Musculoskeletal Resiliency and Adaptation to Sex Steroid Suppression and Replacement During Multi-Stressor Training
Overview
- Phase
- Phase 4
- Intervention
- Multi-Stressor Training
- Conditions
- Musculoskeletal Injury
- Sponsor
- Bradley Nindl
- Enrollment
- 120
- Locations
- 1
- Primary Endpoint
- Biomechanical: Quadriceps Muscle Echointensity, change from baseline and throughout training, mean
- Status
- Recruiting
- Last Updated
- 8 months ago
Overview
Brief Summary
Non-combat-related muscle, tendon and bone injuries are the most common injuries suffered by military personnel, particularly in new recruits. These injuries impact military readiness and are responsible for roughly 60% of limited duty days, 65% of soldiers who are unable to deploy, and nearly $500 million in medical cost to the government annually in the Army alone. Drug interventions must be studied and developed to prevent these negative outcomes and prepare military personnel for the demands of military service. At the current time, military leadership has identified critical gaps in understanding how to minimize these injuries and train soldiers with drug intervention serving among those gaps.
The goal of this study is to determine how a hormonal intervention can change muscle, tendon, and bone function as well as physical and psychological performance in response to mental and physical stress. To do so, we will examine sex hormone (testosterone, estrogen) levels, muscle, tendon, and bone images, blood samples, and physical and mental performance. We will look at things like changes in hormone levels, chemicals released from active skeletal muscles, and your body composition. The results from this study will be used to improve physical readiness training in the military with the goal of reducing injuries.
Detailed Description
Suppression of the reproductive hypothalamic-pituitary-gonadal (HPG) axis is a common physiological response to strenuous military training and can be difficult to replicate in simulated environments. Additionally, whether HPG suppression contributes to the physiological changes, performance decrements, and high MSK injury risk associated with multi-stressor military training is unknown. Thus, we will utilize pharmacological inhibition of the HPG axis to test if estrogen and testosterone replacement will mitigate injury risk and performance decrements following military-relevant multi-stressor training. This project aims to deliver a state-of-the-art evaluation of male and female adaptive responses to multi-stressor training and evidence-based guidance for the safe and ethical use of exogenous hormone replacement as a MSK injury mitigation solution during multi-stressor training and operations.
Investigators
Bradley Nindl
Professor
University of Pittsburgh
Eligibility Criteria
Inclusion Criteria
- •Age 18-40 years
- •body mass index (BMI) 18-30 kg/m2
- •weight stable (±10 lbs) in past 2 months
- •takes part in moderate physical activity for at least 150 minutes/week
- •currently free of upper or lower body /extremity injury or impairment
- •able to commit to study duration
- •agrees to adhere to study requirements
- •not taking prescription medications or be willing to refrain from medication prior to and throughout the study period, unless approved by study physician
- •in men, total testosterone concentration within normal physiological range (300-1000 ng/dL)
- •in women, eumenorrheic (cycles of 26-35 days) and not using hormonal contraceptives for previous 3 months
Exclusion Criteria
- •Current smoker
- •current clinical diagnosis of an eating disorder
- •use of medication incompatible with measurement of reproductive and metabolic hormones or which may interfere with any of the study outcomes
- •current oligo/amenorrhea in women
- •any metabolic or endocrine disease
- •has been diagnosed with a medical condition, physical or psychological, that currently prevents potential subjects from exercising
- •currently pregnant or becomes pregnant during the study
- •history of heart condition OR high blood pressure
- •treating physician requires subject participates in medically supervised physical activity only
- •history of drug addiction, or regular use of recreational drugs
Arms & Interventions
STRESS (men + women): Multi-Stressor Training
Research volunteers will be randomized into the stress exposure group (STRESS) will undergo a 4-week exercise training program consisting of 5 consecutive days of strenuous physical training followed by 2 days of recovery (energy balance, no structured exercise). The exercise training program will consist of military-relevant physical training exercises (e.g., load carriage, aerobic and resistance exercises) that progressively increase in duration and intensity to increase exercise energy expenditure. Participants will perform multiple exercises per day using a variety of endurance and muscle loading modalities designed to mimic movements typically observed during real-life military operations.
