TY - JOUR
AU - Tostes, Rita C
AB - Abstract Introduction Cigarette smoking has major health implications and causes substantial damage to all organ systems. Approximately one-third of men are active smokers worldwide, and most men are unaware that cigarette smoking can contribute to erectile dysfunction (ED). Objectives This article aims to provide a comprehensive overview of research conducted on cigarette smoking and ED, with a particular focus on pathophysiology, electronic cigarettes (e-cigarettes), and smoking cessation. Methods A manual literature search was conducted on all research conducted on cigarette smoking and ED up to October 2022. Results Substantial evidence is now available showing that past and current cigarette smoking has dose-dependent associations with ED in studies controlling for age and important health comorbidities. Cigarette smoke contains nicotine, carbon monoxide, oxidant chemicals, and metals that can damage the endothelium and disrupt erectile processes. For current smokers, smoking abstinence can strengthen the endothelium and reverse diminished erectile function. The effect of e-cigarettes on endothelial damage and ED remains largely untested. E-cigarettes expose users to fine and ultrafine particles and toxins that can increase risk of cardiovascular injury, but these acute effects appear less potent than conventional cigarettes (long-term cardiovascular effects are still unknown). E-cigarettes are therefore likely to have less harmful effects on ED than conventional cigarettes. Conclusions Smoking cessation programs that focus on nicotine replacement therapy (transdermal patches, gum, or inhalers), behavioral counseling, social support, and education programs can be effective approaches to ED treatment in active smokers. Temporarily transferring from regular cigarettes to e-cigarettes—which transmit some of the same carcinogens as conventional cigarettes and are likely to have some long-term cardiovascular effects that disrupt erectile function—might also be useful for long-term smoking cessation and treatment of ED. tobacco, impotence, sexual dysfunction, cigarettes Introduction Erectile dysfunction (ED) refers to a consistent or recurrent inability to attain or maintain an erection that is sufficient for sexual satisfaction.1 ED is a major health care problem that causes substantial distress for those affected and their partners2,3 and is a major contributing factor to health-related quality of life.4-6 Risk of ED increases over the adult life span, and by age 50 years approximately half of all men will experience some level of ED.7,8 In most instances, ED is a physiologic problem that emerges in response to a gradual weakening of the vascular system (endothelial dysfunction) that disrupts processes important for erectile function.9,10 ED can also result from more acute causes, such as drug use and injury (eg, pelvic surgery), which can disrupt nerve signaling to the corpora cavernosa.11,12 Once ED becomes noticeable, psychological factors begin to have a role (eg, sexual performance anxiety).13,14 Treatment for ED typically involves a trial-and-error approach in which patients are initially prescribed low-cost, low-invasive treatments and gradually progress to more invasive, high-cost treatments if the initial treatment is unsuccessful.15,16 Minimally invasive treatment options include testosterone therapy (for hypogonadal men), phosphodiesterase type 5 inhibitors (PDE5Is), vacuum erection devices, and psychosexual and couple therapy.12-14,17-20 Moderately invasive treatments include intraurethral suppositories, injected vasodilator agents, and low-intensity electrocorporeal shock wave therapy.12,21 Penile prosthesis surgery is an effective but invasive treatment that tends to be prescribed only when less invasive treatments have been found to be ineffective.12 PDE5Is are the most common first-line treatment option and are moderately effective in treating ED symptoms.19,20 Several PDE5Is are available that show comparable treatment efficacy.8,19 Mild adverse events (grade 1) associated with PDE5Is include headaches, nasal congestion, flushing, and dyspepsia, as experienced by 10% to 25% of patients.19,20 Economic evaluations of ED treatments show that ED has a substantial economic cost,22 although explicit cost evaluation estimates are somewhat dated and do not reflect present-day cost of treatment.22 As a general principle, the most effective treatments in medicine are those that correct the underlying pathology of the condition (ie, those that address the cause rather than the symptoms). The increased risk of ED across the adult life span7 is thought to reflect relative levels of cardiovascular health that correspond to lifestyle habits and other factors that are known to worsen as people become older.23 Lifestyle has been identified as a major contributor to ED8,23,24 and lifestyle modification (eg, increasing levels of physical activity) as an extremely effective treatment,25-28 with effect sizes comparable to pharmacologic interventions.8 Lifestyle modification is probably the most cost-effective approach to the treatment of ED, and previous reviews have concluded that cigarette smoking in particular is an important independent risk factor.29-32 Despite this important finding, most men are unaware that cigarette smoking can contribute to ED,33 and primary care physicians need to be aware of the molecular mechanisms through which cigarette smoking affects cardiovascular health, if they are to provide credible information to patients on lifestyle modification as a potential treatment. This article reviews the evidence for cigarette smoking as a major contributor to ED, with a particular focus on pathophysiology, electronic cigarettes (e-cigarettes), and smoking cessation. Cigarette smoking In 2015, an estimated 20.2% of the world’s population aged ≥15 years identified as current smokers, with prevalence estimates higher for men (34.1%, 939 million smokers) than women (6.4%, 175 million smokers).34 Cigarette smoking is declining in European, Western Pacific, South-East Asian, and American nations but remains relatively stable in Africa and is increasing in Eastern Mediterranean nations.34 In particular, smoking prevalence among men in Eastern Mediterranean nations is projected to increase from 33.9% in 2015 to 36.2% in 2025 (from 77 to 103 million smokers).34 Globally, cigarette smoking among men is projected to decline from 34.1% in 2015 to 30.0% in 2025, but the total number of cigarette smokers is projected to increase slightly from 939 million men in 2015 to 948 million in 2025, owing to global and regional population rises.34 The total economic cost of cigarette smoking, from health expenditures and productivity losses, is estimated to be US $1.4 trillion per year.34 Cigarette smoke is a concentrated aerosol of liquid particles consisting mainly of nitrogen, oxygen, carbon monoxide (CO), and carbon dioxide.35 Cigarette smoke has >7000 chemical