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Original Investigation |

Sildenafil Use and Increased Risk of Incident Melanoma in US Men:  A Prospective Cohort Study

Wen-Qing Li, PhD1,2; Abrar A. Qureshi, MD, MPH1,2,3; Kathleen C. Robinson, PhD4,5; Jiali Han, PhD1,3,6,7,8,9
[+] Author Affiliations
1Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
2Department of Dermatology, Rhode Island Hospital, Warren Alpert Medical School, Brown University, Providence
3Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
4Department of Dermatology, Massachusetts General Hospital, Boston
5Graduate Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts
6Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts
7Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis
8Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis
9Department of Epidemiology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
JAMA Intern Med. 2014;174(6):964-970. doi:10.1001/jamainternmed.2014.594.
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Importance  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.

Design, Setting, and Participants  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.

Main Outcomes and Measures  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 and Relevance  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.

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Submit a Comment
Melatonin and vitamin D prophylaxis versus melanoma?
Posted on April 11, 2014
David L. Keller, MD, FACP
Independent Commentator
Conflict of Interest: None Declared
The results of this study may be particularly worrisome to men who have used sildenafil and may be at elevated risk of melanoma due to history of extensive sun exposure, basal or squamous cell skin cancers, family history and Parkinson disease (which causes autonomic erectile dysfunction and is associated with elevated risk of melanoma). The April 2014 Mayo Clinic Proceedings contains an editorial advocating adjuvant therapy with vitamin D and melatonin for every stage of melanoma, and as secondary prophylaxis. Given the low risk of harm from these supplements, might it be reasonable for persons at high risk for melanoma to consider taking them as primary prophylaxis? An example might be a man with Parkinson disease-associated sildenafil use, a FH of melanoma, and personal history of sun exposure and basal cell carcinomas.
Parkinson disease is associated with melanoma & erectile dysfunction
Posted on April 9, 2014
David L. Keller, M.D.
Independent Commentator
Conflict of Interest: None Declared
Parkinson disease (PD) is associated with increased risk of melanoma. PD also causes autonomic neuropathy, often resulting in erectile dysfunction. This study has found an increased risk of melanoma among users of sildenafil, a treatment for erectile dysfunction, and the authors describe a plausible biological mechanism for this possible medication side effect. This may indicate that males with PD should exercise caution with regard to the use of medications such as Viagra, and especially with regard to similar medications such as Cialis Daily, a related phosphodiesterase inhibitor which is approved for daily use as a dual treatment for both erectile dysfunction and symptoms of prostate hypertrophy.
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