Estrogen-containing medicines have been used successfully for the past 50 years for the treatment of conditions associated with menopause. Although initially considered a reproductive hormone, millions of years of clinical exposure to estrogen(s) have indicated that its influence extends to a variety of target tissues not generally considered to be involved in reproduction. Specifically, estrogen has positive actions in the skeleton, the cardiovascular system and possibly the central nervous system, activities that combine to have a positive impact on mortality and morbidity. However, despite the medical benefits afforded by estrogen replacement therapy, the number of women who initiate or remain on therapy for longer than one year is relatively small. This is due in part to the fear that estrogens increase the risk for breast cancer. Consequently, it was realized several years ago that novel estrogen receptor modulators were needed, which would retain the beneficial effects of estrogens in most target organs but be inactive in the breast. Although the perfect tissue-selective estrogen remains to be identified, progress in this direction has been made. In the past year, for example, we have seen selective estrogen receptor modulators (SERMs) enter into the clinic for the prevention of osteoporosis. Compounds of this class, which function as estrogens in the skeletal system but oppose estrogen action in the breast, are the first step in developing the perfect hormone replacement therapy. This review summarizes the complex pharmacology of the SERMs and illustrates how they differ mechanistically from estradiol, the physiological ligand of the estrogen receptor.

The Molecular Pharmacology of SERMs.

Aromatase, 17β-hydroxysteroid dehydrogenase and intratissular sex hormone concentrations in cancerous and normal glandular breast tissue in postmenopausal women

This study investigates the direct estrogen receptor interactions and the character of the biological activities of three estrogenic resorcylic acid lactones in the immature rat uterus. These compounds are fungal metabolites (P-1492; zearalenone) or derivatives thereof (P-1496 and P-1560; epimeric zearalanols) that have been associated with estrogenizing syndromes in cattle fed mold-infected grain. The compounds compete with estradiol for binding to the cytoplasmic receptor (P- 1496, 13.6%; P-1492, 1.8%; P-1560, 0.8% that of estradiol), and they translocate estrogen receptor sites to the nucleus, with P- 1496 showing the most prolonged nuclear receptor interaction. The three compounds induce the synthesis of the uterine induced protein (P-1496 > P-1560 > P-1492) and increase uterine weight. Direct binding studies with the most potent compound P-1496, in tritium-labeled form indicates a Kd of 1.8 nM (compared to 0.12 nM for estradiol) for interaction with uterine cytoplasmic receptor. Cytoplasmic receptor ...

Zearalenones: Characterization of the Estrogenic Potencies and Receptor Interactions of a Series of Fungal β-Resorcylic Acid Lactones*

Publisher Summary This chapter describes the mechanisms by which estrogens and antiestrogens regulate the growth of reproductive tissues and of tumors that develop in reproductive tissues During the normal development of the rat, uterine growth takes place over a period of several weeks; however, one can induce this growth in a dramatic fashion simply by injecting a dose of estrogen into an immature rat This hormone-induced uterine growth, which occurs over a period of a few days, involves increases in all metabolic activities and increased water uptake, vascularization, and cell division After exposure to estrogen, the steroid binds to the cytoplasmic receptor present in the target cell The cytoplasmic receptor becomes localized in the nucleus, and the nuclear receptor interacts with chromatin in a manner such that a whole series of biochemical and physiological responses are elicited as long as the level of hormone is adequate Hence, the tissue responds and a part of this response entails the replenishment of cytoplasmic receptor that renews the capacity of the tissue to respond further to hormone This replenishment of cytoplasmic receptor is believed to occur both by the resynthesis of receptor and by the recycling of some receptor from the nucleus back to the cytoplasmic compartment When an antiestrogen or a more active metabolite of the antiestrogen enters the target cell, it also binds to the cytoplasmic receptor The antiestrogen–receptor complex does move into the nucleus and binds to chromatin, but its nuclear interaction must be different because it initiates only some responses In some tissues, like the chick oviduct, it does not appear to evoke any estrogen-like responses, although the receptor does localize in the nucleus After antiestrogen, cell division eventually becomes arrested and likewise there is no net increase in receptor content in the tissue

Estrogen and Antiestrogen Action in Reproductive Tissues and Tumors

Publisher Summary This chapter discusses the cellular receptors and mechanisms of action of steroid hormones. The chapter covers those aspects related to the action of estrogens, androgens, progestins, glucocorticoids, and mineralocorticoids in vertebrates. The search for receptor proteins for these steroid hormones in most instances follows a unique pattern which includes (1) study of the uptake and retention of a radioactive hormone; (2) identification of the hormone presumed to be the active form; (3) detection and isolation of a specific protein that binds an active steroid but not an inactive steroid with a high affinity, and exists in larger amounts in target cells than in insensitive cells; and (4) demonstration that steroid antagonists can interfere with receptor binding of an active steroid. Studies on steroid receptors have been recently extended to several more biodynamic aspects such as qualitative and quantitative analysis of receptor proteins and their relation to biological responses of target cells and to some clinical situations. Concentrated efforts, however, are being made to discover the molecular mechanism whereby a steroid receptor complex may participate in the regulation of gene expression of the target cells. For this reason extensive studies have been carried out on the interaction of the steroid-receptor complex and the nuclear components of target cells. The chemical structures of many representative steroid hormones, natural or synthetic, and their antagonists are shown.

Cellular receptors and mechanisms of action of steroid hormones.

Estrone and estriol, as well as 17(β- estradiol, can induce the synthesis of an estrogenspecific uterine protein under appropriate in vitro conditions. Quantitatively, the induction for all three steroids closely parallels the specific uptake of the steroid into the nuclear fraction. This in turn appears to closely correlate with the relative affinity for the cytoplasmic estrogen binding protein (17β-estradiol > estriol > estrone). For 50% of maximal induced protein response or for half saturation of nuclear or cytosol binding sites, approximately three times as much estrone as estradiol and two times as much estriol as estradiol (estradiol = 2 X 10-9M) is required. Estriol is not metabolized to estradiol to any degree; metabolism of estrone to estradiol does not account for either the in vitro response or nuclear localization. It is concluded that estrone, in its own right, is a biologically active estrogen. (Endocrinology 92: 125, 1973)

Thomas S. Ruh

Papers

Estrone interaction with the rat uterus: in vitro response and nuclear uptake.