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Viagra & Melanoma / Hearing-Vision Risk - Role of Sildenafil in Melanoma Incidence and Mortality
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In this prospective study, men who used sildenafil for ED had a statistically significantly elevated 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.....Since the approved use of sildenafil in 1998 and vardenafil hydrochloride (Levitra) and tadalafil (Cialis) in 2003, PDE5A inhibitors have remained the first-line therapy for ED.12,28 Adverse effects are generally mild,12 although vision-threatening ocular complications and hearing loss have been reported.28,32......For 25 848 participants, the mean (SD) age at baseline was 64.8 (8.8) years; 5.3% (1378 of 25 848) reported taking sildenafil for ED recently, and 6.3% (1618 of 25 848) reported ever using it (Table 1). Sildenafil users were more likely to be older and obese, have a history of more severe or blistering sunburns, and undergo physical examinations but had been exposed to less sunlight as adults.......The possible differences in health status and lifestyle practices between sildenafil users and nonusers may have confounded our findings. Sildenafil use was correlated with factors that may increase melanoma diagnosis, such as more severe or blistering sunburns and more physical examinations. In contrast, users tended to have less exposure to sunlight in adulthood, which may have decreased melanoma risk. Because melanoma and nonmelanoma skin cancer share major risk factors, we sought to address the concern about residual confounding by examining the association of sildenafil use with nonmelanoma skin cancer. Sildenafil use was associated exclusively with melanoma, indicating that our findings were less likely due to sun exposure, physical examinations, or detection bias.
J Sex Med. 2011 Oct;8(10):2894-903. doi: 10.1111/j.1743-6109.2011.02382.x. Epub 2011 Jul 19.
Are phosphodiesterase type 5 inhibitors associated with vision-threatening adverse events? A critical analysis and review of the literature.
RESULTS:
Eight case reports of serious PDE5 inhibitor-associated ocular complications were identified since January 2006 until February 2011. Case reports included cases of anterior and posterior nonarteritic ischemic optic neuropathy, central retinal vein occlusion, cilio-retinal artery occlusion, acute angle closure glaucoma and optic atrophy after sildenafil use.
CONCLUSION:
There is lack of conclusive evidence to indicate a direct cause-effect relationship between PDE5 inhibitor use and vision-threatening ocular events. Men who use PDE5 inhibitors appear to suffer vision-threatening complications at the same frequency as the general population. However, minor visual adverse effects occur in 3-11% of users and they are transient and reversible. https://www.ncbi.nlm.nih.gov/pubmed/21771280
Viagra deafness--sensorineural hearing loss and phosphodiesterase-5 inhibitors.
RESULTS:
Forty-seven cases of sensorineural hearing loss with a temporal association with PDE-5 inhibitor ingestion were obtained from both published literature and pharmacovigilance agencies. Cases had a mean age 56.6 years, male-to-female ratio of 7:1. Eighty-eight percent of reports were unilateral with an even left/right distribution. Hearing loss occurred within 24 hours of ingestion of PDE-5 inhibitor in 66.7% (n = 18) of cases. Sildenafil accounted for over 50% of cases.
CONCLUSION:
There is increasing evidence that PDE-5 inhibitors may induce sensorineural hearing loss via plausible physiological mechanisms. There needs to be more awareness of this disabling side effect among healthcare professionals responsible for prescribing this drug. https://www.ncbi.nlm.nih.gov/pubmed/21520123
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Commentary
June 2014
Role of Sildenafil in Melanoma Incidence and Mortality
In 2014, about 76 100 new melanomas will be diagnosed, and an estimated 9710 persons will die (about 6470 men and 3240 women).1 Patients with melanoma in situ, stage 0, have a 5-year survival rate of 99% when treated with excision, whereas those with melanoma limited to the skin and with a tumor thickness of 2.01 to 4.0 mm, stage II B, have a 5-year survival rate of about 57%. Patients with metastatic melanoma, stage IV, have a 5-year survival rate of 15% to 20%. Despite newly available targeted agents, systemic therapies rarely lead to cures. These sizable survival differences illustrate the need for early detection of melanoma; early detection of primary melanomas followed by surgical excision remains critical.
