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    You are here : Home » MS Research News » Hormones And MS

    Hormones And MS

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    More news can be found in New Pathways Magazine, our bi-monthly publication, and also check daily at MSRC: Latest MS News.

    Testosterone shows nerve-protecting capabilities in mice with MS-like disease

    MouseResearchers funded by the National MS Society have shown that the male sex hormone testosterone prevented or restored impairments in nerve impulse transmission in mice with EAE, an MS-like disease.

    The improvements specifically occurred in an area of the brain associated with cognitive function, lending evidence to the potential for the future use of sex hormones to treat this MS symptom. This team is currently conducting clinical trials to determine whether estriol (another sex hormone, added on to standard therapies) improves disease activity and cognition in women with MS. Rhonda Voskuhl, MD (University of California, Los Angeles) and colleagues report their findings in The Journal of Neuroscience (2012;32:12312).

    Background: Sex hormones may contribute to MS susceptibility and ongoing disease activity by influencing the immune attack on brain and spinal cord tissues. Laboratory studies have shown that the severity of EAE, an MS-like disease, is decreased when testosterone, a male sex hormone, is administered to male and female mice. Dr. Voskuhl was awarded funding from the National MS Society’s targeted research initiative on Gender Differences in MS to undertake a small study of testosterone gel in men with MS. One year of treatment with a gel containing the sex hormone testosterone (applied to the skin) in 10 men with relapsing-remitting multiple sclerosis resulted in significant improvements in cognitive function and in slowing brain tissue loss, indicating possible neuroprotective effects. (Archives of Neurology 2007;64:683).

    In separate studies, this team also has found evidence in MS of tissue loss in an area of the brain called the hippocampus, a region deep in the brain known to be important in cognitive function. (Brain 2008;131:1134). Now, they are studying how testosterone treatment may affect the hippocampus, for clues to understanding its potential for treating cognitive function.

    The Study: Dr. Voskuhl’s team administered testosterone or inactive placebo to mice before and after inducing EAE, an MS-like disease. Using tests that measure electrical conduction, they found that the disease specifically impaired nerve impulse transmission in the hippocampus. Treatment with testosterone before inducing EAE prevented impaired to some extent nerve impulse transmission. Treatment after the disease began reduced signs of disease and restored proper nerve impulse transmission.

    Comment: This study lends further evidence to the potential for the use of sex hormones to treat MS and in particular, cognitive issues. This team is currently conducting two clinical trials of estriol (another gender hormone, added on to standard therapies): one, funded by the National MS Society and NIH, involves 150 women with MS and is testing whether estriol can slow disease course and activity; the other involves 64 women with MS and is testing whether the hormone improves cognition.

    The authors note the testosterone may be neuroprotective like estrogens because it converts to estrogen in the body. “Both sex hormones should be considered as candidate treatments to improve cognition during MS.”

    Source: National US MS Society (07/11/12)

    Estrogen pills may help as MS add-on

    Oestrogen PillsHigh-dose estrogen supplements added to standard interferon-beta therapy in multiple sclerosis could increase treatment responses in at least some women, a researcher said here.

    Delivered in oral contraceptive pills, young female MS patients with relapsing-remitting disease who took ethinyl estradiol at 40 mcg/day plus desogestrel at 125 mcg/day in addition to regular interferon injections for a planned 96 weeks showed significantly fewer brain MRI lesions than patients receiving only the interferon, reported Carlo Pozzilli, MD, of Sapienza University in Rome.

    However, the high-dose estrogen and interferon combination did not appear to reduce relapse rates beyond those seen with interferon alone, he told attendees during a late-breaking abstract session at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis.

    Also, discontinuations among patients taking the hormone pills were common, "indicat[ing] that the oral contraceptives are poorly tolerated," he said.

    But Pozzilli added that additional studies of hormonal treatments for MS were still warranted. For example, he suggested that it would be worthwhile to examine whether baseline hormone levels are associated with clinical responses, in which case patients unlikely to benefit could be spared the add-on treatment.

    Hormones, and especially estrogen, are believed to affect MS disease activity, in large part because of the observation that relapses are rare in female patients when they are pregnant and resume postpartum.

    However, although some evidence has suggested that oral contraceptives reduce disease activity, controlled prospective trials have not been reported before.

    In the randomized study reported by Pozzilli, he and his colleagues recruited female MS patients 18 to 40 years old and with EDSS disability scores of 5.5 or less.

