Adaptions and Resiliency to Multi-Stressor OpeRations (ARMOR)

August 14, 2026 updated by: Bradley Nindl

Musculoskeletal Resiliency and Adaptation to Sex Steroid Suppression and Replacement During Multi-Stressor Training

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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 (through pharmacological suppression or hormonal contraceptive use) contributes to the physiological changes, performance decrements, and high MSK injury risk associated with multi-stressor military training is unknown. Thus, we will 1) utilize pharmacological inhibition of the HPG axis to test if testosterone replacement in men will mitigate injury risk and performance decrements following military-relevant multi-stressor training and 2) investigate how hormonal contraceptive use in women may impact these outcomes. 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.

Study Type

Interventional

Enrollment (Estimated)

120

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Bradley C Nindl, PhD
  • Phone Number: 412-246-0460
  • Email: bnindl@pitt.edu

Study Contact Backup

  • Name: Kristin J Koltun, PhD
  • Phone Number: 412-246-0460
  • Email: kjk116@pitt.edu

Study Locations

  • United States
    • Pennsylvania
      • Pittsburgh, Pennsylvania, United States, 15203
        • Recruiting
        • Neuromuscular Research Laboratory
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  1. Age 18-40 years
  2. body mass index (BMI) 18-30 kg/m2
  3. weight stable (±10 lbs) in past 2 months
  4. takes part in moderate physical activity for at least 150 minutes/week
  5. currently free of upper or lower body /extremity injury or impairment
  6. able to commit to study duration
  7. agrees to adhere to study requirements
  8. not taking prescription medications or be willing to refrain from medication prior to and throughout the study period, unless approved by study physician
  9. in women, eumenorrheic (cycles of 26-35 days) OR using monophasic oral contraceptive pills with norethindrone acetate (e.g., first generation progestin) for previous 3 months

1) Current smoker 2) current clinical diagnosis of an eating disorder 3) use of medication incompatible with measurement of reproductive and metabolic hormones or which may interfere with any of the study outcomes; with the exception of approved contraceptives for the contraceptive STRESS & CONTROL groups 4) current oligo/amenorrhea in women 5) any metabolic or endocrine disease 6) has been diagnosed with a medical condition, physical or psychological, that currently prevents potential subjects from exercising 7) currently pregnant or becomes pregnant during the study 8) history of heart condition OR high blood pressure 9) treating physician requires subject participates in medically supervised physical activity only 10) history of drug addiction, or regular use of recreational drugs 11) currently undergoing treatment for or have a history of mental health conditions 12) Current diagnoses of disorders known to affect bone metabolism including hyperthyroidism, hyperparathyroidism, osteomalacia, Cushing's, diabetes mellitus or renal insufficiency 13) Current use of medications known to affect bone metabolism including estrogens, androgens, anti-estrogens, bisphosphonates (oral bisphosphonates within one year of the baseline visit or IV bisphosphonates within three years of the baseline visit), calcitonin, fluoride, oral or inhaled glucocorticoids, suppressive doses of thyroxine, lithium, pharmacological doses of vitamin D (greater than 2000 IU/day), anti-convulsants, depot medroxyprogesterone within 6 months; with the exception of approved contraceptives for the contraceptive STRESS & CONTROL groups 14) History of deep vein thrombosis, pulmonary embolism, or clotting disorders. 15) History of stroke or myocardial infarction 16) Fracture within the last 6 months. 17) Systolic blood pressure > 160 or diastolic blood pressure > 95 18) Active substance abuse 19) History of hereditary angioedema 20) History of chest pain at rest, during daily activities of living, or when performing physical activity 21) Musculoskeletal injury removing subject from physical activity for more than a month within the past 2 years 22) Recreational drug use more than 2 times per month in each of the previous 6 months 23) Self-reported vision is worse than 20/20. 24) Personal history or history of a first-degree relative with breast cancer 25) Participated and taken investigational drug in any other clinical trial (including bioequivalence study) within six months prior to study drug administration 26) Diagnosed with eating disorder 27) Have food allergies, intolerance, restriction, or special diet needs 28) History of endometriosis 29) Current diagnosis of reproductive health issues, such as ovarian cysts, PCOS, pelvic lesions, undiagnosed ovarian enlargement 30) Have undiagnosed abnormal vaginal bleeding 31) Currently breastfeeding or within 2 months after stopping breastfeeding 32) Frequent headaches accompanied by vision changes (indicative of possible pituitary pathology)

For SUPPRESS and REPLACE:

