Mortality associated with hormone replacement therapy in younger and older women
Cite this article as: Salpeter, S.R., Walsh, J.M.E., Greyber, E. et al. J GEN INTERN MED (2004) 19: 791. doi:10.1111/j.1525-1497.2004.30281.x Abstract OBJECTIVE: To assess mortality associated with hormone replacement in younger and older postmenopausal women. DESIGN: A comprehensive search of medline, cinahl, and embase databases was performed to identify randomized controlled trials of hormone replacement therapy from 1966 to September 2002. The search was augmented by scanning selected journals through April 2003 and references of identified articles. Randomized trials of greater than 6 months’ duration were included if they compared hormone replacement with placebo or no treatment, and reported at least 1 death. MEASUREMENTS: Outcomes measured were total deaths and deaths due to cardiovascular disease, cancer, or other causes. Odds ratios (OR) for total and cause-specific mortality were reported separately for trials with mean age of participants less than and greater than 60 years at baseline. MAIN RESULTS: Pooled data from 30 trials with 26,708 participants showed that the OR for total mortality associated with hormone replacement was 0.98 (95% confidence interval [CI], 0.87 to 1.12). Hormone replacement reduced mortality in the younger age group (OR, 0.61; CI, 0.39 to 0.95), but not in the older age group (OR, 1.03; CI, 0.90 to 1.18). For all ages combined, treatment did not significantly affect the risk for cardiovascular or cancer mortality, but reduced mortality from other causes (OR, 0.67; CI, 0.51 to 0.88). CONCLUSIONS: Hormone replacement therapy reduced total mortality in trials with mean age of participants under 60 years. No change in mortality was seen in trials with mean age over 60 years. Key words hormone replacement therapy postmenopause mortality age factors meta-analysis
Financial support was provided by the Santa Clara Valley Medical Center and the University of California, San Francisco.
Wolf PH, Madans JH, Finucane FF, Higgins M, Kleinman JC. Reduction of cardiovascular disease-related mortality among postmenopausal women who use hormones: evidence from a national cohort. Am J Obstet Gynecol. 1991;164:489–94.
Grodstein R, Stampfer JJ, Colditz GA, et al. Postmenopausal hormone therapy and mortality. N Engl J Med. 1997;336:1769–75.
Bush TL, Barrett-Conner E, Cowan LD, et al. Cardiovascular mortality and contraceptive use of estrogen in women: results from the Lipid Research Clinics Program Follow-up Study. Circulation. 1987;75:1102–9.
Sourander L, Rajala T, Raiha I, Makinen J, Ekkola R, Helenius H. Cardiovascular and cancer morbidity and mortality and sudden cardiac death in postmenopausal women on oestrogen replacement therapy (ERT). Lancet. 1998;352:1965–9.
Petitti DB, Perlman JA, Sidney S. Noncontraceptive estrogens and mortality: long-term follow-up of women in the Walnut Creek Study. Obstet Gynecol. 1987;70:289–93.
Ettinger B, Friedman GM, Bush T, Quesenberry CP. Reduced mortality associated with long-term postmenopausal estrogen therapy. Obstet Gynecol. 1996;87:6–12.
Criqui MH, Suarez L, Barrett-Connor E, McPhillips J, Wingard DL, Garland C. Postmenopausal estrogen use and mortality. Results from a prospective study in a defined, homogeneous community. Am J Epidemiol. 1988;128:606–14.
Cauley JA, Seeley DG, Browner WS, et al. Estrogen replacement therapy and mortality among older women. The study of osteoporotic fractures. Arch Intern Med. 1997;157:2181–7.
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;288:321–33.
Barrett-Conner E. Post-menopausal estrogen and prevention bias. Ann Intern Med. 1991;115:455–6.
Matthews KA, Kuller LH, Wing RR, Meilahn EN, Plantinga PA. Prior to use of estrogen replacement therapy, are users healthier than nonusers? Am J Epidemiol. 1996;143:971–8.
