Curr Diab Rep (2014) 14:545 DOI 10.1007/s11892-014-0545-6
MICROVASCULAR COMPLICATIONS—NEUROPATHY (D ZIEGLER, SECTION EDITOR)
How to Treat Erectile Dysfunction in Men with Diabetes: from Pathophysiology to Treatment Konstantinos Hatzimouratidis & Dimitrios Hatzichristou
# Springer Science+Business Media New York 2014
Abstract Erectile dysfunction (ED) is highly prevalent affecting at least 50 % of men with diabetes mellitus (DM). DM may cause ED through a number of pathophysiological pathways. These include neuropathy, endothelial dysfunction, cavernosal smooth muscle structural/ functional changes, and hormonal changes. Lifestyle changes, diabetes control, and treatment of hypogonadism are important as the first step in ED management since there is no curative treatment for ED. Phosphodiesterase type 5 inhibitors (PDE5i) are the first-line treatment option. Intracavernous administration of vasoactive drugs is commonly used as a second-line medical treatment when PDE5i have failed. Alprostadil is the most widely used drug in this second-line setting. The combination of papaverine, phentolamine, and alprostadil represents the most efficacious intracavernous pharmacologic treatment option that may save non-responders to alprostadil. Penile prosthesis implantation can be considered in treatment refractory cases, with excellent functional and safety results in the properly informed patients.
Keywords Erectile dysfunction . Diabetes . Epidemiology . Pathophysiology . Phosphodiesterase inhibitors . Intracavernosal injections . Penile prosthesis
This article is part of the Topical Collection on Microvascular Complications—Neuropathy
Introduction Sexual health not only reflects an integral part of overall health, but equally important, sexual activity is a predictor of general health [1]. Erectile dysfunction (ED) is defined as the persistent inability to achieve and maintain an erection for a successful intercourse [2]. It is one of the most bothersome sexual dysfunctions in men, together with premature ejaculation [3, 4]. ED shares common risk factors with other diseases such as cardiovascular disease, diabetes, and hyperlipidemia while smoking, limited physical exercise, and obesity are common lifestyle risk factors [5, 6]. Depression is highly prevalent in ED patients affecting the quality of life of both patients and their partners [7]. The prevalence of ED is higher in patients with DM, who are at a significant higher risk for ED [8]. The pathophysiology of the disease is multifactorial, and diabetic patients with ED are considered as one of the most-difficult-to-treat population [9]. The aim of this review is to provide an overview of the epidemiology of ED in patients with DM, discuss the underlying pathophysiologic mechanisms, and present current treatment modalities. For this purpose, a Medline search was conducted using the MeSH terms “erectile dysfunction” and “diabetes mellitus” (all Medline database until March 20, 2014). Only papers published in the English language were considered. This search revealed 1,077 relevant papers. The most important papers based on their scientific value were reviewed and included in the present review.
K. Hatzimouratidis : D. Hatzichristou Center for Sexual and Reproductive Health, Aristotle University of Thessaloniki, Thessaloniki, Greece
Epidemiology
D. Hatzichristou (*) 77 Mitropoleos str., 54622 Thessaloniki, Greece e-mail: [email protected]
ED occurs in about 50 % of men with diabetes mellitus (DM) [6, 10]. The Massachusetts Male Aging Study (MMAS) reported a higher incidence of ED in men with DM compared to
545, Page 2 of 10
those without DM, indentedly of age [6]. In this study, ED was present within 10 years of diagnosis of DM, which was previously undiagnosed in up to 12 % of ED cases [6]. ED occurs at a younger age group in insulin-dependent DM, and the incidence of insulin resistance is three times higher in men with ED than in the general diabetic population [11]. Bacon et al. reported from the Health Professionals Follow-Up Study cohort that men with DM had an age-adjusted relative risk of 1.32 (95 % CI 1.3–1.4) for having ED compared to those without DM [8]. The risk for ED is significantly higher in men with type 1 diabetes compared to type 2 diabetes (relative risk=3.0, 95 % CI 1.5–5.9 vs. 1.3, 95 % CI 1.1–1.5). Moreover, the ED risk is increasing in men with long-standing diagnosis of DM, especially in men with diagnosis given