From the first moment of development in the uterus, the human embryo is exposed to a variety of hormones. Both steroid and peptide hormones play essential roles in the development and differentiation of organs, culminating in a normal functioning individual. The human female synthesizes different sex hormones at various stages of the reproductive cycle beginning with estradiol-17 beta formation in the ovary. In pregnancy, estriol is the principal estrogen produced by the fetal-placental unit. After menopause, estrone is synthesized from androstenedione and dehydroepiandrosterone, androgenic compounds that serve as precursors of the estrogens. When ovarian function has ceased in the postmenopausal woman, estrone is formed in peripheral organs, particularly adipose tissue under the control of the enzyme aromatase. The conjugated estrogens, secreted as glucuronides and sulfates, are also naturally occurring compounds with weak estrogenic activity. Catechol estrogens represent another class of highly active estrogenic compounds discovered in the central nervous system. Although the concentrations of the catechol estrogens are low in relation to those of ovarian estrogens, they appear to play an important role in the evolvement of sexual behavior and possibly in cancer development. Many women are also exposed to other naturally occurring estrogens such as those of equine origin (Premarin(R)) used in the treatment of perimenopausal symptoms. The characteristic responses occurring in hormone-target tissues such as the uterus and breast are produced as a result of estrogens and progestins associating with their intracellular cognate receptor proteins. These receptor molecules, which bind sex hormones with high affinity and specificity, are absolute biologic prerequisites for a cell to respond to the naturally occurring hormones. If the receptor proteins are not expressed in a target cell or if their structures are severely altered, female sex hormones will be unable to produce the normal developmental responses that occur in a woman throughout her life. Sex hormone and peptide hormone receptor levels vary with the tissue of origin and its stage of differentiation as well as with a woman's age and endocrine status. Even the administration of drugs will alter receptor protein levels in the body, thereby changing a person's sensitivity to sex hormones or sex hormone mimics. Our understanding of the mechanisms of signal transduction and the absolute requirement of a receptor protein for expression of a hormone's action opened a new era of application in clinical chemistry. It is now accepted that enzyme immunoassay and ligand-binding measurements of estrogen and progestin receptors in human breast, endometrial, and ovarian carcinomas assist in predicting patient response to administrative hormone therapies such as tamoxifen (Nolvadex(R)) and medroxyprogesterone acetate (Provera(R)). Furthermore, sex hormone receptor levels in biopsies of these carcinomas are related to patient prognosis in that the presence of elevated estrogen and progestin levels indicates the likelihood of an increased disease-free interval and overall survival. Advances in technologies, such as the generation of sequence-specific monoclonal antibodies, synthesis of [I-125] labeled ligands of high specific radioactivity, DNA-band shift assays, gene cloning, polymerase chain reactions, and cell-based bioassays using recombinant DNA approaches, have revealed details of the mechanisms of signal transduction of the regulatory proteins in the steroid hormone receptor/thyroid hormone receptor superfamily. The ability of the estrogen receptor to bind a variety of structurally diverse compounds can be exploited in a clinically useful way to treat cancer, and yet it can be harmful if an endocrine-disrupting agent from the environment associates with the receptor molecule. This new knowledge holds promise that other discoveries relating signal transduction defects to disease expression will improve treatment modalities before the century concludes.
