Androgen Dependent Mammary Gland Virilism in Rats Given the Selective Estrogen Receptor Modulator LY2066948 Hydrochloride

Abstract

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 ≥ 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.

Mammary Gland Evaluation in Juvenile Toxicity Studies

“…16 were characterized in the female HSD rat in these studies. Once the male reached sexual maturity there was a structural change of the mammary gland from a tubuloalveolar to a lobuloalveolar structure, which has been previously described in other adult rat strains, but the precise mechanism(s) for the slowed growth and shift in morphology is unknown (Cardy 1991, Rudmann et al 2005, Lucas et al 2007). …”

“…On the other hand, mammary glands of rodents exhibit several sex-associated structural differences. Male rats have branched mammary epithelium present at birth, though they have been reported to be smaller in size than those of females, and the mammary epithelium of sexually mature males have a permanent lobuloalveolar structure (Cardy 1991, Rudmann et al 2005). Male mice undergo an embryonic regression of the mammary gland buds on embryonic day (E)14 due to an androgen surge.…”

Proliferative and Nonproliferative Lesions of the Rat and Mouse Mammary, Zymbal’s, Preputial, and Clitoral Glands

“…PRL, estrogen, and progesterone are the predominant hormones controlling rodent TEB development to lobular alveolar structures in the virgin rodent (Richards et al 1983). In rats, these hormones are also important in influencing adult mammary gland morphology (Rudmann et al 2005;Lucas et al 2007). As discussed earlier, androgens contribute to the development of both the rat and the mouse mammary gland, and in the adult rat, androgens produced by the ovary effect mammary gland morphology in both the male and the female.…”

“…Alveoli are predominant in the male and also lined by a stratified epithelium. Imbalance of mammotrophic hormones like PRL, estrogens, and androgens may result in the male and female rat mammary gland converting to the morphologic appearance expected of the opposite sex (Rudmann et al 2005;Lucas et al 2007 (Kumar et al 2010). Irregularity of epithelial cell arrangement may be observed in the ductular or alveolar epithelium in the process of regeneration.…”

On-target and Off-target-based Toxicologic Effects

“…(Mutlib et al 2000) Are there differences in anatomy and physiology that may esxplain the species difference? (Rudmann et al 2005) Are there differences in target biology and/or expression distribution in the sensitive species that may explain the species differences? (Morris et al 2010;Waser et al 2011) Are there differences in the affinity of the test agent with the affected tissue or cell type or pathway that may explain the species differences?…”