Caloric Restriction, Exercise
Conditions
Brief summary
The objective of this study is to determine whether maintaining a eugonadal state, during severe, sustained energy deficit, attenuates physiological decrements, particularly the loss of lean body mass.
Detailed description
This study will enroll up to 60 physically active men in a 3-phase randomized, placebo-controlled trial. After completing a 14-day (free-living, phase 1), energy-adequate, diet-acclimation phase (protein, 1.6 g∙kg-1∙d-1; fat 30% total energy intake, with remaining energy derived from carbohydrate), participants will be randomized to one of two experimental groups and undergo a 28-day (live-in, phase 2), 55% energy deficit phase: energy deficit alone (DEF) or energy deficit + exogenous testosterone (DEF+TEST). Recovery (free-living, phase 3) will be assessed after completing phase 2 to determine when body mass has been recovered within ± 2.5% of initial body mass (duration will vary, 42-day maximum for phase 3). This study will delineate the contribution of testosterone declines from the physical and mental demands encountered by Warfighters during military training and combat operations on complex markers of physiological and psychological status, addressing a direct, consistently observed, gap in knowledge.
Interventions
DRUGSesame Oil
200 mg sesame oil by intramuscular injection weekly on days 15, 21, 28, and 35
DRUGtestosterone enanthate
200 mg testosterone enanthate by intramuscular injection weekly on days 15, 21, 28, and 35
Sponsors
United States Army Research Institute of Environmental Medicine
MyoSyntax
Defence Research and Development Canada
United States Department of Defense
Pennington Biomedical Research Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
18 Years to 39 Years
Healthy volunteers
Yes
Inclusion criteria
* Physically active (at least 2 days per week aerobic and/or resistance exercise) * Not taking any prescription medications and/or willing to refrain from all medication use prior to and throughout the entire study period, unless provided/approved by the study physician * Willing to refrain from alcohol, smoking, e-cigarettes, or use of any nicotine product, caffeine, and dietary supplement use throughout the entire study period * At the discretion of the study physician, wash-out period for medications, supplements, and over-the-counter medications is ≥ 1 to 4 weeks * Wash-out period for caffeine and alcohol is ≥ 7 days * Willing to live on the Pennington Biomedical Research Center inpatient unit for 28 consecutive days * Willing to have a urine drug screening * Meets age-specific U.S. Army body composition standards according to Army Regulation 600-9, which includes estimates of percent body fat based on height, weight, and circumference measures (neck and waist) * Total testosterone concentration is within the normal physiological range, total testosterone (300-1,000 ng/dL).
Exclusion criteria
* Musculoskeletal injuries that compromise exercise capability * Diagnosed cardiometabolic disorders (i.e., hypertension, hyperlipidemia, kidney disease, diabetes, etc.) * Allergies or intolerance to foods, vegetarian practices, or history of complications with lidocaine * Anabolic steroid, human growth hormone, or nutritional testosterone precursor-like supplement use within the past 6 months * Will not refrain from smoking (any nicotine product), alcohol, caffeine, or any other dietary supplement during the study * Any use of antibiotics, except topical antibiotics, within 3 months of study participation * Colonoscopy within 3 months of study participation * Chronic use of laxatives, stool softeners, antacids, or anti-diarrheal medications (≥ once a week) * History of gastrointestinal disease (e.g., celiac, irritable bowel syndrome, colitis, Crohn's disease) * Restrained eater (the Three-Factor Eating Questionnaire) as assessed by the study's psychological and behavioral assessment staff * Adults unable to consent * Women * Prisoners * Metal implants, claustrophobia, head size incompatible with MRI equipment, etc. * Sedentary or engages in \<2 days of physical activity per week (aerobic and/or resistance training) * Exceeds age-specific U.S. Army body composition standards according to Army Regulation 600-9 * Previous history of kidney stones unless otherwise approved by the medical investigator * Systolic blood pressure \> 150 or diastolic blood pressure \> 95 mmHg * Previous history of breast or prostate cancer * Previous history of Chronic Obstructive Pulmonary Disease or Obstructive Sleep Apnea * Findings of lab results of prostate-specific antigen \> 3ng/ml, Hematocrit \> 50%, or positive urine drug screening * Based on the investigative team's clinical judgment, a subject may not be appropriate for participation in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Body Composition at the End of Each Study Phase | end of each study phase: Day 11 for Phase 1, Day 39 for Phase 2, up to Day 85 for Phase 3 | Height was measured using a stadiometer. Weight was measured using a calibrated digital scale. Body composition was determined using dual-energy X-ray absorptiometry. These data were used to calculate fat-free body mass, fat mass, and total body tissue mass. |
Countries
United States
Participant flow
Pre-assignment details
Three participants discontinued the study during phase 1, prior to intervention assignment to a study arm: 1 was unable to tolerate study procedures and 2 had conflicting work/time commitments.
