Females, Aging, Metabolism, and Exercise

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