Neuroprotective effects of testosterone treatment in men with multiple sclerosis

Florian Kurth, Eileen Luders, Nancy L Sicotte, Christian Gaser, Barbara S Giesser, Ronald S Swerdloff, Michael J Montag, Rhonda R Voskuhl, Allan Mackenzie-Graham, Florian Kurth, Eileen Luders, Nancy L Sicotte, Christian Gaser, Barbara S Giesser, Ronald S Swerdloff, Michael J Montag, Rhonda R Voskuhl, Allan Mackenzie-Graham

Abstract

Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system. While current medication reduces relapses and inflammatory activity, it has only a modest effect on long-term disability and gray matter atrophy. Here, we have characterized the potential neuroprotective effects of testosterone on cerebral gray matter in a pilot clinical trial. Ten men with relapsing-remitting MS were included in this open-label phase II trial. Subjects were observed without treatment for 6 months, followed by testosterone treatment for another 12 months. Focal gray matter loss as a marker for neurodegeneration was assessed using voxel-based morphometry. During the non-treatment phase, significant voxel-wise gray matter decreases were widespread (p≤ 0.05 corrected). However, during testosterone treatment, gray matter loss was no longer evident. In fact, a significant gray matter increase in the right frontal cortex was observed (p≤ 0.05 corrected). These observations support the potential of testosterone treatment to stall (and perhaps even reverse) neurodegeneration associated with MS. Furthermore, they warrant the investigation of testosterone's neuroprotective effects in larger, placebo controlled MS trials as well as in other neurodegenerative diseases. This is the first report of gray matter increase as the result of treatment in MS.

Figures

Fig. 1
Fig. 1
Regional gray matter volume increase in testosterone treated men with MS. (a) Significant gray matter changes during the observation phase, (b) the transition phase, and (c) the protection phase, threshold at p≤ 0.05, FWE-corrected for multiple comparisons. Displayed are maximum intensity projections superimposed onto the SPM standard glass brain together with a rendering onto the mean template. Decreases are shown in blue, increases in red. Note the significant gray matter increase (accompanied by a lack of significant gray matter decrease) during the protection phase.
Fig. 2
Fig. 2
Regional volume changes over time. (a) Regional GM decreases during the observation phase. Heat maps visualize regional differences in the level of significance, thresholded at p≤ 0.05, FWE-corrected for multiple comparisons. (b) The widespread GM decreases seen during the observation phase (P1) were arrested during testosterone treatment (P2 and P3). No GM decrease was observed during the protection phase (P3). (c) Regional GM increases during the protection phase. Heat maps visualize regional differences in the level of significance. (d) In this cluster, testosterone treatment resulted in a GM increase during the protection phase (P3), which locally reversed the GM loss observed before treatment (P1).

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