Abstract
Dyslipidemia plays a significant role in the atherosclerotic process and has well-established detrimental effects on the cardiovascular system, while hypolipidemic therapy results in significant benefits and substantially reduces cardiovascular events. This review aims to analyze the relationship between dyslipidemia and erectile dysfunction (ED), the extent of this correlation, and the pathophysiological mechanisms mediating this relationship. Secondly, we focus critically on the studies defining the impact of statins on ED, once the outcomes are to some extent conflicting and tried to clarify potential within-class and dose differences. Finally, we present the effects of other hypolipidemic agents, such as fibrates and niacin, on erectile function and discuss available data. These are the three main axes of this review, incorporating current evidence.
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13.1 Introduction
Low-density lipoprotein cholesterol (LDL-C) plays a vital role in the atherosclerotic process, and currently dyslipidemia is considered to be one of the most important risk factors for CV events [1]. The introduction of statins in treatment protocols for patients with dyslipidemia was a major advance for the treatment of CV disease and effectively reduces LDL-C levels and CV events [2, 3]. Because of their effectiveness, 30 million individuals in the USA and up to 200 million individuals worldwide are currently on statin therapy. In addition, the role of statin therapy in primary and secondary prevention of CV events seems to be mediated by other mechanisms (beyond LDL-C reduction) as well. Statins exert beneficial effects even in patients with low, near-baseline LDL-C levels, even <80 mg/dl [4, 5]. Evidence also supports that statin-mediated health benefits are observed well before LDL-C levels decrease [6–9].
Erectile dysfunction (ED) is defined as the persistent inability to attain and/or maintain penile erection sufficient for sexual intercourse. ED is highly prevalent in the general male population and its prevalence increases with age. Traditionally, ED was considered to be either a psychological or an anatomic issue. Thus, the condition was managed by mental health professionals and urologists. However, advances in understanding the pathophysiology of ED in recent years lead the conclusion that origin of ED for the majority of patients is mainly vascular. Specifically, the reduced bioavailability of nitric oxide in the penile tissue in patients with atherosclerosis is the main pathological pathway of erectile dysfunction.
ED is highly prevalent in males with CV risk factors, especially in patients with arterial hypertension, diabetes mellitus, or obesity. The prevalence of ED in patients with dyslipidemia and the effects of statins on erectile function are not completely defined. This review aims to present available data on the relationship between dyslipidemia and ED and critically evaluate existing data about the effects of statins and other hypolipidemic agents on erectile function.
13.2 Epidemiology
In a Canadian Study of primary care physicians, ED was independently associated with cardiovascular disease. However, the study failed to highlight dyslipidemia as an independent risk factor [10]. On the contrary, Smith et al. [11] reported a high prevalence of newly diagnosed hypercholesterolemia and hypertriglyceridemia in men attending an ED clinic. In a large cohort of 272,325 patients with ED, the prevalence of hyperlipidemia was 20.2 %, and the age-specific prevalence ranged from 3.9 to 52.3 % [12]. In addition, ED was significantly more prevalent in individuals with dyslipidemia, coronary artery disease (CAD), and metabolic syndrome. In another study, ED was significantly more prevalent in patients who had both hypercholesterolemia and hypetriglyceridemia [13].
13.3 Pathophysiological Correlation Between ED and Dyslipidemia
Dyslipidemia-induced ED with high LDL-C concentrations as the major culprit has been proposed by Kim [14]. Similar erection response to intracavernous injection of papaverine, a smooth muscle relaxant, of patients with and without hyperlipidemia suggests that the endothelium-dependent relaxation is impaired in ED. This was further supported by in vitro experiments of cavernal tissue, where tissues taken from hyperlipidemic patients demonstrated impaired relaxation response to vasoactive agents, in comparison to tissues from normolipidemic individuals. Oxidized LDL inhibited this relaxation. The production of superoxide radical and the activity of total superoxide dismutase (SOD) (acts as a scavenger) in the hyperlipidemic group were both increased, suggesting a functional impairment of response to endothelial stimuli. Rao et al. [15] confirmed these findings, and others emphasized oxidized LDL as the major factor of impaired relaxation response, as well as the role of nitric oxide (NO), and its reduced generation or bioavailability in penile and vascular tissue [16]. Three experimental studies on rats and mice further support the aforementioned findings. Erectile responses to nerve electrical stimulation, in hypertriglyceridemic rats, was impaired following an increase in triglyceride levels by administration of 10 % fructose and restored when triglycerides were lowered [17]. High-cholesterol diet also had similar detrimental effects on erectile and endothelial function in rats [18, 19].
