Menopausal hormone therapy and the risk of breast cancer
- Wendy Y Chen, MD, MPH
Wendy Y Chen, MD, MPH
- Assistant Professor of Medicine
- Harvard Medical School
- Section Editors
- Robert L Barbieri, MD
Robert L Barbieri, MD
- Editor-in-Chief — Obstetrics, Gynecology and Women's Health
- Section Editor — General Gynecology and Female Reproductive Endocrinology
- Kate Macy Ladd Professor of Obstetrics, Gynecology and Reproductive Biology
- Harvard Medical School
- William F Crowley, Jr, MD
William F Crowley, Jr, MD
- Section Editor — Female Reproductive Endocrinology
- Daniel K Podolsky Professor of Medicine
- Harvard Medical School
- Joann G Elmore, MD, MPH
Joann G Elmore, MD, MPH
- Editor-in-Chief — Primary Care (Adult)
- Section Editor — General Medicine
- Professor of Medicine, Adjunct Professor of Epidemiology
- University of Washington School of Medicine
One of the greatest concerns of women who are considering menopausal hormone therapy (MHT) is the relationship between hormone use and breast cancer. The results of the Women's Health Initiative (WHI) trial of combined estrogen-progestin, a large randomized, controlled trial, are consistent with the increased risk of breast cancer seen in many observational studies of MHT. (See 'Women's Health Initiative' below.)
Observational studies of MHT and breast cancer and the results from the WHI will be reviewed here. The relationship between endogenous hormones and breast cancer and a general discussion of the risks and benefits of MHT are discussed separately. (See "Factors that modify breast cancer risk in women" and "Menopausal hormone therapy: Benefits and risks".)
Support for the association of menopausal hormone therapy (MHT) with breast cancer is derived from studies that suggest that prolonged exposure to higher concentrations of endogenous estrogen increases the risk of breast cancer. These risk factors include:
●Reproductive factors, including age at menarche, age at first live birth, age at menopause, and possibly parity and breast feeding.
●Higher serum estrogen concentrations in postmenopausal women. The association is less clear in premenopausal women.To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- 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. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet 1997; 350:1047.
- Beral V, Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003; 362:419.
- Rossouw JE, Anderson GL, Prentice RL, et al. 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.
- Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. JAMA 2003; 289:3243.
- Chlebowski RT, Rohan TE, Manson JE, et al. Breast Cancer After Use of Estrogen Plus Progestin and Estrogen Alone: Analyses of Data From 2 Women's Health Initiative Randomized Clinical Trials. JAMA Oncol 2015; 1:296.
- McTiernan A, Martin CF, Peck JD, et al. Estrogen-plus-progestin use and mammographic density in postmenopausal women: Women's Health Initiative randomized trial. J Natl Cancer Inst 2005; 97:1366.
- McTiernan A, Chlebowski RT, Martin C, et al. Conjugated equine estrogen influence on mammographic density in postmenopausal women in a substudy of the women's health initiative randomized trial. J Clin Oncol 2009; 27:6135.
- Chlebowski RT, Anderson G, Pettinger M, et al. Estrogen plus progestin and breast cancer detection by means of mammography and breast biopsy. Arch Intern Med 2008; 168:370.
- Chlebowski RT, Anderson G, Manson JE, et al. Estrogen alone in postmenopausal women and breast cancer detection by means of mammography and breast biopsy. J Clin Oncol 2010; 28:2690.
- Buist DS, Anderson ML, Reed SD, et al. Short-term hormone therapy suspension and mammography recall: a randomized trial. Ann Intern Med 2009; 150:752.
- Li CI, Malone KE, Porter PL, et al. Relationship between long durations and different regimens of hormone therapy and risk of breast cancer. JAMA 2003; 289:3254.
- Chen WY, Manson JE, Hankinson SE, et al. Unopposed estrogen therapy and the risk of invasive breast cancer. Arch Intern Med 2006; 166:1027.
- Zhang SM, Manson JE, Rexrode KM, et al. Use of oral conjugated estrogen alone and risk of breast cancer. Am J Epidemiol 2007; 165:524.
