Relationship Between TD and T2DM

As discussed previously, T2DM and IR are two important components of MetS. The prevalence of T2DM has increased dramatically, probably related, in part, to the increased prevalence of obesity, and it is estimated that the number of individuals diagnosed with T2DM in the United States exceeded 15 million in 2004. This trend has been emerging during the past 5 decades. The prevalence of MetS, and its core component of IR, a key component of MetS, is approximately 4.5% in adolescents, and represents a serious public health concern.

Men with low T are at a greater risk of developing T2DM. A meta-analysis by Ding and colleagues of 43 studies including 6427 men confirmed this, and four studies were even powered high enough to show that TD might predict the onset of diabetes. A relationship between low SHBG and T exists such that low T predicts higher glucose and insulin levels as well as increased obesity. Low levels of T and SHBG were thought to play a role in the development of IR and subsequently T2DM, based on the findings of the longitudinal Massachusetts Male Aging Study. Fukui and colleagues demonstrated similar findings in Japanese patients with T2DM when compared with healthy men and suggested that T supplementation in hypogonadal men could decrease IR and atherosclerosis.

A significant inverse relationship between total T and IR in men was noted in a number of studies. Simon and colleagues reported that total T concentrations were significantly associated with fasting plasma insulin, as well as 2-hour plasma insulin levels. Taken together, these findings raise the possibility that T may have a protective function against development or progression of T2DM in men.

Relationship Between TD and Hypertension

Hypertension, dyslipidemia, obesity, and IR comprise the major components of MetS with serious implications on CV disease risk. The relationship among these various components is complex and understanding their underlying pathophysiology requires a comprehensive framework of investigation. Lower total T values were found in men less than 25-years-old presenting with hypertension; and this is independent of age. Conversely, Phillips and colleagues reported that T levels correlated inversely with blood pressure in hypogonadal obese men. Smith and colleagues found that, after 3 months of treatment of prostate cancer patients with GnRH antagonists, T levels predictably decreased into the hypogonadal range, with the consequence that diastolic pressure was elevated, along with mean pulse pressure.

On the other hand, hypogonadal men treated with T replacement therapy experienced amelioration of their high blood pressure. T treatment of abdominally obese men for 9 months reduced diastolic blood pressure significantly. Similar findings were reported in which both resting systolic and diastolic blood pressure were significantly lowered during treatment with intramuscular T undecanoate in 66 hypogonadal men for up to 9.5 years. The investigators noted that the most significant reductions occurred between 6 to 9 months. In addition, Anderson and colleagues reported a significant favorable change in diastolic blood pressure in men treated for 6 months with T-replacement therapy. Given the fact that the relationship between hypertension and TD is complex and poorly investigated, the limited data available still suggest that T-replacement therapy tends to normalize blood pressure; however, this remains to be investigated.

Relationship Between TD and Dyslipidemia

Emerging evidence on the role of T in vascular function is challenging the traditional notion that androgens are atherogenic. This notion stemmed from the fact that women seem to be protected from CV disease in their premenopausal years because of the estrogens they produce. It was then deduced that the higher risk of CV disease in men attributed to T, a postulate that was never proven scientifically. The current thinking is just the reverse; that is, that CV risk is related to low-T levels in men. Further, androgen deficiency has been considered a primary risk factor for dyslipidemia. Reduced-T concentrations are thought to be associated with an atherogenic lipoprotein profile, with increased low-density lipoprotein (LDL) and triglyceride levels. Increased total cholesterol (TC) and LDL cholesterol (LDL-C) have also been associated with lower T levels, in epidemiologic studies. Interestingly, T therapy reduced TC and LDL-C levels, and positive association between high-density lipoprotein (HDL)-C levels and testosterone was noted in several studies.

Increased HDL-C levels were associated with normalizing testosterone levels in patients with TD. However, other studies showed either no changes in HDL-C levels or reduced HDL-C levels. The discrepancies among the various reported studies may be explained by the nature of the study design, doses, and formulations of androgens used for replacement; route and frequency of administration; patient age and hypogonadal states; body fat distribution; or methods of analysis of the lipoproteins and lipids. The observed decline in HDL level in some studies with androgen treatment may have been due to supraphysiological levels of T often seen with intramuscular depot long-acting T esters as suggested in a recent meta-analysis.

