Testosterone Plus Finasteride Therapy to Improve Walking Function After SCI

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270,000 individuals have a spinal cord injury (SCI) in the US. Of these, ~42,000 are eligible for treatment in the Veteran Health System, resulting in direct annual medical expenditures exceeding $716 million per year. Walking impairment is a hallmark consequence of motor incomplete (i)SCI. Preventing neuromuscular deficits after iSCI has the potential to improve walking and positively impact functional independence and quality of life (QOL) in Veterans with SCI. The musculoskeletal decline primarily results from reduced neural drive after iSCI and disuse atrophy caused by reduced standing and walking (i.e., low muscle loading). These issues are exacerbated by the dramatic loss of testosterone (T) following iSCI in men. T replacement therapy (TRT) is a viable therapy to improve musculoskeletal function in non-neurologically impaired hypogonadal men. A prospective clinical trial has reported that TRT improves lower extremity lean mass after motor complete SCI, indicating the ability of TRT to produce musculoskeletal benefit independent of physical rehabilitation. Preclinical work by mentors Borst/Yarrow has shown preserved hindlimb musculature and improved locomotor activity in a rodent iSCI model following T administration. However, the ability of TRT to safely improve neuromuscular and locomotor function remains to be determined in men with iSCI, a population that exhibits impaired neuromuscular activation, reduced muscle mass/strength, and functional limitations after injury. Borst/Yarrow have also demonstrated that finasteride (F), an FDA approved 5α-reductase inhibitor that blocks the conversion of T to dihydrotestosterone, completely prevented prostate enlargement resulting from TRT without compromising the associated musculoskeletal benefits in hypogonadal elderly men, indicating that F co-administration improves the TRT risk-to-benefit ratio. This Career Development Award (CDA)-1 will embed itself in a recently funded VA Merit Award which is focused on evaluating the safety/efficacy of TRT plus finasteride (TRT+F) in hypogonadal men with iSCI who exhibit ambulatory dysfunction. The parent Merit Award is a 12-month double-blind placebo-controlled randomized clinical trial assessing: thigh muscle cross-sectional area (CSA), knee extension (KE) neuro-muscular function including strength and voluntary muscle, bone mineral density/body composition, and safety measures. This CDA-1 will expand beyond the above evaluations by adding several unique gait-related measures (functional outcomes that were not originally proposed) that will be performed at baseline, and at follow-up times of 3 and 6 months of treatment, in order to gauge functional improvements following the TRT+F vs. placebo. Twenty-six participants will be recruited and screened from the NF/SG VHS and will be treated according to the parent Merit protocol. Testosterone-enanthate (Delatestryl®) or placebo will be administered once weekly (i.m.) and finasteride (Proscar®) or placebo will be administered daily (p.o.) in FDA approved doses. The primary goal of this CDA-1 is to determine if TRT improves self-selected walking speed in hypogonadal men with iSCI. The primary outcome is 10m preferred walking speed and secondary outcomes will include walking features (i.e. cadence, step length, step width and step variability using the GaitRite® instrumented walking mat). Secondarily, we will evaluate whether walking speed is associated with thigh muscle quality (torque per unit CSA via MRI), KE torque (via dynamometry), and/or KE voluntary activation (via rate of EMG rise) after iSCI and whether TRT+F alters these associations. We hypothesize that walking speed will improve following TRT+F and that positive associations will be found between walking speed and thigh muscle quality, KE torque and/or KE neuromuscular activation. Analysis of covariance will be used where the dependent variable is defined as the average of the 3 and 6 month walking speeds, with baseline walking speed as a covariate. Pearson Correlations will be assessed for prognostic factors for improvement in walking speed at each time point correlated with baseline parameters.