A. Gulino

Anti-estrogens in fetal and newborn target tissues

The antagonistic effects of progesterone and of the anti-estrogens, tamoxifen and nafoxidine, to estrogen responses were studied in the target tissues of fetal and newborn guinea pigs. In the fetal uterus, progesterone inhibits the stimulatory effect provoked by estradiol on uterine growth, on progesterone receptor and on the acetylation of nuclear histones. Progesterone also blocks the synthesis of new progesterone receptor protein in organ culture. Tamoxifen or nafoxidine (1 or 10 mg/kg/day injected to the mother for 3 days) provoke a uterotrophic effect similar to that of estradiol (1 mg/kg/day injected to the mother for 3 days) but these anti-estrogens have a limited effect on the progesterone receptor. Tamoxifen given together with estradiol antagonizes the effect of the estrogen on the acetylation of histones but the anti-estrogens do not block the effect of estradiol on uterine growth. Histological studies show that both estradiol and tamoxifen provoke a dramatic hypertrophic and hyperplastic effect particularly in the uterine epithelium. In the newborn uterus (6-day old), tamoxifen (s.c. injection of 0.6 micrograms/g body weight) and estradiol (injection of 30 ng/g body weight) provoke a similar uterotrophic effect and both have a limited effect on the progesterone receptor. In the fetal thymus estradiol provokes a selective decrease in the larger and actively proliferating lymphoid cells of the cortical zone. Tamoxifen has a similar effect but to a much lesser extent than estradiol. On the other hand, tamoxifen antagonizes the effect of estradiol on this fetal tissue. It is concluded that during fetal life progesterone antagonizes the effect of estradiol but tamoxifen can act as an agonist or an antagonist of estrogen action which is a function of the type of response or organ considered.

Heterogeneity of Binding Sites for Triphenylethylene Antiestrogens in Estrogen Target Tissues

Most of the interest in understanding the mechanism of action of triphenylethylene antiestrogens (Fig. 1) arises from their ability to induce weak estrogenic effects, to antagonize many of the actions of estrogens and to induce the remission of human breast cancer particularly during the post-menopausal period (Legha et al., 1978). In particular, these compounds are able to suppress estrogen-induced uterine growth (Jordan et al., 1977) and to antagonize estrogen-induced growth of human breast cancer cells which contain estrogen receptor (Lippman et al., 1976). In this regard, triphenylethylene antiestrogens are used for understanding the mechanism by which estrogens regulate cell growth. However, triphenylethylene antiestrogens are also able to inhibit the growth of estrogen sensitive and estrogen receptor containing human breast cancer cells, even in the absence of estrogens (Lippman et al., 1976). The attempt to understand the mechanism of action of both estrogen and antiestrogens awaits the elucidation of the molecular events and interactions which occur at the subcellular and cellular level. In recent years, multiple interactions of triphenylethylene antiestrogens have been reported at the subcellular level: a) the interaction with the estrogen receptor system (Terenius, 1971; Lippman et al., 1976; Horwitz and McGuire, 1978), and b) the binding of these compounds to specific binding sites distinct from the estrogen receptor in several experimental models such as the chick oviduct (Sutherland and Foo, 1979), rat uterus (Faye et al., 1980), fetal guinea pig uterus (Gulino and Pasqualini, 1980), human mammary cancer (Sutherland and Murphy, 1980) and human myometrium (Kon, 1983). The aim of this paper is to summarize the data so far known about the interactions of triphenylethylene antiestrogens with target cells at the subcellular level.