Li et al2 performed an analysis of 25 848 men enrolled in the Health Professionals’ Follow-up Study. After known risk factors were controlled for (eg, number of moles, natural hair color, lifetime number of sunburns, and family history of melanoma), sildenafil citrate (Viagra) users had an elevated risk of melanoma, with a multivariate-adjusted hazard ratio of 1.84 (95% CI, 1.04-3.22). Thus, sildenafil is proposed as a contributor to the development of melanoma. A prospective study with clearly defined inclusion and exclusion criteria and known doses of sildenafil taken is needed before a recommendation can be made to change men’s use of sildenafil. Exposure to UV radiation is the only known modifiable cause of melanoma. Patients at high risk for melanoma because of fair skin, freckling, and tendency to sunburn; those who live in or visit sunny climates; and those who have a family history of melanoma can effectively reduce their risk of melanoma by routinely and thoroughly applying broad-spectrum sunscreen before going outside or by wearing sun-protective clothing.
From 1975 through 1986, the annual percentage increase in men’s age-adjusted incidence rate of melanoma was 5.6%. This slowed to 2.4% per year from 1992 to 2010.1 Sildenafil received approval for the treatment of erectile dysfunction on March 27, 1998.3 The rate of increase in melanoma in men slowed as sildenafil came into use, which raises a cautionary note about the influence of sildenafil in the development of melanoma, but its role in the biologic behavior of melanoma in older men warrants further study.
The findings by Li et al2 suggest a new biologic basis for the sex survival disparity by demonstrating promotion of melanoma cell invasion with sildenafil, which targets cyclic guanosine monophosphate-specific phosphodiesterase (PDE) 5A. Arozarena et al6 demonstrated that PDE5A was downregulated in a substantial collection of melanoma lines expressing oncogenic BRAF, indicating that this inherent phenotype may provide a biomarker for enhanced invasiveness and poor prognostic outcome. While PDE5A drugs could theoretically promote melanoma metastasis, sildenafil did not increase mouse lung colonization by melanoma cells.6 Since PDE5A drugs are used as needed rather than persistently and are cleared rapidly (half-life, about 2 hours), a systemic effect would be intermittent.
The study by Li et al2 identifies older men who use sildenafil and have a history of severe, blistering sunburns as being at risk of melanoma. Because primary care physicians are essentially the providers of care to patients older than 65 years, they are well positioned to detect early melanomas in the elderly. Melanoma screening could be performed by the physician when a sildenafil prescription is written for an older man with a history of sunburns. Some physicians will require training in screening for melanoma to improve their skills and build their confidence. Primary care physicians in Germany, after being trained for 8 hours in visual inspection of the skin, performed melanoma screening and decreased mortality from 1.9/100 000 men prior to screening (1998-1999) to 1.0/100 000 men after screening (2008-2009).7
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June 2014
Sildenafil Use and Increased Risk of Incident Melanoma in US Men
A Prospective Cohort Study
JAMA Intern Med. 2014
In this prospective study, men who used sildenafil for ED had a statistically significantly elevated risk of melanoma. The association remained in the models controlling for the major host characteristics, family history of melanoma, sun exposure behavior, and UV index in the state of residence.
Through selective regulation of cGMP, PDE5A plays an essential role in vascular smooth muscle contraction in the corpus cavernosum.31 The PDE5A inhibitors competitively inhibit the hydrolysis of cGMP, thereby leading to smooth muscle relaxation and penile erection.12,30 Since the approved use of sildenafil in 1998 and vardenafil hydrochloride (Levitra) and tadalafil (Cialis) in 2003, PDE5A inhibitors have remained the first-line therapy for ED.12,28 Adverse effects are generally mild,12 although vision-threatening ocular complications and hearing loss have been reported.28,32
Our study included only confirmed invasive melanomas in the radial and/or vertical growth phase, and our findings suggest an association of PDE5A inhibitors with the risk of melanoma development. The association of PDE5A inhibitors with melanoma progression, recurrence, and metastasis might be stronger, warranting further studies.
The possible differences in health status and lifestyle practices between sildenafil users and nonusers may have confounded our findings. Sildenafil use was correlated with factors that may increase melanoma diagnosis, such as more severe or blistering sunburns and more physical examinations. In contrast, users tended to have less exposure to sunlight in adulthood, which may have decreased melanoma risk. Because melanoma and nonmelanoma skin cancer share major risk factors, we sought to address the concern about residual confounding by examining the association of sildenafil use with nonmelanoma skin cancer.
