Obesity
Conditions
Keywords
hormone therapy, obesity, postmenopause, disease /disorder proneness /risk, insulin sensitivity /resistance, metabolic syndrome, women's health
Brief summary
The purpose of this study is to evaluate potential mechanisms by which estradiol deficiency accelerates fat gain and abdominal fat accumulation in women.
Detailed description
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.
Interventions
DRUGleuprolide acetate
3.75 mg for depot suspension delivered by monthly intramuscular injection for 5 months
DRUGEstradiol Transdermal
0.075 mg patch per day for 5 months
BEHAVIORALprogressive resistance exercise training
45 minute exercise sessions 4 times per week for 5 months
Sponsors
National Institute on Aging (NIA)
University of Colorado, Denver
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 49 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Resting Energy Expenditure (REE) | Before and after 5 months of treatment | Resting energy expenditure measured by indirect calorimeter at baseline and after 5 months of treatment. |
| Cortisol Response (Area Under the Curve) to CRH Under DEX Suppression | Before and after 5 months of treatment | Cortisol response to corticotropin releasing hormone (CRH) during dexamethasone (DEX) suppression; DEX/CRH stimulation test |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Energy Expenditure (TEE) | Before and after 5 months of treatment | 24-hour energy expenditure measured by indirect calorimetry in a room calorimeter |
| Fat Mass | Before and after 5 months of treatment | Total body fat mass measured by DXA |
| Fat-free Mass | Before and after 5 months of treatment | Total body fat-free mass measured by DXA |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| GnRH Agonist + Placebo GnRH agonist + placebo
leuprolide acetate: 3.75 mg for depot suspension delivered by monthly intramuscular injection for 5 months | 23 |
| GnRH Agonist + Placebo + Exercise GnRH agonist + placebo + exercise
leuprolide acetate: 3.75 mg for depot suspension delivered by monthly intramuscular injection for 5 months
progressive resistance exercise training: 45 minute exercise sessions 4 times per week for 5 months | 12 |
| GnRH Agonist + Estradiol GnRH agonist + Estradiol
leuprolide acetate: 3.75 mg for depot suspension delivered by monthly intramuscular injection for 5 months
Estradiol Transdermal: 0.075 mg patch per day for 5 months | 23 |
| GnRH Agonist + Estradiol + Exercise GnRH agonist + Estradiol + exercise
leuprolide acetate: 3.75 mg for depot suspension delivered by monthly intramuscular injection for 5 months
Estradiol Transdermal: 0.075 mg patch per day for 5 months
progressive resistance exercise training: 45 minute exercise sessions 4 times per week for 5 months | 12 |
| Total | 70 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 1 | 0 |
| Overall Study | Lost to Follow-up | 2 | 2 | 1 | 2 |
Baseline characteristics
| Characteristic | GnRH Agonist + Placebo + Exercise | Total | GnRH Agonist + Estradiol + Exercise | GnRH Agonist + Estradiol | GnRH Agonist + Placebo |
|---|---|---|---|---|---|
| Age, Continuous | 36 years STANDARD_DEVIATION 8 | 35.5 years STANDARD_DEVIATION 8.5 | 35 years STANDARD_DEVIATION 9 | 35 years STANDARD_DEVIATION 9 | 36 years STANDARD_DEVIATION 8 |
| Body Composition Fat Mass | 27.8 kilograms STANDARD_DEVIATION 1.9 | 28 kilograms STANDARD_DEVIATION 2 | 28.2 kilograms STANDARD_DEVIATION 2 | 28.2 kilograms STANDARD_DEVIATION 2 | 27.8 kilograms STANDARD_DEVIATION 1.9 |
| Body Composition Total Mass | 74.4 kilograms STANDARD_DEVIATION 2.7 | 75.5 kilograms STANDARD_DEVIATION 2.8 | 76.6 kilograms STANDARD_DEVIATION 3 | 76.6 kilograms STANDARD_DEVIATION 3 | 74.4 kilograms STANDARD_DEVIATION 2.7 |
| Body Mass Index (BMI) | 28 kg/m^2 STANDARD_DEVIATION 6 | 28 kg/m^2 STANDARD_DEVIATION 6 | 28 kg/m^2 STANDARD_DEVIATION 6 | 28 kg/m^2 STANDARD_DEVIATION 6 | 28 kg/m^2 STANDARD_DEVIATION 6 |
| Race/Ethnicity, Customized Asian | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Black | 1 Participants | 9 Participants | 2 Participants | 4 Participants | 2 Participants |
| Race/Ethnicity, Customized Caucasian | 9 Participants | 50 Participants | 9 Participants | 17 Participants | 15 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 2 Participants | 9 Participants | 2 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized More than one race | 1 Participants | 6 Participants | 1 Participants | 0 Participants | 4 Participants |
