Menopausal hormone use and ovarian cancer risk: individual participant meta-analysis of 52 epidemiological studies

Abstract

Background: Half the epidemiological studies with information about menopausal hormone therapy and ovarian cancer risk remain unpublished, and some retrospective studies could have been biased by selective participation or recall. We aimed to assess with minimal bias the effects of hormone therapy on ovarian cancer risk.

Methods: Individual participant datasets from 52 epidemiological studies were analysed centrally. The principal analyses involved the prospective studies (with last hormone therapy use extrapolated forwards for up to 4 years). Sensitivity analyses included the retrospective studies. Adjusted Poisson regressions yielded relative risks (RRs) versus never-use.

Findings: During prospective follow-up, 12 110 postmenopausal women, 55% (6601) of whom had used hormone therapy, developed ovarian cancer. Among women last recorded as current users, risk was increased even with <5 years of use (RR 1·43, 95% CI 1·31-1·56; p<0·0001). Combining current-or-recent use (any duration, but stopped <5 years before diagnosis) resulted in an RR of 1·37 (95% CI 1·29-1·46; p<0·0001); this risk was similar in European and American prospective studies and for oestrogen-only and oestrogen-progestagen preparations, but differed across the four main tumour types (heterogeneity p<0·0001), being definitely increased only for the two most common types, serous (RR 1·53, 95% CI 1·40-1·66; p<0·0001) and endometrioid (1·42, 1·20-1·67; p<0·0001). Risk declined the longer ago use had ceased, although about 10 years after stopping long-duration hormone therapy use there was still an excess of serous or endometrioid tumours (RR 1·25, 95% CI 1·07-1·46, p=0·005).

Interpretation: The increased risk may well be largely or wholly causal; if it is, women who use hormone therapy for 5 years from around age 50 years have about one extra ovarian cancer per 1000 users and, if its prognosis is typical, about one extra ovarian cancer death per 1700 users.

Funding: Medical Research Council, Cancer Research UK.

Figure 1

Trends in hormone therapy use in the USA and the UK since 1970 For source of data, see appendix p 4.

Figure 2

Relative risk of ovarian cancer by duration of use in current and past users of hormone therapy *Risk relative to never-users of hormone therapy, stratified by age at diagnosis, study, and body-mass index, and adjusted for age at menopause, hysterectomy, oral contraceptive use, and parity. p values are two-sided and include the effects of the group-specific variance in never-users.

Figure 3

Study-specific results for the relative risk of ovarian cancer for current-or-recent users versus never-users of hormone therapy For study-specific details and references, see appendix pp 7–10. Dotted lines represent totals for all prospective studies and, separately, for all retrospective studies. Study-specific results are arranged by study design and region; results are given for individual studies with the most statistical information (ie, with variance of log relative risk <0·03). Results for the remaining studies are grouped together here (and given separately for every study in appendix p 14). In comparisons of relative risks in prospective versus retrospective studies, overall heterogeneity p<0·0001; for European studies, heterogeneity p=0·4; and for North American studies, heterogeneity p=0·002. In a comparison of relative risks in prospective studies, Europe versus North American heterogeneity p=0·9; for retrospective studies, Europe versus North American heterogeneity p=0·04. References provided in the appendix. *Risk relative to never-users of hormone therapy, stratified by age at diagnosis, study, and body-mass index, and adjusted for age at menopause, hysterectomy, oral contraceptive use, and parity.

Figure 4

Relative risk of the four most common subtypes of ovarian cancer in current-or-recent users versus never-users of hormone therapy Numbers do not add to totals, because some hormone therapy users were classified as using other or unknown types of hormone therapy and some epithelial tumours are classified as mixed types, other type, or type not specified. *Risks relative to never-users of hormone therapy, stratified by age at diagnosis, study, and body-mass index, and adjusted for age at menopause, hysterectomy, oral contraceptive use, and parity.