DIFFERENTIAL SENSITIVITY OF RAT UTERINE GROWTH AND EPITHELIUM HYPERTROPHY TO ESTROGENS AND ANTIESTROGENS

Triphenylethylene antiestrogens are considered weak estrogen agonists based on their limited ability to induce estrogen responses, in partic ular uterine growth. We compared the uterotrophic activity of naturall y occurring and synthetic estrogens with that of antiestrogens by quan titating uterine wet weight and hypertrophy in the uterine luminal and glandular epithelium. Immature rats received five daily injections of either an estrogen (17beta-estradiol [E2], diethylstilbestrol [DES], or ethynyl estradiol [EE]) or an antiestrogen (tamoxifen [TAM], monohy droxytamoxifen [OH-TAM], or clomiphene citrate [CC]) (0.001-100 mug/ra t/day) subcutaneously in sesame oil and were sacrificed approximately 2 hr after the last injection. Both DES and EE increased uterine weigh t at doses between 0.01-100 mug/rat/day; E2 was about 10-fold less pot ent. The antiestrogens increased uterine weight only slightly. DES, EE , and the three antiestrogens each increased luminal epithelium hypert rophy to over 3-fold above that in controls. While the potencies of th ese synthetic compounds differed (DES = EE > OH-TAM > TAM = CC), each hypertrophic response occurred over two log doses, and the response cu rves displayed identical slopes. E2, however, required a range of four log doses to achieve the same degree of luminal epithelium hypertroph y. The three antiestrogens elicited glandular epithelium hypertrophy u p to 2-fold above controls at the same doses that induced luminal epit helium hypertrophy; the order of potency was OH-TAM > TAM = CC. Howeve r, the three estrogens increased glandular epithelium hypertrophy only marginally. Thus, under dosing conditions commonly used to assess ute rotrophic activity, these ''antiestrogens'' are complete, albeit less potent, estrogen agonists in the luminal epithelium and, unlike estrog ens, induce hypertrophy in the glandular epithelium.