ORLANDO—Although multiple sclerosis (MS) is more common in women, when men develop MS, it tends to be worse. Studies indicate that MS in men is associated with a faster accrual of disability and worse relapse recovery. In addition, research suggests that male gender is a predictor for more severe forms of MS. Also, there appears to be a higher male-to-female ratio in primary progressive MS (PPMS), compared with relapsing forms of MS.
Role of Sex Chromosomes and Hormones
Studies suggest that women are predisposed to higher rates of MS relapses than men. Kalincik et al found that there was approximately a 1:1 male-to-female ratio in PPMS onset, compared with a 1:3 male-to-female ratio in relapsing-onset MS. “One of the interesting paradigms they looked at was the proportion of relapses or the relapse count over the course of 10 years and the female-to-male ratio and how it has increased to become predominately female with a higher relapse count. This certainly suggests that hormones and sex may be driving a relapsing phenotype,” said Dr. Chitnis.
Raghavan et al found that men appeared to have higher Expanded Disability Status Scale scores over disease duration in relapsing forms of MS compared with PPMS. In addition, when researchers observed optic neuritis as a model of relapse recovery, they found that male gender was associated with worse recovery from optic neuritis despite adjusting for disease severity as well as vitamin D levels.
Is Testosterone Neuroprotective?
Previous studies in MS suggest that low testosterone is associated with worse disability. Studies have also associated low testosterone levels with more cognitive decline in MS. Following up on these clinical observations, Dr. Chitnis and colleagues conducted the CLIMB study, a long-term study of how MS changes over time, to observe testosterone levels in men with MS. Data from the study, which involved nearly 100 men with MS, revealed that there were significantly reduced testosterone levels in a majority of the males.
Although lower levels of testosterone may be a risk factor for rapid disability accrual, testosterone supplementation appears to be neuroprotective. “There is a vast amount of literature now demonstrating in animal models particularly that testosterone does appear to be neuroprotective and anti-inflammatory,” said Dr. Chitnis.
According to Ziehn et al, testosterone seemed to be protective against synaptic preservation in animal models. In addition, research has elucidated that testosterone is able to cross the blood-brain barrier in its free form and directly influence neuronal cells. Other studies suggest that testosterone protects spinal cord neurons from glutamate toxicity, and protects from oxidative stress in neuronal cell lines.
Sex-Stratified MS Risk, Prenatal Exposure, and Puberty
To understand whether testosterone levels predispose men to MS, researchers studied a measure called the second-digit-fourth-digit ratio (2D:4D) and found that it was associated with MS in men. Researchers have also discovered that there may be prenatal risk factors that may increase susceptibility in men. While studies suggest that breast-feeding is associated with a reduced risk of MS in boys, maternal illness and pesticide exposure in pregnancy and during the prenatal stage were associated with an increased risk for pediatric-onset MS.
Puberty also may be a turning point for the initiation of MS in boys, said Dr. Chitnis. “Younger males with MS show evidence of earlier puberty than regional controls. It is unclear if they have lower testosterone, however, research does suggest a disturbance in sex hormones early on,” she said.
Testosterone as an MS Therapy?
Several benefits have been associated with testosterone as a potential therapy, such as improved libido, increased muscle strength, improved bone density, and potentially improved memory and other cognitive measures. However, there are serious risks associated with testosterone therapy such as an increased prostate specific antigen, increased susceptibility to cancer, emotional lability, hypertension, increased hemoglobin, and increased cardiovascular events.
There may be benefits with regard to slowing disease progression and cognitive decline that warrant further study, said Dr. Chitnis. She added that future studies should focus on “mechanisms and interactions of sex hormones and testosterone in boys with MS, as well as safety and efficacy of testosterone in men with MS.”
Bove R, Malik MT, Diaz-Cruz C, et al. The 2D:4D ratio, a proxy for prenatal androgen levels, differs in men with and without MS. Neurology. 2015;85(14):1209-1213.
Kalincik T, Vivek V, Jokubaitis V, et al. Sex as a determinant of relapse incidence and progressive course of multiple sclerosis. Brain. 2013;136(Pt 12):3609-3617.
Raghavan K, Healy BC, Carruthers RL, Chitnis T. Progression rates and sample size estimates for PPMS based on the CLIMB study population. Mult Scler. 2015;21(2):180-188.
Ziehn MO, Avedisian AA, Dervin SM, et al. Therapeutic testosterone administration preserves excitatory synaptic transmission in the hippocampus during autoimmune demyelinating disease. J Neurosci. 2012; 32(36):12312-12324.