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Risk Factors for Erectile Dysfunction in Men With HTLV-1
ORIGINAL RESEARCH
EPIDEMIOLOGY & RISK FACTORS
Risk Factors for Erectile Dysfunction in Men With HTLV-1 Cassius José Vitor de Oliveira, MD,1,2 José Abraão Carneiro Neto, MD,1,2 Rosana C. P. Andrade, PhD,2,3 Paulo Novis Rocha, MD, PhD,4 and Edgar Marcelino de Carvalho Filho, MD, PhD2,4,5,6
ABSTRACT
Background: Erectile dysfunction (ED) occurs in more than 50% of patients with human T-cell lymphotropic virus type 1 (HTLV-1) infection. In the general population, atherosclerosis is the main risk factor related to ED. Aim: To compare the contribution of neurologic disorders from HTLV-1 with that of atherosclerosis as risk factors for ED in men with HTLV-1. Methods: In this cross-sectional study, men 18 to 70 years old with HTLV-1 were classified into one of two groups according to the presence or absence of ED. They were compared for obesity, waist circumference, dyslipidemia, metabolic syndrome, diabetes mellitus, high blood pressure, and neurologic manifestations. Comparisons between proportions were performed using the c2 or Fisher exact test. Logistic regression analysis was performed to identify predictors of ED. Subjects with HTLV-1 were classified into three groups based on Osame’s Disability Motor Scale and the Expanded Disability Status Scale: (i) HTLV-1 carriers; (ii) probable HTLV-1eassociated myelopathy or tropical spastic paraparesis; and (iii) definitive HTLV-1eassociated myelopathy or tropical spastic paraparesis. The International Index of Erectile Function was used to determine the degree of ED. Results: In univariate logistic regression, age older 60 years (P ¼ .003), diabetes mellitus (P ¼ .042), and neurologic disease (P < .001) were associated with ED. In the multivariate model, the odds of ED was highest in patients with neurologic disease (odds ratio ¼ 22.1, 95% CI ¼ 5.3e92.3), followed by high blood pressure (odds ratio ¼ 6.3, 95% CI ¼ 1.4-30.5) and age older than 60 years (odds ratio ¼ 4.6, 95% CI ¼ 1.3e17.3). Clinical Implications: In men infected with HTLV-1, neurologic dysfunction is a stronger predictor of ED than risk factors for atherosclerosis. Strengths and Limitations: The small number of patients limited the power of the statistical analysis, but clearly neurologic manifestations had a greater association with ED than risk factors for atherosclerosis, and there was no association between metabolic syndrome and severity of ED. Conclusion: Neurologic impairment is the major cause of ED in individuals infected with HTLV-1 and risk factors for atherosclerosis did not have a strong relation with ED in this population. de Oliveira CJV, Neto JAC, Andrade RCP, et al. Risk Factors for Erectile Dysfunction in Men With HTLV-1. J Sex Med 2017;14:1195e1200. Copyright 2017, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.
Key Words: Erectile Dysfunction; Human T-Lymphotropic Virus 1; Atherosclerosis; Neurologic Disease
INTRODUCTION Human T-cell lymphotropic virus type 1 (HTLV-1) was identified in 1980 and is the etiologic agent of HTLV-1e Received May 19, 2017. Accepted August 1, 2017.
