The last 50 years has seen an exponential rise in the published reports about estrogen action. The model to describe the early events in the mechanism of action of estrogens via the estrogen receptor is updated in this paper to incorporate some of the recent data on the subcellular localization of the receptor. New evidence suggests that the receptor is a nuclear protein, so it appears that estrogens must first diffuse into the nuclear compartment to initiate estrogen action via the receptor complex. This review traces the development of potent estrogenic compounds by the study of their structure-activity relationships. Studies of structure-activity relationships in vivo using Allen Doisy or 3-day uterine weight tests can provide much valuable information, but the assays suffer from the complex problems of pharmacokinetics and metabolic transformation. Studies in vitro using primary cultures of rat pituitary or uterine cells to assay the ability of a compound to induce prolactin synthesis or progesterone receptor synthesis, respectively, can provide essential information about the structural requirements for a compound to produce estrogenic effects. Nevertheless, it should be pointed out that studies in vivo are required to determine whether a compound is metabolically activated to an estrogen. Estrogen receptor binding models are presented to describe the changes in a molecule that will predict high affinity for the ligand and agonist, partial agonist and antagonist properties of the ligand-receptor complex. Most estrogenic pesticides and phytoestrogens comform to the predictions of the estrogen receptor binding model.

Intravenous infusion of L-tryptophan (LTP) in 18 normal subjects produced a significant increase in plasma prolactin (PRL), growth hormone (GH), and self-ratings of drowsiness. There was no correlation between the PRL and GH responses, or between the hormonal responses and drowsiness. Saline infusion did not result in endocrine or psychological changes. The effect of LTP on both PRL and GH was dose-related in that LTP 7.5 g produced greater endocrine responses than 5.0 g. It was not significantly decreased by cyproheptadine, a 5-HT receptor antagonist. Schizophrenic patients receiving neuroleptics had increased PRL response to LTP, possibly because of the drug-induced disinhibition of PRL release. Their GH response to LTP was markedly decreased. The mechanism of this effect requires further investigation.

The last 50 years has seen an exponential rise in the published reports about estrogen action. The model to describe the early events in the mechanism of action of estrogens via the estrogen receptor is updated in this paper to incorporate some of the recent data on the subcellular localization of the receptor. New evidence suggests that the receptor is a nuclear protein, so it appears that estrogens must first diffuse into the nuclear compartment to initiate estrogen action via the receptor complex. This review traces the development of potent estrogenic compounds by the study of their structure-activity relationships. Studies of structure-activity relationships in vivo using Allen Doisy or 3-day uterine weight tests can provide much valuable information, but the assays suffer from the complex problems of pharmacokinetics and metabolic transformation. Studies in vitro using primary cultures of rat pituitary or uterine cells to assay the ability of a compound to induce prolactin synthesis or progesterone receptor synthesis, respectively, can provide essential information about the structural requirements for a compound to produce estrogenic effects. Nevertheless, it should be pointed out that studies in vivo are required to determine whether a compound is metabolically activated to an estrogen. Estrogen receptor binding models are presented to describe the changes in a molecule that will predict high affinity for the ligand and agonist, partial agonist and antagonist properties of the ligand-receptor complex. Most estrogenic pesticides and phytoestrogens comform to the predictions of the estrogen receptor binding model.

In treated hypertensive patients plasma melatonin levels were lower in subjects receiving beta‐adrenoceptor blockers than those treated with diuretics. Melatonin concentrations in middle‐aged and young control subjects were similar to each other and to those of the diuretic‐ treated patients. The results suggest that treatment with beta‐ adrenoceptor blockers causes a persistent reduction in plasma melatonin but it is unclear if this finding has clinical implications.

The aim of the study was to determine whether the dihydroxylated antiestrogen LY117018, with a high affinity for the estrogen receptor and low intrinsic estrogenic activity, could inhibit the uterotropic actions of steroidal [estradiol-17 beta (E2)] and nonsteroidal [ICI 3188 and trianisylchloroethylene (TACE)] estrogens in immature rats and also the uterotropic actions of tamoxifen and monohydroxytamoxifen in the ovariectomized mouse and immature rat. In the first series of experiments, LY117018 was compared with monohydroxytamoxifen. Both antiestrogens inhibited the uterotropic actions of E2 (0.32 micrograms daily), ICI 3188 (5 micrograms daily), and TACE (40 and 160 micrograms daily) in a dose-related manner (0.32-82 micrograms daily). The potency of the antiestrogens against E2 and ICI 3188 was similar, however, at higher doses (20.48 and 82 micrograms daily) LY117018 reduced uterine weights to below the lowest level achieved by monohydroxytamoxifen. In contrast, LY117018 was less effective against the long acting estrogen TACE. The competitive interaction of LY117018 with tamoxifen and monohydroxytamoxifen was compared in 3-day ovariectomized mouse and immature rat uterine weight tests. Tamoxifen and monohydroxytamoxifen were fully estrogenic in the mouse (5 micrograms daily) and partially estrogenic in the rat (1.5-20 micrograms daily). LY117018 was a partial estrogen in the mouse and a weekly active partial estrogen in the rat (2.5-120 micrograms daily). LY117018 produced dose-related decreases in the uterine weight increases induced by tamoxifen and monohydroxytamoxifen in both species. However, in the rat, LY117018 was more effective against the less potent compound tamoxifen, at a 6:1 dosage ratio compared with a 24:1 dosage ratio required for the potent compound monohydroxytamoxifen. LY117018 had a short duration of action as an antiestrogen when compared with monohydroxytamoxifen. LY117018 (120 micrograms) was only completely effective as an antiestrogen if administered repeatedly with E2 whereas a single injection of monohydroxytamoxifen (120 micrograms) was sufficient to inhibit fully E2 action in the uterus for up to 4 days. Because LY117018 has a shorter duration of action than monohydroxytamoxifen, a high dosage ratio of LY117018 over monohydroxytamoxifen is required to maintain effective competitive antagonism in the uterus. Overall, these findings suggest that monohydroxytamoxifen and LY117018 probably act through the same mechanism of action via the estrogen receptor.