BACKGROUND: Gonadal steroids may modulate disease course in multiple sclerosis (MS).
OBJECTIVE: To assess the prevalence and clinical associations of hypogonadism in men with MS.
METHODS: 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.
RESULTS: 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).
CONCLUSIONS: 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.
Bove R, Musallam A, Healy B, Raghavan K, Glanz B, Bakshi R, Weiner H, De Jager P, Miller K, Chitnis T.
Source: Mult Scler. 2014 Apr 7. & Pubmed PMID: 24710799 (11/04/14)
Taking the contraceptive Pill may increase a woman’s chance of developing multiple sclerosis, researchers warn.
The risk of MS could be up to 50 per cent higher among women on the Pill, according to a new US study.
The findings also show young obese women are at greater risk of the disease, probably because they produce higher levels of a hormone known to regulate appetite.
Previous research had suggested that oral contraception could cut MS risk, or delay its onset.
MS is the most common disabling neurological condition, affecting almost 100,000 Britons – around 50 people are diagnosed each week.
It involves damage to myelin, a protective sheath surrounding nerve fibres of the central nervous system, meaning the body’s immune system attacks itself.
Symptoms range from mild, occasional illness involving numbness, muscle weakness and eye problems to rapid and severe deterioration, resulting in serious disability.
US researchers identified 305 women who had been diagnosed with MS during a three-year period.
Their use of the Pill – mainly a combination of two hormones – was compared with 3,050 women who did not have MS.
In total, 29 per cent of the women with MS and 24 per cent of those without MS had used hormonal contraceptives for at least three months in the three years before symptoms began.
Women who had used the Pill were 35 per cent more likely to develop MS than those who did not use them. Those who had used the contraceptives but had stopped at least one month before symptoms started were 50 per cent more likely to develop MS.
Lead researcher Dr Kerstin Hellwig said: ‘These findings suggest that using hormonal contraceptives may be contributing at least in part to the rise in the rate of MS among women.’
Previously animal research led experts to believe female hormones might delay the onset of MS, and a British study suggested Pill users had a 40 per cent lower risk.
The new research was presented at the American Academy of Neurology’s annual meeting in Philadelphia.
In a separate study at the same meeting, researchers looked at a possible link between obesity and MS, by checking the Body Mass Index (BMI) of study volunteers.
BMI was calculated for 210 people with MS and 210 people of the same age and sex who did not have MS at ages 15 and 20 and at the time of the study.
The study found that people who are obese at age 20 are twice as likely to later develop MS as people who are not obese.
The study found that people with higher BMI levels also had higher levels of leptin, a hormone made by fat tissue that regulates weight, appetite and immune response.
Study author Dr Jorge Correale, of the Raúl Carrera Institute for Neurological Research in Buenos Aires, Argentina, said ‘Leptin promotes inflammatory responses in the body, which could potentially explain the link between obesity and MS.’
Source: The Daily Mail © Associated Newspapers Ltd 2014 (28/02/14)
Testosterone treatment was associated with reversal of gray matter atrophy in a population of men with multiple sclerosis (MS), researchers reported here.
In a small pilot study of male multiple sclerosis patients, treatment with 100 mg of testosterone was associated with diminished atrophy of gray matter over a 6-month window and reversal to pre-study levels with significant increase in the right middle frontal gyrus after 12 months of therapy, according to Florian Kurth, MD, of the University of California Los Angeles, and colleagues.
However, there was no association with lesion volume or newly occurring lesions with testosterone treatment, Kurth said during an oral presentation at the Society for Neuroscience meeting.
Kurth also acknowledged the risks of myocardial infarction associated with testosterone therapy, but noted that treatment should be delivered on a patient-by-patient basis that should not overshadow the need for further randomized, controlled trials with larger populations to study this association, adding that the differences from therapy were "not merely cosmetic."
Kurth and his colleagues conducted a pilot clinical trial to study the effect of testosterone on cerebral gray matter in 10 men with relapsing-remitting MS, having noted that gray matter atrophy "correlates better with disability than [white matter] lesions do" in multiple sclerosis.
They also noted that past research has shown that testosterone has neuroprotective properties in men.
Current MS treatments predominantly affect relapse and white matter lesions.
Participants were 29 to 61 and had not received disease-modifying treatment. Over the 18 months of the study, they underwent voxel-based morphometry in MRI scans at baseline, month 6, month 12, and month 18 to measure changes in gray matter volume.
