The 2D:4D Ratio, a Proxy for Prenatal Androgen Levels, Differs in Men with Multiple Sclerosis

Background: The prenatal period is increasingly understood as a period of vulnerability to subsequent development of multiple sclerosis (MS). The ratio of an individual’s second and fourth digit lengths (2D:4D) reflects digit growth that is highly influenced by the ratio of prenatal androgen to estrogen levels (PNAS 2011 108:16289). In MS, low testosterone has been linked with MS risk in adult men, but the effect of prenatal androgen levels on susceptibility to autoimmune diseases have not been explored.

Objectives: To assess the hypothesis that the 2D:4D ratio is increased in men with MS relative to men without MS. Secondarily, to assess whether the 2D:4D ratio, in men with MS, is associated with clinical features of a more aggressive course. 

Methods: We obtained digital scans of the right hand for 138 men with MS and 145 men without autoimmune disease (non-MS). All individuals were aged 18-65, right-handed, and reported no prior hand trauma. Digit length was calculated using digital calipers. Our primary statistical analysis was a cross-sectional comparison of the 2D:4D ratio between MS subjects and HCs using two-sample t-test.

Results: The mean (SD) 2D:4D ratio was higher in MS (0.9548 (0.040)) than in non-MS subjects (0.9456 (0.0324)) (p=0.035). These findings remained significant after we adjusted for age and race. In MS subjects, the 2D:4D ratio was not correlated with MS type, age at first symptoms, or MS Severity Score (p>0.40 for each); nor was it correlated with adult testosterone levels in a subset of 52 men (r=0.056, p=0.69).

Conclusions: In this study, male MS patients had a higher 2D4D ratio than men without MS, suggestive of lower prenatal androgen levels. These findings support an emerging role of low androgens during key developmental periods as a risk factor for MS.