more than 20 years previously. Fedele et al., in a cross-sectional study, reported that the prevalence of ED was 35.8 % [12]. The prevalence rates were age dependent, ranging from 4.6 % for men 20–29 years of age to 45.5 % for men 60–69 years of age. In comparison with men reporting DM lasting ≤5 years, the odds ratios (ORs) for ED were 1.3 and 2.0 for subjects with DM lasting 6–10 and 11–30 years, respectively. In comparison with men with good metabolic control, the ORs for ED were 1.7 and 2.3 in men with fair and poor control, respectively. Finally, this study confirmed that men with type 2 DM reported ED less frequently compared to men with type 1 DM (OR 0.7; 95 % CI 0.6–0.8, corrected for age). Fedele et al. also reported that the incidence of ED in Italian men with DM at a mean follow-up of 2.8 years was 68 cases per 1,000 person-years, more than 2-fold that in the Massachusetts Male Aging Study of the general population [13]. The incidence of ED in this study was twofold higher compared to the Massachusetts Male Aging Study (MMAS). Grover et al., in a crosssectional sample of 3,921 Canadian men (40–88 years) seen by primary care physicians, reported that the overall prevalence of ED was 49.4 % [14]. The relative risk for ED in men with DM increases in patients with DM-associated comorbidities, such as cardiovascular disease (CVD), renal disease, diabetic foot, and retinal disease [12, 14]. It is also important that ED is an early marker of CVD, as ED comes before of coronary artery disease (CAD) in the majority by an average of 2 up to 3 years [15]. Miner et al. reported also that ED is a particularly powerful predictor of CVD in diabetic men [16•]. There is also evidence that phosphodiesterase type 5 inhibitors (PDE5i) may improve endothelial function with a profound positive impact in men’s overall health [17]. ED is highly prevalent in patients with DM-related neuropathy. Glycemic control measured by glycated hemoglobin can predict ED in these patients [18]. ED and metabolic syndrome are significantly connected [19]. The prevalence of ED in patients with metabolic syndrome was 26.7 % compared to 13 % in the control group in a study by Esposito et al. [20]. The same group of authors also reported that in men with type
Curr Diab Rep (2014) 14:545
2 diabetes, those with the highest adherence to the Mediterranean diet had the lowest prevalence of ED and were more likely to be sexually active [21]. DM is also associated with a significant negative impact on all other sexual function domains including sexual drive, ejaculatory function, and sexual satisfaction [22].
Pathophysiology DM may cause ED through a number of pathophysiological pathways [9]. These include neuropathy, endothelial dysfunction, cavernosal smooth muscle structural/functional changes, and hormonal changes (Fig. 1) [23, 24]. Both type 1 and type 2 DM exhibit these changes, though they are more pronounced in type 1 DM [25]. Neuropathy is a significant contributor to the pathophysiology of ED in DM. Several neurophysiological tests (nerve conduction studies, sphincter ani electromyography, heart rate variability testing, and quantitative sensory testing) have showed abnormalities in men with diabetic ED at least as frequent as in men with neuropathic ED [26]. Experimental studies show that apoptotic pathways in the cavernous nerves are important since anti-apoptotic protein expression was lacking in diabetic rat crura and the apoptotic index of diabetic rat crura significantly decreased by insulin treatment [27]. Diabetic neuropathy may be linked to selective neurodegeneration which in turn decreases neuronal nitric oxide synthase (nNOS) activity and diminishes nitric oxide (NO) associated with impaired nitrergic relaxation in the corpus cavernosum [28, 29]. The neurodegeneration seems to be a NO-dependent
Hormonal changes
Cavernosal structural/ functional changes
Diabetic ED
Neuropathy
Fig. 1 Pathophysiology of ED in diabetic men
Endothelial dysfunction
Curr Diab Rep (2014) 14:545
