Menopausal hormones: definitive evidence for breast cancer
Authors: Joanne Kotsopoulos
Journal: The Lancet (2019)

For some women, menopause is an easy life transition, but for others, it means sleepless nights, hot flushes, and often a decline in wellbeing. For decades, women have been prescribed synthetic versions of the hormones that are lost with ovarian functional decline, in pill form or in other formulations (eg, patches, gels, or injections), either as oestrogen alone (usually for women who have had a hysterectomy) or as an oestrogen and progesterone combination (usually for those with an intact uterus) to help mitigate some of the symptoms. Prescribing fell after the publicity stemming from the Women's Health Initiative (WHI) trial reports in 20021Rossouw 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: 321-333Crossref PubMed Scopus (13195) Google Scholar and 2004,2Anderson GL Limacher M Assaf AR et al.Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial.JAMA. 2004; 291: 1701-1712Crossref PubMed Scopus (3850) Google Scholar which showed an increase in the risk of breast cancer with the use of combination therapy (oestrogen and progesterone). Oestrogen alone had no observed effect. The decline in menopausal hormone therapy (MHT) use was followed by a decline in the incidence of breast cancer3Kumle M Declining breast cancer incidence and decreased HRT use.Lancet. 2008; 372: 608-610Summary Full Text Full Text PDF PubMed Scopus (101) Google Scholar (fear of breast cancer likely had the greatest effect on the use of hormone replacement therapy [HRT], but to my knowledge this has not been formally established).3Kumle M Declining breast cancer incidence and decreased HRT use.Lancet. 2008; 372: 608-610Summary Full Text Full Text PDF PubMed Scopus (101) Google Scholar Perhaps breast cancer worry has deprived millions of women of an effective remedy for some of the symptoms of menopause. It is important to know the cancer risks with accuracy if women are suffering the consequences of avoiding MHT, and possibly, raising the risk of osteoporosis and other conditions, such as cardiovascular health or cognitive decline. The WHI published two randomised trials; elsewhere data come from observational studies. In The Lancet, the Collaborative Group on Hormonal Factors in Breast Cancer4Collaborative Group on Hormonal Factors in Breast CancerType and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence.Lancet. 2019; (published online Aug 29.)http://dx.doi.org/10.1016/S0140-6736(19)31709-XGoogle Scholar reports their study in which they combined data from 58 studies, including 24 prospective cohort studies, using a nested case-control study design to focus on the long-term effects of MHT while taking into account age at first use, duration of use, and time elapsed since last use. They compared oestrogen alone versus never use and combination therapy versus never use.4Collaborative Group on Hormonal Factors in Breast CancerType and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence.Lancet. 2019; (published online Aug 29.)http://dx.doi.org/10.1016/S0140-6736(19)31709-XGoogle Scholar The meta-analysis included 108 647 incident invasive breast-cancer cases within the cohorts (mean age at diagnosis was 65 years) who were matched to up to four controls by age, year of birth, and geographical location. The data show that compared with never users, women who initiated MHT shortly after menopause had a significantly increased risk of invasive breast cancer. The relative risks were greater for combination therapy versus never use than for oestrogen alone for similar durations of use. The longer women used MHT, the greater the risk. For example, the hazard ratio associated with 1–4 years of use was 1·17 (95% CI 1·10–1·26) for oestrogen alone and 1·60 (1·52–1·69) for combination therapy, whereas the corresponding estimates for 10–14 years of use were 1·43 (1·37–1·50) and 2·26 (2·16–2·36). In past users of HRT, the relative risks were lower than in current users, but risks remained elevated more than 10 years after stopping—the risk being greater the longer the duration of previous MHT use. Unlike the WHI study, few women initiated hormone use after the age of 60 years. The authors also estimated the absolute risk of breast cancer up to age 70 years associated with 5 years and 10 years of use of MHT, starting at age 50 years for women of average weight in developing countries. The estimated incidence of breast cancer was 6·3% for never users of HRT versus 8·3% for 5 