During the initial 6 months, there was an observation phase during which participants received no treatment. Over the next 6 months, they underwent a "wash-in" period where they were observed for efficacy of treatment. The final 6 months was the "treatment phase" during which it was expected that the full effects of testosterone treatment would be visible on brain scans.
Over the observation period, there was a significant widespread decrease in gray matter. This loss was strongly tempered during the wash-in period, and gray matter volume had returned to baseline levels after 12 months of treatment.
Kurth and colleagues noted that the testosterone treatment did not significantly effect the overall lesion volume or the number of new lesions.
They concluded that these outcomes showed that testosterone may serve as a complementary treatment to current MS therapies, which prevent inflammation and white matter lesions.
The study was supported by NIH and MNSS grants.
The authors declared that they had no conflicts of interest.
Primary source: Society for Neuroscience
Source reference: Kurth F, et al "Testosterone treatment increases regional gray matter in men with multiple sclerosis" SFN 2013; Abstract 792.01.
Source: MedPage Today © 2013 MedPage Today, LLC (18/11/13)
Testosterone Affects MS Outcomes in Men(21/03/13)
A higher testosterone level was associated with less disability and better cognitive outcomes in patients with recent-onset relapsing remitting multiple sclerosis, researchers reported here.
Male MS patients had a significant negative association between testosterone levels and leptin (R=-0.22, P=0.029), as well as between androgen index and vitamin D (R=-0.248, P=0.012), according to Riley Bove, MD, of Brigham and Women's Hospital in Boston, Mass., and colleagues.
After adjusting for patient age and disease duration, leptin levels were also significantly associated with disability scores (R=0.24, P=0.017), Bove said during a poster session at the American Academy of Neurology meeting.
Bove noted that a patient's sex influences MS disease risk and course, which may be affected by hormonal differences, as well as metabolism and vitamin D.
Prior research has shown that testosterone may be neuroprotective and anti-inflammatory, but levels of the hormone may be lower in MS patients than in healthy controls, Bove said.
To explore the issue, the researchers analyzed testosterone associations early in the MS course using a sample of 100 male patients with relapsing-remitting MS who were enrolled in the CLIMB (Comprehensive Longitudinal Investigations of MS at the Brigham and Women's Hospital) study.
At baseline, participants were ages 18 to 65 with a mean age of 39.4, had a mean body mass index (BMI) of 28.8, mean disease duration of 4.55 years, mean expanded disability status scale scores of 1.08, and were in the 94th percentile of disease category. Most participants (95 of the 100) were white.
The research team recorded patient demographic characteristics and MS history. They assessed hormone levels from stored serum and plasma at baseline and over 30 days after steroid use, and included measures of leptin, luteinizing hormone, testosterone, and androgen, as well as vitamin D.
Participants also underwent tests for disability and cognitive status. Cognitive status was measured through the Symbol Digit Modalities Test.
In addition to effects on disability, higher testosterone was significantly associated with less cognitive decline (P=0.007).
Higher testosterone was predictive of smaller 2-year declines in cognitive function, and vitamin D levels were not associated with disability.
The researchers also pointed out a "high prevalence of hypogonadism in men with MS early in their disease course (41% with testosterone lower than 300 ng/dL)."
They acknowledged that their research was limited by a short study period, and that future studies should replicate the current study's tests over a longer time span with a longitudinal assessment of hormonal changes.
The study was funded through the NIH, NMSS, and awards to Harvard University and Brigham and Women's Hospital.
Two co-authors received research support from Merck Serono.
One co-author served as a consultant for EpiVax and Novartis.
Another co-author received consulting fees from Nasvax, EMD Serono, Biogen Indec, Teva, Genentech, GlaxoSmithKline, and Novartis.
Another co-author served as a consultant for Teva Neurosciences and Biogen-Idec.
Another co-author served as a consultant for Biogen-Idec, Sanofi Aventis, Novartis, EMD-Sonero, and Teva Neurosciences, and received grant support from Merck-Serono.
Primary source: American Academy of Neurology
Source reference: Bove R, et al "Hormonal associations in men with recent-onset relapsing remitting multiple sclerosis" AAN 2013; Abstract P02.128.
Source: MedPage Today © 2013 MedPage Today, LLC. (21/03/13)
A new study suggests that treatment with adrenocorticotropic hormone (ACTH) may be helpful for people whose multiple sclerosis (MS) is not well-controlled through their regular treatment. The study was released today and will be presented at the American Academy of Neurology's 65th Annual Meeting in San Diego, March 16 to 23, 2013.
