Females, Aging, Metabolism, and Exercise

Study Overview
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Brief Summary
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This study is designed to determine whether a reduction in hormones (such as occurs during menopause) causes a decrease in calories burned during physical activity. This study will also determine whether a reduction in hormones decreases calories burned while sleeping, resting, and eating and whether an exercise intervention can prevent this.

Detailed Description
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Participants will be women who are nearing menopause based on age (42-52 y) but have normal menstrual cycles. Participants will be randomized to receive monthly injections of placebo or a study drug that reduces sex hormones (GnRH agonist) for 24 weeks. Women who receive GnRH agonist will be further randomized to no exercise or a supervised exercise program. Thus, the 3 treatment groups are: placebo, GnRH agonist, GnRH agonist+exercise. The investigators will measure changes in calories burned during physical activity, sleep, rest, and after a meal after 3 and 6 months of hormone suppression using doubly-labeled water and room calorimetry. Other measures include food intake estimated from food records; body composition measured by dual-energy x-ray absorptiometry (DXA); glucose and insulin responses to an oral glucose tolerance test; and markers of inflammation in the blood.

Official Title
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Bioenergetic and Metabolic Consequences of the Loss of Ovarian Function in Women

Conditions
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Obesity

Intervention / Treatment
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* Drug: GnRH agonist
* Behavioral: Supervised cardiovascular exercise
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy women aged 40 to 60 years Are still experiencing regular menstrual cycles. They must be willing to be randomized to placebo or GnRHAG therapy for 24 weeks Be physically able to be randomized to participate in a programmed exercise training program. The investigators will consent up to 132 subjects with the aim of enrolling 22 in each of the 3 groups (placebo, GnRHAG, or GnRHAG+Exercise). Exclusion Criteria: irregular menstrual cycles defined as 2 or more missed cycles in the previous year serum FSH >25 mIU/mL measured during the first 5 days of the menstrual cycle on hormonal contraceptive or menopausal therapy positive pregnancy test intention to become pregnant or start hormonal contraceptive therapy during the period of study lactation known hypersensitivity to GnRH or leuprolide acetate score >16 on the CESD((Center for Epidemiologic Studies Depression Scale ) severe osteopenia or osteoporosis (i.e., proximal femur or lumbar spine t scores < -2.0) abnormal vaginal bleeding thyroid dysfunction, defined as an ultrasensitive TSH <0.5 or >5.0 mU/L; volunteers with abnormal TSH values will be re-considered for participation in the study after follow-up evaluation by the PCP with initiation or adjustment of thyroid hormone replacement uncontrolled hypertension defined as resting systolic BP >150 mmHg or diastolic BP>90 mmHg; participants who do not meet these criteria at first screening will be re-evaluated, including after follow-up evaluation by the PCP with initiation or adjustment of anti-hypertensive medications cardiovascular disease; subjective or objective indicators of ischemic heart disease (e.g., angina, ST segment depression) or serious arrhythmias at rest or during the graded exercise test (GXT) without follow-up evaluation; follow-up evaluation must include diagnostic testing (e.g., thallium stress test) with interpretation by a cardiologist orthopedic or other problems that would interfere with participation in the exercise program exercising at least 30 minutes per day at a moderate to vigorous intensity most days of the week (defined as >4 d/wk) over the past 6 months BMI <40 kg/m2

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Monthly placebo injections for 6 months | Drug: Placebo<br>* Placebo<br>|
| Active Comparator: GnRH agonist<br>Monthly GnRH agonist injections for 6 months | Drug: GnRH agonist<br>* Drug: leuprolide acetate Other Names: Lupron 3.75 mg for depot suspension delivered by monthly intramuscular injection for 6 months<br>* Other names: Leuprolide Acetate 3.75mg;|
| Active Comparator: GnRH agonist + exercise<br>Monthly GnRH agonist injections for 6 months plus supervised cardiovascular exercise intervention | Drug: GnRH agonist<br>* Drug: leuprolide acetate Other Names: Lupron 3.75 mg for depot suspension delivered by monthly intramuscular injection for 6 months<br>* Other names: Leuprolide Acetate 3.75mg;Behavioral: Supervised cardiovascular exercise<br>* Supervised exercise, 4 days per week for 45 to 60 minutes per session for 6 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Physical Activity Energy Expenditure (PAEE) | PAEE will be calculated as: TEE - REE - TEF, where TEE is total energy expenditure (measured by doubly-labeled water), REE is resting energy expenditure (measured by indirect calorimetry), and TEF is the thermic effect of feeding (estimated using a constant). | Change from baseline to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Fat Mass | Total Fat mass as measured by DXA | Change over 6 months | 
| Total Fat Free Mass | Total Fat Free Mass as measured by DXA | Change over 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hormone therapy, obesity, menopause, disease /disorder proneness /risk, insulin sensitivity /resistance, metabolic syndrome, women's health