compounds (of which >250 are known to be harmful) from many classes, such as nicotine, N-nitrosamines, and polycyclic aromatic hydrocarbons, as well as volatile compounds including aldehydes, aromatic amines, heavy metals, heterocyclic amines, and chemical additives.36,37 Nicotine is recognized as the major component responsible for addiction because the nicotine molecule activates dopaminergic neurons in the mesencephalic and ventral tegmental areas in the reward-processing brain circuitry.38-40 The chemical constituents in cigarette smoke vary according to a number of factors. The type of tobacco, the soil and fertilizer in which the tobacco is grown, the method of curing, the use of filters, and the type of filter paper, as well as design innovations and the addition of humectants, sugars, and flavor-related compounds, all influence the levels of toxicants transferred into the inhaled cigarette smoke.37 Cigarette smoking is considered the leading cause of preventable disease worldwide.41 Since the link between smoking and lung cancer was established in the 1950s,42,43 much research has documented the many harmful effects of smoking cigarettes.37 In 2015, 11.5% of global deaths (6.4 million; 95% uncertainty interval, 5.7-7.0 million) were attributable to smoking, with 52.2% of these deaths occurring in 4 countries: China, India, United States, and Russia.44 The World Health Organization’s 2019 report on the global tobacco epidemic41 also reported that ~1.2 million annual deaths are the result of nonsmokers being exposed to passive/second-hand smoke. Cigarette smoking has many health implications and affects all organ systems.37 Of particular relevance to the current article, cigarette smoking causes major damage to the cardiovascular system and increases risk of coronary heart disease and stroke.45-48 Moreover, exposure to cigarette smoke can damage endothelial cells and impair endothelial vasodilation.37 To understand how damage to the vascular system through cigarette smoking might disrupt erectile processes, it is important to consider the mechanisms of penile erection. Physiology of erection Pressure changes in the cavernosal sinuses govern the process of penile erection. Erectile tissue is composed of arterioles and hollow blood-filled sinuses that are lined with smooth muscle and endothelial cells.49 In the absence of sexual stimulation, cavernosal vasoconstriction keeps the penis in a nonerect state. Moreover, norepinephrine released from the sympathetic innervation of the penis causes a narrowing of the arteriolar lumen and sinusoidal cavities that restricts blood flow and helps maintain low intracavernosal pressure and a nonerect/flaccid penis.9,49 Sexual stimulation activates parasympathetic nerves leading to vasodilation of cavernous and helicine arteries and relaxation of smooth muscle cells in the corpora cavernosa.9 The resulting dilation of the cavernosal arterioles and sinuses leads to increased blood flow and a subsequent rise in intracavernosal pressure. This increase in pressure activates a veno-occlusive mechanism that restricts the outflow of blood and further increases pressure inside the corpora cavernosa. Erection ensues as the elevated pressure expands the outer tunica albuginea causing increased penile length and diameter.9 A number of transmitters are involved in erectile control: nitric oxide (NO), dopamine, acetylcholine, and peptides such as endothelin 1, adrenocorticotropin, and oxytocin.9 NO, released from endothelial cells and parasympathetic nerve terminals, is the most important factor governing relaxation of penile vessels and the corpora cavernosa.50 NO is fashioned from the amino acid L-arginine through enzymatic action of NO synthase (NOS). Neuronal NOS (nNOS) and endothelial NOS (eNOS) are the major active NOS enzymes expressed in penile tissue. nNOS is located in the cavernous nerves of the corpora cavernosa and branches of dorsal penile nerves and nerve plexuses in deep cavernous arteries.51 eNOS is located in endothelial cells lining cavernous tissue and helicine arteries.52 Endothelium-derived NO, generated in response to shear stress associated with increased blood flow and pressure, sustains penile erection and can help ensure erectile function even in the absence of nNOS.53 When NO is released, it diffuses into the adjacent smooth muscle and binds to guanosine cyclase, which catalyzes the conversion of guanosine trisphosphate into cGMP (3′,5′-cyclic guanosine monophosphate). This process activates protein kinase G and decreases cytosolic calcium (Ca2+). The decreased Ca2+ levels induce relaxation of cavernosal smooth muscle cells, which leads to dilation of arterial vessels and increased blood flow into the corpora cavernosa sinuses.49,50 Increased blood flow also leads to compression of the subtunical venules blocking venous outflow (veno-occlusion). This process is then reversed as cGMP is hydrolyzed by the PDE5 enzyme (phosphodiesterase type 5). Impairment of any of these processes can result in ED. Pathophysiology of smoking and ED Cigarette smoke can affect multiple regulatory systems important for erectile function, including activation of the sympathetic nervous system, injury to the endothelium leading to reduced eNOS and nNOS activity, increased generation of superoxide free radicals from cavernosal smooth muscle and endothelial cells, activation of proinflammatory processes, and changes to endothelin 1 and testosterone levels29-32 (Table 1). Activation of the sympathetic nervous system Increased sympathetic activity and conditions associated with increased sympathetic drive, such as mental stress and arterial hypertension, disrupt erectile function.54,55 Therefore, increased sympathetic activation by cigarette smoke is a potential contributing factor to ED. Cigarette smoke affects heart rate variability, an index of activation of the autonomic nervous system, producing marked disruptions in normal autonomic nervous system functioning.56-59 Smoking increases sympathetic activity and decreases parasympathetic modulation to the heart.59 Moreover, nicotine in tobacco smoke increases the expression of tyrosine hydroxylase, raises sympathetic drive and plasma adrenaline concentrations, heightens blood pressure and systemic vascular resistance, and decreases baroreflex responses that generally restrain sympathetic activity in the setting of increased pressor responses.60-64 Normal sympathetic activation is restored after smoking cessation.64 In addition, cigarettes activate the splenocardiac axis—an inflammatory signaling network that is initiated by increased sympathetic nerve activity that underlies the development of cardiovascular disease. Uptake of 18F-flurorodeoxyglucose in positron emission tomography/computer tomography, used to evaluate the metabolic activity of hematopoietic and vascular tissues, is increased in the spleen and aorta of tobacco users, depicting inflammation as a potential mechanism through which cigarettes might