Review Article
Shilpa N. Bhupathiraju, PhD1; JoAnn E. Manson, MD, DrPH2 ABSTRACT Objective: This review provides a comprehensive overview of the most recent findings from the Women’s Health Initiative (WHI) hormone therapy (HT) trials and highlights the role of age and other clinical risk factors in risk stratification. Methods: We review the findings on cardiovascular disease, cancer outcomes, all-cause mortality, and other major endpoints in the two WHI HT trials (conjugated equine estrogens [CEEs, 0.625 mg/day] with or without medroxyprogesterone acetate [MPA, 2.5 mg/day]). Results: The hazard ratio (HR) for coronary heart disease (CHD) was 1.18 (95% confidence interval [CI], 0.95 to 1.45) in the CEE+MPA trial and 0.94 (95% CI, 0.78 to 1.14) in the CEE-alone trial. In both HT trials, there was an increased risk of stroke and deep vein thrombosis and a lower risk of hip fractures and diabetes. The HT regimens had divergent effects on breast cancer. CEE+MPA increased breast cancer risk (cumulative HR, 1.28; 95% CI, 1.11 to 1.48), whereas CEE alone had a protective effect (cumulative HR, 0.79; 95% CI, 0.65 to 0.97). The absolute risks of HT were low in younger women (ages 50 to 59 years) and those who were within 10 years of menopause onset. Furthermore, for CHD, the risks were elevated for
Submitted for publication May 5, 2014 Accepted for publication August 26, 2014 From the 1Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, and 2Division of Preventive Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts. Address correspondence to Dr. JoAnn E. Manson, Division of Preventive Medicine, 900 Commonwealth Avenue, Boston, MA 02215. E-mail: [email protected]. Published as a Rapid Electronic Article in Press at http://www.endocrine practice.org on October 8, 2014. DOI:10.4158/EP14205.RA To purchase reprints of this article, please visit: www.aace.com/reprints. Copyright © 2014 AACE.
women with metabolic syndrome or high low-densitylipoprotein cholesterol concentrations but not in women without these risk factors. Factor V Leiden genotype was associated with elevated risk of venous thromboembolism on HT. Conclusion: HT has a complex pattern of benefits and risks. Women in early menopause have low absolute risks of chronic disease outcomes on HT. Use of HT for management of menopausal symptoms remains appropriate, and risk stratification will help to identify women in whom benefits would be expected to outweigh risks. (Endocr Pract. 2014;20:1201-1213) Abbreviations: CABG = coronary artery bypass graft; CEE = conjugated equine estrogen; CHD = coronary heart disease; CI = confidence interval; HR = hazard ratio; HT = hormone therapy; LDL-C = low-density-lipoprotein cholesterol; MI = myocardial infarction; MPA = medroxyprogesterone acetate; PCI = percutaneous coronary intervention; WHI = Women’s Health Initiative INTRODUCTION Vasomotor symptoms such as hot flashes and night sweats are characteristic of the menopausal transition and affect more than 80% of perimenopausal women (1). By far, the most effective and predominant treatment for such symptoms is the use of hormonal therapy (HT). In the early 1990s, consistent epidemiologic data from several large scale cohorts pointed to a protective role of HT in reduction of cardiovascular disease risk (2,3). By the start of this century, nearly 20% of postmenopausal women were using HT for cardiovascular disease risk reduction (4) despite the lack of large-scale randomized clinical trials. The Women’s Health Initiative (WHI) HT trials, therefore, were conceived with the primary objective of examining the risks and benefits associated with HT when taken to prevent chronic disease by postmenopausal women, aged
ENDOCRINE PRACTICE Vol 20 No. 11 November 2014 1201
Shilpa N. Bhupathiraju, PhD1; JoAnn E. Manson, MD, DrPH2 ABSTRACT Objective: This review provides a comprehensive overview of the most recent findings from the Women’s Health Initiative (WHI) hormone therapy (HT) trials and highlights the role of age and other clinical risk factors in risk stratification. Methods: We review the findings on cardiovascular disease, cancer outcomes, all-cause mortality, and other major endpoints in the two WHI HT trials (conjugated equine estrogens [CEEs, 0.625 mg/day] with or without medroxyprogesterone acetate [MPA, 2.5 mg/day]). Results: The hazard ratio (HR) for coronary heart disease (CHD) was 1.18 (95% confidence interval [CI], 0.95 to 1.45) in the CEE+MPA trial and 0.94 (95% CI, 0.78 to 1.14) in the CEE-alone trial. In both HT trials, there was an increased risk of stroke and deep vein thrombosis and a lower risk of hip fractures and diabetes. The HT regimens had divergent effects on breast cancer. CEE+MPA increased breast cancer risk (cumulative HR, 1.28; 95% CI, 1.11 to 1.48), whereas CEE alone had a protective effect (cumulative HR, 0.79; 95% CI, 0.65 to 0.97). The absolute risks of HT were low in younger women (ages 50 to 59 years) and those who were within 10 years of menopause onset. Furthermore, for CHD, the risks were elevated for
Submitted for publication May 5, 2014 Accepted for publication August 26, 2014 From the 1Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, and 2Division of Preventive Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts. Address correspondence to Dr. JoAnn E. Manson, Division of Preventive Medicine, 900 Commonwealth Avenue, Boston, MA 02215. E-mail: [email protected]. Published as a Rapid Electronic Article in Press at http://www.endocrine practice.org on October 8, 2014. DOI:10.4158/EP14205.RA To purchase reprints of this article, please visit: www.aace.com/reprints. Copyright © 2014 AACE.
women with metabolic syndrome or high low-densitylipoprotein cholesterol concentrations but not in women without these risk factors. Factor V Leiden genotype was associated with elevated risk of venous thromboembolism on HT. Conclusion: HT has a complex pattern of benefits and risks. Women in early menopause have low absolute risks of chronic disease outcomes on HT. Use of HT for management of menopausal symptoms remains appropriate, and risk stratification will help to identify women in whom benefits would be expected to outweigh risks. (Endocr Pract. 2014;20:1201-1213) Abbreviations: CABG = coronary artery bypass graft; CEE = conjugated equine estrogen; CHD = coronary heart disease; CI = confidence interval; HR = hazard ratio; HT = hormone therapy; LDL-C = low-density-lipoprotein cholesterol; MI = myocardial infarction; MPA = medroxyprogesterone acetate; PCI = percutaneous coronary intervention; WHI = Women’s Health Initiative INTRODUCTION Vasomotor symptoms such as hot flashes and night sweats are characteristic of the menopausal transition and affect more than 80% of perimenopausal women (1). By far, the most effective and predominant treatment for such symptoms is the use of hormonal therapy (HT). In the early 1990s, consistent epidemiologic data from several large scale cohorts pointed to a protective role of HT in reduction of cardiovascular disease risk (2,3). By the start of this century, nearly 20% of postmenopausal women were using HT for cardiovascular disease risk reduction (4) despite the lack of large-scale randomized clinical trials. The Women’s Health Initiative (WHI) HT trials, therefore, were conceived with the primary objective of examining the risks and benefits associated with HT when taken to prevent chronic disease by postmenopausal women, aged
ENDOCRINE PRACTICE Vol 20 No. 11 November 2014 1201
