REVIEW Obesity, low testosterone levels and erectile dysfunction

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1 (2009) 21, & 2009 Nature Publishing Group All rights reserved /09 $ REVIEW Obesity, low testosterone levels and erectile dysfunction M Diaz-Arjonilla 1, M Schwarcz 1, RS Swerdloff and C Wang Division of Endocrinology, Department of Medicine, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA, USA Obesity is an important risk factor for many common diseases including cardiovascular disease (CVD), type 2 diabetes, cancer and erectile dysfunction (ED). Adipose tissues produce a number of adipokines and cytokines, which affect endothelial and metabolic function resulting in insulin resistance and the metabolic syndrome (risks factors for CVD). Both ED and metabolic syndrome improve with a reduction in body mass index (BMI). The relationships among obesity, metabolic syndrome, ED, sex hormonebinding globulin (SHBG) and serum total and free testosterone levels are complex and often confusing to the physician. It is known that BMI is inversely proportional to serum total testosterone concentrations; low serum SHBG levels in obesity contribute to the low serum total testosterone. Recent studies show that BMI is also inversely proportional to free testosterone concentration. The characteristic low serum testosterone concentrations observed in obese men are also present in men with the metabolic syndrome and type 2 diabetes mellitus. A small proportion of men with ED have hypogonadism; however, the proportion increases if these men are obese with manifestations of the metabolic syndrome or type 2 diabetes mellitus. ED is a common symptom in patients with type 2 diabetes who also have low testosterone levels. This review describes the relationships between low serum testosterone concentrations and ED in obese patients and those with metabolic syndrome and type 2 diabetes mellitus. (2009) 21, 89 98; doi: /ijir ; published online 9 October 2008 Keywords: body mass index; androgens; metabolic syndrome; type 2 diabetes mellitus; hypogonadism; sexual dysfunction Introduction Obesity, as defined by World Health Organization (WHO), is excess weight gain for a given height. Obesity now represents one of the most common medical conditions in the United States. Obesity among adults in the developed world is defined as a body mass index (BMI) over 30 kg m 2, and morbid obesity constitutes a BMI of 40 or higher. Almost a third of adults in the United States are now obese on the basis of current measured weights and heights. 1 Data from the National Health and Nutrition Examination Study and in the United States showed that the prevalence of Correspondence: Professor C Wang, General Clinical Research Center, Harbor-UCLA Medical Center, 1000 W Carson Street, Torrance, CA 90803, USA. wang@labiomed.org 1 These authors contribute equally to this work. Received 19 August 2008; accepted 28 August 2008; published online 9 October 2008 obesity (33%) in females was not increased between the two periods. Men, however, showed an increase in the prevalence of obesity from 27.5% in to 31.1% in Obesity in adults has become a major public health issue and is associated with increased mortality primarily due to increased risk of cardiovascular disease (CVD) and type 2 diabetes mellitus and increased morbidity from arthritis and sleep-related breathing disorders. 3,4 Recently, two epidemiological studies showed that obesity in childhood and adolescents is associated with an increased risk of CVD in adulthood resulting in substantial morbidity and mortality. 5,6 Obesity is associated with low total testosterone levels that can be explained at least partially by lower sex hormone-binding globulin (SHBG) in obese men. 7 In recent years, epidemiological studies have shown a negative correlation between BMI and total testosterone and to a lesser extent with free and bioavailable (biologically active) testosterone levels Obesity and insulin resistance are two components of the metabolic syndrome and conversely both metabolic syndrome and type 2

2 90 diabetes mellitus have been associated with low testosterone levels Erectile dysfunction (ED) is a multifactorial entity, and cannot be described without addressing important contributing factors, including nitric oxide, endothelial dysfunction, low androgen levels, obesity, metabolic syndrome and type 2 diabetes mellitus. This review will explore the interaction and relationships among obesity, low testosterone concentrations and ED, emphasizing the hormonal characteristics associated with obesity, and include data from our group relating BMI to sex hormones and erectile function. Figure 1 shows our concept reviewing these complex relationships from left to the right. Obesity and the adipose tissue Obesity, characterized by an increase in the adipose tissue mass, is a key pathological contributor to the metabolic syndrome. The primary function of the adipose tissue is for energy storage. In addition, adipose tissues also play an important role in systemic glucose homeostasis. In adult mammals, the major bulk of adipose tissue is a loose association of lipid-filled adipocytes, which are held in a framework of collagen (stroma)-containing vascular cells, fibroblastic connective tissue cells, leukocytes, macrophages and pre-adipocytes. 