contribute to ED. NO and oxidative stress NO is the primary stimulator of smooth muscle relaxation and vasodilation, which are important for penile erection,9 and cigarette smoke–induced decreases in NO availability potentially contribute to ED. An inadequate synthesis of NO occurs in 1 of 2 ways: (1) endothelial injury leading to reduced eNOS activity or (2) decreased activity or levels of penile nNOS. A large body of research has demonstrated that cigarette smoking decreases NO production,35,63 with most studies addressing the effects of cigarette smoking on NO produced by eNOS activation.65-67 Cigarette smoke causes architectural and functional changes to endothelial cells (Figure 1). These include decreased eNOS activity, reduced response to vascular endothelial growth factor, impaired endothelium vasorelaxation, and impaired regulation of thrombotic factors.29,66-73 Less is known about the effects of cigarette smoking on nNOS, but decreased nNOS expression has been shown to contribute to endothelial dysfunction caused by cigarette smoking in humans.74 Mesenteric resistance arteries from smokers and nonsmokers display acetylcholine-induced dilation mediated by eNOS- and nNOS-derived NO. Moreover, the mesenteric resistance arteries of smokers exhibited impaired endothelium-dependent vascular relaxation, decreased NO production, as well as lower expression of total nNOS, total eNOS, and phosphorylated eNOS-pSer1177, as compared with the arteries of nonsmokers. Selective inhibition of nNOS decreased NO production and acetylcholine vasodilation, further supporting that a decrease in nNOS expression contributes to the endothelial dysfunction caused by cigarette smoking.74 Rodent studies have also found that protein expression of penile nNOS is significantly lower in smoking groups as compared with controls.75,76 Figure 1 Open in new tabDownload slide Mechanisms involved in cigarette- and e-cigarette–induced vascular injury (left and right, respectively). Nitric oxide (NO) is the principal stimulator of cavernosal relaxation and penile erection. Cigarette and e-cigarette smoke can cause functional changes to endothelial cells: decreased eNOS, nNOS, and NO signaling; activation of proinflammatory molecules; and activation of proconstrictor pathways in smooth muscle cells. AA, arachidonic acid; AC, adenylyl cyclase; ACh, acetylcholine; ATP, adenosine triphosphate; Ca2+, cytosolic calcium; cAMP, cyclic adenosine monophosphate; cGMP, 3′,5′-cyclic guanosine monophosphate; COX, cyclooxygenase; eNOS, endothelial nitric oxide synthase; ET-1, endothelin 1; GC, guanylyl cyclase; GTP, guanosine triphosphate; IL-1β, interleukin 1 beta; L-arg, L-arginine; M3 receptor, subtype 3 muscarinic receptor; NA, noradrenaline; NANC, nonadrenergic noncholinergic; nNOS, neuronal nitric oxide synthase; Nox, NADPH oxidase; O2.-, superoxide anion; ONOO−, peroxynitrate; PGH2, prostaglandin H2; PLA2, phospholipase A2; ROCK, rho-associated kinase; ROS, reactive oxygen species; TXA2, thromboxane A2. Table 1 Pathophysiology of cigarette smoking and erectile dysfunction. Regulatory system . Description . • Activation of the sympathetic nervous system Increased sympathetic activity can disrupt erectile function. Cigarette smoke can cause disruptions in normal autonomic nervous system functioning through increases in sympathetic activity and decreases in parasympathetic activity. • Nitric oxide and oxidative stress Nitric oxide is the primary stimulator of smooth muscle relaxation. Cigarette smoking reduces availability of nitric oxide through endothelial injury, leading to reduced activity of eNOS or nNOS. • Inflammation/immune system activation Tobacco and nicotine increase inflammatory markers. Inflammation and overactivation of the immune system contribute to erectile dysfunction. This process might operate through immune system effects on nitric oxide bioavailability and signaling. • Testosterone Testosterone regulates sexual desire and modulates nitric oxide release and NOS activity in endothelial cells. Testosterone also regulates the timing of the erectile process as a function of sexual desire. Cigarette smoking effects on testosterone are not well understood, and this process is unlikely to have a major role in erectile dysfunction. Regulatory system . Description . • Activation of the sympathetic nervous system Increased sympathetic activity can disrupt erectile function. Cigarette smoke can cause disruptions in normal autonomic nervous system functioning through increases in sympathetic activity and decreases in parasympathetic activity. • Nitric oxide and oxidative stress Nitric oxide is the primary stimulator of smooth muscle relaxation. Cigarette smoking reduces availability of nitric oxide through endothelial injury, leading to reduced activity of eNOS or nNOS. • Inflammation/immune system activation Tobacco and nicotine increase inflammatory markers. Inflammation and overactivation of the immune system contribute to erectile dysfunction. This process might operate through immune system effects on nitric oxide bioavailability and signaling. • Testosterone Testosterone regulates sexual desire and modulates nitric oxide release and NOS activity in endothelial cells. Testosterone also regulates the timing of the erectile process as a function of sexual desire. Cigarette smoking effects on testosterone are not well understood, and this process is unlikely to have a major role in erectile dysfunction. Abbreviations: eNOS, endothelial nitric oxide synthase; nNOS, neuronal nitric oxide synthase; NOS, nitric oxide synthase. Open in new tab Table 1 Pathophysiology of cigarette smoking and erectile dysfunction. Regulatory system . Description . • Activation of the sympathetic nervous system Increased sympathetic activity can disrupt erectile function. Cigarette smoke can cause disruptions in normal autonomic nervous system functioning through increases in sympathetic activity and decreases in parasympathetic activity. • Nitric oxide and oxidative stress Nitric oxide is the primary stimulator of smooth muscle relaxation. Cigarette smoking reduces availability of nitric oxide through endothelial injury, leading to reduced activity of eNOS or nNOS. • Inflammation/immune system activation Tobacco and nicotine increase inflammatory markers. Inflammation and overactivation of the immune system contribute to erectile dysfunction. This process might operate through immune system effects on nitric oxide bioavailability and signaling. • Testosterone Testosterone regulates sexual desire and modulates nitric oxide release and NOS activity in endothelial cells. Testosterone also regulates the timing of the erectile process as a function of sexual desire. Cigarette smoking effects on testosterone are not well understood, and this process is unlikely to have a major role in erectile dysfunction. Regulatory system . Description . • Activation of the sympathetic nervous system Increased sympathetic activity can disrupt erectile