Basic and Translational Science Treatment With Metformin Improves Erectile Dysfunction in a Murine Model of Obesity Associated With Insulin Resistance F abio H. Silva, Eduardo C. Alexandre, Fabiano B. Calmasini, Marina C. Calixto, and Edson Antunes OBJECTIVE To evaluate the effects of treatment with metformin on a murine model of obesity-associated erectile dysfunction. MATERIAL AND METHODS C57BL/6 male mice were fed for 10 weeks with standard chow or high-fat diet. Lean and obese mice were treated with the insulin sensitizer metformin (300 mg/kg/day, 2 weeks). Intracavernosal pressure (ICP) and in vitro corpus cavernosum (CC) relaxations to both acetylcholine and electrical field stimulation, as well as phenylephrine-induced contractions, were obtained. Levels of cyclic guanosine monophosphate in CC were detected by enzyme immunoassay. RESULTS High-fat-fed mice exhibited higher body weight and insulin resistance. Cavernous nerve stimu- lation caused frequency-dependent ICP increases, which were significantly lower in obese compared with lean mice (P <.05). Two-week therapy with metformin reversed the decreased ICP in obese group. The maximal response to acetylcholine in CC was 35% lower (P <.05) in the obese compared to the lean group, which were restored by metformin treatment. Likewise, the impaired electrical field stimulationeinduced CC relaxations in obese mice were also partly restored by metformin. Contractile responses to phenylephrine were significantly greater (P <.05) in obese compared to lean mice, which were fully restored by metformin. Basal and stimulated cyclic guanosine monophosphate productions in the erectile tissues were significantly lower (P <.05) in the obese group, an effect fully restored by metformin. CONCLUSION Treatment with metformin restored the erectile function in obese mice, through improvement of in vitro endothelial and nitrergic cavernosal relaxations. Therefore, use of metformin may be a good pharmacologic approach to treat insulin resistanceeassociated erectile dysfunction. UROLOGY -: 1.e1–1.e6, 2015. Ó 2015 Elsevier Inc. E rectile dysfunction (ED) is characterized by a persis- tent inability to achieve and/or maintain an erection sufficient for satisfactory sexual performance and has been associated with an abnormal function in the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling pathway and hence, lower NO bioavailability in the erectile tissue. 1 Epidemiologic studies show that obesity is an important risk factor for both ED and insulin resistance (IR). 2-5 Evidence supports a strong causal link between IR and ED. 6-10 In fact, ED has been considered an early clinical manifestation of risk factors for cardiovascular events including acute myocardial infarction. 11 In addition, ED may be the first clinical sign of IR in young men. 8 A recent ran- domized controlled trial in patients with ED with poor response to sildenafil reported that treatment with metformin improves erectile function. 7 IR is a state of dysregulation of glucose-insulin homeo- stasis, in which the ability of insulin to stimulate glucose uptake in peripheral tissues is reduced. 2 Insulin is well known for inducing vascular relaxation through a mechanism that involves endothelium-dependent NO production. 12 Vaso- dilator action of insulin is mediated by the phosphatidyli- nositol 3 kinase (PI3K)-Akt pathway that phosphorylates endothelial NO synthase at Ser 1177 . 12 IR has been strongly associated with decreased NO bioavailability and endothelial dysfunction. 13 Previous studies showed that high-fat-fed obese mice display ED, as demonstrated by reductions of intracavernous pressure (ICP) by cavernosal nerve electro- stimulation and impaired endothelial and nitrergic cav- ernosal relaxations, as well as by increase of contractile response elicited by a1-adrenergic receptor activation. 14,15 Financial Disclosure: The authors declare that they have no relevant financial interests. From the Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, Sao Paulo, Brazil Address correspondence to: F abio Henrique da Silva, Ph.D., Department of Phar- macology, Faculty of Medical Sciences, University of Campinas, Campinas, Sao Paulo 13084-971, Brazil. E-mail: fabiohsilva87@gmail.com Submitted: January 26, 2015, accepted (with revisions): April 28, 2015 ª 2015 Elsevier Inc. All Rights Reserved http://dx.doi.org/10.1016/j.urology.2015.04.035 0090-4295/15 1.e1