Selective androgen receptor modulators (SARMs) have specific impacts on the mouse uterus

Abstract

Selective androgen receptor modulators (SARMs) have been propos ed as therapeutics for women suffering from breast cancer, muscle wasting or urinar y incontinence. The androgen receptor (AR) is expressed in the uterus but the impac t of SARMs on the function of this organ is unknown. We used a mouse model to com pare the impact of SARMs (GTx-007/Andarine(r), GTx-024/Enobosarm(r)), Danazol (a synthetic androstane steroid) and dihydrotestosterone (DHT) on tissue architecture, cell proliferation and gene expression. Ovariectomised mice were treated daily for 7 d ays with compound or vehicle control (VC). Uterine morphometric characteristics were quantified using highthroughput image analysis (StrataQuest; TissueGnostics), protein and gene expression were evaluated by immunohistochemistry and RT-qPCR, respectively. Treatment with GTx-024, Danazol or DHT induced significant increases in body we ight, uterine weight and the surface area of the endometrial stromal and epithelial compartments compared to VC. Treatment with GTx-007 had no impact on these p arameters. GTx-024, Danazol and DHT all significantly increased the percent age of Ki67-positive cells in the stroma, but only GTx-024 had an impact on epithelial cel l proliferation. GTx-007 significantly increased uterine expression of Wnt4 and Wnt7a, whereas GTx-024 and Danazol decreased their expression. In summary, the impact of G Tx-024 and Danazol on uterine cells mirrored that of DHT, whereas GTx-007 had mini mal impact on the tested parameters. This study has identified endpoints that have revealed differences in the effects of SARMs on uterine tissue and provides a templat e for preclinical studies comparing the impact of compounds targeting the AR on endometri al function.