MECHANISMS OF SIGNAL-TRANSDUCTION - SEX-HORMONES, THEIR RECEPTORS ANDCLINICAL UTILITY

From the first moment of development in the uterus, the human embryo i s 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 synt hesizes different sex hormones at various stages of the reproductive c ycle beginning with estradiol-17 beta formation in the ovary. In pregn ancy, estriol is the principal estrogen produced by the fetal-placenta l unit. After menopause, estrone is synthesized from androstenedione a nd dehydroepiandrosterone, androgenic compounds that serve as precurso rs of the estrogens. When ovarian function has ceased in the postmenop ausal woman, estrone is formed in peripheral organs, particularly adip ose tissue under the control of the enzyme aromatase. The conjugated e strogens, secreted as glucuronides and sulfates, are also naturally oc curring compounds with weak estrogenic activity. Catechol estrogens re present another class of highly active estrogenic compounds discovered in the central nervous system. Although the concentrations of the cat echol estrogens are low in relation to those of ovarian estrogens, the y appear to play an important role in the evolvement of sexual behavio r and possibly in cancer development. Many women are also exposed to o ther naturally occurring estrogens such as those of equine origin (Pre marin(R)) used in the treatment of perimenopausal symptoms. The charac teristic responses occurring in hormone-target tissues such as the ute rus and breast are produced as a result of estrogens and progestins as sociating with their intracellular cognate receptor proteins. These re ceptor molecules, which bind sex hormones with high affinity and speci ficity, are absolute biologic prerequisites for a cell to respond to t he naturally occurring hormones. If the receptor proteins are not expr essed in a target cell or if their structures are severely altered, fe male sex hormones will be unable to produce the normal developmental r esponses that occur in a woman throughout her life. Sex hormone and pe ptide hormone receptor levels vary with the tissue of origin and its s tage of differentiation as well as with a woman's age and endocrine st atus. Even the administration of drugs will alter receptor protein lev els in the body, thereby changing a person's sensitivity to sex hormon es or sex hormone mimics. Our understanding of the mechanisms of signa l transduction and the absolute requirement of a receptor protein for expression of a hormone's action opened a new era of application in cl inical chemistry. It is now accepted that enzyme immunoassay and ligan d-binding measurements of estrogen and progestin receptors in human br east, endometrial, and ovarian carcinomas assist in predicting patient response to administrative hormone therapies such as tamoxifen (Nolva dex(R)) and medroxyprogesterone acetate (Provera(R)). Furthermore, sex hormone receptor levels in biopsies of these carcinomas are related t o patient prognosis in that the presence of elevated estrogen and prog estin levels indicates the likelihood of an increased disease-free int erval and overall survival. Advances in technologies, such as the gene ration of sequence-specific monoclonal antibodies, synthesis of [I-125 ] labeled ligands of high specific radioactivity, DNA-band shift assay s, gene cloning, polymerase chain reactions, and cell-based bioassays using recombinant DNA approaches, have revealed details of the mechani sms of signal transduction of the regulatory proteins in the steroid h ormone receptor/thyroid hormone receptor superfamily. The ability of t he estrogen receptor to bind a variety of structurally diverse compoun ds can be exploited in a clinically useful way to treat cancer, and ye t it can be harmful if an endocrine-disrupting agent from the environm ent associates with the receptor molecule. This new knowledge holds pr omise that other discoveries relating signal transduction defects to d isease expression will improve treatment modalities before the century concludes.