14 The composition of white adipose tissue includes 60 85% lipid, 90 99% of which are triglycerides. Adipose tissue also contains small amounts of free fatty acids (FFA), diglycerides, cholesterol and phospholipids. Brown adipose tissue is rich in mitochondria and is responsible for thermogenesis in newborns but disappears in adults. Adipocytes are specially adapted for the uptake and release of energy in the form of FFA that are converted to triglycerides inside the cells, which accumulate as surplus fuel during caloric abundance and released back to the circulation when needed. Other regulators of adipose tissue metabolism include insulin and the sympathetic system. Insulin controls adipose tissue development and function by stimulating glucose uptake and lipogenesis and inhibiting lipolysis. Sympathetic stimulation, in contrast, favors lipolysis and adaptive thermogenesis in brown adipose tissue. Location of adipose tissue can also determine its pathophysiology. Fat can be divided into two types depending on its location: subcutaneous and visceral fat (intraperitoneal, omental and mesenteric fat). These fat depots differ in their function, and increased visceral fat is associated with the metabolic syndrome, low testosterone levels and ED. Exciting new research has demonstrated the role of macrophages in obesity. Adipose tissue and tissue macrophages produce adipokines and cytokines (Figure 1). Adipokines include several novel and highly metabolic active molecules, including leptin, resistin, adiponectin and visfatin among others. Macrophages that infiltrate fat tissues release cytokines such as tumor necrosis factor-a, interleukins 6 and 1 (IL-6 and IL-1). Cytokines may lead to local and generalized inflammation and may also affect vascular (endothelial) function. These adipokines and cytokines are responsible for the obesity-related disorders including hypertension, diabetes, athero- Figure 1 Diagram showing the inter-relationships of obesity, metabolic syndrome, serum testosterone concentration and erectile dysfunction (ED).

3 sclerosis, insulin resistance and also nonalcoholic fatty liver disease Obesity and the metabolic syndrome The metabolic syndrome or insulin resistance syndrome is characterized by a group of risk factors, the most salient being visceral obesity and insulin resistance. Definitions for metabolic syndrome have been proposed by at least four different groups, including the WHO, the National Cholesterol Education Program s Adult Treatment Panel III, International Diabetes Federation and the American College of Endocrinology on Insulin Resistance Syndrome. Most of the definitions include having at least three of the following major components: diabetes or prediabetes (glucose intolerance); elevated triglycerides; low high-density lipoprotein; hypertension or use of antihypertensive agent; and abdominal obesity. 18,19 Visceral adiposity has been shown to strongly correlate with insulin resistance. Clinically, visceral adiposity is measured by waist circumference or waist-to-hip ratio; but the gold standards for measuring visceral fat are CT and MRI imaging studies. Insulin actions are blunted in visceral fat as compared with subcutaneous fat, which can be explained by increased endogenous protein tyrosine phosphatase 1B downregulating the insulin receptors levels found in omental adipocytes. 20 Visceral obesity enhances delivery of FFA to the liver leading to a reduced hepatic insulin clearance and further increase of circulating insulin levels leading to hyperinsulinemia. FFAs then accelerate gluconeogenesis and triglyceride synthesis by the liver, increasing esterification of FFA and reduced hepatic degradation of apolipoprotein B, resulting in increased synthesis and secretion of small very low density lipoprotein particles. The increase in very low density lipoprotein leads to clinical hypertriglyceridemia, another component of the metabolic syndrome. In addition to the effects on the liver, the increase in FFA decreases peripheral glucose disposal primarily in skeletal muscle. 21 Adipocytes are endocrine organs unto themselves and are able to influence hormones such as insulin and leptin. In addition, adipose tissues can produce cytokines and other immune factors through infiltration by inflammatory macrophages. Adipokines and cytokines lead to inflammatory responses affecting vascular endothelial function through nitric oxide and superoxide release and thus mediate the effects of obesity on the vascular system. 