- Email: [email protected]
Pathogenetic aspects of erectile dysfunction in patients with the metabolic syndrome
Original article
Pathogenetic aspects of erectile dysfunction in patients with the metabolic syndrome Keywords Erectile dysfunction Metabolic syndrome Endothelial dysfunction
E.B. Mazo, MD, PhD Russian State Medical University Department of Urology and Surgical Nephrology, Moscow, Russia S.I. Gamidov, MD, PhD Russian State Medical University Department of Urology and Surgical Nephrology, Moscow, Russia V.V. Iremashvili, MD, PhD Russian State Medical University Department of Urology and Surgical Nephrology, Moscow, Russia R.V. Gasanov, MD Russian State Medical University Department of Urology and Surgical Nephrology, Moscow, Russia Corresponding author E-mail: [email protected]
Online 27 February 2008
42
E.B. Mazo, S.I. Gamidov, V.V. Iremashvili and R.V. Gasanov Abstract Background: Although it is well known that the metabolic syndrome is a common cause of erectile dysfunction (ED) the pathogenesis of the latter in this group of patients is poorly understood. The present study aimed to improve our knowledge in this area. Methods: The study included 385 men with ED (control group) who underwent a full evaluation, including laboratory and ultrasound assessment of endothelial function. Results: The full complex evaluation showed that arteriogenic impairment in the cavernosal circulation was the primary pathogenic factor for ED in patients with the metabolic syndrome. The ultrasoundassisted measurement of postocclusive changes in the diameter of the cavernosal arteries, which reflects the local endothelial function, was the most valuable method in the diagnosis of this form of ED. In addition, a considerable number of patients with the metabolic syndrome demonstrated both hormonal and neurological disorders which also contribute to the pathogenesis of ED in this cohort of men. Conclusion: The pathogenesis of ED in patients with the metabolic syndrome is multifactorial in nature: ED is primarily caused by arteriogenic disorders which are combined with neuropathic disorders in almost every second patient and with hormonal factors in every third one. In addition, psychomotor status has an impact on the development of ED in patients with metabolic syndrome. ß 2008 WPMH GmbH. Published by Elsevier Ireland Ltd.
Erectile dysfunction (ED) is one of the most widespread chronic diseases in men [1–3]. Currently, it is widely agreed that atherosclerosis in the cavernosal vessels is the cause of organic ED in the majority of cases [4]. Evidence of this can be seen from the fact that the risk factors for atherosclerosis, such as hypertension (HTN), diabetes mellitus (DM), dyslipidemia, sedentary lifestyle, obesity and smoking, are common in men with organic ED [1–3]. Moreover, the severity of ED is known to correlate with the number and severity of the abovelisted disorders, while the combination of these factors raises the risk of developing ED [5]. The metabolic syndrome (MS) serves as a vivid manifestation of the combination of
Vol. 5, No. 1, pp. 42–47, March 2008
the vascular risk factors, primarily impaired glucose tolerance, abdominal obesity, dyslipidemia, HTN and type 2 DM. In 1988, Gerald Reaven named this constellation of metabolic abnormalities ‘syndrome X’ [6]. The contribution of each component of the MS to the pathogenesis of erectile disorders has increasingly attracted considerable attention from urologists. The results of individual studies have shown that the frequency of ED in patients with MS varies between ethnic groups from 26.7% to 76.2% [7–9]. Even though the basic pathogenetic aspects of cardiovascular and endocrine disease in the MS have been examined in great detail, the etiology of ED in men suffering from syndrome X is not clearly understood and can only be hypothesized.
ß 2008 WPMH GmbH. Published by Elsevier Ireland Ltd.
Original article Furthermore, no clear-cut guidelines for the diagnosis of ED in patients with MS exist as yet, which complicates the recognition and treatment of the condition. In summary, therefore, it seems that further research needs to be done into aspects of the pathogenesis and diagnosis of ED in patients with MS, which was the aim of this study.
