Relationship between obesity, androgen deficiency (hypogonadism), metabolic syndrome and ED. The increase in adipose tissue and its accumulation in abdominal region, increases the production of adipokines and free fatty acids, this in turn, generates insulin resistance and hyperinsulinemia. The excess of insulin reduces the hepatic synthesis of SHBG and IGFBP-1 with the consequent increase of free IGF-1. The high concentrations of IGF-I and insulin act synergically on the testis and the adrenals glands, reducing the androgens secretion. In the testis, moreover, because of the limited effect that the reduced LH concentration exerts on the synthesis of testosterone, the effect is more marked. Probably, the increase in aromatization of androgens by adipose tissue, contributes to the hypoandrogenemia, together with the low levels of FSH which limit the spermatic development, lead to ED and the hypogonadotropic hypogonadism condition, which is an infertility factor. 

Contexts in source publication

Context 1

... male outpatients with T2DM in whom ED was assessed using the International Index of Erectile Function (IIEF-5) questionnaire (Hermans et al., 2009). Patients with ED (n=83) were compared with an age-matched controls (n=51). Patients with poor control have increased risk for ED compared to patients with good control. Body weight and adiposity are significantly associated with ED. Obesity is associated with an odds ratio of 1.5 to 3 for having ED. Other measures of adiposity, including the waist-to-hip ratio and abdominal circumference, are also independently associated with ED. A sedentary life style increases the risk, independently of its effect on body mass index. Arterial hypertension and abnormal plasma lipid level, common co-morbidities of T2DM, are associated with ED. Both are linked with endothelial dysfunction, reduced nitric oxide synthesis and increased free radicals synthesis. Several authors have proposed that treatment of hyperglycemia and cardiovascular risk factors should be part of the treatment of ED. Although this proposal is clinically sound, no major randomized controlled studies are available to support it. Only the EDIC trial (Epidemiology of Diabetes Intervention and Complications study) have partially evaluated it. The EDIC study is an extension of the DDCT trial, a landmark study that demonstrated that the correction of hyperglycemia reduces the incidence of microvascular complications. A substudy of the EDIC trial (Uro-EDIC) was designed to evaluate the impact of the correction of hyperglycemia on the incidence of urologic complications. ED was assessed using the IEFF questionnaire. The effect of treatment was evaluated separately in cases (n=280) with or without (n=291) microvascular complications. No difference was observed in the incidence of ED between men randomized to intensive vs. conventional therapy (OR 1.24, 95% CI 0.68- 2.28) in cases free of microvascular complications at the beginning of the study. In contrast, intensive therapy resulted in a smaller incidence of ED among men with microvascular complications (OR 0.33, 95% CI 0.18-0.60). Regrettably, ED was not included among the study outcomes of the main trials that have evaluated the effect of intensive treatment of hyperglycemia (i.e. ACCORD trial) in men with T2DM. Future studies including validated ED measurements, adequate sample size and important potential confounders are needed to measure the benefit of intensive glycemic control in men with poorly controlled diabetes. The erectile response in mammals is regulated by androgens; in particular it has been confirmed that testosterone is an important regulator of the erectile function (Yassin & Saad, 2008). Is known that 6-12% of men between 40 and 69 years old suffer from hypogonadism. In adult men the disease is manifested by erectile dysfunction, among others. Male hypogonadism, which is also called testosterone deficiency syndrome, is characterized by failure of testicular testosterone production and is especially common in men with T2DM, affecting one third of them. Testosterone acts on the penile tissues involved in the mechanism of erection, so deficiency of this hormone, impairs erectile capacity. The pathophysiological mechanisms of low circulating testosterone concentrations are unknown, but it has been suggested