22 Adipokines are also modulators of insulin sensitivity, leading to both local and systemic insulin resistance. 23 One of the adipokines, adiponectin, favors production of mature adipocytes. Adiponectin also affects lipases, foam cell process and atherosclerosis to increase insulin sensitivity, decrease visceral fat, reduce triglycerides and increase high-density lipoprotein levels Adiponectin is anti-inflammatory and protects the vasculature against atherosclerosis. Obesity reduces the expression and levels of adiponectin. 27 Leptin also plays a role in regulating obesity with complete leptin or leptin receptor deficiency, leading to severe obesity in mice and men. Leptin infusion in complete leptin-deficient mice results in reduction of obesity and increase insulin sensitivity. However, leptin functions as a multifaceted hormone. Leptin levels are elevated in obese patients, in proportion to their BMI. The insulin-sensitizing actions of leptin are blunted in obesity, leading to more insulin resistance. In addition, leptin exhibits proinflammatory actions, increasing macrophage release of cytokines. High leptin levels induce endothelial dysfunction, increase blood pressure and favor atherosclerosis. 28,29 Resistin is also proinflammatory and increases cytokine release and induces adhesion molecules expression increasing the macrophage infiltration to fat tissues. 30 As mentioned previously, obesity affects the release of certain cytokines from macrophages infiltrating into the fat, particularly increasing the release of tumor necrosis factor-a, IL-6 and IL-8. In addition, visceral fat differs from subcutaneous fat in releasing more resistin, IL-6, plasminogen activator inhibitor-1, transforming growth factor b1, IL-8 and IL-10. Elevated tumor necrosis factor-a in adipose is known to contribute to insulin resistance along with IL-6, a cytokine that is elevated in both obesity and type 2 diabetes mellitus. IL-6 reduces insulin sensitivity by inhibiting insulin receptor signal transduction in tissue. 31 In summary, excess adipose tissue in obesity results in increased release of pro-inflammatory cytokines that cause insulin resistance and vascular dysfunction 32,33 (Figure 1, left). Some effects of the cytokines are mitigated by the secretion of adiponectin. Understanding the complex role of adipose tissue and inflammation in obesity helps to provide insights into the link between obesity, insulin resistance and the metabolic syndrome, leading to potential targets as specific therapy for obesity in addition to lifestyle modifications. Obesity, metabolic syndrome, type 2 diabetes mellitus and low testosterone levels The relationship between obesity and androgen deficiency is complex and multifactorial. Numerous epidemiological studies have established an inverse relationship between obesity and low testosterone levels in healthy men Approximately 45 50% of circulating testosterone in adult men is tightly 91

4 92 bound to SHBG with high affinity, 50 55% is loosely bound to albumin and less that 2 3% is free. Free and albumin-bound testosterone are biologically active in the target tissues. SHBG production is suppressed by androgens and stimulated by estrogens. Prevalence of low serum testosterone in obesity varies from 20 to 64% depending on the population and whether total or free testosterone is used to make the diagnosis. 34 The diagnosis of hypogonadism in obese men has posed a dilemma because total testosterone may not be reflective of testosterone action in obese men, 35 and measured levels are often difficult to interpret. SHBG decreases with increasing obesity in both men and women resulting in a consistent decrease in total testosterone measurements, although the free or bioavailable (albumin-bound plus free fraction) testosterone may be within the adult reference range of leaner men. 7,36,37 The exact cause of the low SHBG levels in obesity is not known, but low SHBG levels are associated with insulin resistance. Recent epidemiological studies showed that both serum testosterone and to a lesser extent free testosterone levels are decreased in obese men One explanation is that obese men have increased adipose tissue, and therefore aromatase activity is upregulated, converting more testosterone to estradiol. Urinary estrone and estradiol production rates, in obese men, are positively correlated with the percentage of increase of weight above ideal body weight. 38 Obesity is associated with reduction of luteinizing hormone (LH) secretion. The increased estrogen levels modulate pituitary LH response to gonadotropin-releasing hormone (GnRH). 