The purpose of this study is to evaluate potential mechanisms by which estradiol deficiency accelerates fat gain and abdominal fat accumulation in women.

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 hypothalamic-pituitary-adrenal (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 18 to 49 years
• Regular menses (no missed cycles in previous year; cycle length 25-35 days)
• Positive luteinizing hormone test or a mid-luteal serum progesterone greater than 3 ng/mL
• 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
• On oral or 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, Gonadotropin-releasing hormone (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 and Beck Depression Inventory-II score greater than 18, or clinician recommendation to exclude
• Severe osteopenia or osteoporosis (proximal femur or lumbar spine t scores < -2.0)
• BMI greater than 40 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 (creatinine clearance <50 mL/min by Cockcroft-Gault)
• Chronic hepatobiliary disease, defined as liver function tests (AST, ALT, alkaline phosphatase, total bilirubin) greater than 1.5 times the upper limit of normal
• Thyroid dysfunction, defined as ultra sensitive TSH less than 0.5 or greater than 5.0 mU/L
• Uncontrolled hypertension, defined as resting BP greater than 150/90 mmHg
• Cardiovascular disease, including indicators of ischemic heart disease or serious arrhythmias at rest or during the graded exercise test; follow-up diagnostic testing to rule out cardiovascular disease by a cardiologist will be allowed
• Orthopedic or other problems that would interfere with participation in the exercise program

Of the 79 women enrolled, 9 discontinued. Baseline and outcome measure data are reported for the 70 participants who completed the study. Ethnic data (Hispanic or Latino) are not distinct from racial data. 9 women who identified as Hispanic or Latino are also included in one of the race categories

Adverse events were collected from the time eligibility was established through the completion of the study, over approximately 1 year.

Adverse events were queried every 4 weeks.

This was a mechanistically driven study to isolate the effects of estradiol on bioenergetics and HPA axis activity. It was not a therapeutic clinical trial.