MINIREVIEW Mechanisms of obesity and related pathologies: Androgen deficiency and endothelial dysfunction may be the link between obesity and erectile dysfunction Abdulmaged M Traish1, Robert J Feeley1 and Andre Guay2 Department of Biochemistry and Urology, Boston University School of Medicine, MA, USA Department of Endocrinology, Center for Sexual Function, Lahey Clinic, Peabody, MA, USA Keywords diabetes; dyslipidemia; endothelial dysfunction; erectile dysfunction; hypogonadism; inflammatory responses; metabolic syndrome; testosterone deficiency; vascular disease; visceral obesity Correspondence A M Traish, Laboratories for Sexual Medicine, Institute for Sexual Medicine, Boston University School of Medicine, Center for Advanced Biomedical Research, 700 Albany Street, W607, Boston, MA 02118, USA Fax: +1 617 638 5412 Tel: +1 617 638 4578 E-mail: atraish@bu.edu (Received 27 February 2009, revised 31 July 2009, accepted August 2009) doi:10.1111/j.1742-4658.2009.07305.x Obesity is associated with a high prevalence of erectile dysfunction; however, the pathophysiological link between obesity and erectile dysfunction remains poorly understood In this minireview, we have attempted to evaluate the existing literature pertaining to obesity and erectile dysfunction to determine whether a common pathophysiological link exists Visceral obesity is associated with increased inflammatory responses, which contribute to endothelial dysfunction Furthermore, obesity is also associated with reduced plasma testosterone levels, which contributes to hypogonadism and increases the risk of vascular pathology Endothelial dysfunction and androgen deficiency have previously been linked to the pathophysiological mechanisms of erectile dysfunction The underlying pathophysiological mechanisms of endothelial dysfunction and testosterone deficiency include penile vascular insufficiency as a result of the loss of nitric oxide synthase expression and activity and the loss of tissue compliance, resulting in reduced hemodynamic properties Recent progress in the field of sexual medicine has recognized the impact of vascular disease and hypogonadism on the management of patients with erectile dysfunction We suggest that visceral obesity, a component of the metabolic syndrome, adversely affects endothelial function and testosterone levels, contributing to hypogandism and erectile dysfunction Thus, clinical screening for the risk of erectile dysfunction in obese patients should include the assessment of waist circumference, testosterone levels, body mass index and physical inactivity Introduction Erectile function is a neurovascular process that depends on the health of the central and peripheral nervous systems, the vascular health of the erectile tissue, and on the endocrine milieu [1] Sexual stimula- tion activates the non-adrenergic, noncholinergic nerve and activates the neural nitric oxide (NO) synthase ⁄ cGMP pathway The release of NO facilitates the relaxation of penile cavernosal arteries and Abbreviations BAT, bioavailable testosterone; BMI, body mass index; CVD, cardiovascular disease; E2, estradiol; ED, erectile dysfunction; FT, free testosterone; IIEF, International Index of Erectile Function; IL, interleukin; IR, insulin resistance; LH, leutinizing hormone; MCP-1, monocyte chemoattractant protein-1; M-CSF, macrophage-colony stimulating factor; MetS, metabolic syndrome; NO, nitric oxide; PAI-1, plasminogen activator inhibitor-1; PVD, peripheral vascular disease; SHBG, sex hormone binding globulin; T2DM, type diabetes mellitus; TNFa, tumor necrosis factor-a; TT, total testosterone; VD, vascular disease; WC, waist circumference; WHR, waist-to-hip ratio FEBS Journal 276 (2009) 5755–5767 ª 2009 The Authors Journal compilation ª 2009 FEBS 5755 Obesity and erectile dysfunction A M Traish et al resistance arterioles, which causes vasodilation, and increases blood flow to the corpus cavernosum The increased blood flow stimulates the endothelium lining the lacunar spaces of the corpus cavernosum to release endothelial NO from the endothelium NO synthase These biochemical and physiological processes result in trabecular smooth muscle relaxation and expansion of the sinusoids within the corpora cavernosa, leading to penile engorgement This expansion of the corpora cavernosa against the tunica albuginea results in veno-occlusion and trapping of blood under pressure This process is referred to as the ‘veno-occlusive’ mechanism Neural and endothelial NO synthases are regulated by androgens In addition, the tissue histo-architecture is dependent on androgens Thus, any perturbations or alterations in the neural, vascular or erectile tissue fibroelastic properties will contribute to erectile dysfunction (ED), by altering the venoocclusion mechanism In this minireview, we discuss the relationships between obesity, endothelial dysfunction and reduced plasma androgen levels (hypogonadism), and link these pathological