Testosterone and Neural Function

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

Spinal cord injury (SCI) disrupts the nerves controlling movement, along with those that regulate functions like heart rate and blood pressure (known as the autonomic nervous system, or ANS). Testosterone (T) plays a significant role in brain health and ANS reflex function in non-neurologically impaired men. However, little is known about the relationships between T, nerve function, and ANS dysfunction after SCI. Interestingly, up to 60% of men with SCI exhibit persistently low T concentrations, which may worsen nerve and ANS dysfunction. In uninjured eugonadal people (normal physiologic range of serum T concentrations), a single pharmacologic dose of intranasal T has been shown to quickly improve nerve function, but no study has evaluated if T administration alters nerve and ANS function in men with SCI. Herein, the investigators will conduct the first study to test how a single dose of intranasal T impacts motor and ANS function in this population.

Study Overview

• Status: Recruiting
• Conditions: Spinal Cord Injury
• Intervention / Treatment: Drug: Ayr Saline Nasal Gel; Drug: Natesto testosterone intranasal gel

Detailed Description

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) tone 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 (<264 ng/dL) and hypogonadal 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 10 male Veterans with chronic SCI 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 while measuring beat-to-beat heart rate signals will be used to examine CV ANS reflex function. Because this 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.

• Study Type: Interventional
• Enrollment (Estimated): 15
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Jacob A Goldsmith, PhD; Phone Number: (718) 584-9000; Email: Jacob.Goldsmith@va.gov
• Study Contact Backup: Name: Noam Y Harel, MD PhD; Phone Number: 1742 (718) 584-9000; Email: Noam.Harel@va.gov

Study Locations

• United States
  • New York
    • Bronx, New York, United States, 10468-3904
      • Recruiting
      • James J. Peters VA Medical Center, Bronx, NY
      • Contact: Finn (Fiona) Fox, BS; Phone Number: 3128 718-584-9000; Email: fiona.fox2@va.gov
      • Contact: Astrea Villarroel-Sanchez, MPH; Phone Number: 3107 (718) 584-9000; Email: astrea.villarroel-sanchez@va.gov
      • Principal Investigator: Jacob A Goldsmith, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age 18-80 years
• Time since injury (TSI) more than 12 months
• Traumatic or non-traumatic SCI
• American Spinal Injury Association (ASIA) Injury classification Scale (AIS) A, B, C, or D
• Stable prescription medication regimen for at least 30 days
• Not currently receiving pharmacological treatment for hypogonadism
• Must be able to commit to study requirements of 3 visits within a 30-day period
• Provide informed consent

Exclusion Criteria:

• Extensive history of seizures
• Ventilator dependence or patent tracheostomy site
• History of neurologic disorder other than SCI
• History of moderate or severe head trauma
• Currently receiving treatment for hypogonadism
• History of allergy, hypersensitivity, or other significant adverse reaction to testosterone replacement therapy
• Significant cardiovascular disease or cardiac conduction disease
• Active psychological disorder
• Moderate or severe brain injury, stroke, tumor, multiple sclerosis, or abscess
• Recent history (within 3 months) of substance abuse
• Pressures sores stage 3 or greater
• Active infection
• Frequent severe migraines
• Recent history (within past 6 months) of recurrent autonomic dysreflexia, defined as a syndrome of sudden rise in systolic pressure greater than 20 mm Hg or diastolic pressure greater than 10 mm Hg, without rise in heart rate, accompanied by symptoms such as headache, facial flushing, sweating, nasal congestion, and blurry vision (this will be closely monitored during all screening and testing procedures)
• History of implanted devices with electromagnetic properties: brain/spine/nerve stimulators, aneurysm clips, ferromagnetic metallic implants in the head (except for inside mouth); cochlear implants; cardiac pacemaker/defibrillator; intracardiac lines; currently increased intracranial pressure; or other contraindications to brain or spine stimulation
• Use of medications that significantly lower seizure threshold, such as amphetamines, neuroleptics, dalfampridine, and bupropion.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Participant-blinded (Ayr Saline Gel)	Drug: Ayr Saline Nasal Gel; A single dose of Ayr (one spray per nostril) will be administered to each participant.; Other Names: Saline Nasal Gel
Active Comparator: Intranasal TRT; Participant-blinded (11 mg of Natesto)	Drug: Natesto testosterone intranasal gel; A single dose of Natesto (11 mg total, 5.5 mg per nostril) will be administered to each participant.; Other Names: testosterone intranasal gel

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Electromyographic responses	Response to electrical and magnetic stimulation, singly, will be measured via peak-to-peak amplitude (millivolts) in first dorsal interosseous and abductor pollicis brevis muscles.	up to one day

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum Testosterone	Serum testosterone will be assessed prior to and after administration of intranasal TRT.	up to one day
Cardiovagal Function (heart rate variability)	Changes in beat-by-beat heart rate (beats per minute) signals collected using ECG during a cold face challenge (cardiovagal provocation) to determine cardiovagal reflex function. Changes in the high frequency (0.15-0.4 Hz) component will be used as an indication of parasympathetic activity to the heart.	up to one day

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Investigators: Principal Investigator: Jacob A Goldsmith, PhD, James J. Peters Veterans Affairs Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2024
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): March 31, 2026

Study Registration Dates

• First Submitted: October 25, 2023
• First Submitted That Met QC Criteria: November 8, 2023
• First Posted (Actual): November 14, 2023

Study Record Updates

• Last Update Posted (Actual): April 8, 2024
• Last Update Submitted That Met QC Criteria: April 4, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: electrical stimulation; spinal cord injury; cardiovascular; central nervous system; testosterone; motor function; autonomic; neurophysiology
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Trauma, Nervous System; Spinal Cord Diseases; Spinal Cord Injuries; Physiological Effects of Drugs; Antineoplastic Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Androgens; Anabolic Agents; Testosterone; Methyltestosterone; Testosterone undecanoate; Testosterone enanthate; Testosterone 17 beta-cypionate
• Other Study ID Numbers: B5028-M; 1IK1RX005028-01 (U.S. NIH Grant/Contract: VA Rehabilitation Research & Development)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No