1-32 listed above 33) PSA >3 ng/mL) 34) Serum 25-hydroxyvitamin D < 20 ng/mL 35) Thyroid dysfunction 36) Serum creatinine > 2 mg/dL 37) Personal history or history of a first-degree relative with breast cancer 38) Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 2x the upper limit of normal 39) Serum bilirubin > 2 mg/dL 40) Serum alkaline phosphatase > 150 U/L 41) Plasma hemoglobin < 10 gm/dL 42) Hematocrit > 50 43) In men, Serum testosterone level < 270 or > 1070 ng/dL (< 9 or > 37 nmol/ L) 44) Triglycerides > 150 fasting

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
No Intervention: CONTROL (men + women)
The control group will maintain their habitual exercise, diet, and sleep patterns, all of which will be monitored throughout the study.
Active Comparator: 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.
Other: Multi-Stressor Training
A 4-week physical training program that mimics military training.
Experimental: 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.
Other: Multi-Stressor Training
A 4-week physical training program that mimics military training.
Drug: Goserelin 3.6 MG
Goserelin acetate (Zoladex) is a gonadotropin-releasing hormone agonist (GnRH). GnRH agonists induce a transient increase in sex hormone concentrations, but subsequently inhibit gonadotropin secretion and the production of testosterone in men and estrogen in women. An equilibration period will occur to allow steroid concentrations to reduce.
Other Names:
  • Zoladex
Drug: Testosterone gel (AndroGel 1.25g)
Male subjects will be randomly assigned to receive a topical testosterone gel (1.25g dose).
Experimental: 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.
Other: Multi-Stressor Training
A 4-week physical training program that mimics military training.
Drug: Goserelin 3.6 MG
Goserelin acetate (Zoladex) is a gonadotropin-releasing hormone agonist (GnRH). GnRH agonists induce a transient increase in sex hormone concentrations, but subsequently inhibit gonadotropin secretion and the production of testosterone in men and estrogen in women. An equilibration period will occur to allow steroid concentrations to reduce.
Other Names:
  • Zoladex
Drug: Testosterone gel (AndroGel 5g)
Male subjects will be randomly assigned to receive a topical testosterone gel (5g dose).
Active Comparator: Hormonal Contraceptive Use (women): Multi-stressor training + Hormonal Contraceptive Use
Female participants who report that they are currently using hormonal contraception will undergo the multi-stressor training program.
Other: Multi-Stressor Training
A 4-week physical training program that mimics military training.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Biomechanical: Tendon Cross-Sectional Area, change from baseline and throughout training, mean
Time Frame: Through study completion, an average of 8 weeks
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
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
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
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
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
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
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
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
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
Through study completion, an average of 8 weeks
Biomechanical: Quadriceps Muscle Echointensity, change from baseline and throughout training, mean
Time Frame: Through study completion, an average of 8 weeks
Through study completion, an average of 8 weeks

Secondary Outcome Measures

Outcome Measure
Time Frame
Bone microarchitecture: High Resolution- peripheral Computed Tomography, change from baseline, mean
Time Frame: Through study completion, an average of 8 weeks
Through study completion, an average of 8 weeks
Biochemical: Cell culture, extracellular vesicles, micro- RNAs, change from baseline and throughout study, mean
Time Frame: Through study completion, an average of 8 weeks
Through study completion, an average of 8 weeks
Biochemical: Measures of inflammation (IL6, IL-1B, TNFa, CRP), change from baseline and throughout study, mean
Time Frame: Through study completion, an average of 8 weeks
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
Time Frame: Through study completion, an average of 8 weeks
Through study completion, an average of 8 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Bradley Nindl

Collaborators

U.S. Army Medical Research and Development Command

Investigators

  • Principal Investigator: Bradley C Nindl, PhD, University of Pittsburgh

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 15, 2024

Primary Completion (Estimated)

August 1, 2027

Study Completion (Estimated)

August 1, 2027

Study Registration Dates

First Submitted

June 6, 2024

First Submitted That Met QC Criteria

June 6, 2024

First Posted (Actual)

June 13, 2024

Study Record Updates

Last Update Posted (Actual)

August 18, 2026

Last Update Submitted That Met QC Criteria

August 14, 2026

Last Verified

August 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • STUDY23090134

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Individual participant data that underlie the results reported, after identification (text, tables, figures, and appendices).

IPD Sharing Time Frame

Beginning 1 year and ending 5 years following publication.

IPD Sharing Access Criteria

Investigators whose proposed use of the data has been approved by an independent review committee ("learned intermediary") identified for this purpose. For individual participant data meta-analysis. Proposals should be directed to bnindl@pitt.edu. To gain access, data requesters will need to sign a data access agreement.

IPD Sharing Supporting Information Type

  • SAP

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Subscribe