Patients and methods The results of the examination of 595 patients with organic ED form the basis of this study, which was carried out between 2002 and 2006 at the Russian State Medical University’s Department of Urology. The study was approved by the local Ethics Committee, and a written informed consent was signed by all patients. The selection of patients and the formation of the various groups was carried out as follows. Out of all the patients who were referred to the Russian State Medical University Clinic of Urology, 392 men with organic ED aged 20 to 82 years were selected after the preliminary history-taking, further questioning, investigation of the relevant medical documents, and obtaining written informed consent for participation in the study. Patients who had ED due to pelvic or perineal trauma or minor pelvic radical surgery were excluded from the study. Based on the criteria listed by the National Cholesterol Education Program/ Adult Treatment Panel III (NCEP/ATP III, 2001), the MS was found in 46.4% (182 out of 392) of the patients included in this study. The next step consisted of assessing erectile function using the International Index of Erectile Function (IIEF) questionnaire in 355 patients with MS who where followed up by a cardiologist or an internist, which resulted in diagnosing ED in 203 (57.18%) cases. Thereafter, all patients with the MS and ED (203 + 182) were pooled to make up the main study group (Group 1), while men with organic ED without the MS (n = 210) were assigned to the comparison group (Group 2). All of the patients underwent a comprehensive clinical assessment including both a standard clinical examination (history-taking, physical examination, complete blood count, urine analysis, and blood chemistry) and specific tests to diagnose ED and the MS. For the purpose of differentially diagnosing ED, the
following specific andrologic investigations were applied: IIEF questioning, penile ultrasonography (US), penile color Doppler ultrasonography with the intracorporeal injection of vasoactive agents (CDUS-P) during functional tests. The Beck Depression Inventory was used to identify depressive disorders in patients after adaptation for the Russian Federation. For the evaluation of endothelial function, humeral and cavernosal postcompression tests were carried out and the asymmetrical dimethyl arginine blood levels (ADMA) were assessed. The cavernosal postcompression test was carried out using the Technos MP (Esaote) ultrasound probe, following a procedure adapted by the authors. Thus, the patient is placed in a supine position and the linear transducer LA 523 10-5 is placed longitudinally on the ventral surface of the penis at a distance of 3–4 cm from its base. The transducer’s location is marked. The cavernosal artery diameter is estimated by measuring the distance between the opposite vascular walls 5 min before and after compression. The main parameter estimated was the increase in the diameter of the cavernosal artery (IDCA, %) computed from the formula: IDCA ¼
ðDac Dbc Þ 100% Dbc
where Dbc is the cavernosal artery diameter before compression, and Dac is the cavernosal artery diameter after compression. IDCA values of less than 50% were defined as a sign of local endothelial dysfunction. The ADMA blood levels were evaluated using a serum enzyme-linked innunosorbent assay (ELISA) from CardioS Vasicsmedical Science Labs. High risk, moderate risk or no risk for endothelial dysfunction were defined as ADMA concentrations greater than 0.573 mM, ranging from 0.062 to 0.572 mM, or less than 0.062 mM, respectively. The plasma free testosterone levels were also assessed using an ELISA from the DRG Elisa Kit (DRG Instruments GmbH, Germany). For the evaluation of somatic penile innervation, we assessed the cutaneous sensitivity of the penis and the bulbocavernosal and scrotal reflexes. Autonomous penile innervation was evaluated by means of penile electromyography (EMG), both basal and following the intracavernosal pharmacological test (IPT).
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Original article Table 1 The main physical parameters of patients enrolled in the study Parameter
Group 1 (n = 385)
Group 2 (n = 210)
Height, cm Body weight, kg BMI, kg/m2 Waist circumference, cm
175.19 6.13 103.17 15.09* 33.44 4.28* 114.81 12.15*
175.19 5.86 81.11 10.15 26.60 2.89 94.10 7.93
*
Significant difference between Groups 1 and 2, p < 0.05.
Measurements we made using the ‘Neyromiovik’ electrophysiological instrument (manufactured in Russia) which has a power of 15 Wt and uses superficial non-polar electrodes. The study frequency and peak ranged from 0.1–10 kHz and from 5–10 mV, respectively. The values were recorded for 40 min. The electromyogram was interpreted 10 min after the beginning of the investigation. The metabolic syndrome was diagnosed as recommended by the National Cholesterol Education Program. Thus, the presence of at least three out of the following five criteria was regarded as diagnostic for the metabolic syndrome: (1) abdominal adiposity, defined as a waist circumference of >102 cm or a body mass index (BMI) 28.8 kg/m2; (2) hypertriglyceridemia, defined as an elevated triglyceride level of >1.7 mmol/l; (3) elevated blood pressure, defined as a blood pressure of >130/85 mmHg; (4) abnormal glucose homeostasis, defined as a fasting plasma glucose concentration of >6.1 mmol/l. Insulin resistance was diagnosed if the fasting glucose blood level (mg/dl)/insulin (mcU/ml) ratio was less than 6. The clinical data were analysed using the standard statistical methods available with PC software, namely Microsoft Excel and Statistica 6.0. To estimate the contribution of each MS component to the progression of ED, we performed a multifactorial analysis.
Results To determine the clinical specificities of ED in patients with the MS, we compared the results from the examination of patients in Group 1 with those from Group 2. The mean age of patients in group 1 was 49.74 10.66 years, and was similar to that of group 2 (53.93 13.63 years, p = 0.1). The values for BMI and waist circumference in patients with