Humphrey LL, Chan BKS, Sox HC. Postmenopausal hormone replacement therapy and the primary prevention of cardiovascular disease. Ann Intern Med. 2002;137:273–84.
Fleiss JL. Statistical Methods for Rates and Proportions. New York: Wiley; 1981:217–34.
Jadad AR, Moore A, Carroll D, et al. Assessing the quality or reports of randomized clinical trials. Control Clin Trials. 1996;17:1–12.
Schultz KF, Chalmers I, Hayes RG, Altman DG. Empirical evidence of bias: dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA. 1995;273:408–12.
DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88.
Conteras I, Parra D. Estrogen replacement therapy and the prevention of coronary heart disease in postmenopausal women. Am J Health Syst Pharm. 2000;57:1963–71.
Gorodeski GI. Impact of the menopause on the epidemiology and risk factors of coronary artery heart disease in women. Exp Gerontol. 1994;29:357–75.
Angerer P, Kothny W, Stork S, von Schacky C. Hormone replacement therapy and distensibility of carotid arteries in postmenopausal women: a randomized, controlled trial. J Am Coll Cardiol. 2000;36:1789–96.
Arrenbrecht S, Boermans AJ. Effects of transdermal estradiol delivered by a matrix patch on bone density in hysterectomized, postmenopausal women: a 2-year placebo-controlled trial. Osteoporos Int. 2002;13:176–83.
Binder EF, Williams DB, Schechtman KB, Jeffe DB, Kohrt WM. Effects of hormone replacement therapy on serum lipids in elderly women. A randomized, placebo-controlled trial. Ann Intern Med. 2001;134:754–60.
Cherry N, Gilmour K, Hannaford P, et al. Oestrogen therapy for prevention of reinfarction in postmenopausal women: a randomised placebo controlled trial. Lancet. 2002;360:2001–8.
Gallagher JC, Fowler SE, Detter JR, Sherman SS. Combination treatment with estrogen and calcitriol in the prevention of age-related bone loss. J Clin Endocrinol Metab. 2001;86:3618–28.
Giske LE, Hall G, Rud T, Landgren BM. The effect of 17beta-estradiol at doses of 0.5, 1 and 2 mg compared with placebo on early postmenopausal bone loss in hysterectomized women. Osteoporos Int. 2002;13:309–16.
Guidozzi F, Daponte A. Estrogen replacement therapy for ovarian carcinoma survivors: a randomized controlled trial. Cancer. 1999;86:1013–8.
Hall GM, Daniels M, Doyle DV, Spector TD. Effect of hormone replacement therapy on bone mass in rheumatoid arthritis patients treated with and without steroids. Arthritis Rheum. 1994;37:1499–505.
Hall G, Pripp U, Schenck-Gustafsson K, Landgren BM. Long-term effects of hormone replacement therapy on symptoms of angina pectoris, quality of life and compliance in women with coronary artery disease. Maturitas. 1998;28:235–42.
Herrington DM, Reboussin DM, Brosnihan KB, et al. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med. 2000;343:522–9.
Hodis HN, Mack WJ, Lobo RA, et al. Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2001;135:939–53.
Hulley S, Furberg C, Barrett-Connor E, et al. Noncardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/Progestin Replacement Study follow-up (HERS II). JAMA. 2002;288:58–66.
Komulainen M, Kroger H, Tuppurainen MT, et al. Prevention of femoral and lumbar bone loss with hormone replacement therapy and vitamin D3 in early postmenopausal women: a population-based 5-year randomized trial. J Clin Endocrinol Metab. 1999;84:546–52.
Kyllonen ES, Heikkinen JE, Vaananen HK, et al. Influence of estrogen-progestin replacement therapy and exercise on lumbar spine mobility and low back symptoms in a healthy early postmenopausal female population: a 2-year randomized controlled trial. Eur Spine J. 1998;7:381–6.