function. Cigarette smoke can cause disruptions in normal autonomic nervous system functioning through increases in sympathetic activity and decreases in parasympathetic activity. • Nitric oxide and oxidative stress Nitric oxide is the primary stimulator of smooth muscle relaxation. Cigarette smoking reduces availability of nitric oxide through endothelial injury, leading to reduced activity of eNOS or nNOS. • Inflammation/immune system activation Tobacco and nicotine increase inflammatory markers. Inflammation and overactivation of the immune system contribute to erectile dysfunction. This process might operate through immune system effects on nitric oxide bioavailability and signaling. • Testosterone Testosterone regulates sexual desire and modulates nitric oxide release and NOS activity in endothelial cells. Testosterone also regulates the timing of the erectile process as a function of sexual desire. Cigarette smoking effects on testosterone are not well understood, and this process is unlikely to have a major role in erectile dysfunction. Abbreviations: eNOS, endothelial nitric oxide synthase; nNOS, neuronal nitric oxide synthase; NOS, nitric oxide synthase. Open in new tab Cigarette smoke contributes to whole body vascular injury and impairs eNOS-dependent dilation of large peripheral arteries and resistance arterioles.37 This effect is thought to be partly due to the oxygen-derived free radicals in cigarette smoke causing oxidative damage to endothelial cells and NO shortage.77,78 Cigarette smoke contains reactive oxygen species (ROS): oxygen-derived small molecules generated mainly by the NOX family of NADPH oxidases. ROS interact with many molecules, including proteins, lipids, carbohydrates, and nucleic acids.79,80 These interactions can damage or alter the function of the target molecule. The antagonistic effect of ROS is partly attributed to the fast reaction of superoxide with NO to form peroxynitrite anion (ONOO−), a highly reactive free radical.81 Other sources of free radicals that might deactivate NO and impair endothelial vasodilation include xanthine oxidase, activated leukocytes, and uncoupled eNOS.78,82 eNOS uncoupling occurs due to depletion of BH4 (tetrahydrobiopterin).67 Cigarette smoking, by disrupting the natural balance between oxidation and antioxidation reactions, increases superoxide anion generation, induces oxidative stress,75,78,83-85 impairs acetylcholine-induced relaxation of arteries, and raises mRNA expression of proinflammatory cytokines, 86-88 such as interleukin 1 beta (IL-1β) and IL-6 (Figure 1). These effects are prevented by the inhibition of NADPH or treatment with antioxidants.87,88 In addition, increased NADPH oxidase–derived superoxide in cavernosal tissue coincides with self-reported ED,89 and treatment of rodents with antioxidants or oxygen free radical scavengers increases levels of circulating NO, as well as nNOS and eNOS protein expression, and enhances erectile function.90,91 Inflammation/immune system activation Tobacco and nicotine increase inflammatory markers.92-95 Clinical and experimental evidence indicates that chronic low-grade inflammation and overactivation of the innate immune system contribute to the pathogenesis of ED.96-103 ED is closely aligned with conditions such as diabetes, metabolic syndrome, and cardiovascular disease (atherosclerosis, heart failure, and arterial hypertension) where low-grade inflammation is a contributing factor. Infections and elevated inflammatory markers, such as high-sensitivity C-reactive protein, appear to contribute to ED in patients with diabetes.98,100 A cross-sectional population-based study exploring humoral immunity function indexes showed a significant association between ED and humoral immune genes: platelet-activating factor receptor, CD37 molecule, CD40 molecule, IL-27, IL-7R, CXCR3 (chemokine [C-X-C motif] receptor 3), and proteasome subunit beta type 9.104 The exact mechanisms by which the immune system contributes to ED are not fully understood, but decreased NO bioavailability and signaling are thought to be involved.103,105 Activation of toll-like receptors and the consequential release of proinflammatory cytokines, such as TNF-α (tumour necrosis factor alpha), IL-6, and IL-1β, increase cavernosal tone by decreasing NO bioavailability,98 stimulating RhoA/Rho kinase activity,97,106 and promoting structural cavernosal changes.107 Activation of the NLRP3 inflammasome (nucleotide-binding oligomerization domain leucine-rich repeat containing pyrin 3), a member of the NLR family (Nod-like receptors), also has a role in cavernosal function. NLRP3 decreases cavernosal sensitivity to NO and endothelium-dependent relaxation, important events in ED.108-110 Toll-like receptors and NLRs in the innate immune cells recognize structurally conserved molecules derived from microbes (PAMPs [pathogen-associated molecular patterns]) and injured cells (DAMPs [damage-associated molecular patterns]). These receptors are expressed not only in sentinel cells, such as macrophages and dendritic cells, but also in cells of the adaptive immune system, namely T and B lymphocytes, and in nonimmune cells, including endothelial cells.111,112 Whether cigarette smoke directly leads to DAMP release or aggravates DAMP release as a result of tissue injury during noninfectious inflammation, as in diabetes and heart failure, is unknown. Testosterone Testosterone is another important factor that has a major role in sexual desire and function.113,114 Testosterone not only regulates sexual desire but also modulates NO release from nonadrenergic, noncholinergic fibers and NOS activity in endothelial cells. In smooth muscle, testosterone modulates NO bioavailability and the activity of ROCK (Rho-associated protein kinase), SHBG (sex hormone binding globulin), and PDE5, which regulate Ca2+ levels.32,115 Testosterone additionally regulates the timing of the erectile process as a function of sexual desire.116 There is a positive albeit nonlinear correlation between testosterone and erectile function12,115 such that any further increase in circulating testosterone levels >8.0 nmol/L does not affect erectile function.116 Testosterone replacement therapy improves erectile function in patients with ED who are hypogonadal.17,18 However, the magnitude of the effect is somewhat lower in patients with metabolic imbalances, such as diabetes and obesity.17 In men with normal testosterone levels (9.16-31.79 nmol/L),117 testosterone supplementation does little to improve erectile function.113-115 The research on cigarette smoking and testosterone has produced somewhat surprising findings. A 2016 meta-analysis of 22 observational studies and 13 317 men found that smokers had higher testosterone levels than nonsmokers (mean difference = 1.53 nmol/L; 95% CI, 1.11-1.96).118 Even in studies that show a positive association between cigarette smoking and ED, higher testosterone levels are observed among current smokers.119 This counterintuitive finding