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the MS were significantly higher than those in patients from Group 2 (Table 1). The analysis showed a significant difference between Groups 1 and 2 in the number of smokers: the proportion of smokers was significantly higher in Group 2 than that in Group 1 (59.52 % vs. 36.88 %, p < 0.05). At the same time, the frequency of cardiovascular disease in Group 1 exceeded that in Group 2 (1.42 vs. 1.04, p < 0.05). The mean IIEF erectile function score in patients with MS and ED (Group 1) was significantly lower (12.51 5.10 points) than that in Group 2, where the patients had ED only (15.34 4.94 points, p < 0.05). These data suggest that the combination of ED and the MS results in more severe forms of erectile disorders. Group 1 patients developed ED at an earlier age (43.46 9.87 years) than Group 2 men (50.38 13.35 years, p < 0.05) and its duration at the time of examination in Group 1 was almost twice as long (6.36 4.13 years) as that for group 2 patients (3.55 3.27 years, p < 0.05). In MS patients with four or more of the following risk factors (obesity, HTN, coronary artery disease (CAD), type 2 DM, insulin resistance, dyslipidemia) the IIEF erectile function score was lower than that for patients with less than four risk factors (9.47 3.69 vs. 14.46 5.07 points, p < 0.05). Furthermore, an association between the IIEF erectile function score and the duration of exposure to the risk factors was identified. Patients with a lower IIEF erectile function score had a longer history of obesity (r = 0.36, p < 0.05), HTN (r = 0.37, p < 0.05), type 2 DM (r = 0.40, p < 0.05), CAD (r = 0.14, p < 0.05) and dyslipidemia (r = 0.58, p < 0.05). The combination of several vascular risk factors in one patient obscures the contribution of each of them to the severity of the ED. Therefore, we carried out a multifactorial statistical analysis to estimate the value of each of
Original article the factors in relation to the others, thereby enhancing the significance of the results obtained. According to that analysis, the impact of each of the MS components on the erectile function varies widely, and insulin resistance, hyperinsulinemia, HTN, type 2 DM and the history of vascular risk factors in close relatives are the most aggressive factors that subsequently determine the severity of ED in patients with MS. History-taking and the IPT in Group 1 helped in the recognition of arteriogenic ED (delayed erection and detumescence, an increase in the time required to achieve the maximal erection) in almost 90% of patients. The mean dose of alprostadil (Caverject), a vasoactive agent used for intracavernosal injections, in patients from Group 1 was significantly higher than that for patients in Group 2 (15.6 mg vs. 11.3 mg, p < 0.05). The mean time to the start of an erection after the IPT was 15.8 2.1 mins in Group 1 and 10.12 1.8 mins in Group 2 (p < 0.05). The results from the CDUS-P suggest that two thirds of patients from Group 1 had arteriogenic ED. However, only one third of Group 2 patients had arteriogenic ED, and 50% of them had arterial circulation values that were within normal limits. In Group 1, signs of isolated veno-occlusive insufficiency (VOI) were absent, while in Group 2 these were evident in 11.9% of patients; arteriovenous ED was predominant in patients with the MS (12.6 % vs. 1.43 %, p < 0.05). All Group 1 patients and 92.38% of the men in Group 2 had findings that were compatible with cavernosal artery endothelial dysfunction (IDCA value of less than 50%), as evidenced by postcompression tests. In addition, the mean IDCA values in Group 1 patients were significantly lower (24.6 6.39) than those in Group 2 (34.47 10.17, p < 0.05), which suggests more severe endothelial dysfunction in patients with the MS. The MS was associated with an almost twofold increase in ADMA levels (1.37 0.44 mM vs. 0.71 0.33 mM, p < 0.05), which once again strongly supports a greater severity of endothelial dysfunction in patients with the MS. The results of neurologic investigations have shown that patients with the MS and ED relatively often have penile somatic innervation disorders. A decrease in cutaneous penile sensitivity and a diminution in scrotal and bulbo-
cavernosal reflexes were found in 11.34% of patients in Group 1 and 4.87% in Group 2. Compared to men without carbohydrate metaboliF disorders, many more patients with type 2 DM had neurologic changes (64.03% vs. 2.1%, p < 0.01). The results of the investigations have shown that the frequency of the autonomous innervation disorders in patients and the electrical activity in the corpora cavernosa was significantly higher in Group 1 (42.2 % vs. 9.52 %, p < 0.05). Patients suffering from marked obesity (BMI 35 kg/m2) and insulin resistance had a hyper-reflex type curve relatively more often (57% in Group 1 vs. 43 % in Group 2). Unlike other curve types, these high potentials persisted even in cases with induced erections, which suggests that the functional nature of the penile innervation disorder is shown as an increase in sympathetic nervous system activity. However, the incidence of the curve types with decreased or absent reflexes in diabetic patients was higher (78%), which supports the idea that these patients suffer from a degenerative innervation disorder of the penis. Compared to patients from Group 2, men in Group 1 often had low total (10.63% vs. 2.9%, p < 0.05) and free (36.36% vs. 21.42%, p < 0.05) testosterone blood levels. A decrease in the free testosterone levels was found more often in patients with type 2 DM and CAD (47.2% and 40.81%, respectively). An increase in waist circumference correlated with a drop in the total (r = 0.21, p < 0.05) and free testosterone (r = 0.25, p < 0.05) levels. A positive association between IDCA values and the total (r = 0.41, p < 0.05) and free (r = 0.41, p < 0.05) testosterone levels was noted. Almost all patients with high ADMA levels (95.67%) had a low free testosterone level. Furthermore, the data from the depression questionnaire have shown that patients from Group 1, compared with those in Group 2, suffer from depressive disorders significantly more often (43.37% and 23.37% respectively), and especially suffer from marked depressive disorders (68.26% vs. 30.61%).