that obesity associated with T2DM, helps to reduce testosterone levels by increasing the conversion of testosterone to estradiol in adipose tissue. The increase in the concentration of estradiol leads in turn to a suppression of hipothalamic gonadotrophin releasing hormone (GnRH), which is evidenced by a reduced secretion of pituitary gonadrotropins (luteinizing hormone, LH and follicle stimulating hormone, FSH), which reduces in turn the secretion of testosterone by the Leydig cells and spermatogenesis in the seminiferous tubules, thus manifesting as hypogonadism. This may explain the inverse relationship between BMI and plasma concentrations of testosterone (Dhindsa et al., 2004; Grossmann et al., 2008; Kapoor et al., 2007; Rhoden et al., 2005; Traish et al., 2009). Male hypogonadism is associated with increased adipose tissue. In men with more than 160% of ideal body weight, concentrations of plasma testosterone and sex hormone-binding globulin (SHBG) are usually low while estrogen levels, from the conversion of adrenal androgens in adipose tissue, increase. In men with morbid obesity weighing more than 200% over the ideal weight, free testosterone may decrease. The concentrations of free testosterone and SHBG show an inverse relationship with waist circumference (WC) (Osuna et al., 2006; Pasquali et al., 1997; Svartberg, 2007). With the increase in adipose tissue also increases the production of leptin; favors the insulin resistance and therefore the appearance of hyperinsulinemia. Under these conditions, both leptin and insulin act on Leydig cells and inhibit testosterone synthesis (Pitteloud et al., 2005; Soderberg et al., 2001) (Fig. 6). Androgen deficiency contributes to pathologies associated with the metabolic syndrome, such as obesity, T2DM, hypertension and hyperlipidemia, which affect the endothelium, resulting in multiple vascular diseases, including ED, representing the latter, an infertility factor (Akishita et al., 2007; Traish et al., 2009; Tripathy et al., 2003) (Fig. 6). Also, several studies have shown that low testosterone levels predict development of T2DM in men (Tomar et al., 2006). There is evidence that the treatment with testosterone to DM animal models improves erectile function by influencing the NO/cGMP/PDE5 pathway (Vignozzi et al., 2005). Testosterone supplementation to diabetic animals also down regulates RhoA/Rho-kinase signaling (Vignozzi et al., 2007) improving also erectile function. The use of PDE 5 inhibitors like Sildenafil (Viagra), Tadalafil (Cialis) and Vardenafil (Levitra) for ED treatment has allowed a better management of this condition (Yassin & Saad, 2008). In particular, combined therapy of testosterone and sildenafil, improves erectile function in patients with T2DM (Hidalgo-Tamola & Chitaley, 2009). A role for viral and bacterial pathogens in the development of atherosclerosis has been suggested by multiple studies. Most evidence for this infection theory comes from seroepidemiological and experimental studies with cytomegalovirus (CMV) and Chlamydia pneumonia ( CP), which are intracellular pathogens and can directly infect vascular wall cells, including endothelial cells and smooth muscle cells. Although still under debate, there appears to be an association of CMV and CP with the presence or development of atherosclerotic vascular disease in diabetes. Direct infection of endothelial cells leads to pro-coagulant activity and a local vascular pro-inflammatory response. Although the exact pathogenesis of ED in men with DM is still unclear, endothelial dysfunction plays a pivotal role and some studies suggested an association between ED and CMV and/or CP seropositivity in men with diabetes. Also, levels of the inflammatory markers as C-reactive protein and fibrinogen were elevated in patients with diabetes-associated ED (Blans et al., 2006). A large number of drugs used in the managing of the DM patients may impair sexual function, either by an effect upon erectile and ejaculatory function or sex drive. Some of them are used as part of the diabetes treatment or others associated conditions like hypertension, anxiety and depression. The use of these drugs very rarely produces ED by themselves. Side effects usually appear adjunct to another pathophysiological mechanism (Eardley, 2002; Elías-Calles & Licea, 2003) (Table ...