might be explained by a compensatory mechanism in which the body adapts to the structural and functional damage incurred by cigarette smoke through increases in androgens.29 Alternatively, high testosterone levels induce ROS generation and oxidative stress in vascular smooth muscle and endothelial cells and has proinflammatory effects contributing to vascular damage.120-125 More research is needed to understand the connections among smoking, testosterone, and ED. Nevertheless, given the positive association between cigarette smoking and testosterone,118 coupled with the finding that testosterone supplementation contributes little to erectile function in men with normal testosterone levels,115 the role of testosterone in mediating smoking-induced disruptions to erectile function is probably minimal. Constituents of cigarette smoke Three constituents of cigarette smoke have been identified as particularly important for the cardiovascular system: nicotine, CO, and oxidant gases.36 Of these, oxidant chemicals, particulates, and other combustion products (metals) are damaging to endothelial cells; nicotine also injures endothelial cells and activates the sympathetic nervous system, leading to coronary vasoconstriction, and CO reduces oxygen availability.37,65,126 Most research exploring the constituents of cigarette smoke have focused on nicotine.65 Nicotine has been shown to attenuate sexual arousal in healthy nonsmoking men127 and decrease bioavailability of eNOS-derived NO.65 Nicotine causes damage to the endothelium, with a linear dose-response effect,128-130 and impairs the release of NO.131 Nicotine might impair eNOS-dependent dilation via the production of superoxide anion related to alterations in BH4.65 Nicotine appears to have little effect on nNOS76,132 but could influence endothelial function in other ways—for example, through enhanced release of basic fibroblast growth factor and inhibited production of transforming growth factor β1.37 In addition, nicotine has proinflammatory actions, induces osteogenic transdifferentiation of vascular smooth muscle cells, and stimulates ROS generation that can lead to calcification of arterial tunica media and cause further damage to the vasculature.133 Research in regular smokers has found that nocturnal penile tumescence and rigidity significantly improve after smoking cessation of 24 hours and that improvement continued when patients were receiving nicotine from transdermal patches,134 indicating that factors other than nicotine are involved in ED. Cigarette smoke contains metals, including aluminium, copper, mercury, lead, nickel, and zinc, which catalyze the oxidization of cellular proteins.135 These constituents might contribute to structural damage to the endothelium and detachment of endothelial cells from the walls of blood vessels.37 Cigarette smoke also contains CO, which inhibits smooth muscle cell growth and endothelial cell activation.136 CO has a direct effect on erectile signaling,137 and exposure to CO through cigarette smoke might disrupt the CO/HO pathway (CO/heme oxygenase) that is important for erectile function.137 Observational research Cigarette smoking is probably the most comprehensively researched correlate of ED. A 2018 meta-analysis of 62 population-based studies (223 effect sizes, 240 882 men) found that in studies controlling for important confounding factors (eg, age and healthy living), cigarette smoking was an important independent risk factor for ED.138 The data showed a dose-response effect in which high levels of current cigarette smoking (>20 cigarettes/d; risk ratio [RR] = 1.53; 95% CI, 1.31-1.80) were associated with a higher risk of ED than low levels of cigarette smoking (~8.6 cigarettes/d; RR = 1.26; 95% CI, 1.10-1.44). The meta-analysis also revealed that high levels of past cigarette smoking (~23 pack-years total, <5 years since quit; RR = 1.64; 95% CI, 1.52-1.76) were associated with a higher risk of ED than low levels of past cigarette smoking (~10 pack-years total, >10 years since quit; RR = 1.17; 95% CI, 1.13-1.21).138 World region was identified as an important moderator of past and current cigarette smoking on ED. Current cigarette smoking had a stronger connection to ED in Africa as compared with other continents, and past cigarette smoking had a stronger connection to ED in Asia than North America.138 The mixed findings for regional differences across past and current cigarette smoking might reflect the broad classification of regions tested.138 Continents were dummy coded in meta-regression models, and important subregions, where levels of cigarette smoking tend to be higher (eg, the Eastern Mediterranean), were not separated from larger regions. The magnitude of the association between cigarette smoking and ED might be expected to differ across world regions given that the constituents of cigarettes are less well regulated in some regions139 and brand preferences can differ considerably. For example, 94% of American brands are filtered, as opposed to 79% of UK brands,140 and some brands of cigarette contain about twice as much nicotine and CO as other brands.140 In addition, the meta-analysis found that associations between cigarette smoking and ED do not differ between nonclinical and clinical samples (eg, patients with diabetes or cancer).138 However, differences between specific clinical populations were not explored owing to low statistical power in meta-regression models. Less research has explored the association between passive smoke exposure and ED, and this probably reflects the greater difficulty in accurately assessing exposure to passive smoke. Nevertheless, a prospective study of 2301 men141 found that passive smoking was unrelated to ED after controlling for age and other health-related lifestyle factors (odds ratio [OR] = 1.33; 95% CI, 0.69-2.55). In a study of 1709 men,142 passive exposure to cigarette smoke significantly predicted ED incidence 8 years later, albeit with substantial uncertainty in the magnitude of the effect (OR = 2.07; 95% CI, 1.04-4.13; P = .04). A separate body of research has explored the effect of passive smoking on cardiovascular health. The relative risk of cardiovascular disease in passive smokers is similar to that observed in active smokers despite a near 100-fold lower dose of inhaled cigarette smoke.143 Moreover, studies have found that exposure to passive smoke is associated with a dose-response impairment of endothelium-dependent dilatation in healthy men and women144 and that expression of eNOS is reduced in passive smokers vs nonsmokers.145 Overall, these findings indicate that while the risk of ED from passive smoke is small, long-term chronic exposure might have adverse effects on erectile function. Experimental research Experimental research has provided evidence that exposure to cigarette smoke and nicotine can disrupt erectile processes in humans and other animals. Small-sample studies have found that exposure to cigarette smoke for 8 to 24 