Neuroprotective effects of testosterone treatment in men with multiple sclerosis

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.

Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial

“…The appendix pp 9-14 shows details of the blood laboratory tests for safety, methods for measuring estriol blood concentration, MRI analyses of enhancing lesions 7 and brain volumes, 22,23 and voxel-based morphometry for regional loss of grey matter. 24 …”

Estriol‐mediated neuroprotection in multiple sclerosis localized by voxel‐based morphometry

“…Voxel‐based morphometry analyses were performed as previously described (Kurth et al., 2014). Brain images were preprocessed utilizing Statistical Parametric Mapping 8 (SPM8; http://www.fil.ion.ucl.ac.uk/spm/software/spm8) and the VBM8 toolbox (http://www.neuro.uni-jena.de/vbm) as previously described (Kurth et al., 2014; Luders, Gaser, Narr, & Toga, 2009).…”

“…Brain images were preprocessed utilizing Statistical Parametric Mapping 8 (SPM8; http://www.fil.ion.ucl.ac.uk/spm/software/spm8) and the VBM8 toolbox (http://www.neuro.uni-jena.de/vbm) as previously described (Kurth et al., 2014; Luders, Gaser, Narr, & Toga, 2009). White matter lesions were in‐painted to minimize their impact (Ceccarelli et al., 2012; Chard, Jackson, Miller, & Wheeler‐Kingshott, 2010) based on manual delineations that were used for the analysis of new T2 lesions.…”

“…The lesion in‐painted images were subsequently realigned for each subject using halfway registrations and corrected for bias‐field inhomogeneities. The realigned, bias corrected images were then tissue‐classified into GM, WM, and cerebrospinal fluid (CSF) and registered to Montreal Neurological Institute (MNI) space through linear and nonlinear transformations (Ashburner, 2007; Kurth et al., 2014; Luders et al., 2009) (see http://dbm.neuro.uni-jena.de/vbm8/VBM8-Manual.pdf). More specifically, the tissue classification was based on maximum a posteriori segmentations (Rajapakse, Giedd, & Rapoport, 1997), accounted for partial volume effects (Tohka, Zijdenbos, & Evans, 2004), and was refined by applying a spatially adaptive nonlocal means denoising filter (Manjon, Coupe, Marti‐Bonmati, Collins, & Robles, 2010) as well as a hidden Markov random field model (Cuadra, Cammoun, Butz, Cuisenaire, & Thiran, 2005).…”

Mapping the effects of vitamin D in multiple sclerosis

“…Clinical trials in MS with androgens are limited. In a small pilot study in ten male MS patients, testosterone treatment not only slowed down the progressive grey matter loss but it even induced focal increase of grey matter volume [332][333] . Although no effects on MRI inflammatory activity and EDSS-progression could be found [332] , serum IL-2 decreased and TGFβ increased, accompanied by a decline in the circulating CD4 + T cell proportion [334] .…”