Spinal cord injury (SCI) impairs neuromuscular function below the spinal lesion, typically resulting in muscle atrophy (1), bone loss, and high fracture risk (2). These neuromusculoskeletal deficits limit voluntary locomotor capacity in the impaired limbs and may lower basal metabolic rate (3), predisposing to visceral fat accumulation and a sequelae of metabolic consequences (4) resulting from low energy expenditure. A host of secondary endocrine changes also accompany SCI, including low testosterone (5), which has the potential to hasten the musculoskeletal decline resulting from SCI (6) and to increase fat gain and worsen cardiometabolic health (7). Indeed, the majority of the men with SCI exhibit low testosterone throughout the initial 12 months postinjury (8, 9) and roughly 20–50% of men with SCI display persistently low testosterone (10–12). However, the influence of low testosterone on muscle atrophy, bone loss, and fat accumulation in men with SCI remains understudied, as does the ability of testosterone replacement therapy (TRT) to mitigate these adverse effects of SCI (13).

In men without neurologic injury, low testosterone is associated with low muscle mass and low bone mineral density (BMD), and with increased adiposity (14) and deleterious metabolic outcomes (15). However, inconsistency exists in the literature regarding TRT efficacy across randomized clinical trials (RCTs), with some studies reporting minimal musculoskeletal and body composition benefits and others reporting more substantial improvement (16). For example, several RCTs that administered transdermal TRT to older men without neurologic injury reported small increases in fat-free (lean) mass, ranging from 1–2 kg over 12–36 months of treatment, but no detectable increase was evident in lower extremity muscle strength when compared with placebo (17–22). Other RCTs that provided intramuscular testosterone-enanthate observed a 3–4 kg increase in lean mass after only 5–12 months and an accompanying ~10–25% increase in the lower extremity muscle strength (23–25). Similarly, meta-analyses report that intramuscular TRT produced, on average an approximately 3.5 times greater increase in lean mass than transdermal TRT formulations, along with more significant increases in muscle strength (26) and BMD (27), when compared with their respective placebos.

TRT is also associated with several side effects, the most common of which are increased risks of polycythemia, reduced high-density lipoprotein (HDL) cholesterol, and combined prostate/lower urinary tract-related events (28). Meta-analyses have confirmed that intramuscular TRT increased prostate-specific antigen (PSA) more so than transdermal TRT formulations (29, 30) and that TRT is associated with an increase in prostate volume (31), independent of other prostate events. However, these prostate events are driven by the intraprostatic conversion of testosterone to dihydrotestosterone via the 5α-reductase isozymes and not directly by TRT (16). In this regard, our laboratory (25) and others (32, 33) have reported that finasteride, a type II 5α-reductase inhibitor, reduced circulating dihydrotestosterone by 50–75% and prevented the increase in PSA and prostate growth associated with high-dose intramuscular testosterone-enanthate without inhibiting the beneficial body composition and musculoskeletal changes that result from TRT.

No consensus exists regarding the ability of TRT to improve musculoskeletal health or body composition in the SCI population because, to date, no double-blind, placebo-controlled RCT has assessed TRT efficacy in men with SCI. Indeed, the results of only two small prospective trials exist on this topic in the literature, both open-label, non-placebo-controlled studies (34, 35). In the first, Bauman et al. provided moderate-dose transdermal TRT to men who exhibited low testosterone after chronic motor-complete SCI and observed increased lean mass within the whole body, trunk, and paralyzed lower extremities, along with a concomitant increase in resting metabolic rate (34). In comparison, several studies from the second trial reported that low-dose transdermal TRT did not improve body composition nor basal metabolic rate (35), muscle cross-sectional area (CSA), muscle force production (36–38), nor bone microstructure (39) in men with chronic motor-complete SCI. While neither trial utilized intramuscular TRT, studies from our laboratory demonstrated that the high-dose intramuscular testosterone-enanthate attenuated muscle atrophy and trabecular bone loss that developed in the paralyzed limbs in a rodent severe SCI model (40–43). Moreover, in this rodent SCI model, co-administration of finasteride completely prevented prostate enlargement resulting from high-dose intramuscular TRT without inhibiting these musculoskeletal benefits (41). As such, well-controlled RCTs are needed to determine whether intramuscular TRT paired with finasteride (TRT + finasteride) can safely improve body composition and musculoskeletal health in men with low testosterone after SCI.