weeks disrupts erectile processes in rats.76,77,146 In humans, only acute effects have been explored. In 1 study, 42 regular smokers were given 2 high-nicotine cigarettes, 2 low-nicotine cigarettes, or a placebo and were asked to watch an erotic film with the aim of achieving an erection.147 Those given the high-nicotine cigarettes showed a significantly lower rate of penile diameter change relative to other conditions. In another study, 28 nonsmokers were given 6 mg of nicotine gum (equivalent to smoking 1 cigarette) or an active placebo (gum matched for appearance, taste, and consistency) prior to watching an erotic film.148 Those in the nicotine condition showed significantly reduced penile circumferential change relative to placebo. Experimental studies provide compelling evidence that smoking abstinence can benefit erectile processes in humans. An initial pilot experiment of 10 patients with ED showed significant improvement in nocturnal penile tumescence and rigidity after 24 hours of nonsmoking vs 24 hours of smoking.133 This improvement was maintained in a subsample of 4 men who stopped smoking but were given nicotine replacement therapy (NRT) for a 1-month follow-up period.133 These findings were supported in an experiment in which penile hemodynamics were measured with color Doppler ultrasonography.149 In this experiment, 20 heavy smokers with ED showed improved penile blood flow 24 to 36 hours after smoking withdrawal.149 The first major experiment of long-term smoking cessation assessed 281 men with ED at baseline and 1 year after completing a smoking cessation program in which they were given 2 or 4 mg of nicotine (gum) for 1 to 2 months.150 The study found that erectile function status improved in 25% of the 118 patients who stopped smoking but in none of the 163 patients who continued smoking.150 In a randomized controlled trial (RCT), 719 patients with ED were randomized into a smoking cessation counseling program, a smoking cessation counseling program plus NRT, or a self-help control condition.151 At 6 months, 77 of the 143 quitters (53.8%) reported improvement in erectile function—measured with the International Index of Erectile Function152—as compared with 162 of the 576 nonquitters (28.1%; RR = 2.10; 95% CI, 1.64-2.70).151 A further experiment enrolled 65 male smokers (irrespective of ED status) into an 8-week smoking cessation counseling program plus NRT and measured physiologic parameters (circumference change via penile plethysmography) as well as subjective sexual arousal and function.153 When compared with those who relapsed (n = 45), successful quitters (n = 20) showed enhanced erectile tumescence responses (d = 0.31) and faster onset to reach maximum subjective sexual arousal (d = 0.50). However, quitting smoking had no effect on self-reported sexual function.153 This finding might reflect the population under study being men who were not patients with ED. In a final experiment, 139 patients with known smoking status who underwent robotic prostatectomy were entered into a smoking cessation program involving a wellness coach, tobacco cessation classes, and NRT.154 As compared with those who continued smoking (n = 83), patients who quit smoking (n = 56) showed improved sexual function scores at 24 months posttreatment, albeit with substantial uncertainty in the effect (b = 6.57; 95% CI, 0.92-12.22).154 Overall, despite only 6 published studies on smoking cessation and ED, the available evidence indicates that smoking abstinence can reverse diminished erectile function. E-cigarettes E-cigarettes are devices that are similar to real cigarettes but do not burn tobacco. Rather, e-cigarettes transfer nicotine from the liquid to the vapor phase by heating a nicotine solution. E-cigarettes were developed in China in 2004 as a less dangerous alternative to conventional cigarettes,155 and they continue to be marketed as a safe alternative since the vapor generated in these devices is not the result of tobacco combustion.155-157 Accordingly, e-cigarette usage has soared particularly among adolescents and young adults.158 From 2012 to 2016, average monthly e-cigarette sales rates, as summed across all product types, increased by 132% in the United States alone (from 667 units per 100 000 people in 2012 to 1547 units in 2016),159 and it is estimated that 3.7% of adults use e-cigarettes on a daily basis.157 E-cigarettes are now the most commonly used tobacco product among adolescents and young adults, having surpassed regular cigarette use in the United States in 2014.158 By 2014 all major multinational tobacco companies had entered the e-cigarette market,158 which was worth US $11.26 billion in 2018 and is projected to reach US $18.16 billion by 2024.160 Marketing messages include romance, sexuality, and social bonding, as well as messages suggesting that e-cigarettes are healthy, can be used in smoke-free environments, and are useful for smoking cessation.158 These messages are reflected in the reasons that people give for e-cigarette use, with the main ones being that they are an aid to smoking cessation, a safer alternative to cigarettes, and a convenient way to circumvent smoke-free laws.158 Adolescents and young adults also report that they are attracted to the novelty of e-cigarettes and the flavors.158 The most important component of e-cigarettes is the nicotine cartridge that houses the fluid, or e-liquid, that contains the nicotine (typically 0-24 mg) and other substances. The exact composition varies among and within manufacturers as there are no strong regulations for their production.161 However, in most instances, e-cigarettes contain nicotine, propylene glycol and vegetable glycerine (to produce vapor), flavors (eg, mint, vanilla, chocolate), carcinogens, heavy metals, and other substances.155 Some e-cigarettes contain substances such as rimonabant (often used for weight loss) and amino tadalafil (a PDE5 inhibitor used to treat ED).162 There are >1000 flavoring chemicals that potentially act as toxins,163 and the levels of heavy metals, such as iron, lead, nickel, and cadmium, vary considerably among manufacturers and are thought to originate from the device rather than the liquid.164-166 The widespread use of e-cigarettes, combined with uncertainty regarding their composition, has raised concerns regarding the potential adverse effects of these devices, most notably for risk of cancer, lung disease, and cardiovascular disease.155-158,163-167 Moreover, the constituents of e-cigarettes that affect cardiovascular processes are likely to be relevant to risk of ED. Pathophysiology of e-cigarettes and ED Many constituents of regular cigarettes can be found in e-cigarettes, and this has implications for cardiovascular health and ED.157 E-cigarettes deliver as much nicotine to the systemic circuit as regular cigarette smoking, albeit with a slower absorption rate.168 Like regular cigarettes, e-cigarettes expose users to acrolein and other aldehydes that can affect