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A Comprehensive Review of Metabolic Syndrome Affecting Erectile Dysfunction Ecem Kaya, PhD,* Suresh C. Sikka, PhD, HCLD,† and Serap Gur, PhD*† *Departments of Biochemistry and Pharmacology, Faculty of Pharmacy, Ankara University, Ankara, Turkey; †Department of Urology, Tulane University Health Sciences Center, New Orleans, LA, USA DOI: 10.1111/jsm.12828

ABSTRACT

Introduction. Metabolic syndrome (MetS) is the most important public health issue threatening the health of men and women all over the world. Its current prevalence (i.e., approximately 30%) is continuously increasing. MetS by itself is considered a risk factor for erectile dysfunction (ED). Aim. To focus on the definition epidemiology, pathogenesis, and possible mechanistic links between MetS and ED in order to provide guidelines for treating such individuals. Methods. The search strategies yielded total records screened from PubMed. Main Outcome Measures. Regardless of the definition, MetS consists of insulin resistance, hypertension, dyslipidemia, and obesity. MetS is not an end disease but is a disorder of energy utilization and storage. Results. The prevalence of ED in patients with MetS is almost twice than in those without MetS, and about 40% of patients with ED have MetS. An important mechanism linking MetS and ED is hypogonadism. Conclusions. Recognizing through ED, underlying conditions such as hypogonadism, diabetes and MetS might be a useful motivation for men to improve their health-related choices. The clinical management of MetS can be done by therapeutic interventions that include lifestyle modifications, hormone replacement alone or in combination with phosphodiesterase 5 inhibitors, and other pharmacological treatments. Kaya E, Sikka SC, and Gur S. A comprehensive review of metabolic syndrome affecting erectile dysfunction. J Sex Med 2015;12:856–875. Key Words. Metabolic Syndrome; Insulin Resistance; Obesity; Inflammation; Hypogonadism; Erectile Dysfunction

Introduction

M

etabolic syndrome (MetS) was first defined in the 1920s as an accumulation of certain medical issues comprising hypertension, hyperglycemia, and gout [1]. Although the term “MetS” dates back to at least the late 1950s, it is only in 1998 that a World Health Organization (WHO) task force was associated with this syndrome along with diabetes and its complications. Thus, this MetS is also referred to as insulin resistance syndrome, MetS-X, and cardiometabolic syndrome. MetS is caused when a defect in insulin action results in fasting hyperinsulinemia to maintain euglycemia, contributed by an overabundance of circulating fatty acids [2]. Regardless of the relative J Sex Med 2015;12:856–875

contributions of visceral fat and abdominal subcutaneous fat to insulin resistance, a pattern of abdominal (or upper body) obesity is strongly associated with the insulin resistance and the MetS than does lower body obesity [3]. MetS has been defined by different organizations such as the WHO International Diabetes Federation and Adults Treatment Panel III (ATP III) [4]. Currently, the ATP III definition is most likely used [5]. Regardless of the minor differences in various definitions, at least three of the following factors should be present for MetS diagnosis: (i) central (abdominal) obesity; (ii) hypertension (i.e., raised blood pressure); (iii) increased fasting blood glucose (and/or insulin) levels; (iv) elevated tryglycerides (TGs; i.e., dyslipidemia); and (v) © 2015 International Society for Sexual Medicine