states to ED Obesity is a major risk factor for the metabolic syndrome (MetS), vascular disease (VD), diabetes, hypertension, endothelial dysfunction and androgen deficiency, all of which contribute to the pathophysiology of ED Approximately 25% of obese individuals exhibit MetS [2] and obesity, as manifested by an increased body mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR), which contributes to the increased prevalence of ED [3–6] It is universally accepted that fat is stored when the amount of calories consumed exceeds the amount of calories expended However, whether the increased obesity is attributed solely to increased food intake, reduced energy expenditure, or both, remains controversial [7] Recently, Swinburn et al [8] postulated that increased obesity in the USA is attributed directly to increased food intake (i.e increased calorie consumption) In addition to increased food intake, defective biochemical pathways involved in energy expenditure may contribute significantly to obesity [9] Obesity is a heterogeneous condition and not all obese patients are characterized by co-morbidities; however, the accumulation of visceral fat correlates with a cluster of diabetogenic, atherogenic, prothrombotic and proinflammatory metabolic abnormalities known as the MetS [10,11] Despres et al [10,11] suggested that the most prevalent form of MetS is associated with abdominal (visceral) obesity and that this type of obesity contributes to insulin resistance (IR) and the increased release of cytokines, as well as the impairment, clearance and storage of triglycerides 5756 in subcutaneous fat The World Health Organization defines obesity based on the BMI; however, BMI values not always permit stratification of patients based on their risk for developing subsequent cardiovascular disease (CVD) or type diabetes mellitus (T2DM) When identifying patients who are at high risk for developing VD, it is important to consider that there may be subsets comprising overweight patients, with virtually identical BMI values, who may or may not suffer from dyslipidemia and IR [12] In a recent study, Barter et al [12] suggested that dyslipidemic subjects (n = 715, mean BMI = 28.7) are at a higher risk for developing subsequent CVD and diabetes compared to normolipidemic controls (n = 1073, mean BMI = 28.2) with similar BMI values One proposed hypothesis is that the dyslipidemic patients displayed a marked reduction in circulating androgen levels, and such a decrease in androgens, rather than BMI alone, is a stronger predictor for the onset of CVD and diabetes in obese patients Interestingly, Stefan et al [13] suggested that ‘metabolically benign obesity; may exist, in which obese subjects not exhibit IR or early atherosclerosis and that ectopic fat in the liver, and not visceral fat, may be responsible for this phenotype Androgen measurements in these metabolically benign obese patients may provide further clues regarding this pathophysiological state Central (abdominal) obesity, as assessed by several characteristics including BMI, WC and WHR, is considered as a hallmark of the MetS and is associated with reduced plasma androgen levels [14–19] In this minireview, we discuss the link between obesity and ED by focusing on the potential pathophysiological links including obesity-related androgen deficiency and obesity-induced endothelial dysfunction Obesity promotes inflammatory responses and contributes to endothelial dysfunction The role of endothelial function in erectile physiology is well established Any factor that contributes to endothelial dysfunction will certainly contribute significantly to ED This is supported by the fact that penile vascular hemodynamics depends on the integrity of the vascular bed Furthermore, obesity results in a hypogonadal state that disrupts the endocrine milieu, which is critical for maintaining erectile function Obesity is a chronic disease and is associated with an increased risk of T2DM, hypertension and CVD; however, the exact underlying pathophysiological mechanisms by which obesity increases the risk of VD remains the subject of intensive investigation [20] FEBS Journal 276 (2009) 5755–5767 ª 2009 The Authors Journal compilation ª 2009 FEBS A M Traish et al Visceral adipose tissue is a dynamic endocrine organ and this specific adipose component is considered to directly relate to cardiac risk Visceral adipose tissue secretes a host of biochemical modulators and proinflammatory factors contributing to systemic and peripheral vascular inflammation These include interleukin (IL)-6, IL-1b, plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factor-a (TNFa), angiotensinogen, angiotensin-converting enzyme, vascular endothelial growth factor, and serum amyloid A [21–28] (Fig 1) Adipokines are considered to facilitate monocyte adhesion and migration into the vascular wall and the conversion of monoctyes to macrophages Increased levels of TNFa cause