Abstract
This article reviews epidemiological data on potential adverse effects of hormone replacement therapy (HRT) on the risk of breast, endometrial and ovarian cancer, on the risk of stroke, and on the risk of venous and pulmonary thromboembolism. As for the potential adverse effects on cancer risk, most information on HRT and breast cancer is included in a re-analysis of individual data from 51 epidemiological studies (including over 90% of the world’s data), showing a 2.3% increase of the relative risk of breast cancer for each year of use which, however, levels off after stopping use. This corresponds to a cumulative excess of approximately 2 in 1,000 women who started taking HRT at age 50 and used it for 5 years, 6 in 1,000 women who used it for 10 years and 12 in 1,000 women who used it for 15 years. Unopposed estrogen use is strongly related to endometrial cancer risk mainly in lean women, but the cyclic combined oestrogen-progestin treatment appears to largely or totally reduce this effect if progestin is taken for more than 10 days per cycle. The data on epithelial ovarian cancer allows exclusion of any strong association with HRT, although a moderate positive relationship remains open to debate. As for other adverse effects of HRT, the relationship between HRT and stroke is still debated, although any strong and consistent association can be excluded. Current HRT use, but not past use, is associated with venous and pulmonary thromboembolism. Thus, most adverse effects of HRT are restricted to current or recent use, and long term HRT use should be carefully considered on an individual basis, taking into account any other personal risk factors for breast and endometrial cancer and for venous/pulmonary thromboembolism, and the potential benefits of HRT on cardiovascular disease and osteoporosis.
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References
Brinton LA, Schairer C. Postmenopausal hormone-replacement therapy: time for a reappraisal? N Engl J Med 1997; 336: 1821–2
La Vecchia C. Sex hormones and cardiovascular risk. Hum Reprod 1992; 7: 162–7
Fernandez E, La Vecchia C, Braga C, et al. Hormone replacement therapy and risk of colon and rectal cancer. Cancer Epidemiol Biomarkers Prev 1998; 7: 329–33
Grodstein F, Stampfer MJ, Colditz GA, et al. Postmenopausal hormone therapy and mortality. N Engl J Med 1997; 336: 1769–75
Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 1997; 350: 1047–59
Willis DB, Calle EE, Miracle-McMahill HL, et al. Estrogen replacement therapy and risk of fatal breast cancer in a prospective cohort of postmenopausal women in the United States. Cancer Causes Control 1996; 7: 449–57
Brinton LA, Schairer C. Estrogen replacement therapy and breast cancer risk. Epidemiol Rev 1993; 15: 66–79
Adami H-O, Persson I. Hormone replacement and breast cancer: a remaining controversy? JAMA 1995; 274: 178–9
The Writing Group on the Postmenopausal Estrogen/Progestin Intervention (PEPI) Trial. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. JAMA, 1996; 275: 370–5
Pike MC, Spicer DV, Dahmoush L, et al. Estrogens, progestogens, normal breast cell proliferation, and breast cancer risk. Epidemiol Rev 1993; 15: 17–35
Stanford JL, Thomas D. Exogenous progestins and breast cancer. Epidemiol Rev 1993; 15: 98–107
Bergkvist L, Adami H-O, Persson I, et al. The risk of breast cancer after estrogen and estrogen-progestin replacement. N Engl J Med 1989; 321: 293–7
Persson I, Yuen J, Bergkvist L, et al. Combined oestrogen-progestogen replacement and breast cancer risk [letter]. Lancet 1992; 340; 1044
Hunt K, Vessey M, McPherson K, et al. Long-term surveillance of mortality and cancer incidence in women receiving hormone replacement therapy. Br J Obstet Gynaecol 1987; 94: 620–35
Ewertz M. Influence of non-contraceptive exogenous and endogenous sex hormones on breast cancer risk in Denmark. Int J Cancer 1988; 42: 832–8
Persson I, Thurfjell E, Bergstrom R, et al. Hormone replacement therapy and the risk of breast cancer: nested case-control study in a cohort of Swedish women attending mammography screening. Int J Cancer 1997; 72: 758–61
Colditz GA, Hankinson SE, Hunter DJ, et al. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med 1995; 332: 1589–93