- Schairer C, Lubin J, Troisi R, et al. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 2000; 283:485.
- Ross RK, Paganini-Hill A, Wan PC, Pike MC. Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. J Natl Cancer Inst 2000; 92:328.
- Olsson HL, Ingvar C, Bladström A. Hormone replacement therapy containing progestins and given continuously increases breast carcinoma risk in Sweden. Cancer 2003; 97:1387.
- Stahlberg C, Pedersen AT, Lynge E, et al. Increased risk of breast cancer following different regimens of hormone replacement therapy frequently used in Europe. Int J Cancer 2004; 109:721.
- Fournier A, Berrino F, Riboli E, et al. Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort. Int J Cancer 2005; 114:448.
- Tjønneland A, Christensen J, Thomsen BL, et al. Hormone replacement therapy in relation to breast carcinoma incidence rate ratios: a prospective Danish cohort study. Cancer 2004; 100:2328.
- Bakken K, Fournier A, Lund E, et al. Menopausal hormone therapy and breast cancer risk: impact of different treatments. The European Prospective Investigation into Cancer and Nutrition. Int J Cancer 2011; 128:144.
- Colditz GA. Relationship between estrogen levels, use of hormone replacement therapy, and breast cancer. J Natl Cancer Inst 1998; 90:814.
- Clarke C, Sutherland R. Progestin regulation of cellular proliferation: Update 1993. In: Endocrine Reviews, Horwitz K (Ed), Endocrine Society, Bethesda, MD 1993. p.132.
- Greendale GA, Reboussin BA, Sie A, et al. Effects of estrogen and estrogen-progestin on mammographic parenchymal density. Postmenopausal Estrogen/Progestin Interventions (PEPI) Investigators. Ann Intern Med 1999; 130:262.
- Hofseth LJ, Raafat AM, Osuch JR, et al. Hormone replacement therapy with estrogen or estrogen plus medroxyprogesterone acetate is associated with increased epithelial proliferation in the normal postmenopausal breast. J Clin Endocrinol Metab 1999; 84:4559.
- Cline JM, Soderqvist G, von Schoultz E, et al. Effects of hormone replacement therapy on the mammary gland of surgically postmenopausal cynomolgus macaques. Am J Obstet Gynecol 1996; 174:93.
- Wren B. Hormonal replacement therapy and breast cancer. Eur Menopause J 1995; 2:13.
- Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat 2008; 107:103.
- Chlebowski RT, Anderson GL, Gass M, et al. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA 2010; 304:1684.
- Chlebowski RT, Manson JE, Anderson GL, et al. Estrogen plus progestin and breast cancer incidence and mortality in the Women's Health Initiative Observational Study. J Natl Cancer Inst 2013; 105:526.
- Nanda K, Bastian LA, Schulz K. Hormone replacement therapy and the risk of death from breast cancer: a systematic review. Am J Obstet Gynecol 2002; 186:325.
- Brewster AM, Do KA, Thompson PA, et al. Relationship between epidemiologic risk factors and breast cancer recurrence. J Clin Oncol 2007; 25:4438.
- Sener SF, Winchester DJ, Winchester DP, et al. The effects of hormone replacement therapy on postmenopausal breast cancer biology and survival. Am J Surg 2009; 197:403.
- Christante D, Pommier S, Garreau J, et al. Improved breast cancer survival among hormone replacement therapy users is durable after 5 years of additional follow-up. Am J Surg 2008; 196:505.
- Slanger TE, Chang-Claude JC, Obi N, et al. Menopausal hormone therapy and risk of clinical breast cancer subtypes. Cancer Epidemiol Biomarkers Prev 2009; 18:1188.
- Anderson GL, Chlebowski RT, Aragaki AK, et al. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women's Health Initiative randomised placebo-controlled trial. Lancet Oncol 2012; 13:476.
- Beral V, Reeves G, Bull D, et al. Breast cancer risk in relation to the interval between menopause and starting hormone therapy. J Natl Cancer Inst 2011; 103:296.
