Obesity
Conditions
Keywords
hormone therapy, obesity, menopause, disease /disorder proneness /risk, insulin sensitivity /resistance, metabolic syndrome, women's health
Brief summary
This study is designed to determine whether a reduction in hormones (such as occurs during menopause) causes a decrease in calories burned during physical activity. This study will also determine whether a reduction in hormones decreases calories burned while sleeping, resting, and eating and whether an exercise intervention can prevent this.
Detailed description
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.
Interventions
BEHAVIORALSupervised cardiovascular exercise
Supervised exercise, 4 days per week for 45 to 60 minutes per session for 6 months
DRUGPlacebo
Placebo
DRUGGnRH agonist
Drug: leuprolide acetate Other Names: Lupron 3.75 mg for depot suspension delivered by monthly intramuscular injection for 6 months
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
University of Colorado, Denver
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
40 Years to 60 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Physical Activity Energy Expenditure (PAEE) | Change from baseline to 6 months | PAEE will be calculated as: TEE - REE - TEF, where TEE is total energy expenditure (measured by doubly-labeled water), REE is resting energy expenditure (measured by indirect calorimetry), and TEF is the thermic effect of feeding (estimated using a constant). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Fat Mass | Change over 6 months | Total Fat mass as measured by DXA |
| Total Fat Free Mass | Change over 6 months | Total Fat Free Mass as measured by DXA |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Monthly placebo injections for 6 months
Placebo: Placebo | 10 |
| GnRH Agonist Monthly GnRH agonist injections for 6 months
GnRH agonist: Drug: leuprolide acetate
Other Names:
Lupron 3.75 mg for depot suspension delivered by monthly intramuscular injection for 6 months | 14 |
| GnRH Agonist + Exercise Monthly GnRH agonist injections for 6 months plus supervised cardiovascular exercise intervention
GnRH agonist: Drug: leuprolide acetate
Other Names:
Lupron 3.75 mg for depot suspension delivered by monthly intramuscular injection for 6 months
Supervised cardiovascular exercise: Supervised exercise, 4 days per week for 45 to 60 minutes per session for 6 months | 18 |
| Total | 42 |
Baseline characteristics
| Characteristic | Placebo | GnRH Agonist | GnRH Agonist + Exercise | Total |
|---|---|---|---|---|
| Age, Continuous | 46.2 years STANDARD_DEVIATION 1.7 | 47.1 years STANDARD_DEVIATION 3.7 | 45.7 years STANDARD_DEVIATION 3 | 46.3 years STANDARD_DEVIATION 3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 2 Participants | 3 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 11 Participants | 15 Participants | 33 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Physical Activity Energy Expenditure (PAEE) | 610 kcal/day STANDARD_DEVIATION 315 | 630 kcal/day STANDARD_DEVIATION 217 | 737 kcal/day STANDARD_DEVIATION 295 | 671 kcal/day STANDARD_DEVIATION 276 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 2 Participants | 1 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 1 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 11 Participants | 16 Participants | 32 Participants |
| Sex: Female, Male Female | 10 Participants | 14 Participants | 18 Participants | 42 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 14 | 0 / 18 |
| other Total, other adverse events | 3 / 10 | 4 / 14 | 4 / 18 |
| serious Total, serious adverse events | 0 / 10 | 0 / 14 | 0 / 18 |
Outcome results
Primary
Change in Physical Activity Energy Expenditure (PAEE)
PAEE will be calculated as: TEE - REE - TEF, where TEE is total energy expenditure (measured by doubly-labeled water), REE is resting energy expenditure (measured by indirect calorimetry), and TEF is the thermic effect of feeding (estimated using a constant).
Time frame: Change from baseline to 6 months
Population: Placebo: One participant dropped because they got a new job. GnRH agonist+exercise: One participant dropped because of a health problem unrelated to the study. Results from five participants were not included in the analysis because they did not meet the exercise compliance threshold (completed \<70% of exercise sessions).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Physical Activity Energy Expenditure (PAEE) | 74.5 kcal/day | Standard Error 77.9 |
| GnRH Agonist | Change in Physical Activity Energy Expenditure (PAEE) | -10.2 kcal/day | Standard Error 63.6 |
| GnRH Agonist + Exercise | Change in Physical Activity Energy Expenditure (PAEE) | 61.0 kcal/day | Standard Error 66.4 |
Secondary
Total Fat Free Mass
Total Fat Free Mass as measured by DXA
Time frame: Change over 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Total Fat Free Mass | 0.1 kg | Standard Error 0.34 |
| GnRH Agonist | Total Fat Free Mass | -0.69 kg | Standard Error 0.34 |
| GnRH Agonist + Exercise | Total Fat Free Mass | -0.66 kg | Standard Error 0.59 |
Secondary
Total Fat Mass
Total Fat mass as measured by DXA
Time frame: Change over 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Total Fat Mass | 0.73 kg | Standard Error 0.68 |
| GnRH Agonist | Total Fat Mass | 1.66 kg | Standard Error 0.41 |
| GnRH Agonist + Exercise | Total Fat Mass | 0.89 kg | Standard Error 0.6 |