years of use of the continuous combination MHT—an absolute increase of 2%, or one extra cancer for every 50 users. The main analysis was limited to prospective studies with detailed information on MHT use and adjusted for potential confounders. The complexity of the study design makes it difficult to appraise the results and most of us will take the results on face value. However, it is often difficult to avoid biases in prospective studies in which the period of exposure (HRT use) overlaps with the period of risk (breast cancer incidence). Some women switch from being non-users to users in the follow-up and the duration of use is not a constant but changes each year that hormones are used. It is interesting that MHT had little adverse effect among women who were obese. This might be because the amount of oestradiol from endogenous production in the adipose tissue is greater than that contributed from use of MHT, and endogenous hormone concentrations are higher. In support of this, the estimated 20-year incidence from age 50 to 69 years for a woman with a body-mass index (BMI) higher than 30 who was not on MHT was actually higher than that of a woman of average weight who used oestrogen alone for 5 years. A woman who was a lean never-user of MHT had the lowest 20-year incidence of breast cancer of 5·1%. Both obesity and MHT are risk factors for postmenopausal breast cancer, but it appears that the effects are not additive. Practically, it might be hard for a physician to tell a woman she need not concern herself with the carcinogenic effect of HRT as long as she maintains a BMI higher than 30. How does exogenous hormone use cause breast cancer? Typically, menopause is associated with a substantial and rapid decline in ovarian hormone production. Early age at menopause is a protective risk factor for breast cancer.5Collaborative Group on Hormonal Factors in Breast CancerMenarche, menopause, and breast cancer risk: individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies.Lancet Oncol. 2012; 13: 1141-1151Summary Full Text Full Text PDF PubMed Scopus (459) Google Scholar In descriptive epidemiology, we see a slowing of the age-related rising trend in breast cancer risk after menopause. Simply put, the use of HRT might keep the woman in a de-facto premenopausal state, and she does not have the benefit of menopause on cancer risk reduction. Clinicians must heed the message of this study but also to take a rational and comprehensive approach to the management of menopausal symptoms, with careful consideration of the risks and benefits of initiating MHT for each woman.6Manson JE Current recommendations: what is the clinician to do?.Fertil Steril. 2014; 101: 916-921Summary Full Text Full Text PDF PubMed Scopus (25) Google Scholar This might be dependent on severity of the symptoms, contraindications for MHT (ie, breast cancer, cardiovascular disease, and stroke), and BMI, and could take into account patient preference.6Manson JE Current recommendations: what is the clinician to do?.Fertil Steril. 2014; 101: 916-921Summary Full Text Full Text PDF PubMed Scopus (25) Google Scholar For likely candidates, MHT (preferably oestrogen alone) should be initiated around the time of natural menopause and ideally limited to 5 years of use. I declare no competing interests. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidenceIf these associations are largely causal, then for women of average weight in developed countries, 5 years of MHT, starting at age 50 years, would increase breast cancer incidence at ages 50–69 years by about one in every 50 users of oestrogen plus daily progestagen preparations; one in every 70 users of oestrogen plus intermittent progestagen preparations; and one in every 200 users of oestrogen-only preparations. The corresponding excesses from 10 years of MHT would be about twice as great. Full-Text PDF Open AccessMenopausal hormone therapy and 20-year breast cancer mortalityThe Collaborative Group on Hormonal Factors in Breast Cancer has brought together the worldwide evidence on menopausal hormone therapy (MHT) and the incidence of invasive breast cancer.1 All types of MHT examined, except vaginal oestrogens, were associated with a significant excess incidence of breast cancer. Both among current users and among past users the risks increased steadily with duration of MHT use. Risks were greater for oestrogen-progestagen than for oestrogen-only preparations, and some excess risk persisted for more than a decade after cessation of use. Full-Text PDF