13.4 Statins and ED
13.4.1 Mechanism of Action
Statins are the cornerstone treatment against hypercholesterolemia. Statins lower blood cholesterol concentrations by inhibiting HMG-CoA reductase. This enzyme catalyzes the conversion of HMG-CoA into mevalonic acid, a cholesterol precursor, thus reducing the endogenous cholesterol synthesis. Apart from that, statins exhibit pleiotropic effects. They intervene intracellular molecular signaling pathways, antagonize accumulation of macrophages and inflammatory processes, and exert a protective action on endothelial cell function, increasing serum NO levels. Statins also reduce smooth muscle cell (SMC) proliferation, stabilize the atherosclerotic plaque, and inhibit platelet activation and coagulation process, hence reducing the cardiovascular risk. The well-established adverse effects are myopathy and elevation of liver enzymes [20]. Another, lately investigated possible adverse effect of statins is hypoandrogenemia, attributed to the inhibition of steroid hormones derived from cholesterol, including testosterone [21]. Statins might also decrease libido through central mechanisms [22].
13.4.2 Clinical Studies
The majority of interventional studies involve the use of atorvastatin in a relatively small number of patients. In general, these studies support that the use of statins improve penile rigidity and sexual function when compared to placebo [23–25]. There is also evidence to support that the effects of sildenafil on erectile function in hypercholesterolemic patients is enhanced when combined with statin therapy [26]. In addition, patients who do not respond to sildenafil exhibited a modest improvement in erectile function when treated with statins [27].
A prospective single-blind study compared the effect of atorvastatin and tadalafil on ED. Subjects (n = 120) were randomized to receive atorvastatin 10 mg/day, tadalafil 20 mg three times/week, a combination of the two for 3 months, or no medication. Mean improvement of IIEF score was significantly higher in both tadalafil group compared to control group (p = 0.0001), and atorvastatin group compared to control group (p = 0.001). The improvement in the tadalafil group was more profound than the atorvastatin group. There was no synergic effect of atorvastatin and tadalafil [28].
Not all studies reported favorable outcomes with statin therapy [29, 30]. In a randomized double-blind longitudinal study, 173 men with untreated ED were treated with 40 mg simvastatin daily (n = 90) or placebo (n = 83) for 6 months. Patients with high cardiovascular risk, hypertension, and angina and those already on ED or statin therapy were excluded. No significant difference in erectile function between the simvastatin and placebo groups (p = 0.27) was noted [31].
A cross-sectional study of patients referred to a lipid clinic for dyslipidemia, and 339 age-matched men found that there were more impotent men in the group of patients treated with hypolipidemic drugs (p = 0.003). Multivariate analysis showed that erectile dysfunction was dependent on treatment with fibrate derivatives (odds ratio, 1.46; 1.27–1.68) and statins (odds ratio, 1.51; 1.26–1.80) [32].
Cases of ED associated with statins were collected by the Spanish and French pharmacovigilance system. In the Spanish database, 38 cases were recognized, 93 % of which resolved after statin withdrawal. In the French database, 37 cases were reported, 85 % resolved after withdrawal and 5 cases exhibited a positive rechallenge [33].
In a prospective observational study including 80 men attending cardiovascular risk clinics, IIEF scores were measured prior to initiation and after 6 months of statin therapy. Prior to statin therapy, the mean IIEF score was 18.7, and 52 % had significant reduction of erectile function. After statin therapy, IIEF scores were reduced to 10.4 (p < 0.001), and 22 % experienced new onset ED [34].