Metabolic Syndrome and Erectile Dysfunction reduced high-density lipoprotein cholesterol (HDL-C) levels. It is interesting to note that recent studies have linked MetS with erectile dysfunction (ED) [6,7]. ED is a very common clinical condition that affects a significant proportion of men throughout the world and has a negative impact on quality of life. All epidemiologic studies clearly show an increasing age-related prevalence and severity of ED. It is an increasingly common condition, with population prevalence estimates between 30% and 50% [4,8,9]. It is estimated that 52%, or 18 million American men, between the ages of 40 and 70 years, will be affected with some degree of ED [9,10]. Data from the Massachusetts Male Aging Study (MMAS) documented a tripling of the overall probability of complete ED from 5% in men aged 40 years to 15% in men aged 70 years [9]. In the European Male Aging Study, performed in eight European centers for the investigation of ED in men aged 40–79 years old, the prevalence of ED was higher in the old age groups with a peak at age 70 [11]. In addition, the prevalence of MetS has dramatically increased worldwide in many epidemiologic trials [12]. MetS has a high prevalence around the world as high as 35–39% in the United States and 9.5% in Europe [13]. ED is up to three times more prevalent in men with MetS [6,7]. A total of 79–96% of patients with MetS presents with ED, and 29–66% of patients with ED have MetS [14]. In a study by Heidler et al. [15] including 2,371 men aged 30–69 years, the prevalence of MetS was found in 34% of men above the age of 50. Many in vitro and in vivo studies have reported the emerging role of MetS, including abdominal obesity, impaired glucose metabolism, hypertriglyceridemia, low HDL-C, and hypertension, in the development and progression of sexual symptoms. Notably, MetS in older men (>50 years) was associated with a higher proportion of moderate to severe ED. In addition, Bal et al. [14] studied 393 male patients with ED aged 40–70 years; MetS was not only related to moderate to severe ED, but there were numerous other criteria of MetS that were associated with ED including elevated fasting blood glucose levels, hypertension, waist circumference (WC), altered triglyceride, and HDL-C levels. Both MetS and increased waist-to-hip ratio (WHR) were independently associated with a decreased IIEF-5 score. Demir et al. [16] showed a high correlation between diminished erectile function domain score with an increased number of metabolic risk factors. The MMAS in which a population-based cohort was

857 observed over 15 years demonstrated that the presence of MetS even in those with a body mass index (BMI) below 25 is associated with increased ED risk [17]. Earlier epidemiological studies have demonstrated that low testosterone (T) levels are a predictor of mortality in elderly men [18]. T deficiency and MetS are strongly associated. Hypogonadism was presented more frequently in the patients with MetS. Patients consulting for ED may have T deficiency, providing a valuable opportunity to assess MetS. The incidence of type 2 diabetes mellitus (T2DM) among adults in the United States, including diagnosed and undiagnosed cases, has increased from 7.8% during the period 1988–1994 to 9.3% during 1999–2002 [19]. The growing prevalence of diabetes mellitus has been associated with an increase in important underlying risk factors including sedentary lifestyle [20] and increasing prevalence of obesity [21], along with an aging population. Obesity, a major risk factor for ED in diabetics, has a prevalence of 32.2% in the United States [21]. Patients with nearly 23% of such high-risk adults (those who are overweight and older than 45 years) thought to have prediabetes with fasting glucose ≥100 mg/dL [22]. MetS is a cluster of abnormal metabolic conditions that increases the risk of cardiovascular disease (CVD) and T2DM [23]. As obesity and diabetes are closely related, body weight and adiposity have been shown to be significantly associated with ED [24]. Obesity affects at least 400 million adults worldwide [25]. It is interesting to know that in highincome North America, no state had an obesity prevalence greater than 14% in 1985, but by 2010, every state had a prevalence of 20% or more [26]. Also, the proportion of adults aged 20 years and older with diabetes increased from 9.1% in 1988 to 11.4% in 2001 in the United States [27]. By this rate about 40% of men are expected to be obese by 2020 [28,29]. Obesity is one of the key factor in MetS and its progression. The expression of MetS is highly variable among different ethnicities [17]. In particular, in China, the prevalence of MetS has increased dramatically owing to alterations in lifestyle and dietary habits in recent decades [30]. In economically developed countries, the MetS affects up to 30% of the population, and its incidence continues to increase [31]. A recent study suggests that 73% of male patients with abdominal obesity show symptoms of ED, 47% show T deficiency syndrome, and 62% of men have MetS [32]. J Sex Med 2015;12:856–875