associated myelopathy (HAM), also known as tropical spastic paraparesis (TSP), and of adult T-cell leukemia and lymphoma.1,2 It is estimated that approximately 5 to 10 million 4
Department of Medicine and Diagnostic Support, Federal University of Bahia School of Medicine, Salvador, Bahia, Brazil;
1
Postgraduate Program in Health Sciences, Federal University of Bahia School of Medicine, Salvador, Bahia, Brazil;
5
Instituto Gonçalo Moniz, Fiocruz, Salvador, Bahia, Brazil;
2
Immunology Service, University Hospital Professor Edgard Santos, Federal University of Bahia, Salvador, Bahia, Brazil;
6
3
Physical Therapy Department, University Hospital Professor Edgard Santos, Federal University of Bahia, Salvador, Bahia, Brazil;
Copyright ª 2017, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jsxm.2017.08.001
J Sex Med 2017;14:1195e1200
National Institute of Science and Technology in Tropical Diseases, CNPq/ MCT, Salvador, Bahia, Brazil
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people are infected by HTLV-1 worldwide, mainly in southwestern Japan, the Caribbean, Africa, and South and Central America.3 Only a minority of patients with HTLV-1 develop HAM/TSP, which is caused by an exaggerated inflammatory response and progressive demyelization of the spinal cord leading to low back pain, weakness of the lower limbs, hyperreflexia, and the Babinski sign.2,4,5 The disease typically progresses to the inability to walk because of a spastic paraparesis.2 However, a large percentage of infected patients who do not fulfill the diagnostic criteria for HAM/TSP can have neurologic symptoms, such as weakness of the inferior limbs, paresthesias, and sphincter disorders.6,7 Urinary symptoms, mainly of overactive bladder, occur in up to 100% of patients with HAM/TSP and is observed in approximately 20% of subjects with HTLV-1 who can be considered HTLV-1 carriers.6,8,9 Erectile dysfunction (ED) also has been observed in a large percentage of individuals infected with HTLV-1 with or without evidence of myelopathy. In a study evaluating the frequency of ED in HTLV-1 infection, it was found that ED was present in 35% of HTLV-1 carriers, in 79% of patients with probable HAM/TSP, and in 93.7% of patients with definitive HAM/TSP.9 Although there is a clear relation between ED and the degree of neurologic impairment in HTLV-1, ED also can occur in patients with HTLV-1 without neurologic disease.6,7,9 Actually ED is threefold higher in patients with HTLV-1 without HAM/TSP than in seronegative controls.6 Moreover, severe ED has been observed in young HTLV-1 carriers.9 In the general population, age, atherosclerosis, and diabetes mellitus (DM) are the most important risk factors for ED.10 Atherosclerosis leads to occlusive vessel phenomena that impair adequate blood flow to the penile arteries and microvessels of the cavernous bodies, resulting in ED.10e14 Atherosclerosis has been recognized as an inflammatory illness and HTLV-1 is associated with an exaggerated production of proinflammatory cytokines.15e19 Therefore, the exaggerated inflammatory response observed in HTLV-1 infection could contribute to atherosclerosis and, in consequence, ED. Because ED also is documented in individuals infected with HTLV-1 without evidence of neurologic damage, and atherosclerosis is the major cause of ED in the general population, we evaluated whether there was an association between ED and traditional risk factors for atherosclerosis, such as DM, high blood pressure (HBP), dyslipidemia, metabolic syndrome, and obesity in individuals infected with HTLV-1.
METHODS Study Design and Population This is a cross-sectional study conducted in the multidisciplinary HTLV-1 clinic of the Federal University of Bahia University Hospital (Bahia, Brazil). Patients were enrolled from January 2013 through June 2015. The inclusion criterion was a
de Oliveira et al
positive enzyme-linked immunoassay result for HTLV-1 confirmed by western blot. Exclusion criteria were age younger than 18 or older than 70 years, history of cancer, use of penile prosthesis, psychiatric disorders, and a motor deficit caused by other neurologic disorders. Patients were not using ED medications at the time of the study.
Evaluation of Neurologic Impairment and Clinical Forms of HTLV-1 Infection The degree of neurologic impairment of participants was evaluated by the Osame’s Disability Motor Scale (ODMS) and the Expanded Disability Status Scale (EDSS).2,20 Individuals with an ODMS score equal to 0 and an EDSS score equal to 0 were considered HTLV-1 carriers, or asymptomatic from a neurologic standpoint. Probable HAM/TSP was defined according to the Castro-Costa classification.21 These patients had an ODMS score equal to 0 and an EDSS score higher than 2. Patients with HAM/TSP had an ODMS score of at least 1 and an EDSS score of at least 3. Patients with probable or definitive HAM/TSP were considered to have neurologic disease associated with HTLV-1 infection. The five-item International Index of Erectile Function (IIEF-5) was used to evaluate the degree of ED.22 It is a self-applied questionnaire with scores ranging from 5 to 25. Individuals with an IIEF-5 score higher than 21 are considered to have normal erectile function (scores 5e7 ¼ severe ED, scores 8e11 ¼ moderate ED, scores 11e16 ¼ moderate to light ED, scores 17e21 ¼ light ED).
