IV. a. The Relationship Between T2D and ED—
Several studies have investigated the relationship between diabetes and ED. In a survey of 2869 men, Ponholzer et al (2005) found that having diabetes increases the odds of having ED. The authors found that patients with diabetes were at the greatest risk for developing ED (with an odds ratio [OR] of 3) versus patients having other conditions such as hyperlipidemia (OR 2.29), hypertension (OR 2.05), psychologic stress (OR 1.68), or low physical activity (OR 1.35). ORs for ED were also calculated in population-based studies in Germany (Braun et al, 2000), Italy (Parazzini et al, 2000), and Turkey (Akkus et al, 2002), with data from all 3 countries showing patients with diabetes having a higher OR than those with hypertension (and cardiac disease in Turkey). Sun et al (2006) found that 20.0% of men with ED had diabetes mellitus and that 7.5% of the non-ED group of men had diabetes. The authors adjusted for census regions and 7 comorbidities and report that ED is associated with diabetes especially in young men, with the highest odds occurring in the 26–35 age range. They suggested using ED as a clinical marker for the onset of diabetes in men. Giuliano et al (2004) found that the prevalence of ED in patients with diabetes was 70.6% in a survey of 7689 men, whereas Shabsigh et al (2005) found, conversely, that 25% of patients with severe ED had diabetes in the cross-national survey on men's health issues. Bodie et al (2003) assessed laboratory abnormalities for 3547 men with ED and found that a large number of men presenting with a primary complaint of ED had elevated HbA1c levels. Additionally, Yamasaki et al (2004) measured the prevalence of ED (defined by International Index of Erectile Function < 18) in Japanese men with T2D and found that compared with healthy controls (20% ED prevalence), age-matched diabetics had 3 times the prevalence of ED (60%). Taken together, the aforementioned studies suggest that a strong link exists between diabetes and ED, with either condition being a risk factor for the other.
IV. b. The Relationship Between T2D, ED, and Endothelial Dysfunction—
Peripheral vascular disease caused by endothelial dysfunction is common in both diabetes and ED. Cell-derived microparticles are involved in endothelial dysfunction, and Esposito et al (2007) showed that these particles correlated with ED in diabetic men. HbA1c levels have been shown to increase with the severity of ED (Rhoden et al, 2005a,b,b) and were found to be an independent predictor of the erectile function score in 78 men with T2D (Romeo et al, 2000). Besides usually having elevated HbA1c levels, compared with nondiabetics, diabetics typically have a higher incidence of organic ED (Corona et al, 2004). These authors found that in 1027 consecutive patients presenting with ED, those with diabetes mellitus, compared with those with impaired or normal fasting glucose, had significantly elevated BMI and triglycerides, hypertension, high-density lipoprotein-c (HDLc), and cardiovascular disease, suggesting that there are multiple metabolic parameters for ED in men with diabetes. Lindmark et al (2006) found that glucotoxicity was associated with increased IR but also with increased levels of adipokines like tumor necrosis factor (TNF-α) and c-reactive protein (CRP), which may contribute to IR. Weyer et al (2001) showed an association between reduced levels of adiponectin in T2D and obesity with IR. The many factors that are associated with cardiovascular disease are also active in ED. These include advanced glycation end products, prothrombotic states, hypertension, and dyslipidemias (Rader, 2007).
Corona et al (2006) found a relationship between the prevalence of hypogonadism in 1027 diabetic and nondiabetic patients presenting with ED, with diabetics having a significantly greater prevalence of hypogonadism, especially in the sixth decade of life, compared with nondiabetics. Taking into account all ages, diabetics had a significantly increased prevalence of hypogonadism than did nondiabetics, and hypogonadism has been discussed earlier as a risk factor for ED. Corona et al (2006) also investigated the presence of hypogonadism in 1200 men with ED, of whom 16% had diabetes mellitus. Hypogonadism was found in 24.5% of men with diabetes, versus 12.6% in the rest of the sample. A predominance of secondary hypogonadism over primary testicular failure was also noted. Guay et al (1999) reported that in 990 men with ED, 23.1% had T2D. In this group, 35.6% were also hypogonadal, approaching the 36.0% found in the entire population, emphasizing that numerous chronic illnesses are related to hypogonadism in men with ED. Secondary hypogonadism was also predominant over primary testicular failure, 30.0% vs 6.0%.
