Low testosterone is associated with disability in men with multiple sclerosis

Bove, Riley; Musallam, Alexander; Healy, BC; Raghavan, Kesav; Glanz, BI; Bakshi, Rohit; Weiner, Howard L.; Jager, PL De; Miller, K. K.; Chitnis, Tanuja

doi:10.1177/1352458514527864

Cited by 104 publications

(87 citation statements)

References 41 publications

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“…These studies have provided the support for a small clinical pilot study, suggesting that prolonged testosterone therapy of men with MS may have neuroprotective and antiinflammatory effects and also improve cognitive performance (41). The present study may also gain significance from clinical observations showing that (i) the incidence of MS and the relapse rate throughout the disease are lower in men (42); (ii) low testosterone levels are associated with an increased risk of developing MS (43); (iii) levels of testosterone are decreased in men with MS, and reduced levels of testosterone have been associated with disability (44,45); and (iv) men reach disability milestones more rapidly than women (46).…”

Section: Discussionmentioning

confidence: 74%

Unexpected central role of the androgen receptor in the spontaneous regeneration of myelin

Bielecki

Mattern²,

Ghoumari

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

107

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Lost myelin can be replaced after injury or during demyelinating diseases in a regenerative process called remyelination. In the central nervous system (CNS), the myelin sheaths, which protect axons and allow the fast propagation of electrical impulses, are produced by oligodendrocytes. The abundance and widespread distribution of oligodendrocyte progenitors (OPs) within the adult CNS account for this remarkable regenerative potential. Here, we report a key role for the male gonad, testosterone, and androgen receptor (AR) in CNS remyelination. After lysolecithin-induced demyelination of the male mouse ventral spinal cord white matter, the recruitment of glial fibrillary acidic protein-expressing astrocytes was compromised in the absence of testes and testosterone signaling via AR. Concomitantly, the differentiation of OPs into oligodendrocytes forming myelin basic protein (MBP) + and proteolipid protein-positive myelin was impaired. Instead, in the absence of astrocytes, axons were remyelinated by protein zero (P0) + and peripheral myelin protein 22-kDa (PMP22) + myelin, normally only produced by Schwann cells in the peripheral nervous system. Thus, testosterone favors astrocyte recruitment and spontaneous oligodendrocyte-mediated remyelination. This finding may have important implications for demyelinating diseases, psychiatric disorders, and cognitive aging. The testosterone dependency of CNS oligodendrocyte remyelination may have roots in the evolutionary history of the AR, because the receptor has evolved from an ancestral 3-ketosteroid receptor through gene duplication at the time when myelin appeared in jawed vertebrates.T he remyelination of axons is a complex process, involving interactions between different types of neural cells. It shows a peculiarity that has been observed in both experimental models and demyelinating diseases such as multiple sclerosis (MS) (1). Although most of the remyelination is normally accomplished by oligodendrocytes derived from oligodendrocyte progenitors (OPs), a variable proportion of central nervous system (CNS) axons can be remyelinated by cells with the immunophenotypic and ultrastructural characteristics of Schwann cells, the presence of which is normally limited to the peripheral nervous system (PNS). These cells indeed express protein zero (P0), a sensitive and specific marker of Schwann cells (2). Moreover, analysis by electron microscopy demonstrated that they have the typical morphology of myelinating Schwann cells (1-4). These ultrastructural findings indicate that the expression of P0 by part of the remyelinating cells is not merely ectopic, but that these cells may correspond to authentic Schwann cells. This observation was further supported by their expression of Schwann cell-specific transcription factors (5).Importantly, there is strong evidence that large numbers of the Schwann cells present in demyelinating CNS lesions are derived from OPs. The first evidence came from the transplantation of purified OPs into demyelinating CNS lesions, in which endogenous ...

