Tissue Selective Estrogen Receptor-α Agonists for the Prevention of Obesity , Diabetes , and Metabolic Syndrome

Drugs that interact with estrogen receptors (ERs) are commonly prescribed in reproductive medicine. Estrogens are used in contraceptives, fertility regimens, and menopausal hormone therapy (MHT). Whereas the therapeutic benefits of estrogens in contraceptives and fertility treatment are clear, the use of estrogens in MHT has become increasingly controversial with the findings of the Women’s Health Initiative (WHI) trial.1–3 Prior to the WHI, MHT was the second most frequently prescribed medication in the United States. Since the publication of the results of the WHI in 2002, the number of women using MHT has declined dramatically.4 Discovering safer estrogens could resurrect MHT for its classic indications and offer a new therapeutic strategy for other conditions associated with menopause. Postmenopausal women have been treatedwith estrogens for symptoms such as hot flashes and urogenital atrophy for 70 years. More recently, MHTwas used to prevent osteoporosis, fractures, and cardiovascular disease. The WHI was the first large randomized clinical trial to assess the risks and benefits of MHT.1,3 The conclusion from the WHI was that the risks exceed thebenefits, with an increase in breast cancer that was the most troublesome finding, particularly because there were no protective effects on heart disease. Whereas the results of the WHI remain controversial due to the design of the trial that enrolled subjects several years after onset of menopause (average age was 63 years), there were several clear outcomes. First, the combination of estrogens and progestins is more detrimental than estrogen treatment alone. Progestins were initially added to block the