Context 2

... significantly associated with ED. Obesity is associated with an odds ratio of 1.5 to 3 for having ED. Other measures of adiposity, including the waist-to-hip ratio and abdominal circumference, are also independently associated with ED. A sedentary life style increases the risk, independently of its effect on body mass index. Arterial hypertension and abnormal plasma lipid level, common co-morbidities of T2DM, are associated with ED. Both are linked with endothelial dysfunction, reduced nitric oxide synthesis and increased free radicals synthesis. Several authors have proposed that treatment of hyperglycemia and cardiovascular risk factors should be part of the treatment of ED. Although this proposal is clinically sound, no major randomized controlled studies are available to support it. Only the EDIC trial (Epidemiology of Diabetes Intervention and Complications study) have partially evaluated it. The EDIC study is an extension of the DDCT trial, a landmark study that demonstrated that the correction of hyperglycemia reduces the incidence of microvascular complications. A substudy of the EDIC trial (Uro-EDIC) was designed to evaluate the impact of the correction of hyperglycemia on the incidence of urologic complications. ED was assessed using the IEFF questionnaire. The effect of treatment was evaluated separately in cases (n=280) with or without (n=291) microvascular complications. No difference was observed in the incidence of ED between men randomized to intensive vs. conventional therapy (OR 1.24, 95% CI 0.68- 2.28) in cases free of microvascular complications at the beginning of the study. In contrast, intensive therapy resulted in a smaller incidence of ED among men with microvascular complications (OR 0.33, 95% CI 0.18-0.60). Regrettably, ED was not included among the study outcomes of the main trials that have evaluated the effect of intensive treatment of hyperglycemia (i.e. ACCORD trial) in men with T2DM. Future studies including validated ED measurements, adequate sample size and important potential confounders are needed to measure the benefit of intensive glycemic control in men with poorly controlled diabetes. The erectile response in mammals is regulated by androgens; in particular it has been confirmed that testosterone is an important regulator of the erectile function (Yassin & Saad, 2008). Is known that 6-12% of men between 40 and 69 years old suffer from hypogonadism. In adult men the disease is manifested by erectile dysfunction, among others. Male hypogonadism, which is also called testosterone deficiency syndrome, is characterized by failure of testicular testosterone production and is especially common in men with T2DM, affecting one third of them. Testosterone acts on the penile tissues involved in the mechanism of erection, so deficiency of this hormone, impairs erectile capacity. The pathophysiological mechanisms of low circulating testosterone concentrations are unknown, but it has been suggested that obesity associated with T2DM, helps to reduce testosterone levels by increasing the conversion of testosterone to estradiol in adipose tissue. The increase in the concentration of estradiol leads in turn to a suppression of hipothalamic gonadotrophin releasing hormone (GnRH), which is evidenced by a reduced secretion of pituitary gonadrotropins (luteinizing hormone, LH and follicle stimulating hormone, FSH), which reduces in turn the secretion of testosterone by the Leydig cells and spermatogenesis in the seminiferous tubules, thus manifesting as hypogonadism. This may explain the inverse relationship between BMI and plasma concentrations of testosterone (Dhindsa et al., 2004; Grossmann et al., 2008; Kapoor et al., 2007; Rhoden et al., 2005; Traish et al., 2009). Male hypogonadism is associated with increased adipose tissue. In men with more than 160% of ideal body weight, concentrations of plasma testosterone and sex hormone-binding globulin (SHBG) are usually low while estrogen levels, from the conversion of adrenal androgens in adipose tissue, increase. In men with morbid obesity weighing more than 200% over the ideal weight, free testosterone may decrease. The concentrations of free testosterone and SHBG show an inverse relationship with waist circumference (WC) (Osuna et al., 2006; Pasquali et al., 1997; Svartberg, 2007). With the increase in adipose tissue also increases the production of leptin; favors the insulin resistance and therefore the appearance of hyperinsulinemia. Under these conditions, both leptin and insulin act on Leydig cells and inhibit testosterone synthesis (Pitteloud et al., 2005; Soderberg et al., 2001) (Fig. 6). Androgen deficiency contributes to pathologies associated with the metabolic syndrome, such as obesity, T2DM, hypertension and hyperlipidemia, which affect the endothelium, resulting in multiple vascular diseases, including ED, representing the latter, an infertility factor (Akishita et al., 2007; Traish et al., 2009; Tripathy et al., 2003) (Fig. 6). Also, several studies have shown that low testosterone levels predict development of T2DM in men (Tomar et al., 2006). There is evidence that the treatment with testosterone to DM animal models improves erectile function by influencing the NO/cGMP/PDE5 pathway (Vignozzi et al., 2005). Testosterone supplementation to diabetic animals also down regulates RhoA/Rho-kinase signaling (Vignozzi et al., 2007) improving also erectile function. The use of PDE 5 inhibitors like Sildenafil (Viagra), Tadalafil (Cialis) and Vardenafil (Levitra) for ED treatment has allowed a better management of this condition (Yassin & Saad, 2008). In particular, combined therapy of testosterone and sildenafil, improves erectile function in patients with T2DM (Hidalgo-Tamola & Chitaley, 2009). A role for viral and bacterial pathogens in the development of atherosclerosis has been suggested by multiple studies. Most evidence for this infection theory comes from seroepidemiological and experimental studies with cytomegalovirus (CMV) and Chlamydia pneumonia ( CP), which are intracellular pathogens and can directly infect vascular wall cells, including endothelial cells and smooth muscle cells. Although still under debate, there appears to be an association of CMV and CP with the presence or development of atherosclerotic vascular disease in diabetes. Direct infection of endothelial cells leads to pro-coagulant activity and a local vascular pro-inflammatory response. Although the exact pathogenesis of ED in men with DM is still unclear, endothelial dysfunction plays a pivotal role and some studies suggested an association between ED and CMV and/or CP seropositivity in men with diabetes. Also, levels of the inflammatory markers as C-reactive protein and fibrinogen were elevated in patients with diabetes-associated ED (Blans et al., 2006). A large number of drugs used in the managing of the DM patients may impair sexual function, either by an effect upon erectile and ejaculatory function or sex drive. Some of them are used as part of the diabetes treatment or others associated conditions like hypertension, anxiety and depression. The use of these drugs very rarely produces ED by themselves. Side effects usually appear adjunct to another pathophysiological mechanism (Eardley, 2002; Elías-Calles & Licea, 2003) (Table ...