Prevention of Obesity in Women Via Estradiol Regulation

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

79 participants

Study Classification

INTERVENTIONAL

Study Start Date

2008-05-31

Study Completion Date

2014-06-30

Brief Summary

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

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Detailed Description

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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.

Conditions

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Obesity

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

TRIPLE

Participants Investigators Outcome Assessors

Study Groups

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1

GnRH agonist + placebo

Group Type PLACEBO_COMPARATOR

leuprolide acetate

Intervention Type DRUG

3.75 mg for depot suspension delivered by monthly intramuscular injection for 5 months

2

GnRH agonist + placebo + exercise

Group Type ACTIVE_COMPARATOR

leuprolide acetate

Intervention Type DRUG

3.75 mg for depot suspension delivered by monthly intramuscular injection for 5 months

progressive resistance exercise training

Intervention Type BEHAVIORAL

45 minute exercise sessions 4 times per week for 5 months

3

GnRH agonist + Estradiol

Group Type EXPERIMENTAL

leuprolide acetate

Intervention Type DRUG

3.75 mg for depot suspension delivered by monthly intramuscular injection for 5 months

Estradiol Transdermal

Intervention Type DRUG

0.075 mg patch per day for 5 months

4

GnRH agonist + Estradiol + exercise

Group Type EXPERIMENTAL

leuprolide acetate

Intervention Type DRUG

3.75 mg for depot suspension delivered by monthly intramuscular injection for 5 months

Estradiol Transdermal

Intervention Type DRUG

0.075 mg patch per day for 5 months

progressive resistance exercise training

Intervention Type BEHAVIORAL

45 minute exercise sessions 4 times per week for 5 months

Interventions

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leuprolide acetate

3.75 mg for depot suspension delivered by monthly intramuscular injection for 5 months

Intervention Type DRUG

Estradiol Transdermal

0.075 mg patch per day for 5 months

Intervention Type DRUG

progressive resistance exercise training

45 minute exercise sessions 4 times per week for 5 months

Intervention Type BEHAVIORAL

Other Intervention Names

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Lupron Climara

Eligibility Criteria

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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

Minimum Eligible Age

18 Years

Maximum Eligible Age

49 Years

Eligible Sex

FEMALE

Accepts Healthy Volunteers

Yes