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Introduction: Results form the Women’s Health Initiative (WHI)--a large randomized clinical trial--confirmed what other studies had long suggested: long-term use of postmenopausal hormones containing estrogen plus progestin increase the risk of breast cancer [1].
For postmenopausal hormones containing estrogen alone, results are not yet conclusive. The WHI found no increase in breast cancer risk [2] and the Nurses’ Health Study found an increase in risk only after 20 or more years of use [3]. However, other cohort studies and pooled analyses have found use of hormones containing estrogen alone increase breast cancer risk. Overall, the evidence shows that postmenopausal hormones containing estrogen plus progestin increases breast risk to a greater degree than those containing estrogen-alone.
Find more information on the strengths and weaknesses of different types of studies.
See how this risk factor compares with other risk factors for breast cancer.
Study selection criteria: Available randomized clinical trials, prospective cohort studies and pooled analyses with at least 100 breast cancer cases with data on estrogen alone and/or estrogen with progestin therapy.
Table note: Relative risk above 1 indicates increased risk. Relative risk below 1 indicates decreased risk.
Study
|
Study Population
(number of participants)
|
Postmenopausal Hormone Use
|
Relative Risk of Breast Cancer in Women Using
Estrogen Alone Compared to Women Who Never Used Hormones,
RR (95% CI)
|
Relative Risk of Breast Cancer in Women Using
Estrogen Plus Progestin Compared to Women Who Never Used Hormones,
RR (95% CI)
|
Recency
of Use
|
Duration
of Use
|
Randomized clinical trials
|
Women's Health Initiative [1]
|
16,608
(290 cases)
|
Current use
|
5.2 years
|
|
1.26
(1.00-1.59)
|
Women's Health Initiative [2]
|
10,739*
(237 cases)
|
Current use
|
7.1 years
|
0.80
(0.62-1.04)
|
|
Cohort studies
|
Million Women Study [3]
|
828,923
(9,364 cases)
|
Current use
|
Any
|
1.3
(1.21-1.40)
|
2.0
(1.88-2.12)
|
Breast Cancer Detection Demonstration Project [4]
|
46,355
(2,082 cases)
|
Current or recent use (within the past 4 years)
|
10 years for estrogen alone
4 years for estrogen plus progestin
|
1.2
(1.0-1.4)
|
1.4
(1.1-1.8)
|
Nurses' Health Study [5,6]
|
58,520
(1,761 cases)
|
Current use
|
10 years
|
|
1.7
(1.2-2.4)
|
|
28,835*
(934 cases)
|
Current use
|
<5 years
|
0.96
(0.75-1.22)
|
|
|
|
|
5-9.9 years
|
0.90
(0.73-1.12)
|
|
|
|
|
10-14.9 years
|
1.06
(0.86-1.30)
|
|
|
|
|
15-19.9 years
|
1.18
(0.95-1.48)
|
|
|
|
|
>=20 years
|
1.42
(1.13-1.77)
|
|
EPIC [7]
|
54,548
(948 cases)
|
Current, recent, or past use
|
>=4 years
|
0.3
(0.1-1.8)
|
1.9
(1.2-3.2)
|
Danish Cancer Registry [8]
|
48,812
(869 cases)
|
Current, recent, or past use
|
Any
|
1.35
(1.01-1.80)
|
1.52
(1.21-1.93)†
|
Olsson et al. [9]
|
29,508
(556 cases)
|
Ever use
|
>= 4 years
|
0.58
(0.22-1.55)‡
|
3.13
(1.70-5.75)§
|
Cancer Prevention Study II-Nutrition Cohort [10]
|
67,754
(471 cases)
|
Current use |
10-19 years for estrogen alone
>10 years for estrogen plus progestin |
Ductal breast cancer:
0.95
(0.77-1.17)
Lobular breast cancer:
1.59
(1.07-2.35) |
Ductal breast cancer:
2.07
(1.70-2.52)
Lobular breast cancer:
2.19
(1.50-3.22) |
| |
|
Past use |
>5 years |
Ductal breast cancer:
0.94
(0.75-1.18)
Lobular breast cancer:
0.86
(0.54-1.37) |
Ductal breast cancer:
1.53
(1.14-2.06)
Lobular breast cancer:
1.06
(0.52-2.17) |
Women's Health Study-US [11,12]
|
17,835
(411 cases)
|
Current use
|
>=5 years
|
|
1.76
(1.29-2.39)
|
|
12,718
(305 cases)
|
Current use
|
>=8 years
|
1.35
(0.90-2.02)
|
|
Norwegian Women and Cancer study [13]
|
31,451
(376 cases)
|
Ever or current use |
>=5 years |
1.0
(0.4-2.5)
|
2.8
(2.0-4.0)
|
| Danish Nurse Cohort [14] |
10,874
(244 cases)
|
Ever use |
Any |
1.96
(1.16-3.35)||
|
2.70
(1.96-3.73)|| |
Persson et al. [15]
|
11,231
(198)
|
Current, recent, or past use
|
>=6 years
|
1.1
(0.7-1.7)
|
1.7
(1.1-2.6)
|
WHILA-Sweden [16]
|
6,586
(101 cases)
|
Ever use
|
>4 years
|
|
3.2
(1.4-7.2)
|
Pooled analyses
|
CGHFBC [17]
|
|
Current or recent use (within the past 4 years)
|
>=5 years
|
1.34
|
1.53
|
Collins et al. [18]
|
|
Current or recent use (past 1-4 years)
|
>=5 years
|
1.24
(1.07-1.44)
|
1.89
(1.54-2.31)
|
* Study population restricted to postmenopausal women who had undergone hysterectomy.
