Skip to main content

Some NLM-NCBI services and products are experiencing heavy traffic, which may affect performance and availability. We apologize for the inconvenience and appreciate your patience. For assistance, please contact our Help Desk at info@ncbi.nlm.nih.gov.

Case Reports in Women's Health logoLink to Case Reports in Women's Health
editorial
. 2020 Nov 12;29:e00270. doi: 10.1016/j.crwh.2020.e00270

Menopausal hormone therapy and breast cancer risk: All progestogens are not the same

Irene Lambrinoudaki 1,⁎,1
PMCID: PMC7683312  PMID: 33294389

Menopausal hormone therapy (MHT) is the treatment of choice for the management of bothersome menopausal symptoms, for the treatment of urogenital atrophy and for the prevention of osteoporotic fractures in symptomatic women at risk [1]. If given during the menopausal transition or soon after menopause, MHT may prevent cardiovascular disease [1]. Hormone replacement therapy (HRT), furthermore, should be administered to all women with premature ovarian insufficiency (POI) irrespective of the presence of menopausal symptoms, unless contra-indicated, for the prevention of chronic disease associated with premature estrogen decline [2]. The fear of breast cancer, however, deters many clinicians from prescribing MHT or HRT and makes women reluctant to receive it over the long term.

In this context, Vinogradova et al. [3] preformed a large case-control study using two large UK general practice databases with the objective to assess breast cancer risk associated with different types and durations of MHT. 98,611 women aged 50–79 with breast cancer were matched to 457,398 control women, based on age, general practice and index date. Estrogen-only therapy for up to 9 years increased only marginally the risk of breast cancer (OR 1.14, CI 1.08–1.21), whereas estrogen–progestin combination therapy for the same duration was associated with a more pronounced increase in breast cancer risk (OR 1.70, CI 1.64 to 1.76). The risk differed according to the progestin used, being higher with medroxyprogesterone acetate, levonorgestrel and norethisterone (OR 1.87 CI 1.71 to 2.05, 1.79 CI 1.68 to 1.90 and 1.88 CI 1.79 to 1.99 respectively) and lower with dydrogesterone (OR 1.24 CI 1.03 to 1.48) for more than 5 years of therapy. The excess risk dissipated in past users.

The study confirmed what we already knew from the WHI studies [4,5]: The excess risk of breast cancer associated with MHT is mainly conferred by the progestin. The risk presented in this study is lower than the risk published in a recent large meta-analysis [6]. The main message of this study, however, is that progestins do not exert a class effect on the breast. On the contrary, the risk of breast cancer varies between the various progestins used in MHT. Dydrogesterone-containing MHT regimens appear to have a lesser effect on the breast than medroxyprogesterone-, levonorgestrel- and norethisterone-containing MHT regimens. The findings of this study are in agreement with the results of the E3N study, a large prospective French cohort of 80,000 postmenopausal women followed up for a mean of 8 years. The risk of breast cancer varied significantly according to the progestogen used: the relative risk was 1.16 (CI 0.94–1.43) for estrogen–dydrogesterone and 1.69 (CI 1.50–1.91) for estrogen combined with other progestogens [7].

In conclusion, clinicians have to put the risk of breast cancer associated with MHT into clinical context: The risk associated with long-term estrogen use is much lower than the risk conferred by obesity, inactivity and alcohol use [8]. Furthermore, the findings of this study are not relevant to women with POI, in whom risks are calculated in comparison to women with regular menstruation. In general, tailoring hormone therapy to the needs of the individual woman ensures its long-term safety.

Acknowledgments

Contributors

Irene Lambrinoudaki is the sole author of this editorial.

Conflict of Interest

The author has no conflict of interest regarding the publication of this editorial.

Funding

No funding from an external source supported the publication of this editorial.

Provenance and peer review

This editorial was commissioned and not externally peer reviewed.

References

  • 1.Armeni E., Lambrinoudaki I., Ceausu I., Depypere H., Mueck A., Pérez-López F.R., Schouw Y.T., Senturk L.M., Simoncini T., Stevenson J.C., Stute P., Rees M. Maintaining postreproductive health: a care pathway from the European menopause and Andropause society (EMAS) Maturitas. 2016;89:63–72. doi: 10.1016/j.maturitas.2016.04.013. [DOI] [PubMed] [Google Scholar]
  • 2.Panay N., Anderson R.A., Nappi R.E., Vincent A.J., Vujovic S., Webber L., Wolfman W. Premature ovarian insufficiency: an International Menopause Society White Paper. Climacteric. 2020 Oct;23(5):426–446. doi: 10.1080/13697137.2020.1804547. Epub 2020 Sep 8. [DOI] [PubMed] [Google Scholar]
  • 3.Vinogradova Y. Use of hormone replacement therapy and risk of breast cancer: nested case-control studies using the QResearch and CPRD databases. BMJ. 2020 Oct 28;371 doi: 10.1136/bmj.m3873. PMID: 33115755. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Chlebowski R.T., Rohan T.E., Manson J.E., Aragaki A.K., Kaunitz A., Stefanick M.L. Breast Cancer after use of estrogen plus progestin and estrogen alone: analyses of data from 2 Women’s Health Initiative randomized clinical trials. JAMA Oncol. 2015;1:296–305. doi: 10.1001/jamaoncol.2015.0494. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Chlebowski R.T., Anderson G.L., Aragaki A.K., Manson J.E., Stefanick M.L., Pan K. 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;324:369–380. doi: 10.1001/jama.2020.9482. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.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 doi: 10.1016/S0140-6736(19)31709-X. 1159-68. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Fournier A., Berrino F., Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res. Treat. 2008;107:103–111. doi: 10.1007/s10549-007-9523-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Lambrinoudaki I., Armeni E. Menopausal hormone therapy and breast cancer: need to put risks in perspective. Maturitas. 2020 Jan;131:89–90. doi: 10.1016/j.maturitas.2019.09.001. [DOI] [PubMed] [Google Scholar]

Articles from Case Reports in Women's Health are provided here courtesy of Elsevier

RESOURCES