Discussion The results of the current study suggest that patients with the MS develop ED relatively earlier and in more severe forms. The degree of impact of the MS components on the sever-
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Original article ity of ED may vary widely. Insulin resistance, hyperinsulinemia, HTN, and type 2 DM more often cause more severe forms of ED. An increase in the number of risk factors raises the probability of the development of more severe forms of ED. The dependence of the ED severity on the character and number of the MS components is in agreement with the works of other authors. However, according to their data, the major factors that determine the severity of ED in patients with the MS were confined to the fasting blood glucose levels, waist circumference and HTN [7–9]. Analysis of the data obtained has allowed us to delineate the mechanisms underlying the pathogenesis of ED in patients with the MS. ED in patients with the MS is mainly arteriogenic in nature, which has been confirmed by the results of history-taking, IPT, CDUS-P and postcompression tests. Apart from this, arteriogenic disorders were combined with low androgen blood levels and with penile autonomous and somatic innervation in 36.36 % and 42.2 % of patients, respectively. Endothelial dysfunction is one of the early manifestations of systemic vascular disorders. The application of postcompression tests for diagnosing ED has allowed us to characterize more accurately the hemodynamic disorders underlying erection dysfunction in patients with the MS. It was the results of these diagnostic methods, rather than those of CDUS-P which is, by far, considered to be ‘the gold standard’ for the diagnosis of vasculogenic ED, that corresponded to the clinical picture of the condition and to the IPT values. Common complaints, such as delayed erection and detumescence, an increase in the time to the achievement of erection, as well as a decrease in cavernosal artery circulation velocity confirmed by the IPT data, were found in almost 90% of the patients, but were not completely reflected in the results of CDUS-P which only helped in the recognition of arteriogenic ED in 75.72% of cases. This fact is attributable to the temporary improvement in endothelial dysfunction resulting from the use of vasoactive agents for CDUS-P which might bring the cavernosal artery circulation values to within normal limits. The clinical signs and CDUS-P findings in 12.6% of patients from group 1 were compatible with arteriovenous ED.
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Venous-occlusive insufficiency in patients with the MS may be accounted for by degenerative changes in the corpora cavernosa. Although we did not perform morphological investigations, the results of the comprehensive examination provided evidence for structural changes in the corpora cavernosa. All these patients had type 2 DM of long duration and had low levels of male sex hormones that resulted in impairment in the relaxation of the smooth muscles of the corpora cavernosa. Furthermore, the penile EMG helped to identify the curve types with decreased or absent reflexes in almost all of the patients, which once again confirms a decrease in the electrical activity of the smooth muscles in the corpora cavernosa. Thus, based on the results obtained, we assume that penile vascular disorders in patients with a long history of the MS result both from a decrease in the cavernosal artery circulation velocity and a rise in the venous outflow that is particularly typical of type 2 DM patients. The severity of neurological disorders of the penis in patients with the MS varies with the nature and duration of its components. The initial stages of the disease are characterized by a frequent occurrence of relatively mild and transient functional changes as evidenced by the EMG as response curves with exaggerated reflexes. These disorders have been mainly revealed in those patients with marked obesity and insulin resistance. The registration of these potentials, even in patients with induced erection, indicates there is a high sympathetic tone in patients with the MS that is caused by compensatory hyperinsulinemia. This increased sympathetic activity leads to the impairment of the neural regulation in the corpora cavernosa and, therefore, causes ED. At the same time, late complications, including those typical of diabetic patients, result in more marked and persistant disorders in the penile autonomous innervation as evidenced by the curve types with decreased or absent reflexes. Since such penile disorders are caused by diabetic polyneuropathy, their frequency correlates with the duration of DM (r = 0.65, p < 0.05). Alongside the vascular disorders, structural changes to the penile nerves lead to more severe forms of ED in patients with the MS. A decrease in sex hormone levels also plays a large part in the pathogenesis of ED in patients
Original article with the MS, which is supported by the relatively high prevalence of a decrease in free testosterone concentration in these patients. The high frequency of androgen deficiency among those men with late complications of the MS, such as type 2 DM and CAD, suggests that the hormonal disorders tend to develop later than the endothelial dysfunction. Patients with low testosterone levels have severe endothelial dysfunction of the cavernosal arteries. Also, the negative impact of androgen deficiency on endothelial function can be supported by the high ADMA concentration in these patients, as almost all of the patients with low free and total testosterone levels had ADMA levels in the high risk range. Furthermore, low androgen levels can diminish libido which, in turn, furthers the worsening of spontaneous and adequate erections. Organic conditions such as obesity, HTN, CAD, and type 2 DM, could not but adversely affect the psychoemotional status of the men in the study. Their responses to the Beck Depression Inventory have shown that the frequency of depressive disorders in patients with ED and the MS is high (43.37%). Not only does the low psychoemotional status of the
patient worsen the erection quality, but it also promotes the progression of other MS components. This is due to the fact that stress factors and depression result in the activation of the sympathetic nervous system, which, in turn, is one of the major triggers for metabolic disorders. Timely sexual rehabilitation, weight reduction and correction of other metabolic disorders would enable clinicians to both improve the penile hemodynamics and normalize patients’ psychoemotional status, which can increase the efficacy of the therapy.
Conclusion Thus, the pathogenesis of ED in patients with the MS is multifactorial in nature: erectile dysfunction is primarily caused by arteriogenic disorders which are coupled with neuropathic disorders in almost one out of every two patients and with hormonal factors in one in three. The VOI’s role in the pathophysiology of ED in patients with the MS is relatively low. Apart from the above factors, psychoemotional status is of great importance in the development of ED in patients with the MS.
References [1] Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinley JB. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994;151(1):54–61. [2] Nicolosi A, Moreira Jr ED, Shirai M, Bin Mohd Tambi MI, Glasser DB. Epidemiology of erectile dysfunction in four countries: crossnational study of the prevalence and correlates of erectile dysfunction. Urology 2003;61(1):201–6. [3] Anon. Consensus development conference statement. National Institutes of Health.
Impotence. December 7–9, 1992. Int J Impot Res 1993;5(4):181–284. [4] Melman A, Gingell JC. The epidemiology and pathophysiology of erectile dysfunction. J Urol 1999;161(1):5–11. [5] Parazzini F, Menchini Fabris F, Bortolotti A, Calabro` A, Chatenoud L, Colli E, et al. Frequency and determinants of erectile dysfunction in Italy. Eur Urol 2000;37(1): 43–9. [6] Reaven GM. Role of insulin resistance in human disease. Diabetes 1988;37(12): 1595–607.
