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Women fall ill with MS at a higher rate than men. Researchers are targeting hormones for therapy.
In 10 seconds? Male sex hormone testosterone controls a molecule that prevents many men from developing MS. Tests on female lab mice confirmed that MS symptoms could be stopped by using that protective molecule.
How does the ‘testosterone-shield work’? Researchers have found that the male sex hormone in lab mice led to the production of a ‘protective molecule’ – called IL-33 – that prevents immune cells from attacking the nervous system, like in MS.
Wow, this sounds promising! When MS flares up, the body mobilises an army of disease-fighting T-cells. But unfortunately, these cells attack the body's own myelin, the protective coating for nerves, which results in the degenerative illness.
And why does MS affect females more? Females have 7–8 times less testosterone than males, and without the protection provided by the male hormone, they develop more Th17 cells – these are immune cells that devastate the nervous system in MS patients. However, adding IL-33 stopped MS symptoms in female mice during the study.
So, do men have it easier? Not necessarily. Women are less ‘protected’ and develop MS at an earlier age, but they mostly have the type characterised by relapses and periods of recovery. Men tend to fall ill at a later age, but deteriorate faster. Interestingly, pregnancy – probably due to the altered hormone state – reduces relapses in women.
Will testosterone therapy help us slow MS? It would be a good alternative to current therapies, which focus on suppressing the immune system and puts patients in danger of other illnesses. In men, a year-long testosterone treatment can partially reverse MS symptoms, but the use of testosterone can affect pre-existing prostate cancer.
How about other hormones? A Phase II trial proved that oestrogen treatment for women can reduce relapses in women, but can it can also increase the risk of developing cancer in the breasts or uterus. ACTH (Adrenocorticotropic hormone) therapy is already in use for relapses in MS, but there is no consensus about when to start the treatment and what dosage to use. Still, in some cases these treatments – when tailored according to gender – could offer new ways of treating MS.
Abstract: Inflammation that complicates many autoimmune diseases, such as multiple sclerosis (MS), has been correlated to abnormal differentiation of Th17 cells. However, the reasons that promote Th17 cell-driven autoimmunity are yet to be discovered. In this study, we sought evidence that DNA-damage-inducible transcript 4 (DDIT4) and its associated long noncoding RNA DDIT4 (lncDDIT4) inhibit Th17 cell differentiation. We recruited 36 patients. Six MS patients and five healthy volunteers (controls) contributed PBMCs as material for microarray analysis. Microarray assays of lncDDIT4 and DDIT4 RNA expression identified outstanding differences between MS and control subjects, which were verified with real-time quantitative PCR. We then interrupted the expression of lncDDIT4 and DDIT4 mRNA in MS patients' naive CD4+ T cells and observed the resulting changes in Th17 cells. The expression of lncDDIT4 and DDIT4 mRNA were higher both in PBMCs and CD4+ T cells of MS patients than in healthy controls. DDIT4 (2.79-fold upregulation) was then recognized as a candidate for the cis-regulated target of lncDDIT4 (4.32-fold upregulation). Isolation of naive CD4+ T cells revealed enhanced levels of lncDDIT4 and DDIT4 after stimulated with Th17-inducing cytokines, but not after Th1, Th2, or T regulatory cell induction. Overexpression of lncDDIT4 in naive CD4+ T cells inhibited IL-17 transcription through increased DDIT4 expression and decreased activation of the DDIT4/mTOR pathway. Consistently, silencing lncDDIT4 in naive CD4+ T cells enhanced Th17 differentiation through increased activation of the DDIT4/mTOR pathway. However, these results vanished when DDIT4 was silenced. This outcome suggests that lncDDIT4 regulates Th17 cell differentiation by directly targeting DDIT4.
Pub.: 31 Jan '18, Pinned: 01 Feb '18
Abstract: It has been known for decades that females are more susceptible than men to inflammatory autoimmune diseases, including multiple sclerosis (MS), rheumatoid arthritis, and psoriasis. In addition, female patients with these diseases experience clinical improvements during pregnancy with a temporary "rebound" exacerbation postpartum. These clinical observations indicate an effect of sex hormones on disease and suggest the potential use of the male hormone testosterone and the pregnancy hormone estriol, respectively, for the treatment of MS. A growing number of studies using the MS animal model experimental autoimmune encephalomyelitis (EAE) support a therapeutic effect of these hormones. Both testosterone and estriol have been found to induce anti-inflammatory as well as neuroprotective effects. Findings from two recent pilot studies of transdermal testosterone in male MS patients and oral estriol in female MS patients are encouraging. In this paper, we review the preclinical and clinical evidence for sex hormone treatments in MS and discuss potential mechanisms of action.
Pub.: 08 Aug '09, Pinned: 01 Feb '18
Abstract: There is significant animal model data demonstrating a benefit of testosterone on both inflammatory and neuroprotective mechanisms relevant to multiple sclerosis (MS). Several studies have demonstrated lowered testosterone levels in up to 40% of men with MS. Lower testosterone levels were correlated with worsened scores of physical and cognitive disability. There is increasing data suggesting a role of testosterone in MS risk. A pilot study has demonstrated significant benefits of testosterone replacement therapy on cognitive, radiological, and immunological outcome measures in men with MS. Larger studies in other conditions have demonstrated concerns in terms of cardiovascular risk, which indicate the need for careful monitoring upon administration to MS patients. Further studies are needed to develop safer testosterone preparations, which preserve its multiple beneficial effects, as well as multicenter clinical trials to evaluate safety, dosing, and efficacy in larger populations of men with MS. Additionally, studies are needed to further explore the role of androgens as a risk factor for MS, particularly at key life transitions.