The primary purpose of this pilot RCT study was to determine effect sizes and variance of responses for body composition and musculoskeletal outcomes in response to TRT + finasteride vs. vehicle+placebo in men with low to low–normal testosterone and impaired gait after chronic motor-incomplete SCI. Efficacy-based outcomes were whole-body, upper body, and lower extremity fat-free (lean) mass; whole-body, trunk, and android (visceral) fat mass; knee extensor (KE) muscle cross-sectional area (CSA) and maximal voluntary isometric contraction (MVIC); total hip, femoral neck, lumbar spine, and distal femur areal (a) BMD; and circulating bone resorption and formation markers. The secondary purposes were to obtain effect sizes and variance of response for change in prostate volume and initial estimates comparing the prevalence of other adverse events (AE).

In the 1950s, Cooper et al. published two case series demonstrating that high urinary nitrogen excretion, and a negative nitrogen balance persisted for several months after SCI, and that high-dose intramuscular testosterone (50–100 mg/day) mitigated nitrogen excretion and normalized nitrogen balance in this population (59, 60). As a result, Cooper et al. suggested testosterone treatment may attenuate muscle loss and possibly bone loss after SCI (59, 60). In the 70+ years since these findings, we are aware of only two small prospective clinical trials that assessed musculoskeletal or body composition responses to TRT in men with SCI (34, 35), both being open-label, non-placebo-controlled studies. In the first, Bauman et al. reported that transdermal TRT increased whole-body, trunk, and lower-extremity lean mass, and resting energy expenditure by 7–9% in men (N = 11) with chronic motor-complete SCI (34), with improvements persisting 6 months after TRT cessation (61). In contrast, several studies from the second trial indicated that transdermal TRT did not improve body composition or basal metabolic rate (35), nor increase whole-muscle CSA, muscle fiber CSA, electrical-stimulation evoked muscle contractile properties (36–38), or bone microstructural parameters (39) in the paralyzed limbs of men (N = 11) with chronic motor-complete SCI. At first, these trials may appear contradictory, although careful examination of each study design provides insight. For example, Bauman et al. (34) administered moderate-dose transdermal TRT (5–10 mg/day; 35–70 mg/week) to men with baseline total testosterone of 250 ± 95 ng/dL, indicating frankly low testosterone. This TRT regimen restored circulating testosterone to the mid-normal physiologic range (432–502 ng/dL) over 6 to 12 months. In comparison, Gorgey et al. (35) provided low-dose transdermal TRT (2–6 mg/day; 14–42 mg/week) for 16 weeks to men whose baseline testosterone was within the eugonadal range on average (431 ± 215 ng/dL) and did not detect any change in circulating testosterone. Collectively, these results demonstrate inconsistency surrounding the impact of TRT on body composition and markers of musculoskeletal health in men with SCI and suggest that higher TRT doses may be required to improve such outcomes after SCI, as has been shown in rodent experimental SCI models (40), and/or that longer TRT durations are needed to observe benefits in persons with SCI.

