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Low testosterone associated with obesity and the metabolic syndrome contributes to sexual dysfunction and cardiovascular disease risk in men with type 2 diabetes.

Wang C, Jackson G, Jones TH, Matsumoto AM, Nehra A, Perelman MA, Swerdloff RS, Traish A, Zitzmann M, Cunningham G - Diabetes Care (2011)

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology, Department of Medicine, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, California, USA. wang@labiomed.org

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Men with obesity, the metabolic syndrome, and type 2 diabetes have low total and free testosterone and low sex hormone–binding globulin (SHBG)... This review focuses on the multidirectional impact of low testosterone associated with obesity and the metabolic syndrome and its effects on erectile dysfunction and CVD risk in men with type 2 diabetes... Conversely, high BMI, central adiposity, and the metabolic syndrome are associated with and predict low serum total and to a lesser extent free testosterone and SHBG levels... Because obesity suppresses SHBG and as a result total testosterone concentrations, alterations in SHBG confound the relationship between testosterone and obesity... These studies indicate that interactions between low testosterone and visceral adiposity acting through proinflammatory agents (Fig. 1) result in insulin resistance and vascular endothelial dysfunction, which are potential causal factors for increased CVD and ED... Animal studies have demonstrated testosterone effects on nerve structure and function, nitric oxide synthase activity, and smooth muscle growth and differentiation, which mediate penile erections... Obesity and androgen deficiency are associated with increased proinflammatory cytokines, which also results in vascular endothelial dysfunction... The Look Ahead study reported that weight loss and increased physical activity were mildly beneficial in maintaining erections or improving ED in men with type 2 diabetes... Although improvement in glucose control is associated with some improvement in erectile function in some studies, most clinicians have not found this to be a reliable and effective treatment for ED... Testosterone replacement in the hypogonadal man with type 2 diabetes and/or metabolic syndrome should aim to have beneficial effects on multiple outcomes including sexual health; general well-being; body composition; and reducing CVD risk factors, including central adiposity, glycemic control, and atherogenic lipid profile... The effect of testosterone on lipid profile was investigated in several studies including those on coronary heart disease, metabolic syndrome, and diabetes... The majority of studies have found that testosterone therapy results in a small but significant fall in total cholesterol and in some LDL cholesterol (Table 2)... There is some evidence that after an initial decrease, HDL cholesterol levels then return to baseline... Most reports found no change in triglycerides.

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Complex multidirectional interactions between testosterone and obesity, metabolic syndrome, and type 2 diabetes mediated by cytokines and adipokines leading to comorbidities such as ED and increased CVD risk. FFA, free fatty acids; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; PAI-1, plasminogen activator inhibitor-1.
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Figure 1: Complex multidirectional interactions between testosterone and obesity, metabolic syndrome, and type 2 diabetes mediated by cytokines and adipokines leading to comorbidities such as ED and increased CVD risk. FFA, free fatty acids; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; PAI-1, plasminogen activator inhibitor-1.

Mentions: Obesity is a proinflammatory state resulting in increased release and secretion of proinflammatory cytokines and adipokines, free fatty acids, and estrogens from adipose tissue. These increases are important risk factors that may contribute to the development of metabolic syndrome and type 2 diabetes as well as androgen deficiency (20). Visceral fat is an active secretory tissue producing inflammatory cytokines, adipokines, biochemical modulators, and other proinflammatory factors including interleukin (IL)-6, IL-1β, plasminogen activator inhibitor-1, tumor necrosis factor (TNF)-α, angiotensinogen, vascular endothelial growth factor, and serum amyloid A (Fig. 1). These factors contribute to systemic and peripheral vascular inflammation and dysfunction (21). As shown in Fig. 1, one potential mechanism of how visceral adiposity and inflammatory response modulate insulin sensitivity involves the release of free fatty acids. Free fatty acids activate nuclear factor-κB pathways resulting in increased synthesis of TNF-α. TNF-α further activates lipolysis as well as increased synthesis of IL-6 and macrophage chemoattractant protein-1, which increases recruitment of more macrophages and modulates insulin sensitivity. Increased production of TNF-α also enhances expression of adhesion molecules in both endothelium and vascular smooth muscle cells. IL-6 stimulates hepatic synthesis of C-reactive protein, a nonspecific marker of vascular inflammation. In addition, TNF-α contributes to the dysregulation of insulin modulation of endothelin-1–mediated vasoconstriction and nitric oxide–mediated vasodilation, hence promoting vasoconstriction. Release of adipokines facilitates monocyte adhesion and migration into the vessel wall as well as the conversion of monoctyes to macrophages.