Lindsay R, Hart DM, Aitken JM, MacDonald EB, Anderson JB, Clarke AC. Long-term prevention of postmenopausal osteoporosis by oestrogen. Evidence for an increased bone mass after delayed onset of oestrogen treatment. Lancet. 1976;1:1038–41.
MacDonald AG, Murphy EA, Capell HA, Bankowska UZ, Ralston SH. Effects of hormone replacement therapy in rheumatoid arthritis: a double blind placebo-controlled study. Ann Rheum Dis. 1994;53:54–7.
Mijatovic V, Netelenbos C, van der Mooren MJ, de Valk-de Roo GW, Jakobs C, Kenemans P. Randomized, double-blind, placebo-controlled study of the effects of raloxifene and conjugated equine estrogen on plasma homocysteine levels in healthy postmenopausal women. Fertil Steril. 1998;70:1085–9.
Mosekilde L, Beck-Nielsen H, Sorensen OH, et al. Hormonal replacement therapy reduces forearm fracture incidence in recent postmenopausal women—results of the Danish Osteoporosis Prevention Study. Maturitas. 2000;36:181–93.
Mulnard RA, Cotman RA, Kawas C, et al. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease. JAMA. 2000;283:1007–15.
Nachtigall LE, Nachtigall RH, Nachtigall RD, Beckman EM. Estrogen replacement therapy II: a prospective study in the relationship to carcinoma and cardiovascular and metabolic problems. Obstet Gynecol. 1979;54:74–9.
Os I, Hofstad AE, Brekke M, et al. The EWA (estrogen in women with atherosclerosis) study: a randomized study of the use of hormone replacement therapy in women with angiographically verified coronary artery disease. Characteristics of the study population. Effects on lipids and lipoproteins. J Intern Med. 2000;247:433–41.
PEPI Trial Writing Group. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. The Writing Group for the PEPI Trial. JAMA. 1995;273:199–208.
Perez-Jaraiz MD, Revilla M, Alvarez de los Heros JI, Villa LF, Rico H. Prophylaxis of osteoporosis with calcium, estrogens and/or eelcatonin: comparative longitudinal study of bone mass. Maturitas. 1996;23:327–32.
Ravn P, Bidstrup M, Wasnich RD, et al. Alendronate and estrogen-progestin in the long-term prevention of bone loss: four-year results from the early postmenopausal intervention cohort study. A randomized, controlled trial. Ann Intern Med. 1999;131:935–42.
Raz R, Stamm WE. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N Engl J Med. 1993;329:753–6.
Recker RR, Davies KM, Dowd RM, Heaney RP. The effect of low-dose continuous estrogen and progesterone therapy with calcium and vitamin D on bone in elderly women. A randomized, controlled trial. Ann Intern Med. 1999;130:897–904.
Viscoli CM, Brass LM, Kernan WN, Sarrel PM, Suissa S, Horwitz RI. A clinical trial of estrogen-replacement therapy after ischemic stroke. N Engl J Med. 2001;345:1243–9.
Waters D, Alderman EL, Hsia J, et al. Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women. JAMA. 2002;288:2432–40.
Watts NB, Nolan JC, Brennan JJ, Yang HM. Esterified estrogen therapy in postmenopausal women. Relationships of bone marker changes and plasma estradiol to BMD changes: a two-year study. Menopause. 2000;7:375–82.
Grodstein F, Clarkson TB, Manson JE. Understanding the divergent data on postmenopausal hormone therapy. N Engl J Med. 2003;348:645–50.
Manson JE, Hsia J, Johnson KC, et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med. 2003;349:523–34.
Kanaya AM, Herrington D, Vittinghoff E, et al. Glycemic effects of postmenopausal hormone therapy: the Heart and Estrogen/Progestin Replacement Study. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2003;138:1–9.
Davidson MH, Maki KC, Marx P, et al. Effects of continuous estrogen and estrogen-progestin replacement regimens on cardiovascular risk markers in postmenopausal women. Arch Intern Med. 2000;160:3315–25.