cardiovascular health and function.157 Acrolein is an unsaturated carbonyl compound that has been identified as a key toxicant in cigarette smoke that contributes to cell death and lung cancer.35-37 E-cigarettes increase sympathetic activation64 and oxidative stress,169 although to a lesser extent than conventional cigarettes,170,171 and cause substantial damage to endothelial cells.164 One experiment exposed human vascular endothelial cells to standard cigarettes and e-cigarettes and found that e-cigarette vapor is capable of inducing ROS, DNA damage, and cell death.172 The study additionally revealed that antioxidant treatment provides partial rescue of induced cell death, indicating that ROS have an important role in e-cigarette–induced cytotoxicity. E-cigarettes also increase levels of soluble NOX2-derived peptide and 8-iso-prostaglandin F2α and decrease NO bioavailability.169 In sum, these findings suggest an important role of oxidative stress in e-cigarette–induced endothelial dysfunction. E-cigarettes induce phospholipase C activation, Ca2+ release from endoplasmic reticulum (ER), SOCE (store-operated Ca2+ entry), and protein kinase Cα phosphorylation, which can lead to depleted ER Ca2+ stores, SOCE inhibition, ER stress, and chronic inflammation.173 Similar to conventional cigarettes, nicotine and no-nicotine e-cigarettes appear to stimulate inflammatory responses.174,175 One study examined lung inflammation through bronchoalveolar lavage and brushings, and although e-cigarettes were associated with less lung inflammation than traditional cigarettes, e-cigarette users and cigarette smokers exhibited increased inflammatory cell counts, higher levels of cytokines, and greater expression of genes related to smoking pathways, including the genes of xenobiotic metabolism, aryl hydrocarbon receptor signaling, and oxidative stress, as compared with never smokers.176 E-cigarette–induced proinflammatory responses in experimental rodents are also accompanied by dysregulated repair responses, such as increased levels of various homeostasis/repair mediators in the lung, namely myogenic, lipogenic, and extracellular matrix markers.177 An important consideration is whether e-cigarettes are less harmful than traditional cigarettes. Regular cigarette smokers typically inhale 8 to 10 times over 5 to 8 minutes, resulting in an arterial spike in nicotine, whereas e-cigarette use tends to be more intermittent throughout the day, resulting in more stable levels of nicotine.168 The result is less potent pharmacologic effects that appear to be less damaging to the cardiovascular system than nicotine from traditional cigarettes.168 Acrolein is thought to account for much of the total noncancer risk of smoking.157 The levels of acrolein and other aldehydes are generally lower in e-cigarettes than in traditional cigarettes, but some devices at high battery power and voltage could generate aldehyde levels approaching those of conventional cigarettes.168 Overall, the levels of toxicants present in e-cigarette aerosol are several orders of magnitude lower than those present in tobacco cigarette smoke,178 and the toxins and carcinogens present in the urine and saliva samples of e-cigarette users are significantly lower than in those using traditional cigarettes and similar to those using nicotine replacement therapies.179 Nevertheless, the nonlinear dose-response relationship between cigarette smoking and cardiovascular injury (as observed in research on passive smoking) means that this might not necessarily result in comparable harm reduction.157 The use of e-cigarettes has implications for processes that can disrupt erectile function, including potential damage to the endothelium.157,180 As of this writing, we are aware of only 1 observational study that has explored whether e-cigarette use relates to ED. In this study of 45 971 US adults, current users of e-cigarettes were more likely to report ED than those who had never used e-cigarettes (OR = 2.24; 95% CI, 1.50-3.34).181 In most instances, e-cigarettes deliver lower levels of carcinogens than conventional cigarettes and therefore should result in a lower risk to users.158 However, e-cigarettes expose users to ultrafine particles and toxins that can increase risk of cardiovascular injury. The similar, though less potent, effects of e-cigarettes on cardiovascular health158 mean that e-cigarettes will likely have some long-term effects on ED. Given the greater use of e-cigarettes among young adults and the higher risk of ED among older adults, epidemiologic studies that control for age, continued cigarette use (60%-90% of e-cigarette users continue to smoke conventional cigarettes158,182), and other markers of cardiovascular health (eg, diet, physical activity) would be particularly useful in establishing risk of ED associated with long-term e-cigarette use. Smoking cessation Article 14 of the World Health Organization’s Framework Convention on Tobacco Control stipulates that member nations develop evidence-based guidelines and take effective measures to promote cessation of tobacco use and adequate treatment for tobacco dependence.183 For smokers aware of the dangers of cigarette smoking (eg, high-income countries), most report that they want to quit, but national smoking cessation services with full or partial cost coverage are available in only 23 countries, representing 32% of the global population.41 Effective smoking cessation strategies include high taxes, health warnings, education programs about the dangers of smoking, social support, psychological treatments (eg, counseling), and pharmacotherapy (eg, Varenicline; NRT via transdermal patches, gum, or inhaler).184-190 A combination of these factors is thought to have contributed to the overall decline in cigarette smoking in European, Western Pacific, South-East Asian, and American nations.34 NRT has been the most comprehensively tested treatment for smoking cessation. A 2018 meta-analysis of 136 high-quality rated RCTs found that the RR of abstinence for any form of NRT (inhaler, gum, patch) relative to control was 1.55 (95% CI, 1.49-1.61).188 Adverse events from NRT relate to the type of product and include skin irritation from transdermal patches and mouth irritation from nicotine gum.188 Serious adverse events, such as chest pain from NRT, are extremely rare.188 NRT and varenicline appear equally effective for smoking cessation,189 and no pharmacologic treatment appears to have an increased incidence of adverse events.189 A 2019 meta-analysis of 24 smoking cessation interventions in low- and middle-income countries revealed that NRT was effective in these regions, that behavioral counseling was more effective than minimal interventions (brief advice), but that minimal interventions were more effective than no intervention.190 Counseling programs vary substantially among experimental studies, and it is not clear whether pharmacotherapy plus counseling is substantially more effective than counseling