SELECTIVE ESTROGEN-RECEPTOR MODULATORS - AN ALTERNATIVE TO HORMONE REPLACEMENT THERAPY

Estrogen is a key regulatory hormone, which in addition to its role in reproduction, affects a number of physiological systems, including th e skeleton and cardiovascular system. The important role of estrogen i n various tissues is perhaps most evident in postmenopausal women who, in addition to menopausal symptoms, experience increases in osteoporo sis and coronary heart disease as their estrogen levels decline. Estro gen replacement, while effective against osteoporosis and heart diseas e, produces a number of side effects associated with the breast and ut erus which limits compliance. Selective estrogen receptor modulators ( SERMs), such as raloxifene and tamoxifen, produce beneficial estrogen- like effects on bone and lipid metabolism, while antagonizing estrogen in reproductive tissue. SERMs can be distinguished from each other in reproductive tissue, particularly the uterus, by their activity profi le. For example, while triphenylethylenes like tamoxifen behave as par tial agonists, raloxifene (a benzothiophene) behaves as a complete ant agonist in the uterus. The SERM profile is distinct from that of full estrogens (i.e. 17 beta-estradiol or 17 alpha-dihydroequilenin) which behave as estrogen agonists in all tissues and pure estrogen antagonis ts (i.e. ICI-164,384) which exhibit only an estrogen antagonist profil e in a battery of tissue types. The precise mechanism by which SERMs p roduce this tissue-selective pharmacology remains a question. It is cl ear, however, that for raloxifene, both the estrogen agonist effects o n bone and cholesterol metabolism as well as the estrogen antagonist e ffects in uterine and mammary tissue involve high affinity interaction with the estrogen receptor. The estrogen antagonist activity is media ted via classical pharmacological competition for estrogen receptor bi nding. The estrogen agonist activity, in bane for example, appears to involve novel post-receptor pathways and non-classical estrogen respon se element(s) which are activated by SERMs. These novel response eleme nts may represent natural pathways which respond to estrogen metabolit es in vivo.