the enhanced expression of adhesion molecules in both the endothelium and in vascular smooth muscle cells, and IL-6 stimulates liver production of C-reactive protein, a nonspecific marker of vascular inflammation [29–32] Yudkin [33] suggested a mechanism whereby TNFa released from fat stores surrounding a vessel may contribute to the dysregulation of insulin modulation of endothelin-1 mediated vasoconstriction and NO-mediated vasodilatation favoring vasoconstriction Fig Visceral adipose tissue as a potential endocrine organ Visceral fat is considered to comprise an active endocrine organ, which increases the production of inflammatory cytokines (e.g IL-6, TNFa) as well as lipoprotein lipase, angiotensinogen, free fatty acids, resistin, leptin, lactate, PAI-1, insulin and adipsin, and reduces the levels of adiponectin When coupled with visceral fat hypoxia, the tissue also produces other adipokines, resulting in inflammation, contributing to the onset of hypertension, dyslipidemia, diabetes, thrombosis and atherosclerosis In addition, increased conversion of cortisone to cortisol and increased aromatization of androgens to estrogens results in reduced testosterone levels Thus, visceral fat contributes to PVD, including the vascular bed of the penis, with adverse effects on endothelial function and reduced circulating androgen levels These processes result in reduced penile tissue compliance and diminished penile hemodynamics, and hence a physiological response, leading to ED Adapted from Lyon et al [18] Trayhum et al [24] and Eckel et al [25] Obesity and erectile dysfunction A decrease in adiponectin levels observed in obese patients is also thought to contribute to IR and coronary heart disease (Fig 1) [10,21,34] Indeed, Pietilainen et al [35,36] suggested that only obese subjects who also have reduced adiponectin levels exhibited endothelial dysfunction Adiponectin may play a larger role than previously thought in both the amelioration and pathogenesis of endothelial dysfunction Sowers [34] reported that: ‘Adiponectin reduces endothelial cell apoptosis and may reduce the risk for atherosclerosis by reducing vascular expression of adhesion molecules and foam cell formation and vascular smooth muscle cell proliferation … Weight loss in obese and overweight persons has been found to increase adiponectin levels’ Couillard et al [37] noted that oxidized low density lipoprotein levels were increased in obese men and that obesity increases IR, which activates the endothelium to produce adhesion molecules, facilitating macrophage migration with concomitant endothelial dysfunction Gustafson et al [25] also noted the up-regulation of additional adhesion molecules, such as vascular cell adhesion molecule-1, intracellular adhesion molecule-1 and chemokine monocyte chemoattractant protein-1 (MCP-1) These serum factors may be secondary to the elevated levels of angiotensinogen and angiotensinconverting enzymes observed in obese patients Increased MCP-1 and macrophage-colony stimulating factor (M-CSF) expression in obese subjects are linked to visceral adiposity with an increased risk of T2DM and coronary heart disease [38] Kim et al [39] investigated the effects of exercise in 160 Korean adults separated into an exercise and nonexercise groups The authors suggested that central obesity with high visceral fat is strongly associated with blood levels of C-reactive protein, IR and endothelial dysfunction-related factors However, they did not observe a significant difference in endothelial dysfunction between exercise and non-exercise participants They also note that the relative importance of central adiposity (as opposed to total body adiposity) in endothelial dysfunction is still unclear Perhaps, the use of flow-mediated dilation may have been a better parameter to capture endothelial dysfunction Employing the latter approach together with ultrasonography would have been a better clinical marker and may have provided more reliable information In summary, increased visceral adiposity is associated with increased proinflammatory factors such as increased PAI-1, TNFa, leptin, IL-6 and angiotensinogen, as well as reduced adiponectin levels This imbalance in such cytokines and adipokines results in increased nuclear factor kB It also results in a decrease in NO synthase and NO activity, an increase FEBS Journal 276 (2009) 5755–5767 ª 2009 The Authors Journal compilation ª 2009 FEBS 5757 Obesity and erectile dysfunction A M Traish et al Fig Visceral adiposity-induced endothelial dysfunction Visceral obesity induced endothelial dysfunction is mediated, in part, by leptin, IL-6, free fatty acids (FFA), adiponectin, angiotensin II and TNFa These factors have a downstream effect on the activity of NO synthase (NOS) and NO synthesis, adhesion molecules, MCP-1 and M-CSF Adapted from Chudek and Wiecek [37] in adhesion molecules, and an increase in MCP-1 and M-CSF, causing endothelial injury