Effect of Weight and Insulin Sensitivity on Reproductive Function in PCOS

Phase 3

Terminated

Interventions: Behavioral: Dietary Restriction
Behavioral: Exercise Training
Drug: Metformin

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.

Recruitment & Eligibility

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 Exclusion Criteria

Smoking
History of drug or alcohol abuse (up to 14 drinks a week are allowed) within the past two years
History or presence of an eating disorder as determined by Interview for Diagnosis of Eating Disorders (IDED-IV)
Beck Depression Index (BDI) score of ≥15 at screening or baseline

Other Exclusion Criteria

Individuals who have lost more than 5kg (11lbs) in the past 6 months
Individuals who are pregnant or breast-feeding or whom become pregnant during the study
Individuals engaged in a regular program of physical fitness involving some heavy physical activity (e.g., jogging or riding fast on a bicycle for 30 minutes or more) at least five times per week over the past year
Individuals who have metallic objects in their body
Individuals who donated blood within 30 days prior to the date of randomization
Individuals unwilling to be assigned at random to either one of the intervention groups
Unwilling or unable to adhere to the rigors of the data collection (determined by food and activities diaries at screening, see below) and clinical evaluation schedule over the entire 24 week intervention period
Individuals who plan to move out of the area within the next 12 months or plan to be out of the study area for more than 4 weeks in the next 12 months
Individuals who reside too far from Pennington

Arm && Interventions

Group	Intervention	Description
Dietary Restriction	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.
Exercise	Exercise Training	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.
Metformin	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.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.