Many factors contribute to the current epidemic of obesity. Although estrogen status is not commonly recognized as a determinant of obesity risk in women, there is strong evidence from large randomized controlled trials that estradiol- (E2) based hormone therapy (HT) reduces weight gain by about 40% in postmenopausal women. Importantly, there is also strong evidence that E2 reduces abdominal fat accumulation, a fundamental component of the Metabolic Syndrome. Some studies suggest risks of HT outweigh the benefits for some women. However, this does not negate the importance of learning the mechanisms by which E2 influences energy balance and fat patterning.

This study uses gonadotropin releasing hormone (GnRH) analog therapy to determine the effects of chronic (5-month) sex hormone suppression on resting energy expenditure (REE), altered hypothalamic-pituitary-adrenal (HPA) axis activity, and fat gain.

It is hypothesized that REE will be reduced in response to chronic sex hormone suppression, promoting fat gain. It is also hypothesized that stress-induced HPA axis activity will be amplified during sex hormone suppression; altered HPA axis activity leading to cortisol excess causes abdominal fat accumulation. Finally, it is hypothesized that E2 add-back therapy will lessen these responses.

Participants will be randomized so that half of the women in each treatment arm will participate in an exercise training program, consisting of progressive resistance exercise to prevent the decline in fat-free mass (FFM) and the increase in fat mass that has been observed in young women in response to GnRH analog therapy.

Inclusion Criteria:

• Healthy premenopausal women, aged 20 to 40 years

• Regular menses (no missed cycles in previous year; cycle length 25-35 days)

• Ovulatory, verified across 2 cycles during screening (positive LH surge)

• Nonsmokers

• Willing to receive all study interventions

• Physically able and willing to be randomized to participate in a supervised resistance exercise training program

Exclusion Criteria:

• Already performing high-intensity resistance exercise training more than 1 day per week

• On diabetes medications

• Use of hormonal contraception in the past 3 months

• Use of oral and oral inhaled glucocorticoids

• Positive pregnancy test

• Intention to become pregnant or start hormonal contraceptive therapy during the period of study

• Lactation

• Hypersensitivity to extrinsic peptide hormones, mannitol, GnRH, leuprolide acetate, benzyl alcohol (the vehicle for injection of leuprolide acetate), or transdermal patch

• Score greater than 16 on the Center for Epidemiologic Studies Depression Scale

• Severe osteopenia or osteoporosis

• Obesity (BMI greater than 30 kg/m2), weight change of more than �� 2 kg in last 6 months, or weight-reduced by more than 5 kg from maximal body weight

• Abnormal vaginal bleeding

• History of breast cancer or other estrogen-dependent neoplasms

• History of venous thromboembolic events

• Moderate or severe renal impairment

• Chronic hepatobiliary disease (liver, gallbladder, bile ducts)

• Thyroid dysfunction

• Uncontrolled hypertension

• Cardiovascular disease

• Orthopedic or other problems that would interfere with participation in the exercise program