Herein, we conducted a double-blind, placebo-controlled pilot study that enrolled men with low to low–normal testosterone and ambulatory dysfunction after chronic motor-incomplete SCI and randomized participants to receive TRT + finasteride vs. vehicle+placebo for 12 months. Our focus was to collect preliminary data on efficacy-based body composition, muscle, and bone outcomes that are relevant to the SCI population, while concomitantly assessing prostate size and incidence of AEs that are associated with TRT administration (28). We utilized the broad framework recommended in the Institute of Medicine (IOM) report “Testosterone and Aging: Clinical Research Directions,” (62) which included conducting short-term, double-blind, placebo-controlled RCTs to assess efficacy-based primary outcomes; including participants with testosterone below the physiologic range of young adult men; and ensuring participant safety by including prostate-related exclusion criteria, regular monitoring of PSA, prostate changes, and other AEs. However, our RCT did not specifically enroll older men, as suggested in the IOM report (62), because low testosterone develops at earlier ages in response to SCI (12). However, more than half of our participants were > 60 years of age, and all except one were above the age of 50 years. We evaluated a combinatory regimen that included high-dose intramuscular TRT with finasteride because meta-analyses indicate that intramuscular TRT more distinctly increased lean mass, muscle strength (26), and BMD (27) than transdermal TRT formulations, when compared with their respective placebos, and because several RCTs reported that TRT + finasteride markedly improved body composition, muscle strength, and BMD in older men without neurologic injury (25, 32, 33), while limiting prostate symptoms associated with intramuscular TRT. Herein, we report that TRT + finasteride consistently elevated total testosterone and its bioavailable and free testosterone subfractions (large to very large effect sizes throughout), while concomitantly reducing dihydrotestosterone (large to very large effect sizes) at the majority of the timepoints. From an efficacy standpoint, TRT + finasteride produced moderate to very large ES at both 6 and 12 months for several efficacy outcomes, including (1) whole-body, upper body, and lower body lean mass, (2) trunk fat mass, (3) KE whole-muscle CSA, and (4) femoral neck and distal femur aBMD. In addition, moderate to very large effect sizes were detected at several distinct timepoints from 6 months onward for whole-body and visceral fat mass, KE MVIC, and all other efficacy-based outcomes in response to TRT + finasteride. From a safety standpoint, small effect sizes favoring smaller prostate increases in TRT + finasteride vs. vehicle+placebo were present at 6 and 12 months. Moreover, no differences in the incidence of AEs commonly associated with TRT existed between groups (28).

Intramuscular TRT dose-dependently increases circulating testosterone and its bioactive metabolites—dihydrotestosterone and estradiol (63)—via localized tissue-specific actions of the 5α-reductase and aromatase enzymes (64), respectively. In our study, intramuscular TRT increased circulating testosterone into the mid-to-high physiologic range and also reduced SHBG, similar to a previous RCT that utilized an identical TRT dose (65), which produced higher bioavailable (non-SHBG-bound) and free (unbound) testosterone. TRT + finasteride also increased estradiol and reduced dihydrotestosterone by 50–60%, like previous RCTs that utilized this combinatory drug regimen (25, 32, 33). Our study design cannot distinguish whether the SHBG and estradiol changes were solely due to high-dose TRT or whether these changes were influenced by finasteride co-administration. However, Amory et al. reported no changes in SHBG and estradiol in men receiving finasteride or dutasteride, a dual-type I/II 5α-reductase inhibitor, over 12 months (66) and our laboratory previously reported that older men receiving TRT alone exhibited increased estradiol and that finasteride co-administration did not alter this response (25), suggesting these changes likely resulted primarily from TRT with little influence from finasteride. Interestingly, previous RCTs have shown that higher TRT doses produced greater muscular benefit in older men without neurologic injury and that neither 5α-reductase (25, 32, 67) nor aromatase (68) activity is required for muscle gain. Furthermore, the conversion of testosterone to dihydrotestosterone via the type II 5α-reductase enzyme is not required for the lipolytic or BMD benefits of TRT in older men, but this conversion exacerbates prostate growth associated with TRT (25, 33). In comparison, the aromatization of testosterone partially mediates the TRT-induced regulation of bone metabolism (69, 70), BMD (71), and lipolysis in men (68). As such, the increases in testosterone and estradiol and the simultaneous reduction in dihydrotestosterone resulting from TRT + finasteride likely underlie our results.

We observed a 4–5% greater increase in whole-body lean mass in TRT + finasteride vs. vehicle+placebo at both 6 and 12 months (very large effect sizes at both), which is comparable to that occurring in hypogonadal older men without neurologic injury who received TRT + finasteride (25). This lean mass gain was relatively consistent in the upper body and impaired lower extremities, similar to the findings of Bauman et al. (34), and was accompanied by 8–11% higher KE whole-muscle CSA (very large effect sizes throughout) and a > 15% increase in KE MVIC at 6 months onward (moderate to large effect sizes), similar to that observed in other RCTs that administered intramuscular TRT to older men without neurologic injury (23–25). Notably, prior research indicates that the preservation and/or restoration of KE strength is a key predictor of walking function in persons with motor-incomplete SCI (72), providing a rationale to assess gait parameters in future TRT studies conducted in the incomplete SCI population. In comparison, Gorgey et al. reported that low-dose transdermal TRT did not increase circulating testosterone (35) nor increase lean mass, muscle CSA, or electrical stimulation-evoked muscle force production in the paralyzed limbs of men with chronic complete SCI over 4 months (36–38). Given this, our data appear to be the first direct evidence to suggest that TRT produces muscular benefit in men with chronic SCI, when given in a sufficient dose and duration.