| Race/Ethnicity, Customized Native American | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Refused to answer | 0 Participants | 2 Participants | 0 Participants | 2 Participants | 0 Participants |
| Region of Enrollment United States | 12 participants | 70 participants | 12 participants | 23 participants | 23 participants |
| Sex: Female, Male Female | 12 Participants | 70 Participants | 12 Participants | 23 Participants | 23 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 23 | 0 / 12 | 0 / 23 | 0 / 12 |
| serious Total, serious adverse events | 0 / 23 | 0 / 12 | 1 / 23 | 0 / 12 |
Outcome results
Primary
Cortisol Response (Area Under the Curve) to CRH Under DEX Suppression
Cortisol response to corticotropin releasing hormone (CRH) during dexamethasone (DEX) suppression; DEX/CRH stimulation test
Time frame: Before and after 5 months of treatment
Population: Women who completed the DEX/CRH stimulation test before and after the intervention. The Outcome Measure evaluation was only conducted in a subgroup of women - those in the Drug intervention arms. This evaluation was not done in the exercise arms.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| GnRHag+PL | Cortisol Response (Area Under the Curve) to CRH Under DEX Suppression | 189 ng/mL x min |
| GnRHag+PL+ex | Cortisol Response (Area Under the Curve) to CRH Under DEX Suppression | -3115 ng/mL x min |
Comparison: The primary analysis was the comparison of within-group changes in the E2 and placebo groups for cortisol AUC in response to Dex/CRH and between-group differences in the changes. Within-group changes and between-group differences in changes were evaluated by linear contrast using an ANCOVA model with adjustment for pre-intervention values of outcomes.p-value: <0.05ANCOVA
Primary
Resting Energy Expenditure (REE)
Resting energy expenditure measured by indirect calorimeter at baseline and after 5 months of treatment.
Time frame: Before and after 5 months of treatment
Population: Participants who completed 24-h visits in the room calorimeter before and after the intervention. This could not be accomplished in all participants in the trial because of scheduling difficulties and/or lack of availability of the calorimeter. The primary analysis was by drug group only (placebo vs estradiol), collapsed across exercise grouping.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| GnRHag+PL | Resting Energy Expenditure (REE) | -37.8 kcal/d |
| GnRHag+PL+ex | Resting Energy Expenditure (REE) | -87.2 kcal/d |
| GnRHag+E2 | Resting Energy Expenditure (REE) | 14.6 kcal/d |
| GnRHag+E2+ex | Resting Energy Expenditure (REE) | -19.3 kcal/d |
Comparison: The primary analysis was the effect of PL vs E2 collapsed across exercise (2-group comparison). The analysis of effects of exercise was exploratory (evaluated within-group changes only).p-value: <0.05ANCOVA
Secondary
Fat-free Mass
Total body fat-free mass measured by DXA
Time frame: Before and after 5 months of treatment
Population: Participants who completed outcome measurements before and after the interention
| Arm | Measure | Value (MEAN) |
|---|---|---|
| GnRHag+PL | Fat-free Mass | -1.0 kg |
| GnRHag+PL+ex | Fat-free Mass | 0.1 kg |
| GnRHag+E2 | Fat-free Mass | 0.0 kg |
| GnRHag+E2+ex | Fat-free Mass | 1.0 kg |
Secondary
Fat Mass
Total body fat mass measured by DXA
Time frame: Before and after 5 months of treatment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| GnRHag+PL | Fat Mass | 0.5 kg |
| GnRHag+PL+ex | Fat Mass | -0.6 kg |
| GnRHag+E2 | Fat Mass | 0.4 kg |
| GnRHag+E2+ex | Fat Mass | -0.8 kg |
Secondary
Total Energy Expenditure (TEE)
24-hour energy expenditure measured by indirect calorimetry in a room calorimeter
Time frame: Before and after 5 months of treatment
Population: Participants who completed 24-h visits in the room calorimeter before and after the intervention
| Arm | Measure | Value (MEAN) |
|---|---|---|
| GnRHag+PL | Total Energy Expenditure (TEE) | -108.8 kcal/d |
| GnRHag+PL+ex | Total Energy Expenditure (TEE) | -166.5 kcal/d |
| GnRHag+E2 | Total Energy Expenditure (TEE) | -92.7 kcal/d |
| GnRHag+E2+ex | Total Energy Expenditure (TEE) | -107.4 kcal/d |
Comparison: The primary analysis compared the GnRHag+E2 and GnRHag+PL groups, pooled across exercise status. Differences in change over time between groups were tested by using an ANCOVA model, first with treatment group alone, and again adding FM and FFM to the model.p-value: <0.05ANCOVA