† RR for sequential estrogen plus testosterone-derived progestin therapy.
‡ RR for estradiol-only therapy. Results for estriol-only therapy were RR of 1.29 (0.79-2.13) among all women compared to never users. For women who used estriol-only therapy for 1-48 months, the WHILA study found a RR of 0.87 (0.41-1.85) and for women who used estriol-only therapy for more than 48 months, the study found a RR of 1.98 (1.04-3.79).
§ RR for continuous combined estrogen plus progestin therapy. RR for sequential estrogen plus progestin therapy was 1.22 (0.74-2.00).
|| Study population restricted to women who had not undergone hysterectomy.
References
1. 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. 288(3):321-33, 2002.
2. The Women’s Health Initiative Steering Committee (Stefanick ML et al.). Effects of conjugated equine estrogen on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA. 295(14):1647-57, 2006.
3. Beral V for the Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 362:419-27, 2003.
4. Schairer C, Lubin J, Troisi R, et al. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA. 283(4):485-491, 2000.
5. Colditz GA and Rosner B. Cumulative risk of breast cancer to age 70 according to risk factor status: data from the Nurses’ Health Study. Am J Epidemiol. 152(10):950-64, 2000.
6. Chen WY, Manson JE, Hankinson SE, et al. Unopposed estrogen therapy and risk of invasive breast cancer. Arch Intern Med. 166(9):1027-1032, 2006.
7. 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. 114(3):448-54, 2005.
8. Ewertz M, Mellemkjaer L, Poulsen AH, et al. Hormone use for menopausal symptoms and risk of breast cancer. A Danish cohort study. Br J Cancer. 92(7):1293-7, 2005.
9. Olsson HL, Ingvar C, Bladstrom A. Hormone replacement therapy containing progestins and given continuously increases breast carcinoma risk in Sweden. Cancer. 97(6):1387-92, 2003.
10. Calle EE, Feigelson HS, Hildebrand JS, Teras LR, Thun MJ, Rodriguez C. Postmenopausal hormone use and breast cancer associations differ by hormone regimen and histologic subtype. Cancer. 115(5):936-45, 2009.
11. Porch JV, Lee IM, Cook NR, Rexrode KM, Burin JE. Estrogen-progestin replacement therapy and breast cancer risk: the Women’s Health Study (United States). Cancer Causes Control. 13(9):847-54, 2002.
12. Zhang SM, Manson JE, Rexrode KM, Cook NR, Buring JE, Lee IM. Use of oral conjugated estrogen alone and risk of breast cancer. Am J Epidemiol. 165(5):524-9, 2007.
13. Bakken K, Alsaker E, Eggen AE, Lund E. Hormone replacement therapy and incidence of hormone-dependent cancers in the Norwegian Women and Cancer study. Int J Cancer. 112(1):130-4, 2004.
14. 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. 109(5):721-7, 2004.
15. Persson I, Weiderpass E, Bergkvist L, et al. Risks of breast and endometrial cancer after estrogen and estrogen-progestin replacement. Cancer Causes & Control. 10(4):253-260, 1999.
16. Jernstrom H, Bendahl PO, Lidfeldt J, Nerbrand C, Agardh CD, Samsioe G. A prospective study of different types of hormone replacement therapy use and the risk of subsequent breast cancer: the women’s health in the Lund area (WHILA) study (Sweden). Cancer Causes Control. 14(7):673-80, 2003.
17. 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. 350:1047-1059, 1997.
18. Collins JA, Blake JM, Crosignani PG. Breast cancer risk with postmenopausal hormonal treatment. Hum Reprod Update. 11(6):545-60, 2005.
Updated 09/12/09