Definition of Atherosclerosis Risk Factors DM and HBP were defined by clinical history or documentation of a fasting blood sugar level higher than 125 mg/dL or higher than 175 mg/dL after a meal and blood pressure higher than 140 and 85 mm Hg, respectively.23,24 Hypercholesterolemia was defined as a total cholesterol level higher than 200 mg/dL, low high-density lipoprotein (HDL) cholesterol was defined as a level lower than 40 mg/dL, and high lowdensity lipoprotein (LDL) cholesterol was defined as a level higher than 150 mg/dL.25,26 Hypertriglyceridemia was defined as a triglyceride level higher than 150 mg/dL in blood collected after 10 to 12 hours of fasting.25,26 Overweight and obesity were determined by body mass index (BMI) and waist circumference.26,27 Waist circumference was measured between the iliac crest and the bottom-most rib with the individual in the standing position. Increased waist circumference was defined as larger than 102 cm.26 BMI was calculated by dividing the patient’s weight (kilograms) by the square of height (meters). Values from 18.5 to 24.9 kg/m2 were considered normal, those from 25.0 to 29.9 kg/m2 were considered overweight, and those above 30 kg/m2 were considered obesity.26 Metabolic syndrome was defined by the presence of three of the following five criteria: HBP; increased abdominal fat (abdominal circumference > 102 cm in men); serum HDL cholesterol level lower than 40 mg/dL; serum fasting glucose J Sex Med 2017;14:1195e1200
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Risk Factors for ED in HTLV-1
Table 1. Demographic, clinical, and laboratory data from 84 subjects with HTLV-1 infection stratified by presence or absence of ED
Table 2. Risk factors for ED in 84 subjects with HTLV-1 infection by univariate logistic regression 95% CI
ED, n (%) Variables
Yes (n ¼ 43)
No (n ¼ 41)
P value
Age (y) .003 <60 23 (53.5) 35 (85.4) 60 20 (46.5) 6 (14.6) Clinic forms of HTLV-1 infection <.001 Asymptomatic 18 (41.9) 37 (90.2) Probable HAM/TSP 11 (25.6) 2 (4.9) HAM/TSP 14 (32.6) 2 (4.9) Risk factors for atherosclerosis DM 8 (18.6) 1 (2.4) .03 HBP 16 (37.2) 8 (19.5) .12 High LDL cholesterol 10 (23.3) 8 (19.5) .87 Low HDL cholesterol 17 (39.5) 12 (29.3) .44 High triglycerides 15 (34.9) 10 (24.4) .41 Metabolic syndrome 11 (25.5) 4 (9.7) .08 Abdominal circumference 15 (34.9) 11 (26.8) .57 BMI .51 Low weight 2 (4.7) 0 (0.0) Normal 18 (41.9) 16 (39) Overweight 14 (32.6) 14 (34.1) Obesity 9 (20.9) 11 (26.8) BMI ¼ body mass index; DM ¼ diabetes mellitus; ED ¼ erectile dysfunction; HAM ¼ human T-cell lymphotropic virus type 1eassociated myelopathy; HBP ¼ high blood pressure; HDL ¼ high-density lipoprotein; HTLV-1 ¼ human T-cell lymphotropic virus type 1; LDL ¼ low-density lipoprotein; TSP ¼ tropical spastic paraparesis.
level higher than 100 mg/dL; and triglyceride level higher than 150 mg/dL.23,24
Ethical Issues This study was approved by the research ethics committee of the Federal University of Bahia University Hospital, and all patients provided a written informed consent.
Statistical Analysis Continuous variables were expressed as mean and SD and categorical variables were presented as absolute and relative frequencies. Patients were stratified into one of two groups according to the presence or absence of ED. The Student t-test was used to compare means and the c2 or Fisher exact test, as indicated, was used to compare proportions between groups. The Spearman correlation technique was used to evaluate the correlation between ED and the degree of neurologic impairment measured by the EDSS and between ED and obesity determined by the BMI. A binary logistic regression analysis was conducted to identify independent predictors of ED. The results were considered statistically significant at a P value less than 0.05 in the final analyses. All statistical analyses were performed using SPSS 17 (SPSS, Inc, Chicago, IL, USA). J Sex Med 2017;14:1195e1200
Independent variables
OR
Lower
Upper
P value
Age > 60 y DM HBP Metabolic syndrome Neurologic disease
5.07 9.14 2.44 3.18 12.84
1.76 1.08 0.90 0.92 3.88
14.54 76.76 6.57 10.96 42.49
.003 .042 .077 .067 .001
ED ¼ erectile dysfunction; DM ¼ diabetes mellitus; HBP ¼ high blood pressure; HTLV-1 ¼ human T-cell lymphotropic virus type 1; OR ¼ odds ratio.