process based on evidence on oxidative damage through the formation of oxygen free radicals [30, 31]. Endothelial dysfunction is an important component of diabetic ED [32]. The activity of endothelial nitric oxide synthase (eNOS) is reduced as well as the effect of released NO [33]. Hyperglycemia in people with DM results in accumulation of advanced glycation end products (AGEs). AGE accumulation results in vascular thickening, decreased elacticity, and atherosclerosis [34]. Experimental data have shown that AGEs are, among others, responsible for impaired endothelial and neuronal NO-mediated cavernosal smooth muscle relaxation in rats by generating reactive oxygen species (ROS) [30]. Increased levels of endothelin (ET-1) and upregulation of the endothelin receptors (ETA and ETB) in the corpus cavernosum contribute to penile vasocontristriction [35, 36]. These effects result in ultrastructural change of atheroscleroticlike lesions [35]. ET-1-induced vasoconstriction is also linked to RhoA/Rho-kinase pathway. This pathway mediates ED through suppression of NOS and decreased production of NO in the corpora cavernosa [37–39]. Several structural changes have been described in diabetic men. Smooth muscle content is reduced while collagen deposition is increased. Thickening of the basal lamina and loss of endothelial cells have been also reported [40]. The relaxation response mediated by endothelial and neurogenic NO in corpus cavernosum is significantly impaired [30, 41]. AGEs play a fundamental role decreasing the compliance of the corpora cavernosa and impairing smooth muscle relaxation by generating free radicals or reactive oxygen species that react with NO [42, 43]. Cavernosal smooth muscle relaxation may also occur due to a decrease in cGMP-dependent protein kinase-1 (PKG-1) that diminish activity of the cGMP intracellular pathway [44]. Low testosterone levels (including total, free, and bioavailable testosterone) are a common finding in men with type 2 diabetes. Most of them present with clinical symptoms of hypogonadism including ED and decreased libido [45, 46]. Hypogonadism in diabetic men is commonly associated with age, obesity, metabolic syndrome, and insulin resistance. The prevalence of insulin resistance and metabolic syndrome in men with ED is as high as 79 and 35 %, respectively [11]. Early detection of metabolic disease in patients with ED may be a gateway to the reduction of endothelial dysfunction in younger men with increased cardiovascular risk but who present for treatment of ED alone [47]. The complex pathophysiology of ED in DM makes any single molecular target treatment almost condemned to fail. Moreover, targeted treatments must select patients in early stages before irreversible changes occur. Cellek et al. described two phase of neurodegeneration due to apoptotic cell death in the ganglia [48]. In the first phase, nitrergic nerve fibers lose some of their neuronal nitric oxide synthase content and function. In the second phase, nitrergic degeneration takes
Page 3 of 10, 545
place in the cell bodies in the ganglia, leading to complete loss of nitrergic function. The changes in the first phase are reversible with insulin replacement but the neurodegeneration in the second phase is irreversible. Despite these unfavorable data, clinicians need the translational input of scientific teams to move beyond symptom-based treatments to target specific molecular mechanisms [49].
Diagnosis The diagnostic algorithm for ED in diabetic patients is similar to other patient cohorts. Diagnosis of ED is based on sexual and medical history [50]. The use of several validated questionnaires such as the International Index for Erectile Function (IIEF) is helpful in order to categorize ED into severity groups but it is not mandatory in everyday clinical practice. The role of physical examination is limited. Clinical signs of cardiovascular disease and neuropathy can be identified while penile examination can identify other comorbidities such as Peyronie’s disease. Hormonal assessment based on testosterone and prolactin is important due to their high prevalence in diabetic men and their implication for treatment [45]. Testosterone should be measured in early morning, preferably on more than one occasion. It is also important to measure serum hormone-binding globulin (SHBG) in order to calculate bioavailable testosterone. When hypogonadism is defined, the clinician should initiate a workup to identify the possible causes of hypogonadism and differentiate between primary (testicular) and central (pituitary) etiology based on LH/FSH assessment. Of course, in patients without a history of confirmed DM, a diagnostic workup is necessary to provide a diagnosis (e.g., fasting and postprandial glucose, glycated hemoglobin, etc.). Specialized examinations are not necessary in the majority of diabetic patients with ED [2].