Pub.: 09 Jan '18, Pinned: 01 Feb '18
Abstract: The incidence, severity and progression of autoimmune diseases (e.g. scleroderma, multiple sclerosis, rheumatoid arthritis) and certain inflammatory diseases (e.g. asthma) are sex-biased where these pathologies dominate in women. However, other immune disorders such as sepsis, post-surgery infections and gout display higher incidence and severity in men. The molecular and cellular basis underlying this sex dimorphism remains incompletely elucidated but may provide important insights for sex-specific pharmacotherapy. Nevertheless, the sex as a variable in biochemical and preclinical research on inflammation is often neglected. Thus, respective animal studies are routinely performed with males, and experiments with isolated cells rarely report the sex of the donor. However, sex differences on the cellular level do exist, in particular related to inflammatory processes that prompt for sex-specific appreciation of inflammation research. For instance, the biosynthesis of pro-inflammatory eicosanoids is sex-biased where leukotriene (LT) formation is under control of testosterone that regulates the subcellular localization of the key enzyme 5-lipoxygenase, with possible implications for gender-tailored pharmacotherapy of LT-related disorders (i.e. asthma). Moreover, prostaglandin (PG) production is sex-biased, and sex-dependent efficacy of aspirin was evident in several clinical trials. Here, we highlight the sex bias in eicosanoid biology possibly underlying the obvious sex disparities in inflammation, stimulating scientists to take sex into account when studying the pathophysiology and pharmacotherapy of inflammatory diseases.
Pub.: 26 Jun '17, Pinned: 01 Feb '18
Abstract: The high female-to-male sex ratio of multiple sclerosis (MS) prevalence has continuously confounded researchers, especially in light of male patients' accelerated disease course at later stages of MS. Although multiple studies have concentrated on estrogenic mechanisms of disease modulation, fairly little attention has been paid to androgenic effects in a female system, and even fewer studies have attempted to dissociate hormonal effects on the neurodegenerative and neuroinflammatory processes of MS. Herein, we demonstrate the differential effects of hormone treatment on the acute inflammatory and chronic neurodegenerative phases of murine experimental autoimmune encephalomyelitis. Although s.c. treatment with testosterone and aromatase inhibitor applied beginning on the day of immunization ameliorated initial course of disease, similar treatment administered therapeutically exacerbated chronic disease course. Spinal cord analyses of axonal densities reflected the clinical scores of the chronic phase. In vitro, testosterone treatment not only decreased Th1 and Th17 differentiation in an aromatase-independent fashion, but also exacerbated cell death in induced pluripotent stem cell-derived primary human neurons under oxidative stress conditions in an aromatase inhibitor-dependent manner. Thus, through the alleviation of inflammatory processes and the exacerbation of neurodegenerative processes, androgens may contribute to the epidemiologic sex differentials observed in MS prevalence and course.
Pub.: 22 Jun '17, Pinned: 01 Feb '18
Abstract: Multiple sclerosis is one of the most salient degenerative disorders of CNS with dysregulated immune process that resulted in axonal damage and demyelination. In the present investigation, the serum level of testosterone was assessed in women who were struggling with multiple sclerosis (MS). Also, the level of omega-3, vitamin D, and the irregular menstruation in women 5 years before the onset MS symptoms were surveyed. Although the levels of omega-3 and vitamin D in women MS patients were non-significant and significantly less than the healthy ones, they were significantly less in the whole population of MS patients. However, the MS patients more experienced more irregular menstruation some years before the onset of MS with the low level of testosterone. Based on the presented findings, it might be said that the vitamin D intake has significant protective role in women and men MS patients unlike the omega-3 that had significant protective role just in men. However, vitamin D metabolism encoding genes of CYP27B1 and CYP24A1 and predicting MS risk gene of HLA-DRB1*15:01 define its fate as well. Besides, vitamin D intake, through the proliferation decrement of pro-inflammatory cells, decreases of pro-inflammatory markers (IL-6, TNF-α, INF-γ) and auto-immune pathways have potential role in recovery of irregular menstruation in women with the low level of testosterone as a red warning factor of MS development. The low level of testosterone and vitamin D consumption increase the neural damage and pro-inflammatory pathways in MS patients, and the difference among the investigations is related to the long-standing history of MS that influences severity of damage to the neural cells and biomolecules and complicate its recovery.
Pub.: 15 Dec '16, Pinned: 01 Feb '18
Abstract: Gonadal steroids may modulate disease course in multiple sclerosis (MS).To assess the prevalence and clinical associations of hypogonadism in men with MS.Male patients, aged 18-65 years, with relapsing-remitting MS (RRMS) or clinically-isolated syndrome (CIS) and their first symptom < 10 years prior were selected from a longitudinal clinical study. We measured their hormones in stored morning blood samples, and collected their Expanded Disability Status Scale (EDSS) scores every 6 months and their Symbol Digit Modalities Test (SDMT) results annually.Our analysis included 96 men with a mean age of 40 years, EDSS of 1.1 and disease duration of 4.6 years. Of these men, 39% were hypogonadal (total testosterone < 288 ng/dL); none showed compensatory elevations in luteinizing hormone. Their low testosterone levels and testosterone:estradiol ratios were negatively correlated with body mass index (BMI) and leptin, and showed no correlation with 25-hydroxy-vitamin D levels. In our primary cross-sectional analyses, there was a negative age-adjusted correlation between total testosterone and EDSS (p = 0.044). In the age-adjusted longitudinal analyses, higher baseline testosterone levels were associated with less decline in SDMT (p = 0.012).Men with MS may experience hypogonadotropic hypogonadism. Low testosterone levels may be associated with worse clinical outcomes. A potential neuroprotective role for testosterone warrants further investigation.
Pub.: 09 Apr '14, Pinned: 01 Feb '18