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Among women aged 55 years and older, use of HRT (≥ 0.5 year) after adjusting for relevant confounders was associated with a statistically non-significant decrease in Breslow thickness of 15.2% (95% CI= –41.1 to 22.0%). The results for increasing cumulative prescription duration of HRT or increasing cumulative dose of HRT were similar (respectively –6.5%; 95% CI: –22.6 to 14.0% and –4.9%; 95% CI: –19.9 to 13.0%).

Discussion

The results of this study could not confirm that the use of OC or HRT (> 0.5 year in the 3 years before CM) has a significant influence on Breslow thickness of CM. However, the association between estrogen use and Breslow thickness of CM seems to be modified by age (Table 2 and 4). Thus, also because of limited sample size, we cannot exclude decreased Breslow depth of CM among patients aged 55 years and older and using HRT (i.e. possible type II error due to lack of power in the subgroup analyses). Moreover, because of collinearity, it is not possible to differentiate between effect modifying by age or different effects of ethinylestradiol (OC) and estrogens used in HRT (estradiol, conjugated estrogens). In explanation, synthetic estrogens may have no effect on Breslow depth whereas natural estrogens do or estrogens might only have effects on Breslow depth in postmenopausal women.

Nevertheless, the observed effects may be caused by an increased incidence of thin melanomas in this population instead of growth inhibition of CM. [5] Thus, the observed effects could also support a specific increase in the incidence of superficial spreading melanomas.

This nested case-control study is large and population-based. Pharmacy data are gathered prospectively, and therefore avoid recall bias. As we had detailed drug-dis- pensing information, we were able to study dose-effect responses, differentiate between OC and HRT, and could also exclude low-dosed topically applied estrogens. estrogensandmelanoma'sbreslowthickness

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Although we corrected for the pathological subtypes, we cannot exclude residual confounding. PHARMO and PALGA data, for instance, do not include data on most risk factors of (thick) melanomas such as family history of melanoma, skin type and other phenotypic characteristics, sun exposure history or socioeconomic status. As these factors are unlikely to affect the likelihood of estrogen prescription, confounding by indication seems unlikely, except possibly socioeconomic status. In addition, there is no biologic basis to assume that menopausal complaints (e.g., flushing and vaginal atrophy) or possible causes of menopause (e.g., hysterectomy) are associated with the Breslow depth of melanomas of the skin.

Conclusion

Our study does not show a statistically significant association between the use of oral contraceptives or hormonal replacement therapy and the Breslow thickness of cutaneous melanoma. However, we cannot exclude decreased Breslow thickness among women using estrogens, especially among older women.

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Chapter 10

General discussion, future perspectives