Actions of estrogen and estrogen receptors in nonclassical target tissues.

Hormonal effects on classical endocrine target organs such as the female reproductive tract, mammary gland, ovary, and neuroendocrine system have been thoroughly studied, with significant advancements in our understanding of estrogen actions and disease conditions from both cell culture as well as new experimental animal models. Knowledge of the highly appreciated effects of estrogen in nonclassical endocrine organ systems, arising from epidemiological and clinical findings in the cardiovascular, immune, GI tract, and liver, is only now becoming clarified from the development and use of knock-out or transgenic animal models for the study of both estrogen and ER activities. There are considerable epidemiological data showing that premenopausal females (Barrett-Connor 1997; Crabbe et al. 2003) have reduced risk for cardiovascular disease. However, a recent large clinical trial failed to show cardioprotection for postmenopausal females on estrogen-progestin replacement (Rossouw et al. 2002). In fact, the Women's Health Initiative Study showed increased cardiovascular risk for females taking an estrogen-progestin combination. These studies suggest that we need a better understanding of the mechanisms responsible for cardioprotection in females.