Low Testosterone Linked to Disability in Men With MS

Low testosterone levels in men with multiple sclerosis (MS) may be linked to increased risk of disability, according to findings from a new longitudinal study. The authors concluded that testosterone supplementation may have a better benefit-to-risk ratio in MS patients than in the general population.

The study appears in the current edition of the Multiple Sclerosis Journal (Bove et al., 2014). It was authored by Riley M. Bove, M.D., an instructor at Harvard Medical School, as well as an associate neurologist at Brigham and Women's Hospital in Boston, along with colleagues.

In an interview with MSDF, Dr. Bove explained her team's rationale for undertaking the study. "We were intrigued by animal data suggesting that testosterone has anti-inflammatory and neuroprotective potential, and also by a hypothesis that MS in men may arise after they start to experience the normal age-related declines in androgen levels," she said.

Dr. Bove said she and her co-workers were also interested in looking for male-specific risk factors for disability in MS, since much previous gender-related research has focused primarily on women.

Limitations of previous studies

In addition, she said, although earlier studies have found a link between low levels of testosterone in men with MS relative to healthy controls, those studies have been subject to some significant limitations. Those include a lack of control of potential confounding due to participants' recent use of steroids, variations in how hypogonadism was defined, and circadian variations in testosterone levels. Some of the findings were also weakened by the inclusion of men with advanced disease, in whom chronic illness might suppress testosterone levels, she said.

Looking to bridge those gaps in knowledge, Dr. Bove and her group studied a cohort of 96 men who had enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis study at Brigham and Women's Hospital. The men ranged in age from 18 to 65 years, with a mean age of 40. All had been diagnosed with relapsing-remitting MS or clinically isolated syndrome and had experienced their first symptoms less than 10 years previously.

Upon entering the study, the men's Expanded Disability Status Scale (EDSS) scores stood at a mean of 1.1, while mean disease duration was 4.6 years.

First, the researchers assessed hormone levels in stored morning blood samples that had been drawn when the men entered the study. Only samples drawn within 10 years of initial symptoms were included in the study.

"Since we did not have blood samples from men before they had MS," Dr. Bove explained, "looking at samples of men early in MS course was the closest we could come to determining testosterone levels before patients accumulated any significant burden of disability."

Next, they checked correlations between testosterone and other endocrine modulators of MS, including vitamin D, body mass index, and leptin. 

Lastly, they looked for associations between baseline levels of testosterone and disability. That analysis included both cross-sectional and longitudinal evaluations, including periodic assessments of clinical disability and cognitive function. Patients were followed for at least 2 years following their blood draws.

Low testosterone: a common finding

Reporting their findings, the researchers said 39% of the men in the cohort were hypogonadal, with total testosterone levels below 288 ng/dL. None showed compensatory elevations in luteinizing hormone.

As to testosterone's correlations with other hormonal markers, the researchers said they found negative partial Pearson correlations between baseline testosterone levels and both leptin and BMI. They came up with similar findings between testosterone-to-estradiol ratios and both leptin and BMI, they said. However, they saw no link between androgen measures and vitamin D.

When the researchers assessed the cross-sectional relationship between testosterone and disease outcomes, they found that lower testosterone levels were significantly associated with higher EDSS scores (p = 0.044). And that was true even after they controlled for duration of disease. However, testosterone levels didn't appear to be associated with cognitive function, as assessed by the Symbol Digit Modalities Test (SDMT).

The longitudinal analysis, adjusted for age, showed that higher testosterone levels at baseline were associated with smaller declines in SDMT (p = 0.012), the researchers said.

The case for testosterone supplementation

So, based on what's known now, does it make sense for clinicians to consider testosterone supplementation in selected patients with MS?

Dr. Bove told MSDF she believes large, randomized, placebo-controlled trials are needed before routine use of testosterone therapy can be recommended. "Given the very important potential adverse effects of testosterone supplementation, at this time we would recommend that it only be considered in men with clear signs and symptoms of hypogonadism whose prostate and hematocrit levels are being appropriately monitored."

