks
Population: All analyses were performed by intention-to-treat.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atorvastatin | Area Under the Curve (AUC) for Glucose During OGTT | Before treatment | 15693 mg*minute/dL | Standard Deviation 2162 |
| Atorvastatin | Area Under the Curve (AUC) for Glucose During OGTT | After treatment | 16136 mg*minute/dL | Standard Deviation 2569 |
| Placebo | Area Under the Curve (AUC) for Glucose During OGTT | Before treatment | 15309 mg*minute/dL | Standard Deviation 3692 |
| Placebo | Area Under the Curve (AUC) for Glucose During OGTT | After treatment | 15448 mg*minute/dL | Standard Deviation 3165 |
Comparison: What is being compared for this analysis is the change from baseline for Atorvastatin to the change from baseline for Placebo.p-value: 0.6195% CI: [-1811, 2983]Linear mixed-effects models
Secondary
AUC for Insulin
Area under the curve for insulin during OGTT: A 75 gram oral glucose tolerance test was performed with blood draws at 0, 30, 60, 90 and 120 minutes.
Time frame: baseline and 6 weeks
Population: All analyses were performed by intention-to-treat.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atorvastatin | AUC for Insulin | Before treatment | 12738 uU*minute/mL | Standard Deviation 10010 |
| Atorvastatin | AUC for Insulin | After treatment | 17479 uU*minute/mL | Standard Deviation 11929 |
| Placebo | AUC for Insulin | Before treatment | 9338 uU*minute/mL | Standard Deviation 5208 |
| Placebo | AUC for Insulin | After treatment | 9132 uU*minute/mL | Standard Deviation 4466 |
Comparison: What is being compared for this analysis is the change from baseline for Atorvastatin to the change from baseline for Placebo.p-value: 0.0795% CI: [-287, 7056]Linear mixed-effects models
Secondary
DHEAS
Dehydroepiandrosterone sulfate
Time frame: baseline and 6 weeks
Population: All analyses were performed by intention-to-treat.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atorvastatin | DHEAS | Before treatment | 1630.0 ng/ml | Standard Deviation 873.1 |
| Atorvastatin | DHEAS | After treatment | 1326.4 ng/ml | Standard Deviation 854.3 |
| Placebo | DHEAS | Before treatment | 1701.5 ng/ml | Standard Deviation 681.3 |
| Placebo | DHEAS | After treatment | 1739.5 ng/ml | Standard Deviation 781.8 |
Comparison: What is being compared for this analysis is the change from baseline for Atorvastatin to the change from baseline for Placebo.p-value: 0.0295% CI: [-655.3, -73.2]Linear mixed-effects models
Secondary
Fasting Glucose
Time frame: baseline and 6 weeks
Population: All analyses were performed by intention-to-treat.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atorvastatin | Fasting Glucose | Before treatment | 87.7 mg/dl | Standard Deviation 9 |
| Atorvastatin | Fasting Glucose | After treatment | 87.8 mg/dl | Standard Deviation 8.5 |
| Placebo | Fasting Glucose | Before treatment | 85.3 mg/dl | Standard Deviation 8 |
| Placebo | Fasting Glucose | After treatment | 88.9 mg/dl | Standard Deviation 10.7 |
Comparison: What is being compared for this analysis is the change from baseline for Atorvastatin to the change from baseline for Placebo.p-value: 0.4595% CI: [-12.4, 5.8]Linear mixed-effects models
Secondary
Fasting Insulin
Time frame: baseline and 6 weeks
Population: All analyses were performed by intention-to-treat.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atorvastatin | Fasting Insulin | Before treatment | 18.6 uU/ml | Standard Deviation 10.1 |
| Atorvastatin | Fasting Insulin | After treatment | 21.0 uU/ml | Standard Deviation 11.8 |
| Placebo | Fasting Insulin | Before treatment | 16.8 uU/ml | Standard Deviation 9.5 |
| Placebo | Fasting Insulin | After treatment | 15.9 uU/ml | Standard Deviation 6.7 |
Comparison: What is being compared for this analysis is the change from baseline for Atorvastatin to the change from baseline for Placebo.p-value: 0.3395% CI: [-2.8, 7.9]Linear mixed-effects models
Secondary
HDL Cholesterol
Time frame: baseline and 6 weeks
Population: All analyses were performed by intention-to-treat.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atorvastatin | HDL Cholesterol | After treatment | 47.8 mg/dl | Standard Deviation 11.8 |
| Atorvastatin | HDL Cholesterol | Before treatment | 44.4 mg/dl | Standard Deviation 14.6 |
| Placebo | HDL Cholesterol | After treatment | 46.8 mg/dl | Standard Deviation 8.4 |
| Placebo | HDL Cholesterol | Before treatment | 46.5 mg/dl | Standard Deviation 8.6 |
