Background
Mounting evidence suggests that a number of biological, genetic, and environmental factors contribute to one’s risk of developing multiple sclerosis (MS). One of the more widely accepted factors is sex; females are reported to be three times more likely to develop MS than males, and this effect seems to only occur after the age of 12. According to a recently published article by Jennifer Ahn, University of Toronto graduate student and recipient of the Lawrason Foundation MS Society of Canada Doctoral Studentship, the observation that a higher risk of developing MS among females than males after age 12 implies that puberty may be playing a role. One explanation is that an increase in levels of testosterone in males during puberty may have a protective effect against MS, as testosterone has been shown to have a positive effect in reducing MS disease. The role that female hormones play in MS is less defined, as studies have produced mixed results that require further research. In a study by Ms. Ahn and colleagues involving clinical data analysis and studies with mice, the impact of puberty on risk of developing MS in young females is explored.
The Study
The study involved participants from the Canadian Pediatric Demyelinating Disease Study, an initiative supported by a collaborative grant from the MS Scientific Research Foundation. The study, led by renowned pediatric neurologist and researcher Dr. Brenda Banwell and immunology expert Dr. Shannon Dunn, involved 23 centres across Canada, and sought to follow children with early demyelinating events over time to determine why some go on to develop MS and others fully recover. In the study, Ms. Ahn identified 94 participants from the pediatric multi-site study who reached their first menstrual cycle during analysis, 40 of whom were diagnosed with MS. The first menstrual cycle is often considered the central event of female puberty. Ms. Ahn and colleagues sought to determine if age of first menstrual cycle was associated with risk of developing MS.
To further support this work and determine the mechanism underlying a potential puberty-effect in MS, the researchers also looked at pubertal status in mice with an MS-like disease. Mice in the pre-pubertal group were treated with surgery in order to prevent entry into puberty, whereas mice in the post-pubertal group were given a sham procedure and started to cycle normally. This allowed the researchers to determine if puberty affects the risk of a mouse developing MS-like disease, irrespective of age. Additional experiments involving the white blood cells extracted from the two groups of mice were also undertaken to compare the inflammatory nature of the cells.
Results
Analysis of the clinical data collected from the 94 Canadian Pediatric Demyelinating Disease Study participants revealed that the first menstrual cycle (onset of puberty) occurred at a younger age in females who developed MS after an early demyelinating event, compared to those who did not go on to develop MS, even when age and other MS risk factors like low vitamin D status were adjusted for. In the animal experiments, it was found that there were more mice who developed an MS-like disease in the post-pubertal group (mice that reached puberty) than in the pre-pubertal group (mice that did not reach puberty). Further analysis revealed that white blood cells from the post-pubertal mice were very active and produced higher levels of inflammatory substances than cells from the pre-pubertal mice. According to the researchers, these findings indicate a robust autoimmune response in post-pubertal female mice. Additional cell experiments also conferred that pubertal status influences susceptibility to MS-like disease in mice.
Comment
Although the study highlights potential biological mechanisms that could explain how puberty influences development of MS, the exact process is still unclear. What is clear is that pubertal status of a female – meaning when she reaches puberty – may enhance risk of MS, especially in female adolescents who present with early events of demyelination. In mice it was also evident that onset of puberty more than likely led to an MS-like state, possibly through an enhanced autoimmune reaction in the central nervous system.
Much research is underway to better understand the preponderance of MS among females, in order to develop tools to identify and treat high-risk individuals. This study employs a novel approach in that it looks at MS in a younger population, which could help point to potential early MS triggers and explanations for the disparity between males and females. Data generated from this study not only unveils a potential risk factor for MS, but may ultimately point to mechanisms of MS development based on changes that occur in the body (i.e. changes to the immune and hormonal systems) during and shortly after puberty.
Source
Ahn JJ et al. Puberty in females enhances the risk of an outcome of multiple sclerosis in children and the development of central nervous system autoimmunity in mice. Multiple Sclerosis Journal. 2014 Dec 22 [Epub ahead of print].