Polycystic Ovary Syndrome
Conditions
Keywords
Exercise, Diet, Insulin resistance, Weight
Brief summary
Polycystic ovary syndrome (PCOS) is the most common reproductive disorder in women of reproductive age and despite decades of research the etiology the disorder is not known. The characteristic hyperandrogenism and anovulation is associated with abnormal neuroendocrine function and insulin resistance. Obesity is a common correlated phenotype of Polycystic ovary syndrome and weight gain worsens the reproductive and metabolic complications. Currently there is no evidence-based treatment plan for infertility in Polycystic ovary syndrome; yet weight loss by dietary restriction and regular exercise are strongly advocated. Weight loss and increased insulin sensitivity appear to drive improvements in reproductive outcomes in women with Polycystic ovary syndrome; however, the mechanism connecting these changes with the reproductive axis is not fully understood.
Detailed description
The goal of this study is to determine (using dietary restriction, exercise training, metformin or no treatment), the effects of weight loss and/or improved insulin sensitivity on reproductive function (neuroendocrine and ovarian) in obese women with Polycystic ovary syndrome.
Interventions
DRUGMetformin
Subjects randomized to the metformin treatment group will receive 1000 mg extended release metformin hydrochloride tablets (Bristol Myers Squibb) twice per day with food approximately 8 hours apart.
BEHAVIORALDietary Restriction
Subjects randomized to the dietary restriction group will reduce their energy intake by 25% of their weight maintenance energy intake determined at baseline. Total energy expenditure as measured by a 14-day doubly labeled water (DLW) study will be used to determine the baseline energy intake of each subject. There will be no gradual ramping of dietary restriction. The 25% energy reduction goal will apply from the first day of the intervention for a period of 24 weeks. Subjects will be asked to not modify their normal level of physical activity.
BEHAVIORALExercise Training
For the aerobic training component, subjects are required to meet a weekly energy expenditure target of 10 kcal per kg of body weight per week (KKW). The resistance training program will be performed 2 days a week. The resistance program includes 9 exercises. The 9 primary exercises are seated chest press, seated row, shoulder press, lat pull down, double leg press, leg extension, leg curl, back extension and abdominal crunch.
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Pennington Biomedical Research Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
20 Years to 40 Years
Healthy volunteers
No
Inclusion criteria
* 20 - 40 years, inclusive * Body mass index ≥ 25 kg/m2 * History of irregular menstrual cycles (fewer than 6 cycles in the past year) * Clinical and/or biochemical androgen excess (Free androgen index\>3.85 and/or hirsuitism rating ≥8) * Anovulatory menstrual cycles (determined during screening)
Exclusion criteria
* Ovulatory menstrual cycles (determined during screening by luteal phase serum progesterone \>3ng/mL) * History or clinical appearance of cardiovascular disease, diabetes (Type 1 or Type 2) and any other significant reproductive, metabolic, hematologic, pulmonary, gastrointestinal, neurologic, immune, hepatic, renal, urologic disorders, or cancer. * Hemoglobin, hematocrit, red blood cell count, or iron level below the lower limit of normal at the screening visit confirmed by a test repeated within two weeks * Regular use of medications for weight control, glucose intolerance, thyroid disease * Use of hormonal contraception containing medroxyprogesterone acetate (A 3 month washout period will be permitted for oral, vaginal and transdermal contraceptives). Psychiatric and Behavioral
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Luteinizing Hormone (LH) Pulse Frequency | Baseline and Week 24 | Change in Luteinizing Hormone (LH) Pulse Frequency measured over a 12-hour period (7:00 PM - 7:00 AM). The Mean and Standard Deviation (SD) are the number of pulses recorded on the 12-hour period (7:00 PM - 7:00 AM) and presented as the change from baseline to week 24. Only participants who completed the PULSE trial are included in present outcome measure as the primary outcome was established as change from pre-to-post-intervention LF pulse frequency. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Insulin Sensitivity Expressed as Glucose Disposal Rate (GDR) | Baseline and Week 24 | Change in insulin sensitivity measured by the euglycemic hyperinsulinemic clamp. Unit of measure established as glucose disposal rate (GDR) adjusted to account for kilograms of fat-free mass (FFM)+17.7 per minute to reflect the amount of exogenous glucose necessary to fully compensate for hyperinsulinemia and expressed as a function of metabolic body size. Only participants who completed the PULSE trial are included in present outcome measure as the primary outcome was established as change from pre-to-post-intervention Insulin Sensitivity expressed as Glucose Disposal Rate. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Metformin Subjects randomized to the metformin treatment group will receive 1000 mg extended release metformin hydrochloride tablets (Bristol Myers Squibb) twice per day with food approximately 8 hours apart.
Metformin: Subjects randomized to the metformin treatment group will receive 1000 mg extended release metformin hydrochloride tablets (Bristol Myers Squibb) twice per day with food approximately 8 hours apart. | 7 |
| Dietary Restriction Subjects randomized to the dietary restriction group (DR) will reduce their energy intake by 25% from their weight maintenance energy intake determined at baseline by doubly labeled water.There will be no gradual ramping of dietary restriction. The 25% energy reduction goal will apply from the first day of the intervention for a period of 24 weeks. Subjects will be asked to not modify their normal level of physical activity.