39 LH action is also affected by increased leptin, decreasing the LH action on the Leydig cells, 40 resulting in decreased testosterone secretion. The decrease in total and free testosterone is associated with not only intraabdominal fat but also total body fat and subcutaneous body fat. 41 Only visceral fat was inversely related to total and free testosterone after adjustment for SHBG, whereas, the inverse relationship between subcutaneous fat and total testosterone was dependent on lower SHBG levels. 42 Our group has studied the relationship of BMI versus total and free testosterone, dihydrotestosterone and SHBG levels in healthy male volunteers who were screened before enrollment in male contraceptive trials. Data were obtained from 210 male volunteers between the ages 20 and 50 years and with mean BMI of 27.0 kg m 2 (range ). All participants were deemed healthy on the basis of no significant medical history, normal physical examination and semen analyses. Figures 2a d showed that the serum total (r ¼ 0.32, To0.001), free testosterone (r ¼ 0.30, Po0.001) and dihydrotestosterone (r ¼ 0.45, Po0.003) levels were significantly inversely related to increasing BMI. Serum SHBG levels also decreased with BMI (r ¼ 0.33, Po0.001). Serum estradiol levels did not show any significant relationship with BMI in these nonobese patients. These participants in the male contraceptive studies had no symptoms of hypogonadism. It is not clear whether these obese men with low testosterone levels are hypogonadal; however, if they have symptoms consistent with hypogonadism and a testosterone well below the adult male range, a short trial of testosterone may be warranted. Obesity is a major contributor to the development of the metabolic syndrome, which increases the risk for development of type 2 diabetes mellitus and CVD. Metabolic syndrome is also associated with low serum testosterone, and several studies have examined the effect of metabolic syndrome on androgens and the effect of replacement Conclusions are varied because of the difficulty in separating the components of the metabolic syndrome and the interrelationship between the factors governing the syndrome. Most studies show that exogenous testosterone treatment of hypogonadal men has favorable effects on body composition, insulin sensitivity, lipids and hypertension. 47 In a population-based cross-sectional study (the Kuopio Ischemic Heart Disease Risk Factor Study) among 1896 nondiabetic men between 42 and 60 years old, those with metabolic syndrome (WHO criteria) had 19% lower levels of total testosterone, 11% lower free testosterone (calculated) and 18% lower levels of SHBG as compared with men without the metabolic syndrome. A total of 6% of men with metabolic syndrome had clinical hypogonadism. 49 In a longitudinal follow-up study of the same cohort conducted 11 years after the initial assessment, 651 middle-aged Finnish men with metabolic syndrome had increased risk of having low total and free testosterone levels. 46 Conversely, in the same cohort, low serum testosterone and SHBG levels independently predict the development of metabolic syndrome on follow-up. 45 Insulin resistance is another major contributing factor to the metabolic syndrome. Testosterone levels in men were related to insulin sensitivity and men with low testosterone levels have higher rate of insulin resistance and mitochondrial dysfunction. 45,50,51 Acute withdrawal of testosterone replacement in hypogonadal men decreased insulin sensitivity without changes in body weight, suggesting a direct effect of low testosterone levels on insulin sensitivity. 52 However, in studies in normal men who had induced hypogonadism, insulin sensitivity was not related to the serum testosterone level. 53 Diabetes is clearly related to hypogonadism, and studies have shown that 20 50% of men with type 2 diabetes mellitus have low serum total or free testosterone The low serum testosterone levels are associated with lower serum LH and FSH levels, suggesting that the lower serum testosterone levels is due to hypogonadotropic hypogonadism in type 2

5 93 Figure 2 Correlations between body mass index (BMI) and serum testosterone (a), free testosterone (b), dihydrotestosterone (c) and SHBG (d) concentrations in healthy adult men. diabetes mellitus. 57 Presence of clinical symptoms of hypogonadism together with biochemical evidence of low testosterone levels occurs in about 14% of men with type 2 diabetes. 58 Type 1 diabetes is not associated with low serum testosterone levels, suggesting that insulin resistance, visceral obesity, hyperlipidemia and metabolic syndrome commonly associated with type 2 diabetes may be causal factors for the low testosterone levels. 59 Obesity, metabolic syndrome, type 2 diabetes mellitus, low testosterone levels and ED Obesity and the metabolic syndrome are associated with ED and sexual dysfunction. 