In a study of 1,899 men, there was no association between hyperlipidemia drug treatment and ED, except among younger men (<55) who had diabetes and/or CVD, where a strong association was observed (OR = 10.39, 95 % CI: 3.25, 33.20). In a statins-only analysis, the OR for treated hyperlipidemia was still substantial (OR = 8.86, 95 % CI: 2.69, 29.20), but no information was given regarding the type of statins and dosage [35].
Do et al. [36] assessed the same relation between statins and ED using a case/non-case method within the French Pharmacovigilance System Database. Among the total of spontaneous reports selected (110 685), exposure to statins was identified in 4,471 cases, of which 51 reports (1.1 %) concerned ED, whereas 431 (0.4 %) cases of ED were found in the 106 214 reports without exposure to statins (p < 0.0001). No relationship was found between statin dosage, duration of statin therapy, and ED.
Corona et al. [37] reported that in a cohort of 3,484 men with ED, individuals who were treated with statins had significantly lower levels of total and free testosterone when compared to the rest of the sample (p < 0.0001 for both). Statin treatment was also associated with reduced testis volume and a higher prevalence of hypogonadism-related symptoms and signs (p < 0.01). Also, in the statins group, follicle-stimulating hormone levels were significantly higher compared to the untreated group, suggesting a possible mechanism for statin-related ED. These findings were confirmed by Cohen [38] who also noted an exacerbated free and total testosterone level reduction in individuals with preexisting hypoandrogenic anabolic deficiency state (decreased pregnenolone and DHEA concentrations).
In contrast to the aforementioned studies, a double-blind, randomized, placebo-controlled, clinical trial in patients with ED and endothelial dysfunction reported no significant difference in penile erection between those treated with simvastatin and the placebo group [39].
In another most recent prospective study, ED was assessed in a group treated with rosuvastatin 10–20 mg daily (n = 46) and atorvastatin arm (n = 44). The investigators reported no adverse effect on ED in those treated with atorvastatin, whereas the IIEF score was significantly lower after 6 months of rosuvastatin treatment (p = 0.019). This is the first study to suggest that different types of statins may have a different effect on ED [40] (Table 13.1).
13.4.3 Experimental Data
In an experimental study (Wistar rats), it was found that pretreatment with atorvastatin increased the potency of sildenafil-induced relaxation (p < 0.01), the plasma NOx concentrations, and sildenafil-induced hypotension and tachycardia [41]. These findings suggest a synergy through NO-mediated mechanisms, in the vascular relaxation. In another study, atorvastatin ameliorated sildenafil-induced penile erections in spontaneously hypertensive rats, by interfering with the Rho-kinase signaling pathway within the penis [42]. Atorvastatin benefits on erectile function were also observed in diabetic rats and diabetic rabbits [43]. Similar beneficial effects on erectile function were also observed with rosuvastatin in obese diabetic rats [44]. Simvastatin showed similar benefits in restoring erectile function when added to insulin, by inhibiting the RhoA-/Rho-kinase pathway [45].
13.5 Other Hypolipidemics and Erectile Dysfunction
Case reports or small series of patients who were treated with gemfibrozil suggest that ED might appear after 1–3 weeks of treatment and subside after withdrawal of the drug [46–49]. A review of clinical trial experience with fenofibrate reported ED as an adverse effect on 1.3 % of the patients [50].
In a single-center prospective randomized placebo-controlled parallel-group trial of 160 male patients with ED and dyslipidemia, niacin was associated with improvement of erectile function compared to placebo for 12 weeks [51]. In another single-blind, one-arm study of 54 men with untreated ED, niacin had beneficial effects on erectile function when given combined with propionyl-L-carnitine and L-arginine for 3 months [52].
13.6 Conclusions
This review sought to summarize available evidence regarding the relationship between ED and dyslipidemia. Most evidence support that dyslipidemia is associated with ED through induction of impaired relaxation response upon cavernal tissue. Hypercholesterolemia decreases the gene expression of endothelium-specific cell-to-cell junction proteins and decreased endothelial content in the corpus cavernosum. High levels of ox-LDL induce lower bioavailability of NO.
