Endocrine Abstracts

The uterus is an androgen-responsive tissue and AR is expressed in cells within the endometrium and myometrium. We have demonstrated that treatment of ovariectomised mice with the potent androgen dihydrosterone (DHT) induces a uterotrophic response with changes in expression of genes involved in cell-cycle progression, Wnt signalling and an expansion of the glandular epithelium. Selective androgen receptors modulators (SARMs) are AR ligands in development as potential therapeutic agents for conditions associated with muscle wasting but their tissue-specific effects on the uterus are unknown. In this study we used a uterine bioassay to compare the impacts of SARMs (GTx-007, GTx-024) with Danazol and DHT. Adult female mice (C57BL/6J) were ovariectomised and treated with either (a) vehicle solution [0.4% methycellulose/5% ethanol], (b) DHT, (c) GTx-024 (Ostarine), (d) GTx-007 (Andarine) or (e) Danazol by daily subcutaneous injections for 7 days [n=10–14/treatment group]. Uteri were collected and analysed by RT-qPCR, immunohistochemistry and uterine morphometric analyses. Treatment with DHT, GTx-024 or Danazol significantly increased uterine weight and size; GTx-007 was not uterotrophic. Immunostaining of AR increased in the myometrium, stroma and glandular epithelium following treatment with GTx-024 and DHT, while Danazol increased AR expression only in the endometrial stromal compartment. Endometrial and myometrial cell proliferation was differentially affected by treatments. Expression of candidate AR-regulated genes (Igf1, Wnt4, Wnt7a, Cdh1, Foxa2, Rb1, Mki67, Fgf7) was altered in a treatment-specific manner, with DHT, GTx-024 and Danazol inducing similar expression patterns. Both DHT and GTx-024 stimulated formation of endometrial glands. In summary, while GTx-024 appears to exhibit identical uterine effects to those of DHT, Danazol only partially reflects these changes and GTx-007 appears to have no uterotrophic effects. These results have implications for the use of SARMs in women.