Male Hormones promote myelin repair

Hussain R, Ghoumari AM, Bielecki B, Steibel J, Boehm N, Liere P, Macklin WB, Kumar N, Habert R, Mhaouty-Kodja S, Tronche F, Sitruk-Ware R, Schumacher M, Ghandour MS. The neural androgen receptor: a therapeutic target for myelin repair in chronic demyelination. Brain. 2013;136:132-46. 

Myelin regeneration is a major therapeutic goal in demyelinating diseases, and the failure to remyelinate rapidly has profound consequences for the health of axons and for brain function. However, there is no efficient treatment for stimulating myelin repair, and current therapies are limited to anti-inflammatory agents. Males are less likely to develop multiple sclerosis than females, but often have a more severe disease course and reach disability milestones at an earlier age than females, and these observations have spurred interest in the potential protective effects of androgens. Here, we demonstrate that testosterone treatment efficiently stimulates the formation of new myelin and reverses myelin damage in chronic demyelinated brain lesions, resulting from the long-term administration of cuprizone, which is toxic for oligodendrocytes. In addition to the strong effect of testosterone on myelin repair, the number of activated astrocytes and microglial cells returned to low control levels, indicating a reduction of neuroinflammatory responses. We also identify the neural androgen receptor as a novel therapeutic target for myelin recovery. After the acute demyelination of cerebellar slices in organotypic culture, the remyelinating actions of testosterone could be mimicked by 5α-dihydrotestosterone, a metabolite that is not converted to oestrogens, and blocked by the androgen receptor antagonist flutamide. Testosterone treatment also failed to promote remyelination after chronic cuprizone-induced demyelination in mice with a non-functional androgen receptor. Importantly, testosterone did not stimulate the formation of new myelin sheaths after specific knockout of the androgen receptor in neurons and macroglial cells. Thus, the neural brain androgen receptor is required for the remyelination effect of testosterone, whereas the presence of the receptor in microglia and in peripheral tissues is not sufficient to enhance remyelination. The potent synthetic testosterone analogue 7α-methyl-19-nortestosterone, which has been developed for long-term male contraception and androgen replacement therapy in hypogonadal (small testis) males and does not stimulate prostate growth, also efficiently promoted myelin repair. These data establish the efficacy of androgens as remyelinating agents and qualify the brain androgen receptor as a promising drug target for remyelination therapy, thus providing the preclinical rationale for a novel therapeutic use of androgens in males with multiple sclerosis.

This study suggests that male hormones may be used to promote myelin repair. This is a testable hypothesis in MS a there are hormone therapies

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  • Mouse,

    I recall a few years ago there was a small trial which showed a signficant reduction in brain loss for those receiving testosterone patches. Unfortunately, while testosterone looks promisingm, it sounds like a Simvastin scenario – unlikely to find any company to fund a trial. There is a trial of a female hormone, but ended being compaxone + female hormone.

    A pity that academia can't take forward some of these trials e.g. small trial using testosterone patches and if successful GPs cna prescribe. I can't believe there's a safety concenr – has to weighed against a possible slow down in atrophy.

  • Interesting. I was tested last year in April and found to have extremely low testosterone levels. I started taking supplemental testosterone last May. In September the numbness and other symptoms started, and I was diagnosed with MS in November. From the MRI, it does not appear I have old lesions, just new.

    Could there be a relationship between increasing (or changing) testosterone levels and developing MS? Thanks!

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