Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Hormone replacement therapy and the risk of breast cancer

Abstract

Hormone replacement therapy (HRT) is given to relieve the climacteric symptoms of menopause. Use of HRT reduced after a report from the Women's Health Initiative linked it to an increased risk of breast cancer. This association has been confirmed in several other studies, including the Million Women Study. The risk of breast cancer is greater for formulations that contain both estrogen and progesterone, compared with estrogen alone. The breast cancer risk associated with HRT is higher for estrogen receptor-positive cancers than for estrogen receptor-negative cancers, and for low-grade cancers compared with high-grade cancers. After cessation of HRT the increased risk of breast cancer dissipates within 2 years. The rapidity of the decline suggests that a proportion of breast cancers that are hormone dependent will regress if the hormonal stimulation is removed. In evaluating a woman who is considering HRT, factors that have been associated with an increased risk include the initiation of hormone use immediately after menopause, a lean body mass and high mammographic breast density.

Key Points

  • Hormone replacement therapy (HRT) is associated with an increase in the risk of breast cancer, and the risk increases with duration of use

  • The risk associated with HRT is greater for estrogen–progesterone combination than for estrogen alone

  • The risk of breast cancer dissipates within 2 years of cessation of treatment

  • Cancers associated with HRT tend to be low grade and estrogen receptor positive

  • Women with a lean body mass or high breast density face a higher risk of HRT-associated breast cancer than other women

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1

    Barrett-Connor, E. & Stuenkel, C. A. Hormone replacement therapy (HRT)—risks and benefits. Int. J. Epidemiol. 30, 423–426 (2001).

    CAS  Article  Google Scholar 

  2. 2

    Allen, N. E. et al. Menopausal hormone therapy and risk of endometrial carcinoma among postmenopausal women in the European Prospective Investigation Into Cancer and Nutrition. Am. J. Epidemiol. 172, 1394–1403 (2010).

    Article  Google Scholar 

  3. 3

    Pachman, D. R., Jones, J. M. & Loprinzi, C. L. Management of menopause-associated vasomotor symptoms: current treatment options, challenges and future directions. Int. J. Womens Health 2, 123–135 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Ravdin, P. M. et al. The decrease in breast-cancer incidence in 2003 in the United States. N. Engl. J. Med. 356, 1670–1674 (2007).

    CAS  Article  Google Scholar 

  5. 5

    Hersh, A. L., Stefanick, M. L. & Stafford, R. S. National use of postmenopausal hormone therapy: annual trends and response to recent evidence. JAMA 291, 47–53 (2004).

    CAS  Article  Google Scholar 

  6. 6

    Buist, D. S. et al. Hormone therapy prescribing patterns in the United States. Obstet. Gynecol. 104, 1042–1050 (2004).

    Article  Google Scholar 

  7. 7

    Collins, J. A., Blake, J. M. & Crosignani, P. G. Breast cancer risk with postmenopausal hormonal treatment. Hum. Reprod. Update 11, 545–560 (2005).

    CAS  Article  Google Scholar 

  8. 8

    Chlebowski, R. T. et al. Breast cancer after use of estrogen plus progestin in postmenopausal women. N. Engl. J. Med. 360, 573–587 (2009).

    CAS  Article  Google Scholar 

  9. 9

    Prentice, R. L. et al. Conjugated equine estrogens and breast cancer risk in the Women's Health Initiative clinical trial and observational study. Am. J. Epidemiol. 167, 1407–1415 (2008).

    Article  Google Scholar 

  10. 10

    Rossouw, J. E. 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 288, 321–333 (2002).

    CAS  Article  Google Scholar 

  11. 11

    Chlebowski, R. T. et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. JAMA 289, 3243–3253 (2003).

    CAS  Article  Google Scholar 

  12. 12

    Anderson, G. L. et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 291, 1701–1712 (2004).

    CAS  Article  Google Scholar 

  13. 13

    Anderson, G. L. et al. Prior hormone therapy and breast cancer risk in the Women's Health Initiative randomized trial of estrogen plus progestin. Maturitas 55, 103–115 (2006).

    CAS  Article  Google Scholar 

  14. 14

    Stefanik, M. L. et al. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA 295, 1647–1657 (2006).

    Article  Google Scholar 

  15. 15

    Prentice, R. L. et al. Estrogen plus progestin therapy and breast cancer in recently postmenopausal women. Am. J. Epidemiol. 167, 1207–1216 (2008).

    Article  Google Scholar 

  16. 16

    Chlebowski, R. T. et al. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA 304, 1684–1692 (2010).