Day NE. Epidemiology: the role of multi-stage models. Cancer Surv 1983; 2: 579–93
Henderson BE. The cancer question: an overview of recent epidemiologic and retrospective data. Am J Obstet Gynecol 1989; 161: 1859–64
Steinberg KK, Thacker SB, Smith SJ, et al. A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer. JAMA 1991; 265: 1985–90
La Vecchia C, Negri E, Franceschi S, et al. Hormone replacement treatment and breast cancer risk: a cooperative Italian study. Br J Cancer 1995; 72: 244–8
Mack TM, Ross RK. Risks and benefits of long-term treatment with estrogens. Schweiz Med Wochenschr 1989; 119: 1811–20
Tavani A, Braga C, La Vecchia C, et al. Hormone replacement treatment and breast cancer risk: an age-specific analysis. Cancer Epidemiol Biomarkers Prev 1997; 6: 11–4
Lobo RA. Benefits and risks of estrogen replacement therapy. Am J Obstet Gynecol 1995; 173: 982–90
Parazzini F, La Vecchia C, Negri E, et al. Determinants of estrogen replacement therapy use in Northern Italy. Rev Epidemiol Sante Publique 1993; 41: 53–8
Parazzini F, La Vecchia C, Bocciolone L, et al. The epidemiology of endometrial cancer. Gynecol Oncol 1991; 41: 1–16
Smith DC, Prentice R, Thompson DJ, et al. Association of exogenous estrogen and endometrial carcinoma. N Engl J Med 1975; 293: 1164–7
Ziel HK, Finkle WD. Increased risk of endometrial carcinoma among users of conjugated estrogens. N Engl J Med 1975; 293: 1167–70
Schwartzbaum JA, Hulka BS, Fowler Jr WC, et al. The influence of exogenous estrogen use on survival after diagnosis of endometrial cancer. Am J Epidemiol 1987; 126: 851–60
Shapiro S, Kaufman DW, Slone D, et al. Recent and past use of conjugated estrogens in relation to adenocarcinoma of the endometrium. N Engl J Med 1980; 303: 485–9
Grady D, Gebretsadik T, Kerlikowske K, et al. Hormone replacement therapy and endometrial cancer risk: a meta-analysis. Obstet Gynecol 1995; 85: 304–13
Day NE. Time as a determinant of risk in cancer epidemiology: the role of multi-stage models. Cancer Surv 1983; 2: 577–93
Finkle WD, Greenland S, Miettinen OS, et al. Endometrial cancer risk after discontinuing use of unopposed conjugated estrogens (California, United States). Cancer Causes Control 1995; 6: 99–102
La Vecchia C, Franceschi S, Gallus G, et al. Oestrogens and obesity as risk factors for endometrial cancer in Italy. Int J Epidemiol 1982; 11: 120–6
Baron JA, La Vecchia C, Levi F. The antiestrogenic effect of cigarette smoking in women. Am J Obstet Gynecol 1990; 162: 502–14
Brinton LA, Hoover RN, for the Endometrial Cancer Collaborative Group. Estrogen replacement therapy and endometrial cancer risk: unresolved issues. Obstet Gynecol 1993; 81: 265–71
Levi F, La Vecchia C, Gulie C, et al. Oestrogen replacement treatment and the risk of endometrial cancer: an assessment of the role of covariates. Eur J Cancer 1993; 29A: 1445–9
Pike MC. Age-related factors in cancer of the breast, ovary, and endometrium. J Chronic Dis 1987; 40Suppl. 2: 59S–69
Jick SS, Walker AM, Jick H. Estrogens, progesterone, and endometrial cancer. Epidemiology 1993; 4: 20–4
Parazzini F, Negri E, La Vecchia C, et al. Population attributable risk for endometrial cancer in Northern Italy. Eur J Cancer Clin Oncol 1989; 25: 1451–6
Leather AT, Savvas M, Studd JWW. Endometrial histology and bleeding patterns after 8 years of continuous combined estrogen and progestogen therapy in postmenopausal women. Obstet Gynecol 1991; 78: 1008–10
Voigt LF, Weiss NS, Chu J, et al. Progestagen supplementation of exogenous oestrogens and risk of endometrial cancer. Lancet 1991; 338: 274–7
Beresford SAA, Weiss NS, Voigt LF, et al. Risk of endometrial cancer in relation to use of oestrogen combined with cyclic progestagen therapy in postmenopausal women. Lancet 1997; 349: 458–61
Pike MC, Peters RK, Cozen W, et al. Estrogen-progestin replacement therapy and endometrial cancer. J Natl Cancer Inst 1997; 89: 1110–6
Grady D, Ernster VL. Hormone replacement therapy and endometrial cancer: are current regimen safe? J Natl Cancer Inst 1997; 89: 1088–9
La Vecchia C, Negri E, Levi F, et al. Cancer mortality in Europe: effects of age, cohort of birth and period of death. Eur J Cancer 1998; 34: 118–41