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MetS-ED Mets MetS-ED Mets Mets-ED Mets Mets-ED Mets Mets-ED Mets Mets-ED Mets ED Control Total 29.4 ± 5.7 29.8 ± 3.6 23.3 ± 4.5 22.2 ± 1.9 120.8 ± 8.1 116.9 ± 6.6 75.2 ± 7.9 73.1 ± 6.4 98.1 ± 10.7 87.0 ± 5.6 N/A N/A 192 33 225 [41] N/A N/A 28.3 ± 3.1 27.5 ± 3.6 129.7 ± 15.6 127.2 ± 13.8 84.5 ± 11.0 81.7 ± 7.2 N/A N/A N/A N/A N/A N/A N/A [40] 55.8 ± 7.7 52.5 ± 4.8 29.8 ± 4.4 26.9 ± 4.6 151 ± 22.0 128 ± 13.0 88 ± 10.0 78 ± 7.0 106.6 ± 11.2 94.2 ± 11.3 9.7 ± 7.2 29.7 ± 0.5 37 28 65 [38] Reference number

Patient number

IIEF score

WC (cm)

DBP (mm Hg)

SBP (mm Hg)

BMI (kg/m2)

ED Control ED Control ED Control ED Control ED Control ED Control ED Control Total Age (years)

Study population Clinical data

Obesity There is at least 400 million obese people worldwide [25]. In United States alone, 65% of adults are

Table 1

According to the MMAS, 52% of men showed some degree of ED between ages 40 and 70 [9]. Longitudinal data analysis from MMAS study showed that the presence of ED had a predictor value for future development of MetS in men with normal weight at baseline [17]. Increased blood pressure levels with high levels of C-reactive protein (CRP), insulin resistance index, and carotid intima-media thickness in ED patients are strongly linked to MetS [33]. Many patients with MetS have diminished International Index of Erectile Function (IIEF) scores which become more significant with increasing metabolic risk factors [16,34]. A significant negative linear correlation between IIEF score and CRP levels exists, suggesting that a high level of this mediator is related to the severity of ED [35,36]. MetS is associated with deterioration in the hemodynamic parameters of the cavernosal arteries, particularly a diminished mean peak systolic velocity on Penile Duplex Doppler Ultrasound (PDDU) [37]. From all the components of MetS, obesity (measured by bioimpedance) and high blood pressure are independently associated with deterioration of the hemodynamic profile in PDDU measurements [37]. Thus, screening of ED patients for clinical components of MetS (e.g., waist and hip circumference and BMI) is necessary for establishing a link between MetS and ED [38,39] (Table 1).

Comparable clinical data in patients with erectile dysfunction and metabolic syndrome

Assessment of ED in Patients with MetS

49.4 ± 12.5 48.2 ± 14.6 26.5 ± 3.3 24.7 ± 2.3 N/A N/A N/A N/A N/A N/A 19.8 ± 2.3 28.3 ± 1.2 115 50 165 [42]

Study population

54.1 ± 8.2 45.9 ± 4.6 32.0 ± 4.8 32.7 ± 4.5 139.8 ± 16.5 136.5 ± 12.2 81.7 ± 8.8 82.1 ± 7.4 N/A N/A N/A N/A 36 21 57 [43]

53.2 ± 5.6 48.4 ± 6.4 31.8 ± 4.3 32.1 ± 5.1 140.2 ± 14.4 138.1 ± 13.3 81.9 ± 7.6 82.9 ± 8.2 113.9 ± 10.8 113.9 ± 12.9 N/A N/A 27 43 70 [44]

59.5 ± 9.6 56.3 ± 11.1 25.9 ± 2.9 24.3 ± 2.6 N/A N/A N/A N/A N/A N/A 12.7 ± 5.7 12.7 ± 5.7 38 65 103 [45]

Interestingly, 79% of men presenting ED have BMI of 25 kg/m2 or higher; men with BMI in the range of over 30 kg/m2 have three times greater risk of sexual dysfunction compared with normal men. Visceral obesity leads to the enhanced inflammatory responses and, thus, greater endothelial dysfunction and decreased plasma T levels; these favor the development of hypogonadism and increase the risk of vascular diseases like ED. Earlier epidemiological studies have found that low T levels are a predictor of mortality in elderly men, and hypogonadism was presented more frequently in the patients with MetS as well as T2DM [11,12,31]. This review focuses on the role of MetS in patients with ED involving data from many preclinical and clinical studies.