RESULTS One hundred two men were evaluated and 18 were excluded; reasons for exclusion were age older than 70 years (n ¼ 11), cancer (n ¼ 2), inability to stay standing (n ¼ 2), penile prosthesis (n ¼ 2), and neurologic impairment from poliomyelitis (n ¼ 1). The mean age ± SD of the 84 participants was 54 ± 10.5 years, and the overall frequency of ED was 51.2%. Table 1 lists the demographic, clinical, and laboratory data of 84 subjects with HTLV-1 stratified by the presence or absence of ED. ED was associated with age older than 60 years, degree of neurologic involvement, and DM but not with HBP, high LDL cholesterol, low HDL cholesterol, high triglycerides, metabolic syndrome, or BMI. There also was no association between metabolic syndrome and severity of ED. Metabolic syndrome was observed in 34% of patients with light and moderate to light ED and in 25% of patients with severe ED. To further explore the risk factors for ED in subjects with HTLV-1, we conducted univariate and multivariate logistic regression analyses. On univariate analysis (Table 2), symptomatic HTLV-1 infection (patients with HAM/TSP or probable HAM/TSP) showed the greatest association with ED, followed by DM and age older than 60 years. Metabolic syndrome and HBP showed a trend but were not statistically significantly associated with ED. In multivariate analysis, symptomatic HTLV-1 infection remained the most important risk factor for ED (adjusted odds ratio ¼ 22.1, 95% ¼ CI 5.3e92.3), followed distantly by HBP (adjusted odds ratio ¼ 6.3, 95% CI ¼ 1.4e30.5), and age older than 60 years (adjusted odds ratio ¼ 4.6, 95% CI ¼ 1.3e17.3; Table 3). Because of the strong association between ED and neurologic manifestations of HTLV-1, we evaluated the risk factors for ED in 18 patients who did not have probable or definitive HAM/ TSP. Most (55.5%) were younger than 60 years, DM was documented in only three subjects (16.7%), metabolic syndrome and/or increased abdominal circumference were noted in five (27.8%), and obesity was noted in four (22.2%). In 9 of the 18 patients, there were no risk factors for atherosclerosis and no psychiatric or hormonal disorders that could explain the ED. Of these individuals, six had moderate ED and three had moderate to severe or severe ED.
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Table 3. Independent predictors of ED in 84 subjects with HTLV-1 infection by multivariate logistic regression model* 95% CI Independent variables
OR
Lower
Upper
P value
Age > 60 y HBP Neurologic disease
4.64 6.31 22.13
1.25 1.39 5.31
17.25 28.69 92.25
.022 .017 <.001
ED ¼ erectile dysfunction; HBP ¼ high blood pressure; HTLV-1 ¼ human T-cell lymphotropic virus type 1; OR ¼ odds ratio. *Five variables were entered in the single-step multivariate logistic regression model: age older than 60 years, HBP, diabetes mellitus, metabolic syndrome, and neurologic disease. The table presents only variables that achieved statistical significance.