and dysfunction [40] (Fig 2) This leads to a pathophysiological state involving reduced hemodynamics to the peripheral tissues, including the penis Thus, inflammatory cytokines produced by visceral obesity can have a profound and damaging effect on the endothelium not only in the systemic vascular circulation, but also in the peripheral vascular bed, such as the penis, and can contribute to endothelial dysfunction leading to ED Obesity and its comorbidites are associated with reduced plasma testosterone levels Metabolic alterations associated with obesity include increased insulin, glucose and C-peptide levels, as well as reduced plasma testosterone levels [14–18,41–45] A negative correlation between obesity, total testosterone (TT), free testosterone (FT) and bioavailable testosterone (BAT) levels was inferred from evidence derived from a host of epidemiological studies [46–48] Svartberg et al [15,16] investigated the relationship between WC and TT, FT, and sex hormone binding globulin (SHBG) levels in 1548 community dwelling men (aged 25–84 years) The authors showed WC to be inversely related to FT and SHBG levels A significant inverse correlation between TT and obesity was reported in other studies [42,43,45] It should be noted that, in massively obese men, serum TT and SHBG were markedly reduced [49] Visceral obesity may serve as an endocrine disrupter and influence the endocrine milieu by reducing the levels of luetinizing hormone 5758 (LH) and testosterone resulting in hypogondoropichypogonadism The increased aromatase activity of the visceral and peripheral fat further diminishes the levels of testosterone and increases the levels of estradiol (E2), which further contributes to preferential deposition of more visceral fat and exacerbates the vicious cycle of reduced LH and testosterone with progressive hypogonadism and increased obesity Corona et al [50–52] reported a higher prevalence of hypogonadism in MetS patients and these men had an increased WC and hyperglycemia The authors suggested that WC and hypogonadism may predict the condition of MetS These observations are supported by studies conducted by Tsao et al [53] who showed that WC was correlated with sexual dysfunction in young males In addition, Corona et al [54] reported that obese patients with ED had reduced SHBG-bound and unbound testosterone levels even after adjusting for obesity-related comorbidities The authors suggested that obesity itself may be the underlying cause for a hypoandrogenic state Kaplan et al [55] examined testosterone levels in 864 subjects with and without MetS and found that obese men with MetS had significantly decreased TT compared to non-obese men with MetS Kapoor et al [56] investigated the relationship between ED versus TT, BAT and FT levels in 198 men with T2DM The authors also assessed the degree to which cardiovascular risk factors such as hypertension, visceral adiposity, smoking and alcohol consumption contributed to ED in men with T2DM The authors suggested that ED is associated with low BAT and FT, but not TT, and that ED is more frequently observed in men with higher WC, who smoke, and who have hypertension They also found that 55–58% of their diabetic patients with ED had low TT levels In another study, Hofstra et al [57] assessed the prevalence of isolated hypogonadotrophic hypogonadism in 160 obese men and found that TT and FT were inversely related to BMI These men had decreased libido and ED compared to eugonadal men The author concluded that reduced TT levels, well into the hypogonadal range, are common in male obesity In summary, considerable evidence exists linking obesity to reduced TT levels [18,41,58–67]; however, detailed pathophysiological mechanisms of obesity-induced androgen deficiency and hypogonadism-induced obesity remain the subject of intense investigation Several hypotheses have discussed the relationship of androgen deficiency and obesity That obesity is commonly associated with low TT levels is attributed, in part, to decreased SHBG levels FT and BAT levels are less affected in obese subjects early in the process FEBS Journal 276 (2009) 5755–5767 ª 2009 The Authors Journal compilation ª 2009 FEBS A M Traish et al This is in accordance with findings obtained by Mohr et al [68] who suggested that an over-reliance on TT levels in the diagnosis of androgen deficiency may result in substantial misclassification A plausible mechanism that may account for a decrease in FT involves elevated serum leptin levels in individuals with large fat reserves In obese individuals, elevated leptin levels may interfere with LH ⁄ human chorionic gonadotropin-stimulated androgen production, suppressing androgen biosynthesis [18,69] Another postulated hypothesis is that high E2 levels in obese men may be attributed to an increased peripheral aromatization of testosterone and the increased E2 levels may alter LH levels in obesity, thus modulating the pituitary gonadal