T stimulates the activities of several lipoprotein-modifying enzymes involved in HDL metabolism, thus leading to efficient catabolism of plasma HDL and hence efficient reverse cholesterol transport. Estradiol and testosterone have been suggested to exert opposite effects on lipid profiles, in particular HDL-C, and estrogens are associated with unfavorable lipid profiles in men. This observation supports the conclusion of Tivesten and colleagues. who suggested that low T levels in conjunction with elevated estradiol levels in men are likely to be associated with lower extremity peripheral vascular disease (PAD).

TD and Obesity

Obesity is an independent risk of CV disease and a cornerstone of other CV risks, especially MetS and IR. Men with MetS had significantly higher prevalence of TD, with waist circumference (WC) and hyperglycemia most strongly predicting such condition. The investigators noted that lower total T levels contributed to elevated insulin levels and hypothesized that body fat distribution influences this relationship. Wannamethee and colleagues studied 2924 men with no history of T2DM or CV disease, and found that both body mass index (BMI) and WC had the strongest association with MetS; whereas percentage body fat had the weakest association. WC, BMI, insulin, and homeostatic model assessment (HOMA) of IR were significantly and negatively correlated to T levels.

Reduced total T levels have been related to central or abdominal obesity, and increased WC in a number of studies. These findings were confirmed and amplified in a study by Svartberg and colleagues who demonstrated that free-T and SHBG levels were inversely related to WC in 1548 community-dwelling men (age 25–84 years).

Elevated leptin levels may interfere with LH-hCG–stimulated androgen production, thus suppressing androgenic hormone formation in obese individuals. Similarly, elevated cortisol levels may cause central suppression of central gonadotropins. In addition, increased aromatase activity, in visceral adipose tissue, results in elevated circulating levels of estradiol, which suppresses T production via negative feedback mechanism. Decreased SHBG or cytokine-mediated inhibition of testicular steroid production is among the other possible mechanisms by which obesity contributes to reduced T levels.

Relationship Between TD, MetS, and Erectile Dysfunction

Men with MetS have increased risk of erectile dysfunction (ED). Because MetS increases CV risk, it is not surprising that ED may also be a predictor of subsequent CV disease. This is not surprising since medical conditions that comprise the components of MetS are also thought to be the major causes of ED. The prevalence of ED among men with MetS increases with the number of MetS components. Patients with three to five components of MetS exhibited 20%, 30%, and 35% incidence of ED, respectively. This finding is consistent with the suggestion that MetS is an independent risk factor for ED, and the more specific risk factor of WC has also been found to be an independent predictor. A recent study by Zhody and colleagues investigated androgen deficiency in relation to ED and MetS by analyzing BMI measurements in 158 obese men. The investigators found a significant statistical association between increasing BMI and the following parameters: increased systolic blood pressure, reduced serum T, reduced penile duplex parameters, increased triglycerides, decreased HDL, and increased LDL. With increasing BMI, the frequency of TD and ED increased, whereas total serum T showed a strong negative correlation. To assess the effect of BMI on vasculogenic ED, the investigators examined this relationship in the absence of other risk factors and found that for a BMI less than 25, 3 out of 13 men (23.1%) had vasculogenic ED, as compared with 32 out of 54 men (59.3%) with a BMI greater than 25, suggesting that TD is related to both ED and MetS.

Based on basic research and clinical studies, androgens regulate multiple signaling pathways and the structural integrity of penile cavernosal tissue and cellular components. These include: (1) regulation of nitric oxide synthase expression and activity, (2) regulation of phosphodiesterase type 5 expression and activity, (3) regulation of the alpha adrenoceptor expression and function, (4) regulation of smooth muscle cell metabolism and responses, (5) regulation of connective tissue synthesis and deposition, (6) regulation of differentiation of progenitor vascular-stroma cells into myogenic and adipogenic lineages, and (7) maintaining nerve fiber network function. Alterations in these functions are manifested as changes in tissue response to endogenous vasodilators causing diminished blood inflow (failure to fill); alterations in the fibroelastic properties and expandability with inadequate compliance of the corpus cavernosum, concomitant with increased blood outflow (failure to accumulate blood under pressure); and dysfunctional venoocclusive mechanism, contributing to ED (failure to contain blood).