Treatment The treatment of ED in diabetic men requires a multimodal approach [9]. Prevention should be the first concern although it may be difficult to achieve. In this context, a very important—but often neglected—aspect is the control of hyperglycemia before structural changes occur. But even after this point, it is also necessary to provide adequate DM control and treat diabetic comorbidities since there is no curative treatment for ED today. This approach is important because uncontrolled DM will exacerbate the pathophysiologic changes described above and ED will deteriorate. Therefore, an efficacious treatment will subsequently fail if DM is left untreated. Lifestyle changes should be an integral part of any treatment for ED. These include increased physical activity, weight
545, Page 4 of 10
loss, and a Mediterranean diet. Their positive impact on the treatment is achieved through improvement of the endothelial function [51, 52]. In clinical trials, the Mediterranean diet has been found to be more effective than a control diet in ameliorating or restoring ED in people with obesity or metabolic syndrome [21]. Hormonal changes should be treated since the efficacy of treatments are significantly reduced in these men. Several medications commonly used in diabetic men (e.g., antihypertensives and antidepressants) should be addressed due to their negative impact in sexual function. If appropriate, these medications can be replaced by other associated with less adverse impact on sexual function (e.g., change of diuretics of beta-blockers with calcium channel antagonists, use of angiotensin receptor antagonists) [53]. These drugs may even enhance sexual function not only due to endotheliumdependent vasodilatation but also to oxidative stress and events involved in monocyte attraction and adhesion [54]. Finally, the physician should not forget that patient and partner counselling should be also an integral part of any treatment for ED [55]. While all treatments can be offered to patients with ED, the treatment strategy usually moves from the least to the more invasive options [2]. The proper selection of treatment options should be made addressing the patient and his partner needs and expectations from their sexual life. Clinical follow-up is as important as treatment selection. Physicians should assess not only efficacy and side effects but also patient and partner satisfaction from treatment. Primary care physicians and diabetologists as well as other specialties involved in the treatment of ED should be able to provide basic consultation and treatment. Non-responders to pharmacotherapy and complex clinical cases should be referred to experts. Finally, penile prosthesis implantation should be offered only by properly trained urologists. Given the close association of CVD and DM, the assessment and treatment of CVD is even more important in diabetic men. The third Princeton Consensus Panel was a multispecialty collaborative consensus meeting dedicated to optimizing sexual function and preserving cardiovascular health [56]. These instructions were built on the two previous Princeton conferences [57]. Patients were stratified to three categories based on the cardiovascular risk. The low-risk category group included patients with less than three risk factors for CAD, mild, stable angina, uncomplicated past myocardial infarction, and successful coronary revascularization. The intermediate risk group included patients with greater than or equal to three risk factors for CAD, moderate, stable angina, and myocardial infarction less than 6 weeks. The high-risk group included patients with high-risk arrhythmias, unstable or refractory angina, and myocardial infarction less than 2 weeks. Patients in the low-risk category can be offered ED treatment without any specific cardiac evaluation. Patients in the intermediate category should be referred to a
Curr Diab Rep (2014) 14:545
cardiologist for further evaluation and a stress test is recommended in order to further stratify these patients into the lowor high-risk group. Finally, patients in the high-risk category should not be offered any form of treatment since sexual intercourse is contraindicated.