alone.190 However, a dose-response pattern has been observed between dosage of NRT and duration of counseling.191 An active field of research is exploring whether e-cigarettes can be used effectively as smoking cessation devices to help long-term smokers quit conventional cigarettes. A 2018 meta-analysis of 25 observational studies158 showed that smokers who used e-cigarettes were in fact less likely to stop smoking conventional cigarettes (OR = 0.68; 95% CI, 0.54-0.85). However, further research published in 2019 appeared to show the opposite pattern, with e-cigarettes associated with an increased rate of smoking cessation among adults in the United States.192,193 A 2019 RCT of 886 active smokers compared e-cigarettes against NRT for smoking cessation.194 The 1-year abstinence rate was 18% in the e-cigarette group as compared with 10% in the NRT group (RR = 1.83; 95% CI, 1.30-2.58). In other words, e-cigarettes were more effective for smoking cessation than NRT, with both products accompanied by behavioral support.194 Nevertheless, among nonsmokers there have been concerns that e-cigarettes could also be a gateway to smoking.158,195 A 2017 meta-analysis of 9 longitudinal studies found that after controlling for important confounding factors, being an e-cigarette user was associated with an almost 4-fold increase in odds of becoming a conventional cigarette smoker.195 The goal of any intervention program is to optimize the dose-response relationship specific to the long-term objectives. Given the lower levels of cardiovascular injury incurred from e-cigarettes, transferring from conventional cigarettes to e-cigarettes—which have lower CO production but contain aldehydes, nicotine, and heavy metals—is likely to produce a meaningful benefit to ED symptoms. Indeed, 1 study noted that switching from conventional cigarettes to e-cigarettes improved endothelial function at 1-month follow-up as measured by flow-mediated dilation.196 Even if e-cigarettes are useful for smoking cessation,194 transdermal nicotine patches, which do not contain aldehydes or metals, might be a better approach to reducing ED. However, nicotine can incur some damage to the endothelium37 and stimulate ROS generation and inflammation,133 meaning that smoking abstinence (eg, psychological treatment) might be preferable to pharmacologic intervention. Behavioral counseling can be useful for smoking cessation when used as a stand-alone treatment and when combined with other therapies.188 Longer-duration and more personalized interventions also tend to be more successful for smoking cessation197-199 but incur greater cost. In the absence of a structured intervention, even brief advice has been found to boost smoking cessation rates, albeit to a lesser extent than behavioral counseling.188 This has implications for primary care physicians treating patients with ED. For such patients, a physician will have little more than 15 minutes to discuss ED issues, including its underlying causes, commonality among men of the patient’s age, and potential treatment options. PDE5Is are often presented as a first-line treatment option to combat ED symptoms,15,16 but many men will be interested in treating the underlying cause, typically cardiovascular injury, which can be corrected through lifestyle modification. In an initial short consultation, it should be possible for physicians to outline important steps to reduce symptoms of ED. When treating patients who are current smokers, physicians should aim to provide detailed information on the mechanisms through which cigarettes and e-cigarettes injure the vascular system and disrupt processes important for erectile function. This is important as patients tend to respond better to treatment advice if they understand the processes through which the treatment operates. Also important is the manner in which the information is delivered.200 For pharmacotherapy, people tend to follow instructions, at least until the problem corrects itself, and adherence levels tend to be high. However, for behavioral intervention, adherence levels are often much lower, and this might reflect patients’ interpreting physician instructions as “general good advice” (ie, “to be healthy”) rather than an actual “treatment.”23 To maximize adherence levels, physicians should communicate to patients that lifestyle modification is a specific treatment that will help correct the underlying pathology of the condition. Conclusion Cigarette smoking continues to be the leading cause of preventable disease worldwide.41 Approximately one-third of all men identify as current smokers,34 and the worldwide number of cigarette smokers is set to increase slightly over the coming years.34 Several treatment options are available that can help men attain and maintain an erection that is sufficient for sexual satisfaction.23 However, lifestyle modification is the cheapest, most risk-free, and often most effective treatment for standard age-associated ED.8,23 Cigarette smoke contains CO, aldehydes, nicotine, and heavy metals that can injure endothelial cells and decrease the bioavailability of NO.37 Past and current cigarette smoking has dose-dependent associations with ED,138 and smoking abstinence can strengthen the endothelium and improve erectile function.149-154 E-cigarettes transmit some of the same carcinogens as conventional cigarettes, although at lower dosages, and are likely to have some long-term cardiovascular effects that could disrupt erectile function.180,181 However, the association between e-cigarette use and ED remains largely untested. Most men are unaware that cigarette smoking can contribute to ED,33 and primary care physicians should offer patients with ED detailed explanations about how cigarette smoke can disrupt processes important for erectile function to enhance the likelihood of long-term smoking cessation. More research is needed to identify the most effective smoking cessation interventions and how various e-cigarette brands and their constituents relate to ED. Funding None declared. Conflicts of interest: None declared. References 1. McCabe MP , Sharlip ID, Atalla E, et al. Definitions of sexual dysfunctions in women and men: a consensus statement from the Fourth International Consultation on Sexual Medicine 2015 . J Sex Med . 2016 ; 13 ( 2 ): 135 – 143 . Google Scholar Crossref Search ADS PubMed WorldCat 2. Fisher WA , Eardley I, McCabe M, Sand M. Erectile dysfunction (ED) is a shared sexual concern of couples I: couple conceptions of ED . J Sex Med . 2009 ; 6 : 2746 – 2760 . 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TI - Cigarette smoking and erectile dysfunction: an updated review with a focus on pathophysiology, e-cigarettes, and smoking cessation
JO - Sexual Medicine Reviews
DO - 10.1093/sxmrev/qeac007
DA - 2023-01-19
UR - https://www.deepdyve.com/lp/oxford-university-press/cigarette-smoking-and-erectile-dysfunction-an-updated-review-with-a-Xwg2ccYMw4
SP - 61
EP - 73
VL - 11
IS - 1
DP - DeepDyve
ER -