BMI = body mass index; DBP = diastolic blood pressure; ED = erectile dysfunction; IIEF = international index of erectile function; MetS = metabolic syndrome; N/A = not applicable; SBP = systolic blood pressure; WC = waist circumference

Kaya et al.

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Metabolic Syndrome and Erectile Dysfunction

Figure 1 Increased adiposity leading to metabolic syndrome (MetS) and erectile dysfunction (ED) interactions.

overweight or obese according to the National Health and Nutrition Examination Survey [46]. Industrialized Western countries have an epidemic of obesity with the rate of MetS reaching 25–30% in the white male population in the United States, Germany, and Greece [47–49]. In fact, the past decade has noticed impressive increase in the prevalence of obesity, mainly due to sedentary lifestyles and high saturated fat diet [50]. The visceral obesity associated with CVD plays a significant role in the pathophysiology of MetS and ED [51]. In a recent review by Corona et al. [52], obesity and especially central obesity are correlated with both arteriogenic ED and decreased T levels. Obesity associated with the MetS is also involved in chronic inflammation which plays a major role in the pathogenesis of many disorders including lower urinary tract syndrome and ED. When obesity is associated with low-inflammation state, it increases cytokine production from visceral adipose tissue (adipocytokines) thereby causing endothelial dysfunction and insulin resistance [53]. In fact, adipose tissue cells regulate the pathways responsible for energy balance through hormonal and neural signals and chemical messengers such as tumor necrosis factor-alpha (TNF-α), angiotensinogen, and leptin complex [54,55]. In addition, low T levels also lead to accumulation of the excessive fat, while obese men with BMI > 35 kg/m2 have significantly higher plasma estradiol and lower T levels compared with controls [56]. Increased adiposity is associated with many metabolic alterations linked to ED including insulin resistance, dyslipidemia, increased oxida-

tive stress, lipid peroxidation, and hypertension, all key components of the MetS [57]. On the other hand, the disturbances in the regulation of male sexual function, through a reduction of total testosterone (TT) and free T levels, have been observed in many obese men establishing a vicious cycle (Figure 1) [58].

Hypogonadism The prevalence of hypogonadism was three times higher in ED men with MetS than in those without MetS [59]. The MetS associated with low T levels is related to several potential mechanisms leading to many health issues [60,61]. Hypogonadism is associated with an increased risk of coronary artery diseases (CADs), visceral obesity, low HDL-C, elevated TGs, elevated low-density lipoprotein cholesterol (LDL-C), and impaired plasminogen activator inhibitor-1 (PAI-1) [62]. Hypogonadism in aging is also associated with increased body weight, adipose tissue, and estrogens, resulting from peripheral conversion of T to estradiol. T therapy improves MetS especially in overweight elderly men. The negative feedback mechanism from excess estradiol results in a paradoxically low luteinizing hormone (LH) secretion from the pituitary despite a physiologically low T level [63]. Estrogen has a significantly negative role on male sexual behavior resulting in decreased intracavernosal pressure and impaired cyclic guanosine monophosphate-nitric oxide (NO)mediated cavernosal smooth muscle relaxation [64,65]. J Sex Med 2015;12:856–875

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Table 2

Laboratory comparable data of groups with erectile dysfunction

Groups

Total testosterone (ng/mL)

ED Control ED Control ED Control ED Control

4.9 ± 2.2 5.2 ± 1.9 N/A N/A 6.7 6.5 16.5 ± 5.6 15.6 ± 2.4

TG (mg/dL)

Fasting blood glucose (mg/dL)

HDL cholesterol (mg/dL)

LDL cholesterol (mg/dL)

Total cholesterol (mg/dL)

