The original report from the Women's Health Initiative (WHI) changed our understanding of the benefits and risks of hormone therapy. Since that time, reanalysis of the WHI and additional data from other studies have further refined these concepts. Here we provide an update on recent advances in the field. Menopausal hormone therapy continues to have a clinical role in the management of vasomotor symptoms. However, our understanding of the role of hormones in cardiovascular disease and breast cancer continues to evolve. Further analyses of the effect of age and proximity to menopause at the time of initiation of therapy, duration of treatment, dose, route of administration, and the persistence of risks and benefits after stopping hormone therapy are described. In addition, recent data have emerged suggesting that there may be a link between hormone therapy and cancers of the lung and ovary. Finally, we discuss new advances in hormone therapy that will likely lead to a more favorable benefit-to-risk ratio, enabling safer effective menopausal symptom relief. O ver the past several decades, a large number of observational studies suggested that the use of hormone therapy in menopause not only relieved vasomotor symptoms, but also reduced the risk of several chronic medical conditions such as osteoporosis and cardiovascular disease. However, in 2002, the results of a prospective randomized trial, the Women's Health Initiative (WHI), demonstrated that many of the benefits identified in observational studies were not present in a population randomized to treatment; some hypothesized that the previously purported benefits may have been due not to the therapy but rather to confounding and selection biases, as well as other methodological limitations. In response to the findings of the WHI and other randomized trials, menopausal hormone therapy (MHT) use declined dramatically. The WHI confirmed a decreased risk of osteoporosis and fractures in menopausal women assigned to hormone therapy; it also confirmed an increased risk of breast cancer previously identified in women who use combination estrogen plus progestin (E ϩ P) hormone therapy. However, the WHI trial also revealed that women assigned to MHT had an increase in coronary disease, stroke, and venous thromboembolic events. In the past few years, there has been renewed interest in the risks of MHT, especially that of breast cancer as well as the apparent elevation, rather than reduction, in the risk of coronary events. Since the original publication of the WHI results in 2002, a large number of subsequent studies have looked at these concepts in detail. In addition, recent data have emerged suggesting that there may be a link between hormone therapy and cancers of the lung and ovary. Further analyses of the effect of age and proximity to menopause at the time of initiation of therapy, duration of treatment, dose, route of administration, and the persistence of risks and benefits after stopping hormone therapy have all recently been described. Here we provide an overview of recent developments in this field, including the central role of timing of initiation. Coronary Heart Disease (CHD) The original report from the WHI demonstrated that women randomized to conjugated equine estrogens (CEEs) combined with medroxyprogesterone acetat