    Participants who had previously received interferon-beta were excluded, as were those taking glatiramer acetate (Copaxone) within three months of screening. Other exclusions included relapse within the previous month, gynecological diseases, recent pregnancy, and use of immunosuppressants in the past year.

    The 150 patients eventually enrolled in the trial were randomized to receive interferon-beta-1a (Rebif) at 44 mcg three times a week by injection alone or in combination with one of two oral contraceptive pills -- one containing 40 mcg of ethinyl estradiol and 125 mcg of desogestrel (high-dose estrogen), or one with 20 mcg ethinyl estradiol and 150 mcg of desogestrel (low-dose estrogen).

    Treatment was intended to continue for 96 weeks. Premature discontinuations in the three groups were as follows:

    Interferon alone: 5 patients
    High-dose estrogen: 14 (one who stopped interferon, 13 who stopped hormones)
    Low-dose estrogen: 16 (seven who quit interferon, 12 who quit hormones, three who stopped both)
    As a result, mean durations of actual hormonal treatment were less than planned, ranging from 19 to 21 months.

    Nevertheless, according to the study's primary endpoint, the cumulative number of "combined unique active" lesions on MRI -- a combination of new gadolinium-enhancing T1 lesions and new or enlarging T2 lesions -- was 2.29 in the high-dose estrogen group versus 3.18 with interferon alone (P<0.05).

    A smaller, nonsignificant reduction relative to the interferon-only control was seen in the low-dose estrogen group (2.94 cumulative lesions, P=0.09).

    The effect of high-dose estrogen was especially prominent for new gadolinium-enhancing T1 lesion counts. These were reduced by 65% relative to the interferon-only control (P<0.05) at week 48 and by 54% (P=0.06) at week 96.

    Also significant was a higher number of patients in the high-dose estrogen group at week 96 who were free of gadolinium-enhancing lesions (92% versus 74%, P<0.05).

    Effects on new and enlarging T2 lesions were similar but failed to reach statistical significance, Pozzilli said.

    There also appeared to be no benefit whatsoever in annualized relapse rates, which were virtually identical in the control and high-dose groups (0.32 and 0.33, respectively) and were higher with low-dose estrogen (0.44).

    Rates of disability progression were also indistinguishable between treatment arms.

    Pozzilli outlined future research aims as including additional MRI evaluations, such as measures of brain volume and "black holes" over time, as well as possible effects on cognitive function as well as potential predictors of clinical response to add-on estrogen supplements.

    The study was supported by Ateneo and the Italian Multiple Sclerosis Federation.

    Pozzilli reported serving on scientific advisory boards for Novartis, Merck Serono, Biogen Idec, sanofiaventis and Bayer Schering and has received funding for travel and speaker honoraria from sanofiaventis, Biogen Idec AG, Bayer Schering, Teva Neurosciences, Merck Serono and Novartis, and receives research support from Merck Serono, Biogen Idec, Bayer Schering and sanofi-aventis. Other authors declared they had no relevant financial interests.

    Primary source: European Committee for Treatment and Research in Multiple Sclerosis
    Source reference:
    Pozzilli C, et al "Efficacy and safety of oral contraceptives as add-on therapy in patients with relapsing-remitting multiple sclerosis receiving subcutaneous interferon beta-1a: A multicenter, randomized investigator-run clinical trial" ECTRIMS 2012; Abstract 171.

    Source: Medpage Today © 2012 MedPage Today, LLC (15/10/12)

    Hormone therapy viable option for MS flares

    HormonesAdrenocorticotropic hormone (ACTH) gel is an effective treatment for multiple sclerosis exacerbations in patients failing methylprednisolone therapy, a researcher said here.

    A retrospective, single-center review indicated that, of 18 patients with acute MS flares treated with ACTH gel (Acthar) who had failed treatment with methylprednisolone, 17 had responses rated by the treating physician as good or better, according to Maura Fernandez, MD, of the University of Southern California (USC) in Los Angeles.

    The results confirm that ACTH gel is a viable alternative for multiple sclerosis (MS) patients who cannot tolerate or otherwise fail standard corticosteroid therapy, she said at a poster presentation at the joint meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

    But Fernandez noted that the drug's high cost relative to methylprednisolone remains a major stumbling block to greater use of the product.

    The mechanism of ACTH in MS exacerbations is not fully understood. As its name suggests, the hormone stimulates endogenous corticosteroid release. But some research points to steroid-independent effects, such as direct anti-inflammatory activity mediated by the melanocortin system, Fernandez explained.

    Such an action could explain why patients who fail conventional corticosteroid therapy do respond to ACTH treatment.

