Vinogradova et al.  undertook a nested case-control study using prospectively collected electronic health records from two largest UK primary care databases in order to assess the risk of breast cancer associated with different types and duration of menopausal hormone therapy (MHT). They identified 98,611 women aged 50-79 with a primary diagnosis of breast cancer between 1998 and 2018, matched by age, general practice, and index date to 457,498 female controls. The study reported the increased risk of breast cancer associated with recent long term (≥5 years) use of combined estrogen plus progestogen (E+P) therapy (adjusted odds ratio was 1.79, with the 95% confidence interval of 1.73 to 1.85). And there was a more noticeable decline in the risk once treatment was stopped. In the recent long term (≥5 years) E+P group, the increased risk was the lowest for estradiol plus dydrogesterone (1.24, 1.03 to 1.48), which was similar with past long term use of E+P (1.16, 1.11 to 1.21) and recent long-term estrogen only treatments (1.15, 1.09 to 1.21). Past long term estrogen only therapy and past short term use of E+P were not associated with increased risk. The suggest that the levels of risks varied between types of used MHT, with the highest risk observed for combined treatments (with progestogens other than dydrogesterone) and for longer duration of use.
Vinogradova et al.  reported a nest analysis on the association between the long term MHT use and breast cancer risk in the 2020 July issue of BMJ. The findings were broadly similar to those of the 2019 Lancet meta-analysis , but with lower risks for combined MHT. Both of these two studies suggested that breast cancer risk increased steadily with the duration of MHT use and were greater for E+P than estrogen-only preparations. Only few cases of dydrogesterone and micronized progesterone users were included in the Lancet meta-analysis , so the study showed no difference between different progestin regimens. While in this BMJ study, with enough cases to analyze, a much lower risk was observed among dydrogesterone users. This provided a support that breast cancer risk mainly depends on the types of progestogen used . Trabert and colleagues  revealed that women with higher circulating progesterone levels had a 16% increased risk of postmenopausal breast cancer. Some large studies also found that estradiol combined with natural progesterone or dydrogesterone showed a much weaker or no association with breast cancer compared with other synthetic progestogens [5-8]. The timing and type of progesterone exposure may be highly relevant to breast cancer risk.
In contrast to the recent findings in both the Lancet and BMJ meta-analyses, especially in regards to estrogen alone users, the WHI randomized clinical trial  showed a protective effect trend (at least no increase at all) on breast cancer. A small increase in recent long-term estrogen only treatments might partly be explained by different types of estrogen, which were estradiol and conjugated equine estrogen, respectively. This may show us a clue for further future studies aimed at evaluating the effect of the different types of estrogen on breast cancer risk.
Although the BMJ large observational study colored the view of MHT and breast cancer, the findings should be interpreted with caution. Some limitations were found due to the nature of a retrospective case-control study. In addition, data of micronized progesterone were not included in the studies. In fact, any association of potential breast cancer risk with MHT is rare and no greater than other endogenous and lifestyle risks factors . As the Chinese saying goes: “Don’t give up eating for fear of choking”, hence we should maintain a positive and cautious attitude towards MHT once considering the full range of risk and benefits.
Xiong Wei, MD
Yu Qi, MD
Department of Gynecological Endocrinology
Peking Union Medical College Hospital
National Clinical Research Center for Obstetric & Gynecologic Diseases
- Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of breast cancer: nested case-control studies using the Q Research and CPRD databases. BMJ. 2020;371:m3873.
- 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;394(10204):1159-1168.
- 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(3):321-333.
- Trabert B, Bauer DC, Buist DSM, et al. Association of Circulating Progesterone With Breast Cancer Risk Among Postmenopausal Women. JAMA Netw Open. 2020;3(4): e 203645.
- Gompel A, Plu-Bureau G. Progesterone, progestins and the breast in menopause treatment. Climacteric. 2018;21(4):326-332.
- Stute P, Wildt L, Neulen J. The impact of micronized progesterone on breast cancer risk: a systematic review. Climacteric. 2018;21(2):111-122.
- Fournier A, Mesrine S, Boutron-Ruault MC, et al. Estrogen-progestagen menopausal hormone therapy and breast cancer: does delay from menopause onset to treatment initiation influence risks? J Clin Oncol. 2009, 27(31):5138-5143.
- Lyytinen H, Pukkala E, Ylikorkala O. Breast cancer risk in postmenopausal women using estradiol-progestogen therapy. Obstet Gynecol. 2009;113(1):65-73.
- 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.
- Hodis HN, Sarrel PM. Menopausal hormone therapy and breast cancer: what is the evidence from randomized trials?. Climacteric. 2018;21(6):521-528.
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