axis [70,71] Another link between androgen deficiency and obesity may involve IR, which has been shown to contribute towards a reduction in circulating androgen levels [72] Alternatively, excess cortisol secretion is considered to be associated with increased BMI, WC and WHR, potentially suppressing testosterone production via the hypothalamic–pituitary axis [73] Decreased SHBG and increased aromatization of testosterone to E2 in fat cells or cytokine-mediated inhibition of testicular steroid production in obesity may represent a pathophysiological mechanism in obesity [45] Therefore, men with visceral obesity are in a vicious cycle because testosterone deficiency leads to reduced lipolysis, a reduced metabolic rate, visceral fat deposition and IR Obesity and its comorbidities increase the risk of ED Based on a large number of studies, obesity may represent a significant independent risk factor for ED [74–83] Corona et al [50,51] demonstrated that 96.5% of men with MetS, who also were obese, had ED Similar findings were reported in men with organic ED, in which approximately 43% of men with MetS had ED and the severity of ED increased with the components of the MetS [84] Interestingly, the severity of ED was positively associated with both MetS and IR In a recent study, Corona et al [54] found that, in 2435 male patients with ED, impaired penile blood flow had a closer association with obesity-related comorbidites than with obesity itself Clearly, ED represents a risk factor and may be a warning signal for MetS and IR, with both being risk factors for CVD Interestingly, the largest increase in the incidence of MetS occurred between men with moderate ED and men with severe ED (21.7–70%) Corona et al [54] also demonstrate that the prevalence of fasting blood sugar > 110 mgỈdL)1, a component of MetS, increases Obesity and erectile dysfunction with the severity of ED Interestingly, these observations were not corroborated by Paick et al [85,86], who did not find a significant relationship between ED severity and MetS parameters, except for hypertension They hypothesized that the relationship between MetS and ED severity is not clear-cut and that it may be selective for specific MetS components Wang et al [87] showed that MetS correlated with peripheral vascular disease (PVD), suggesting a link between ED and PVD The prevalence of ED among men with MetS increases with the number of MetS components [88,89], suggesting that MetS is an independent risk factor for ED [90] and WC may represent an independent predictor of ED [91] That obesity-related comoribidies, such as hypertension, contribute to impaired penile blood flow is in line with the emerging data supporting a strong link between MetS and ED Although there is a tight link between hypogonadism and obesity, not all hypogonadal patients suffer from ED Kupelian et al [92–94] further suggested that ED may be a warning sign for the onset of MetS in men with a BMI < 25 and that early intervention should be initiated to prevent VD and ED Although ED might be considered as a warning sign for MetS, as noted earlier, the relationship between these two conditions is complex because components of MetS, such as hypertension, clearly play a role in the etiology of ED Therefore, it is likely that each condition potentiates the other in a vicious cycle A study by Zohdy et al [95] related MetS and androgen deficiency with ED in 158 obese men and showed that, with increasing BMI, the frequency of hypogonadism and ED was increased, whereas TT showed a strong negative correlation The authors found that, for a BMI < 25, three out of 13 men ( 23.1%) had vasculogenic ED compared to 32 out of 54 men (59.3%) with a BMI ‡ 25 By contrast, Kupelian et al [92,93] suggested that ED is a better predictor of MetS in men with a BMI < 25, although Kupelian et al [92–94] did not consider other etiologies of ED These observations are not congruent with other reports [95] Corona et al [54] reported that obesity is associated with low levels of androgens in men with ED, even after adjustment for comorbidities, and that obesity-associated comorbidities, especially hypertension, are among the most important determinants of arteriogenic obesity-associated ED [54] Although it is clear from the many aforementioned studies that obesity and ED are tightly linked, Riedner et al [75] found that different assessment parameters of central obesity have different degrees for predicting the odds of developing ED The authors presented data to suggest that a WC > 102 cm has an odds FEBS Journal 276 (2009) 5755–5767 ª 2009 The Authors Journal compilation ª 2009 FEBS 5759 Obesity and erectile dysfunction A M Traish et al ratio of 19.37, which outranks the odds ratios of 11.72 and 8.56 for abdominal circumference > 106 cm and a WHR > 0.91, respectively However, these results only applied to subjects aged > 60 years, with men aged 40–60 years not showing a significant correlation