    Fernandez and colleagues pulled records from the USC MS Comprehensive Care Center from 2008 to 2011 to assess outcomes in patients receiving ACTH gel who had poor responses or intolerance to methylprednisolone. The latter had been given intravenously at 1 g/day for 3 to 5 days or orally for 7 to 10 days.

    ACTH gel was given by intramuscular or subcutaneous injection at 1 mL daily for 5 to 7 days.

    Patient characteristics were typical of the relapsing-remitting MS population except that only one of the 18 patients was male.

    All but one of the patients had excessive adverse events or other safety issues as the primary reason for treatment failure with methylprednisolone. The adverse events included insomnia, anxiety, and psychosis.

    ACTH treatment responses rated as "good" were reported in 10 patients. Four were rated as "very good" and three as "excellent." Only minimal change was reported for the sole remaining patient.

    Additionally, the adverse events seen with methylprednisolone were not reported in patients taking ACTH, Fernandez and colleagues stated.

    Fernandez said her group currently has a randomized trial underway to more directly compare efficacy of ACTH versus methylprednisolone for MS exacerbations.

    ACTH and intravenous methylprednisolone are the two FDA-approved treatments for MS exacerbations in patients with relapsing forms of the disease. In part because of cost and easy accessibility, methylprednisolone has become the most common treatment for MS flares.

    A 5-day course of IV methylprednisolone at 1 g/day costs a few hundred dollars. A 5-mL vial of the ACTH gel, on the other hand, sells for about $30,000. However, its manufacturer has instituted an access program to provide the drug at reduced cost to patients who can't afford it. Fernandez said that health insurers generally do not cover ACTH for this indication.

    The two products were more cost-competitive prior to 2007, when the ACTH gel's manufacturer, Questcor, raised its price by more than 10-fold. The company said the hike was necessary to stave off bankruptcy and to fund research necessary to win FDA approval of label changes that were eventually allowed in 2010.

    Although ACTH has been recognized as effective against MS flares for many years, the new price differential naturally meant that providers and insurers looked to the cheaper corticosteroid alternative as first-line therapy. Fernandez and colleagues noted that there has been little directly comparative data to suggest that one treatment is better than the other.

    As a result, ACTH gel has largely been reserved for use as a rescue treatment in patients with severe flares that do not respond to methylprednisolone, but too few studies have examined its efficacy in this setting.

    The study was funded by Questcor.

    Fernandez had no relevant financial interests. One investigator reported relationships with Acorda, Bayer, Biogen Idec, Questcor, and Teva.

    Primary source: Consortium of Multiple Sclerosis Centers-Americas Committee for Treatment and Research in Multiple Sclerosis
    Source reference:
    Berkovich R, et al "Adrenocorticotropic hormone treatment of multiple sclerosis exacerbations" CMSC-ACTRIMS 2012; Abstract DX66.

    Source: Medpage Today © 2012 Everyday Health, Inc. (05/06/12)

    Menopause impact negligible in Multiple Sclerosis

    Hormones The clinical course of multiple sclerosis does not appear to be affected by advent of menopause, researchers said here.

    The two year change in the Expanded Disability Status Scale increased 0.139 points in a two-year period among pre-menopausal women and 0.122 points in menopausal women (P=0.83), according to Riley Bove, MD, a research fellow at the Multiple Sclerosis Center at Brigham & Women's Hospital and Harvard Medical School.

    In reviewing data from the Partners Multiple Sclerosis Center in Boston, Bove and colleagues also found that changes in MRI scans were also similar for both groups of women -- the brain parenchymal fraction declined 0.001 in both groups (P=0.70), and T2 lesion volume decreased 0.002 in pre-menopausal women and increased 0.025 in menopausal women, (P=0.34). Neither change achieved statistical significance.

    On the other hand, on the Short Form-36 self-assessment of physical functioning, menopausal women scored lower (P<0.001) than premenopausal women, Bove and colleagues noted in their poster presentation at the American Academy of Neurology meeting.

    "There is a scientific rationale for menopause and worsening multiple sclerosis symptoms because menopause modulates other neurologic diseases including dementia, Alzheimer's disease, epilepsy, rheumatoid arthritis and lupus and other inflammatory diseases," Bove told MedPage Today. "So there would be an expectation that it might be similar in multiple sclerosis."

    But when the research team looked at hard clinical outcomes such as MRI brain scans, the evidence was not there.