Patients number (n)

Reference number

146.5 ± 72.4 155.1 ± 91.6 185.8 ± 114.3 172.7 ± 122.6 102 ± 35.42 106.3 ± 31.88 114.8 ± 54.4 138.7 ± 47.6

115.7 ± 28.1 102.9 ± 29.7 N/A N/A 84.6 ± 10.8 81 ± 9 89.7 ± 25.6 88.6 ± 11.2

47.2 ± 9.4 54.1 ± 11.5 46.2 ± 10.3 50.4 ± 12.6 54.14 ± 11.6 50.27 ± 7.73 50.6 ± 12.2 47.6 ± 8.9

N/A N/A 122.4 ± 33.4 123.7 ± 35.8 119.87 ± 30.93 119.87 ± 27.06 N/A N/A

N/A N/A 202.3 ± 35.5 205.7 ± 40.5 N/A N/A N/A N/A

37 28 N/A N/A 192 33 115 50

[78] [40] [41] [42]

ED = erectile dysfunction; HDL = high density lipoprotein; LDL = low density lipoprotein; N/A = not applicable; TG = triacylglycerol

Hypogonadism constitutes a possible link between MetS and ED [66], probably associated with insulin resistance. Acute withdrawal of T in hypogonadal men for 2 weeks reduced insulin sensitivity without apparent changes in body composition, suggesting that sex steroids directly modulate insulin resistance [67]. Sex hormonebinding globulin (SHBG) levels are reduced in obese men as a result of increased circulating insulin levels that are associated with the insulin resistance of obesity [68]. The central obesity of MetS results in an increase in aromatase activity, which facilitates the one-way conversion of T to estradiol [52]. Obese men display elevated estrogen levels which can cause receptor-mediated inhibition of the hypothalamic-pituitary-gonadal axis. Hence, ED in the older obese patient may result from a pathophysiological estradiol-T imbalance [69]. By lowering levels of estradiol, there would be a reciprocal increase in levels of T [70]. Although androgen and estradiol are physiological antagonists in many organs, the impact of estradiol on the T homeostasis and impact on natural erection is still unclear. Such interactions especially related to obesity and diabetes affecting erectile tissue are an area that needs further research utilizing both in vivo and in vitro models and clinical trials.

T2DM T2DM characterized by insulin resistance is often associated with MetS and causes ED [68]. Diabetes per se, independent of MetS, was not associated with hypogonadism [71], although diabetic patients are more insulin resistant than the rest of the population [72]. Epidemiological studies in men have also shown a close association between low serum T levels and T2DM [73–75]. Insulin resistance by altering vascular response to insulin leads to vasoconstriction rather than vasodilation J Sex Med 2015;12:856–875

(as in healthy subjects) and may contribute to impaired erection [76]. It is interesting to note that duration and severity of ED have been observed to correlate with glycemic control [77]. The determination of glycemia and the total amount of fatty substances (cholesterol and TGs) in the blood are required for the initial metabolic evaluation of the patients (Table 2) [33,42,78,79].

CVD Many reports suggest that ED is a marker of systemic vascular disease and subclinical CAD, and many predict future CVD events [80–82]. It is also related to the degree of severity of the coronary lesions [83]. Coexistence of MetS, ED, and T deficiency can further increase risk [84]. In addition, obesity and overweight as well as other lifestyle conditions are risk factors for CVD [85]. The five most prevalent cardiometabolic factors are low HDL-C, overweight/obesity, abdominal obesity, hypercholesterolemia, and insulin resistance [86]. However, reduced androgen levels associated with hypogonadism or androgen deprivation therapy increase cardiovascular risk factors producing marked adverse effects [20,87]. The vascular changes that occur in the penile arteries are a reflection of the coronary arteries as shown that in patients with established CVD.

Inflammation

MetS is also considered as a state of low-grade chronic inflammation due to complex interplay between genetic and environmental factors over longer duration that may be related to ED (Figure 1) [88]. How these inflammatory mediators interact with each other over time resulting in MetS and associated ED need further explanation.

