Essential role of endogenous estrogen in directly stimulating mammary growth demonstrated by implants containing pure antiestrogens.

The mammogenic actions of estrogen, although undisputed, lack definition due to uncertainties concerning the relative importance of systemic vs. local actions of the hormone. In addition to its well known, indirect effects on mammary tissue through pituitary intermediaries such as PRL and GH, recent evidence points to, but does not prove, direct estrogen action on mammary targets. The ability of exogenous estrogen to directly and locally stimulate mammary growth in vivo was previously shown in endocrine-ablated animals using small plastic pellets containing estradiol. The more important question of whether the direct action of endogenous estrogen is required for normal mammary growth and morphogenesis in the endocrine-intact animal is now investigated using direct-acting, slow-release plastic implants containing pure antiestrogens (antiestrogens with no estrogenic properties) inserted into the growth region of mammary glands. Local growth inhibition only in the immediate vicinity of the implants and not in other glands in the same mouse demonstrated the requirement of mammary tissues for endogenous, locally acting estrogen. Local actions of antiestrogens on ducts mimicked the ovariectomy-induced loss of systemic estrogen with respect to time course and morphology, with complete inhibition of ductal growth in 14 days. A second effect, in which locally acting antiestrogens simplified the pattern of ductal branching, was observed in both immature and mature animals. Two distinct mitogenic pathways, one governing ductal elongation and the other ductal maintenance, were thus affected. The inhibitory effects of antiestrogen treatment were fully reversible and not accompanied by obvious cytotoxicity. We conclude from these studies of localized estrogen receptor blockade that with respect to ductal mammogenesis, the action of estrogen is direct (acting at the level of the gland itself) and not primarily through the stimulation of pituitary mammogens.