Cohort study data published in the American Journal of Epidemiology do not support a strong association between premenopausal progestogen use and subsequent risk for cutaneous melanoma. However, a modest increased risk for melanoma was observed in women using multiple progestogens before menopause.

Investigators abstracted data from the E3N study, an ongoing prospective cohort of 98,995 French women age 40 to 65 years. At a baseline examination in 1990, women completed a questionnaire assessing medical and lifestyle variables. Follow-up questionnaires were administered every 2 to 3 years thereafter, with response rates of 80% to 85% at each time point. The analysis compared melanoma rates in women with and without premenopausal exposure to progestogen. Questionnaire data on menopause status, melanoma risk factors, and progestogen use were extracted. Progestogen treatments were considered exposure only if initiated before menopause. Progestogen-only contraceptives and progestogen with simultaneous estrogen use were excluded as exposures.

The presence of melanoma was captured in follow-up questionnaires and confirmed by pathology. Extracted melanoma risk factors included ultraviolet light exposure, which was ascertained by comparing place of residence against a European database of mean daily ultraviolet radiation doses in French counties. Other risk factors included hair color, complexion, number of nevi and freckles, skin sensitivity, and comorbid conditions. Cox proportional hazards regression models were used to assess melanoma risk in women with and without progestogen exposure. Models were adjusted for age and melanoma risk factors.

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Across 969,511 person-years of follow-up, 540 melanoma cases were ascertained. The mean cumulative duration of premenopausal progestogen use was 3.4 years across the total cohort. In progestogen users, the mean age at initiation was 43.1 years. At the end of follow-up, the majority of women with progestogen exposure were past users (87.9%). Ever use of premenopausal progestogens was associated with a modest increase in melanoma risk in the age-adjusted model (hazard ratio [HR], 1.23; 95% CI, 1.02-1.47), but not in the fully-adjusted model (HR, 1.15; 95% CI, 0.95-1.39). No specific progestogen was associated with increased melanoma risk over other progestogens (P =.22), although use of multiple progestogens was associated with increased melanoma risk (HR, 1.33; 95% CI, 1.04-1.70). In progestogen users, duration of use, age at start and last use, and time since first and last use had no apparent effect on melanoma risk. Results were not significantly changed in analyses that excluded women who continued progestogen use after menopause. Adjustments for residential and recreational ultraviolet exposure did not modify results significantly. However, compared with never users, progestogen users had lower residential sun exposure (P <.01) and were more likely to report sunscreen use (P =.04).

These data “do not support a strong influence of progestogens on melanoma risk,” the investigators concluded, although exposure to multiple concurrent progestogens appeared to increase risk. As study limitations, investigators noted that little information was available on monthly dose of progestogen, causing a potential underestimation of melanoma risk. Further study is necessary to investigate the phototoxic effect of progestogens in premenopausal women.  

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Reference

Cervenka I, Rahmoun MA, Mahamat-Saleh Y, Boutron-Ruault MC, Fournier A, Kvaskoff M. Premenopausal use of progestogens and cutaneous melanoma risk: a French prospective cohort study [published online October 29, 2019]. Am J Epidemiol. doi:10.1093/aje/kwz240