Monday, 27 April 2015

AAN 2015: low testosterone level in the womb increase risk of MS

Low androgens in utero linked to increase risk of MS in males #AAN2015 #MSBlog #MSResearch

"I note there has been some recent discussions about testosterone and MS. Two presentations at the AAN link low testosterone levels in utero or early childhood with an increased risk of MS. The first study shows that the ratio of the length of the ring finger to the index finger, the so called 2D:4D ratio, is higher in male MSers than controls. A lower 2D:4D ratio is associated with lower prenatal (before birth) or in utero (in the womb) androgen levels (testosterone is one of the androgens). The second study, done by the brilliant Julia Pakpoor (still in medical school) using NHS hospital records report a strong positive association (a five-fold elevation of rates) between testicular hypofunction and the subsequent development of MS in males. If these studies are correct this is another emerging risk factor that can be targeted when thinking of preventing, or at least lowering, the risk of developing MS. The latter must not be confused with the hypothesis that testosterone may be used as a disease-modifying therapy to treat MS. I am aware that there is emerging evidence for this, but until properly designed and powered studies are done we can't be sure. We also need to be aware that testosterone supplementation comes with risk, the most concerning include cancer and cardiovascular events (myocardial infarction and stroke)."


Study 1

Bove et al. The male 2D:4D digit ratio: a proxy for prenatal androgen exposure and a risk biomarker for multiple sclerosis. AAN 2015: S38.005.

OBJECTIVE: To compare the 2D:4D digit ratio, a proxy for prenatal androgen levels, in men with and without multiple sclerosis (MS).

BACKGROUND: In adult men with MS, low testosterone levels are associated with worse disease severity. We hypothesized that low prenatal androgen levels, during this key period of hormonal modulation, might represent a risk factor for MS. A higher ratio of an individual’s second and fourth digit lengths (2D:4D ratio) may reflect lower prenatal androgen levels. (PNAS 2011 108:16289)

DESIGN/METHODS: We obtained two digital scans of the right hand for 100 men with MS presenting to a scheduled clinic visit, and 130 men without autoimmune disease (HCs). All individuals were aged 18-65, right-handed, and reported no prior hand trauma. Digit length was calculated using digital calipers by two investigators blinded to disease status. The 2D:4D ratio was averaged over the two scans. 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 age of MS subjects was 42.4 and of HCs was 41.3 (p=0.49, two-sample t-test). The mean (SD) 2D:4D ratio was higher in MS patients (0.954 (0.0399)) than in HCs (0.9443 (0.0335)) (adjusted difference= 0.00985; 95% CI: 0.00031-0.0194; p=0.0431). There was no effect of age on these findings in an age-adjusted linear regression. Finally, in the 44 MS patients who had both morning testosterone levels and a 2D:4D ratio available for analysis, there was no correlation between the two measures (Pearson’s r = 0.07, p = 0.6507).

CONCLUSIONS: In this study, male MS patients had a higher 2D4D ratio than HCs, 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.

STUDY SUPPORTED BY: NMSS, American Brain Foundation.

Study 2

Pakpoor et al. Testicular Hypofunction and Multiple Sclerosis Risk: A Record-Linkage Study. AAN 2015: P1.101.

OBJECTIVE: To investigate a potential association between testicular hypofunction (TH), as a proxy for low testosterone levels, and multiple sclerosis (MS) risk.

BACKGROUND: Gender is an important factor influencing MS risk. MS in males typically onsets at a later age, which coincides with an age-related decline in testosterone.

DESIGN/METHODS: We analysed linked English national Hospital Episode Statistics from 1999 to 2011. A TH cohort of 5049 males was constructed by identifying the first episode of day-case care or hospital admission in which TH was coded. A reference cohort (3.4 million males) and obesity cohort (given the possibility of obesity being a confounding factor) were constructed in similar ways. We searched for any subsequent day-case or inpatient admission for, or death from, MS in these cohorts. We calculated rates for MS, stratified and then standardized by age, sex, calendar year of first recorded admission, region of residence, and socio-economic status. Further, using the same methodology we analysed the dataset for the risk of TH following MS.

RESULTS: The standardised rates of MS were 37.79 per 100,000 person-years in the TH cohort and 8.17 per 100,000 person-years in the reference cohort. The adjusted rate ratio (RR) was 4.62 (95% confidence interval 2.30-8.24, p<0.0001). In the TH cohort, all MS cases occurred more than one year after the first TH episode. The RR of MS following obesity in males was 1.47 (95% CI 1.20-1.80, p=0.0001). The difference is significant and obesity is unlikely to be an important confounder. The RR of TH following an admission for MS was 1.07 (95% CI 0.43-2.2, p=0.98).

CONCLUSIONS: We report a strong positive association (a five-fold elevation of rates) between TH and subsequent MS in males. This is the first human study to link low testosterone to increased MS risk and future work should characterize the relationship.

CoI: this study was performed by members of team G


  1. So is there no role for genetics in how your fingers relate to each other? Do all women have a high 2D:4D ratio?

  2. Profs interesting study ... It could then draw a parallel to the estrogen in women? And there would indeed be a relationship of contraceptive use and the development of MS in women?


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