Participants by arm
| Arm | Count |
|---|---|
| Energy Deficit Participants randomly assigned to the control condition will be subject to exercise-induced energy expenditure resulting in a 55% energy deficit and will be administered sesame oil placebo injections during phase 2 of the trial.
Sesame Oil: 200 mg sesame oil by intramuscular injection weekly on days 15, 21, 28, and 35 | 26 |
| Energy Deficit + Testosterone Participants randomly assigned to the intervention condition will be subject to exercise-induced energy expenditure resulting in a 55% energy deficit and will be administered testosterone enanthate injections during phase 2 of the trial.
testosterone enanthate: 200 mg testosterone enanthate by intramuscular injection weekly on days 15, 21, 28, and 35 | 24 |
| Total | 50 |
Baseline characteristics
| Characteristic | Total | Energy Deficit + Testosterone | Energy Deficit |
|---|---|---|---|
| Absolute Intake Carbohydrate | 270 kilocalories per day STANDARD_DEVIATION 107 | 258 kilocalories per day STANDARD_DEVIATION 99 | 281 kilocalories per day STANDARD_DEVIATION 114 |
| Absolute Intake Energy | 2456 kilocalories per day STANDARD_DEVIATION 863 | 2432 kilocalories per day STANDARD_DEVIATION 777 | 2478 kilocalories per day STANDARD_DEVIATION 950 |
| Absolute Intake Fat | 104 kilocalories per day STANDARD_DEVIATION 43 | 106 kilocalories per day STANDARD_DEVIATION 38 | 103 kilocalories per day STANDARD_DEVIATION 49 |
| Absolute Intake Protein | 115 kilocalories per day STANDARD_DEVIATION 39 | 118 kilocalories per day STANDARD_DEVIATION 39 | 113 kilocalories per day STANDARD_DEVIATION 40 |
| Age, Continuous | 25 years STANDARD_DEVIATION 5 | 25 years STANDARD_DEVIATION 1 | 25 years STANDARD_DEVIATION 1 |
| Alanine Aminotransferase | 22.2 international units per liter STANDARD_DEVIATION 8.2 | 23.6 international units per liter STANDARD_DEVIATION 1.7 | 20.9 international units per liter STANDARD_DEVIATION 1.6 |
| Body Mass Composition Fat | 17.2 kilograms STANDARD_DEVIATION 6.7 | 17.0 kilograms STANDARD_DEVIATION 1.4 | 17.4 kilograms STANDARD_DEVIATION 1.3 |
| Body Mass Composition Fat-free | 58.2 kilograms STANDARD_DEVIATION 8.2 | 60.7 kilograms STANDARD_DEVIATION 2.1 | 56.0 kilograms STANDARD_DEVIATION 1.1 |
| Body Mass Composition Total | 78.7 kilograms STANDARD_DEVIATION 12.1 | 80.9 kilograms STANDARD_DEVIATION 2.8 | 76.6 kilograms STANDARD_DEVIATION 2 |
| Body Mass Index | 25 kilograms per square meter STANDARD_DEVIATION 3 | 25 kilograms per square meter STANDARD_DEVIATION 1 | 24 kilograms per square meter STANDARD_DEVIATION 1 |
| Cortisol | 14.2 micrograms per deciliter STANDARD_DEVIATION 4.6 | 13.4 micrograms per deciliter STANDARD_DEVIATION 3.9 | 14.9 micrograms per deciliter STANDARD_DEVIATION 5.1 |
| Diastolic Blood Pressure | 73 millimeters mercury STANDARD_DEVIATION 7 | 72 millimeters mercury STANDARD_DEVIATION 2 | 74 millimeters mercury STANDARD_DEVIATION 2 |
| Estradiol | 42.5 picograms per milliliter STANDARD_DEVIATION 14.2 | 43 picograms per milliliter STANDARD_DEVIATION 3 | 42 picograms per milliliter STANDARD_DEVIATION 3 |
| Follicle Stimulating Hormone | 3.6 milli-international units per milliliter STANDARD_DEVIATION 2.1 | 3 milli-international units per milliliter STANDARD_DEVIATION 0.4 | 4 milli-international units per milliliter STANDARD_DEVIATION 0.4 |
| Free Testosterone | 9.3 nanograms per deciliter STANDARD_DEVIATION 2.8 | 10 nanograms per deciliter STANDARD_DEVIATION 1 | 9 nanograms per deciliter STANDARD_DEVIATION 1 |
| Glucose | 88.5 milligrams per deciliter STANDARD_DEVIATION 5.8 | 88 milligrams per deciliter STANDARD_DEVIATION 1 | 89 milligrams per deciliter STANDARD_DEVIATION 1 |