Available data regarding the effects of statins on erectile function is conflicting. Experimental data point towards a beneficial effect of statins on erectile function through several mechanisms. Clinical data, however, does not confirm these beneficial effects in all cases. Available clinical studies show positive, neutral, or even negative effects on erectile function. However, existing data is not of the highest quality. Many studies are observational with all inherent limitations of this study type, and available prospective randomized studies have usually small study samples and short follow-up. Moreover, the assessment of erectile function in other studies was not based on validated methods. Finally, information regarding a dose-dependent effect or within-class differences are inconclusive.
Information regarding other hypolipidemic agents, apart from statins, is scant and fragmented. Gemfibrozil appears to have detrimental effects on erectile function, while niacin might beneficially affect erectile function; however, available data needs to be confirmed by appropriately designed and adequately powered clinical trials.
References
Ference BA, Yoo W, Alesh I, Mahajan N, Mirowska KK, Mewada A et al (2012) Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis. J Am Coll Cardiol 60(25):2631–2639
Ray KK, Seshasai SR, Erqou S, Sever P, Jukema JW, Ford I et al (2010) Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65,229 participants. Arch Intern Med 170(12):1024–1031
Taylor F, Huffman MD, Macedo AF, Moore TH, Burke M, Davey Smith G et al (2013) Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 1:CD004816
Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ et al (2008) Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 359(21):2195–2207
Mihaylova B, Emberson J, Blackwell L, Keech A, Simes J, Barnes EH et al (2012) The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 380(9841):581–590
Di Sciascio G, Patti G, Pasceri V, Gaspardone A, Colonna G, Montinaro A (2009) Efficacy of atorvastatin reload in patients on chronic statin therapy undergoing percutaneous coronary intervention: results of the ARMYDA-RECAPTURE (Atorvastatin for Reduction of Myocardial Damage During Angioplasty) randomized trial. J Am Coll Cardiol 54(6):558–565
Vale N, Nordmann AJ, Schwartz GG, de Lemos J, Colivicchi F, den Hartog F et al (2011) Statins for acute coronary syndrome. Cochrane Database Syst Rev (6):CD006870
Athyros VG, Kakafika AI, Tziomalos K, Karagiannis A, Mikhailidis DP (2009) Pleiotropic effects of statins–clinical evidence. Curr Pharm Des 15(5):479–489
Athyros VG, Tziomalos K, Florentin M, Karagiannis A, Mikhailidis DP (2010) Statin loading in patients undergoing percutaneous coronary intervention for acute coronary syndromes: a new pleiotropic effect? Curr Med Res Opin 26(4):839–842
Grover SA, Lowensteyn I, Kaouache M, Marchand S, Coupal L, DeCarolis E et al (2006) The prevalence of erectile dysfunction in the primary care setting: importance of risk factors for diabetes and vascular disease. Arch Intern Med 166(2):213–219
Smith NJ, Sak SC, Baldo O, Eardley I (2007) The prevalence of newly diagnosed hyperlipidaemia in men with erectile dysfunction. BJU Int 100(2):357–361
Seftel AD, Sun P, Swindle R (2004) The prevalence of hypertension, hyperlipidemia, diabetes mellitus and depression in men with erectile dysfunction. J Urol 171(6 Pt 1):2341–2345
Gunduz MI, Gumus BH, Sekuri C (2004) Relationship between metabolic syndrome and erectile dysfunction. Asian J Androl 6(4):355–358
Kim SC (2000) Hyperlipidemia and erectile dysfunction. Asian J Androl 2(3):161–166