Intervention: Multi-Stressor Training
SUPPRESS (men): Multi-Stressor Training + Zoladex + AndroGel 1.25g
In addition to participating in the multi-stressor training program, male participants randomized to the GnRH suppressed (SUPPRESS) group will be administered a long-acting GnRH agonist (Zoladex) by trained medical professionals to suppress endogenous gonadal steroids. Following GnRH agonist administration, men will be administered 1.25g/day (SUPPRESS) of topical 1% testosterone gel (AndroGel, Abbvie, North Chicago, IL) to be applied to the shoulders, upper arms, and/or stomach area daily.
Intervention: Goserelin 3.6 MG
SUPPRESS (men): Multi-Stressor Training + Zoladex + AndroGel 1.25g
In addition to participating in the multi-stressor training program, male participants randomized to the GnRH suppressed (SUPPRESS) group will be administered a long-acting GnRH agonist (Zoladex) by trained medical professionals to suppress endogenous gonadal steroids. Following GnRH agonist administration, men will be administered 1.25g/day (SUPPRESS) of topical 1% testosterone gel (AndroGel, Abbvie, North Chicago, IL) to be applied to the shoulders, upper arms, and/or stomach area daily.
Intervention: Multi-Stressor Training
SUPPRESS (men): Multi-Stressor Training + Zoladex + AndroGel 1.25g
In addition to participating in the multi-stressor training program, male participants randomized to the GnRH suppressed (SUPPRESS) group will be administered a long-acting GnRH agonist (Zoladex) by trained medical professionals to suppress endogenous gonadal steroids. Following GnRH agonist administration, men will be administered 1.25g/day (SUPPRESS) of topical 1% testosterone gel (AndroGel, Abbvie, North Chicago, IL) to be applied to the shoulders, upper arms, and/or stomach area daily.
Intervention: Testosterone gel (AndroGel 1.25g)
SUPPRESS (women): Multi-stressor training + Zoladex + Placebo patch
In addition to participating in the multi-stressor training program, male participants randomized to the GnRH suppressed (SUPPRESS) group will be administered a long-acting GnRH agonist (Zoladex) by trained medical professionals to suppress endogenous gonadal steroids. Following GnRH agonist administration, women in the SUPRESS group will receive a placebo transdermal patch.
Intervention: Goserelin 3.6 MG
SUPPRESS (women): Multi-stressor training + Zoladex + Placebo patch
In addition to participating in the multi-stressor training program, male participants randomized to the GnRH suppressed (SUPPRESS) group will be administered a long-acting GnRH agonist (Zoladex) by trained medical professionals to suppress endogenous gonadal steroids. Following GnRH agonist administration, women in the SUPRESS group will receive a placebo transdermal patch.
Intervention: Multi-Stressor Training
SUPPRESS (women): Multi-stressor training + Zoladex + Placebo patch
In addition to participating in the multi-stressor training program, male participants randomized to the GnRH suppressed (SUPPRESS) group will be administered a long-acting GnRH agonist (Zoladex) by trained medical professionals to suppress endogenous gonadal steroids. Following GnRH agonist administration, women in the SUPRESS group will receive a placebo transdermal patch.
Intervention: Placebo Patch
REPLACE (men): Multi-Stressor Training + Zoladex + AndroGel 5g
Following GnRH agonist administration, men will be administered 5g/day (REPLACE) of topical 1% testosterone gel (AndroGel, Abbvie, North Chicago, IL) to be applied to the shoulders, upper arms, and/or stomach area daily.
Intervention: Goserelin 3.6 MG
REPLACE (men): Multi-Stressor Training + Zoladex + AndroGel 5g
Following GnRH agonist administration, men will be administered 5g/day (REPLACE) of topical 1% testosterone gel (AndroGel, Abbvie, North Chicago, IL) to be applied to the shoulders, upper arms, and/or stomach area daily.
