Testicular hypofunction and multiple sclerosis: Cause or consequence?

Abstract

I read with interest the article by Pakpoor and colleagues investigating the risk of hospital admission for multiple sclerosis (MS) after admission for testicular hypofunction. 1Although interesting, the study is far from proving a causal effect of testicular hypofunction on MS risk. Given that there is a negative age-adjusted correlation with testosterone levels and disability, 2 it would be interesting if the authors couldshow that the patients with admissions for testicular hypofunction and then MS did not have any admissions that could be related to MS prior to the testicular hypofunction admission. Furthermore, it would also be of interest to see the risk for testicular hypofunction admission after being admitted for MS. Depending on the results of these investigations, this would shed further light on a causal or consequential role of testosterone in MS. Potential Conflicts of InterestNothing to report. We thank Dr Voci for his comments on our article reporting that male subjects with testicular hypofunction (TH) have a 5-fold higher rate of subsequent multiple sclerosis (MS). The possibility of reverse causality whereby MS may cause TH is an important consideration. However, in all the cases reported by us, the time lapse between the first episode of day-case care or hospital admission for MS occurred at least 1 year after the first episode of day-case care or hospital admission for TH, making a reverse sequence of events unlikely. Furthermore, using the same methodology and reference cohort as in our original study, we analyzed the data set for the risk of TH following an admission for MS. The rate ratio was 1.07 (95% confidence interval 5 0.43-2.2, p 5 0.98), based on 7 observed and 6.6 expected cases.Dr Voci also felt it important that we demonstrate that patients admitted with TH who were subsequently admitted for MS did not have any prior admissions that could have been related to MS. We agree with Dr Voci and, in our article, we did this by excluding all subjects from the TH cohort who had any episode of day-case care or admission for MS at the same time as, or before, their first admission for TH. In the data here, on MS before TH, a concurrent or previous admission for TH before MS was excluded, thus ensuring that in considering both analyses (TH before MS, and MS before TH) no one was double-counted. Repeating our study using other diagnoses, symptoms, or signs suggestive of MS prior to TH would be a complex undertaking given the considerable variety of ways in which MS can present.We hope our study of an association between TH and subsequent MS stimulates further work to confirm or refute our findings. We cannot establish causation, which would require a different study design, but our findings are consistent with a hypothesis that supports a role for low testosterone levels in the complex causative cascade underlying MS.

Effect of Multiple Sclerosis and Its Treatments on Male Fertility: Cues for Future Research

“…These findings are in agreement with the fact that age at diagnosis in men is higher than in women, and that this age corresponds with the age when testosterone levels start to decline [37]. However, it is not possible to discriminate whether there is a causal relationship, a longitudinal association, or if the results are only a casualty [38]. An increased risk of MS has been reported in transgender women after hormonal transition that suppresses testosterone levels [39], suggesting a protective role of the hormone.…”

The Adaptive Immune System in Multiple Sclerosis: An Estrogen-Mediated Point of View

“…Epidemiological studies have shown differences in the prevalence and progression of the disease between men and women. The relapsing forms of MS are more frequent in young women [20]; the disease in men usually develops at an older age, with a more severe and progressive course, possibly in relation to an incipient decline in androgen secretion [21]. Moreover, the relapse rate decreases during late pregnancy as hormonal secretions increase [22].…”

Host Genetics and Gut Microbiome: Perspectives for Multiple Sclerosis

“…Epidemiology studies have shown a sex difference in the prevalence and progression of the disease: MS has a 2:1~3:1 female to male ratio [4]. The relapsing form of MS is more frequent in young women [5] while in men MS shows higher incidence at older ages and a more severe progressive course [6].…”