Phosphodiesterase Type 5 Inhibitors PDE5i are currently the first-line treatment option for the majority of patients with ED based on their efficacy and safety profile. These include sildenafil (25, 50, and 100 mg on demand), tadalafil (10 and 20 mg on demand, 2.5 and 5 mg for daily dosing), vardenafil (5, 10, and 20 mg on demand, 10 mg on demand in the form of orodipersible tablet), and avanafil (50, 100, and 200 mg on demand). The latter has been added into the therapeutic armamentarium in 2014. There are several other PDE5i available only in certain parts of the world (lodenafil, mirodenafil, and udenafil). Although their efficacy (erections lasting long enough for successful intercourse) is about 60–70 % in the general ED population, it is considerably lower in diabetic men (Table 1). Sildenafil improved erections in 66.6 % of men compared to 28.6 % in men using placebo (using the General Assessment Question, GAQ) [60]. In this study, successful intercourse attempts has been reported by 63 % of men compared to 33 % in men taking placebo. These findings have been confirmed by three other randomized, placebo-controlled studies [58, 59, 62]. Rendell et al. reported improved erections in 56 % patients in the sildenafil group compared to 10 % in the placebo group (p
MICROVASCULAR COMPLICATIONS—NEUROPATHY (D ZIEGLER, SECTION EDITOR)
How to Treat Erectile Dysfunction in Men with Diabetes: from Pathophysiology to Treatment Konstantinos Hatzimouratidis & Dimitrios Hatzichristou
# Springer Science+Business Media New York 2014
Abstract Erectile dysfunction (ED) is highly prevalent affecting at least 50 % of men with diabetes mellitus (DM). DM may cause ED through a number of pathophysiological pathways. These include neuropathy, endothelial dysfunction, cavernosal smooth muscle structural/ functional changes, and hormonal changes. Lifestyle changes, diabetes control, and treatment of hypogonadism are important as the first step in ED management since there is no curative treatment for ED. Phosphodiesterase type 5 inhibitors (PDE5i) are the first-line treatment option. Intracavernous administration of vasoactive drugs is commonly used as a second-line medical treatment when PDE5i have failed. Alprostadil is the most widely used drug in this second-line setting. The combination of papaverine, phentolamine, and alprostadil represents the most efficacious intracavernous pharmacologic treatment option that may save non-responders to alprostadil. Penile prosthesis implantation can be considered in treatment refractory cases, with excellent functional and safety results in the properly informed patients.
Keywords Erectile dysfunction . Diabetes . Epidemiology . Pathophysiology . Phosphodiesterase inhibitors . Intracavernosal injections . Penile prosthesis
This article is part of the Topical Collection on Microvascular Complications—Neuropathy
Introduction Sexual health not only reflects an integral part of overall health, but equally important, sexual activity is a predictor of general health [1]. Erectile dysfunction (ED) is defined as the persistent inability to achieve and maintain an erection for a successful intercourse [2]. It is one of the most bothersome sexual dysfunctions in men, together with premature ejaculation [3, 4]. ED shares common risk factors with other diseases such as cardiovascular disease, diabetes, and hyperlipidemia while smoking, limited physical exercise, and obesity are common lifestyle risk factors [5, 6]. Depression is highly prevalent in ED patients affecting the quality of life of both patients and their partners [7]. The prevalence of ED is higher in patients with DM, who are at a significant higher risk for ED [8]. The pathophysiology of the disease is multifactorial, and diabetic patients with ED are considered as one of the most-difficult-to-treat population [9]. The aim of this review is to provide an overview of the epidemiology of ED in patients with DM, discuss the underlying pathophysiologic mechanisms, and present current treatment modalities. For this purpose, a Medline search was conducted using the MeSH terms “erectile dysfunction” and “diabetes mellitus” (all Medline database until March 20, 2014). Only papers published in the English language were considered. This search revealed 1,077 relevant papers. The most important papers based on their scientific value were reviewed and included in the present review.
K. Hatzimouratidis : D. Hatzichristou Center for Sexual and Reproductive Health, Aristotle University of Thessaloniki, Thessaloniki, Greece
Epidemiology
D. Hatzichristou (*) 77 Mitropoleos str., 54622 Thessaloniki, Greece e-mail: [email protected]
ED occurs in about 50 % of men with diabetes mellitus (DM) [6, 10]. The Massachusetts Male Aging Study (MMAS) reported a higher incidence of ED in men with DM compared to
545, Page 2 of 10