60,61 Risk factors that play a role in ED include age, obesity, hypertension, hyperlipidemia and diabetes mellitus, which are similar to those for CVD (Figure 1 right). Studies have shown that ED may be an early biomarker of general endothelial dysfunction, atherosclerosis and CVD How obesity affects ED is not entirely clear. It is known that low serum androgens play a role in ED, although only about 5% of patients with ED have hypogonadism. As discussed in the above section, in obese individuals, serum testosterone (total and free) and SHBG concentrations are decreased and proinflammatory cytokines and adipokines levels are elevated. The endothelial dysfunction that occurs in obesity and insulin resistance may be responsible for the increased risk of ED and CVD. 66,67 We have examined the relationship between BMI and sexual function quantified through a validated questionnaire 68 addressing sexual desire, enjoyment, activity, satisfaction with erection and fullness of erection in a subset of healthy young men after screening for male contraceptive clinical trials (n ¼ 155) as described above. The questionnaire has been used in several studies as a measure of overall sexual function We found two questions that were related to erectile function: fullness of erection (r ¼ 0.18, Po0.023, Figure 3a) and satisfaction of erection (r ¼ 0.21, Po0.010, Figure 3b) that significantly correlate negatively for BMI after adjustment for total testosterone levels. Correlation was not with other portions of the sexual questionnaire: sexual desire, sexual activity and partner enjoyment or self-enjoyment. These data demonstrate that

6 94 Figure 3 Correlations between BMI and self-reported satisfaction with erection (a) and percentage of of full erection (b) in healthy adult men. erectile function may in part be related to BMI, but sexual dysfunction is multifactorial and serum hormones and obesity influence only some aspects of overall function. Large population-based epidemiological studies such as the Massachusetts Male Aging study link ED and obesity. The incidence of impotence (mild to severe) occurred in 52% of men aged between 40 and 70 years, and the higher probability of ED after adjusting for age correlated with diabetes mellitus and hypertension, markers of the metabolic syndrome. 72 The same cohort of men were studied after an average of 8.8 years, and the data showed that cigarette smoking and BMI significantly predicted the risk of developing ED. 73,74 Of the 154 patients who were overweight, 41% had moderate or complete ED, which was significantly more than that of leaner patients after controlling for other risk factors, such as smoking, hypertension, physical activity, alcohol consumption, cholesterol, age and antihypertensive medications. Physical activity was also associated with ED with sedentary men posing the highest risk. These studies give some insight into possible attenuation of ED in men who can modify their risk factors. The prevalence of ED is not a phenomenon unique to the United States. In a multinational population-based survey of men, it was reported that ED is increased in obese men across several countries including the United States and European countries. 75 There are many other studies indicating a relationship between obesity, especially central obesity, and ED and the quality of erections Recently, a further follow-up, longitudinal analyses of a cohort of men (401 men) with ED from the Massachusetts Male Aging study aimed to investigate factors associated with progression or remission of ED. Age and BMI were related to remission and progression of ED, whereas smoking and health status were associated with progression only. The results suggest that lifestyle modifications may significantly improve health status including ED. 81 A randomized controlled trial studied pro-inflammatory cytokines and endothelial function in 55 obese men with ED and matched controls. Over a period of two years, weight loss and increased physical activity improved sexual function in onethird of the men. Those with significant weight loss had lower serum concentration of inflammatory markers. 82 Although men with ED are more likely to be obese and may have lower testosterone levels, the exact relationships between low testosterone levels, obesity and ED are less clear. In a cohort of men, after adjusting for age, BMI and presence of a partner, the risk of self-reported ED was decreased with increasing total and bioavailable serum testosterone concentrations. 83 Obesity has also been related to lower testosterone and poor penile hemodynamics. 84 As anticipated, the metabolic syndrome and insulin resistance are associated with ED. 85,86 In the Massachusetts Male Aging Study, ED was predictive of the presence of the metabolic syndrome only in nonobese men. In obese men, this association disappeared. 87 In patients with sexual dysfunction seeking treatment, 29% had the metabolic syndrome and the prevalence of low testosterone levels was significantly higher in men with the metabolic syndrome. The presence of hypogonadism in men with metabolic syndrome increases the symptoms of sexual dysfunction such as low sexual desire. 88,89 In patients with type 2 diabetes mellitus, ED is common and is caused mainly by vascular and neurological complications, but low testosterone levels may contribute to ED, libido and body composition changes in these patients. 90 In men with ED attending a sexual dysfunction clinic, 16% had type 2 diabetes mellitus. Of the patients who had both ED and diabetes mellitus, low serum testosterone levels were present in 24.5% compared with 12.6% in those who did not have diabetes even after adjustment for age and BMI. Patients with

