Exogenous hormone use and cutaneous melanoma risk in women: The European prospective investigation into cancer and nutrition

Background Several studies reported a positive association between exogenous hormone use and cutaneous melanoma risk in women. However, evidence of an influence of oral contraceptive (OC) or menopausal hormone therapy (MHT) use on melanoma development is still limited. Our objective was to investigate these associations in a large European prospective cohort study. Methods EPIC is a multicentre prospective cohort involving ∼ 520,000 participants (367,903 women) from 23 centres in 10 European countries (France, Italy, Spain, the UK, the Netherlands, Greece, Germany, Sweden, Denmark, and Norway), who were followed-up from 1992–2000. Information on OC and MHT use at baseline was derived from country-specific self-administered questionnaires. We used Cox proportional hazards regression models, stratified on centre and age at recruitment, to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of melanoma risk. We performed stratified analyses according to melanoma site and histological type using competing-risk models. Country-specific estimates were also computed, and Chi 2 tests were used to test for homogeneity. Results A total of 1696 incident cases of primary melanoma were identified among 334,483 women for the OC analysis and 770 cases among 134,758 postmenopausal women for the MHT analysis. Almost two thirds of women reported to have ever used OCs or MHT, although patterns of use varied across countries. Overall, ever use of OCs was positively associated with melanoma risk (HR = 1.12, 95% CI = 1.01–1.26), with a positive linear association with duration of use (≤ 5 years: HR = 1.12, CI = 0.98–1.28; u003e 5 years: HR = 1.21, CI = 1.06–1.39 vs. never use, P trend  = 0.005). Among postmenopausal women, ever use of MHT was not associated with melanoma risk (HR = 1.08, 95% CI = 0.93–1.27), whether women also previously used OCs or not (P homogeneity  = 0.86). However, we observed considerable heterogeneity across countries: ever use of MHT was positively associated with melanoma risk in Spain (HR = 2.42, 95% CI = 1.06–5.52), Germany (HR = 2.91, 95% CI = 1.34–6.34) and France (HR = 1.55, 95% CI = 1.11–2.17), but not in other countries (P homogeneity  = 0.0009). Regarding MHT types, compared to never users, current users of unopposed estradiol were at increased risk of melanoma (HR = 1.44, 95% CI = 1.05–1.97), regardless of the country (P homogeneity  = 0.53). We found no association between duration of MHT, or cumulated duration of MHT and OC, and melanoma risk. Among MHT users, age at first use was not associated with melanoma risk. No heterogeneity was found across melanoma subtypes (P homogeneity  = 0.52) and sites (P homogeneity  = 0.33). Conclusions The findings from this large prospective study suggest some associations between exogenous hormone use and melanoma risk. The strong heterogeneity across European countries may suggest variability in users’ profile across countries or differential effects of specific formulas on melanoma risk. Further research is thus critical to disentangle the links between exogenous hormones and melanoma risk.