Females, Aging, Metabolism, and Exercise

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

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.

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.

Inclusion Criteria:

1. Healthy women aged 40 to 60 years
2. Are still experiencing regular menstrual cycles.
3. They must be willing to be randomized to placebo or GnRHAG therapy for 24 weeks
4. 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