- Prentice RL, Chlebowski RT, Stefanick ML, et al. Estrogen plus progestin therapy and breast cancer in recently postmenopausal women. Am J Epidemiol 2008; 167:1207.
- Sellers TA, Mink PJ, Cerhan JR, et al. The role of hormone replacement therapy in the risk for breast cancer and total mortality in women with a family history of breast cancer. Ann Intern Med 1997; 127:973.
- Colditz GA, Rosner BA, Speizer FE. Risk factors for breast cancer according to family history of breast cancer. For the Nurses' Health Study Research Group. J Natl Cancer Inst 1996; 88:365.
- Tamimi RM, Hankinson SE, Chen WY, et al. Combined estrogen and testosterone use and risk of breast cancer in postmenopausal women. Arch Intern Med 2006; 166:1483.
- Chen WY, Colditz GA, Rosner B, et al. Use of postmenopausal hormones, alcohol, and risk for invasive breast cancer. Ann Intern Med 2002; 137:798.
- Rosenberg L, Palmer JR, Wise LA, Adams-Campbell LL. A prospective study of female hormone use and breast cancer among black women. Arch Intern Med 2006; 166:760.
- Cobleigh MA, Berris RF, Bush T, et al. Estrogen replacement therapy in breast cancer survivors. A time for change. Breast Cancer Committees of the Eastern Cooperative Oncology Group. JAMA 1994; 272:540.
- Vassilopoulou-Sellin R, Theriault R, Klein MJ. Estrogen replacement therapy in women with prior diagnosis and treatment for breast cancer. Gynecol Oncol 1997; 65:89.
- Vassilopoulou-Sellin R, Asmar L, Hortobagyi GN, et al. Estrogen replacement therapy after localized breast cancer: clinical outcome of 319 women followed prospectively. J Clin Oncol 1999; 17:1482.
- DiSaia PJ, Grosen EA, Kurosaki T, et al. Hormone replacement therapy in breast cancer survivors: a cohort study. Am J Obstet Gynecol 1996; 174:1494.
- Natrajan PK, Soumakis K, Gambrell RD Jr. Estrogen replacement therapy in women with previous breast cancer. Am J Obstet Gynecol 1999; 181:288.
- Beckmann MW, Jap D, Djahansouzi S, et al. Hormone replacement therapy after treatment of breast cancer: effects on postmenopausal symptoms, bone mineral density and recurrence rates. Oncology 2001; 60:199.
- Col NF, Hirota LK, Orr RK, et al. Hormone replacement therapy after breast cancer: a systematic review and quantitative assessment of risk. J Clin Oncol 2001; 19:2357.
- O'Meara ES, Rossing MA, Daling JR, et al. Hormone replacement therapy after a diagnosis of breast cancer in relation to recurrence and mortality. J Natl Cancer Inst 2001; 93:754.
- Holmberg L, Iversen OE, Rudenstam CM, et al. Increased risk of recurrence after hormone replacement therapy in breast cancer survivors. J Natl Cancer Inst 2008; 100:475.
- Fahlén M, Fornander T, Johansson H, et al. Hormone replacement therapy after breast cancer: 10 year follow up of the Stockholm randomised trial. Eur J Cancer 2013; 49:52.
- Colditz GA. Menopausal hormone therapy after breast cancer. Breast Cancer Res 2005; 7:168.
- North American Menopause Society. Estrogen and progestogen use in postmenopausal women: 2010 position statement of The North American Menopause Society. Menopause 2010; 17:242.
- ENDOGENOUS HORMONES
- EXOGENOUS HORMONE THERAPY
- Epidemiologic data
- Women's Health Initiative
- - Combination therapy
- Absolute risk
- Post-WHI rates
- - Unopposed estrogen
- - Mammographic density
- - Abnormal mammography
- Duration of use
- Effect of progestins
- - Type of progestin
- - Mortality
- Timing of hormone therapy
- OTHER ISSUES
- Women with a family history of cancer
- Effect of testosterone
- Effect of alcohol
- Women with premature ovarian failure
- Effect of race on risk
- Personal history of breast cancer
- - Observational data
- - Clinical trial data
- INFORMATION FOR PATIENTS