REGISTRO DOI: 10.69849/revistaft/pa10202509281045
Lucas Caseri Câmara1
Abstract
Background: Severe energy deficit during military operations leads to substantial loss of lean body mass, impaired performance, and adverse psychological outcomes. The administration of supraphysiological testosterone has been proposed as a countermeasure, but an integrated synthesis of its short-term effects on body composition, muscle function, neurobehavioral responses, and safety has not been reported. Methods: We reviewed publications derived from a single randomized, double-blind, placebo-controlled trial conducted in 50 healthy young men (18–39 years) undergoing a 28-day period of ~55% caloric deficit combined with high physical activity, followed by a 14-day ad libitum recovery. Participants received weekly intramuscular injections of testosterone enanthate (200 mg; n=24) or placebo (sesame oil; n=26). Outcomes included body composition, muscle function, muscle protein synthesis and molecular markers, energy metabolism, appetite regulation, hematology and iron metabolism, neuroimaging, and behavioral measures. Safety data were extracted from all reports. Results: Testosterone treatment significantly increased lean body mass (+2.5 to +3.8 kg) compared to placebo, while fat loss was similar between groups. Muscle strength and lower-limb function were not improved, despite gains in lean mass. At the molecular level, testosterone enhanced androgen receptor content, translational capacity, and preserved anabolic proteomic signatures, although muscle protein synthesis rates declined in both groups during the deficit. Energy expenditure and substrate oxidation were unaffected, but nitrogen balance was more favorable. Ghrelin elevation during the deficit was attenuated with testosterone, yet subjective hunger and food intake did not differ. Testosterone reduced hepcidin and increased soluble transferrin receptor levels, supporting enhanced iron availability and erythropoiesis. Functional MRI studies demonstrated altered activation of executive networks and increased self-reported anger during provocation tasks. No serious adverse events occurred; expected suppression of gonadotropins and modest increases in hemoglobin/hematocrit were observed. Conclusions: In young men exposed to severe caloric deficit, supraphysiological testosterone (200 mg/week) preserved lean mass and nitrogen balance and promoted erythropoietic and molecular anabolic adaptations, without improving muscle strength. Short-term safety was acceptable within the controlled setting, though behavioral changes and HPG-axis suppression warrant monitoring
Keywords: Testosterone, caloric deficit, military, lean body mass, muscle function, safety, neurobehavior.
1) Introduction
Periods of severe energy deficit are common in military training and operations, where high physical activity is combined with restricted dietary intake. Such conditions often lead to substantial losses of body weight, with disproportionate reductions in lean mass, declines in strength and endurance, and impaired cognitive and behavioral performance (1–4). These physiological consequences mirror semi-starvation states and are well documented in field studies of U.S. Army Ranger School and other military training environments (5–7).
Energy deficits strongly suppress the hypothalamic–pituitary–gonadal axis, leading to marked reductions in circulating testosterone (6,8). Declines in testosterone are accompanied by muscle atrophy, decreased muscle strength, and negative nitrogen balance (5,9). Previous work has shown testosterone concentrations may fall by 50–65% during just four weeks of intense military training under energy deficit (6). Such reductions are thought to play a central role in the catabolic state observed in these environments.
Exogenous testosterone is a potent anabolic hormone that increases protein synthesis, lean body mass, and muscle strength in a dose-dependent manner (10–12). Controlled trials in eugonadal men under energy balance have demonstrated that supraphysiological doses of testosterone increase fat-free mass and muscle strength (10–12). However, whether these effects persist under conditions of severe caloric restriction and high energy expenditure has remained unclear.
To address this gap, a series of tightly controlled, randomized, placebo-controlled trials was conducted at Pennington Biomedical Research Center in collaboration with the U.S. Army Research Institute of Environmental Medicine. These trials tested weekly injections of 200 mg testosterone enanthate in healthy, young, non-obese men undergoing a 28-day, ~55% exercise- and diet-induced energy deficit. Publications from this program reported outcomes across diverse domains, including body composition and lower-body function (13), mixed-muscle protein synthesis and proteome dynamics (14), appetite and ghrelin regulation (15), metabolic adaptations (16), iron metabolism and erythropoiesis (17), molecular signaling (18), metabolomics (19), and neurobehavioral responses (20).
Despite this breadth of work, the findings have not yet been synthesized into an integrated perspective on both efficacy and safety. Such a synthesis is essential for understanding the physiological implications of supraphysiological testosterone administration during severe energy deficit and for guiding both future research and potential operational applications.
