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Erectile dysfunction in uremic dialysis patients: Diagnostic evaluation in the sildenafil era
ORGAN DYSFUNCTION IN UREMIA
Erectile Dysfunction in Uremic Dialysis Patients: Diagnostic Evaluation in the Sildenafil Era Guido Bellinghieri, MD, Domenico Santoro, MD, Bruno Lo Forti, MD, Agostino Mallamace, MD, Rosa Maria De Santo, PhD, and Vincenzo Savica, MD ● The two words that mean sexual dysfunction, impotence and erectile dysfunction (ED), express two different concepts. Impotence is a general male sexual dysfunction that includes libidinal, orgasmic, and ejaculatory dysfunction. ED is the inability to achieve or maintain an erection sufficient to allow satisfactory sexual intercourse and is part of the general male sexual dysfunction termed impotence that includes libidinal, orgasmic, and ejaculatory dysfunction. Uremic men of different ages report a variety of sexual problems, including sexual hormonal pattern alterations, reduction in or loss of libido, infertility, and impotence, conditioning their well-being status. In evaluating and treating sexual dysfunction, a nephrologist must consider factors involved in its pathogenesis, such as hypothalamic-pituitary-gonadal axis alterations, psychological problems related to chronic disease, secondary hyperparathyroidism, anemia, autonomic neuropathy, derangements in arterial supply or venous outflow, and the normal structure of cavernous body smooth muscle cells. The introduction of sildenafil to treat impotent patients has completely changed the approach to evaluating these subjects because this drug is considered an effective well-tolerated treatment for men with ED. In the past, we proposed an algorithm that gave the opportunity to explore the previously mentioned factors using such instrumental interventions as the nocturnal penile tumescence test, penile echo color Doppler, nervous conduction velocity, and cavernous body biopsy, addressed to prescribe needed surgical or medical interventions. The complexity of the proposed algorithm requires many diagnostic procedures and much time and economic resources to localize the pathological lesions responsible for ED. Because of the new oral drug sildenafil, we propose a new algorithm to test the possibility of obtaining an erection and classify patients as responders or nonresponders to the sildenafil test. © 2001 by the National Kidney Foundation, Inc. INDEX WORDS: Impotence; diagnosis; sildenafil; dialysis; algorithm.
U
NTIL THE 20th century, sex, bounded by cultural, religious, and legal factors, was a private issue, and publications about sexual behavior were rare. This has changed over the past 15 to 20 years, and recent interest in the topic has escalated rapidly as a result of media coverage.1 The two words that mean sexual dysfunction, impotence and erectile dysfunction (ED), express two different concepts. Impotence is a general male sexual dysfunction that includes libidinal, orgasmic, and ejaculatory dysfunction. ED is the inability to achieve or maintain an erection sufficient to allow satisfactory sexual intercourse and is part of the general male sexual dysfunction termed impotence, which includes libidinal, orgasmic, and ejaculatory dysfunction.2 Sexual dysfunction is a common and often distressing side effect of renal failure. Uremic men of different ages report a variety of sexual problems, including sexual hormonal pattern alterations, reduction in or loss of libido, infertility, and impotence, conditioning their well-being status. The pathogenesis of ED includes physiological, psychological, and organic causes. For this
reason, careful assessment is required to determine the nature of the problem to prescribe the most effective treatment.3 Sexual function, as an integrated part of quality of life and the rehabilitation program, requires a careful approach to the patient to obtain a good level of compliance. In evaluating and treating sexual dysfunction, a nephrologist must consider factors involved in the pathogenesis, such as hypothalamic-pituitarygonadal axis alterations, psychological problems related to chronic disease, secondary hyperparathyroidism, anemia, autonomic neuropathy, derangements in arterial supply or venous outflow, and the normal structure of cavernous body smooth muscle cells.4 The most common impotence-related risk factors are diabetes, hypertension, and smoking. Moderately common are corFrom the Divisions of Nephrology and Surgery, University of Messina, Italy. Address reprint requests to Guido Bellinghieri, MD, Viale Regina Margherita 69, 98100 Messina, Italy. E-mail: [email protected] © 2001 by the National Kidney Foundation, Inc. 0272-6386/01/3804-0122$35.00/0 doi:10.1053/ajkd.2001.27417
American Journal of Kidney Diseases, Vol 38, No 4, Suppl 1 (October), 2001: pp S115-S117
S115
S116
