A selective estrogen receptor modulator (SERM) is a nonsteroidal compound with 
tissue specific estrogen receptor (ER) agonist or antagonist activities. In 
animals, SERMs may produce morphologic changes in hormonally-sensitive tissues 
like the mammary gland. Mammary glands from female rats given the SERM LY2066948 
hydrochloride (LY2066948) for 1 month at >or= 175 mg/kg had intralobular ducts 
and alveoli lined by multiple layers of vacuolated, hypertrophied epithelial 
cells, resembling in part the morphology of the normal male rat mammary gland. 
We hypothesized that these SERM-mediated changes represented an 
androgen-dependent virilism of the female rat mammary gland. To test this 
hypothesis, the androgen receptor antagonist flutamide was co-administered with 
LY2066948 (175 mg/kg) to female rats for 1 month. Female rats given SERM alone 
had hyperandrogenemia and the duct and alveolar changes described here. 
Flutamide cotreatment did not affect serum androgen levels but completely 
blocked the SERM-mediated mammary gland change. In the mouse, a species that 
does not have the sex-specific differences in the mammary gland observed in the 
rat, SERM treatment resulted in hyperandrogenemia but did not alter mammary 
gland morphology. These studies demonstrate that LY2066948 produces 
species-specific, androgen-dependent mammary gland virilism in the female rat.