Stefan M. Gold

Estrogen and testosterone therapies in multiple sclerosis

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.

Stress and hypothalamic–pituitary–adrenal axis function in experimental autoimmune encephalomyelitis and multiple sclerosis—A review

Multiple sclerosis (MS) is an inflammatory and degenerative disease of the CNS with an assumed autoimmune-mediated pathogenesis. Stressful life events have been hypothesized as potential triggers of disease exacerbation. Animal studies using experimental autoimmune encephalomyelitis (EAE), as a model for MS, suggest that decreased hypothalamic-pituitary-adrenal (HPA) function may play a role in the increased susceptibility and severity of the disease. Histopathological studies of the hypothalamus point to disturbances in corticotropin-releasing hormone (CRH) regulation as a result of MS lesions in this area. Functional endocrine tests (e.g., the combined Dexamethasone-CRH test) showed a disturbed negative feedback after steroid application in MS patients. Hyper- and hypoactivity of the HPA axis, have been described to be associated with more severe courses. This paper presents an overview of the evidence for a role of HPA dysfunction in EAE and MS based on stress-experimental studies.

Physical exercise in multiple sclerosis: supportive care or a putative disease- modifying treatment

Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disease affecting young adults and leading to considerable disability. For many years, patients have been advised to avoid physical activity. Today, however, an increasing number of studies have shown beneficial effects of exercise training in MS. It has been reported that such programs not only improve fitness parameters but can also enhance quality of life and beneficially affect some suggestive disability measures. Pilot studies even indicate a neuroprotective potential. This review summarizes the findings of the major clinical trials on exercise in MS. Possible biological effect mediators, such as neurotrophic factors or anti-inflammatory cytokines, will be discussed. Exercise management guidelines will be proposed and possible further research strategies are presented.

Estrogen treatment in multiple sclerosis

Currently available treatments for multiple sclerosis (MS) reduce inflammatory lesions on MRI and decrease clinical relapses but have limited effects on disability. Novel treatment options that target both the inflammatory as well as the neurodegenerative component of the disease are therefore needed. A growing body of evidence from basic science and clinical studies supports the therapeutic potential of estrogens in MS. Mechanisms of action include both immunomodulatory and directly neuroprotective pathways. A first pilot trial of oral estriol treatment showed encouraging results. There are now several phase II trials underway to further determine the efficacy of estrogen treatment in MS.

Estrogen treatment decreases matrix metalloproteinase (MMP)-9 in autoimmune demyelinating disease through estrogen receptor alpha (ERα)

Matrix metalloproteinases (MMPs) have a crucial function in migration of inflammatory cells into the central nervous system (CNS). Levels of MMP-9 are elevated in multiple sclerosis (MS) and predict the occurrence of new active lesions on magnetic resonance imaging (MRI). This translational study aims to determine whether in vivo treatment with the pregnancy hormone estriol affects MMP-9 levels from immune cells in patients with MS and mice with experimental autoimmune encephalomyelitis (EAE). Peripheral blood mononuclear cells (PBMCs) collected from three female MS patients treated with estriol and splenocytes from EAE mice treated with estriol, estrogen receptor (ER) α ligand, ERβ ligand or vehicle were stimulated ex vivo and analyzed for levels of MMP-9. Markers of CNS infiltration were assessed using MRI in patients and immunohistochemistry in mice. Supernatants from PBMCs obtained during estriol treatment in female MS patients showed significantly decreased MMP-9 compared with pretreatment. Decreases in MMP-9 coincided with a decrease in enhancing lesion volume on MRI. Estriol treatment of mice with EAE reduced MMP-9 in supernatants from autoantigen-stimulated splenocytes, coinciding with decreased CNS infiltration by T cells and monocytes. Experiments with selective ER ligands showed that this effect was mediated through ERα. In conclusion, estriol acting through ERα to reduce MMP-9 from immune cells is one mechanism potentially underlying the estriol-mediated reduction in enhancing lesions in MS and inflammatory lesions in EAE.

