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Reproductive factors and risk of melanoma: still unresolved

The hypothesis that sex steroids may be important in the development of melanoma arose from two main observations: the age-specific pattern of melanoma incidence differs between the sexes; and that women diagnosed with melanoma have a survival advantage over men. The incidence of melanoma is generally higher in women than men up to about age 50 after which it is higher for men, suggesting a role for hormonal factors that change around the time of menopause. Laboratory studies in animal models and cell lines also support a role for sex steroids in melanoma progression (as reviewed by Nosrati and Wei); however, to date there is a lack of supportive epidemiological evidence. The observed sex-differences in agespecific incidence rates and the survival advantage for women likely have both a biological and behavioural aetiology. In this issue of the BJD, Støer et al. report on the association between reproductive factors and cutaneous melanoma in the Norwegian Women and Cancer (NOWAC) cohort, including an evaluation by site and histological subtype. None of the factors examined (age at menarche, menstrual cycle length, parity, age at first and last births, breastfeeding duration and menopausal status) were found to be associated significantly with melanoma risk overall, although some heterogeneity across histological types and body sites was observed. Notably, postmenopausal women were less likely to develop melanoma on the trunk compared with premenopausal women, a finding that the authors acknowledge may be the result of residual confounding by age, as trunk melanomas are more common in younger women. The latter observation may reflect a birth cohort effect, with more recent birth cohorts more likely to engage in indoor tanning. A meta-analysis of mostly case–control studies published in 2011 reported that higher parity was associated inversely with melanoma, whereas late age at first pregnancy significantly increased risk; no association was found between age at menarche, age at menopause or menopausal status and melanoma. A later meta-analysis confirmed an association between older age at first birth and melanoma risk, but only among case–control and not cohort studies. Many of the studies included in both reviews were not able to account for the confounding influence of sun exposure and pigmentary characteristics. Thus, in aggregate, the findings to date are inconsistent, and differ according to study design. The association between hormonal factors, both endogenous and exogenous, has been sparsely studied in large prospective studies such as NOWAC, and thus the findings reported by Støer et al. are an important addition to the literature. Study strengths include the large size (165 712 women), complete ascertainment of registry-confirmed cases, long duration of follow-up (median 18 years), and adjustment for measures of sun exposure and pigmentation. Limitations acknowledged by the authors include the potential for misclassification because of the self-reported nature of reproductive history. The role for hormonal factors in the aetiology of melanoma is thus yet to be elucidated; however, on balance and in the context of strong phenotypic and environmental risk factors, it appears that the effects, if any, are weak. The most likely explanation for the observed male : female divergence in agespecific incidence and pre-/postmenopausal differences is behavioural and birth cohort effects rather than endogenous hormones per se.