Sildenafil use and increased risk of incident melanoma in US men: a prospective cohort study.
OBJECTIVE
The RAS/RAF/mitogen-activated protein kinase and extracellular signal-regulated kinase (ERK) kinase/ERK cascade plays a crucial role in melanoma cell proliferation and survival. Sildenafil citrate (Viagra) is a phosphodiesterase (PDE) 5A inhibitor commonly used for erectile dysfunction. Recent studies have shown that BRAF activation down-regulates PDE5A levels, and low PDE5A expression by BRAF activation or sildenafil use increases the invasiveness of melanoma cells, which raises the possible adverse effect of sildenafil use on melanoma risk.


OBJECTIVE
To evaluate the association between sildenafil use and risk of incident melanoma among men in the United States.


METHODS
Our study is a prospective cohort study. In 2000, participants in the Health Professionals' Follow-up Study were questioned regarding sildenafil use for erectile dysfunction. Participants who reported cancers at baseline were excluded. A total of 25,848 men remained in the analysis.


METHODS
The incidence of skin cancers, including melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC), was obtained in the self-reported questionnaires biennially. The diagnosis of melanoma and SCC was pathologically confirmed.


RESULTS
We identified 142 melanoma, 580 SCC, and 3030 BCC cases during follow-up (2000-2010). Recent sildenafil use at baseline was significantly associated with an increased risk of subsequent melanoma with a multivariate-adjusted hazard ratio (HR) of 1.84 (95% CI, 1.04-3.22). In contrast, we did not observe an increase in risk of SCC (HR, 0.84; 95% CI, 0.59-1.20) or BCC (1.08; 0.93-1.25) associated with sildenafil use. Moreover, erectile function itself was not associated with an altered risk of melanoma. Ever use of sildenafil was also associated with a higher risk of melanoma (HR, 1.92; 95% CI, 1.14-3.22). A secondary analysis excluding those reporting major chronic diseases at baseline did not appreciably change the findings; the HR of melanoma was 2.24 (95% CI, 1.05-4.78) for sildenafil use at baseline and 2.77 (1.32-5.85) for ever use.


CONCLUSIONS
Sildenafil use may be associated with an increased risk of developing melanoma. Although this study is insufficient to alter clinical recommendations, we support a need for continued investigation of this association.
Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts2Department of Dermatology, Rhode Island Hospital, Warren Alpert Medical School, Brown University, Providence.
Wen-Qing
WQ
Li
Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts2Department of Dermatology, Rhode Island Hospital, Warren Alpert Medical School, Brown University, Providence3Channing Division of Network Medicine, Depa.
Abrar A
AA
Qureshi
Department of Dermatology, Massachusetts General Hospital, Boston5Graduate Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts.
Kathleen C
KC
Robinson
Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts3Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts6Department of.
Jiali
J
Han
D000368:Aged; D002280:Basal Cell Carcinoma / Q000139:chemically induced / Q000453:epidemiology; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000453:epidemiology; D007172:Erectile Dysfunction / Q000188:drug therapy*; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008545:Melanoma / Q000139:chemically induced* / Q000453:epidemiology; D008875:Middle Aged; D058986:Phosphodiesterase 5 Inhibitors / Q000009:adverse effects*; D010879:Piperazines / Q000009:adverse effects*; D011446:Prospective Studies; D011687:Purines / Q000009:adverse effects; D000068677:Sildenafil Citrate; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000453:epidemiology; D013450:Sulfones / Q000009:adverse effects*; D014481:United States / Q000453:epidemiology
D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate