Abnormal uterine bleeding and uterine pathology in women on tamoxifen therapy
- Steven R Goldstein, MD
Steven R Goldstein, MD
- Professor of Obstetrics and Gynecology
- New York University School of Medicine
- Jamie N Bakkum-Gamez, MD
Jamie N Bakkum-Gamez, MD
- Associate Professor of Obstetrics and Gynecology
- Mayo Clinic, Rochester, Minnesota
- 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
- Barbara Goff, MD
Barbara Goff, MD
- Section Editor — Gynecologic Oncology
- Professor of Gynecologic Oncology
- University of Washington
- Harold Burstein, MD, PhD
Harold Burstein, MD, PhD
- Section Editor — Breast Cancer
- Associate Professor of Medicine
- Harvard Medical School
Tamoxifen is a nonsteroidal selective estrogen receptor modulator that is used primarily for adjuvant treatment of estrogen receptor-positive breast cancer in premenopausal women, and in some postmenopausal women . It is also used for chemoprevention in women at increased risk for breast cancer.
Tamoxifen is associated with increased risks of uterine pathology, including endometrial polyps, endometrial carcinoma and hyperplasia, uterine sarcoma, and uterine carcinosarcoma.
Uterine pathology in women on tamoxifen is reviewed here. Use of tamoxifen for breast cancer therapy or breast cancer prevention and management of other adverse effects associated with tamoxifen are reviewed separately. (See "Adjuvant endocrine therapy for non-metastatic, hormone receptor-positive breast cancer" and "Selective estrogen receptor modulators and aromatase inhibitors for breast cancer prevention" and "Managing the side effects of tamoxifen".)
Mechanism of action — Tamoxifen is a competitive inhibitor of estrogen, binding to the estrogen receptor in the breast, which blocks tumor proliferation [2,3]. However, tamoxifen has a complex mechanism of action against tissues. While it is anti-estrogenic in the breast, it can be either an estrogen antagonist or agonist at different sites of the female reproductive tract.
Endometrial and menstrual effects — Tamoxifen is a mixed estrogen antagonist and agonist (referred to as a selective estrogen receptor modulator [SERM]).
- Early Breast Cancer Trialists' Collaborative Group (EBCTCG), Dowsett M, Forbes JF, et al. Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet 2015; 386:1341.
- Osborne C, Elledge RM, Fuqua SA. Estrogen Receptors in Breast Cancer Therapy. Sci Med 1996; 3:32.
- Jordan VC, Morrow M. Tamoxifen, raloxifene, and the prevention of breast cancer. Endocr Rev 1999; 20:253.
- Sunderland MC, Osborne CK. Tamoxifen in premenopausal patients with metastatic breast cancer: a review. J Clin Oncol 1991; 9:1283.
- Hachisuga T, Tsujioka H, Horiuchi S, et al. K-ras mutation in the endometrium of tamoxifen-treated breast cancer patients, with a comparison of tamoxifen and toremifene. Br J Cancer 2005; 92:1098.
- Tsujioka H, Hachisuga T, Fukuoka M, et al. Monitoring of endometrial K-ras mutation in tamoxifen-treated patients with breast cancer. Int J Gynecol Cancer 2009; 19:1052.
- Geiser AG, Hummel CW, Draper MW, et al. A new selective estrogen receptor modulator with potent uterine antagonist activity, agonist activity in bone, and minimal ovarian stimulation. Endocrinology 2005; 146:4524.
- Buijs C, Willemse PH, de Vries EG, et al. Effect of tamoxifen on the endometrium and the menstrual cycle of premenopausal breast cancer patients. Int J Gynecol Cancer 2009; 19:677.
- Cheng WF, Lin HH, Torng PL, Huang SC. Comparison of endometrial changes among symptomatic tamoxifen-treated and nontreated premenopausal and postmenopausal breast cancer patients. Gynecol Oncol 1997; 66:233.
- Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998; 90:1371.
- Hu R, Hilakivi-Clarke L, Clarke R. Molecular mechanisms of tamoxifen-associated endometrial cancer (Review). Oncol Lett 2015; 9:1495.
- Runowicz CD, Costantino JP, Wickerham DL, et al. Gynecologic conditions in participants in the NSABP breast cancer prevention study of tamoxifen and raloxifene (STAR). Am J Obstet Gynecol 2011; 205:535.e1.
- Committee Opinion No. 601: Tamoxifen and uterine cancer. Obstet Gynecol 2014; 123:1394.
- http://seer.cancer.gov/statfacts/html/breast.html (Accessed on March 22, 2016).
- Freeman EW, Sammel MD, Gracia CR, et al. Follicular phase hormone levels and menstrual bleeding status in the approach to menopause. Fertil Steril 2005; 83:383.