Relationship Between TD and T2DM

As discussed previously, T2DM and IR are two important components of MetS. The prevalence of T2DM has increased dramatically, probably related, in part, to the increased prevalence of obesity, and it is estimated that the number of individuals diagnosed with T2DM in the United States exceeded 15 million in 2004. This trend has been emerging during the past 5 decades. The prevalence of MetS, and its core component of IR, a key component of MetS, is approximately 4.5% in adolescents, and represents a serious public health concern.

Men with low T are at a greater risk of developing T2DM. A meta-analysis by Ding and colleagues of 43 studies including 6427 men confirmed this, and four studies were even powered high enough to show that TD might predict the onset of diabetes. A relationship between low SHBG and T exists such that low T predicts higher glucose and insulin levels as well as increased obesity. Low levels of T and SHBG were thought to play a role in the development of IR and subsequently T2DM, based on the findings of the longitudinal Massachusetts Male Aging Study. Fukui and colleagues demonstrated similar findings in Japanese patients with T2DM when compared with healthy men and suggested that T supplementation in hypogonadal men could decrease IR and atherosclerosis.

A significant inverse relationship between total T and IR in men was noted in a number of studies. Simon and colleagues reported that total T concentrations were significantly associated with fasting plasma insulin, as well as 2-hour plasma insulin levels. Taken together, these findings raise the possibility that T may have a protective function against development or progression of T2DM in men.

Relationship Between TD and Hypertension

Hypertension, dyslipidemia, obesity, and IR comprise the major components of MetS with serious implications on CV disease risk. The relationship among these various components is complex and understanding their underlying pathophysiology requires a comprehensive framework of investigation. Lower total T values were found in men less than 25-years-old presenting with hypertension; and this is independent of age. Conversely, Phillips and colleagues reported that T levels correlated inversely with blood pressure in hypogonadal obese men. Smith and colleagues found that, after 3 months of treatment of prostate cancer patients with GnRH antagonists, T levels predictably decreased into the hypogonadal range, with the consequence that diastolic pressure was elevated, along with mean pulse pressure.

On the other hand, hypogonadal men treated with T replacement therapy experienced amelioration of their high blood pressure. T treatment of abdominally obese men for 9 months reduced diastolic blood pressure significantly. Similar findings were reported in which both resting systolic and diastolic blood pressure were significantly lowered during treatment with intramuscular T undecanoate in 66 hypogonadal men for up to 9.5 years. The investigators noted that the most significant reductions occurred between 6 to 9 months. In addition, Anderson and colleagues reported a significant favorable change in diastolic blood pressure in men treated for 6 months with T-replacement therapy. Given the fact that the relationship between hypertension and TD is complex and poorly investigated, the limited data available still suggest that T-replacement therapy tends to normalize blood pressure; however, this remains to be investigated.

Relationship Between TD and Dyslipidemia

Emerging evidence on the role of T in vascular function is challenging the traditional notion that androgens are atherogenic. This notion stemmed from the fact that women seem to be protected from CV disease in their premenopausal years because of the estrogens they produce. It was then deduced that the higher risk of CV disease in men attributed to T, a postulate that was never proven scientifically. The current thinking is just the reverse; that is, that CV risk is related to low-T levels in men. Further, androgen deficiency has been considered a primary risk factor for dyslipidemia. Reduced-T concentrations are thought to be associated with an atherogenic lipoprotein profile, with increased low-density lipoprotein (LDL) and triglyceride levels. Increased total cholesterol (TC) and LDL cholesterol (LDL-C) have also been associated with lower T levels, in epidemiologic studies. Interestingly, T therapy reduced TC and LDL-C levels, and positive association between high-density lipoprotein (HDL)-C levels and testosterone was noted in several studies.

Increased HDL-C levels were associated with normalizing testosterone levels in patients with TD. However, other studies showed either no changes in HDL-C levels or reduced HDL-C levels. The discrepancies among the various reported studies may be explained by the nature of the study design, doses, and formulations of androgens used for replacement; route and frequency of administration; patient age and hypogonadal states; body fat distribution; or methods of analysis of the lipoproteins and lipids. The observed decline in HDL level in some studies with androgen treatment may have been due to supraphysiological levels of T often seen with intramuscular depot long-acting T esters as suggested in a recent meta-analysis.