between ED and these anthropometrical measurements Andersen et al [83] investigated the relationship between obesity and ED in a younger cohort of Danish men between aged 20–45 years and reported that obesity (BMI > 30) is associated with ED among younger men aged 20–45 years, with an odds ratio of 2.74 In a different study, it was found that men with a BMI > 28.7 carry a 30% higher risk for ED than those with a normal BMI of 25 [96,97] Clearly, different studies in humans have used different anthropometrical measurements to assess obesity and this, in addition to the age of the cohort being studied, has influenced the strength of the correlation between ED and obesity The International Index of Erectile Function (IIEF) provides an important assessment of ED [98], with a low score representing increased ED severity A study of 110 obese, sedentary men (BMI ‡ 30, < hỈweek)1 physical activity) in which ED was correlated with BMI and WHR demonstrated that BMI and WHR had significant age-adjusted negative correlation coefficients with ED [81,88] The authors noted that the lower IIEF score, the stronger the correlation with a high BMI and WHR value Esposito et al [80,89] examined the effects of a weight loss program on ED in 55 non-obese and 55 obese, sedentary men for years and found that the scores for 17 out of 55 (31%) subjects increased on the IIEF rating scale, indicating ED improvement In the control group, only three out of 55 patients had responded positively The mean increase in IIEF score in the intervention group was three points, indicating a highly significant change Esposito et al [89] demonstrated that the ‘Mediterranean Diet’ improved ED in subjects with MetS Men on this diet also showed a significant increase in the IIEF score, as a measure of improvement of erectile function Obesity is associated with disturbances in penile hemodymanics in humans and may be an independent factor for vasculogenic ED [95] Wingard et al [99] demonstrated that, in obese animals, the electric field stimulation responses (intracavernosal pressure) were reduced by more than 30% Furthermore, expression of protein kinase C a and Rho-kinase a, b and d were dramatically increased in penile tissue from obese animals, suggesting increased tissue contractility and reduced relaxation, thus impeding erectile function Although many of these studies point towards a strong association between obesity and ED, further 5760 research is needed to verify whether individual MetS components in isolation, such as hypertension alone, can account for this broader correlation between MetS and ED Mulhall et al [100] suggested that, to date, no studies have demonstrated unequivocally that obesity is a risk factor for ED, independent of associated vascular risk factors However, these authors acknowledge that obesity may play a role in the etiology of ED by citing the results of the Massachusetts Male Aging Study, which found that men who were obese at baseline, regardless of their follow-up BMI, as well as men who led sedentary lifestyles, were at the greatest risk for suffering from ED These observations were corroborated in recent studies [101,102] This evidence points towards obesity as having caused irreversible damage to the vasculature by middle age However, as Mulhall et al [100] point out, the results of the Massachusetts Male Aging Study are limited in that only two time points were used, a small sample size was examined, and a short period for follow-up was used, which could have preceded the onset of ED Despite many studies attempting to determine the role of obesity in ED, the pathophysiological mechanisms are not well understood Vascular risk factors commonly associated with obesity may play a key role in the pathogenesis of ED Erectile function is a neurovascular process that requires the health of the central and peripheral nervous system, as well as the vascular bed of the penis, and depends on a functional venoocclusive mechanism [3] The latter is maintained by the hormonal milieu Thus, androgen deficiency and endothelial dysfunction as manifested in obesity will contribute to veno-occlusive dysfunction and ED Given that obesity-related health risks are evident among individuals with excessive abdominal obesity, specifically visceral adipose tissue, which has been shown to induce endothelial dysfunction via the release of proinflammatory cytokines, further investigation into the possible link of obesity with ED is warranted [10,81,88] In addition, treatment strategies that target obesity may prove to be beneficial in reducing ED Although it is widely acknowledged that androgens are critical to normal erectile function, the quantitative role of obesity-induced alterations in this process requires further investigation Although androgens are critical to normal erectile function, healthy lifestyle factors such as a reduction in caloric intake with a a concomitant increase in physical