Rao K, Du GH, Yang WM (2006) Hyperlipidemia and erectile dysfunction. Zhonghua nan ke xue = Natl J Androl 12(7):643–646
Vrentzos GE, Paraskevas KI, Mikhailidis DP (2007) Dyslipidemia as a risk factor for erectile dysfunction. Curr Med Chem 14(16):1765–1770
Srilatha B, Adaikan PG (2006) Characterization of hypertriglyceridemia-induced erectile dysfunction. Urology 67(3):642–646
Ryu JK, Zhang LW, Jin HR, Piao S, Choi MJ, Tuvshintur B et al (2009) Derangements in endothelial cell-to-cell junctions involved in the pathogenesis of hypercholesterolemia-induced erectile dysfunction. J Sex Med 6(7):1893–1907
Demir O, Murat N, Soner BC, Demir T, Bal E, Can E et al (2010) Acute effects of hypercholesterolemic diet on erectile responses in rats. Urol Int 85(1):112–117
Stancu C, Sima A (2001) Statins: mechanism of action and effects. J Cell Mol Med 5(4):378–387
Rizvi K, Hampson JP, Harvey JN (2002) Do lipid-lowering drugs cause erectile dysfunction? A systematic review. Fam Pract 19(1):95–98
Tuccori M, Montagnani S, Mantarro S, Capogrosso-Sansone A, Ruggiero E, Saporiti A et al (2014) Neuropsychiatric adverse events associated with statins: epidemiology, pathophysiology, prevention and management. CNS Drugs. doi:10.1007/s40263-013-0135-1
Saltzman EA, Guay AT, Jacobson J (2004) Improvement in erectile function in men with organic erectile dysfunction by correction of elevated cholesterol levels: a clinical observation. J Urol 172(1):255–258
Herrmann HC, Levine LA, Macaluso J Jr, Walsh M, Bradbury D, Schwartz S et al (2006) Can atorvastatin improve the response to sildenafil in men with erectile dysfunction not initially responsive to sildenafil? Hypothesis and pilot trial results. J Sex Med 3(2):303–308
Bank AJ, Kelly AS, Kaiser DR, Crawford WW, Waxman B, Schow DA et al (2006) The effects of quinapril and atorvastatin on the responsiveness to sildenafil in men with erectile dysfunction. Vasc Med 11(4):251–257
Gokkaya SC, Ozden C, Levent Ozdal O, Hakan Koyuncu H, Guzel O, Memis A (2008) Effect of correcting serum cholesterol levels on erectile function in patients with vasculogenic erectile dysfunction. Scand J Urol Nephrol 42(5):437–440
Dadkhah F, Safarinejad MR, Asgari MA, Hosseini SY, Lashay A, Amini E (2010) Atorvastatin improves the response to sildenafil in hypercholesterolemic men with erectile dysfunction not initially responsive to sildenafil. Int J Impot Res 22(1):51–60
Gokce MI, Gulpinar O, Ozturk E, Gulec S, Yaman O (2012) Effect of atorvastatin on erectile functions in comparison with regular tadalafil use. A prospective single-blind study. Int Urol Nephrol 44(3):683–687
Pedersen TR, Faergeman O (1999) Simvastatin seems unlikely to cause impotence. BMJ 318(7177):192
Scandinavian Simvastatin Survival Study (1994) Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease. Lancet 344(8934):1383–1389
Trivedi D, Kirby M, Wellsted DM, Ali S, Hackett G, O’Connor B et al (2013) Can simvastatin improve erectile function and health-related quality of life in men aged >/=40 years with erectile dysfunction? Results of the erectile dysfunction and statins trial [ISRCTN66772971]. BJU Int 111(2):324–333
Bruckert E, Giral P, Heshmati HM, Turpin G (1996) Men treated with hypolipidaemic drugs complain more frequently of erectile dysfunction. J Clin Pharm Ther 21(2):89–94
Carvajal A, Macias D, Sainz M, Ortega S, Martin Arias LH, Velasco A et al (2006) HMG CoA reductase inhibitors and impotence: two case series from the Spanish and French drug monitoring systems. Drug Saf 29(2):143–149
Solomon H, Samarasinghe YP, Feher MD, Man J, Rivas-Toro H, Lumb PJ et al (2006) Erectile dysfunction and statin treatment in high cardiovascular risk patients. Int J Clin Pract 60(2):141–145