onary artery disease, peripheral vascular disease, alcohol abuse, multiple medications, anxiety or depression, relationship problems, and hormonal abnormalities.5 Impotence can also be accentuated by various pharmacological agents, including antihypertensives and antidepressants. In the Massachusetts Male Aging Studies, ED was associated with three treated medical conditions: diabetes, hypertension, and heart disease. As many as 25% of cases of ED may be attributable to medications administered to treat a concomitant illness, especially arterial hypertension.6 Physicians need to ask patients about sexual function and discuss the possibility of ED caused by antihypertensive therapy. The association between hypertension and ED is well known, but the effects of the disease per se are difficult to distinguish from effects of antihypertensive drugs. The most common antihypertensive drugs that may produce ED are diuretics (thiazides and spironolactone), alpha-methyldopa, clonidine, reserpine, -blockers, and verapamil. Alpha-methyldopa and reserpine induce ED through an increase in prolactin levels. The other antihypertensive drugs most likely cause ED by reducing blood pressure to less than the critical level necessary to maintain sufficient blood flow for a penile erection, especially with an atherosclerotic artery.7 Cardiovascular diseases can influence sexual performance through many mechanisms. ED is present in 45% of men after myocardial infarction, but the same prevalence is present in men before cardiac accidents. Psychological factors can have an important role in this type of ED because men can be afraid to have sexual intercourse with their partners.8 A detailed medical history of impotence can provide useful information during the initial evaluation of a patient with impotence. A history of normal erection function before the development of renal failure suggests a secondary cause of impotence. Symptoms or physical findings of neuropathy, such as neurogenic bladder, can suggest a neurogenic cause. Similarly, symptoms or signs of peripheral vascular disease may indicate the presence of vascular obstruction. It also is important to look for the presence of such secondary sexual characteristics as facial, axillary, and pubic hair; the lack of these signs can indicate primary or secondary hypogonadism.9 Psychoso-
BELLINGHIERI ET AL
cial factors should be studied, including evaluation of the partner’s perceptions and expectations, to identify causative or contributory issues and guide decisions regarding further diagnostic procedures and treatment. Because impotence is a functional disorder and not a life-threatening disease, further diagnostic tests can be performed according to the treatment desired by the patient and the patient’s goal for therapy. Most patients will initially choose noninvasive therapy with a vacuum constriction device or pharmacological injections, although intracavernous injection of a vasodilatator agent, such as prostaglandin E1 (PGE1), can be of value in ruling out significant vascular problems and predicting the response to intracavernous injection therapy.10 Nocturnal penile tumescence (NPT) testing is not routinely indicated because of limitations in diagnostic accuracy and the lack of reliable normative data, but NPT testing may be of value in confirming ED primarily caused by psychogenic factors. The assumption is that a man with a psychological cause of impotence would still experience erections while asleep, whereas the absence of an adequate erection would make an organic cause more likely.9 Further diagnostic testing (eg, cavernosometry, duplex ultrasonography, penile angiography, and nerve conduction) to determine the presence of vasculogenic or neurogenic causes may be considered for patients for whom noninvasive therapies have failed and who are willing to consider vascular surgery or a penile prosthesis. Because the clinical value of these invasive studies is uncertain and the long-term effectiveness of vascular surgery or a penile prosthesis is low, this approach should be reserved for carefully screened and informed patients.10 The introduction of sildenafil as therapy for impotent patients has completely changed the approach to evaluating these subjects because this drug is considered an effective well-tolerated treatment for men with ED.11 In the past, we proposed an algorithm that gave the opportunity to explore the previously mentioned factors using some instrumental interventions, such as the NPT test, penile echo color Doppler, nervous conduction velocity, or cavernous body biopsy, addressed to prescribe needed surgical or medical interventions.3 This last approach includes not only the well-known drugs used to normalize
NEW ALGORITHM FOR IMPOTENCE IN DIALYSIS PATIENTS
S117
ers or nonresponders to the sildenafil test (Fig 1). In nonresponders, it is necessary to explore other factors (hormonal, psychological, neurological, vascular, cavernous body alteration, or particular drugs) involved in inducing or maintaining the ED, as shown in Fig 1. REFERENCES
Fig 1. New diagnostic therapeutic algorithm for the evaluation of ED. Abbreviation: Hb, hemoglobin.