- American College of Obstetricians and Gynecologists. ACOG Committee Opinion No. 440: The Role of Transvaginal Ultrasonography in the Evaluation of Postmenopausal Bleeding. Obstet Gynecol 2009; 114:409.
- Committee on Practice Bulletins—Gynecology. Practice bulletin no. 128: diagnosis of abnormal uterine bleeding in reproductive-aged women. Obstet Gynecol 2012; 120:197. Reaffirmed 2016.
- Taponeco F, Curcio C, Fasciani A, et al. Indication of hysteroscopy in tamoxifen treated breast cancer patients. J Exp Clin Cancer Res 2002; 21:37.
- Dijkhuizen FP, Mol BW, Brölmann HA, Heintz AP. The accuracy of endometrial sampling in the diagnosis of patients with endometrial carcinoma and hyperplasia: a meta-analysis. Cancer 2000; 89:1765.
- Ozdemir S, Celik C, Gezginç K, et al. Evaluation of endometrial thickness with transvaginal ultrasonography and histopathology in premenopausal women with abnormal vaginal bleeding. Arch Gynecol Obstet 2010; 282:395.
- Goldstein SR. Unusual ultrasonographic appearance of the uterus in patients receiving tamoxifen. Am J Obstet Gynecol 1994; 170:447.
- Achiron R, Lipitz S, Sivan E, et al. Changes mimicking endometrial neoplasia in postmenopausal, tamoxifen-treated women with breast cancer: a transvaginal Doppler study. Ultrasound Obstet Gynecol 1995; 6:116.
- Goldstein SR, Neven P, Cummings S, et al. Postmenopausal Evaluation and Risk Reduction With Lasofoxifene (PEARL) trial: 5-year gynecological outcomes. Menopause 2011; 18:17.
- Goldstein SR, Nanavati N. Adverse events that are associated with the selective estrogen receptor modulator levormeloxifene in an aborted phase III osteoporosis treatment study. Am J Obstet Gynecol 2002; 187:521.
- Chang J, Powles TJ, Ashley SE, et al. Variation in endometrial thickening in women with amenorrhea on tamoxifen. Breast Cancer Res Treat 1998; 48:81.
- Wickerham DL, Fisher B, Wolmark N, et al. Association of tamoxifen and uterine sarcoma. J Clin Oncol 2002; 20:2758.
- Cohen I, Altaras MM, Shapira J, et al. Time-dependent effect of tamoxifen therapy on endometrial pathology in asymptomatic postmenopausal breast cancer patients. Int J Gynecol Pathol 1996; 15:152.
- Machado F, Rodríguez JR, León JP, et al. Tamoxifen and endometrial cancer. Is screening necessary? A review of the literature. Eur J Gynaecol Oncol 2005; 26:257.
- Neven P, De Muylder X, Van Belle Y, et al. Longitudinal hysteroscopic follow-up during tamoxifen treatment. Lancet 1998; 351:36.
- Cohen I. Endometrial pathologies associated with postmenopausal tamoxifen treatment. Gynecol Oncol 2004; 94:256.
- Dal Cin P, Timmerman D, Van den Berghe I, et al. Genomic changes in endometrial polyps associated with tamoxifen show no evidence for its action as an external carcinogen. Cancer Res 1998; 58:2278.
- Althuis MD, Sexton M, Langenberg P, et al. Surveillance for uterine abnormalities in tamoxifen-treated breast carcinoma survivors: a community based study. Cancer 2000; 89:800.
- McGurgan P, Taylor LJ, Duffy SR, O'Donovan PJ. Does tamoxifen therapy affect the hormone receptor expression and cell proliferation indices of endometrial polyps? An immunohistochemical comparison of endometrial polyps from postmenopausal women exposed and not exposed to tamoxifen. Maturitas 2006; 54:252.
- Schlesinger C, Kamoi S, Ascher SM, et al. Endometrial polyps: a comparison study of patients receiving tamoxifen with two control groups. Int J Gynecol Pathol 1998; 17:302.
- Cohen I, Bernheim J, Azaria R, et al. Malignant endometrial polyps in postmenopausal breast cancer tamoxifen-treated patients. Gynecol Oncol 1999; 75:136.
- Ricciardi E, Vecchione A, Marci R, et al. Clinical factors and malignancy in endometrial polyps. Analysis of 1027 cases. Eur J Obstet Gynecol Reprod Biol 2014; 183:121.
- Lee SC, Kaunitz AM, Sanchez-Ramos L, Rhatigan RM. The oncogenic potential of endometrial polyps: a systematic review and meta-analysis. Obstet Gynecol 2010; 116:1197.
- McGonigle KF, Lantry SA, Odom-Maryon TL, et al. Histopathologic effects of tamoxifen on the uterine epithelium of breast cancer patients: analysis by menopausal status. Cancer Lett 1996; 101:59.
- Dominick S, Hickey M, Chin J, Su HI. Levonorgestrel intrauterine system for endometrial protection in women with breast cancer on adjuvant tamoxifen. Cochrane Database Syst Rev 2015; :CD007245.
- Fisher B, Costantino JP, Redmond CK, et al. Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst 1994; 86:527.
- Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 2005; 97:1652.
- Iqbal J, Ginsburg OM, Wijeratne TD, et al. Endometrial cancer and venous thromboembolism in women under age 50 who take tamoxifen for prevention of breast cancer: a systematic review. Cancer Treat Rev 2012; 38:318.
- Davies C, Pan H, Godwin J, et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 2013; 381:805.
- Bergman L, Beelen ML, Gallee MP, et al. Risk and prognosis of endometrial cancer after tamoxifen for breast cancer. Comprehensive Cancer Centres' ALERT Group. Assessment of Liver and Endometrial cancer Risk following Tamoxifen. Lancet 2000; 356:881.
- Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet 1998; 351:1451.
- Nelson HD, Smith ME, Griffin JC, Fu R. Use of medications to reduce risk for primary breast cancer: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 2013; 158:604.
- Bernstein L, Deapen D, Cerhan JR, et al. Tamoxifen therapy for breast cancer and endometrial cancer risk. J Natl Cancer Inst 1999; 91:1654.
- Markovitch O, Tepper R, Fishman A, et al. Long-term follow-up of postmenopausal breast cancer patients following discontinuation of tamoxifen therapy. Maturitas 2008; 59:387.
- Markovitch O, Tepper R, Fishman A, et al. Aromatase inhibitors reverse tamoxifen induced endometrial ultrasonographic changes in postmenopausal breast cancer patients. Breast Cancer Res Treat 2007; 101:185.
- Cuzick J, Sestak I, Cawthorn S, et al. Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial. Lancet Oncol 2015; 16:67.
- Hoogendoorn WE, Hollema H, van Boven HH, et al. Prognosis of uterine corpus cancer after tamoxifen treatment for breast cancer. Breast Cancer Res Treat 2008; 112:99.
- Magriples U, Naftolin F, Schwartz PE, Carcangiu ML. High-grade endometrial carcinoma in tamoxifen-treated breast cancer patients. J Clin Oncol 1993; 11:485.
- Bland AE, Calingaert B, Secord AA, et al. Relationship between tamoxifen use and high risk endometrial cancer histologic types. Gynecol Oncol 2009; 112:150.
- Barakat RR, Wong G, Curtin JP, et al. Tamoxifen use in breast cancer patients who subsequently develop corpus cancer is not associated with a higher incidence of adverse histologic features. Gynecol Oncol 1994; 55:164.
- Fung MF, Reid A, Faught W, et al. Prospective longitudinal study of ultrasound screening for endometrial abnormalities in women with breast cancer receiving tamoxifen. Gynecol Oncol 2003; 91:154.
- Bertelli G, Venturini M, Del Mastro L, et al. Tamoxifen and the endometrium: findings of pelvic ultrasound examination and endometrial biopsy in asymptomatic breast cancer patients. Breast Cancer Res Treat 1998; 47:41.
- Berlière M, Charles A, Galant C, Donnez J. Uterine side effects of tamoxifen: a need for systematic pretreatment screening. Obstet Gynecol 1998; 91:40.
- Berlière M, Radikov G, Galant C, et al. Identification of women at high risk of developing endometrial cancer on tamoxifen. Eur J Cancer 2000; 36 Suppl 4:S35.
- Lavie O, Barnett-Griness O, Narod SA, Rennert G. The risk of developing uterine sarcoma after tamoxifen use. Int J Gynecol Cancer 2008; 18:352.
- Yildirim Y, Inal MM, Sanci M, et al. Development of uterine sarcoma after tamoxifen treatment for breast cancer: report of four cases. Int J Gynecol Cancer 2005; 15:1239.
- Arici DS, Aker H, Yildiz E, Tasyurt A. Mullerian adenosarcoma of the uterus associated with tamoxifen therapy. Arch Gynecol Obstet 2000; 264:105.
- Engin H. High-grade endometrial stromal sarcoma following tamoxifen treatment. Gynecol Oncol 2008; 108:253.
- Mourits MJ, De Vries EG, Willemse PH, et al. Tamoxifen treatment and gynecologic side effects: a review. Obstet Gynecol 2001; 97:855.
