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A multidisciplinary commentary on “Breast effects of oral, combined 17beta-estradiol, and progesterone capsules in menopausal women: a randomized controlled trial” by Liu JH et al.

Point of view of the Medical Epidemiologist

Concerns about the use of menopausal hormone therapy (MHT) include adverse effects on the breast, including increased risk of breast cancer [1,2], abnormal mammograms and an increase in breast density [3]. There is evidence that the adverse effects of MHT on the breast may be a function of the progestogen used, such that progesterone (P4) may pose less risk than other progestogens [4]. The REPLENISH study compared four different doses of oral 17β estradiol and progesterone (E2P4) (1mg E2/100mg P4, 0.5mg E2/100mg P4, 0.5mg E2/50mg P4, 0.25mg E2/50mgP4) with placebo and was primarily a safety study [5]. The primary safety endpoint was the risk of endometrial hyperplasia over 12 months, and the initial report showed no increased risk of endometrial hyperplasia in the active treatment groups. A new paper from the REPLENISH study has now been published on breast findings [6], specifically BI-RADS categories 3 or 4 (3 indicates a lesion that is probably benign and four indicates a lesion is suspicious for malignancy [7]). There were 152 women randomized to the placebo group and between 418 and 427 women randomized to the four active treatment groups. The proportion of women in each treatment group with mammography data (~ 300 women per group) classified as BI-RADS 3 or 4 at 12 months were not different from the placebo group, statistically.

The study results are consistent with the women receiving the highest dose of E2P4 having double the risk of being classified as BI-RADS group 3 or 4 after 12 months, compared with the women in the placebo group, but the study was not powered to detect this difference, as follows. The proportion of women in the placebo group classified as BI-RADS categories 3 or 4 at 12 months was 3.1%. As the number of women in the placebo group with mammographic data available was only 98, the confidence interval (CI) around this proportion was wide (0.6 to 8.7%). The point estimates for the proportion of women in each treatment group with mammography data classified as BI-RADS 3 or 4 at 12 months ranged between 1.7% (lowest dose), and 3.7% (highest dose) and none of these proportions were different from the placebo group, statistically. However, the upper limits of the 95% CIs for the proportions in the active treatment groups ranged from 3.8 (lowest dose) to 6.5% (highest dose). A post-hoc power calculation showed that the study only had a power of 74% to detect a 3-fold increase in the likelihood of detecting a mammogram classified as BI-RADS 3 or 4, in any one of the treatment groups, compared with placebo. The study may have been sufficiently long at 12 months for the primary endpoint of endometrial hyperplasia but may not have been sufficiently long to assess the impact of exposure to E2P4 on the breast. A recent meta-analysis reports that, although the relative risk (RR) of breast cancer for women whose exposure to combined MHT for less than one year is significant at 1.20 (CI 1.01-1.43), the risk is considerably higher for those exposed for 1-4 years (RR 1.60 95%CI 1.52-1.69) [8]. The REPLENISH authors were conservative in their conclusions, stating: “E2P4 may not be associated with increased risk of abnormal mammograms versus placebo”. Information is needed about long-term exposure to E2P4 in larger groups to be confident of its safety in relation to the breast.

Robin Bell
Deputy Director of the Women’s Health Research Program, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia

Point of view of the Obstetrician-Gynecologist

A double-blind, phase 3, placebo-controlled, multicenter trial in the US enrolled 1,340 postmenopausal non-hysterectomized women with moderate to severe vasomotor symptoms (REPLENISH). Randomized to five groups, the participants received oral doses of 1mg E2/100 mgP4, 0.5mg E2/100mg P4, 0.5mg E2/50mg P4, or 0.25mgE2/50mgP4, or placebo. Primary efficacy endpoints of REPLENISH were vasomotor symptoms and endometrial hyperplasia. Breast examinations and mammograms (MG) served as additional safety endpoints and are the subject of this current report (1). MGs were performed at screening and after one year at the study end. All were normal (BI-RADS 1 or 2) at entry. Of the study-end, 93 (2.9%) mammograms were abnormal (probably benign BI-RADS 3) or suspicious for malignancy, BI-RADS 4). The incidence was 1.7% to 3.7% with active doses and 3.1% with placebo. Breast cancer incidence was 0.36% with active doses and 0% with placebo. Breast tenderness varied from 2.4% to 10.8% with E2/P4 vs 0.7% with placebo. The authors conclude that E2/P4 may not be associated with an increased risk of abnormal mammograms, and breast tenderness was low relative to most reported studies.

When applying estrogen in non-hysterectomized peri- and postmenopausal women, international guidelines on MHT recommend combining a progestogen for endometrial protection [9]. However, long-term combined estrogen-progestogen therapy has been associated with a minor increase in breast cancer risk. Bioidentical hormones, including micronized progesterone (MP), were investigated to verify different, even beneficial, impacts on the mammary gland. Reviewed experience with MP [10] has shown that (a) mammographic density may either increase or remain unchanged, (b) proliferation induction was less pronounced compared to ‘conventional’ MHT, and (c) breast cancer was not affected for up to 5 years treatment.