7 diabetes mellitus and low testosterone levels had symptoms of reduced libido and mood in addition to ED. 91 In a cross-sectional cohort study, ED was related to metabolic factors, smoking and depression, but only to very low testosterone levels (below 8nmoll 1 or 230 ng per 100 ml), 92 suggesting that ED is related to serum testosterone levels only when it is significantly below the adult range. 93 A recent study in type 2 diabetes mellitus showed that overt hypogonadism (total serum testosterone o8 nmol l 1 and bioavailable testosterone o2.5 nmol l 1 with clinical symptoms) was present in 17 and 14% of men and that the incidence increases with age. ED was the most common symptom in diabetic men with hypogonadism (70%) and was associated with decreased libido, fatigue, mood changes and decreased muscle strength. 94 Androgen treatment of hypogonadal men with obesity and diabetes mellitus Many studies have shown that testosterone treatment of hypogonadal young and older men improves sexual function, increases lean mass and decreases fat mass. 69,71,95 99 However, studies of androgen treatment in elderly hypogonadal and eugonadal men have not shown improvement in insulin resistance. 53, In men with low serum testosterone (for example, o8 or 230 nmol l 1 ) with obesity, metabolic syndrome and diabetes mellitus, treatment with testosterone is warranted as in any other hypogonadal men, and the sexual function may improve. 103 In obese middle-aged men, testosterone treatment reduced visceral adipocity, insulin resistance, serum cholesterol and glucose levels. 104 The mechanisms by which testosterone reduces visceral fat and insulin resistance have not been completely elucidated. Several studies have shown that testosterone replacement has a favorable impact on body mass, insulin secretion and sensitivity, lipid profile and blood pressure in hypogonadal men with the metabolic syndrome as well as type 2 diabetes mellitus. 47,56,105,106 There are many reasons why testosterone would reverse some of the factors contributing to visceral obesity, the metabolic syndrome and type 2 diabetes mellitus. Testosterone significantly inhibits lipoprotein lipase activity, which reduces triglycerides uptake into adipocytes in the abdominal adipose tissue. 107 Testosterone and dihydrotestosterone regulate lineage determination in mesenchymal pluripotent cells by promoting their commitment to the myogenic lineage and inhibiting their differentiation into the adipogenic lineage through an androgen receptor-mediated pathway. 108 In addition, testosterone treatment decreased endogenous inflammatory cytokines (tumor necrosis factor-a and IL-1b) and lipids (total cholesterol) and increased IL-10 in hypogonadal men. 109 Testosterone treatment reduced leptin and adiponectin levels in hypogonadal type 2 diabetic men after 3 months of testosterone replacement. 110 All these previously reported studies on the effect on testosterone treatment in hypogonadal men with the metabolic syndrome or type 2 diabetes mellitus have very few patients, and the beneficial effects of testosterone have to be confirmed in large-scale, adequately powered placebo-controlled, randomized clinical trials. In conclusion, available data clearly show a relationship between obesity, low testosterone levels and ED. Obesity adversely affects endothelial function and lowers serum testosterone levels through the development of insulin resistance and metabolic syndrome. Metabolic disturbances as well as production of cytokines and adipokines by inflamed fat cells may be causal factors in the development of ED. The onset of ED and the associated risk of CVD may be delayed through lifestyle modifications that affect obesity, such as diet and exercise. Very low testosterone levels contribute to the development of ED in obesity, metabolic syndrome and type 2 diabetes mellitus. Whether or not testosterone treatment of obese individuals decreases the risk of metabolic syndrome and type 2 diabetes mellitus remains controversial. Acknowledgments This review was supported by Endocrinology and Metabolism Training Grant (T32 DK007571) and the General Clinical Research Center at Harbor UCLA (RR MO ). 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