Hall SA, Kupelian V, Rosen RC, Travison TG, Link CL, Miner MM et al (2009) Is hyperlipidemia or its treatment associated with erectile dysfunction?: Results from the Boston Area Community Health (BACH) survey. J Sex Med 6(5):1402–1413
Do C, Huyghe E, Lapeyre-Mestre M, Montastruc JL, Bagheri H (2009) Statins and erectile dysfunction: results of a case/non-case study using the French pharmacovigilance system database. Drug Saf 32(7):591–597
Corona G, Boddi V, Balercia G, Rastrelli G, De Vita G, Sforza A et al (2010) The effect of statin therapy on testosterone levels in subjects consulting for erectile dysfunction. J Sex Med 7(4 Pt 1):1547–1556
Cohen PG (2011) Statins and male hypogonadism. J Sex Med 8(6):1826
Mastalir ET, Carvalhal GF, Portal VL (2011) The effect of simvastatin in penile erection: a randomized, double-blind, placebo-controlled clinical trial (Simvastatin treatment for erectile dysfunction-STED TRIAL). Int J Impot Res 23(6):242–248
Nurkalem Z, Yildirimturk O, Ozcan KS, Kul S, Canga Y, Satilmis S et al (2014) The effect of rosuvastatin and atorvastatin on erectile dysfunction in hypercholesterolemic patients. Kardiol Pol 72(3):275–279
Castro MM, Rizzi E, Rascado RR, Nagassaki S, Bendhack LM, Tanus-Santos JE (2004) Atorvastatin enhances sildenafil-induced vasodilation through nitric oxide-mediated mechanisms. Eur J Pharmacol 498(1–3):189–194
Fibbi B, Morelli A, Marini M, Zhang XH, Mancina R, Vignozzi L et al (2008) Atorvastatin but not elocalcitol increases sildenafil responsiveness in spontaneously hypertensive rats by regulating the RhoA/ROCK pathway. J Androl 29(1):70–84
Morelli A, Chavalmane AK, Filippi S, Fibbi B, Silvestrini E, Sarchielli E et al (2009) Atorvastatin ameliorates sildenafil-induced penile erections in experimental diabetes by inhibiting diabetes-induced RhoA/Rho-kinase signaling hyperactivation. J Sex Med 6(1):91–106
Wingard CJ, Moukdar F, Prasad RY, Cathey BL, Wilkinson L (2009) Reversal of voltage-dependent erectile responses in the Zucker obese-diabetic rat by rosuvastatin-altered RhoA/Rho-kinase signaling. J Sex Med 6(Suppl 3):269–278
Park K, Cho SY, Kim SW (2011) Erectile response to type 5 phosphodiesterase inhibitor could be preserved with the addition of simvastatin to conventional insulin treatment in rat model of diabetes. Int J Androl 34(5 Pt 2):e468–e474
Bain SC, Lemon M, Jones AF (1990) Gemfibrozil-induced impotence. Lancet 336(8727):1389
Bharani A (1992) Sexual dysfunction after gemfibrozil. BMJ Clin Res Ed 305(6855):693
Figueras A, Castel J, Capella D (1993) Gemfibrozil-induced impotence. Ann Pharmacother 27(7/8):982
James CW, Wu TS, McNelis KC (2002) Sexual dysfunction secondary to gemfibrozil. Pharmacotherapy 22(1):123–125
Blane GF (1989) Review of European clinical experience with fenofibrate. Cardiology 76(Suppl 1):1–10; discussion –3
Ng CF, Lee CP, Ho AL, Lee VW (2011) Effect of niacin on erectile function in men suffering erectile dysfunction and dyslipidemia. J Sex Med 8(10):2883–2893
Gianfrilli D, Lauretta R, Di Dato C, Graziadio C, Pozza C, De Larichaudy J et al (2012) Propionyl-L-carnitine, L-arginine and niacin in sexual medicine: a nutraceutical approach to erectile dysfunction. Andrologia 44(Suppl 1):600–604
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Pittaras, A., Avranas, K., Imprialos, K., Faselis, C., Kokkinos, P. (2015). The Association Between Dyslipidemia and Its Treatment with Erectile Dysfunction. In: Viigimaa, M., Vlachopoulos, C., Doumas, M. (eds) Erectile Dysfunction in Hypertension and Cardiovascular Disease. Springer, Cham. https://doi.org/10.1007/978-3-319-08272-1_13
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