Metabolic Syndrome and Erectile Dysfunction

Adipocytokines Chronic inflammation with visceral obesity and insulin resistance is involved in the production of abnormal adipocytokines such as TNF-α, interleukin-1 (IL-1), IL-6, leptin, PAI-1, CRP, and adiponectin by adipose tissue (Figure 1) [89,90]. Adipocytokines are hormones that act either synergistically or competitively with insulin, which explains their modulatory role in insulin resistance [91,92]. These hormones have been linked to the pathogenesis of MetS and its comorbidities including ED through their effects on vascular function and inflammation [93]. Inflammatory cytokines from adipose tissue could affect cavernosal blood vessel endothelial function even without their increase in plasma concentration [92]. Recent data have revealed that the plasma concentration of inflammatory markers/mediators, such as TNF-α, IL-6, hsCRP, fibrinogen, and PAI-1 levels, are increased in the insulin-resistant dependent obesity and T2DM [94]. Recent evidence suggests that sexual performance as assessed by the IIEF-5 score correlates inversely with the circulating levels of endothelial inflammatory parameters such as IL-1 and IL-6 [95]. TNF-α TNF-α is one of the most powerful inflammatory adipocytokines stimulating the acute phase of inflammation [96,97] and appears to act locally to reduce the insulin sensitivity of adipocytes [89]. Evidence suggests that TNF-α induces adipocytes apoptosis and promotes insulin resistance [98]. Plasma TNF-α is positively associated with the body weight, WC, and TGs, while a negative association exists between the plasma TNF-α and HDL-C among others [98]. Chronic exposure of tissues to elevated insulin levels leads to activation of the renin-angiotensin system through TNF-α, favoring increased production of angiotensinogen and angiotensin II, and thus blood pressure [99,100]. TNF-α contributes to the dysregulation of insulin modulation of endothelin-1-mediated vasoconstriction and NO-mediated vasodilation. It is likely that TNF-α may reduce NO release and its metabolites, which, in turn, affects penile erection [101]. It has been suggested that increased expression of TNF-α in obesity and subsequent reduced expression of adiponectin plays a significant role in development of the MetS [102]. Expression levels of TNF-α are increased during weight gain and decrease during periods of weight loss [103,104]. Circulating levels of TNF-α were elevated 15-fold

861 in rabbit fed with high fat diet (HFD) [105]. In addition, neutralizing TNF-α action by infliximab (a chimeric monoclonal antibody against TNF-α) ameliorated responsiveness of penile tissue to acetylcholine in HFD rabbits [106].

IL-6 IL-6 is released by both adipose tissue and skeletal muscle in humans [107]. It has been shown to be positively associated with BMI, fasting insulin, and the development of T2DM, and negatively associated with HDL-C [106,108]. It exerts its effects by inhibiting the tissue plasminogen activator [109]. IL-6 has been implicated in the regulation of insulin sensitivity and possibly body weight in rodents [110,111]. Strategies aimed at reduction of circulating levels of IL-6 may prevent inflammation-induced insulin resistance mainly because it has both an inflammatory and an antiinflammatory action [112,113]. Leptin Leptin synthesized by adipocytes regulates energy intake and utilization. It controls obesity and androgen action via feedback mechanism in the hypothalamus [114,115]. T replacement therapy (TRT) modifies leptin levels, controls obesity, and decreases leptin and adiponectin levels in type 2 diabetic men [116,117]. During T2DM, the diabetic Zucker fatty rat shows glucose intolerance [118,119] and an autosomal recessive mutation in the leptin gene (Table 3) [122]. High leptin is related to hyperinsulinemia, insulin resistance, and hyperlipidemia at an early age with progression to proteinuria and glomerular injury [123]. In addition, leptin is directly correlated with BMI [116,124]. The inverse relationship between T levels and obesity is probably related to raised serum leptin levels in men who have large fat reserves. In obese people, elevated leptin levels implicate with LH/human chorionic gonadotropin-stimulated androgen production and inhibiting androgen hormone formation [125]. PAI-1 PAI-1 is a regulatory protein of the coagulation cascade. Plasma PAI-1 levels are increased in abdominally obese subjects especially during active inflammation [126,127]. Increased PAI-1 occurs with obesity, high insulin resistance, and with low T [128,129]. Although PAI-1 is synthesized by many cell types, adipose tissue is thought J Sex Med 2015;12:856–875