activity have been shown to maintain normal erectile function and to improve sexual function in men with ED [78–81,88,89,102–106] Mechanistically, a reduction in abdominal visceral fat may improve conduit and resistance artery endothelial function, aided by increased NO bioavailability [107] FEBS Journal 276 (2009) 5755–5767 ª 2009 The Authors Journal compilation ª 2009 FEBS A M Traish et al Testosterone treatment for ED ameliorates MetS components and improves endothelial function [108– 111] Testosterone therapy in men with androgen deficiency demonstrated an improvement in erectile function [112–114] and increased muscle mass and decreased visceral fat [115–121] Furthermore, androgens have been shown to inhibit the expression and release of cytokines and chemokines [122–124] Androgen deprivation therapy is associated with increased levels of proinflammatory factors and decreased antiinflammatory cytokines [125,126] Interestingly, testosterone therapy prevents a gain in visceral adipose tissue in non-obese aging men, and reduces the production of proinflammatory cytokines [127–129] It is therefore reasonable to suggest that androgens attenuate adipogenesis as well as inflammatory factor production Because androgen deficiency is linked to the development of IR and T2DM, and the latter contributes profoundly to endothelium dysfunction and ED [130,131], the concept of androgen deficiency reinforces the important role of androgens in vascular health and erectile function Summary and conclusions Visceral obesity, in particular, is characterized by increased inflammatory factors, decreased plasma TT levels and endothelial dysfunction Obesity is associated with decreased TT, BAT and FT levels, as well as elevated E2 levels Such a decrease in TT levels is not associated with increased gonadotropin levels; thus, a hypogonadotropic hypogonadal cycle emerges and persists During this vicious hypogonadal state, the deposition of visceral fat ensues, contributing to central obesity In this pathological state, aromatase activity is increased, resulting in the metabolism of testosterone to E2, contributing further to the decrease in testosterone concentrations and the preferential accumulation of abdominal fat, leading to androgen deficiency and a hypogonadal state Thus, obesity disrupts the endocrine milieu, which produces an altered penile vascular structure by modulating vascular smooth muscle and endothelial function, resulting in an abnormal hemodynamic state and ED Obesity-induced pathological states (Fig 3) have a direct impact on erectile function because the latter depends on (a) the structural integrity of the vascular bed of the penis; (b) the endothelium lining the cavernosal arteries and the helicine arterioles, as well as the endothelium lining the lacunar spaces of the corpus cavernsoum; and (c) the endocrine milieu that regulates the fibroelastic properties of the penis via tissue maintenance and remodeling The evidence Obesity and erectile dysfunction Fig Proposed link between obesity, inflammatory responses, androgen deficiency, endothelial dysfunction and ED Based on the information available in the contemporary literature, we suggest that visceral obesity contributes to ED via three interdependent (overlapping) pathophysiological mechanisms: (a) inflammatory cytokines that contribute to endothelial dysfunction and microvascular disease and reduced androgen levels; (b) the insult on the endothelium resulting in endothelial injury and reduced NO synthase activity and NO production, leading to reduced tissue relaxation and poor hemodynamics; and (c) disruption of the endocrine milieu, with a concomitant decrease in testosterone levels and increased E2 levels, thus disrupting tissue homeostasis, tissue histo-architecture and erectile tissue compliance These pathophysiological states contribute directly to ED in obesity presented in the literature regarding obesity and ED, and as discussed in this minireview, strongly suggests a link between obesity and ED This link is supported by the adverse effects of obesity on endothelial function, circulating androgen levels, an 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Diabetes Metab Res Rev 22, 423–436 FEBS Journal 276 (2009) 5755–5767 ª 2009 The Authors Journal compilation ª 2009 FEBS 5767 ... pathophysiological links including obesity- related androgen deficiency and obesity- induced endothelial dysfunction Obesity promotes inflammatory responses and contributes to endothelial dysfunction The role of endothelial. .. measurements to assess obesity and this, in addition to the age of the cohort being studied, has influenced the strength of the correlation between ED and obesity The International Index of Erectile Function... the literature regarding obesity and ED, and as discussed in this minireview, strongly suggests a link between obesity and ED This link is supported by the adverse effects of obesity on endothelial