1 The Women s Health Initiative: The Role of Hormonal Therapy in Disease Prevention Robert B. Wallace, MD, MSc Departments of Epidemiology and Internal Medicine University of Iowa College of Public Health Iowa City, IA The Women s Health Initiative (WHI) clinical trials on hormone therapy (HT) in postmenopausal women have changed clinical thinking on estrogen therapy in substantial ways, and have clarified clinical guidelines on disease prevention in post-menopausal women. These trials (1,2,3), along with the HERS Trial (4), a secondary prevention trial of HT and coronary artery disease, have been to date the only randomized, double-blind trials of estrogen therapy with sufficient statistical power to explore a broad range of important disease outcomes in post-menopausal women. WHI HT findings have been widely discussed and at times controversial (5), perhaps in part because their findings have been inconsistent with established clinical lore and practice, particularly with respect to the impact of HT on atherosclerotic diseases. Also, WHI findings also caused some reconsideration of basis research programs predicated on the notion that HT was cardio- and neuro-protective in animal models. However, WHI methods and findings have stood up to substantial scrutiny and have in my view become the standard for complex, long-term trials of hormonal intervention in older women. WHI comprised two HT trials: estrogen plus progestin (Prempro ) for women with an intact uterus (E+P); and estrogen alone (E-alone) (Premarin ) for women with prior hysterectomy. They were not intended to explore treatment of menopausal symptoms.
2 Rather, they addressed the value of long-term HT in the prevention of major chronic conditions of women after menopause. The primary outcomes were all-cause mortality, coronary mortality and several major conditions: coronary disease, stroke, breast cancer, hip and other fractures, pulmonary embolism and colo-rectal cancer. As well, there was a global index of these disease outcomes (2). In execution and interpretation, the WHI HT trials were complex, with too much detail for this presentation. Basic WHI HT trial findings are briefly summarized in the table. Major outcomes, primary and secondary, were defined before trial initiation. An ancillary study of dementia outcomes [WHIMS: the WHI Memory Study (6,7)] began within two years of study onset. In general, the findings were similar across the age spectrum under study (50-79 years at entry), although there was some variation. As the table shows, some conditions were increased by HT, and others were decreased. Neither intervention had an impact on total mortality. Coronary disease, breast cancer and pulmonary embolism rates were significantly increased by E+P, but this was not seen with E-alone. Both interventions caused an increase in stroke rates and a decrease in hip fracture rates. E+P caused a decrease in colon cancer rates, but this was not seen with E-alone. Dementia rates were increased with E+P; a similar trend was seen with E-alone, but it was not statistically significant. There was a significant overall increase in dementia outcome rates when the findings from both trials were combined. When there were differential effects between E +P and E-alone, it has been suggested that the progestin (medroxyprogesterone acetate) may be responsible for some of these
3 differences. This may be correct, but the issue will require further study, particularly since the two trial populations were dissimilar in some respects. For example, the E-alone participants had a higher mean body mass index and more years of prior exposure to HT than E + P participants, so interpretation of trial differences must be cautious. Many of the findings were consistent with prior observational epidemiologic studies, with the most important exception being the cardio-vascular outcomes. Also of note, in the E+P trial after one year, there very few differences between intervention and placebo groups in a variety of quality-of-life measures (8), suggesting that in this population there were no important effects in the variety of physical and behavioral domains studied. The WHI has made critically important contributions to our knowledge of disease prevention in post-menopausal women, and has challenged current clinical practice and prevention policies. Given that some types of HT will likely cause some excess morbidity, a particular problem emerges in the treatment of menopausal symptoms, since few other effective treatments exist. Also, many women seek advice on the value of HT at the time of menopause, and provision of counseling is now more complex. Perhaps most importantly, WHI has hopefully changed the decision process related to HT use at the time of menopause, and refocused attention on a very important issue: the best regimen for disease prevention in the patient s next thirty years of life. The U.S. Preventive Services Task Force has recommended against HT for chronic disease prevention in post-menopausal women (9), reinforcing the need for an overall prevention focus.
4 More detailed analyses of WHI HT findings will be forthcoming. Additionally, two other WHI trials are not yet complete: long-term interventions with calcium/vitamin D, and low fat diet. The WHI will continue to help guide our clinical preventive strategies and policies for several years to come. Keywords: women s health, estrogen, progestin, hormone therapy, chronic disease
5 Summary of Findings from the Women s Health Initiative Hormone Therapy Trials Intervention Trial Clinical Outcome E + P E Alone All-cause mortality 0 0 Coronary Heart Disease + 0 Stroke + + Breast cancer + 0 Hip fracture - - Colo-rectal cancer - 0 Pulmonary embolism + 0 Global Index ~ + 0 Dementia = no significant change compared with placebo + = statistically significantly higher rates in the hormone intervention group versus placebo - = statistically significant lower rates in the hormone intervention group versus placebo ~ = global index consisting of cumulative events including non-fatal myocardial infarction and CHD death, stroke, pulmonary embolism, invasive breast cancer, hip fracture, colo-rectal cancer, endometrial cancer and death due to other causes.
6 References 1. Women's Health Initiative Study Group. Design of the Women's Health Initiative clinical trial and observational study. The Control Clin Trials. 1998;19: Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288: Women's Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA. 2004;291: Grady D. Herrington D. Bittner V. Blumenthal R. et al. HERS Research Group. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA. 2002;288: Goldman JA. The Women s Health Initiative 2004 Review and Critique. Medscape Ob/Gyn & Women s Health. 2004;6(3). 6. Shumaker SA. Legault C. Rapp SR. et al. WHIMS Investigators. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA. 2003;289: Shumaker SA. Legault C. Kuller L. et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study. JAMA. 2004;291: Hays J. Ockene JK. Brunner RL. et al. Women's Health Initiative Investigators. Effects of estrogen plus progestin on health-related quality of life. N Engl J Med. 2003;348: U. S. Preventive Services Task Force. Chemoprevention for hormone replacement therapy. (Release Date: 2002)
7 [Dr. Wallace is the site principal investigator for the Women s Health Initiative at the University of Iowa. The opinions are solely those of the author and not the Women s Health Initiative investigators, the National Institutes of Health, the American College of Preventive Medicine or any other organization or association]