Mammographic breast density is based on varying proportions of fat, connective and epithelial tissue. The BI-RADS classification determines almost entirely fatty, scattered areas of fibroglandular density, heterogeneously dense and extremely dense aspects [11]. Hygroscopic hyaluronan-proteoglycan aggregates cause the change in the mammary stroma and increased water accumulation in the extracellular matrix. Proteoglycans may also influence the malignant transformation of breast cells and the progression of tumours [12]. A mammographically dense breast tissue indicates increased breast cancer risk [13] but not mortality [14] and will decrease mammography sensitivity.

Interpretation of mammographic density is subjective, as moderate inter- and intra-observer variabilities have been reported [15] with subsequent differing results. The presented multicenter study, however, established an institutional review board for approval of their mammograms. The results demonstrate the breast-friendly effect of MHT based on E2/P4. MHT containing MP for more than five years has been reported by the two prospective cohort studies E3N and MISSION [16], suggesting a small increase in BC risk. However, in order to balance the impact of non-modifiable (e.g. genetics, parity, breast density) and modifiable BC risk factors (e.g. alcohol, smoking, overweight, physical inactivity), women should be counselled that the possible BC risks with long-term combined MHT are small ( <1 per 1000 women per year of use ) and lower than risks associated with lifestyle factors ( obesity, physical activity, alcohol consumption). Any MHT requires regular checkups, including breast imaging in the following order of ultrasound, magnetic resonance, and mammography.

Hermann P. G. Schneider
Emeritus Professor of Obstetrics & Gynecology, Retired Chief of the Department of Obstetrics & Gynecology, University of Muenster Medical School, Muenster, Germany


  1. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J and Writing Group for the Women’s Health Initiative I. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288:321-33.
  2. Beral V, Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003;362:419- 27.
  3. McTiernan A, Martin CF, Peck JD, Aragaki AK, Chlebowski RT, Pisano ED, Wang CY, Brunner RL, Johnson KC, Manson JE, Lewis CE, Kotchen JM, Hulka BS and Women’s Health Initiative Mammogram Density Study I. Estrogen-plus-progestin use and mammographic density in postmenopausal women: Women’s Health Initiative randomized trial. J Natl Cancer Inst. 2005;97:1366-76.
  4. Asi N, Mohammed K, Haydour Q, Gionfriddo MR, Vargas OL, Prokop LJ, Faubion SS and Murad MH. Progesterone vs. synthetic progestins and the risk of breast cancer: a systematic review and meta-analysis. Syst Rev. 2016;5:121.
  5. Lobo RA, Archer DF, Kagan R, Kaunitz AM, Constantine GD, Pickar JH, Graham S, Bernick B and Mirkin S. A 17beta-Estradiol-Progesterone Oral Capsule for Vasomotor Symptoms in Postmenopausal Women: A Randomized Controlled Trial. Obstet Gynecol. 2018;132:161-170.
  6. Liu JH, Black DR, Larkin L, Graham S, Bernick B and Mirkin S. Breast effects of oral, combined 17beta-estradiol, and progesterone capsules in menopausal women: a randomized controlled trial. Menopause. 2020.
  8. Collaborative Group on Hormonal Factors in Breast C. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. Lancet. 2019;394:1159-1168.
  9. The 2017 hormone therapy position statement of the North American Menopause Society. Menopause 2017; 24:728-53.
  10. Stute P, Wildt L, Neulen J. The impact of micronized progesterone on breast cancer risk. Climacteric 2018; 21: 111-122.
  11. D’Orsi CJ, Sickles E, Mendelson E et al., eds. Atlas Breast Imaging Reporting and Data System. 2013.
  12. Kuhl H, Schneider HPG. Progesterone-promoter or inhibitor of breast cancer. Climacteric 2013; 16(Suppl1) 54-68.
  13. Vachon CM, van Gils CH, Sellers TA et al. Mammographic density, breast cancer risk and risk prediction. Breast Cancer Res 2007; 9: 217. 1.
  14. Gierach GL, Ichikawa L, Kerlikowski K et al. Relationship between mammographic density and breast cancer death in the Breast Cancer Surveillance Consortium. J Natl Cancer Inst 2012; 104: 1218-27.
  15. Kerlikowski K, Grady D, Barklay J et al. Variability and accuracy in mammographic interpretation using the American College of Radiology Breast Imaging Reporting and Data System. J Natl Cancer Inst 1998; 90: 1801-9. 1.
  16. Fournier A, Mesrine S, Dossus L et al. Risk of breast cancer after stopping menopausal hormone therapy in the E3N cohort. Breast Cancer Res Treat 2014; 145: 535-43.

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