Rhonda Voskuhl, M.D., agrees. In providing independent commentary on the study, Dr. Voskuhl, who is the director of the Multiple Sclerosis Program at the University of California, Los Angeles, told MSDF in an interview, "The current observations suggest potential beneficial effects on important MS disabilities. However, a placebo-controlled trial of testosterone in men with MS is needed to provide these patients with important information when they must make this decision regarding supplementation."

Still, she said, the findings, coupled with those from previous studies, strengthen the case for supplementation. "Beneficial effects (in both men with MS and nonMSers) include increased muscle mass and strength, increased bone mineral density, less fatigue and improved sexual function. Treatment of older men has also shown beneficial effects on cognitive function. However, these beneficial effects must be weighed against possible adverse effects of worsening preexisting prostate cancer or increasing risk of cardiovascular events in older men and/or those with a known history of cardiac problems."

Dr. Voskuhl emphasized that one of the major goals for MS researchers is to find a neuroprotective treatment that can be combined with currently available anti-inflammatory treatments, the hypothesis being that that sort of dual-treatment approach may be needed to halt progression.

Might testosterone reverse damage?

She sees testosterone supplementation as very promising in that respect.

Citing evidence of that, she pointed to a recent pilot study she conducted along with colleagues. That protocol involved yearlong administration of testosterone supplements to 10 men with MS (Kurth et al., 2014).

The researchers found that, based on MRI assessments, testosterone supplementation was associated with decreases in loss of gray matter. In fact, the researchers observed a significant gray matter increase in the right frontal cortex.

The researchers said this was the first report of actual gray matter increases resulting from a treatment for MS. They added that the findings should spur further studies of testosterone's neuroprotective effects in larger, placebo-controlled MS trials as well as in other neurodegenerative diseases.

Other independent comments regarding the potential value of testosterone therapy came from David Baker, Ph.D., an MS researcher at Barts and The London School of Medicine and Dentistry. 

In his blog, "Multiple Sclerosis Research: A Blog for People With MS and Their Families," he wrote, "We know that sex hormones are very effective at controlling MS, since before the advent of Tysabri [natalizumab], pregnancy was the most effective treatment against MS as well as a host of other autoimmune diseases. In the female, oestrogen therapies are being investigated; for the men, testosterone."

Could testosterone affect progression? Dr. Baker thinks perhaps so but emphasizes that much remains to be learned: "There have been some promising reports, but there is not sufficient evidence there at the moment." Even so, he said, one could easily make a link between testosterone and its interactions with other hormones such as erythropoietin, which may also have neuroprotective potential.

He emphasized, along with Drs. Bove and Voskuhl, that proper dosing of testosterone is of crucial importance. "Testosterone does many things—some you may want … and some you may not," he wrote. "It is essential, therefore, that research be done to find out if it really does work, if it is safe, and what the correct dose should be."

Key open questions

• Do low testosterone levels precede the onset of MS, with the implication that they are a contributing factor? Or do they decline even in the very early stages of MS as a result of inflammation?
• Might testosterone supplementation help retard or even halt the progression of MS?
• Is the risk versus benefit of testosterone supplementation different for patients with MS than for the general population? 
• If supplementation is found to be a useful strategy, what might be the best method for determining optimal dosing in individual patients?
• In which patients would testosterone supplementation be contraindicated?

Disclosures and sources of funding

This work was supported by the National Multiple Sclerosis Society; the National Multiple Sclerosis Society/American Brain Foundation Clinician Scientist Award; the Harvard Catalyst/The Harvard Clinical and Translational Science Center; the National Center for Research Resources; the National Center for Advancing Translational Sciences, National Institutes of Health; Harvard University and its affiliated academic health care centers. Some of the authors of the study disclosed competing interests involving a variety of commercial entities including Merck Serono, Novartis, Teva Neurosciences, Biogen Idec, EMD Serono, and Sanofi Aventis. Neither commentator, Dr. Voskuhl nor Dr. Baker, has disclosed potential conflicts of interest relative to this paper.