Evolution of the tissue selective estrogen complex (TSEC).

Estrogens mediate gene transcription and signaling of numerous cellular processes in a variety of tissues, including the bone, breast, and endometrium, through binding and activation of estrogen receptors (ERs). Estrogen-mediated ER agonist activity has shown benefit in conditions related to estrogen deficiency in women; however, these effects have been associated with stimulation of breast and uterine tissues. Due to the complexity of ER signaling, selective estrogen receptor modulators (SERMs) can exhibit ER agonist or antagonist activity depending on the target tissue. A newer approach to menopausal therapy, the tissue selective estrogen complex (TSEC), pairs a SERM with one or more estrogens with the goal of maintaining the benefits of estrogens without the stimulatory effects on the breast and uterus. Preclinically, different TSECs have been associated with distinct gene expression profiles compared with each other and with their individual SERM/estrogen components. Studies in cultured breast cancer cells and animal models have demonstrated a lack of estrogen-induced stimulation with TSECs in the mammary gland and endometrium. In the breast, biochemical analyses indicate that degradation of the ER is an important mechanism by which TSECs exert their antagonistic effects. TSECs have also shown positive effects similar to estrogens in other tissue types, including bone and the central nervous system, although mechanisms underlying these activities are less clear. Overall, preclinical studies have shown that estrogens, SERMs, and TSECs each exert distinct and tissue specific molecular and pharmacologic effects.