862 Table 3

Kaya et al. Preclinical data from obese rat models with erectile dysfunction (ED) Reference number

Study population

Results

16- to 20-week-old LDZR and ODZR with MetS

A depressed voltage-dependent erectile response An enhanced contractile response of the cavernosal tissues An augmented vasoconstrictor actions Impaired insulin-induced relaxation in penile arteries

17- to 18-week-old OZR and LZR A high-fat diet lean T2DM model

Decreased insulin resistance, elevated nonfasting plasma glucose levels, hyperlipidemia, insulin concentration Decreased ICP/mean arterial pressure, neuronal nitric oxide synthase expression in the penis

[120]

[121] [119]

ICP = Intracavernosal pressure; LDZR = lean diabetic Zucker rats; LZR = Lean Zucker rats; MetS = metabolic syndrome; ODZR = obese diabetic Zucker rats; OZR = obese Zucker rats; T2DM = type 2 diabetes mellitus

to be a major source of PAI-1 in the obese, and circulating PAI-1 levels correlate with visceral adiposity [57]. TNF-α is a key mediator of obesitylinked increases in PAI-1 expression. PAI-1 has been reported to influence accumulation of visceral fat and to contribute directly to complications of obesity, including the development of T2DM [130]. Therefore, it has been postulated that PAI-1 levels are a major link between obesity, T2DM, and cardiovascular events probably leading to ED [130,131]. According to Caron et al. [132], the level of the PAI-1 is partly dependent on hormonal status in men and is related positively to BMI and TGs and negatively to T, thus responsible for endocrinopathy-related ED.

Adiponectin Adiponectin regulates food intake and body weight, controls lipid and glucose metabolism, increases insulin sensitivity, and protects against chronic inflammation [133]. Adiponectin functions as an insulin-sensitizing agent by reducing hepatic glucose production and enhancing insulin action in the liver resulting in lower glucose, free fatty acids, and TG concentrations [134]. Low concentrations are associated with insulin resistance and hyperinsulinemia [135]. The antiinflammatory molecule, adiponectin, is negatively associated with the body weight, WC, TGs, fasting insulin, insulin resistance, BMI, and blood pressure, whereas a positive association exists between adiponectin and HDL-C. In clinical studies, adiponectin concentrations are lower in patients with obesity, T2DM, hypertension, or CAD, whereas high adiponectin concentrations may protect the cardiovascular system and reduce the incidence of myocardial infarction [136]. J Sex Med 2015;12:856–875

Treatment Modalities for MetS

TRT Although much controversy has recently been discussed regarding safe use of T, it remains a significant factor in the management of most patients with ED. In randomized control trials, TRT significantly decreased insulin resistance in addition to its advantage for controlling obesity [87]. T therapy is safe and convenient while rapidly correcting low T levels (Table 4) [151]. Several studies have reported that TRT restores MetS and central obesity [52], reduces the WC and lipid levels, and improves insulin sensitivity and glycemic control in hypogonadal men with T2DM [152–154]. Table 4 shows the effects of TRT on different clinical trials [138,142,155]. Recently, it was reported that one-third of men with diabetes presented with late-onset hypogonadism [156], and treatment with T resulted in improvement in HbA1c, fasting blood glucose, and reduction in WC and WHR. T is a determinant of glucose homeostasis and lipid metabolism aside from its hormonal regulatory role. In patients with MetS and a deficiency of T levels, TRT is likely beneficial [84,157] Hypogonadal men with specific sexual dysfunctions such as ED, diminished libido, or both are candidates for TRT [158]. It is a general agreement that levels