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 characterised 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. © 2014 American Neurological Association & Pubmed 25131454 (21/08/14)
For decades, women with multiple sclerosis have noticed that they tend to do better while they are pregnant. That has led to an experimental drug for the disease that's based on a hormone associated with pregnancy.
The hormone is a form of estrogen called estriol. It's abundant in a woman's body only when she is pregnant. Adding estriol to treatment with an existing MS drug cut relapses by 47 percent in a study of 158 women presented at the American Academy of Neurology meeting in April.
The result is "quite remarkable," says Rhonda Voskuhl, an author of the study and a neurologist at the University of California, Los Angeles. It suggests that estriol could greatly enhance the effectiveness of current MS drugs, Voskuhl says. Those drugs, which are designed to modulate the immune system, can cost up to $60,000 a year.
Multiple sclerosis is a disease that damages the myelin sheath covering nerve fibers. Researchers believe the damage is caused at least in part because the body's own immune cells begin attacking myelin. About 400,000 people in the United States have multiple sclerosis, with symptoms ranging from muscle weakness or paralysis to difficulty thinking.
The new research on estriol was inspired by decades of anecdotal reports from women like Melissa Sherak Glasser of Woodland Hills, Calif. Glasser is 41 now, but was diagnosed with MS when she was just 15.
She remembers putting one hand into a tub of bathwater to check the temperature and being surprised that it felt cold. "Then I put my other hand in and it was burning hot and I thought OK, something's wrong," she says.
An MRI scan showed that Glasser had MS. But Glasser didn't let the disease slow her down much. She was a cheerleader in high school, then went to college and graduate school and got married, despite relapses that caused temporary blindness, vertigo and difficulty walking.
When Glasser was in her mid-20s, she got pregnant. And one day, during an episode of morning sickness, she realized something surprising: her MS symptoms had gone away. "I felt so horrible with all the pregnancy hormones, and I had to laugh," she says.
Glasser reported this to neurologists at UCLA who had been monitoring her MS since she was diagnosed more than a decade earlier. They weren't surprised. They'd heard stories like that before from women with MS. And pregnancy's effect on MS symptoms had been confirmed by a large scientific study in 1998.
So by the time Glasser became pregnant for the first time (she has four children now and was free of MS symptoms during all four pregnancies), Voskuhl and other researchers were already hard at work trying to identify the factor that was protecting pregnant women with MS. "If we could just figure it out, we would have an inroad to a major discovery," Voskuhl says.
The researchers knew that during pregnancy, a woman's immune system changes. "Pregnancy involves a fetus, which has half of the father's proteins on it," Voskuhl says. "So it's half foreign. In order to not reject that half-foreign fetus, the mother's immune system shifts."
Voskuhl figured that whatever was causing that shift was also protecting the woman's nerve fibers from MS. And she suspected a key factor was the hormone estriol.
So the researchers gave estriol to mice with multiple sclerosis and waited to see whether it would help them. "And indeed it did," Voskuhl says. "The mice were not paralyzed, they were walking around fine. It was just a dramatic reduction in their disease." Doses of the pregnancy hormone even worked in male mice.
Voskuhl was confident that estriol could help people with MS. But it took more than a decade to find out.
Drug companies weren't interested in estriol because it isn't a patented chemical, Voskuhl says. So she turned to the National Institutes of Health, the National Multiple Sclerosis Society and foundations, including one set up by the family of Melissa Sherak Glasser.
Ultimately, Voskuhl got the millions of dollars she needed to conduct a two-year trial of estriol in women who also were taking the widely used MS drug Copaxone. The success of that trial clears the way for a much larger study that can be submitted to the Food and Drug Administration for approval.
Glasser is confident that estriol will ultimately be approved as a treatment for MS and hopes to be one of the first people in the U.S. to get a prescription.
Source: Copyright 2014 NPR (02/06/14)
Long-term influence of combined oral contraceptive use on the clinical course of relapsing-remitting multiple sclerosis.
OBJECTIVE: To assess the long-term effects of combined oral contraceptives (COCs) on the clinical course of relapsing-remitting multiple sclerosis (RRMS), focusing on disability progression and evolution to secondary-progressive multiple sclerosis (SPMS).
DESIGN: Retrospective and exploratory study.
SETTING: Academic medical center.
PATIENT(S): A total of 174 women with clinically confirmed MS; of these, 33 had evolved to SPMS at the time of enrollment in the study, whereas 141 still had a relapsing-remitting form of disease.
INTERVENTION(S): Women were interviewed to obtain gynecologic and obstetric history.
MAIN OUTCOME MEASURE(S): Expanded Disability Status Scale (EDSS); Multiple Sclerosis Severity Score (MSSS); annualized relapse rate; evolution to SPMS.
RESULT(S): Mean ± SD duration of disease was 14.3 ± 9.8 years. Compared with non-users of COCs, COC users had lower EDSS scores and MSSS only in the subset of the population with prior or current immunomodulatory treatment. Nonuse of COCs was a predictor of disease evolution in SPMS, whether treated or not with immunomodulatory drugs. The annualized relapse rate was not influenced by COC use. No differences in EDSS scores and evolution to SPMS depending on COC formulation were detected.
CONCLUSION(S): Our results suggest that COC use is associated with a less severe disease and less severe evolution. Whether different doses or types of progestin may have different effects remains to be defined.
Gava G, Bartolomei I, Costantino A, Berra M, Venturoli S, Salvi F, Meriggiola MC.
Sources: Fertil Steril. 2014 Apr 29. pii: S0015-0282(14)00309-4. doi: 10.1016/j.fertnstert.2014.03.054. [Epub ahead of print] & Pubmed PMID: 24794311 (12/05/14)
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)