DISCUSSION HAM/TSP is a severe disease caused by HTLV-1 but it occurs only in a small percentage of infected individuals.5 However, evidence accumulated in the past 10 years has indicated that a large percentage of individuals with HTLV-1 have other clinical manifestations, including ED.6e8 Indeed, a large percentage of individuals with HTLV-1 have moderate or severe ED.9 In this study, although we found that age, atherosclerosis, and DM could contribute to the ED observed in HTLV-1, the main cause of ED in these individuals was neurologic disease. Moreover, in half the subjects with HTLV-1 and ED but without evidence of neurologic disease, no other risk factor except HTLV-1 infection was documented. In a Brazilian study of individuals without HTLV-1, 52% of men 40 to 70 years old had some degree of ED.28 The pathophysiology of ED can be vascular, neurogenic, psychogenic, and endocrine.29 Erection is a vascular event and atherosclerosis is the main cause of ED.30 The prevalence of ED increases with age and in men older than 70 years the prevalence of ED is up to 80%.31 Atherosclerosis also increases with age and the risk factors for atherosclerosis, such as dyslipidemia, metabolic syndrome, obesity, DM, and HBP, are strongly associated with ED.32,33 In the present study, when the entire sample of subjects with HTLV-1 was evaluated for ED and risk factors for atherosclerosis, only DM was associated with ED. However, this association was found in only 10% of subjects. There was no association of ED with high LDL cholesterol, low HDL cholesterol, high triglycerides, abdominal circumference, or obesity. In the multivariate logistic regression model, the association between DM and ED disappeared. In this analysis, the occurrence of neurologic disease increased the odds of ED by 22 times, whereas HBP and age older than 60 years increased those odds by 6.3 and 4.6 times, respectively. This reinforces the findings of a previous study linking ED with the degree of neurologic manifestations in HTLV-1.9 It has been estimated that in the general population only 10% to 19% of ED is neurogenic, but in HTLV-1 infection up to 95% of patients who have definitive or probable HAM/TSP have
ED.9,34 However, a large number of patients with HTLV-1 considered HTLV-1 carriers have ED.6 The main pathologic finding in patients with HAM/TSP is degeneration of the white matter in the lateral column of the thoracic spine. It is not clear why patients might only present ED or urologic manifestations of a neurogenic bladder, but it is known that only 1.7% of subjects with HTLV-1 who have these manifestations progress to HAM/TSP.5 These data emphasize the necessity of better understanding the pathogenesis of ED and other urologic manifestations in patients with HTLV-1 who do not fulfill the criteria for HAM/TSP. It is likely that the inflammatory response and damage of the spinal cord that cause neurogenic bladder or ED do not progress to induce more severe neurologic damage as observed in HAM/TSP. Studies using magnetic resonance imaging of the lumbar and sacral medullae and electromyography are in progress and could explain the occurrence of ED in HTLV-1 carriers in the absence of apparent neurologic disease, risk factors for atherosclerosis, psychiatric disease, or hormonal disorders. An important limitation of the present study is the small sample, which makes the estimates imprecise. However, the statistically significant associations reported are valid and emphasize the importance of neurologic disease as an important cause of ED in patients with HTLV-1. Although we found that age, atherosclerosis, and HBP can contribute to ED in this population, neurologic damage by the viral infection is the most important risk factor for ED in patients with HTLV-1. Moreover, we speculate that ED could be the unique or first manifestation of neurologic disease related to HTLV-1.
ACKNOWLEDGMENTS We thank Cristiano Franco, Glória Orge, Lúcia Passos, and the student Victor Hugo for their contribution in the preparation of this article. Corresponding Author: Edgar Marcelino de Carvalho Filho, MD, PhD, Immunology Service, University Hospital Professor Edgard Santos, Federal University of Bahia, 5o andar, Rua João das Botas, s/n, Canela, 40110060, Salvador, Bahia, Brazil. Tel: 55-71-3245-5493; Fax: 55-71-3245-7110; E-mail: imuno@ ufba.br Conflicts of Interest: The authors report no conflicts of interest. Funding: This study was funded by Brazilian National Research Council (CNPq).
