- Increases in both breast density [1, 2] and breast cancer risk [3, 4] have been shown in patients taking oral or transdermal combined estrogen and progesterone hormone supplements (i.e. hormone replacement therapy, HRT).
- In women who have had breast cancer, oral or transdermal HRT have been shown to increase risk of breast cancer recurrence [5].
- Data are conflicting as to whether taking oral or transdermal estrogen alone in women who have had a hysterectomy increases breast density [5-9] or breast cancer risk [3, 4].
- There are minimal data on the effect of vaginal estrogen on breast density.
- In women who have not had breast cancer, vaginal estrogen has not been shown to increase breast cancer risk.
- In women who have had breast cancer, vaginal estrogen has not been shown to increase breast cancer recurrence, except in one study that reported an increased risk in breast cancer survivors who took aromatase inhibitors [6]. Vaginal estrogen has not been shown to increase death from breast cancer in breast cancer survivors [6, 13].
A large meta-analysis of prospective observational studies found that ever users of HRT had a 30% greater risk of developing breast cancer than never users [relative risk (RR) 1.29 (95% CI 1.27, 1.30)][3]. Risk increased with duration of use for both current and past users, with higher risk at any given duration of use for current users [current users, RR 1.20 (95% CI 1.01-1.43) for <1 year of use to 2.51 (95% CI 2.35-2.68) for ≥ 15 years of use; past users, RR 1.02 (95% CI 0.95-1.10) for <1 year of use to 1.30 (95% CI 1.25-1.37) for ≥ 15 years of use]. Similarly, the Women’s Health Initiative randomized trial found nearly 30% greater risk after a median 20 years of follow-up among women randomized to estrogen and medroxyprogesterone acetate (hazard ratio 1.28; 95% CI 1.13-1.45) [4].
Data are conflicting as to whether taking oral or transdermal estrogen alone in women who have had a hysterectomy increases breast density [7-11] or breast cancer risk [3, 4]. There are minimal data on the effect of vaginal estrogen on breast density. Vaginal estrogen has not been shown to increase breast cancer risk [3, 12] in women who have not had breast cancer.
In women who have had breast cancer, oral or transdermal HRT have been shown to increase risk of breast cancer recurrence [5]. Vaginal estrogen has not been shown to increase risk of breast cancer recurrence, except in one study that reported an increased risk in breast cancer survivors who used vaginal estrogen and took aromatase inhibitors [6]. Vaginal estrogen has not been shown to increase death from breast cancer in women who have had breast cancer [6, 13].
References Cited
1. Azam S, Jacobsen KK, Aro AR, Lynge E, Andersen ZJ. Hormone replacement therapy and mammographic density: a systematic literature review. Breast Cancer Res Treat 2020;182(3):555-579.
2. McTiernan A, Martin CF, Peck JD, et al.; Women’s Health Initiative Mammogram Density Study Investigators. Estrogen-plus-progestin use and mammographic density in postmenopausal women: Women’s Health Initiative randomized trial. J Natl Cancer Inst 2005;97(18):1366-76.
3. Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. Lancet 2019 28;394(10204):1159-1168.
4. Chlebowski RT, Anderson GL, Aragaki AK, et al. Association of Menopausal Hormone Therapy With Breast Cancer Incidence and Mortality During Long-term Follow-up of the Women’s Health Initiative Randomized Clinical Trials. JAMA 2020;324(4):369-380.
5. Poggio F, Del Mastro L, Bruzzone M, et al. Safety of systemic hormone replacement therapy in breast cancer survivors: a systematic review and meta-analysis. Breast Cancer Res Treat 2022;191(2):269-275.
6. Cold S, Cold F, Jensen MB, Cronin-Fenton D, Christiansen P, Ejlertsen B. Systemic or Vaginal Hormone Therapy After Early Breast Cancer: A Danish Observational Cohort Study. J Natl Cancer Inst 2022;114(10):1347-1354.
7. Greendale GA, Reboussin BA, Slone S, Wasilauskas C, Pike MC, Ursin G. Postmenopausal hormone therapy and change in mammographic density. J Natl Cancer Inst 2003;95(1):30-7.
8. Grady D, Vittinghoff E, Lin F, et al. Effect of ultra-low-dose transdermal estradiol on breast density in postmenopausal women. Menopause 2007;14:391-396.
9. Maskarinec G, Pagano I, Lurie G, Kolonel LN. A longitudinal investigation of mammographic density: the multiethnic cohort. Cancer Epidemiol Biomarkers Prev. 2006;15(4):732-9.
10. 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;20;27(36):6135-43.
11. Aiello EJ, Buist DS, White E. Do breast cancer risk factors modify the association between hormone therapy and mammographic breast density? (United States). Cancer Causes Control 2006;17(10):1227-35.
12. Crandall CJ, Hovey KM, Andrews CA, et al. Breast cancer, endometrial cancer, and cardiovascular events in participants who used vaginal estrogen in the Women’s Health Initiative Observational Study. Menopause 2018 Jan;25(1):11-20.
13. McVicker L, Labeit AM, Coupland CAC, et al. Vaginal Estrogen Therapy Use and Survival in Females With Breast Cancer. JAMA Oncol 2024;10(1):103-108.