    CAS  Article  Google Scholar 

  17. 17

    Beral, V. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 362, 419–427 (2003).

    CAS  Article  Google Scholar 

  18. 18

    Beral, V., Reeves, G., Bull, D. & Green, J. Breast cancer risk in relation to the interval between menopause and starting hormone therapy. J. Natl Cancer Inst. 103, 296–305 (2011).

    CAS  Article  Google Scholar 

  19. 19

    Santen, R. J. Does menopausal hormone therapy initiate new breast cancers or promote the growth of existing ones? Womens Health (Lond. Engl.) 4, 207–210 (2008).

    CAS  Article  Google Scholar 

  20. 20

    [No authors listed] 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 350, 1047–1059 (1997).

  21. 21

    Pike, M. C., Spicer, D. V., Dahmoush, L. & Press, M. F. Estrogens, progestogens, normal breast cell proliferation, and breast cancer risk. Epidemiol. Rev. 15, 17–35 (1993).

    CAS  Article  Google Scholar 

  22. 22

    Ross, R. K., Paganini-Hill, A., Wan, P. C. & Pike, M. C. Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. J. Natl Cancer Inst. 92, 328–332 (2000).

    CAS  Article  Google Scholar 

  23. 23

    Saxena, T. et al. Menopausal hormone therapy and subsequent risk of specific invasive breast cancer subtypes in the California Teachers Study. Cancer Epidemiol. Biomarkers Prev. 19, 2366–2378 (2010).

    CAS  Article  Google Scholar 

  24. 24

    Calle, E. E. et al. Postmenopausal hormone use and breast cancer associations differ by hormone regimen and histologic subtype. Cancer 115, 936–945 (2009).

    CAS  Article  Google Scholar 

  25. 25

    Bergkvist, L., Adami, H. O., Persson, I., Hoover, R. & Schairer, C. The risk of breast cancer after estrogen and estrogen-progestin replacement. N. Engl. J. Med. 321, 293–297 (1989).

    CAS  Article  Google Scholar 

  26. 26

    Ewertz, M. et al. Hormone use for menopausal symptoms and risk of breast cancer. A Danish cohort study. Br. J. Cancer 92, 1293–1297 (2005).

    CAS  Article  Google Scholar 

  27. 27

    Petrelli, J. M., Calle, E. E., Rodriguez, C. & Thun, M. J. Body mass index, height, and postmenopausal breast cancer mortality in a prospective cohort of US women. Cancer Causes Control 13, 325–332 (2002).

    Article  Google Scholar 

  28. 28

    Zumoff, B. Relationship of obesity to blood estrogens. Cancer Res. 42 (Suppl.), 3289s–3294s (1982).

    CAS  PubMed  Google Scholar 

  29. 29

    Dupont, W. D. et al. Estrogen replacement therapy in women with a history of proliferative breast disease. Cancer 85, 1277–1283 (1999).

    CAS  Article  Google Scholar 

  30. 30

    Kerlikowske, K. et al. Breast cancer risk by breast density, menopause, and postmenopausal hormone therapy use. J. Clin. Oncol. 28, 3830–3837 (2010).

    Article  Google Scholar 

  31. 31

    Narod, S. A. & Foulkes, W. D. BRCA1 and BRCA2: 1994 and beyond. Nat. Rev. Cancer 4, 665–676 (2004).

    CAS  Article  Google Scholar 

  32. 32

    Finch, A. et al. The impact of prophylactic salpingo-oophorectomy on menopausal symptoms and sexual function in women who carry a BRCA mutation. Gynecol. Oncol. 121, 163–168 (2011).

    CAS  Article  Google Scholar 

  33. 33

    Eisen, A. et al. Hormone therapy and the risk of breast cancer in BRCA1 mutation carriers. J. Natl Cancer Inst. 100, 1361–1367 (2008).

    CAS  Article  Google Scholar 

  34. 34

    Kumle, M. Declining breast cancer incidence and decreased HRT use. Lancet 372, 608–610 (2008).

    Article  Google Scholar 

  35. 35

    Lee, S. A., Ross, R. K. & Pike, M. C. An overview of menopausal oestrogen-progestin hormone therapy and breast cancer risk. Br. J. Cancer 92, 2049–2058 (2005).

    CAS  Article  Google Scholar 

  36. 36

    Prasad, R. et al. Short-term biologic response to withdrawal of hormone replacement therapy in patients with invasive breast carcinoma. Cancer 98, 2539–2546 (2003).