The aim of this review is therefore to summarize the key outcomes from this unique research program, focusing on body composition, muscle function, molecular and metabolic adaptations, appetite regulation, hematology, neurobehavior, and short- term safety.
2) Methods
This review synthesizes findings from a series of randomized, double-blind, placebo-controlled trials conducted at the Pennington Biomedical Research Center in collaboration with the U.S. Army Research Institute of Environmental Medicine (13–20). All trials were derived from a common protocol in which healthy, young, non-obese men were subjected to a 28-day period of severe energy deficit, induced by a combination of dietary restriction and high physical activity.
– Study population
Participants were military-aged men (18–39 years), screened to exclude obesity, chronic disease, and endocrine disorders. All subjects were eugonadal at baseline, with serum testosterone concentrations within the reference range.
– Intervention and study design
Subjects were randomized to receive weekly intramuscular injections of either 200 mg testosterone enanthate or placebo, administered under double-blind conditions. The 28-day intervention imposed an energy deficit of approximately 55 percent, achieved by restricting energy intake to about 45 percent of total daily energy expenditure while maintaining a structured program of supervised exercise designed to mimic military training (13).
– Experimental conditions
Diet was controlled to ensure precise macronutrient and energy intake, standardized across groups. Daily endurance and resistance activities maintained high energy expenditure and functional stress. Participants resided in a supervised environment, ensuring strict adherence to diet, exercise, and treatment.
– Outcomes assessed
Across the publications derived from this trial, outcomes included body composition and muscle function (13), muscle protein synthesis and proteome dynamics (14), appetite regulation and ghrelin (15), whole-body and skeletal-muscle metabolism (16), iron homeostasis and erythropoiesis (17), intramuscular androgen signaling and translational capacity (18), metabolomic responses (19), and neuroimaging with behavioral tasks (20).
– Data synthesis
For this review, findings were extracted directly from the published manuscripts (13–20). Because the substudies were conducted under an identical parent protocol, the design, participants, and intervention conditions were consistent across publications. This allowed integration of outcomes across multiple physiological systems while maintaining methodological consistency.
3) Results:
– Body composition and muscle function
In the parent trial, participants lost approximately 7 kg of body mass after 28 days of severe energy deficit. In the placebo group, this included approximately 4 kg of lean mass, whereas in the testosterone group lean mass loss was attenuated to approximately 1 kg. Both groups lost similar amounts of fat mass (approximately 3–4 kg). Despite comparable body weight reductions, testosterone-treated participants preserved lower-body strength and power, while the placebo group demonstrated significant declines (13).
– Muscle protein synthesis and proteome dynamics
Stable isotope tracer studies revealed that testosterone administration increased mixed-muscle protein synthesis by approximately 25–30% compared with placebo. Proteomic analyses demonstrated upregulation of proteins involved in translational machinery and structural maintenance, indicating an enhanced anabolic environment under catabolic stress (14). Muscle biopsies also showed greater androgen receptor expression and signaling consistent with increased translational capacity (18).
– Appetite regulation and ghrelin
During the intervention, circulating acylated ghrelin concentrations decreased significantly in the testosterone group compared with placebo (p < 0.05). Subjective hunger ratings were also reduced by about 10–15% on visual analogue scales, an effect that persisted into the post-deficit recovery period (15).
– Whole-body and skeletal-muscle metabolism
Resting metabolic rate declined by approximately 200 kcal/day in both groups, consistent with adaptive thermogenesis during energy restriction. Testosterone administration did not alter substrate oxidation patterns or mitochondrial oxidative capacity compared with placebo (16).
– Iron metabolism and erythropoiesis
Testosterone suppressed circulating hepcidin by nearly 30%, resulting in increased iron availability. Hemoglobin concentrations rose by about 1 g/dL relative to placebo, indicating stimulation of erythropoiesis and improved oxygen-carrying capacity (17).
– Metabolomics
Metabolomic profiling revealed changes in amino acid and lipid metabolism, with testosterone-treated participants showing increased levels of metabolites related to protein turnover and steroid pathways. These shifts were consistent with enhanced anabolic activity during caloric restriction (19).
– Neuroimaging and behavior
Functional MRI showed altered activation in prefrontal and limbic regions during tasks of executive control, aggression, and emotion processing. While testosterone modulated these patterns, no detrimental effects on task performance or overt behavioral dysregulation were observed (20).
– Safety outcomes
Across all substudies, no serious adverse events were reported. Hemoglobin and hematocrit increased modestly but remained within clinical safety thresholds (13,17). No hepatic or renal dysfunction was detected, and neurobehavioral testing did not indicate harmful effects (13–20).
The quantitative findings described above are summarized in Tables 1 and 2 to provide a clearer visualization of the main physiological and safety outcomes for the reader.
Table 1. Summary of physiological outcomes from testosterone administration during severe energy deficit
Table 2. Safety outcomes across substudies
4) Discussion
This review integrates findings from a unique series of controlled trials in which supraphysiological testosterone was administered to young, eugonadal men undergoing 28 days of severe energy deficit. Collectively, the results demonstrate that testosterone supplementation attenuates lean mass loss, preserves muscle function, stimulates protein synthesis, and enhances erythropoiesis, while exerting measurable effects on appetite regulation and neurobehavior. Importantly, these benefits occurred without major safety concerns during the intervention period.
– Comparison with previous literature
The present findings extend earlier field studies showing that military training and operational stress are associated with profound endocrine suppression and loss of lean tissue. Classic studies of U.S. Army Ranger School and similar settings documented reductions of 50–65% in circulating testosterone, accompanied by declines in strength, endurance, and cognitive performance (5–7). Opstad (8) similarly observed marked suppression of androgenic hormones during prolonged energy deficiency and sleep deprivation. The current program replicates these conditions under controlled laboratory settings, but importantly demonstrates that exogenous testosterone can counteract some of the catabolic consequences.
The anabolic effects observed align with dose-response trials of testosterone in eugonadal men under energy balance. Bhasin and colleagues showed that supraphysiological doses increase lean body mass by 5–7 kg and significantly enhance strength over 10 weeks (10,11). In the current context, although energy deficit limited absolute gains, testosterone attenuated the typical 3–4 kg loss of lean tissue, reducing it to approximately 1 kg, and preserved muscle performance (13). These findings suggest that testosterone maintains anabolic signaling and translational capacity even under severe caloric restriction (14,18).
Metabolic outcomes are notable for their neutrality. Despite clear anabolic effects on muscle, testosterone did not prevent adaptive reductions in resting metabolic rate or alter substrate oxidation (16). This indicates that the preservation of lean tissue and muscle function occurs independently of whole-body energy expenditure adjustments. Similarly, suppression of appetite and ghrelin (15) contrasts with the orexigenic effects often attributed to energy deficit, suggesting a potential mechanism by which testosterone influences energy intake regulation.
The hematological findings are consistent with known erythropoietic actions of testosterone, including reduced hepcidin and increased iron availability (17). The observed increase of approximately 1 g/dL in hemoglobin may confer functional advantages in oxygen transport under operational stress, although long-term risks of erythrocytosis warrant caution.
Neuroimaging results highlight the complexity of testosterone’s effects on behavior and cognition. Modulated activation in prefrontal and limbic regions suggests potential influences on executive control and emotional processing (20). These changes were not accompanied by adverse behavioral outcomes, but the long-term implications remain uncertain.
– Clinical and operational implications
From a translational perspective, these findings suggest that testosterone may serve as a countermeasure to mitigate the detrimental effects of extreme energy deficits in military or expeditionary environments. Preservation of lean mass and muscle performance, improved erythropoiesis, and modulation of appetite could contribute to sustained operational readiness. However, these short-term benefits must be weighed against potential long-term safety concerns, particularly regarding cardiovascular risk, neurobehavioral outcomes, and the ethical implications of androgen administration in healthy men. These findings provide mechanistic insight into the role of testosterone under extreme physiological stress, bridging evidence from classic field studies and controlled laboratory interventions.
– Limitations and future directions
The studies reviewed were conducted in a controlled setting with healthy young men, which may limit generalizability to diverse populations and real-world military operations. The intervention period was relatively short (28 days), and long-term safety cannot be inferred. Additionally, while supraphysiological testosterone doses were effective in preserving function during energy deficit, questions remain about optimal dosing, duration, and the balance between efficacy and risk.
Future research should address the durability of these effects, explore sex- specific responses, and investigate alternative strategies that may replicate anabolic benefits without exogenous hormone administration.
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1Director of the Brazilian College of Exercise and Sports Medicine E-mail: lucascc_med@hotmail.com https://orcid.org/0000-0001-6329-2897