NTRODUCTION Isoflavones are naturally occurring plant chemicals belonging to the "phytoestrogen" class; they are currently heralded as offering potential alternative therapies for a range of hormone-dependent conditions, including cancer, menopausal symptoms, cardiovascular disease and osteoporosis. Recent epidemiologic evidence and experimental data from animal studies that have been reviewed recently (Anderson and Garner 1997[] , Cassidy 1996[] , Knight and Eden 1996[] , Messina et al. 1994[] , Murkies et al. 1998[] , Setchell 1995 and 1998[] [] ) are highly suggestive of beneficial effects of isoflavones on human health, but the clinical data supportive of such effects are either not available, or are awaiting the design and execution of appropriate large-scale clinical studies. Nevertheless, data from limited small pilot studies are promising, and this has spurred the current interest in this area. Biological actions.   The isoflavones are strikingly similar in chemical structure to mammalian estrogens (Setchell and Adlercreutz 1988[] ). The phenolic ring is a key structural element of most compounds that bind to estrogen receptors (Leclerq and Heuson 1979[] ). When the structures of the isoflavone metabolite equol and estradiol are overlaid, they can be virtually superimposed; the distance between the hydroxyl groups at each end of both molecules is virtually identical (Fig. 1[] ).On the basis of structure alone, it is not surprising that isoflavones bind to estrogen receptors (ER)3 ; however, their actions are more those of partial estrogen agonists and antagonists, a concept that is difficult to fully understand, but that continues to fascinate steroid biochemists and endocrinologists (Jordon 1990[] , Mendelson 1996[] ). To complicate matters further, estrogens can have nonclassical actions distinct from their classical genomic actions (Brann et al. 1995[] ); these include effects on plasma membranes and on cell signaling pathways (Kim et al. 1998[] ). What this implies from a clinical perspective is that at certain concentrations, which may depend on many factors including receptor numbers, occupancy and competing estrogen concentration, rather than acting as estrogen mimics and initiating estrogen-like actions, they may antagonize and inhibit estrogen action. These effects will also be tissue specific. This phenomenon is a well-known characteristic of steroid action, and is one that has driven pharmacologists to search for new molecules with selective estrogen action. The recently approved drug, Raloxifen, a selective estrogen receptor modulator is an example (Dodge et al. 1997[] ). Structure-activity relationships may provide clues to the molecular basis for this agonism and antagonism (Brzozowski et al. 1997 ), and the absence of a specific lipophilic region in phytoestrogens may affect binding to the ER (Cunningham et al. 1997 ). Differences in the ability of isoflavones to bind to ER, induce estrogen regulated end products and activate cell proliferation in estrogen-sensitive human breast cancer cell lines may help to explain this difference in biological activity. However, predicting the effects of isoflavones in vivo is more difficult because the route of administration, chemical form of the phytoestrogen, its metabolism, bioavailability, half-life, timing and level of exposure, intrinsic estrogenic state and nonhormonal secondary mediated actions of isoflavones also have to be considered in the design of clinical studies investigating their effects. The recent discovery of a second estrogen receptor further complicates our understanding of the mechanism of action of isoflavones (Kuiper et al. 1998 ). Kuiper et al. (1996) cloned a novel member of the nuclear receptor family, named ERß to distinguish it from the "classical" ER subtype, and the two receptors may play different roles in gene regulation (Paech et al. 1997 ). It is conceivable that there will be further estrogen receptors discovered in the future, given that there are a large number of so-called orphan receptors (Willy and Mangelsdorf 1998 ) that have been identified and are awaiting the recognition of specific ligands and function. The tissue distribution (Fig. 2 )and relative ligand binding affinities of the ERß and ER differ, and this finding may help to explain the selective action of estrogens in different tissues. It is fascinating that ERß is found in brain, bone, bladder and vascular epithelia (Kuiper et al. 1997 , Paech et al. 1997 , Tetsuka et al. 1997 ), tissues that are responsive to classical hormone replacement therapy (HRT). Furthermore, the relative molar binding affinities of different estrogenic compounds reveal that phytoestrogens and some environmental xenoestrogens have significantly higher affinities for ERß than ER (Kuiper et al. 1997 ), suggesting that this new receptor may be important to the action of nonsteroidal estrogens. Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.