Opportunities for future research

Remarkable progress has been made in SERM development. Profiles of new SERMs indicate great potential for efficacy in the prevention and treatment settings, in more than one physiological system, and with improved risk/benefit ratios. The concept of what is achievable with respect to broad-spectrum disease prevention and what constitutes an "ideal" SERM is likely to undergo considerable reevaluation over time. The development of new, more broadly efficacious SERMs will require continued exploration of the effects of estrogen at the cellular and molecular level in tissues and physiologic systems throughout the body. A better understanding is needed of the mechanisms of the biological actions that are mediated through major forms of the estrogen receptor. High priority must be placed on elucidation of the role of the coregulators of estrogen receptor (ER) action. The quest for a SERM(s) with the "optimal clinical profile" also constitutes a major research challenge with respect to designing clinical trials that are simultaneously parsimonious with respect to time, monetary, and human resources and yet capable of delivering unequivocal outcomes with respect to primary end points. A vigorous research effort is needed to identify highly sensitive and specific surrogate measures to facilitate future clinical studies. Research to identify and validate relevant measures of safety is also essential to inform the risk/benefit balance and, thus, the ultimate usefulness of SERMs and their potential for long-term use. Future advances in the modulation of ER action are likely to have profound effects--not only on diseases and conditions known (or later discovered) to be related to estrogen action, but on the development of paradigms for understanding and modifying the action of other nuclear hormone receptors in the prevention and treatment of additional age- and disease-related pathologies.