The Role of Androgens in Neurophysiological and Autonomic Function in Male Veterans With Spinal Cord Injury

Spinal cord injury (SCI) disrupts sensorimotor function and corticospinal excitability, resulting in muscle weakness and autonomic nervous system (ANS) dysfunction that detracts from cardiovascular (CV) health. These deficits may be exacerbated by low testosterone (T), which develops in most men during the acute/subacute phases of SCI and persists in 45-60% of men thereafter. Low T (hypogonadism) is associated with multiple health impairments, including reduced lean tissue mass and increased fat mass, systemic inflammation, and risk for CV and neurodegenerative diseases. Moreover, low T is associated with CV ANS dysfunction and impaired cardiovagal (parasympathetic) reflex function following SCI. In men with low T after SCI, restoring T concentrations to the normal (eugonadal) range with T replacement therapy (TRT) improves energy expenditure, body composition, CV function, and markers of cardiometabolic health. Evidence from animal models also demonstrates that T is neuroprotective, upregulates neurotrophic factors, and promotes neuroplasticity and myelin regeneration. However, the neural effects of intranasal TRT are unknown.

T is the most abundant bioactive androgen within the circulation. It exerts direct biological actions by binding androgen receptors (ARs), affecting transcription, as well as non-genomic mechanisms in the brain, spinal cord, heart, and numerous other tissues throughout the body. The majority of circulating T is bound to sex-hormone binding globulin (SHBG) and albumin, with only 1-4% circulating unbound (free T). Free T and albumin-bound T are collectively termed bioavailable T, as SHBG-bound T cannot readily dissociate to engage cellular receptors. In this regard, a high prevalence of men with SCI not only exhibit low total T, but also exhibit a marked reduction in bioavailable T because there is a >10-fold increase in SHBG after SCI, resulting in lower proportions of free and albumin-bound T.

The primary goal of this proposal is to perform a small pilot/feasibility study to assess neurophysiological and cardiovagal responses to a single dose of intranasal TRT in a cohort of these men who exhibit low Total T (<300 ng/dL), low Free T (<46 pg/mL), or low bioavailable T (<110 ng/dL) and hypogonadal signs/symptoms.

Primary Aim: To investigate the acute effects of a single dose of intranasal TRT (11 mg) compared with placebo on CNS excitability and cardiovagal reflex function 30 minutes after administration in 15 male Veterans (10 with chronic SCI and 5 uninjured controls) who have low baseline total T concentrations. CNS excitability will be assessed using hand muscle electromyography (EMG) output determined by recruitment curves evoked by non-invasive single-pulse transcranial magnetic stimulation (TMS) and cervical transcutaneous spinal cord stimulation (TSCS). A cold face challenge (CFC) while measuring beat-to-beat heart rate signals will be used to examine CV ANS reflex function. Because this Exploratory Aim is a pilot/feasibility study, formal hypothesis testing would be premature. However, based on the literature, the investigators expect that elevating circulating concentrations of T into the high normal physiologic range via intranasal TRT will result in improved neural and cardiovagal function for 6-8 hours after the dose.

The results of this pilot study will inform feasibility and identify modifications needed to design a larger eventual trial to evaluate the efficacy and safety of intranasal TRT. Ours will be the first clinical study to collect pilot/feasibility data on an intranasal TRT formulation that has the potential to improve neural function after SCI. This is significant because our results are expected to provide evidence demonstrating the feasibility of a novel intranasal therapeutic strategy in Veterans with SCI.