| Height | 178 centimeters STANDARD_DEVIATION 7 | 178 centimeters STANDARD_DEVIATION 2 | 178 centimeters STANDARD_DEVIATION 1 |
| Hematocrit | 44 percentage STANDARD_DEVIATION 3 | 45 percentage STANDARD_DEVIATION 0.5 | 44 percentage STANDARD_DEVIATION 0.5 |
| Hemoglobin | 15 grams per deciliter STANDARD_DEVIATION 1 | 15 grams per deciliter STANDARD_DEVIATION 0.2 | 15 grams per deciliter STANDARD_DEVIATION 0.2 |
| High-Density Lipoprotein Cholesterol | 54.7 milligrams per deciliter STANDARD_DEVIATION 11.9 | 57 milligrams per deciliter STANDARD_DEVIATION 3 | 53 milligrams per deciliter STANDARD_DEVIATION 2 |
| Insulin | 8.8 micro-international units per milliliter STANDARD_DEVIATION 11.8 | 9.7 micro-international units per milliliter STANDARD_DEVIATION 15.3 | 7.9 micro-international units per milliliter STANDARD_DEVIATION 7.3 |
| Insulin-like Growth Factor-1 | 278 nanograms per milliliter STANDARD_DEVIATION 80 | 280 nanograms per milliliter STANDARD_DEVIATION 72 | 277 nanograms per milliliter STANDARD_DEVIATION 88 |
| Low-Density Lipoprotein Cholesterol | 95.4 milligrams per deciliter STANDARD_DEVIATION 24.4 | 91 milligrams per deciliter STANDARD_DEVIATION 4 | 100 milligrams per deciliter STANDARD_DEVIATION 5 |
| Luteinizing Hormone | 4.1 milli-international units per milliliter STANDARD_DEVIATION 1.7 | 3.7 milli-international units per milliliter STANDARD_DEVIATION 1.3 | 4.4 milli-international units per milliliter STANDARD_DEVIATION 2 |
| Peak Oxygen Uptake | 3.5 liters per minute STANDARD_DEVIATION 0.7 | 3.6 liters per minute STANDARD_DEVIATION 0.8 | 3.4 liters per minute STANDARD_DEVIATION 0.6 |
| Prostate-Specific Antigen | 0.72 nanograms per milliliter STANDARD_DEVIATION 0.5 | 0.72 nanograms per milliliter STANDARD_DEVIATION 0.1 | 0.65 nanograms per milliliter STANDARD_DEVIATION 0.1 |
| Race/Ethnicity, Customized Hispanic | 3 Participants | 3 Participants | 0 Participants |
| Race/Ethnicity, Customized Non-Hispanic Black | 13 Participants | 6 Participants | 7 Participants |
| Race/Ethnicity, Customized Non-Hispanic White | 30 Participants | 14 Participants | 16 Participants |
| Race/Ethnicity, Customized Other | 4 Participants | 1 Participants | 3 Participants |
| Relative Intake Carbohydrate | 3.6 kilocalories/kilogram body mass/day STANDARD_DEVIATION 1.6 | 3.4 kilocalories/kilogram body mass/day STANDARD_DEVIATION 1.7 | 3.8 kilocalories/kilogram body mass/day STANDARD_DEVIATION 1.6 |
| Relative Intake Energy | 32 kilocalories/kilogram body mass/day STANDARD_DEVIATION 13 | 31.7 kilocalories/kilogram body mass/day STANDARD_DEVIATION 13.4 | 33.1 kilocalories/kilogram body mass/day STANDARD_DEVIATION 13.4 |
| Relative Intake Fat | 1.4 kilocalories/kilogram body mass/day STANDARD_DEVIATION 0.6 | 1.4 kilocalories/kilogram body mass/day STANDARD_DEVIATION 0.6 | 1.4 kilocalories/kilogram body mass/day STANDARD_DEVIATION 0.7 |
| Relative Intake Protein | 1.5 kilocalories/kilogram body mass/day STANDARD_DEVIATION 0.6 | 1.5 kilocalories/kilogram body mass/day STANDARD_DEVIATION 0.6 | 1.5 kilocalories/kilogram body mass/day STANDARD_DEVIATION 0.5 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 50 Participants | 24 Participants | 26 Participants |
| Sex Hormone Binding Globulin | 34.5 nanomoles per liter STANDARD_DEVIATION 14.5 | 37.4 nanomoles per liter STANDARD_DEVIATION 3.6 | 32.0 nanomoles per liter STANDARD_DEVIATION 1.8 |
| Systolic Blood Pressure | 118 millimeters mercury STANDARD_DEVIATION 9 | 119 millimeters mercury STANDARD_DEVIATION 2 | 117 millimeters mercury STANDARD_DEVIATION 2 |