Sildenafil use was associated exclusively with melanoma, indicating that our findings were less likely due to sun exposure, physical examinations, or detection bias. The homogeneity of the cohort decreases the misclassification of work-related sun exposures or health awareness. Erectile function itself was not associated with melanoma either. Together, these results suggest an association between sildenafil use and melanoma, regardless of other characteristics. Even so, from findings in an observational study, we cannot rule out the possibility of residual confounding by unmeasured or imperfectly measured confounders.
we found a significant association of melanoma with both sildenafil recent use and ever use, wherein the HR for ever use appeared even stronger, which could partly indicate a possible cumulative effect of sildenafil use. However, we did not collect information on frequency and dosage of sildenafil use and were not able to analyze the association with cumulative sildenafil use.
Findings in a well-established, long-term cohort study suggest a positive association between PDE5A inhibitor (sildenafil) use for ED and risk of subsequent melanoma. Our study cannot prove cause and effect. A longer follow-up and more detailed assessment of the dose and frequency of sildenafil use at multiple times in the HPFS would be necessary for future studies. We also plan to work on clinical databases to examine this association. Further studies are needed to confirm our findings in other populations, particularly in a dose-dependent manner, and to investigate underlying biological mechanisms. It would also be very important to examine the possible latency of exposure to PDE5A inhibitor (sildenafil) use and melanoma risk. Our results should be interpreted cautiously and are insufficient to alter current clinical recommendations. Nevertheless, our data provide epidemiological evidence on possible skin adverse effects of PDE5A inhibitors and support continued investigation of this relationship.
Abstract
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.
The association between sildenafil use and melanoma remained significant after excluding the outcomes occurring in the first 2 years (HR, 2.19; 95% CI, 1.18-4.07), and excluding all users of other treatments for ED (2.18; 1.15-4.15). The age-standardized absolute risk associated with sildenafil use was 81.0 cases per 100 000 person-years (216.4/100 000 person-years in users vs 135.4/100 000 person-years in nonusers).
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.
The RAS/RAF/mitogen-activated protein kinase and extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK signaling pathway couples signals from cell surface receptors to transcription factors and regulates cell fate downstream of receptor tyrosine kinases, cytokines, and heterotrimetric G-protein-coupled receptors.1 Melanoma is a major public health problem, particularly in the Western world,2 with 76 000 estimated new cases in the United States in 2012.3 The biological mechanism underlying melanoma development is complex, with the RAS/RAF/MEK/ERK pathway playing a key role in melanoma cell proliferation and survival.1 Hyperactivation of ERK has been found in most human melanomas, commonly regulated through BRAF (OMIM *164757) or NRAS (OMIM *164790) somatic mutations.1,4 Approximately 50% of melanoma tumors have BRAF mutations (mostly V600E mutation), leading to elevated kinase activity.5,6 Drugs inhibiting this pathway, particularly targeting BRAF, have shown therapeutic efficacy.6,7 The cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase (PDE) 5A was recently demonstrated as a downstream target of BRAF.8,9 Through the MEK/ERK cascade, activated BRAF down-regulates PDE5A, which lowers cGMP degradation and leads to an increase in intracellular calcium ion Ca2+, triggering invasion and metastasis of melanoma cells.8-11 In contrast, rescuing expression of PDE5A in melanoma cells decreased their invasiveness.8 Down-regulation of PDE5A was also seen in NRAS-mutant cell lines, indicating that activation of mitogen-activated protein kinase signaling leads to PDE5A down-regulation in melanoma cell lines, irrespective of genetic background.8 Phosphodiesterase 5A is the target of sildenafil citrate, commercially known as Viagra, which has been widely prescribed for erectile dysfunction (ED).12,13 Treatment with sildenafil and other PDE5A inhibitors can promote melanoma cell invasion, particularly in the BRAF-mutated melanoma cell lines.8 This indicates that PDE5A suppression by sildenafil use mimics an effect of BRAF/NRAS activation and thus may potentially function as one of the “hits” for melanomagenesis. Most recently, 2 PDE5 inhibitors were shown to promote melanin synthesis,14 which may exacerbate melanoma development.15 These pieces of evidence prompted our hypothesis regarding the potential link between sildenafil use and melanoma.16
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