TRT is known to reduce visceral fat mass in men with central adiposity (73). We observed a greater reduction in adiposity in TRT + finasteride vs. vehicle+placebo, which was most evident in the trunk and visceral depot that displayed ~11–14% greater fat mass reduction at 12 months (large effect sizes for both). These reductions in whole-body and trunk fat were similar in magnitude to previous RCTs administering TRT + finasteride in older men without neurologic injury (25, 32). While we did not investigate the mechanisms underlying the lipolytic effects of TRT, this likely relied on the aromatization of testosterone (68). For example, Holland et al. reported that high-dose testosterone-enanthate reversed visceral fat accumulation in orchiectomized rats through an estrogen-dependent mechanism that suppressed several genes that influence fat accumulation, including lipoprotein lipase and fatty acid synthase (74). Alternatively, it is possible that fat loss resulting from TRT may be influenced by increased resting and/or activity-dependent energy expenditure. In this regard, Bauman et al. reported that TRT increased resting energy expenditure by ~8% or ~ 115 kcal/day in men with motor-complete SCI (34) and preclinical studies demonstrate that testosterone treatment restored voluntary physical activity in orchiectomized rodents in a manner that relied on aromatase (75, 76). Moreover, estradiol is known to promote the recovery of respiratory function and improve respiratory neuroplasticity in the rodent C2-hemisection model, which has the potential to indirectly benefit physical function (77). As such, our results provide a rationale to discern the mechanism(s) through which TRT + finasteride stimulates fat loss after SCI and to determine whether a visceral fat reduction of the magnitude observed herein is sufficient to improve cardiometabolic health in persons with chronic SCI, especially given that high visceral fat mass predicts increased cardiometabolic risk in persons with chronic SCI (7, 78) and that low testosterone is associated with a harmful cardiometabolic profile in this population (4).

Increased bone resorption and/or reduced bone formation after SCI leads to imbalanced bone turnover and progressive cancellous and cortical bone loss (2), contributing to the 100-fold higher lower-extremity fracture risk in men with SCI at age 50, compared to the general population (79). In older men without neurologic injury, TRT increases hip and lumbar spine BMD (80), when provided in a sufficient dose and duration. However, only one small exploratory study has assessed the skeletal responses to TRT in persons with SCI, reporting that 16 weeks of low-dose transdermal TRT did not improve MRI-derived bone microstructural parameters at the proximal, mid-diaphyseal, or distal femur (39). In comparison, we observed a 6–8% increase in distal femur aBMD at 6 and 12 months (medium to large effect sizes at both) in response to TRT + finasteride, along with hip and spine aBMD changes that were comparable to previous RCTs administering TRT + finasteride to older men (25, 33). The differences in skeletal responses between the Holman et al. exploratory study (39) and our findings are likely due to differences in study duration and design (16-weeks non-placebo controlled RCT vs. 12 months double-blind, placebo-controlled RCT) or to differences in TRT modality and dose (transdermal TRT, 2–6 mg/day or 14–42 mg/week vs. intramuscular TRT, 125 mg/week) that influence the circulating testosterone and/or estradiol responses. Indeed, in rodent SCI models, the bone responses to TRT are dose-dependent, with higher doses producing more profound skeletal benefit (40), and may be influenced by the aromatization to estradiol, as has been shown in adult men (64). The aBMD improvements we observed were accompanied by lower circulating CTX-1, TRAcP 5b (bone resorption markers), and osteocalcin (bone formation marker) in TRT + finasteride (moderate to very large effect sizes), consistent with reduced bone turnover due to the known antiresorptive actions of testosterone (70). Given the high incidence of distal femur fractures following SCI (2), we are encouraged by the distal femur aBMD increase, which was larger in magnitude and more consistent than BMD changes at the hip, possibly due to the high concentration of trabeculae at the distal femur. In this regard, Snyder et al. reported that TRT increased volumetric BMD more so in trabecular bone compartments vs. cortical-rich peripheral bone, across several skeletal sites, in older hypogonadal men (80). Similarly, in a rodent SCI model, we have shown that high-dose intramuscular testosterone-enanthate prevented trabecular bone loss at several key sublesional sites, including the femoral neck, distal femur, and proximal tibia, but did not impact cortical bone at these sites (40–42). In line with this speculation, over the initial 6 months of the study, TRT + finasteride increased aBMD at the lumbar spine, which is an area rich in trabecular bone, although these apparent changes reverted by 12 months, likely due to participant withdrawals in both groups over the final 6 months. As such, future studies assessing TRT-induced skeletal changes should incorporate imaging modalities that can distinguish trabecular and cortical bone compartments with those that can predict bone mechanical characteristics in response to torsional and compressive loading, such as computerized tomography with finite element analysis, along with more standard DXA measurements (81), to ensure a more complete understanding of the impact of TRT on bone structure and strength.