    CAS  Article  Google Scholar 

  37. 37

    Milla-Santos, A. et al. Anastrozole as neoadjuvant therapy for patients with hormone-dependent, locally-advanced breast cancer. Anticancer Res. 24, 1315–1318 (2004).

    CAS  PubMed  Google Scholar 

  38. 38

    Dhodapkar, M. V., Ingle, J. N. & Ahmann, D. L. Estrogen replacement therapy withdrawal and regression of metastatic breast cancer. Cancer 75, 43–46 (1996).

    Article  Google Scholar 

  39. 39

    Welch, H. G. Overdiagnosis and mammography screening. BMJ 339, 182–183 (2009).

    Article  Google Scholar 

  40. 40

    Zackrisson, S., Andersson, I., Janzon, L., Manjer, J. & Garne, J. P. Rate of over-diagnosis of breast cancer 15 years after end of Malmö mammographic screening trial: follow-up study. BMJ 332, 689–692 (2006).

    Article  Google Scholar 

  41. 41

    Cuzick, J. et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol. 11, 1135–1141 (2010).

    CAS  Article  Google Scholar 

  42. 42

    Doll, R., Peto, R., Boreham, J. & Sutherland, I. Mortality in relation to smoking: 50 years' observations on male British doctors. BMJ 328, 1519 (2004).

    Article  Google Scholar 

  43. 43

    Lodovici, M. & Bigagli, E. Biomarkers of induced active and passive smoking damage. Int. J. Environ. Res. Public Health 6, 874–888 (2009).

    CAS  Article  Google Scholar 

  44. 44

    Russo, J. & Russo, I. H. Genotoxicity of steroidal estrogens. Trends Endocrinol. Metab. 15, 211–214 (2004).

    CAS  Article  Google Scholar 

  45. 45

    Wellings, S. R., Jensen, H. M. & Marcum, R. G. An atlas of subgross pathology of the human breast with special reference to possible precancerous lesions. J. Natl Cancer Inst. 55, 231–273 (1975).

    CAS  PubMed  Google Scholar 

  46. 46

    Jordan, V. C., Mittal, S., Gosden, B., Koch, R. & Lieberman, M. E. Structure-activity relationships of estrogens. Environ. Health Perspect. 61, 97–110 (1985).

    CAS  Article  Google Scholar 

  47. 47

    [No authors listed] Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet 347, 1713–1727 (1996).

  48. 48

    Horwitz, K. B., Dye, W. W., Harrell, J. C., Kabos, P. & Sartorius, C. A. Rare steroid receptor-negative basal-like tumorigenic cells in luminal subtype human breast cancer xenografts. Proc. Natl Acad. Sci. USA 105, 5774–5779 (2008).

    CAS  Article  Google Scholar 

  49. 49

    Horwitz, K. B. & Sartorius, C. A. Progestins in hormone replacement therapies reactivate cancer stem cells in women with preexisting breast cancers: a hypothesis. J. Clin. Endocrinol. Metab. 93, 3295–3298 (2008).

    CAS  Article  Google Scholar 

  50. 50

    Joshi, P. A. et al. Progesterone induces adult mammary stem cell expansion. Nature 465, 803–807 (2010).

    CAS  Article  Google Scholar 

  51. 51

    Asselin-Labat, M. L. et al. Control of mammary stem cell function by steroid hormone signalling. Nature 465, 798–802 (2010).

    CAS  Article  Google Scholar 

  52. 52

    Schramek, D. et al. Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer. Nature 468, 98–102 (2010).

    CAS  Article  Google Scholar 

  53. 53

    Cummings, S. R. et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N. Engl. J. Med. 361, 756–765 (2009).

    CAS  Article  Google Scholar 

  54. 54

    Narod, S. A. Age of diagnosis, tumor size, and survival after breast cancer: implications for mammographic screening. Breast Cancer Res. Treat. doi:10.1007/s10549-010-1318-9.

  55. 55

    Holmberg, L. et al. Increased risk of recurrence after hormone replacement therapy in breast cancer survivors. J. Natl Cancer Inst. 100, 475–482 (2008).

    CAS  Article  Google Scholar 

  56. 56

    Lee, A. H. & Ellis, I. O. The Nottingham prognostic index for invasive carcinoma of the breast. Pathol. Oncol. Res. 14, 113–115 (2008).

    Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Ethics declarations

Competing interests

The author declares no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Narod, S. Hormone replacement therapy and the risk of breast cancer. Nat Rev Clin Oncol 8, 669–676 (2011). https://doi.org/10.1038/nrclinonc.2011.110

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing