Estrogen therapy may confer a survival benefit in melanoma patients, while combined estrogen and progesterone therapies are associated with increased mortality, results from a large retrospective analysis of patient data show.

“This reversal was unexpected and raises important questions about the distinct biological effects of these hormones in melanoma,” first author Tara McCaffrey, a third-year student at The Johns Hopkins School of Medicine in Baltimore, MD, tells The Dermatology Digest. The study will be presented at the annual meeting of the Society for Investigative Dermatology in San Diego, CA.

Compare Mortality

While prior studies have explored the role of hormones in melanoma biology and the risk of developing melanoma, clinical data on how exogenous hormone therapies impact melanoma outcomes have been limited and often conflicting, she notes. Working with senior author Kristin Bibee, MD, of the Department of Dermatology at the University of Virginia in Charlottesville, VA, McCaffrey and colleagues drew from more than 120 million de-identified electronic medical records in the TriNetX network to compare mortality among 10,227 adult melanoma patients exposed to estrogen, 718 to progesterone, and 34,549 exposed to both hormones, against 313,691 controls with no hormone exposure.

They used propensity score matching adjusted for demographics and common indications for hormone use, calculated mortality risk, and generated Kaplan-Meier survival curves over a 5-year period, excluding patients diagnosed with melanoma more than 20 years ago.

After matching, estrogen-exposed melanoma patients had significantly decreased mortality compared with control melanoma patients not exposed to estrogen (HR 0.645, 95% CI 0.576–0.721, P=0.039). In contrast, melanoma patients exposed to both estrogen and progesterone showed significantly increased mortality (HR 1.41, 95% CI 1.339–1.484, P<0.001), while progesterone exposure alone showed no significant impact on mortality (HR 1.158, 95% CI 0.772–1.738, p=0.950).

Consider Hormonal History

“Although this study demonstrates a correlation rather than causation, it underscores the importance of considering hormonal history when assessing melanoma risk and prognosis,” McCaffrey says. “Dermatologists should be aware that exogenous hormone therapy, particularly the distinction between estrogen alone and the combination of estrogen and progesterone, may influence melanoma outcomes. The observed association between estrogen alone and improved survival highlights a potential protective role that merits further investigation.”

She points out certain limitations of the study, including its reliance on ICD-coded electronic health records, which may introduce the potential for misclassification and unmeasured confounding. “Although we used propensity score matching to adjust for common hormone therapy indications, we could not assess hormone dosage, duration, or specific formulations,” she says. “Additionally, deaths occurring outside institutions that contribute to TriNetX may not be recorded, which could lead to underestimation of mortality.”

Protective Effect of Estrogen Therapy

Christine Ko, MD, Professor of Dermatology at Yale University School of Medicine in New Haven, CT, who was not affiliated with the work, says that the study “shows an interesting protective effect of estrogen therapy on melanoma outcomes, although estrogen plus progesterone therapy was not beneficial. Hormonal effects on melanoma survival may be complex and [may not be accurately] studied through retrospective analysis.” When asked about the mechanism behind the protective effect of estrogen therapy on melanoma outcomes observed in the study, Ko says “I don’t think it is completely known. There are different theories. There is also evidence that a G protein-coupled estrogen receptor inhibits melanoma growth.”

Neither the study authors nor Ko report having relevant financial disclosures.

— Doug Brunk