[7] Gu¨ndu¨z MI, Gu¨mu¨s BH, Sekuri C. Relationship between metabolic syndrome and erectile dysfunction. Asian J Androl 2004;6(4): 355–8. [8] Esposito K, Giugliano F, Martedı` E, Feola G, Marfella R, D’Armiento M, et al. High proportions of erectile dysfunction in men with the metabolic syndrome. Diabetes Care 2005; 28(5):1201–3. [9] Demir T, Demir O, Kefi A, Comlekci A, Yesil S, Esen A. Prevalence of erectile dysfunction in patients with metabolic syndrome. Int J Urol 2006;13(4):385–8.
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47
Pathogenetic aspects of erectile dysfunction in patients with the metabolic syndrome Keywords Erectile dysfunction Metabolic syndrome Endothelial dysfunction
E.B. Mazo, MD, PhD Russian State Medical University Department of Urology and Surgical Nephrology, Moscow, Russia S.I. Gamidov, MD, PhD Russian State Medical University Department of Urology and Surgical Nephrology, Moscow, Russia V.V. Iremashvili, MD, PhD Russian State Medical University Department of Urology and Surgical Nephrology, Moscow, Russia R.V. Gasanov, MD Russian State Medical University Department of Urology and Surgical Nephrology, Moscow, Russia Corresponding author E-mail: [email protected]
Online 27 February 2008
42
E.B. Mazo, S.I. Gamidov, V.V. Iremashvili and R.V. Gasanov Abstract Background: Although it is well known that the metabolic syndrome is a common cause of erectile dysfunction (ED) the pathogenesis of the latter in this group of patients is poorly understood. The present study aimed to improve our knowledge in this area. Methods: The study included 385 men with ED (control group) who underwent a full evaluation, including laboratory and ultrasound assessment of endothelial function. Results: The full complex evaluation showed that arteriogenic impairment in the cavernosal circulation was the primary pathogenic factor for ED in patients with the metabolic syndrome. The ultrasoundassisted measurement of postocclusive changes in the diameter of the cavernosal arteries, which reflects the local endothelial function, was the most valuable method in the diagnosis of this form of ED. In addition, a considerable number of patients with the metabolic syndrome demonstrated both hormonal and neurological disorders which also contribute to the pathogenesis of ED in this cohort of men. Conclusion: The pathogenesis of ED in patients with the metabolic syndrome is multifactorial in nature: ED is primarily caused by arteriogenic disorders which are combined with neuropathic disorders in almost every second patient and with hormonal factors in every third one. In addition, psychomotor status has an impact on the development of ED in patients with metabolic syndrome. ß 2008 WPMH GmbH. Published by Elsevier Ireland Ltd.
Erectile dysfunction (ED) is one of the most widespread chronic diseases in men [1–3]. Currently, it is widely agreed that atherosclerosis in the cavernosal vessels is the cause of organic ED in the majority of cases [4]. Evidence of this can be seen from the fact that the risk factors for atherosclerosis, such as hypertension (HTN), diabetes mellitus (DM), dyslipidemia, sedentary lifestyle, obesity and smoking, are common in men with organic ED [1–3]. Moreover, the severity of ED is known to correlate with the number and severity of the abovelisted disorders, while the combination of these factors raises the risk of developing ED [5]. The metabolic syndrome (MS) serves as a vivid manifestation of the combination of
Vol. 5, No. 1, pp. 42–47, March 2008
the vascular risk factors, primarily impaired glucose tolerance, abdominal obesity, dyslipidemia, HTN and type 2 DM. In 1988, Gerald Reaven named this constellation of metabolic abnormalities ‘syndrome X’ [6]. The contribution of each component of the MS to the pathogenesis of erectile disorders has increasingly attracted considerable attention from urologists. The results of individual studies have shown that the frequency of ED in patients with MS varies between ethnic groups from 26.7% to 76.2% [7–9]. Even though the basic pathogenetic aspects of cardiovascular and endocrine disease in the MS have been examined in great detail, the etiology of ED in men suffering from syndrome X is not clearly understood and can only be hypothesized.
ß 2008 WPMH GmbH. Published by Elsevier Ireland Ltd.
Original article Furthermore, no clear-cut guidelines for the diagnosis of ED in patients with MS exist as yet, which complicates the recognition and treatment of the condition. In summary, therefore, it seems that further research needs to be done into aspects of the pathogenesis and diagnosis of ED in patients with MS, which was the aim of this study.
