Commentary on "menopausal hormone treatment in postmenopausal women: risks and benefits".

In this issue of the Southern Medical Journal, Dous and colleagues present the course of events before and since the 2002 publication of the results of the Women’s Health Initiative (WHI), a double-blind, randomized placebo-controlled intervention of conjugated estrogen and medroxyprogesterone acetate in postmenopausal women. Menopausal hormone treatment (MHT) using either estrogen alone or estrogen plus a progestin has undergone dramatic shifts in use by consumers and physicians based on the media reports of the WHI outcomes. The initial report indicated an increased risk of coronary heart disease (CHD), but this was subsequently refuted in a second publication in 2003. By 2007, studies stratifying by age and years since menopause again indicated no increased risk of CHD in younger women. All women experience a decrease in serum estradiol, testosterone, and other ovarian hormones with the expiration of oocytes and the follicular cells surrounding them. This agerelated event is associated with significant signs and symptoms for many women. The most obvious is that menstrual periods cease. The absence of menses is associated with hot flushes, night sweats, dizziness, mood changes, palpitation, fatigue, and other symptoms. Many women who elect not to use MHT experience a decline in their quality of life. In the mid-1900s the association of low estrogen levels with menopausal symptoms and the finding that exogenous estrogen could improve hot flushes, night sweats, and some other menopausal symptoms came into vogue. Results of clinical observation studies and lipid trial results in the 1980s and early 1990s highlighted the decrease in cardiovascular disease in postmenopausal women using MHT. These women had reduced cholesterol levels and elevated high-density lipoprotein-cholesterol, which contributed to the improved CHD. There were numerous basic research studies indicating attenuation of atherosclerosis in a variety of animal models of ovarian depletion with the replacement of estrogen. The 1990s heralded a new era of clinical research, and the National Institutes of Health became sensitive to the fact that women had not been involved in major clinical studies evaluating cardiovascular disease and that studies to develop treatments shown to reduce heart disease used only men as subjects. This sensitivity was exemplified with the appointment of Dr Bernadette Healy to head the National Institutes of Health in 1991. She successfully lobbied Congress to increase funding to study women’s health a neglected area of investigation. Out of this was born the WHI. This study was the trump card that would confirm the observational studies that postmenopausal women using MHT did indeed have lower rates of cardiovascular disease. A second study enrolled 100,000 women in the observational arm of the WHI. The WHI was designed to confirm or refute the findings in observational studies that were being seen as having inherent bias in recruitment. To meet this objective, women from 50 to 79 years of age were enrolled. To minimize bias resulting from unblinding, the women were not to experience menopausal hot flushes, because improvement in hot flushes would signal to the participant and investigators that these women could be using MHT. The publication of a study on the use of estrogen plus a progestin involving 16,800 women threw the world of menopausal treatment into chaos. The initial report in 2002 indicated that there was an increased incidence of CHD events, with an odds ratio of 1.29 (95% confidence interval 1.02Y1.63) in the women taking estrogen plus a progestin compared with placebo after 5.2 years of follow-up. This increased risk was readily apparent in the first year of use and continued throughout the study. The WHI investigators had overturned dogma and stunned those who believed that estrogen plus a progestin did reduce the risk of heart disease. The effect was immediate and Invited Commentary