those without DM, indentedly of age [6]. In this study, ED was present within 10 years of diagnosis of DM, which was previously undiagnosed in up to 12 % of ED cases [6]. ED occurs at a younger age group in insulin-dependent DM, and the incidence of insulin resistance is three times higher in men with ED than in the general diabetic population [11]. Bacon et al. reported from the Health Professionals Follow-Up Study cohort that men with DM had an age-adjusted relative risk of 1.32 (95 % CI 1.3–1.4) for having ED compared to those without DM [8]. The risk for ED is significantly higher in men with type 1 diabetes compared to type 2 diabetes (relative risk=3.0, 95 % CI 1.5–5.9 vs. 1.3, 95 % CI 1.1–1.5). Moreover, the ED risk is increasing in men with long-standing diagnosis of DM, especially in men with diagnosis given more than 20 years previously. Fedele et al., in a cross-sectional study, reported that the prevalence of ED was 35.8 % [12]. The prevalence rates were age dependent, ranging from 4.6 % for men 20–29 years of age to 45.5 % for men 60–69 years of age. In comparison with men reporting DM lasting ≤5 years, the odds ratios (ORs) for ED were 1.3 and 2.0 for subjects with DM lasting 6–10 and 11–30 years, respectively. In comparison with men with good metabolic control, the ORs for ED were 1.7 and 2.3 in men with fair and poor control, respectively. Finally, this study confirmed that men with type 2 DM reported ED less frequently compared to men with type 1 DM (OR 0.7; 95 % CI 0.6–0.8, corrected for age). Fedele et al. also reported that the incidence of ED in Italian men with DM at a mean follow-up of 2.8 years was 68 cases per 1,000 person-years, more than 2-fold that in the Massachusetts Male Aging Study of the general population [13]. The incidence of ED in this study was twofold higher compared to the Massachusetts Male Aging Study (MMAS). Grover et al., in a crosssectional sample of 3,921 Canadian men (40–88 years) seen by primary care physicians, reported that the overall prevalence of ED was 49.4 % [14]. The relative risk for ED in men with DM increases in patients with DM-associated comorbidities, such as cardiovascular disease (CVD), renal disease, diabetic foot, and retinal disease [12, 14]. It is also important that ED is an early marker of CVD, as ED comes before of coronary artery disease (CAD) in the majority by an average of 2 up to 3 years [15]. Miner et al. reported also that ED is a particularly powerful predictor of CVD in diabetic men [16•]. There is also evidence that phosphodiesterase type 5 inhibitors (PDE5i) may improve endothelial function with a profound positive impact in men’s overall health [17]. ED is highly prevalent in patients with DM-related neuropathy. Glycemic control measured by glycated hemoglobin can predict ED in these patients [18]. ED and metabolic syndrome are significantly connected [19]. The prevalence of ED in patients with metabolic syndrome was 26.7 % compared to 13 % in the control group in a study by Esposito et al. [20]. The same group of authors also reported that in men with type
Curr Diab Rep (2014) 14:545
2 diabetes, those with the highest adherence to the Mediterranean diet had the lowest prevalence of ED and were more likely to be sexually active [21]. DM is also associated with a significant negative impact on all other sexual function domains including sexual drive, ejaculatory function, and sexual satisfaction [22].
Pathophysiology DM may cause ED through a number of pathophysiological pathways [9]. These include neuropathy, endothelial dysfunction, cavernosal smooth muscle structural/functional changes, and hormonal changes (Fig. 1) [23, 24]. Both type 1 and type 2 DM exhibit these changes, though they are more pronounced in type 1 DM [25]. Neuropathy is a significant contributor to the pathophysiology of ED in DM. Several neurophysiological tests (nerve conduction studies, sphincter ani electromyography, heart rate variability testing, and quantitative sensory testing) have showed abnormalities in men with diabetic ED at least as frequent as in men with neuropathic ED [26]. Experimental studies show that apoptotic pathways in the cavernous nerves are important since anti-apoptotic protein expression was lacking in diabetic rat crura and the apoptotic index of diabetic rat crura significantly decreased by insulin treatment [27]. Diabetic neuropathy may be linked to selective neurodegeneration which in turn decreases neuronal nitric oxide synthase (nNOS) activity and diminishes nitric oxide (NO) associated with impaired nitrergic relaxation in the corpus cavernosum [28, 29]. The neurodegeneration seems to be a NO-dependent
Hormonal changes
Cavernosal structural/ functional changes
Diabetic ED
Neuropathy
Fig. 1 Pathophysiology of ED in diabetic men
Endothelial dysfunction
Curr Diab Rep (2014) 14:545