STATEMENT OF AUTHORSHIP Category 1 (a) Conception and Design Cassius José Vitor de Oliveira; José Abraão Carneiro Neto; Rosana C. P. Andrade; Paulo Novis Rocha; Edgar Marcelino de Carvalho Filho J Sex Med 2017;14:1195e1200
Risk Factors for ED in HTLV-1 (b) Acquisition of Data Cassius José Vitor de Oliveira; José Abraão Carneiro Neto; Rosana C. P. Andrade; Paulo Novis Rocha; Edgar Marcelino de Carvalho Filho (c) Analysis and Interpretation of Data Cassius José Vitor de Oliveira; José Abraão Carneiro Neto; Rosana C. P. Andrade; Paulo Novis Rocha; Edgar Marcelino de Carvalho Filho Category 2 (a) Drafting the Article Cassius José Vitor de Oliveira; José Abraão Carneiro Neto; Rosana C. P. Andrade; Paulo Novis Rocha; Edgar Marcelino de Carvalho Filho (b) Revising It for Intellectual Content Cassius José Vitor de Oliveira; José Abraão Carneiro Neto; Rosana C. P. Andrade; Paulo Novis Rocha; Edgar Marcelino de Carvalho Filho Category 3 (a) Final Approval of the Completed Article Cassius José Vitor de Oliveira; José Abraão Carneiro Neto; Rosana C. P. Andrade; Paulo Novis Rocha; Edgar Marcelino de Carvalho Filho
REFERENCES 1. Poiesz BJ, Ruscetti FW, Gazdar AF, et al. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci U S A 1980;77:7415-7419. 2. Osame M, Usuku K, Izumo S, et al. HTLV-I associated myelopathy, a new clinical entity. Lancet 1986;1:1031-1032. 3. Gessain A, Cassar O. Epidemiological aspects and world distribution of HTLV-1 Infection. Front Microbiol 2012;3:388. 4. Araujo A, Lima MA, Silva MT. Human T-lymphotropic virus 1 neurologic disease. Curr Treat Options Neurol 2008;10: 193-200. 5. Tanajura D, Castro N, Oliveira P, et al. Neurological manifestations in human T-cell lymphotropic virus type 1 (HTLV-1)e infected individuals without HTLV-1eassociated myelopathy/ tropical spastic paraparesis: a longitudinal cohort study. Clin Infect Dis 2015;61:49-56. 6. Caskey MF, Morgan DJ, Porto AF, et al. Clinical manifestations associated with HTLV type I infection: a cross-sectional study. AIDS Res Hum Retroviruses 2007;23:365-371. 7. Poetker SK, Porto AF, Giozza SP, et al. Clinical manifestations in individuals with recent diagnosis of HTLV type I infection. J Clin Virol 2011;51:54-58.
1199 11. Katsiki N, Wierzbicki AS, Mikhailidis DP. Erectile dysfunction and coronary heart disease. Curr Opin Cardiol 2015;30: 416-421. 12. Junuzovic D, Mehmedbasic S. [Erectile dysfunction—incidence, causes and risk factors]. Med Arh 2004;58:35-38 [in Bosnian]. 13. Golijanin D, Singer E, Davis R, et al. Doppler evaluation of erectile dysfunction—part 1. Int J Impot Res 2007;19:37-42. 14. Golijanin D, Singer E, Davis R, et al. Doppler evaluation of erectile dysfunction—part 2. Int J Impot Res 2007;19:43-48. 15. Yudkin JS, Stehouwer CD, Emeis JJ, et al. C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arterioscler Thromb Vasc Biol 1999;19:972-978. 16. Ziccardi P, Nappo F, Giugliano G, et al. Reduction of inflammatory cytokine concentrations and improvement of endothelial functions in obese women after weight loss over one year. Circulation 2002;105:804-809. 17. Starling AL, Coelho-Dos-Reis JG, Peruhype-Magalhaes V, et al. Immunological signature of the different clinical stages of the HTLV-1 infection: establishing serum biomarkers for HTLV-1eassociated disease morbidity. Biomarkers 2015; 20:502-512. 18. Nascimento MC, Primo J, Bittencourt A, et al. Infective dermatitis has similar immunological features to human T lymphotropic virus-type 1eassociated myelopathy/tropical spastic paraparesis. Clin Exp Immunol 2009;156:455-462. 19. Santos SB, Oliveira P, Luna T, et al. Immunological and viral features in patients with overactive bladder associated with human T-cell lymphotropic virus type 1 infection. J Med Virol 2012;84:1809-1817. 20. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983; 33:1444-1452. 21. De Castro-Costa CM, Araujo AQ, Barreto MM, et al. Proposal for diagnostic criteria of tropical spastic paraparesis/HTLV-Ie associated myelopathy (TSP/HAM). AIDS Res Hum Retroviruses 2006;22:931-935. 22. Rosen RC, Cappelleri JC, Smith MD, et al. Development and evaluation of an abridged, 5-item version of the International Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction. Int J Impot Res 1999;11:319-326. 23. Genuth S, Alberti KG, Bennett P, et al. Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care 2003;26: 3160-3167.
8. Castro NM, Rodrigues W Jr, Freitas DM, et al. Urinary symptoms associated with human T-cell lymphotropic virus type I infection: evidence of urinary manifestations in large group of HTLV-I carriers. Urology 2007;69:813-818.