Comparison: What is being compared for this analysis is the change from baseline for Atorvastatin to the change from baseline for Placebo.p-value: 0.2695% CI: [-2.7, 9.5]Linear mixed-effects models
Secondary
LDL Cholesterol
Time frame: baseline and 6 weeks
Population: All analyses were performed by intention-to-treat.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atorvastatin | LDL Cholesterol | Before treatment | 140.7 mg/dl | Standard Deviation 24.6 |
| Atorvastatin | LDL Cholesterol | After treatment | 68.5 mg/dl | Standard Deviation 19.3 |
| Placebo | LDL Cholesterol | After treatment | 118.8 mg/dl | Standard Deviation 26.8 |
| Placebo | LDL Cholesterol | Before treatment | 131.3 mg/dl | Standard Deviation 21.6 |
Comparison: What is being compared for this analysis is the change from baseline for Atorvastatin to the change from baseline for Placebo.p-value: <0.00195% CI: [-79.3, -35.9]Linear mixed-effects models
Secondary
Peak Brachial Artery Conductance (BAC)
Pneumatic cuffs were positioned on the upper arm and wrist of the experimental arm. The brachial artery was imaged using an ATL Doppler ultrasound probe (5-12MHz linear array scanhead, HDI 5000, Advanced Technology Laboratories, Bothell, WA). Mean blood flow velocity (MBV) and brachial artery diameter (BAD) were recorded at baseline. Then the wrist cuff was inflated to 200-250 mmHg. After a minute, with the wrist cuff still inflated, the arm cuff was inflated to 200-250 mmHg. After 10 minutes the arm cuff was released to induce reactive hyperemia in the brachial artery. Upon release of the arm cuff, we continuously measured blood pressure (BP), heart rate (HR), and MBV, and intermittently measured BAD in the experimental arm. Brachial artery conductance (BAC)was calculated as MBV/MAP and FMD was calculated as percent change in BAD from baseline.
Time frame: baseline and 6 weeks
Population: All analyses were performed by intention-to-treat.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atorvastatin | Peak Brachial Artery Conductance (BAC) | Before treatment | 5.4 ml/sec/mm Hg | Standard Deviation 2.9 |
| Atorvastatin | Peak Brachial Artery Conductance (BAC) | After treatment | 6.9 ml/sec/mm Hg | Standard Deviation 2.8 |
| Placebo | Peak Brachial Artery Conductance (BAC) | Before treatment | 3.6 ml/sec/mm Hg | Standard Deviation 3 |
| Placebo | Peak Brachial Artery Conductance (BAC) | After treatment | 4.3 ml/sec/mm Hg | Standard Deviation 3.3 |
Comparison: What is being compared for this analysis is the change from baseline for Atorvastatin to the change from baseline for Placebo.p-value: 0.3995% CI: [-0.9, 2.3]Linear mixed-effects models
Secondary
Total Cholesterol
Time frame: baseline and 6 weeks
Population: All analyses were performed by intention-to-treat.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atorvastatin | Total Cholesterol | Before treatment | 215.8 mg/dl | Standard Deviation 39 |
| Atorvastatin | Total Cholesterol | After treatment | 132.0 mg/dl | Standard Deviation 19.7 |
| Placebo | Total Cholesterol | Before treatment | 202.8 mg/dl | Standard Deviation 28.3 |
| Placebo | Total Cholesterol | After treatment | 192.1 mg/dl | Standard Deviation 33.6 |
Comparison: What is being compared for this analysis is the change from baseline for Atorvastatin to the change from baseline for Placebo.p-value: <0.00195% CI: [-95.2, -46.4]Linear mixed-effects models
Secondary
Total Testosterone
Time frame: baseline and 6 weeks
Population: All analyses were performed by intention-to-treat.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atorvastatin | Total Testosterone | Before treatment | 61.3 ng/dl | Standard Deviation 16.9 |
| Atorvastatin | Total Testosterone | After treatment | 47.1 ng/dl | Standard Deviation 21.4 |
| Placebo | Total Testosterone | Before treatment | 92.3 ng/dl | Standard Deviation 49.8 |
| Placebo | Total Testosterone | After treatment | 75.7 ng/dl | Standard Deviation 43.6 |
Comparison: What is being compared for this analysis is the change from baseline for Atorvastatin to the change from baseline for Placebo.p-value: 0.8895% CI: [-24.1, 27.8]Linear mixed-effects models
Secondary
Triglycerides
Time frame: baseline and 6 weeks
Population: All analyses were performed by intention-to-treat.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atorvastatin | Triglycerides | Before treatment | 153.3 mg/dl | Standard Deviation 84.9 |
| Atorvastatin | Triglycerides | After treatment | 78.5 mg/dl | Standard Deviation 24.8 |
| Placebo | Triglycerides | Before treatment | 125.5 mg/dl | Standard Deviation 54.2 |
