Elsevier

The Lancet

Volume 365, Issue 9470, 30 April–6 May 2005, Pages 1543-1551
The Lancet

Articles
Endometrial cancer and hormone-replacement therapy in the Million Women Study

https://doi.org/10.1016/S0140-6736(05)66455-0Get rights and content

Summary

Background

Postmenopausal women who use hormone-replacement therapy (HRT) containing oestrogen alone are at increased risk of endometrial cancer. To minimise this risk, many HRT users who have not had a hysterectomy use combined oestrogen-progestagen preparations or tibolone. Limited information is available on the incidence of endometrial cancer in users of these therapies.

Methods

716 738 postmenopausal women in the UK without previous cancer or previous hysterectomy were recruited into the Million Women Study in 1996–2001, provided information about their use of HRT and other personal details, and were followed up for an average of 3·4 years, during which time 1320 incident endometrial cancers were diagnosed.

Findings

320 953 women (45%) reported at recruitment that they had used HRT, among whom 69 577 (22%) last used continuous combined therapy (progestagen added daily to oestrogen), 145 486 (45%) last used cyclic combined therapy (progestagen added to oestrogen, usually for 10–14 days per month), 28 028 (9%) last used tibolone, and 14 204 (4%) last used oestrogen-only HRT. These HRT types had sharply contrasting effects on the overall risk of endometrial cancer (p<0·0001 for heterogeneity). Compared with never users of HRT, risk was: reduced with last use of continuous combined preparations (relative risk 0·71 [95% CI 0·56–0·90]; p=0·005); increased with last use of tibolone (1·79 [1·43–2·25]; p<0·0001) and oestrogen only (1·45 [1·02–2·06]; p=0·04); and not significantly altered with last use of cyclic combined preparations (1·05 [0·91–1·22]; p=0·5). A woman's body-mass index significantly affected these associations, such that the adverse effects of tibolone and oestrogen-only HRT were greatest in non-obese women, and the beneficial effects of combined HRT were greatest in obese women.

Interpretation

Oestrogens and tibolone increase the risk of endometrial cancer. Progestagens counteract the adverse effect of oestrogens on the endometrium, the effect being greater the more days every month that they are added to oestrogen and the more obese that women are. However, combined oestrogen-progestagen HRT causes a greater increase in breast cancer than the other therapies do. Thus, when endometrial and breast cancers are added together, there is a greater increase in total cancer incidence with use of combined HRT, both continuous and cyclic, than with use of the other therapies.

Introduction

Use of oestrogen-only hormone-replacement therapy (HRT) increases the risk of endometrial cancer.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 To counteract this effect, many postmenopausal women who have not had a hysterectomy use combined HRT—regimens containing progestagens and oestrogens. Epidemiological evidence suggests that use of such combined oestrogen-progestagen therapy attenuates, and perhaps even reverses, the oestrogen-associated increase in endometrial cancer.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 However, published findings are sparse and mostly come from the USA, where HRT preparations often differ from those available elsewhere. Furthermore, tibolone, a synthetic steroid with oestrogenic, progestagenic, and androgenic properties, has not been licensed in the USA, but is prescribed for HRT in many countries, and has been linked to an increased risk of endometrial cancer.14, 15 We report here on the relation between use of different types of HRT and incidence of endometrial cancer in the Million Women Study, a cohort study including about one of every four women in the UK who were aged 50–64 years in 1996–2001.16, 17

Section snippets

Data collection, follow-up, and definitions

Between May, 1996, and March, 2001, more than a million women joined the study.16, 17 They completed a recruitment questionnaire containing questions about sociodemographic and other personal factors, including use of HRT. A follow-up questionnaire was sent to study participants 2–3 years after recruitment, to update information on use of HRT and other factors. These questionnaires can be viewed on the study website. To date, 1·3 million study participants have been flagged on the NHS Central

Results

716 738 postmenopausal women with no previous cancer or hysterectomy were recruited in 1996–2001, flagged on the NHS Central Registers, and followed up for incident cancer. Average age at entry into the study was 57·5 years. 320 953 women (45%) reported that they had ever used HRT, and among them 22% last used continuous combined preparations, 45% last used cyclic combined preparations, 9% last used tibolone, 4% last used oestrogen-only HRT, 2% last used other or more than one HRT type, and 18%

Discussion

In this large cohort study, the types of HRT commonly used in the UK were shown to have sharply contrasting effects on the risk of developing endometrial cancer. Compared with never users of HRT, the overall incidence of endometrial cancer was increased in users of tibolone and oestrogen-only therapy and decreased in users of continuous combined HRT. However, the effect of the commonly used types of HRT varied, depending on a woman's body-mass index. Among women who were not overweight, use of

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