process based on evidence on oxidative damage through the formation of oxygen free radicals [30, 31]. Endothelial dysfunction is an important component of diabetic ED [32]. The activity of endothelial nitric oxide synthase (eNOS) is reduced as well as the effect of released NO [33]. Hyperglycemia in people with DM results in accumulation of advanced glycation end products (AGEs). AGE accumulation results in vascular thickening, decreased elacticity, and atherosclerosis [34]. Experimental data have shown that AGEs are, among others, responsible for impaired endothelial and neuronal NO-mediated cavernosal smooth muscle relaxation in rats by generating reactive oxygen species (ROS) [30]. Increased levels of endothelin (ET-1) and upregulation of the endothelin receptors (ETA and ETB) in the corpus cavernosum contribute to penile vasocontristriction [35, 36]. These effects result in ultrastructural change of atheroscleroticlike lesions [35]. ET-1-induced vasoconstriction is also linked to RhoA/Rho-kinase pathway. This pathway mediates ED through suppression of NOS and decreased production of NO in the corpora cavernosa [37–39]. Several structural changes have been described in diabetic men. Smooth muscle content is reduced while collagen deposition is increased. Thickening of the basal lamina and loss of endothelial cells have been also reported [40]. The relaxation response mediated by endothelial and neurogenic NO in corpus cavernosum is significantly impaired [30, 41]. AGEs play a fundamental role decreasing the compliance of the corpora cavernosa and impairing smooth muscle relaxation by generating free radicals or reactive oxygen species that react with NO [42, 43]. Cavernosal smooth muscle relaxation may also occur due to a decrease in cGMP-dependent protein kinase-1 (PKG-1) that diminish activity of the cGMP intracellular pathway [44]. Low testosterone levels (including total, free, and bioavailable testosterone) are a common finding in men with type 2 diabetes. Most of them present with clinical symptoms of hypogonadism including ED and decreased libido [45, 46]. Hypogonadism in diabetic men is commonly associated with age, obesity, metabolic syndrome, and insulin resistance. The prevalence of insulin resistance and metabolic syndrome in men with ED is as high as 79 and 35 %, respectively [11]. Early detection of metabolic disease in patients with ED may be a gateway to the reduction of endothelial dysfunction in younger men with increased cardiovascular risk but who present for treatment of ED alone [47]. The complex pathophysiology of ED in DM makes any single molecular target treatment almost condemned to fail. Moreover, targeted treatments must select patients in early stages before irreversible changes occur. Cellek et al. described two phase of neurodegeneration due to apoptotic cell death in the ganglia [48]. In the first phase, nitrergic nerve fibers lose some of their neuronal nitric oxide synthase content and function. In the second phase, nitrergic degeneration takes
Page 3 of 10, 545
place in the cell bodies in the ganglia, leading to complete loss of nitrergic function. The changes in the first phase are reversible with insulin replacement but the neurodegeneration in the second phase is irreversible. Despite these unfavorable data, clinicians need the translational input of scientific teams to move beyond symptom-based treatments to target specific molecular mechanisms [49].
Diagnosis The diagnostic algorithm for ED in diabetic patients is similar to other patient cohorts. Diagnosis of ED is based on sexual and medical history [50]. The use of several validated questionnaires such as the International Index for Erectile Function (IIEF) is helpful in order to categorize ED into severity groups but it is not mandatory in everyday clinical practice. The role of physical examination is limited. Clinical signs of cardiovascular disease and neuropathy can be identified while penile examination can identify other comorbidities such as Peyronie’s disease. Hormonal assessment based on testosterone and prolactin is important due to their high prevalence in diabetic men and their implication for treatment [45]. Testosterone should be measured in early morning, preferably on more than one occasion. It is also important to measure serum hormone-binding globulin (SHBG) in order to calculate bioavailable testosterone. When hypogonadism is defined, the clinician should initiate a workup to identify the possible causes of hypogonadism and differentiate between primary (testicular) and central (pituitary) etiology based on LH/FSH assessment. Of course, in patients without a history of confirmed DM, a diagnostic workup is necessary to provide a diagnosis (e.g., fasting and postprandial glucose, glycated hemoglobin, etc.). Specialized examinations are not necessary in the majority of diabetic patients with ED [2].
