• estrogens;
  • conjugated equine estrogen;
  • 17β-estradiol;
  • Alzheimer's disease;
  • cognition;
  • memory

Abstract: Menopause is associated with a significant decline in levels of estrogen, which reportedly leads to several distressing symptoms and adverse health effects on various target tissues including those on bones, heart, and brain. Although effective, the long-term safety and feasibility of therapy with both unopposed and opposed oral conjugated equine estrogen has been questioned by the recent findings of both the Women's Health Initiative (WHI) and the Women's Health Initiative Memory Study (WHIMS). The findings of both these studies have raised several critical issues related to hormone therapy that need to be systematically evaluated in clinical studies. Specifically, these issues relate to the differential efficacy and adverse-effects profile of various forms of estrogen and progestins, the importance of the route of administration of estrogen, the best timing to initiate postmenopausal hormone therapy, and the efficacy of cyclic versus continuous hormone therapy. This article focuses on estrogen and discusses issues related to selecting the best form and route of administration of the hormone. It includes information on basic clinical pharmacology of various forms of estrogen, neuroendocrinology of the menopause, neurobiology of estradiol and estrone, and results of selected basic science and human intervention studies with relevance to identifying the best form and route of administration of estrogen.