- Wysowski DK, Honig SF, Beitz J. Uterine sarcoma associated with tamoxifen use. N Engl J Med 2002; 346:1832.
- Ueda SM, Kapp DS, Cheung MK, et al. Trends in demographic and clinical characteristics in women diagnosed with corpus cancer and their potential impact on the increasing number of deaths. Am J Obstet Gynecol 2008; 198:218.e1.
- Kloos I, Delaloge S, Pautier P, et al. Tamoxifen-related uterine carcinosarcomas occur under/after prolonged treatment: report of five cases and review of the literature. Int J Gynecol Cancer 2002; 12:496.
- Wickerham DL, Fisher B, Wolmark N, et al. Association of tamoxifen and uterine sarcoma. J Clin Oncol 2002; 20:2758.
- Moinfar F, Azodi M, Tavassoli FA. Uterine sarcomas. Pathology 2007; 39:55.
- http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm154510.htm (Accessed on October 12, 2010).
- Ahonkallio SJ, Liakka AK, Martikainen HK, Santala MJ. Feasibility of endometrial assessment after thermal ablation. Eur J Obstet Gynecol Reprod Biol 2009; 147:69.
- Krogh RA, Lauszus FF, Guttorm E, Rasmussen K. Surgery and cancer after endometrial resection. Long-term follow-up on menstrual bleeding and hormone treatment by questionnaire and registry. Arch Gynecol Obstet 2009; 280:911.
- Valle RF, Baggish MS. Endometrial carcinoma after endometrial ablation: high-risk factors predicting its occurrence. Am J Obstet Gynecol 1998; 179:569.
- Feldman S, Shapter A, Welch WR, Berkowitz RS. Two-year follow-up of 263 patients with post/perimenopausal vaginal bleeding and negative initial biopsy. Gynecol Oncol 1994; 55:56.
- 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.
- Cruz Jurado J, Richart Aznar P, García Mata J, et al. Management of patients with metastatic breast cancer. Adv Ther 2011; 28 Suppl 6:50.
- Loprinzi CL, Barton DL, Sloan JA, et al. Mayo Clinic and North Central Cancer Treatment Group hot flash studies: a 20-year experience. Menopause 2008; 15:655.
- Chin J, Konje JC, Hickey M. Levonorgestrel intrauterine system for endometrial protection in women with breast cancer on adjuvant tamoxifen. Cochrane Database Syst Rev 2009; :CD007245.
- Trinh XB, Tjalma WA, Makar AP, et al. Use of the levonorgestrel-releasing intrauterine system in breast cancer patients. Fertil Steril 2008; 90:17.
- Lyytinen HK, Dyba T, Ylikorkala O, Pukkala EI. A case-control study on hormone therapy as a risk factor for breast cancer in Finland: Intrauterine system carries a risk as well. Int J Cancer 2010; 126:483.
- Chan SS, Tam WH, Yeo W, et al. A randomised controlled trial of prophylactic levonorgestrel intrauterine system in tamoxifen-treated women. BJOG 2007; 114:1510.
- Gardner FJ, Konje JC, Bell SC, et al. Prevention of tamoxifen induced endometrial polyps using a levonorgestrel releasing intrauterine system long-term follow-up of a randomised control trial. Gynecol Oncol 2009; 114:452.
- Kesim MD, Aydin Y, Atis A, Mandiraci G. Long-term effects of the levonorgestrel-releasing intrauterine system on serum lipids and the endometrium in breast cancer patients taking tamoxifen. Climacteric 2008; 11:252.
- Wong AW, Chan SS, Yeo W, et al. Prophylactic use of levonorgestrel-releasing intrauterine system in women with breast cancer treated with tamoxifen: a randomized controlled trial. Obstet Gynecol 2013; 121:943.
- Mechanism of action
- Endometrial and menstrual effects
- - Premenopausal women
- - Postmenopausal women
- CLINICAL PRESENTATION AND EVALUATION
- Abnormal uterine bleeding
- - Evaluation
- Medical history
- Determining menopausal status
- Pelvic ultrasound and endometrial sampling
- Incidental findings on pelvic ultrasound
- RISKS AND MANAGEMENT OF UTERINE PATHOLOGY
- Endometrial polyps
- Endometrial hyperplasia
- Endometrial carcinoma
- - Risk of malignancy
- Postmenopasual versus premenopausal women
- Duration of therapy
- Risk after discontinuation of tamoxifen
- - Management
- - Prognosis
- - Screening
- Uterine sarcoma and carcinosarcoma
- MANAGEMENT ISSUES
- Persistent AUB without uterine pathology
- Progestins for prevention and treatment
- SUMMARY AND RECOMMENDATIONS