T stimulates the activities of several lipoprotein-modifying enzymes involved in HDL metabolism, thus leading to efficient catabolism of plasma HDL and hence efficient reverse cholesterol transport. Estradiol and testosterone have been suggested to exert opposite effects on lipid profiles, in particular HDL-C, and estrogens are associated with unfavorable lipid profiles in men. This observation supports the conclusion of Tivesten and colleagues. who suggested that low T levels in conjunction with elevated estradiol levels in men are likely to be associated with lower extremity peripheral vascular disease (PAD).

TD and Obesity

Obesity is an independent risk of CV disease and a cornerstone of other CV risks, especially MetS and IR. Men with MetS had significantly higher prevalence of TD, with waist circumference (WC) and hyperglycemia most strongly predicting such condition. The investigators noted that lower total T levels contributed to elevated insulin levels and hypothesized that body fat distribution influences this relationship. Wannamethee and colleagues studied 2924 men with no history of T2DM or CV disease, and found that both body mass index (BMI) and WC had the strongest association with MetS; whereas percentage body fat had the weakest association. WC, BMI, insulin, and homeostatic model assessment (HOMA) of IR were significantly and negatively correlated to T levels.

Reduced total T levels have been related to central or abdominal obesity, and increased WC in a number of studies. These findings were confirmed and amplified in a study by Svartberg and colleagues who demonstrated that free-T and SHBG levels were inversely related to WC in 1548 community-dwelling men (age 25–84 years).

Elevated leptin levels may interfere with LH-hCG–stimulated androgen production, thus suppressing androgenic hormone formation in obese individuals. Similarly, elevated cortisol levels may cause central suppression of central gonadotropins. In addition, increased aromatase activity, in visceral adipose tissue, results in elevated circulating levels of estradiol, which suppresses T production via negative feedback mechanism. Decreased SHBG or cytokine-mediated inhibition of testicular steroid production is among the other possible mechanisms by which obesity contributes to reduced T levels.

Relationship Between TD, MetS, and Erectile Dysfunction

Men with MetS have increased risk of erectile dysfunction (ED). Because MetS increases CV risk, it is not surprising that ED may also be a predictor of subsequent CV disease. This is not surprising since medical conditions that comprise the components of MetS are also thought to be the major causes of ED. The prevalence of ED among men with MetS increases with the number of MetS components. Patients with three to five components of MetS exhibited 20%, 30%, and 35% incidence of ED, respectively. This finding is consistent with the suggestion that MetS is an independent risk factor for ED, and the more specific risk factor of WC has also been found to be an independent predictor. A recent study by Zhody and colleagues investigated androgen deficiency in relation to ED and MetS by analyzing BMI measurements in 158 obese men. The investigators found a significant statistical association between increasing BMI and the following parameters: increased systolic blood pressure, reduced serum T, reduced penile duplex parameters, increased triglycerides, decreased HDL, and increased LDL. With increasing BMI, the frequency of TD and ED increased, whereas total serum T showed a strong negative correlation. To assess the effect of BMI on vasculogenic ED, the investigators examined this relationship in the absence of other risk factors and found that for a BMI less than 25, 3 out of 13 men (23.1%) had vasculogenic ED, as compared with 32 out of 54 men (59.3%) with a BMI greater than 25, suggesting that TD is related to both ED and MetS.

Based on basic research and clinical studies, androgens regulate multiple signaling pathways and the structural integrity of penile cavernosal tissue and cellular components. These include: (1) regulation of nitric oxide synthase expression and activity, (2) regulation of phosphodiesterase type 5 expression and activity, (3) regulation of the alpha adrenoceptor expression and function, (4) regulation of smooth muscle cell metabolism and responses, (5) regulation of connective tissue synthesis and deposition, (6) regulation of differentiation of progenitor vascular-stroma cells into myogenic and adipogenic lineages, and (7) maintaining nerve fiber network function. Alterations in these functions are manifested as changes in tissue response to endogenous vasodilators causing diminished blood inflow (failure to fill); alterations in the fibroelastic properties and expandability with inadequate compliance of the corpus cavernosum, concomitant with increased blood outflow (failure to accumulate blood under pressure); and dysfunctional venoocclusive mechanism, contributing to ED (failure to contain blood).