TRT is associated with increased risk for several side effects, including polycythemia, a small HDL cholesterol reduction, and combined prostate/lower urinary tract-related events, including increased PSA, prostate enlargement, and prostate nodules necessitating biopsy (28). However, a complex relationship exists between these side effects and the change in the sex-hormone milieu after TRT, with estradiol serving as a better predictor of the hemoglobin and HDL changes than testosterone or dihydrotestosterone (82). Given this, it is essential to mention that our TRT + finasteride regimen occasionally increased testosterone above the physiologic range and produced highly elevated estradiol, necessitating downward TRT dose adjustments in some participants. Regardless, TRT + finasteride produced no incidence of polycythemia, defined in our study as hematocrit >52% or hemoglobin >17.5 g/dL. The increased polycythemia risk in men receiving TRT has raised concern regarding potential cardiovascular risks, particularly in older men with mobility limitations (83). For example, the Testosterone in Older Men with Sarcopenia (TOM) Trial, which enrolled older men with low testosterone and mobility limitations not resulting from neuromuscular disease, was discontinued based on recommendations of the Data Safety Monitoring Board due to a higher incidence of cardiovascular-related AEs in the testosterone vs. placebo group (83). Although a recent multisite RCT that evaluated 5,000+ hypogonadal men with pre-existing cardiovascular risk factors reported that TRT did not increase major adverse cardiovascular events over a 4-years follow-up, when compared with placebo (84). Additionally, TRT + finasteride produced negligible PSA change and a lesser prostate size increase than vehicle+placebo (small effect sizes), along with no prostate nodules or indurations, confirming previous studies that report TRT + finasteride may produce lower prostate risk than TRT-alone (25, 32, 33). This remains important in the SCI population because testosterone is independently associated with prostate size in men with SCI (85) and because benign prostate hyperplasia may produce complications when assessing neurogenic bladder issues common in men with SCI (86) and may limit ease of intermittent catheterization (87).

As with all studies, several limitations warrant discussion. First, we enrolled men with low to low–normal testosterone and ambulatory dysfunction after chronic motor-incomplete SCI resulting from trauma, vascular, or orthopedic pathology. As such, our results should not be generalized to other populations, such as those with SCI due to differing pathology, those with acute or subacute SCI or complete (AIS A/B) SCI, or men with normal testosterone after SCI. Second, while we comprehensively assessed sex-steroid hormones, including total testosterone and its subfractions, estradiol, dihydrotestosterone, and SHBG, we did not assess gonadotropins, so we cannot discern whether low testosterone was due to primary or secondary causes. Third, this study was terminated prior to achieving our a priori enrollment target, in part, due to the emergence of the SARS-CoV-2 (COVID-19) pandemic and the resulting nationwide VA-mandated halt on in-person research visits. Given this, randomization resulted in somewhat differing baseline KE whole-muscle CSA, KE MVIC, and prostate volume values between groups. As such, our results are considered preliminary and require confirmation. However, this pilot study fulfilled its primary purpose, which was to elicit preliminary data on TRT + finasteride efficacy in the chronic incomplete SCI population that can be targeted for confirmation in larger, more comprehensive clinical trials.