Treatment The treatment of ED in diabetic men requires a multimodal approach [9]. Prevention should be the first concern although it may be difficult to achieve. In this context, a very important—but often neglected—aspect is the control of hyperglycemia before structural changes occur. But even after this point, it is also necessary to provide adequate DM control and treat diabetic comorbidities since there is no curative treatment for ED today. This approach is important because uncontrolled DM will exacerbate the pathophysiologic changes described above and ED will deteriorate. Therefore, an efficacious treatment will subsequently fail if DM is left untreated. Lifestyle changes should be an integral part of any treatment for ED. These include increased physical activity, weight
545, Page 4 of 10
loss, and a Mediterranean diet. Their positive impact on the treatment is achieved through improvement of the endothelial function [51, 52]. In clinical trials, the Mediterranean diet has been found to be more effective than a control diet in ameliorating or restoring ED in people with obesity or metabolic syndrome [21]. Hormonal changes should be treated since the efficacy of treatments are significantly reduced in these men. Several medications commonly used in diabetic men (e.g., antihypertensives and antidepressants) should be addressed due to their negative impact in sexual function. If appropriate, these medications can be replaced by other associated with less adverse impact on sexual function (e.g., change of diuretics of beta-blockers with calcium channel antagonists, use of angiotensin receptor antagonists) [53]. These drugs may even enhance sexual function not only due to endotheliumdependent vasodilatation but also to oxidative stress and events involved in monocyte attraction and adhesion [54]. Finally, the physician should not forget that patient and partner counselling should be also an integral part of any treatment for ED [55]. While all treatments can be offered to patients with ED, the treatment strategy usually moves from the least to the more invasive options [2]. The proper selection of treatment options should be made addressing the patient and his partner needs and expectations from their sexual life. Clinical follow-up is as important as treatment selection. Physicians should assess not only efficacy and side effects but also patient and partner satisfaction from treatment. Primary care physicians and diabetologists as well as other specialties involved in the treatment of ED should be able to provide basic consultation and treatment. Non-responders to pharmacotherapy and complex clinical cases should be referred to experts. Finally, penile prosthesis implantation should be offered only by properly trained urologists. Given the close association of CVD and DM, the assessment and treatment of CVD is even more important in diabetic men. The third Princeton Consensus Panel was a multispecialty collaborative consensus meeting dedicated to optimizing sexual function and preserving cardiovascular health [56]. These instructions were built on the two previous Princeton conferences [57]. Patients were stratified to three categories based on the cardiovascular risk. The low-risk category group included patients with less than three risk factors for CAD, mild, stable angina, uncomplicated past myocardial infarction, and successful coronary revascularization. The intermediate risk group included patients with greater than or equal to three risk factors for CAD, moderate, stable angina, and myocardial infarction less than 6 weeks. The high-risk group included patients with high-risk arrhythmias, unstable or refractory angina, and myocardial infarction less than 2 weeks. Patients in the low-risk category can be offered ED treatment without any specific cardiac evaluation. Patients in the intermediate category should be referred to a
Curr Diab Rep (2014) 14:545
cardiologist for further evaluation and a stress test is recommended in order to further stratify these patients into the lowor high-risk group. Finally, patients in the high-risk category should not be offered any form of treatment since sexual intercourse is contraindicated.
Phosphodiesterase Type 5 Inhibitors PDE5i are currently the first-line treatment option for the majority of patients with ED based on their efficacy and safety profile. These include sildenafil (25, 50, and 100 mg on demand), tadalafil (10 and 20 mg on demand, 2.5 and 5 mg for daily dosing), vardenafil (5, 10, and 20 mg on demand, 10 mg on demand in the form of orodipersible tablet), and avanafil (50, 100, and 200 mg on demand). The latter has been added into the therapeutic armamentarium in 2014. There are several other PDE5i available only in certain parts of the world (lodenafil, mirodenafil, and udenafil). Although their efficacy (erections lasting long enough for successful intercourse) is about 60–70 % in the general ED population, it is considerably lower in diabetic men (Table 1). Sildenafil improved erections in 66.6 % of men compared to 28.6 % in men using placebo (using the General Assessment Question, GAQ) [60]. In this study, successful intercourse attempts has been reported by 63 % of men compared to 33 % in men taking placebo. These findings have been confirmed by three other randomized, placebo-controlled studies [58, 59, 62]. Rendell et al. reported improved erections in 56 % patients in the sildenafil group compared to 10 % in the placebo group (p