Dietary Restriction: Subjects randomized to the dietary restriction group will reduce their energy intake by 25% of their weight maintenance energy intake determined at baseline. Total energy expenditure as measured by a 14-day doubly labeled water (DLW) study will be used to determine the baseline energy intake of each subject. There will be no gradual ramping of dietary restriction. The 25% energy reduction goal will apply from the first day of the intervention for a period of 24 weeks. Subjects will be asked to not modify their normal level of physical ac | 7 |
| Exercise Subjects randomized to the exercise training group will complete a structured program of aerobic training 3 to 4 times per week and resistance exercises 2 times per week.
Exercise Training: For the aerobic training component, subjects are required to meet a weekly energy expenditure target of 10 kcal per kg of body weight per week (KKW).
The resistance training program will be performed 2 days a week. The resistance program includes 9 exercises. The 9 primary exercises are seated chest press, seated row, shoulder press, lat pull down, double leg press, leg extension, leg curl, back extension and abdominal crunch. | 8 |
| Control Subjects randomized to the no treatment control group will be asked to continue, as normal their usual dietary and exercise regimen. Subjects will be asked to not begin diet or exercise regimens through the 24-week study or to begin medical treatment for PCOS. | 10 |
| Total | 32 |
Baseline characteristics
| Characteristic | Metformin | Dietary Restriction | Exercise | Control | Total |
|---|---|---|---|---|---|
| Age, Continuous | 28.0 years STANDARD_DEVIATION 5 | 31.3 years STANDARD_DEVIATION 6.2 | 29.1 years STANDARD_DEVIATION 3.8 | 27.6 years STANDARD_DEVIATION 5.6 | 28.9 years STANDARD_DEVIATION 5.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 6 Participants | 8 Participants | 9 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 6 Participants | 2 Participants | 6 Participants | 18 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 1 Participants | 6 Participants | 4 Participants | 14 Participants |
| Sex: Female, Male Female | 7 Participants | 7 Participants | 8 Participants | 10 Participants | 32 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 7 | 0 / 8 | 0 / 10 |
| other Total, other adverse events | 5 / 7 | 5 / 7 | 5 / 8 | 8 / 10 |
| serious Total, serious adverse events | 1 / 7 | 0 / 7 | 0 / 8 | 0 / 10 |
Outcome results
Primary
Luteinizing Hormone (LH) Pulse Frequency
Change in Luteinizing Hormone (LH) Pulse Frequency measured over a 12-hour period (7:00 PM - 7:00 AM). The Mean and Standard Deviation (SD) are the number of pulses recorded on the 12-hour period (7:00 PM - 7:00 AM) and presented as the change from baseline to week 24. Only participants who completed the PULSE trial are included in present outcome measure as the primary outcome was established as change from pre-to-post-intervention LF pulse frequency.
Time frame: Baseline and Week 24
Population: Study stopped due to poor recruitment, enrollment, and retention.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Luteinizing Hormone (LH) Pulse Frequency | -4.0 Number of pulses | Standard Deviation 11.3 |
| Dietary Restriction | Luteinizing Hormone (LH) Pulse Frequency | -1.5 Number of pulses | Standard Deviation 7 |
| Exercise | Luteinizing Hormone (LH) Pulse Frequency | -6.5 Number of pulses | Standard Deviation 13.4 |
| Control | Luteinizing Hormone (LH) Pulse Frequency | -3.0 Number of pulses | Standard Deviation 2.6 |
Secondary
Insulin Sensitivity Expressed as Glucose Disposal Rate (GDR)
Change in insulin sensitivity measured by the euglycemic hyperinsulinemic clamp. Unit of measure established as glucose disposal rate (GDR) adjusted to account for kilograms of fat-free mass (FFM)+17.7 per minute to reflect the amount of exogenous glucose necessary to fully compensate for hyperinsulinemia and expressed as a function of metabolic body size. Only participants who completed the PULSE trial are included in present outcome measure as the primary outcome was established as change from pre-to-post-intervention Insulin Sensitivity expressed as Glucose Disposal Rate.
Time frame: Baseline and Week 24
Population: Study stopped due to poor recruitment, enrollment, and retention.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Insulin Sensitivity Expressed as Glucose Disposal Rate (GDR) | -1.8 mg/kg/min | Standard Deviation 5.5 |
| Dietary Restriction | Insulin Sensitivity Expressed as Glucose Disposal Rate (GDR) | 1.0 mg/kg/min | Standard Deviation 1.7 |
| Exercise | Insulin Sensitivity Expressed as Glucose Disposal Rate (GDR) | 0.8 mg/kg/min | Standard Deviation 0.9 |
| Control | Insulin Sensitivity Expressed as Glucose Disposal Rate (GDR) | 22.4 mg/kg/min | Standard Deviation 3.3 |