ESSENTIAL ROLE OF ENDOGENOUS ESTROGEN IN DIRECTLY STIMULATING MAMMARYGROWTH DEMONSTRATED BY IMPLANTS CONTAINING PURE ANTIESTROGENS

The mammogenic actions of estrogen, although undisputed, lack definiti on due to uncertainties concerning the relative importance of systemic vs. local actions of the hormone. In addition to its well known, indi rect effects on mammary tissue through pituitary intermediaries such a s PRL and GH, recent evidence points to, but does not prove, direct es trogen 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 contain ing estradiol. The more important question of whether the direct actio n of endogenous estrogen is required for normal mammary growth and mor phogenesis in the endocrine-intact animal is now investigated using di rect-acting, slow-release plastic implants containing pure antiestroge ns (antiestrogens with no estrogenic properties) inserted into the gro wth region of mammary glands. Local growth inhibition only in the imme diate vicinity of the implants and not in other glands in the same mou se demonstrated the requirement of mammary tissues for endogenous, loc ally acting estrogen. Local actions of antiestrogens on ducts mimicked the ovariectomy-induced loss of systemic estrogen with respect to tim e course and morphology, with complete inhibition of ductal growth in 14 days. A second effect, in which locally acting antiestrogens simpli fied the pattern of ductal branching, was observed in both immature an d mature animals. Two distinct mitogenic pathways, one governing ducta l elongation and the other ductal maintenance, were thus affected. The inhibitory effects of antiestrogen treatment were fully reversible an d not accompanied by obvious cytotoxicity. We conclude from these stud ies of localized estrogen receptor blockade that with respect to ducta l mammogenesis, the action of estrogen is direct (acting at the level of the gland itself) and not primarily through the stimulation of pitu itary mammogens.