Low testosterone associated with obesity and the metabolic syndrome contributes to sexual dysfunction and cardiovascular disease risk in men with type 2 diabetes.

Wang C, Jackson G, Jones TH, Matsumoto AM, Nehra A, Perelman MA, Swerdloff RS, Traish A, Zitzmann M, Cunningham G - Diabetes Care (2011)

Complex multidirectional interactions between testosterone and obesity, metabolic syndrome, and type 2 diabetes mediated by cytokines and adipokines leading to comorbidities such as ED and increased CVD risk. FFA, free fatty acids; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; PAI-1, plasminogen activator inhibitor-1.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3120209&req=5

Figure 1: Complex multidirectional interactions between testosterone and obesity, metabolic syndrome, and type 2 diabetes mediated by cytokines and adipokines leading to comorbidities such as ED and increased CVD risk. FFA, free fatty acids; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; PAI-1, plasminogen activator inhibitor-1.
Mentions: Obesity is a proinflammatory state resulting in increased release and secretion of proinflammatory cytokines and adipokines, free fatty acids, and estrogens from adipose tissue. These increases are important risk factors that may contribute to the development of metabolic syndrome and type 2 diabetes as well as androgen deficiency (20). Visceral fat is an active secretory tissue producing inflammatory cytokines, adipokines, biochemical modulators, and other proinflammatory factors including interleukin (IL)-6, IL-1β, plasminogen activator inhibitor-1, tumor necrosis factor (TNF)-α, angiotensinogen, vascular endothelial growth factor, and serum amyloid A (Fig. 1). These factors contribute to systemic and peripheral vascular inflammation and dysfunction (21). As shown in Fig. 1, one potential mechanism of how visceral adiposity and inflammatory response modulate insulin sensitivity involves the release of free fatty acids. Free fatty acids activate nuclear factor-κB pathways resulting in increased synthesis of TNF-α. TNF-α further activates lipolysis as well as increased synthesis of IL-6 and macrophage chemoattractant protein-1, which increases recruitment of more macrophages and modulates insulin sensitivity. Increased production of TNF-α also enhances expression of adhesion molecules in both endothelium and vascular smooth muscle cells. IL-6 stimulates hepatic synthesis of C-reactive protein, a nonspecific marker of vascular inflammation. In addition, TNF-α contributes to the dysregulation of insulin modulation of endothelin-1–mediated vasoconstriction and nitric oxide–mediated vasodilation, hence promoting vasoconstriction. Release of adipokines facilitates monocyte adhesion and migration into the vessel wall as well as the conversion of monoctyes to macrophages.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology, Department of Medicine, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, California, USA. wang@labiomed.org

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Men with obesity, the metabolic syndrome, and type 2 diabetes have low total and free testosterone and low sex hormone–binding globulin (SHBG)... This review focuses on the multidirectional impact of low testosterone associated with obesity and the metabolic syndrome and its effects on erectile dysfunction and CVD risk in men with type 2 diabetes... Conversely, high BMI, central adiposity, and the metabolic syndrome are associated with and predict low serum total and to a lesser extent free testosterone and SHBG levels... Because obesity suppresses SHBG and as a result total testosterone concentrations, alterations in SHBG confound the relationship between testosterone and obesity... These studies indicate that interactions between low testosterone and visceral adiposity acting through proinflammatory agents (Fig. 1) result in insulin resistance and vascular endothelial dysfunction, which are potential causal factors for increased CVD and ED... Animal studies have demonstrated testosterone effects on nerve structure and function, nitric oxide synthase activity, and smooth muscle growth and differentiation, which mediate penile erections... Obesity and androgen deficiency are associated with increased proinflammatory cytokines, which also results in vascular endothelial dysfunction... The Look Ahead study reported that weight loss and increased physical activity were mildly beneficial in maintaining erections or improving ED in men with type 2 diabetes... Although improvement in glucose control is associated with some improvement in erectile function in some studies, most clinicians have not found this to be a reliable and effective treatment for ED... Testosterone replacement in the hypogonadal man with type 2 diabetes and/or metabolic syndrome should aim to have beneficial effects on multiple outcomes including sexual health; general well-being; body composition; and reducing CVD risk factors, including central adiposity, glycemic control, and atherogenic lipid profile... The effect of testosterone on lipid profile was investigated in several studies including those on coronary heart disease, metabolic syndrome, and diabetes... The majority of studies have found that testosterone therapy results in a small but significant fall in total cholesterol and in some LDL cholesterol (Table 2)... There is some evidence that after an initial decrease, HDL cholesterol levels then return to baseline... Most reports found no change in triglycerides.

Show MeSH
Related in: MedlinePlus