serum prolactin levels (bromocriptine) or restore testosterone serum levels, but also specific drugs able to normalize the low hemoglobin serum concentration (erythropoietin, iron, folic acid) or locally enhance the synthesis (PGE1) or reduce the catabolism of nitric oxide (sildenafil), the main factors in starting or maintaining an erection.10 The complexity of the proposed algorithm requires many diagnostic procedures and much time and economic resources to localize the pathological lesions responsible for the ED. Because of the new oral drug sildenafil, we propose a new algorithm to test the possibility of obtaining an erection and classify patients as respond-
1. Guay AT: Erectile dysfunction: Are you prepared to discuss it? Postgrad Med 97:127-143, 1995 2. Korenman SG: Advances in the understanding and management of erectile dysfunction. J Clin Endocrinol Metab 60:1985-1988, 1995 3. Massry SG, Bellinghieri G: Sexual dysfunction, in Massry SG, Glassock RJ (eds): Textbook of Nephrology (ed 3). Baltimore, MD, William & Wilkins, 1995, pp 1416-1421 4. Kaufman JM, Hatzichristolou DG, Mulhall JP, Fitch WP, Goldstein I: Impotence and chronic renal failure: A study of the hemodynamic pathophysiology. J Urol 151:612618, 1994 5. Spector IP, Carey MP: Incidence and prevalence of the sexual dysfunction: A critical review of the empirical literature. Arch Sex Behav 19:389-408, 1990 6. Feldman HA, Johannes CB, Derby CA, Kleinman KP, Mohr BA, Araujo AB, McKinlay JB: Erectile dysfunction and coronary risk factors: Prospective results from the Massachusetts Male Aging Study. Prev Med 30:328-338, 2000 7. Barksdale JD, Gardner SF: The impact of first-line antihypertensive drugs on erectile dysfunction. Pharmacotherapy 19:573-581, 1999 8. Feldman HA, Goldstein I, Hatzichristou D, Krane RJ, McKinlay JB: Impotence and its medical and psychological correlates: Result from the Massachusetts Male Aging Study. J Urol 151:54-61, 1994 9. Palmer BF: Sexual dysfunction in uremia. J Am Soc Nephrol 10:1381-1388, 1999 10. Jackson S, Lue T: Erectile dysfunction: Therapy health outcomes. Urology 51:874-882, 1998 11. Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA, for the Sildenafil Study Group: Oral sildenafil in the treatment of erectile dysfunction. N Engl J Med 338:1397-1404, 1998
Erectile Dysfunction in Uremic Dialysis Patients: Diagnostic Evaluation in the Sildenafil Era Guido Bellinghieri, MD, Domenico Santoro, MD, Bruno Lo Forti, MD, Agostino Mallamace, MD, Rosa Maria De Santo, PhD, and Vincenzo Savica, MD ● The two words that mean sexual dysfunction, impotence and erectile dysfunction (ED), express two different concepts. Impotence is a general male sexual dysfunction that includes libidinal, orgasmic, and ejaculatory dysfunction. ED is the inability to achieve or maintain an erection sufficient to allow satisfactory sexual intercourse and is part of the general male sexual dysfunction termed impotence that includes libidinal, orgasmic, and ejaculatory dysfunction. Uremic men of different ages report a variety of sexual problems, including sexual hormonal pattern alterations, reduction in or loss of libido, infertility, and impotence, conditioning their well-being status. In evaluating and treating sexual dysfunction, a nephrologist must consider factors involved in its pathogenesis, such as hypothalamic-pituitary-gonadal axis alterations, psychological problems related to chronic disease, secondary hyperparathyroidism, anemia, autonomic neuropathy, derangements in arterial supply or venous outflow, and the normal structure of cavernous body smooth muscle cells. The introduction of sildenafil to treat impotent patients has completely changed the approach to evaluating these subjects because this drug is considered an effective well-tolerated treatment for men with ED. In the past, we proposed an algorithm that gave the opportunity to explore the previously mentioned factors using such instrumental interventions as the nocturnal penile tumescence test, penile echo color Doppler, nervous conduction velocity, and cavernous body biopsy, addressed to prescribe needed surgical or medical interventions. The complexity of the proposed algorithm requires many diagnostic procedures and much time and economic resources to localize the pathological lesions responsible for ED. Because of the new oral drug sildenafil, we propose a new algorithm to test the possibility of obtaining an erection and classify patients as responders or nonresponders to the sildenafil test. © 2001 by the National Kidney Foundation, Inc. INDEX WORDS: Impotence; diagnosis; sildenafil; dialysis; algorithm.