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
Rodriguez C, Calle EE, Coates RJ, et al. Estrogen replacement therapy and fatal ovarian cancer. Am J Epidemiol 1995; 141: 828–35
Adami H-O, Persson I, Hoover R, et al. Risk of cancer in women receiving hormone replacement therapy. Int J Cancer 1989; 44: 833–9
Schairer C, Adami H-O, Hoover R, et al. Causes-specific mortality in women receiving hormone replacement therapy. Epidemiology 1997; 8: 59–65
Hildreth NG, Kelsey JL, LiVolsi VA, et al. An epidemiologic study of epithelial carcinoma of the ovary. Am J Epidemiol 1981; 114: 398–405
Weiss NS, Lyon JL, Krishnamurthy S, et al. Noncontraceptive estrogen use and the occurrence of ovarian cancer. J Natl Cancer Inst 1982; 68: 95–8
Franceschi S, La Vecchia C, Helmrich SP, et al. Risk factors for epithelial ovarian cancer in Italy. Am J Epidemiol 1982; 115: 714–9
Tzonou A, Day NE, Trichopoulos D, et al. The epidemiology of ovarian cancer in Greece: a case-control study. Eur J Cancer Clin Oncol 1984; 20: 1045–52
Harlow BL, Weiss, NS, Roth GJ, et al. Case-control study of borderline ovarian tumors: reproductive history and exposure to exogenous female hormones. Cancer Res 1988; 48: 5849–52
Kaufman DW, Kelly JP, Welch WR, et al. Noncontraceptive estrogen use and epithelial ovarian cancer. Am J Epidemiol 1989; 130: 1142–51
Booth M, Beral V, Smith P. Risk factors for ovarian cancer: a case-control study. Br J Cancer 1989; 60: 592–8
Polychronopoulou A, Tzonou A, Hsieh C, et al. Reproductive variables, tobacco, ethanol, coffee and somatometry as risk factors for ovarian cancer. Int J Cancer 1993; 55: 402–7
Parazzini F, La Vecchia C, Negri E, et al. Estrogen replacement therapy and ovarian cancer risk [letter] Int J Cancer 1994; 57: 135–6
Purdie D, Green A, Bain C, et al. Reproductive and other factors and risk of epithelial ovarian cancer: an Australian case-control study. Int J Cancer 1995; 62: 678–84
Risch HA. Estrogen replacement therapy and risk of epithelial ovarian cancer. Gynecol Oncol 1996; 63: 254–7
Hempling RE, Wong C, Piver MS, et al. Hormone replacement therapy as a risk factor for epithelial ovarian cancer: results of a case-control study. Obstet Gynecol 1997; 89: 1012–6
Whittemore AS, Harris R, Itnyre J, et al. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. II. Invasive epithelial ovarian cancers in White women. Am J Epidemiol 1992; 136: 1184–203
Harris R, Whittemore AS, Itnyre J, et al. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. III. Epithelial tumors of low malignant potential in White women. Am J Epidemiol 1992; 136: 1204–11
Hunt K, Vessey M, McPherson K. Mortality in a cohort of long-term users of hormone replacement therapy: an updated analysis. Br J Obstet Gynaecol 1990; 97: 1080–6
Garg PP, Kerlikowske K, Subak L, et al. Hormone replacement therapy and the risk of epithelial ovarian carcinoma: a meta-analysis. Obstet Gynecol 1998; 92: 472–9
Caine YG, Bauer KA, Barzegar S, et al. Coagulation activation following estrogen administration to postmenopausal women. Thromb Haemost 1992; 68: 392–5
Pfeffer RI. Estrogen use, hypertension and stroke in postmenopausal women. J Chronic Dis 1978; 31: 389–98
Petitti DB, Wingerd J, Pellegrin, F, et al. Risk of vascular disease in women: smoking, oral contraceptives, noncontraceptive estrogens and other factors. JAMA 1979; 242: 1150–4
Hammond CB, Jelovsek FR, Lee KL, et al. Effects of long-term estrogen replacement therapy: metabolic effects. Am J Obstet Gynecol 1979; 133: 525–36
Rosenberg SH, Fausone V, Clark R. The role of estrogens as a risk factor for stroke in postmenopausal women. West J Med 1980; 133: 292–6
Wilson PW, Garrison RJ, Castelli WP. Postmenopausal estrogen use, cigarette smoking and cardiovascular morbidity in women over 50: the Framingham study. N Engl J Med 1985; 313: 1038–43
Busch TL, Barrett-Connor E, Cowan LD, et al. Cardiovascular mortality and noncontraceptive use of estrogen in women: results from the lipid research clinics program follow-up study. Circulation 1987; 75: 1102–9
Boysen G, Nyboe J, Appleyard M, et al. Stroke incidence and risk factors for stroke in Copenhagen, Denmark. Stroke 1988; 19: 1345–53
Paganini-Hill A, Ross RK, Henderson BE. Postmenopausal oestrogen treatment and stroke: a prospective study. BMJ 1988; 297: 519–22
Thompson SG, Meade TW, Greenberg G. The use of hormonal replacement therapy and the risk of stroke and myocardial infarction in women. J Epidemiol Community Health 1989; 43: 173–8
Stampfer MJ, Colditz GA, Willett WC, et al. Postmenopausal estrogen therapy and cardiovascular disease: ten-year follow-up from the Nurses Health Study. N Engl J Med 1991; 325: 756–62
Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992; 117: 1016–37
Finucane FF, Madans JH, Bush TL, et al. Decreased risk of stroke among postmenopausal hormone users: results from a national cohort. Arch Intern Med 1993; 153: 73–9
Grodstein F, Stampfer MJ, Manson JE, et al. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Med 1996; 335: 453–61
Falkeborn M, Persson I, Terént A, et al. Hormone replacement therapy and the risk of stroke: follow-up of a population-based cohort in Sweden. Arch Intern Med 1993; 153: 1201–9
Longstreth WT, Nelson LM, Koepsell TD, et al. Subarachnoid hemorrhage and hormonal factors in women: a population-based case-control study. Ann Intern Med 1994; 121: 168–73
Pedersen AT, Lidegaard O, Kreiner S, et al. Hormone replacement therapy and risk of non-fatal stroke. Lancet 1997; 350: 1277–83
Matthews KA, Kuller LH, Wing RR, et al. Prior to use of estrogen replacement therapy, are users healthier than nonusers? Am J Epidemiol 1996; 143: 971–8
Kroon UB, Silfverstolpe G, Tengborn L. The effects of transdermal estradiol and oral conjugated oestrogens on haemostasis variables. Thromb Haemost 1994; 71: 420–3
Petitti DB, Sidney S, Bernstein A. et al. Stroke in users of low-dose oral contraceptives. N Engl J Med 1996; 335: 8–15
Boston Collaborative Drug Surveillance Program. Surgically confirmed gallbladder disease, venous thromboembolism and breast tumours in relation to postmenopausal estrogen therapy. N Engl J Med 1974; 290: 15–9
Nachtigall LE, Nachtigall RH, Nachtigall RD, et al. Estrogen replacement therapy. II: a prospective study in the relationship to carcinoma and cardiovascular and metabolic problems. Obstet Gynecol 1979; 54, 74–9
Petitti DB, Wingerd J, Pelegrin F, et al. Oral contraceptives, smoking, and other factors in relation to risk of venous thromboembolic disease. Am J Epidemiol 1978; 108: 480–5
Devor M, Barrett-Connor E, Renvall M, et al. Estrogen replacement therapy and the risk of venous thrombosis. Am J Med 1992; 92: 275–82
Daly E, Vessey MP, Hawkins MM, et al. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 1996; 348: 977–80
Jick H, Derby LE, Wald Myers M, et al. Risk of hospital admission for idiopathic venous thromboembolism among users of postmenopausal oestrogens. Lancet 1996; 348: 981–3
Grodstein F, Stampfer MJ, Goldhaber SZ, et al. Prospective study of exogenous hormones and risk of pulmonary embolism in women. Lancet 1996; 348: 983–7
Daly E, Vessey MP, Painter R, et al. Case-control study of venous thromboembolism risk in users of hormone replacement therapy [letter]. Lancet 1996; 348: 1027
Rosenberg L, Palmer JR, Adams-Campbell LL. Postmenopausal female hormone use and venous thromboembolic disease in Black women [letter]. Am J Obstet Gynecol 1997; 177: 1275
Pérez Gutthann S, García Rodríguez LA, Castellsague J, et al. Hormone replacement therapy and risk of venous thromboembolism: population based case-control study. BMJ 1997; 314: 796–800
Varas-Lorenzo C, García-Rodríguez LA, Cattaruzzi C, et al. Hormone replacement therapy and the risk of hospitalization for venous thromboembolism: a population-based study in southern Europe. Am J Epidemiol 1998; 147: 387–90
McKenna MJ. Risk of venous thrombosis with hormone replacement therapy [letter]. Lancet 1996; 348: 1668
Hulley S, Grady D, Bush T, for the Heart and Estrogen/Progestin Replacement Study (HERS) Research Group, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998; 280: 605–13
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Tavani, A., La Vecchia, C. The Adverse Effects of Hormone Replacement Therapy. Drugs Aging 14, 347–357 (1999). https://doi.org/10.2165/00002512-199914050-00003
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DOI: https://doi.org/10.2165/00002512-199914050-00003