| Placebo | Triglycerides | After treatment | 132.5 mg/dl | Standard Deviation 45.7 |
Comparison: What is being compared for this analysis is the change from baseline for Atorvastatin to the change from baseline for Placebo.p-value: <0.00195% CI: [-126.2, -38.1]Linear mixed-effects models
Post Hoc
Body Mass Index
Time frame: baseline and 6 weeks
Population: All analyses were performed by intention-to-treat.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atorvastatin | Body Mass Index | Before treatment | 40.1 kg/m2 | Standard Deviation 11.8 |
| Atorvastatin | Body Mass Index | After treatment | 38.2 kg/m2 | Standard Deviation 8.4 |
| Placebo | Body Mass Index | Before treatment | 36.0 kg/m2 | Standard Deviation 10.4 |
| Placebo | Body Mass Index | After treatment | 35.8 kg/m2 | Standard Deviation 10.8 |
Comparison: What is being compared for this analysis is the change from baseline for Atorvastatin to the change from baseline for Placebo.p-value: 0.6395% CI: [-0.6, 1]Linear mixed-effects models
Post Hoc
Diastolic Blood Pressure
Time frame: baseline and 6 weeks
Population: All analyses were performed by intention-to-treat.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atorvastatin | Diastolic Blood Pressure | Before treatment | 70.8 mm Hg | Standard Deviation 14.8 |
| Atorvastatin | Diastolic Blood Pressure | After treatment | 64.3 mm Hg | Standard Deviation 12.3 |
| Placebo | Diastolic Blood Pressure | Before treatment | 64.6 mm Hg | Standard Deviation 8 |
| Placebo | Diastolic Blood Pressure | After treatment | 65.4 mm Hg | Standard Deviation 8.1 |
Comparison: What is being compared for this analysis is the change from baseline for Atorvastatin to the change from baseline for Placebo.p-value: 0.0595% CI: [-15.8, 0.1]Linear mixed-effects models
Other Pre-specified
High-sensitivity C-reactive Protein (hsCRP)
high sensitive C-reactive protein as a measure of inflammation
Time frame: baseline and 6 weeks
Population: All analyses were performed by intention-to-treat.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atorvastatin | High-sensitivity C-reactive Protein (hsCRP) | Before treatment | 8.0 mg/L | Standard Deviation 9.6 |
| Atorvastatin | High-sensitivity C-reactive Protein (hsCRP) | After treatment | 4.3 mg/L | Standard Deviation 5.4 |
| Placebo | High-sensitivity C-reactive Protein (hsCRP) | Before treatment | 7.2 mg/L | Standard Deviation 7.7 |
| Placebo | High-sensitivity C-reactive Protein (hsCRP) | After treatment | 6.0 mg/L | Standard Deviation 7.3 |
Comparison: What is being compared for this analysis is the change from baseline for Atorvastatin to the change from baseline for Placebo.p-value: 0.2195% CI: [-6.4, 1.5]Linear mixed-effects models
Post Hoc
Mean Ovarian Volume
Pelvic ultrasound was performed using the 6.5 megahertz (MHz) probe of an ATL 400 machine to characterize ovarian size and morphology. Since in vitro studies demonstrate that statins inhibit ovarian theca-interstitial cell proliferation, we hypothesized that statins might reduce ovarian volume in PCOS.
Time frame: baseline and 6 weeks
Population: All analyses were performed by intention-to-treat.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atorvastatin | Mean Ovarian Volume | Before treatment | 15.1 mm3 | Standard Deviation 8.8 |
| Atorvastatin | Mean Ovarian Volume | After treatment | 19.2 mm3 | Standard Deviation 7 |
| Placebo | Mean Ovarian Volume | Before treatment | 25.4 mm3 | Standard Deviation 13.7 |
| Placebo | Mean Ovarian Volume | After treatment | 25.2 mm3 | Standard Deviation 9.9 |
Comparison: What is being compared for this analysis is the change from baseline for Atorvastatin to the change from baseline for Placebo.p-value: 0.4895% CI: [-6.8, 13.7]Linear mixed-effects models
Post Hoc
Systolic Blood Pressure
Time frame: baseline and 6 weeks
Population: All analyses were performed by intention-to-treat.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atorvastatin | Systolic Blood Pressure | Before treatment | 119.8 mm Hg | Standard Deviation 15.8 |
| Atorvastatin | Systolic Blood Pressure | After treatment | 112.0 mm Hg | Standard Deviation 13.2 |
| Placebo | Systolic Blood Pressure | Before treatment | 114.5 mm Hg | Standard Deviation 14.4 |
| Placebo | Systolic Blood Pressure | After treatment | 111.4 mm Hg | Standard Deviation 8.8 |
Comparison: What is being compared for this analysis is the change from baseline for Atorvastatin to the change from baseline for Placebo.p-value: 0.2795% CI: [-16.9, 5]Linear mixed-effects models