U
NTIL THE 20th century, sex, bounded by cultural, religious, and legal factors, was a private issue, and publications about sexual behavior were rare. This has changed over the past 15 to 20 years, and recent interest in the topic has escalated rapidly as a result of media coverage.1 The two words that mean sexual dysfunction, impotence and erectile dysfunction (ED), express two different concepts. Impotence is a general male sexual dysfunction that includes libidinal, orgasmic, and ejaculatory dysfunction. ED is the inability to achieve or maintain an erection sufficient to allow satisfactory sexual intercourse and is part of the general male sexual dysfunction termed impotence, which includes libidinal, orgasmic, and ejaculatory dysfunction.2 Sexual dysfunction is a common and often distressing side effect of renal failure. Uremic men of different ages report a variety of sexual problems, including sexual hormonal pattern alterations, reduction in or loss of libido, infertility, and impotence, conditioning their well-being status. The pathogenesis of ED includes physiological, psychological, and organic causes. For this
reason, careful assessment is required to determine the nature of the problem to prescribe the most effective treatment.3 Sexual function, as an integrated part of quality of life and the rehabilitation program, requires a careful approach to the patient to obtain a good level of compliance. In evaluating and treating sexual dysfunction, a nephrologist must consider factors involved in the pathogenesis, such as hypothalamic-pituitarygonadal axis alterations, psychological problems related to chronic disease, secondary hyperparathyroidism, anemia, autonomic neuropathy, derangements in arterial supply or venous outflow, and the normal structure of cavernous body smooth muscle cells.4 The most common impotence-related risk factors are diabetes, hypertension, and smoking. Moderately common are corFrom the Divisions of Nephrology and Surgery, University of Messina, Italy. Address reprint requests to Guido Bellinghieri, MD, Viale Regina Margherita 69, 98100 Messina, Italy. E-mail: [email protected] © 2001 by the National Kidney Foundation, Inc. 0272-6386/01/3804-0122$35.00/0 doi:10.1053/ajkd.2001.27417
American Journal of Kidney Diseases, Vol 38, No 4, Suppl 1 (October), 2001: pp S115-S117
S115
S116
onary artery disease, peripheral vascular disease, alcohol abuse, multiple medications, anxiety or depression, relationship problems, and hormonal abnormalities.5 Impotence can also be accentuated by various pharmacological agents, including antihypertensives and antidepressants. In the Massachusetts Male Aging Studies, ED was associated with three treated medical conditions: diabetes, hypertension, and heart disease. As many as 25% of cases of ED may be attributable to medications administered to treat a concomitant illness, especially arterial hypertension.6 Physicians need to ask patients about sexual function and discuss the possibility of ED caused by antihypertensive therapy. The association between hypertension and ED is well known, but the effects of the disease per se are difficult to distinguish from effects of antihypertensive drugs. The most common antihypertensive drugs that may produce ED are diuretics (thiazides and spironolactone), alpha-methyldopa, clonidine, reserpine, -blockers, and verapamil. Alpha-methyldopa and reserpine induce ED through an increase in prolactin levels. The other antihypertensive drugs most likely cause ED by reducing blood pressure to less than the critical level necessary to maintain sufficient blood flow for a penile erection, especially with an atherosclerotic artery.7 Cardiovascular diseases can influence sexual performance through many mechanisms. ED is present in 45% of men after myocardial infarction, but the same prevalence is present in men before cardiac accidents. Psychological factors can have an important role in this type of ED because men can be afraid to have sexual intercourse with their partners.8 A detailed medical history of impotence can provide useful information during the initial evaluation of a patient with impotence. A history of normal erection function before the development of renal failure suggests a secondary cause of impotence. Symptoms or physical findings of neuropathy, such as neurogenic bladder, can suggest a neurogenic cause. Similarly, symptoms or signs of peripheral vascular disease may indicate the presence of vascular obstruction. It also is important to look for the presence of such secondary sexual characteristics as facial, axillary, and pubic hair; the lack of these signs can indicate primary or secondary hypogonadism.9 Psychoso-
BELLINGHIERI ET AL