Depression and Immunity: Inflammation and Depressive Symptoms in Multiple Sclerosis

An increasing body of evidence suggests that patients who have major depressive disorder show alterations in immunologic markers including increases in proinflammatory cytokine activity and inflammation. Inflammation of the central nervous system is a pathologic hallmark of multiple sclerosis (MS). Patients affected by this disease also show a high incidence of depression. Accumulating evidence from animal studies suggests that some aspects of depression and fatigue in MS may be linked to inflammatory markers. This article reviews the current knowledge in the field and illustrates how the sickness behavior model may be applied to investigate depressive symptoms in inflammatory neurologic diseases.

Hypothalamo-pituitary-adrenal axis activity predicts disease progression in multiple sclerosis.

Clinical studies have shown that groups of multiple sclerosis (MS) patients exhibit a chronically activated hypothalamo-pituitary-adrenal (HPA) axis. However, the association of HPA axis activity and disease progression in MS is unknown. In this longitudinal study over a 3-year follow-up period, we report that patients who exhibited stronger HPA reactivity at baseline were significantly more likely to experience progression as measured by the Expanded Disability Status Scale (EDSS) during the follow-up period. Furthermore, HPA axis activity correlated with progression ratings and cognitive impairment three years later. Tests of HPA axis activity may be useful biomarkers for disease progression in MS.

Stress regulation in multiple sclerosis-current issues and concepts

Since its first description by Charcot, psychological stress has been considered a triggering factor for exacerbations in multiple sclerosis, but until recently the clinical evidence for a causal relation was weak. Over the past years, a growing number of studies have started to elucidate this association and highlight potential mechanisms, including brain-immune communication. On 5 June 2005, a panel of international researchers discussed the current evidence. This article summarizes the observational, animal experimental, as well as human experimental findings on stress regulation in MS, as well as studies on the functioning of the major stress response systems, ie, the hypothalamo-pituitary-adrenal (HPA) axis and the autonomous nervous system (ANS) in MS. Consensus statements from the group to these aspects are given. Research objectives and strategies are delineated, as well as clinical implications. Multiple Sclerosis 2007; 13: 143–148. http://msj.sagepub.com

Stress and disease progression in multiple sclerosis and its animal models.

Since the first description of multiple sclerosis (MS) by Charcot, stress has been hypothesized to be a potential trigger of relapses. In recent years, data from observational studies in MS patients have provided some support for an association between stress and MS relapses. Furthermore, studies employing the MS animal model experimental autoimmune encephalomyelitis have shown that certain stressors can exacerbate the disease if administered prior to disease induction. Several lines of research have explored the 2 major stress response systems – the hypothalamic-pituitary-adrenal axis and the autonomic nervous system – and their relation to disease course in MS and experimental autoimmune encephalomyelitis. These studies provide evidence that insensitivity of the immune system to signals from these systems may play a role in inflammatory events. These findings can be integrated into a biological model of stress response system alterations in MS.

Responsiveness of patient-based and external rating scales in multiple sclerosis: head-to-head comparison in three clinical settings.

BACKGROUNDnPatient-based rating scales and especially quality of life scales have received increasing attention as secondary outcome measures in multiple sclerosis (MS). Responsiveness to health-related change of quality of life scales is thus an important property when these measures are to be used successfully in clinical trials.nnnMETHODSnWe conducted an analysis of 3 cohorts of MS patients to examine responsiveness of the Hamburg Quality of Life Questionnaire for Multiple Sclerosis (HAQUAMS). One cohort consisted of patients from the outpatient clinic whose overall health status deteriorated over the course of one year (n=53), one study investigated two neurorehabilitation programs (n=20 each) and a third study investigated a low-level aerobic fitness training intervention (n=15).nnnRESULTSnThe total score of the HAQUAMS and several subscales was found to be responsive in all three settings. In addition, we provide minimally important difference (MID) estimates based on anchor- and distribution-based methods for all scales of the HAQUAMS.nnnCONCLUSIONSnThe HAQUAMS is responsive to change in observational and intervention studies in MS in adequately powered trials.