Dana M Otzel ^1,2 Larissa Nichols ¹ Christine F Conover ¹ Stephen A Marangi ¹ Jayachandra R Kura ¹ Dominic K Iannaccone ¹ David J Clark ^1,2 Chris M Gregory ³ Christopher F Sonntag ¹ Anita Wokhlu ^1,2 Hans K Ghayee ^1,2 Michael J McPhaul ⁴ Charles E Levy ¹ Charles A Plumlee ¹ Robert B Sammel ^1,5 Kevin T White ⁶ Joshua F Yarrow ^1,2,7,8*

• ¹ North Florida/South Georgia Veterans Health System, Veterans Health Administration, United States Department of Veterans Affairs, Gainesville, United States
• ² University of Florida, Gainesville, Florida, United States
• ³ Medical University of South Carolina, Charleston, South Carolina, United States
• ⁴ Quest Diagnostics Nichols Institute, San Juan Capistrano, California, United States
• ⁵ South Texas Veterans Health Care System, Veterans Health Administration, United States Department of Veterans Affairs, San Antonio, Texas, United States
• ⁶ James A. Haley Veterans’ Hospital, United States Department of Veterans Affairs, Tampa, Florida, United States
• ⁷ VA Eastern Colorado Health Care System, Veterans Health Administration, United States Department of Veterans Affairs, Denver, Colorado, United States
• ⁸ University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Background: High-dose testosterone replacement therapy (TRT) paired with finasteride (type II 5αreductase inhibitor) improves body composition, muscle strength, and bone mineral density (BMD) in older men, without inducing prostate enlargement, a side-effect associated with TRT. Men with spinal cord injury (SCI) exhibit neuromuscular impairment, muscle atrophy, bone loss, and increased central adiposity, along with low testosterone. However, sparse evidence supports TRT efficacy after SCI.Methods: This pilot parallel-group, double-blind, placebo-controlled randomized clinical trial (RCT) enrolled men (N=12) with low to low-normal testosterone and gait impairments after chronic motorincomplete SCI. Participants received high-dose intramuscular TRT (testosterone-enanthate, 125 mg/week) with finasteride (5 mg/day) vs vehicle+placebo for 12-months. Change relative to baseline was determined for body composition and musculoskeletal outcomes, and prostate size, with effects sizes calculated between groups using Hedges' g. Adverse events and feasibility were assessed.Results: TRT+finasteride consistently increased testosterone (g=1.16-3.08) and estradiol (g=0.43-3.48), while concomitantly reducing dihydrotestosterone (g=0.31-2.27). Very large effect sizes at both 6-and 12-months, suggest TRT+finasteride increased whole-body fat-free (lean) mass (+3-4% vs baseline, g=2.12-2.14) and knee extensor (KE) whole-muscle cross-sectional area (+8-11% vs baseline, g=2.06-2.53) more than vehicle+placebo. Moderate to large effect sizes suggest TRT+finasteride increased KE maximal voluntary isometric torque (+15-40% vs baseline, g=0.47-1.01) and femoral neck and distal femur BMD from 6-months onwards (g=0.51-1.13), compared with vehicle+placebo, and reduced fat mass 9-14% within the whole-body, trunk, and android (visceral) region at 12-months (g=0.77-1.27). TRT+finasteride also produced small effect sizes favoring lesser prostate growth than vehicle+placebo (g=0.31-0.43). Participant retention, drug compliance, and incidence and severity of adverse events were similar between groups.Conclusions: These data provide proof-of-concept and rationale for larger RCTs aimed at discerning the impact of TRT+finasteride on body composition, musculoskeletal health, and physical function in men with SCI, along with effect size and variance of responses to assist in planning subsequent trials.