Vehkavaara S, Silveira A, Hakala-Ala-Pietila T, et al. Effects of oral and transdermal estrogen replacement therapy on markers of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in postmenopausal women. Thromb Haemost. 2001;85:619–25.
Conard J, Compel A, Pelissier C, Mirabel C, Basdevant A. Fibrinogen and plasminogen modifications during oral estradiol replacement therapy. Fertil Steril. 1997;68:449–53.
Demirol A, Baykal C, Kirazli S, Ayhan A. Effects of hormone replacement on hemostasis in spontaneous menopause. Menopause. 2001;8:135–40.
Manning PJ, Allum A, Jones S, Sutherland WH, Williams SM. The effect of hormone replacement therapy on cardiovascular risk factors in type 2 diabetes: a randomized controlled trial. Arch Intern Med. 2001;161:1772–6.
Haines C, Chung T, Chang A, Masarei J, Tomlinson B, Wong E. Effect of oral estradiol on Lp(a) and other lipoproteins in postmenopausal women. A randomized, double-blind, placebo-controlled, crossover study. Arch Intern Med. 1996;156:866–72.
Walsh BW, Kuller LH, Wild RA, et al. Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA. 1998;279:1445–51.
Ventura P, Cagnacci A, Malmusi S, et al. Continuous combined hormone replacement therapy with oral 17beta-estradiol and norethisterone acetate improves homocysteine metabolism in postmenopausal women. Menopause. 2001;8:252–8.
Samaras K, Hayward CS, Sullivan D, Kelly RP, Campbell LV. Effects of postmenopausal hormone replacement therapy on central abdominal fat, glycemic control, lipid metabolism, and vascular factors in type 2 diabetes: a prospective study. Diabetes Care. 1999;22:1401–7.
Friday KE, Dong C, Fontenot RU. Conjugated equine estrogen improves glycemic control and blood lipoproteins in postmenopausal women with type 2 diabetes. J Clin Endocrinol Metab. 2001;86:48–52.
Cicinelli E, Ignarro LJ, Matteo MG, Galantino P, Schonauer LM, Falco N. Effects of estrogen replacement therapy on plasma levels of nitric oxide in postmenopausal women. Am J Obstet Gynecol. 1999;180:334–9.
Saitta A, Altavilla D, Cucinotta D, et al. Randomized, double-blind, placebo-controlled study on effects of raloxifene and hormone replacement therapy on plasma NO concentrations, endothelin-1 levels, and endothelium-dependent vasodilation in postmenopausal women. Arterioscler Thromb Vasc Biol. 2001;21:1512–9.
Guzic-Salobir B, Keber I, Seljeflot I, Arnesen H, Vrabic L. Combined hormone replacement therapy improves endothelial function in healthy postmenopausal women. J Intern Med. 2001;250:508–15.
Manwaring P, Phoon S, Diamond T, Howes LG. Effects of hormone replacement therapy on cardiovascular responses in postmenopausal women with and without type 2 diabetes. Maturitas. 2002;43:157–64.
Penotti M, Sironi L, Castiglioni E, et al. Blood flow in the internal carotid and middle cerebral arteries: effects of continuous oral conjugated equine estrogens administration with monthly progestogen supplementation on postmenopausal women. Menopause. 1999;6:225–9.
Affinito P, Palomba S, Bonifacio M, et al. Effects of hormonal replacement therapy in postmenopausal hypertensive patients. Maturitas. 2001;40:75–83.
Lau TK, Wan D, Yim SF, Sanderson JE, Haines CJ. Prospective, randomized, controlled study of the effect of hormone replacement therapy on peripheral blood flow velocity in postmenopausal women. Fertil Steril. 1998;70:284–8.
Light KC, Hinderliter AL, West SG, et al. Hormone replacement improves hemodynamic profile and left ventricular geometry in hypertensive and normotensive postmenopausal women. J Hypertens. 2001;19:269–78.
