Endocrine Abstracts

Global knockout models of the androgen receptor (ARKO) illustrates the many roles androgens and their receptor have in the development of male reproductive organs and the gender differences in many features like the musculoskeletal system. However, neither the global ARKO nor orchidectomy models discriminate between direct and indirect effects of androgens. To determine direct and indirect effects of androgens on muscle, we developed a muscle-specific ARKO (called satARKO for satellite cell-specific ARKO). In this model, we found a partial loss of androgen-responsiveness of the levator ani as well as of other muscles. However, there is still an important response to orchidectomy in the muscle of satARKO, which is corrected by administration of testosterone, dihydrotestosterone or the selective androgen receptor modulator Enobosarm. Surprisingly, myostatin is one of the most responsive genes in mouse muscle and we identified the androgen-regulated enhancer involved. This is counterintuitive as myostatin is a well known negative regulator of muscle mass. We propose that myostatin upregulation serves to mitigate the proliferative response to androgens. Similarly, the ARKO in bone cells did not replicate the ARKO phenotype. We are now looking at kidney and brain as suspects for the indirect effects of androgens on the musculoskeletal system.

The observation that in human serum, sex steroids bind with high affinity to sex hormone binding globulin (SHBG) led to the contested free hormone hypothesis. Unfortunately, rodent models do not have the higher serum levels of sex hormone binding globulin seen in humans. We studied the free hormone hypothesis in a mouse model which overexpresses SHBG in its circulation.

DOI: 10.1530/endoabs.54.IS8