Based on our findings, we suggest several future directions to advance TRT-related research within the SCI population. First, large, well-controlled RCTs are needed to validate the observations reported herein. When designing such studies, we suggest (1) enrolling men with chronic incomplete SCI who exhibit unequivocally low testosterone and signs and/or symptoms of hypogonadism and that meet other Endocrine Society (88) and Society for Endocrinology (89) recommendations to ensure appropriateness of testosterone therapy, (2) employing a multisite approach to increase likelihood of meeting recruitment goals, (3) utilizing a study duration of 12 months or longer to ensure sufficient time exists to detect musculoskeletal and body composition changes, (4) incorporating an intramuscular TRT titration protocol to ensure circulating testosterone does not exceed the physiologic range for adult men, and (5) following framework in the IOM report on “Testosterone and Aging: Clinical Research Directions” concerning the assessment of efficacy and safety outcomes (62). Second, it remains essential to determine the potential clinical relevance of TRT-induced body composition and musculoskeletal changes. Several vital questions that warrant investigation, include: Are body composition changes of the magnitude reported herein sufficient to impact cardiometabolic health? Do TRT-induced muscular adaptations improve physical function and/or quality of life or reduce frailty or disability status in those with motor-incomplete SCI? Are BMD changes that result from TRT sufficient to increase bone strength or reduce fracture risk after SCI, particularly in the highly fracture-prone regions that surround the knee? Third, studies are needed to assess whether intramuscular TRT lessens muscle and bone loss throughout the acute to subacute post-SCI recovery period when the majority of the men exhibit low testosterone (8, 9), especially considering that high-dose intramuscular testosterone treatment has been shown to mitigate nitrogen excretion and normalize nitrogen balance in the weeks to months after SCI (59, 60). Fourth, it is essential to discern whether intramuscular TRT improves muscle and bone integrity and body composition in persons with complete SCI, given that these individuals typically display more severe muscle and bone loss and higher fracture risk than those with incomplete SCI and that no pharmacologic has shown consistent success in improving musculoskeletal integrity after complete SCI (1, 2). In this regard, assessing the impact of intramuscular TRT with and without activity-based physical rehabilitation or other therapeutic modalities that impart mechanical strains in the impaired limbs would assist in understanding the unique interplay between the nervous, endocrine, and musculoskeletal systems during paralysis (90). Finally, from a mechanistic perspective, assessing the individual and combined effects of intramuscular TRT and finasteride is necessary to impart an understanding of how each drug impacts safety and efficacy in this population and to better discern the influence(s) of testosterone and dihydrotestosterone on tissues of interest.

In summary, we report findings from the first double-blind, placebo-controlled RCT assessing TRT efficacy in persons with SCI. The effect sizes detected herein suggest TRT + finasteride increased circulating testosterone and estradiol into the high physiologic range, while concomitantly reducing dihydrotestosterone, which was the underlying premise of this study. From an efficacy standpoint, TRT + finasteride produced large to very large effect sizes for key body composition, muscle, and bone outcomes at both 6 and 12 months, in a magnitude similar to that occurring in older hypogonadal men without neurologic injury in response to intramuscular TRT (25, 32), and for all other efficacy outcomes at select timepoints after 6 months. These data suggest that a minimum 6-months regimen of high-dose intramuscular TRT may be required to improve body composition and musculoskeletal integrity in the SCI population. From a safety standpoint, small effect sizes favored lesser prostate growth in TRT + finasteride, with similar AE rates detected in both groups, suggesting that known prostate-related side effects of high-dose TRT may be minimized by finasteride co-administration, as has been observed in other populations (25, 32, 33). Collectively, these findings provide proof-of-concept and rationale for future RCTs focused on determining the ability of intramuscular TRT with finasteride to safely improve body composition, musculoskeletal health, and physical function in men with low testosterone and impaired gait after SCI, along with effect sizes and variability data to assist in planning such trials.