Gallinelli A, Angioni S, Matteo ML, Montaldo PL, Fenu MA, Volpe A. Variations of cardiac performance and inotropism in healthy postmenopausal women treated with estroprogestin replacement therapy. Menopause. 1999;6:49–55.
Kannel WB, Hjortland MC, McNamara PM, Gordon T. Menopause and risk of cardiovascular disease: the Framingham study. Ann Intern Med. 1976;85:447–52.
Colditz GA, Willett WC, Stampfer MJ, Rosner B, Speizer FE, Hennekens CH. Menopause and the risk of coronary heart disease in women. N Engl J Med. 1987;316:1105–10.
Hough JL, Zilversmit DB. Effect of 17 beta estradiol on aortic cholesterol content and metabolism in cholesterol-fed rabbits. Arteriosclerosis. 1986;6:57–63.
Williams JK, Adams MR, Klopfenstein HS. Estrogen modulates responses of atherosclerotic coronary arteries. Circulation. 1990;81:1680–7.
Wagner JD, Clarkson TB, St Clair RW, Schwenke DC, Shively CA, Adams MR. Estrogen and progesterone replacement therapy reduces low density lipoprotein accumulation in the coronary arteries of surgically postmenopausal cynomolgus monkeys. J Clin Invest. 1991;88:1995–2002.
Kushwaha RS, Lewis DS, Carey KD, McGill HC Jr. Effects of estrogen and progesterone on plasma lipoproteins and experimental atherosclerosis in the baboon (Papio sp.). Arterioscler Thromb. 1991;11:23–31.
Rosenfeld ME, Kauser K, Martin-McNulty B, Polinsky P, Schwartz SM, Rubanyi GM. Estrogen inhibits the initiation of fatty streaks throughout the vasculature but does not inhibit intraplaque hemorrhage and the progression of established lesions in apolipoprotein E deficient mice. Atherosclerosis. 2002;164:251–9.
Hodis HN, Mack WJ, Azen SP, et al. Hormone therapy and the progression of coronary-artery atherosclerosis in postmenopausal women. N Engl J Med. 2003;349:535–45.
Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA. 1998;280:605–13.
Miller J, Chan BK, Nelson HD. Postmenopausal estrogen replacement and risk for venous thromboembolism: a systematic review and meta-analysis for the U.S. Preventive Services Task Force. Ann Intern Med. 2002;136:680–90.
Pradhan AD, Manson JE, Rossouw JE, et al. Inflammatory biomarkers, hormone replacement therapy, and incident coronary heart disease: prospective analysis from the Women’s Health Initiative observational study. JAMA. 2002;288:980–7.
Rabbani LE, Seminario NA, Sciacca RR, Chen HJ, Giardina EG. Oral conjugated equine estrogen increases plasma von Willebrand factor in postmenopausal women. J Am Coll Cardiol. 2002;40:1991–9.
Brussaard HE, Leuven JA, Krans HM, Kluft C. The effect of 17 beta-oestradiol on variables of coagulation and fibrinolysis in post-menopausal women with type 2 diabetes mellitus. Vascul Pharmacol. 2002;39:141–7.
Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy post-menopausal women: the Women’s Health Initiative Randomized Trial. JAMA. 2003;289:3243–53.
Beral V. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003;362:419–27.
Nanda K, Bastian LA, Hasselblad V, Simel DL. Hormone replacement therapy and the risk of colorectal cancer: a meta-analysis. Obstet Gynecol. 1999;93:880–8.
Cardozo L, Lose G, McClish D, Versi E, de Konning Glans H. A systematic review of estrogens for recurrent urinary tract infections: third report of the Hormones and Urogenital therapy (HUT) committee. Int Urogynecol J. 2001;12:15–20.
Ionnidis JP, Lau J. Pooling research results: benefits and limitations of meta-analysis. Jt Comm J Qual Improv. 1999;25:462–9.
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