cial factors should be studied, including evaluation of the partner’s perceptions and expectations, to identify causative or contributory issues and guide decisions regarding further diagnostic procedures and treatment. Because impotence is a functional disorder and not a life-threatening disease, further diagnostic tests can be performed according to the treatment desired by the patient and the patient’s goal for therapy. Most patients will initially choose noninvasive therapy with a vacuum constriction device or pharmacological injections, although intracavernous injection of a vasodilatator agent, such as prostaglandin E1 (PGE1), can be of value in ruling out significant vascular problems and predicting the response to intracavernous injection therapy.10 Nocturnal penile tumescence (NPT) testing is not routinely indicated because of limitations in diagnostic accuracy and the lack of reliable normative data, but NPT testing may be of value in confirming ED primarily caused by psychogenic factors. The assumption is that a man with a psychological cause of impotence would still experience erections while asleep, whereas the absence of an adequate erection would make an organic cause more likely.9 Further diagnostic testing (eg, cavernosometry, duplex ultrasonography, penile angiography, and nerve conduction) to determine the presence of vasculogenic or neurogenic causes may be considered for patients for whom noninvasive therapies have failed and who are willing to consider vascular surgery or a penile prosthesis. Because the clinical value of these invasive studies is uncertain and the long-term effectiveness of vascular surgery or a penile prosthesis is low, this approach should be reserved for carefully screened and informed patients.10 The introduction of sildenafil as therapy for impotent patients has completely changed the approach to evaluating these subjects because this drug is considered an effective well-tolerated treatment for men with ED.11 In the past, we proposed an algorithm that gave the opportunity to explore the previously mentioned factors using some instrumental interventions, such as the NPT test, penile echo color Doppler, nervous conduction velocity, or cavernous body biopsy, addressed to prescribe needed surgical or medical interventions.3 This last approach includes not only the well-known drugs used to normalize
NEW ALGORITHM FOR IMPOTENCE IN DIALYSIS PATIENTS
S117
ers or nonresponders to the sildenafil test (Fig 1). In nonresponders, it is necessary to explore other factors (hormonal, psychological, neurological, vascular, cavernous body alteration, or particular drugs) involved in inducing or maintaining the ED, as shown in Fig 1. REFERENCES
Fig 1. New diagnostic therapeutic algorithm for the evaluation of ED. Abbreviation: Hb, hemoglobin.
serum prolactin levels (bromocriptine) or restore testosterone serum levels, but also specific drugs able to normalize the low hemoglobin serum concentration (erythropoietin, iron, folic acid) or locally enhance the synthesis (PGE1) or reduce the catabolism of nitric oxide (sildenafil), the main factors in starting or maintaining an erection.10 The complexity of the proposed algorithm requires many diagnostic procedures and much time and economic resources to localize the pathological lesions responsible for the ED. Because of the new oral drug sildenafil, we propose a new algorithm to test the possibility of obtaining an erection and classify patients as respond-
1. Guay AT: Erectile dysfunction: Are you prepared to discuss it? Postgrad Med 97:127-143, 1995 2. Korenman SG: Advances in the understanding and management of erectile dysfunction. J Clin Endocrinol Metab 60:1985-1988, 1995 3. Massry SG, Bellinghieri G: Sexual dysfunction, in Massry SG, Glassock RJ (eds): Textbook of Nephrology (ed 3). Baltimore, MD, William & Wilkins, 1995, pp 1416-1421 4. Kaufman JM, Hatzichristolou DG, Mulhall JP, Fitch WP, Goldstein I: Impotence and chronic renal failure: A study of the hemodynamic pathophysiology. J Urol 151:612618, 1994 5. Spector IP, Carey MP: Incidence and prevalence of the sexual dysfunction: A critical review of the empirical literature. Arch Sex Behav 19:389-408, 1990 6. Feldman HA, Johannes CB, Derby CA, Kleinman KP, Mohr BA, Araujo AB, McKinlay JB: Erectile dysfunction and coronary risk factors: Prospective results from the Massachusetts Male Aging Study. Prev Med 30:328-338, 2000 7. Barksdale JD, Gardner SF: The impact of first-line antihypertensive drugs on erectile dysfunction. Pharmacotherapy 19:573-581, 1999 8. Feldman HA, Goldstein I, Hatzichristou D, Krane RJ, McKinlay JB: Impotence and its medical and psychological correlates: Result from the Massachusetts Male Aging Study. J Urol 151:54-61, 1994 9. Palmer BF: Sexual dysfunction in uremia. J Am Soc Nephrol 10:1381-1388, 1999 10. Jackson S, Lue T: Erectile dysfunction: Therapy health outcomes. Urology 51:874-882, 1998 11. Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA, for the Sildenafil Study Group: Oral sildenafil in the treatment of erectile dysfunction. N Engl J Med 338:1397-1404, 1998