Effects of testosterone undecanoate on performance during multi-stressor military operations: A trial protocol for the Optimizing Performance for Soldiers II study

Alyssa N Varanoske, Melissa N Harris, Callie Hebert, Emily E Howard, Neil M Johannsen, Steven B Heymsfield, Frank L Greenway, Lee M Margolis, Harris R Lieberman, David D Church, Arny A Ferrando, Jennifer C Rood, Stefan M Pasiakos, Alyssa N Varanoske, Melissa N Harris, Callie Hebert, Emily E Howard, Neil M Johannsen, Steven B Heymsfield, Frank L Greenway, Lee M Margolis, Harris R Lieberman, David D Church, Arny A Ferrando, Jennifer C Rood, Stefan M Pasiakos

Abstract

Background: Previously, young males administered 200 mg/week of testosterone enanthate during 28 days of energy deficit (EDef) gained lean mass and lost less total mass than controls (Optimizing Performance for Soldiers I study, OPS I). Despite that benefit, physical performance deteriorated similarly in both groups. However, some experimental limitations may have precluded detection of performance benefits, as performance measures employed lacked military relevance, and the EDef employed did not elicit the magnitude of stress typically experienced by Soldiers conducting operations. Additionally, the testosterone administered required weekly injections, elicited supra-physiological concentrations, and marked suppression of endogenous testosterone upon cessation. Therefore, this follow-on study will address those limitations and examine testosterone's efficacy for preserving Solder performance during strenuous operations.

Methods: In OPS II, 32 males will participate in a randomized, placebo-controlled, double-blind trial. After baseline testing, participants will be administered either testosterone undecanoate (750 mg) or placebo before completing four consecutive, 5-day cycles simulating a multi-stressor, sustained military operation (SUSOPS). SUSOPS will consist of two low-stress days (1000 kcal/day exercise-induced EDef; 8 h/night sleep), followed by three high-stress days (3000 kcal/day and 4 h/night). A 23-day recovery period will follow SUSOPS. Military relevant physical performance is the primary outcome. Secondary outcomes include 4-comparment body composition, muscle and whole-body protein turnover, intramuscular mechanisms, biochemistries, and cognitive function/mood.

Conclusions: OPS II will determine if testosterone undecanoate safely enhances performance, while attenuating muscle and total mass loss, without impairing cognitive function, during and in recovery from SUSOPS.

Trial registration: ClinicalTrials.gov Identifier: NCT04120363.

Keywords: Anabolism; And hypogonadism; BIA, bioelectrical impedance analysis; D2O, deuterium; DSMB, data and safety monitoring board; DXA, dual-energy x-ray absorptiometry; ECW, extracellular water; EDef, energy deficit; EIEE, exercise-induced energy expenditure; Energy deficit; Exercise; FBR, fractional breakdown rate; FFM, fat-free mass; FSR, fractional synthetic rate; HR, heart rate; HRR, heart rate reserve; ICW, intracellular water; ID, identification; IRB, Institutional Review Board; MRE, Meal; Optimizing Performance for Soldiers Trial I, OPS II; Optimizing Performance for Soldiers Trial II, PAR-Q+; Pennington Biomedical Research Center, PLA; Physical Activity Readiness Questionnaire+, PB; Ready-to-Eat, OPS I; Skeletal muscle; Sleep deprivation; TBW, total body water; TDEE, total daily energy expenditure; TDEI, total daily energy intake; TEST, testosterone experimental group; VO2max, maximal cardiorespiratory fitness; VO2peak, peak oxygen uptake; WBGT, wet bulb globe temperature; placebo experimental group, PS; protein breakdown, PBRC; protein synthesis, Q; ratings of perceived exertion, SUSOPS; repetition maximum, RNA; respiratory exchange ratio, RM; ribonucleic acid, RPE; sustained, multi-stressor military operations; whole-body nitrogen flux, RER.

Conflict of interest statement

The authors declare that they have no competing interests. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Army or the Department of Defense. Any citations of commercial organizations and trade names in this report do not constitute an official Department of the Army endorsement of approval of the products or services of these organizations.

© 2021 Published by Elsevier Inc.

Figures

Fig. 1
Fig. 1
Study design. Phases 1 (days 1–7) and 3 (days 28–50) are run-in and free-living with a standardized diet with energy derived from 15% protein (PRO), 55% carbohydrates (CHO), and 30% fat (FAT). Phase 2 (days 8–27) is a highly controlled, multi-stressor military operation (SUSOPS), consisting of four consecutive cycles of undulating stress, starting with 2 days of ‘low’ stress (1000 kcal/day exercise-induced energy deficit [EDef]; 8 h/night sleep; denoted by bolded number), followed by 3 days of ‘high’ stress (3000 kcal/day exercise-induced EDef, 4 h/night sleep; denoted by red bolded and underlined number). Participants will be randomized to receive either a single intramuscular injection of testosterone undecanoate (750 mg) or an iso-volumetric placebo (sesame oil solution) on day 8. Participants will consume the same total calories and macronutrient distribution in Phase 2, but food will be derived from the Meal, Ready-to-Eat, a US combat ration ([MRE] menu 39; Ameriqual, Evansville, IN, USA). Physical performance outcomes are the primary study outcomes, which will be measured in each phase of the study. Secondary outcomes include body composition, whole-body and skeletal muscle homeostasis, endocrine-, metabolic-, and safety-related biomarkers, and cognitive function/mood. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

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