Intervention: Multi-Stressor Training
REPLACE (men): Multi-Stressor Training + Zoladex + AndroGel 5g
Following GnRH agonist administration, men will be administered 5g/day (REPLACE) of topical 1% testosterone gel (AndroGel, Abbvie, North Chicago, IL) to be applied to the shoulders, upper arms, and/or stomach area daily.
Intervention: Testosterone gel (AndroGel 5g)
REPLACE (women): Multi-Stressor Training + Zoladex + Climara Pro Patch
Following GnRH agonist administration, women, the REPLACE group will receive a transdermal estradiol (0.045 mg/day) + levonorgestrel (0.015 mg/day) patch (Climara Pro, Bayer, NJ) to be placed on a clean, dry area of the skin on the lower
Intervention: Goserelin 3.6 MG
REPLACE (women): Multi-Stressor Training + Zoladex + Climara Pro Patch
Following GnRH agonist administration, women, the REPLACE group will receive a transdermal estradiol (0.045 mg/day) + levonorgestrel (0.015 mg/day) patch (Climara Pro, Bayer, NJ) to be placed on a clean, dry area of the skin on the lower
Intervention: Multi-Stressor Training
REPLACE (women): Multi-Stressor Training + Zoladex + Climara Pro Patch
Following GnRH agonist administration, women, the REPLACE group will receive a transdermal estradiol (0.045 mg/day) + levonorgestrel (0.015 mg/day) patch (Climara Pro, Bayer, NJ) to be placed on a clean, dry area of the skin on the lower
Intervention: Estradiol / Levonorgestrel Transdermal System [Climara Pro]
Outcomes
Primary Outcomes
Biomechanical: Quadriceps Muscle Echointensity, change from baseline and throughout training, mean
Time Frame: Through study completion, an average of 8 weeks
Body composition: Lean mass, change from baseline, mean
Time Frame: Through study completion, an average of 8 weeks
Biomechanical: Tendon Shear Wave Elastography, change from baseline and throughout training, mean
Time Frame: Through study completion, an average of 8 weeks
Biomechanical: Tendon Thickness, change from baseline and throughout training, mean
Time Frame: Through study completion, an average of 8 weeks
Body Composition: Fat mass, change from baseline, mean
Time Frame: Through study completion, an average of 8 weeks
Body Composition: Body mass, change from baseline and throughout training, mean
Time Frame: Through study completion, an average of 8 weeks
Body Composition: Body Fat Percentage, change from baseline, mean
Time Frame: Through study completion, an average of 8 weeks
Biomechanical: Quadriceps Muscle Cross-sectional Area, change from baseline and throughout training, mean
Time Frame: Through study completion, an average of 8 weeks
Biomechanical: Tendon Cross-Sectional Area, change from baseline and throughout training, mean
Time Frame: Through study completion, an average of 8 weeks
Biochemical: Bone turnover markers (CTx + P1NP), change from baseline, mean
Time Frame: Through study completion, an average of 8 weeks
Biochemical: Sex steroid hormones (Testosterone, Sex Hormone Binding Globulin, Estradiol), change from baseline and throughout training, mean
Time Frame: Through study completion, an average of 8 weeks
Secondary Outcomes
- Bone microarchitecture: High Resolution- peripheral Computed Tomography, change from baseline, mean(Through study completion, an average of 8 weeks)
- Biochemical: Cell culture, extracellular vesicles, micro- RNAs, change from baseline and throughout study, mean(Through study completion, an average of 8 weeks)
- Biochemical: Measures of inflammation (IL6, IL-1B, TNFa, CRP), change from baseline and throughout study, mean(Through study completion, an average of 8 weeks)
- Biochemical: Measures of anabolism (Growth Hormone, Insulin-like growth factor-1), change from baseline and throughout study, mean(Through study completion, an average of 8 weeks)