The study involved 23 people with MS who were taking beta-interferon treatment and had at least one relapse or brain scan showing new disease activity within the previous year. They were considered to have "breakthrough" MS, which means that their treatment that had been working previously stopped being effective, leading to worsening disability and more frequent relapses, as well as increased evidence of disease activity on brain scans.
The study participants were given either ACTH or methylprednisolone as pulse therapy monthly in addition to their regular treatment for one year. The people with MS knew which treatment they were receiving, but the researchers examining them did not.
The participants were tested every three months for 15 months. Over that time, those receiving ACTH had fewer relapses, or 0.08 cumulative relapses per patient compared to 0.8 relapses per patient for those receiving methylprednisolone. Those taking ACTH also had no cases of psychiatric side effects, while those taking methylprednisolone had a cumulative number of 0.55 psychiatric episodes per patient.
"These results are of interest because few treatments are available for people with breakthrough MS," said study author Regina Berkovich, MD, PhD, of Keck Medical Center of USC in Los Angeles. "Further studies, including randomized controlled trials, are needed to validate these preliminary findings, but the results suggest a potential benefit of ACTH pulse therapy in breakthrough MS."
While ACTH has been approved for use in MS relapses for many years, its cost has limited its use to only those patients who are in need of a relapse treatment alternative to corticosteroids. This is believed to be the first study to have been done on its use as a chronic treatment for MS. ACTH is not FDA-approved for use as chronic treatment for MS.
The study was supported by a research grant from Questcor Pharmaceuticals, Inc., maker of ACTH.
Source: Eureka Alert! Copyright ©2013 by AAAS, the science society.(11/03/13)
Testosterone and its derivatives could constitute an efficient treatment against myelin diseases such as multiple sclerosis, reveals a study by researchers from the Laboratoire d'Imagerie et de Neurosciences Cognitives. Myelin composes the sheaths that protect the nerve fibers and allow the speed of nerve impulses to be increased. A deficit in the production of myelin or its destruction cause serious illnesses for which there is no curative treatment. The researchers have shown that in mice brains whose nerve fibers have been demyelinated, testosterone and a synthetic analog induce the regeneration of oligodendrocytes, the cells responsible for myelination, and that they stimulate remyelination. This work is published on January in the journal Brain.
Multiple sclerosis (MS) is a degenerative disease of myelin, which is accompanied by severe inflammation of the central nervous system. Affecting around 80,000 people in France, it is characterized by motor and vision disorders and by neurological impairments such as elocution difficulties. MS is also known to have a hormonal component. In fact, women are twice as susceptible as men, even though the prognosis is less good for males. In addition, it has been observed that pregnant women suffering from MS do better during pregnancy when their hormone levels are high.
The team headed by Dr Said Ghandour had already demonstrated the protective effect of testosterone on oligodendrocytes (the cells responsible for myelination). For this study, the researchers firstly induced chronic demyelination of the nerve fibers in the brain of mice. To do this, they added cuprizone, a molecule that sequesters copper, to their diet. The mice then exhibited chronic demyelination, analogous to that observed during the progressive phase of MS. They were then treated with testosterone for 6 to 9 weeks.
As a result, their nerve fibers were once again myelinated and their symptoms were remarkably alleviated. The same effects were obtained using a synthetic testosterone analogue, 7-alpha-methyl-19-nortestosterone (MENT). The researchers then showed that these androgens bring about the transformation of neural stem cells into oligodendrocytes and promote the synthesis of myelin by oligodendrocytes, thus maintaining the integrity of the nerve fibers.
They then repeated the experiment, but this time using two transgenic mouse strains: one with a mutated androgen receptor and the other with a receptor that had been selectively inactivated in the central nervous system. In these androgen-insensitive mice, testosterone did not stimulate remyelination of the nerve fibers. These results identify the androgen receptor as a promising therapeutic target for treating diseases such as MS. They open the way to the use of androgens-including that of testosterone analogues such as MENT, which is well tolerated in humans-to promote the regeneration of myelin. Further work will focus on the possibility of using testosterone blood levels as biomarkers to evaluate the progression of demyelinating diseases.
More information: Hussain, R. et al. The neural androgen receptor: a therapeutic target for myelin repair in chronic demyelination, Brain, January 2013. Volume 136(1): pages 132-146. doi:10.1093/brain/aws284 Journal reference: Brain.
Source: Medical Xpress © Medical Xpress 2011-2013 (31/01/13)
Researchers 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(15/10/12)
High-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)