Patients and methods The results of the examination of 595 patients with organic ED form the basis of this study, which was carried out between 2002 and 2006 at the Russian State Medical University’s Department of Urology. The study was approved by the local Ethics Committee, and a written informed consent was signed by all patients. The selection of patients and the formation of the various groups was carried out as follows. Out of all the patients who were referred to the Russian State Medical University Clinic of Urology, 392 men with organic ED aged 20 to 82 years were selected after the preliminary history-taking, further questioning, investigation of the relevant medical documents, and obtaining written informed consent for participation in the study. Patients who had ED due to pelvic or perineal trauma or minor pelvic radical surgery were excluded from the study. Based on the criteria listed by the National Cholesterol Education Program/ Adult Treatment Panel III (NCEP/ATP III, 2001), the MS was found in 46.4% (182 out of 392) of the patients included in this study. The next step consisted of assessing erectile function using the International Index of Erectile Function (IIEF) questionnaire in 355 patients with MS who where followed up by a cardiologist or an internist, which resulted in diagnosing ED in 203 (57.18%) cases. Thereafter, all patients with the MS and ED (203 + 182) were pooled to make up the main study group (Group 1), while men with organic ED without the MS (n = 210) were assigned to the comparison group (Group 2). All of the patients underwent a comprehensive clinical assessment including both a standard clinical examination (history-taking, physical examination, complete blood count, urine analysis, and blood chemistry) and specific tests to diagnose ED and the MS. For the purpose of differentially diagnosing ED, the
following specific andrologic investigations were applied: IIEF questioning, penile ultrasonography (US), penile color Doppler ultrasonography with the intracorporeal injection of vasoactive agents (CDUS-P) during functional tests. The Beck Depression Inventory was used to identify depressive disorders in patients after adaptation for the Russian Federation. For the evaluation of endothelial function, humeral and cavernosal postcompression tests were carried out and the asymmetrical dimethyl arginine blood levels (ADMA) were assessed. The cavernosal postcompression test was carried out using the Technos MP (Esaote) ultrasound probe, following a procedure adapted by the authors. Thus, the patient is placed in a supine position and the linear transducer LA 523 10-5 is placed longitudinally on the ventral surface of the penis at a distance of 3–4 cm from its base. The transducer’s location is marked. The cavernosal artery diameter is estimated by measuring the distance between the opposite vascular walls 5 min before and after compression. The main parameter estimated was the increase in the diameter of the cavernosal artery (IDCA, %) computed from the formula: IDCA ¼
ðDac Dbc Þ 100% Dbc
where Dbc is the cavernosal artery diameter before compression, and Dac is the cavernosal artery diameter after compression. IDCA values of less than 50% were defined as a sign of local endothelial dysfunction. The ADMA blood levels were evaluated using a serum enzyme-linked innunosorbent assay (ELISA) from CardioS Vasicsmedical Science Labs. High risk, moderate risk or no risk for endothelial dysfunction were defined as ADMA concentrations greater than 0.573 mM, ranging from 0.062 to 0.572 mM, or less than 0.062 mM, respectively. The plasma free testosterone levels were also assessed using an ELISA from the DRG Elisa Kit (DRG Instruments GmbH, Germany). For the evaluation of somatic penile innervation, we assessed the cutaneous sensitivity of the penis and the bulbocavernosal and scrotal reflexes. Autonomous penile innervation was evaluated by means of penile electromyography (EMG), both basal and following the intracavernosal pharmacological test (IPT).
Vol. 5, No. 1, pp. 42–47, March 2008
43
Original article Table 1 The main physical parameters of patients enrolled in the study Parameter
Group 1 (n = 385)
Group 2 (n = 210)
Height, cm Body weight, kg BMI, kg/m2 Waist circumference, cm
175.19 6.13 103.17 15.09* 33.44 4.28* 114.81 12.15*
175.19 5.86 81.11 10.15 26.60 2.89 94.10 7.93
*
Significant difference between Groups 1 and 2, p < 0.05.
Measurements we made using the ‘Neyromiovik’ electrophysiological instrument (manufactured in Russia) which has a power of 15 Wt and uses superficial non-polar electrodes. The study frequency and peak ranged from 0.1–10 kHz and from 5–10 mV, respectively. The values were recorded for 40 min. The electromyogram was interpreted 10 min after the beginning of the investigation. The metabolic syndrome was diagnosed as recommended by the National Cholesterol Education Program. Thus, the presence of at least three out of the following five criteria was regarded as diagnostic for the metabolic syndrome: (1) abdominal adiposity, defined as a waist circumference of >102 cm or a body mass index (BMI) 28.8 kg/m2; (2) hypertriglyceridemia, defined as an elevated triglyceride level of >1.7 mmol/l; (3) elevated blood pressure, defined as a blood pressure of >130/85 mmHg; (4) abnormal glucose homeostasis, defined as a fasting plasma glucose concentration of >6.1 mmol/l. Insulin resistance was diagnosed if the fasting glucose blood level (mg/dl)/insulin (mcU/ml) ratio was less than 6. The clinical data were analysed using the standard statistical methods available with PC software, namely Microsoft Excel and Statistica 6.0. To estimate the contribution of each MS component to the progression of ED, we performed a multifactorial analysis.