| Total Cholesterol | 165 milligrams per deciliter STANDARD_DEVIATION 30 | 162 milligrams per deciliter STANDARD_DEVIATION 6 | 168 milligrams per deciliter STANDARD_DEVIATION 7 |
| Total Testosterone | 461 nanograms per deciliter STANDARD_DEVIATION 118 | 495 nanograms per deciliter STANDARD_DEVIATION 27 | 430 nanograms per deciliter STANDARD_DEVIATION 19 |
| Triglyceride | 74.6 milligrams per deciliter STANDARD_DEVIATION 40.2 | 72 milligrams per deciliter STANDARD_DEVIATION 7 | 77 milligrams per deciliter STANDARD_DEVIATION 9 |
| Weight | 78 kilograms STANDARD_DEVIATION 12 | 81 kilograms STANDARD_DEVIATION 3 | 76 kilograms STANDARD_DEVIATION 2 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 0 / 24 |
| other Total, other adverse events | 26 / 26 | 23 / 24 |
| serious Total, serious adverse events | 0 / 26 | 4 / 24 |
Outcome results
Primary
Body Composition at the End of Each Study Phase
Height was measured using a stadiometer. Weight was measured using a calibrated digital scale. Body composition was determined using dual-energy X-ray absorptiometry. These data were used to calculate fat-free body mass, fat mass, and total body tissue mass.
Time frame: end of each study phase: Day 11 for Phase 1, Day 39 for Phase 2, up to Day 85 for Phase 3
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Energy Deficit | Body Composition at the End of Each Study Phase | Fat-free Mass at end of Phase 1 | 58.3 kilograms |
| Energy Deficit | Body Composition at the End of Each Study Phase | Total Body Mass at end of Phase 2 | 73.3 kilograms |
| Energy Deficit | Body Composition at the End of Each Study Phase | Total Body Mass at end of Phase 3 | 76.5 kilograms |
| Energy Deficit | Body Composition at the End of Each Study Phase | Fat Mass at end of Phase 3 | 12.8 kilograms |
| Energy Deficit | Body Composition at the End of Each Study Phase | Fat-free Mass at end of Phase 3 | 60.5 kilograms |
| Energy Deficit | Body Composition at the End of Each Study Phase | Fat-free Mass at end of Phase 2 | 58.0 kilograms |
| Energy Deficit | Body Composition at the End of Each Study Phase | Fat Mass at end of Phase 1 | 16.8 kilograms |
| Energy Deficit | Body Composition at the End of Each Study Phase | Fat Mass at end of Phase 2 | 12.2 kilograms |
| Energy Deficit | Body Composition at the End of Each Study Phase | Total Body Mass at end of Phase 1 | 78.3 kilograms |
| Energy Deficit + Testosterone | Body Composition at the End of Each Study Phase | Fat Mass at end of Phase 2 | 12.0 kilograms |
| Energy Deficit + Testosterone | Body Composition at the End of Each Study Phase | Total Body Mass at end of Phase 3 | 79.3 kilograms |
| Energy Deficit + Testosterone | Body Composition at the End of Each Study Phase | Fat-free Mass at end of Phase 1 | 57.9 kilograms |
| Energy Deficit + Testosterone | Body Composition at the End of Each Study Phase | Fat Mass at end of Phase 1 | 16.8 kilograms |
| Energy Deficit + Testosterone | Body Composition at the End of Each Study Phase | Fat Mass at end of Phase 3 | 12.8 kilograms |
| Energy Deficit + Testosterone | Body Composition at the End of Each Study Phase | Total Body Mass at end of Phase 1 | 78.0 kilograms |
| Energy Deficit + Testosterone | Body Composition at the End of Each Study Phase | Fat-free Mass at end of Phase 2 | 60.4 kilograms |
| Energy Deficit + Testosterone | Body Composition at the End of Each Study Phase | Fat-free Mass at end of Phase 3 | 63.1 kilograms |
| Energy Deficit + Testosterone | Body Composition at the End of Each Study Phase | Total Body Mass at end of Phase 2 | 75.8 kilograms |