Sorry about this rather long post, but there's a bit going in this area concerning MS and male and female hormones. This first part is about the latest research with estrogen like compounds and MS and the second part is about male hormones ...
It's interesting to note that this topic about hormones and MS started to emerge here in 2010, with some good research coming out in 2008 to indicate that hormones (both male and female) could possibly have a significant impact on MS progression, occurrence, and disability. Over the past 4 or 5 years there has been a bit of research in this area. Fast forward to December 2014, where research has been published in the prestigious National Academy of Sciences concerning a compound that has been developed [indazole chloride (Ind-Cl)] that has been successfully used to treat mice with EAE. This compound basically acts like estrogen in the body. It's essentially a drug that acts like estrogen but does not have all of estrogenâ€™s negative effects.
What's especially noteworthy about ind-Cl and MS, according to this study, is that it was able to stop the symptoms of MS and actually reverse ongoing motor deficit due to MS in transgenic mice (how often does that happen?). In other words, this specific compound was believed to have been able to re-myelinate damaged axons. The thinking is that this compound (or a compound like this) could be used in the future not only with MS patients but also could be used for treatment of traumatic brain and spinal cord injuries. A few good recent articles about this research include:http://www.sciencenutshell.com/indazole ... sclerosis/http://multiplesclerosisnewstoday.com/2 ... like-drug/
The "cure thing" makes me wonder but the science is fairly remarkable and adds more weight to the ongoing discussion and research in the hormones and MS front. Compounds such as ind-Cl could have some key benefit to treating the progressive forms of MS.
The summary/highlights of the study include:
Scientists Block Multiple Sclerosis in Mice Using Estrogen-Like Drug
Multiple functional therapeutic effects of the estrogen receptor Î² agonist indazole-Cl in a mouse model of multiple sclerosis
Spencer M. Moorea, Anna J. Khalaja,b,Shalini Kumarc,Zachary Winchestera,b,JaeHee Yoona, Timothy Yooa, Leonardo Martinez-Torresa,b, Norio Yasuid, John A. Katzenellenbogend, and Seema Kaushalya Tiwari-Woodruffa,b,c,e,1
Currently available immunomodulatory therapies do not stop the pathogenesis underlying multiple sclerosis (MS) and are only partially effective in preventing the onset of permanent disability in patients with MS. Identifying a drug that stimulates endogenous remyelination and/or minimizes axonal degeneration would reduce the rate and degree of disease progression. Here, the effects of the highly selective estrogen receptor (ER) Î² agonist indazole chloride (Ind-Cl) on functional remyelination in chronic experimental autoimmune encephalomyelitis (EAE) mice were investigated by assessing pathologic, functional, and behavioral consequences of both prophylactic and therapeutic (peak EAE) treatment with Ind-Cl. Peripheral cytokines from autoantigen-stimulated splenocytes were measured, and central nervous system infiltration by immune cells, axon health, and myelination were assessed by immunohistochemistry and electron microscopy. Therapeutic Ind-Cl improved clinical disease and rotorod performance and also decreased peripheral Th1 cytokines and reactive astrocytes, activated microglia, and T cells in brains of EAE mice. Increased callosal myelination and mature oligodendrocytes correlated with improved callosal conduction and refractoriness. Therapeutic Ind-Cl-induced remyelination was independent of its effects on the immune system, as Ind-Cl increased remyelination within the cuprizone diet-induced demyelinating model. We conclude that Ind-Cl is a refined pharmacologic agent capable of stimulating functionally relevant endogenous myelination, with important implications for progressive MS treatment.
In the search for effective multiple sclerosis treatment, much effort has been invested in estrogens and estrogen receptor (ER) agonists because of their neuroprotective benefits. However, because estrogens can produce ERÎ±-based feminizing effects and cancer, ERÎ² agonists represent more desirable therapeutic candidates. The structurally unique ERÎ² ligand indazole chloride (Ind-Cl), a halogen-substituted phenyl-2H-indazole core, is a preclinical development candidate with a strong dossier. Our results indicate that Ind-Cl is effective in functionally ameliorating disease even when treatment is initiated at peak experimental autoimmune encephalomyelitis clinical disease. Ind-Clâ€™s immunomodulatory and direct remyelinating effects result in motor dysfunction amelioration. These findings support Ind-Cl's potential to provide unique therapeutic benefits to patients with multiple sclerosis, as well as patients affected by other demyelinating disorders.
On the testosterone front a bit of connection is being made between disability & occurrence of MS with levels of testosterone:
Recent Studies on MS and Testosterone:
Risk of MS increased by low testicular function
Testicular hypofunction and multiple sclerosis risk: A record-linkage study.
Pakpoor J, Goldacre R, Schmierer K, Giovannoni G, Goldacre MJ.
The influence of gonadal hormones on multiple sclerosis is not well characterized and has thus far been investigated primarily in animal models or as a proposed therapeutic approach.
We investigated a potential association between testicular hypofunction, as a proxy for low testosterone levels, and multiple sclerosis risk through analysis of linked English national Hospital Episode Statistics from 1999 to 2011.
We report a strong positive association between testicular hypofunction and subsequent multiple sclerosis, rate ratio 4.62 (95% confidence interval 2.3-8.24, p<0.0001).
Future work should aim more directly to elucidate the relationship between testosterone levels and MS in both males and females.
Source: ANN NEUROL 2014. Â© 2014 American Neurological Association & Pubmed 25131454 (21/08/14)
Low testosterone is associated with disability in men with multiple sclerosis
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)
Testosterone halts gray matter atrophy in MS
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 Â© 2013 MedPage Today, LLC (18/11/13)
Testosterone Affects MS Outcomes in Men
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 Â© 2013 MedPage Today, LLC. (21/03/13)
Can hormone help treat multiple sclerosis long-term?
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 Â©2013 by AAAS, the science society.(11/03/13)
Androgenic hormones could help treat multiple sclerosis, study finds
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 Â© Medical Xpress 2011-2013 (31/01/13)
Testosterone shows nerve-protecting capabilities in mice with MS-like disease
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 Societyâ€™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. Voskuhlâ€™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. â€œBoth sex hormones should be considered as candidate treatments to improve cognition during MS.â€
Source: National US MS Society (07/11/12)