Results To determine the clinical specificities of ED in patients with the MS, we compared the results from the examination of patients in Group 1 with those from Group 2. The mean age of patients in group 1 was 49.74 10.66 years, and was similar to that of group 2 (53.93 13.63 years, p = 0.1). The values for BMI and waist circumference in patients with
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the MS were significantly higher than those in patients from Group 2 (Table 1). The analysis showed a significant difference between Groups 1 and 2 in the number of smokers: the proportion of smokers was significantly higher in Group 2 than that in Group 1 (59.52 % vs. 36.88 %, p < 0.05). At the same time, the frequency of cardiovascular disease in Group 1 exceeded that in Group 2 (1.42 vs. 1.04, p < 0.05). The mean IIEF erectile function score in patients with MS and ED (Group 1) was significantly lower (12.51 5.10 points) than that in Group 2, where the patients had ED only (15.34 4.94 points, p < 0.05). These data suggest that the combination of ED and the MS results in more severe forms of erectile disorders. Group 1 patients developed ED at an earlier age (43.46 9.87 years) than Group 2 men (50.38 13.35 years, p < 0.05) and its duration at the time of examination in Group 1 was almost twice as long (6.36 4.13 years) as that for group 2 patients (3.55 3.27 years, p < 0.05). In MS patients with four or more of the following risk factors (obesity, HTN, coronary artery disease (CAD), type 2 DM, insulin resistance, dyslipidemia) the IIEF erectile function score was lower than that for patients with less than four risk factors (9.47 3.69 vs. 14.46 5.07 points, p < 0.05). Furthermore, an association between the IIEF erectile function score and the duration of exposure to the risk factors was identified. Patients with a lower IIEF erectile function score had a longer history of obesity (r = 0.36, p < 0.05), HTN (r = 0.37, p < 0.05), type 2 DM (r = 0.40, p < 0.05), CAD (r = 0.14, p < 0.05) and dyslipidemia (r = 0.58, p < 0.05). The combination of several vascular risk factors in one patient obscures the contribution of each of them to the severity of the ED. Therefore, we carried out a multifactorial statistical analysis to estimate the value of each of
Original article the factors in relation to the others, thereby enhancing the significance of the results obtained. According to that analysis, the impact of each of the MS components on the erectile function varies widely, and insulin resistance, hyperinsulinemia, HTN, type 2 DM and the history of vascular risk factors in close relatives are the most aggressive factors that subsequently determine the severity of ED in patients with MS. History-taking and the IPT in Group 1 helped in the recognition of arteriogenic ED (delayed erection and detumescence, an increase in the time required to achieve the maximal erection) in almost 90% of patients. The mean dose of alprostadil (Caverject), a vasoactive agent used for intracavernosal injections, in patients from Group 1 was significantly higher than that for patients in Group 2 (15.6 mg vs. 11.3 mg, p < 0.05). The mean time to the start of an erection after the IPT was 15.8 2.1 mins in Group 1 and 10.12 1.8 mins in Group 2 (p < 0.05). The results from the CDUS-P suggest that two thirds of patients from Group 1 had arteriogenic ED. However, only one third of Group 2 patients had arteriogenic ED, and 50% of them had arterial circulation values that were within normal limits. In Group 1, signs of isolated veno-occlusive insufficiency (VOI) were absent, while in Group 2 these were evident in 11.9% of patients; arteriovenous ED was predominant in patients with the MS (12.6 % vs. 1.43 %, p < 0.05). All Group 1 patients and 92.38% of the men in Group 2 had findings that were compatible with cavernosal artery endothelial dysfunction (IDCA value of less than 50%), as evidenced by postcompression tests. In addition, the mean IDCA values in Group 1 patients were significantly lower (24.6 6.39) than those in Group 2 (34.47 10.17, p < 0.05), which suggests more severe endothelial dysfunction in patients with the MS. The MS was associated with an almost twofold increase in ADMA levels (1.37 0.44 mM vs. 0.71 0.33 mM, p < 0.05), which once again strongly supports a greater severity of endothelial dysfunction in patients with the MS. The results of neurologic investigations have shown that patients with the MS and ED relatively often have penile somatic innervation disorders. A decrease in cutaneous penile sensitivity and a diminution in scrotal and bulbo-
cavernosal reflexes were found in 11.34% of patients in Group 1 and 4.87% in Group 2. Compared to men without carbohydrate metaboliF disorders, many more patients with type 2 DM had neurologic changes (64.03% vs. 2.1%, p < 0.01). The results of the investigations have shown that the frequency of the autonomous innervation disorders in patients and the electrical activity in the corpora cavernosa was significantly higher in Group 1 (42.2 % vs. 9.52 %, p < 0.05). Patients suffering from marked obesity (BMI 35 kg/m2) and insulin resistance had a hyper-reflex type curve relatively more often (57% in Group 1 vs. 43 % in Group 2). Unlike other curve types, these high potentials persisted even in cases with induced erections, which suggests that the functional nature of the penile innervation disorder is shown as an increase in sympathetic nervous system activity. However, the incidence of the curve types with decreased or absent reflexes in diabetic patients was higher (78%), which supports the idea that these patients suffer from a degenerative innervation disorder of the penis. Compared to patients from Group 2, men in Group 1 often had low total (10.63% vs. 2.9%, p < 0.05) and free (36.36% vs. 21.42%, p < 0.05) testosterone blood levels. A decrease in the free testosterone levels was found more often in patients with type 2 DM and CAD (47.2% and 40.81%, respectively). An increase in waist circumference correlated with a drop in the total (r = 0.21, p < 0.05) and free testosterone (r = 0.25, p < 0.05) levels. A positive association between IDCA values and the total (r = 0.41, p < 0.05) and free (r = 0.41, p < 0.05) testosterone levels was noted. Almost all patients with high ADMA levels (95.67%) had a low free testosterone level. Furthermore, the data from the depression questionnaire have shown that patients from Group 1, compared with those in Group 2, suffer from depressive disorders significantly more often (43.37% and 23.37% respectively), and especially suffer from marked depressive disorders (68.26% vs. 30.61%).
