Androgen mediated pleiotropy?

The case for diverse pathological effects arising from androgen-mediated pleiotropic mechanisms is increasingly clear beyond conditions already discussed such as PCOS and SBMA. The AR and its role in health is a fast-expanding research area of high priority ​(Takayama, 2017)​. The largest genome-wide association study to date in AGA research established a statistically significant positive association between AGA and other age and androgen related traits such as bone mineral density and early puberty, supporting a case for an androgen mediated pleiotropy underlying multiple conditions, as proposed by Yap et al ​(Yap et al., 2018)​. Considering the common androgenic pathogenesis of both AGA and BPH, Ramsamy et al. found that as the grade of AGA increased, there was an increase in the size of the prostate, with 66.7% of men evaluated experiencing severe AGA having an enlarged prostate ​(Subramaniyan et al., 2016)​. AGA patients are more prone to prostate enlargement and related symptoms ​(Monib et al., 2018)​.

Pleiotropic epigenetic factors can mediate a multi-system and clinically significant repression of AR expression. AIS type II is a type of Androgen Insensitivity Syndrome that presents clinically without mutation in the AR gene sequence ​(N. C. Hornig et al., 2016)​. Fewer than 40% of patients with diagnosed Partial AIS exhibit AR gene mutation, suggesting epigenetic involvement in androgen-insensitive phenotypes without sequence alterations. Hornig et al. recently provided a molecular diagnosis for the clinical presentation of AIS type II. Identifying significant reduction in AR mRNA levels in the genital fibroblasts of 57% of the cases, they additionally demonstrated methylation levels of two CpG sites in the proximal AR promoter region inversely correlated significantly to the expression of AR mRNA expression levels ​(Nadine C Hornig et al., 2018)​.

Noting the incomplete understanding of major chronic disease and the advancing understanding of the effects of androgens on major contributors to global mortality including immune function, cancer, cardiovascular disease and diabetes, Schooling considered the potential for androgens to be considered in a pleiotropic context to explain the higher vulnerability to disease mortality and earlier death observed in males than women. She suggests that “considering androgens as potential contributors to major diseases represents a major paradigm shift that flies in the face of individual level data from observational studies”, and that a “rethink of the role of androgens, particularly, in immune function, cancer and cardiovascular disease, as potentially providing an underlying explanatory mechanism that could address the noted sex disparity in life expectancy, help identify new specific targets of intervention, explain unexpected side effects of commonly used drugs and eventually provide targets for precision medicine” ​(Schooling, 2015)​. In this context, PFS is likely to provide novel insights and considerable translational benefits to wider biological understanding and of mechanistic factors in better-recognised disease states.

Page Bibliography

  1. Hornig, N. C., Ukat, M., Schweikert, H. U., Hiort, O., Werner, R., Drop, S. L. S., Cools, M., Hughes, I. A., Audi, L., Ahmed, S. F., Demiri, J., Rodens, P., Worch, L., Wehner, G., Kulle, A. E., Dunstheimer, D., Müller-Roßberg, E., Reinehr, T., Hadidi, A. T., … Holterhus, P.-M. (2016). Identification of an AR Mutation-Negative Class of Androgen Insensitivity by Determining Endogenous AR Activity. The Journal of Clinical Endocrinology & Metabolism, 4468–4477. https://doi.org/10.1210/jc.2016-1990
  2. Hornig, Nadine C, Rodens, P., Dörr, H., Hubner, N. C., Kulle, A. E., Schweikert, H.-U., Welzel, M., Bens, S., Hiort, O., Werner, R., Gonzalves, S., Eckstein, A. K., Cools, M., Verrijn-Stuart, A., Stunnenberg, H. G., Siebert, R., Ammerpohl, O., & Holterhus, P.-M. (2018). Epigenetic Repression of Androgen Receptor Transcription in Mutation-Negative Androgen Insensitivity Syndrome (AIS Type II). The Journal of Clinical Endocrinology & Metabolism, 4617–4627. https://doi.org/10.1210/jc.2018-00052
  3. Monib, K. M. E., Hussein, M. S., & Kandeel, W. S. (2018). The relation between androgenetic thin hair diagnosed by trichoscope and benign prostatic hyperplasia. Journal of Cosmetic Dermatology, 1502–1506. https://doi.org/10.1111/jocd.12835
  4. Schooling, C. M. (2015). Could androgens be relevant to partly explain why men have lower life expectancy than women? Journal of Epidemiology and Community Health, 324–328. https://doi.org/10.1136/jech-2015-206336
  5. Subramaniyan, R., Ramsamy, K., & Patra, A. (2016). An observational study of the association between androgenetic alopecia and size of the prostate. International Journal of Trichology, 62. https://doi.org/10.4103/0974-7753.188034
  6. Takayama, K. (2017). The biological and clinical advances of androgen receptor function in age-related diseases and cancer [Review]. Endocrine Journal, 933–946. https://doi.org/10.1507/endocrj.ej17-0328
  7. Yap, C. X., Sidorenko, J., Wu, Y., Kemper, K. E., Yang, J., Wray, N. R., Robinson, M. R., & Visscher, P. M. (2018). Dissection of genetic variation and evidence for pleiotropy in male pattern baldness. Nature Communications. https://doi.org/10.1038/s41467-018-07862-y