    "This data suggest that there is no strong signal for menopause to change the disease course," Philip De Jager, MD, associate professor of neurology at Brigham & Women's Hospital and Harvard Medical School and one of the principal investigators in the study, told MedPage Today.

    For the study, the researchers identified 128 women who were pre-menopausal -- ages 38 to 46 -- and 78 menopausal women -- ages 54 to 62 -- with multiple sclerosis. They also compared them with men who had multiple sclerosis -- 41 men ages 38 to 46 and 19 men ages 54 to 62 included in the analysis. Bove said the main purpose of including men in the study was to rule out that any influence age might have on changes in disease course.

    In self-reports, menopausal women showed deteriorating symptoms, but men in the same age group did not, raising a signal that menopause might be a contributing factor. "That's kind of what people are seeing in clinic is that women report things that may have more to do with menopause than with multiple sclerosis," she said.

    "The next step for us is to actually follow women and men from age of about 40 to 60," she said. "We have a pretty substantial number of people we can follow through the menopausal transition. The symptoms of menopause and peri-menstrual symptoms and all those things are notoriously hard to capture empirically because fluctuating hormones in different people will have contradictory effects."

    The researchers said they cannot make strong recommendations for patient management at this time.

    "I think it is certainly reasonable to [tell patients] you may experience more fatigue, you may feel worse or you may feel better or it may fluctuate," Bove said. "We should warn them that they may have subjective phenomena but at present there is no data to support that menopause may be making their condition worse."

    De Jager has disclosed commercial interests with Merck Serono, Teva Neuroscience and Biogen Idec.

    Bove had no disclosures.

    Primary source: American Academy of Neurology
    Source reference:
    Bove R et al, "Menopause may not modulate disease course in multiple sclerosis" AAN 2012; P06.183.

    Source: MedPage Today © 2012 Everyday Health, Inc (27/04/12)

    'Pushing Limits' - new drug strategies for Multiple Sclerosis, Alzheimer's

    MS Drug ResearchResearchers at the University of Houston (UH) are recommending a new strategy for developing drugs to treat cancer, multiple sclerosis, Alzheimer's and cardiovascular diseases.

    In an invited review published in the October issue of Nature Reviews Drug Discovery, scientists at the Center for Nuclear Receptors and Cell Signaling (CNRCS) at UH outline the results of years of research following the team's 1996 discovery of the estrogen receptor beta (ERβ).

    "We have known for some time that female sex hormones - estrogens - influence a number of functions in the human body," said Dr. Jan-Åke Gustafsson, UH professor and CNRCS director. "Only recently have we and others found that one of the estrogen receptors - ERβ - is a potential target for the treatment of Alzheimer's and other chronic diseases."

    Gustafsson is best known as a leading expert on estrogen receptors, being credited with the earlier discovery of ERβ during his tenure at the Karolinska Institutet in Stockholm, Sweden. In Houston since 2009, Gustafsson has hand-selected a team of experts to build on his initial breakthrough. For this latest review, the team was invited to share the most recent results of their research.

    The two estrogen receptors, estrogen receptor alpha (ERα) and ERβ, have their effects on cells via activation by hormones circulating in the body. The influence of these receptors in the human body spans such diverse functions as fertility, metabolism, and the cardiovascular and nervous systems. Due to their expanded role in human health, these receptors represent an ideal target for drugs and therapeutic treatments.

    Studies conducted following Gustafsson's discovery of ERβ have shown intriguing differences in tissue distribution and gene regulation when compared to the role of ERα. There has since been an intense effort in both academia and industry to develop ERβ-specific research tools and potential therapeutics for a multitude of conditions.

    One successful example of using ERβ as a drug target has proven the receptor as an effective cancer cell combatant in breast cancer tissue. Closer examination of human breast cancer cell lines determined that, while ERα alone may stimulate the development of tumors, the combined presence of ERα and ERβ reduced and prevented tumor development.

    "These modulators are well-established in the treatment of breast cancer and osteoporosis," Gustafsson said. "We now are pushing the limits of their influence to develop new treatments and ultimately save lives."

    CNRCS researchers continue to examine the two estrogen receptor subtypes in various animal disease models, focused on identifying therapeutic opportunities. ERβ remains the most likely target for expanding treatments beyond breast cancer. The widespread involvement of ERβ presents the greatest probability for impacting these other diseases. Early results indicate that the selective activation of ERβ may represent a safe, disease-modifying therapy for the treatment of Alzheimer's disease.

    Source: Medical News Today © MediLexicon International Ltd 2004-2011 (24/10/11)

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