Discussion The results of the current study suggest that patients with the MS develop ED relatively earlier and in more severe forms. The degree of impact of the MS components on the sever-
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Original article ity of ED may vary widely. Insulin resistance, hyperinsulinemia, HTN, and type 2 DM more often cause more severe forms of ED. An increase in the number of risk factors raises the probability of the development of more severe forms of ED. The dependence of the ED severity on the character and number of the MS components is in agreement with the works of other authors. However, according to their data, the major factors that determine the severity of ED in patients with the MS were confined to the fasting blood glucose levels, waist circumference and HTN [7–9]. Analysis of the data obtained has allowed us to delineate the mechanisms underlying the pathogenesis of ED in patients with the MS. ED in patients with the MS is mainly arteriogenic in nature, which has been confirmed by the results of history-taking, IPT, CDUS-P and postcompression tests. Apart from this, arteriogenic disorders were combined with low androgen blood levels and with penile autonomous and somatic innervation in 36.36 % and 42.2 % of patients, respectively. Endothelial dysfunction is one of the early manifestations of systemic vascular disorders. The application of postcompression tests for diagnosing ED has allowed us to characterize more accurately the hemodynamic disorders underlying erection dysfunction in patients with the MS. It was the results of these diagnostic methods, rather than those of CDUS-P which is, by far, considered to be ‘the gold standard’ for the diagnosis of vasculogenic ED, that corresponded to the clinical picture of the condition and to the IPT values. Common complaints, such as delayed erection and detumescence, an increase in the time to the achievement of erection, as well as a decrease in cavernosal artery circulation velocity confirmed by the IPT data, were found in almost 90% of the patients, but were not completely reflected in the results of CDUS-P which only helped in the recognition of arteriogenic ED in 75.72% of cases. This fact is attributable to the temporary improvement in endothelial dysfunction resulting from the use of vasoactive agents for CDUS-P which might bring the cavernosal artery circulation values to within normal limits. The clinical signs and CDUS-P findings in 12.6% of patients from group 1 were compatible with arteriovenous ED.
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Venous-occlusive insufficiency in patients with the MS may be accounted for by degenerative changes in the corpora cavernosa. Although we did not perform morphological investigations, the results of the comprehensive examination provided evidence for structural changes in the corpora cavernosa. All these patients had type 2 DM of long duration and had low levels of male sex hormones that resulted in impairment in the relaxation of the smooth muscles of the corpora cavernosa. Furthermore, the penile EMG helped to identify the curve types with decreased or absent reflexes in almost all of the patients, which once again confirms a decrease in the electrical activity of the smooth muscles in the corpora cavernosa. Thus, based on the results obtained, we assume that penile vascular disorders in patients with a long history of the MS result both from a decrease in the cavernosal artery circulation velocity and a rise in the venous outflow that is particularly typical of type 2 DM patients. The severity of neurological disorders of the penis in patients with the MS varies with the nature and duration of its components. The initial stages of the disease are characterized by a frequent occurrence of relatively mild and transient functional changes as evidenced by the EMG as response curves with exaggerated reflexes. These disorders have been mainly revealed in those patients with marked obesity and insulin resistance. The registration of these potentials, even in patients with induced erection, indicates there is a high sympathetic tone in patients with the MS that is caused by compensatory hyperinsulinemia. This increased sympathetic activity leads to the impairment of the neural regulation in the corpora cavernosa and, therefore, causes ED. At the same time, late complications, including those typical of diabetic patients, result in more marked and persistant disorders in the penile autonomous innervation as evidenced by the curve types with decreased or absent reflexes. Since such penile disorders are caused by diabetic polyneuropathy, their frequency correlates with the duration of DM (r = 0.65, p < 0.05). Alongside the vascular disorders, structural changes to the penile nerves lead to more severe forms of ED in patients with the MS. A decrease in sex hormone levels also plays a large part in the pathogenesis of ED in patients
Original article with the MS, which is supported by the relatively high prevalence of a decrease in free testosterone concentration in these patients. The high frequency of androgen deficiency among those men with late complications of the MS, such as type 2 DM and CAD, suggests that the hormonal disorders tend to develop later than the endothelial dysfunction. Patients with low testosterone levels have severe endothelial dysfunction of the cavernosal arteries. Also, the negative impact of androgen deficiency on endothelial function can be supported by the high ADMA concentration in these patients, as almost all of the patients with low free and total testosterone levels had ADMA levels in the high risk range. Furthermore, low androgen levels can diminish libido which, in turn, furthers the worsening of spontaneous and adequate erections. Organic conditions such as obesity, HTN, CAD, and type 2 DM, could not but adversely affect the psychoemotional status of the men in the study. Their responses to the Beck Depression Inventory have shown that the frequency of depressive disorders in patients with ED and the MS is high (43.37%). Not only does the low psychoemotional status of the
patient worsen the erection quality, but it also promotes the progression of other MS components. This is due to the fact that stress factors and depression result in the activation of the sympathetic nervous system, which, in turn, is one of the major triggers for metabolic disorders. Timely sexual rehabilitation, weight reduction and correction of other metabolic disorders would enable clinicians to both improve the penile hemodynamics and normalize patients’ psychoemotional status, which can increase the efficacy of the therapy.
Conclusion Thus, the pathogenesis of ED in patients with the MS is multifactorial in nature: erectile dysfunction is primarily caused by arteriogenic disorders which are coupled with neuropathic disorders in almost one out of every two patients and with hormonal factors in one in three. The VOI’s role in the pathophysiology of ED in patients with the MS is relatively low. Apart from the above factors, psychoemotional status is of great importance in the development of ED in patients with the MS.
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