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Section: Discussionmentioning

confidence: 74%

Unexpected central role of the androgen receptor in the spontaneous regeneration of myelin

Bielecki

Mattern²,

Ghoumari

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

107

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“…We have previously reported associations between lower adult endogenous testosterone levels and higher EDSS. 8 Thus, we also asked whether a higher 2D:4D ratio, possibly through downstream effects on immune regulation or neuroprotection, might also be associated with a more aggressive MS course. We found no association between 2D:4D ratio and MS severity.…”

Section: Ms Clinical Outcomesmentioning

confidence: 99%

“…Patients met the diagnostic criteria of MS by the 2005 McDonald criteria; 51 had provided blood samples for a testosterone level within 10 years of their first MS symptom onset, as previously described. 8 Men without MS. Concurrently with our recruitment of patients with MS, we recruited men from a large medical office building, which houses the MS Center. Participants included individuals presenting to a number of medical offices or the phlebotomy laboratory in the building, postal and construction workers, janitorial and medical staff, as well as individuals (spouses, partners, friends) accompanying MS Center patients to their visits.…”

mentioning

confidence: 99%

The 2D:4D ratio, a proxy for prenatal androgen levels, differs in men with and without MS

et al. 2015

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The 2D:4D ratio, a proxy for prenatal androgen levels, differs in men with and without MS ABSTRACT Objective: To determine whether the 2D:4D ratio (ratio of the second and fourth digit lengths), a proxy for lower prenatal androgen to estrogen ratio, differs in men with and without multiple sclerosis (MS) using a case-control study design. Methods:We obtained 2 digital scans of the right hand for men with MS presenting to a scheduled clinic visit at a large MS referral center, and for men without autoimmune or endocrine diseases. All individuals were aged 18 to 65 years, right-handed, and reported no prior digit trauma. We calculated a mean 2D:4D ratio using digital calipers. In participants with MS, we assessed age at first MS symptoms, MS type, and the MS Severity Score; 51 had provided a testosterone level within 10 years of symptom onset. Our primary analysis was a cross-sectional comparison of the 2D:4D ratio between men with and without MS, using a 2-sample t test for independent samples assuming unequal variance.Results: In total, we scanned 137 men with MS and 145 men without MS. A statistically significant association between 2D:4D ratio and MS status was observed in the univariate logistic regression model (p , 0.05). These differences were not associated with age or race, which differed between the 2 groups. In participants with MS, the 2D:4D ratio was not correlated with MS type, age at first symptoms, or MS Severity Score (p . 0.15 for each), and it was not correlated with adult testosterone levels (r 5 0.06, p 5 0.68, n 5 51).Conclusions: During the prenatal period, low androgens could represent a risk factor for MS.

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“…The small sample size may account for these contradictory results, suggesting that larger studies are needed for more detailed examination of hormonal status and its relation to disease activity in MS. A recent longitudinal study, comprising 96 male patients with MS or clinically isolated syndrome, has found hypogonadal status (testosterone levels below the lower limit of normal) in 39% of the subjects. A negative age-adjusted correlation between total testosterone and EDSS has been revealed and higher baseline testosterone levels have been associated with less cognitive decline, measured by SDMT during longitudinal follow-up [133].…”

Section: Clinical Evidence For the Effects Of Sex Hormones On Diseasementioning

confidence: 99%

Sex Hormones and Multiple Sclerosis

Trenova¹

2016

Trending Topics in Multiple Sclerosis

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Experimental and clinical data about the influence of sex hormones on the course of multiple sclerosis (MS) grow rapidly during the past two decades. Estrogens, progesterone, and androgens have been shown to ameliorate experimental autoimmune encephalomyelitis (EAE) in animals, and pregnancy in women is associated with a dramatic reduction in disease activity. Immunomodulatory and neuroprotective properties of sex hormones are the most probable underlying mechanisms, creating a background for testing similar hormonal treatments in humans. Several pilot studies in this field present promising results, but larger trials are necessary to identify the adverse events and to estimate precisely the place of sex steroids in multiple sclerosis therapeutic strategies.The objective of this chapter is to summarize the recent advances in the research about the effects of sex steroids in EAE and MS and to create a ground for the development of more powerful treatments in the future.

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Low testosterone is associated with disability in men with multiple sclerosis

Cited by 104 publications

References 41 publications

Unexpected central role of the androgen receptor in the spontaneous regeneration of myelin

Unexpected central role of the androgen receptor in the spontaneous regeneration of myelin

The 2D:4D ratio, a proxy for prenatal androgen levels, differs in men with and without MS

Sex Hormones and Multiple Sclerosis

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