Testosterone May Be Neuroprotective for Men With MS

Susan Jeffrey

May 17, 2007

May 17, 2007 — A small exploratory trial shows that treatment with testosterone gel was safe and well tolerated by men with relapsing remitting multiple sclerosis (RRMS) and was associated with some improvement in cognitive performance and slowing of brain atrophy over a 1-year period. However there was no effect on gadolinium-enhancing lesion numbers or volume on magnetic resonance imaging (MRI).

The results are published in the May issue of the Archives of Neurology.

"Overall, in this first trial of testosterone treatment in men with RRMS, the treatment was shown to be safe and well-tolerated and led to increases in lean body mass," the researchers, with first author Nancy L. Sicotte, MD, from the David Geffen School of Medicine at the University of California, Los Angeles, conclude. "In addition, exploratory findings reported herein suggest a possible neuroprotective effect of testosterone treatment in men, which warrants further investigation."

Testosterone in MS

Men are less susceptible than women to many autoimmune diseases, including MS, particularly during the reproductive years, the authors write. One of the possible causes for this is the effect of sex hormones or sex chromosomes, they note.

Testosterone has been shown to be immunomodulatory and has a protective effect in animal models of many autoimmune diseases, including experimental autoimmune encephalomyelitis, an animal model of MS. Other studies have suggested some neuroprotective effects, they add.

In this pilot study, Dr. Sicotte and colleagues investigated the effect of testosterone supplementation in 10 men with clinically definite RRMS using transdermal gel (AndroGel, Solvay Pharmaceuticals). Each man acted as his own control to minimize the impact of the heterogeneity of disease course between individuals.

The subjects were followed for 6 months without treatment, and then crossed over to 12 months of daily treatment with 10 mg of gel containing 100 mg of testosterone applied to the upper arm. Clinical measures of disability and cognition were taken using the Paced Auditory Serial Addition Task (PASAT) of the Multiple Sclerosis Functional Composite and the 7/24 Spatial Recall Test. Monthly measures of enhancing lesion activity and brain volumes were done using MRI.

At baseline, all subjects had testosterone levels in the lower range of normal, with a mean of 493 ng/dL; after treatment, levels increased by an average of 50% into the higher range of normal, they note.

Cognitive Improvement, Slowing Brain Atrophy

Testosterone treatment was associated with improvement in cognitive performance on the PASAT that was significant by month 12 (P = .008). Consistent with this was a trend toward improvement in spatial memory in immediate- and delayed-recall subtests of the 7/24 Spatial Recall Test, the authors note.

Brain atrophy was slowed significantly with treatment. In the first 9 months of the study, including the 6 months of pretreatment and first 3 months of treatment, brain volume decreased by an annualized rate of 0.81% per year. In the subsequent 9 months, incorporating a total of 12 months of treatment, brain atrophy was slowed by 67% to an annualized rate of -0.26%.

"Because the protective effect of testosterone treatment on brain atrophy was observed in the absence of an appreciable anti-inflammatory effect, this protection may not be limited to MS but may be applicable to those with noninflammatory neurodegenerative diseases," the authors write.

Lean body mass increased significantly during testosterone treatment, with a mean increase of 1.7 kg at month 12 compared with the pretreatment levels.

At baseline, this group had low levels overall of enhancing lesion activity, the authors write, with a median number of 0, and median lesion volume of 0.04 cm3; there was no relationship between baseline lesion activity and baseline testosterone levels. They found no effect of treatment on enhancing lesion activity, either in increasing or decreasing the numbers or volumes of enhancing lesions.

The authors speculate that the exclusion of subjects already on treatment may have resulted in a selection bias toward relatively milder disease and less inflammatory activity on MRI. "Thus, in this subject group, we can only conclude that testosterone treatment did not significantly increase inflammatory activity on otherwise relatively quiescent MRIs."

No changes were seen on the Expanded Disability Status Scale score, the 9-Hole Peg Test, or the 25-ft timed walk. There were no subjective reports of adverse effects, and no abnormalities on blood test results, they note. Prostate exam results were stable throughout the study.

"As is the case with any initial pilot clinical trial, conclusions from our study must be made with caution, primarily because of the small sample size," the authors write. Nevertheless, they conclude, "These exploratory findings suggest that testosterone treatment is safe and well tolerated and has potential neuroprotective effects in men with relapsing-remitting MS."

The study was supported by grants from the National Multiple Sclerosis Society, the General Research Centers at Harbor-UCLA Medical Center, the Sherak Family Foundation, and the Skirball Foundation.

Arch Neurol. 2007; 64:683-688.


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