Teststerone mediating neuroprotective effects

Kurth F, Luders E, Sicotte NL, Gaser C, Giesser BS, Swerdloff RS, Montag MJ, Voskuhl RR, Mackenzie-Graham A. Neuroprotective effects of testosterone treatment in men with multiple sclerosis. Neuroimage Clin. 2014 Mar 6;4:454-60. doi: 10.1016/j.nicl.2014.03.001. eCollection 2014.

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.

Sex hormones can influence many different factors In this study they were measuring shrinkage (blue) and enhancement (red) with testosterone treatment

This is one of those interesting anecdotes, that will need repeating. The brain imaging during the run-in suggested shrinkage and following treatment this shrinkage slowed and some areas increased in size. This could be “regression to mean” were disease related effects tend to attenuate with time after an active run in. However, could this be a repair effect that was found in some earlier animal studies. If there was enlargement of areas how was this achieved..nerve regrowth,  nerve repair?

or was it an anti-inflammatory effect facilitating repair as the people on the trial were not taking other DMT.
Therefore, the question is where next? More trials?…Two phase III..or phase II of more RRMSers on DMT. 

What’s the pathway to prescription?

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    • This is where the problem goes, We are hearing this week that the government is seeking to fast track treatments to get data whilst the pharma gets the data for the licencing trial but pharma has to pay.. There was no apparent provision for investigator led studies and this is were a problem lies.

      Should we all be on testosterone. Should we all start giving hormone replacement. These agents are not without their problems, in this report problems were not high on the agenda
      We have something that appears to be woefully underpowered along with many other phase II studies giving hope. Hope is good but we have to think about how we deliver this hope.
      I suspect that no one who believes in evidence based medicines are going to change their practise until they get better evidence n=10 will not change many peoples views.

      Putting every one on a statin is an easy option at £2 a month, but the evidence…Is it good enough? No based on the words of Sir Jeremy and based on what we ask pharma to do. Where is the dose response? Do you need such a high dose?.

      Is it now time to stop the "look-see" studies and make people do them properly if they work there is good enough evidence that a proper phase II is done,if the drug is known to be safe then phase III powering may be the option and lets get an answer one way or the the other.

      But if two trials are needed then we should not start until this is done as it cannot be ethical to start one study and then finish it and then start from scratch again. Otherwise do we have to change the rules to allow one trial.Surely in the case of progressive MS it should be treated as an orphan condition where one trial is enough.

      With the BPA could we start doing a register and get people on these agents and see what happens but what do we compare it to to know whether it is working. What happens when something else comes along? We need to get the regulators to change this solution is political.

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