Estrogen treatment in multiple sclerosis

https://doi.org/10.1016/j.jns.2009.05.028Get rights and content

Abstract

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.

Section snippets

Inflammation and neurodegeneration in MS

Multiple sclerosis (MS) is a heterogeneous inflammatory, demyelinating disease of a presumed Th1-autoimmune origin. However, over the last decade, abundant neuroimaging studies have indicated a significant neurodegenerative process in MS [1], [2], [3], [4], [5], [6], particularly in gray matter [5], [6], [7], [8]. Gray matter atrophy has been shown to correlate better with permanent disability than markers of inflammation [3], [5], [6]. Pathological findings in MS have described cortical

The need for new treatment options in MS

The currently approved treatments for relapsing–remitting (RR) MS (Interferon-β; Glatiramer Acetate and Mitoxantrone) as well as emerging therapies including monoclonal antibodies (such as Natalizumab, Alemtuzumab, and Rituximab) and oral drugs currently in Phase III trials (Cladribine, Fingolimod (FTY 72), Teriflunomide, Oral fumarate, and Laquinimod) all target the inflammatory component of MS pathogenesis. While these may exert some indirect neuroprotective effects via inhibition of

Protective mechanisms of estrogens in animal models

It has been previously shown by numerous laboratories that the clinical severity of both active and adoptive experimental autoimmune encephalomyelitis (EAE) is reduced by estrogen (estriol or 17β-estradiol) treatment in several strains of mice (SJL, C57BL/6, B10.PL, B10.RIII) [22], [23], [24], [25], [26], [27], [28], [29], [30]. Estriol treatment has also been shown to be effective in EAE when administered after disease onset [22].

Protective mechanisms of estrogen treatment (both estriol and

Safety and risks of estriol treatment for multiple sclerosis

Concerns regarding the use of estrogens as therapeutic agents have been raised after results became available from the Women's Health Initiative (WHI), a set of clinical trials in a very large group of postmenopausal women receiving hormone-replacement-therapy (HRT) [60]. Participants were treated with conjugated equine estrogens (Premarin) with or without medroxyprogesterone acetate (Provera) versus placebo. The estrogen+progestin trial arm was stopped due increased the risk for a number of

Phase I trial of oral estriol in MS

Estriol was administered in a pilot clinical trial to women with MS in an attempt to recapitulate the protective effect of pregnancy on disease [83]. A cross-over study was used whereby patients were followed for 6 months pre-treatment to establish baseline disease activity, which included cerebral MRI every month and neurological examination every 3 months. The patients were then treated with oral estriol (8 mg/day) for 6 months, then observed for 6 more months in the post-treatment period

Conclusions

A large body of evidence supports the therapeutic potential of estrogens in inflammatory autoimmune diseases. Mechanisms of action include both immunomodulatory and neuroprotective pathways thus suggesting that estrogens could beneficially affect the inflammatory as well as the neurodegenerative component of the disease. We now also have pilot clinical evidence for the effectiveness of estriol in MS. Ongoing phase II/III trials of estrogens in MS will provide more definitive evidence regarding

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