The pathophysiologic mechanisms encompassing the complexity of T deficiency, IR, T2D, and vessel damage may stem from the unrecognized endocrine function of the adipose tissue resulting from visceral obesity (Jang et al, 2003; Gustafson et al, 2007). This adipose tissue of the visceral fat responds to multiple signals to produce proinflammatory substances and adipokines, resulting in altered lipid and glucose metabolism, oxidative stress, endoplasmic reticulum stress, increased fatty acid content, and adipose tissue necrosis (Gustafson, 2007). The effects of these factors are not limited to the adipose tissue but may also affect skeletal muscle and liver. The adipokines and inflammatory factors produced by the visceral fat include interleukin (IL)-6, IL1b, plasminogen activator inhibitor 1, TNF-α, angiotensin converting enzymes, vascular endothelial growth factor, angiotensinogen, and serum amyloid A proteins, among others. Some of these adipokines and proinflammatory factors may stimulate recruitment of macrophages, which stimulate increased adipogenesis, with concomitant reduction in anti-inflammatory factors, such as adiponectin. Furthermore, IL6 and TNF-α are associated with obesity and IR and impair insulin signaling in mature adipocytes. Further, androgens have been shown to inhibit the expression and release of cytokines and chemokines (Malkin et al, 2004; Kapoor et al, 2006; Norata et al, 2006). Androgen deprivation therapy is thought to be associated with increased levels of proinflammatory factors and decreased anti-inflammatory cytokines (Maggio et al, 2005, 2006). Interestingly, T therapy prevents gain in visceral adipose tissue in nonobese aging men, and reduces the production of proinflammatory cytokines (Schroeder et al, 2004; Nielsen et al, 2007; Allan et al, 2008a,b). It is therefore reasonable to suggest that androgens attenuate adipogenesis as well as inflammatory factor production. Because androgen deficiency is linked to the development of IR and T2D and the latter contributes profoundly to endothelium dysfunction (Ginsberg, 2000; Cersosimo and DeFronzo, 2006), the concept of androgen deficiency reinforces the important role of androgens in vascular health (Figure 2).
IV. c. The Relationship of Androgens in Phosphodiesterase Action in Diabetic Patients With ED—
An animal study conducted by Zhang et al (2006) used 2 different models of chemical diabetes and found that T reinstates sildenafil responsiveness in both, suggesting that T supplementation in human diabetics with ED receiving pharmacologic treatment might be advantageous in diabetic men in whom phosphodiesterase type 5 inhibitors given for ED do not work. Indeed, studies have tested this concept, and Kalinchenko et al (2003) assessed diabetic ED patients and found that different baseline T levels in these patients determined a differential response to sildenafil. Responders typically had a total T value of 18.6 ± 1.2 nmol/L, whereas nonresponders had a total value of 6.9 ± 1.3 nmol/L. The authors found that although sildenafil therapy alone was insufficient to reverse ED in diabetic patients with low T levels, administration of oral T in combination with sildenafil reverses ED in these patients. In addition to low T levels predicting a poor response to sildenafil in diabetic individuals, Park et al (2005) found uncontrolled diabetes itself to be a risk factor in predicting poor response to sildenafil in 162 consecutive elderly ED patients (mean age 64.1 years). Fonseca et al (2004) also showed that the efficacy of tadalafil treatment in 519 diabetic patients was a function of glycemic control. The authors found that though this treatment had a significant benefit in all HbA1c ranges, there was a downward trend of drug efficacy with increasing HbA1c values. As such, predicting the efficacy of pharmacologic treatment in patients with ED and diabetes is tenuous, and may be governed by the severity of the metabolic and hormonal profile of these individuals. Apart from lowering blood sugar, another approach is to affect the IR, which predominates in T2D. Kovanecz et al (2006) used the insulin sensitizer pioglitazone in diabetic rats with corpora cavernosa fibrosis. This drug treatment ameliorated the fibrosis, oxidative stress, and veno-occlusive dysfunction, suggesting a separate protective effect on the smooth muscle.