24. Mancia G, De Backer G, Dominiczak A, et al. 2007 Guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007;25:1105-1187.
9. Oliveira P, Castro NM, Muniz AL, et al. Prevalence of erectile dysfunction in HTLV-1einfected patients and its association with overactive bladder. Urology 2010;75:1100-1103.
25. Sanjay S, Bharti GS, Manish G, et al. Metabolic syndrome: an independent risk factor for erectile dysfunction. Indian J Endocrinol Metab 2015;19:277-282.
10. Sullivan ME, Keoghane SR, Miller MA. Vascular risk factors and erectile dysfunction. BJU Int 2001;87:838-845.
26. Alberti KG, Zimmet P, Shaw J. Metabolic syndrome—a new world-wide definition. A consensus statement from the
J Sex Med 2017;14:1195e1200
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de Oliveira et al
International Diabetes Federation. Diabet Med 2006;23: 469-480.
31. Kubin M, Wagner G, Fugl-Meyer AR. Epidemiology of erectile dysfunction. Int J Impot Res 2003;15:63-71.
27. World Health Organization (WHO). Global Health Observatory (GHO). Available at: http://www.who.int/gho/ncd/risk_factors/ overweight/en/. Published 2014. Accessed August 14, 2017.
32. El-Sakka AI, Morsy AM, Fagih BI, et al. Coronary artery risk factors in patients with erectile dysfunction. J Urol 2004; 172:251-254.
28. Moreira ED Jr, Abdo CH, Torres EB, et al. Prevalence and correlates of erectile dysfunction: results of the Brazilian Study of Sexual Behavior. Urology 2001;58:583-588. 29. Melman A, Gingell JC. The epidemiology and pathophysiology of erectile dysfunction. J Urol 1999;161:5-11.
33. Feldman HA, Johannes CB, Derby CA, et al. Erectile dysfunction and coronary risk factors: prospective results from the Massachusetts Male Aging Study. Prev Med 2000; 30:328-338.
30. Pastuszak AW. Current diagnosis and management of erectile dysfunction. Curr Sex Health Rep 2014;6:164-176.
34. Nehra A, Moreland RB. Neurologic erectile dysfunction. Urol Clin North Am 2001;28:289-308.
J Sex Med 2017;14:1195e1200
EPIDEMIOLOGY & RISK FACTORS
Risk Factors for Erectile Dysfunction in Men With HTLV-1 Cassius José Vitor de Oliveira, MD,1,2 José Abraão Carneiro Neto, MD,1,2 Rosana C. P. Andrade, PhD,2,3 Paulo Novis Rocha, MD, PhD,4 and Edgar Marcelino de Carvalho Filho, MD, PhD2,4,5,6
ABSTRACT
Background: Erectile dysfunction (ED) occurs in more than 50% of patients with human T-cell lymphotropic virus type 1 (HTLV-1) infection. In the general population, atherosclerosis is the main risk factor related to ED. Aim: To compare the contribution of neurologic disorders from HTLV-1 with that of atherosclerosis as risk factors for ED in men with HTLV-1. Methods: In this cross-sectional study, men 18 to 70 years old with HTLV-1 were classified into one of two groups according to the presence or absence of ED. They were compared for obesity, waist circumference, dyslipidemia, metabolic syndrome, diabetes mellitus, high blood pressure, and neurologic manifestations. Comparisons between proportions were performed using the c2 or Fisher exact test. Logistic regression analysis was performed to identify predictors of ED. Subjects with HTLV-1 were classified into three groups based on Osame’s Disability Motor Scale and the Expanded Disability Status Scale: (i) HTLV-1 carriers; (ii) probable HTLV-1eassociated myelopathy or tropical spastic paraparesis; and (iii) definitive HTLV-1eassociated myelopathy or tropical spastic paraparesis. The International Index of Erectile Function was used to determine the degree of ED. Results: In univariate logistic regression, age older 60 years (P ¼ .003), diabetes mellitus (P ¼ .042), and neurologic disease (P < .001) were associated with ED. In the multivariate model, the odds of ED was highest in patients with neurologic disease (odds ratio ¼ 22.1, 95% CI ¼ 5.3e92.3), followed by high blood pressure (odds ratio ¼ 6.3, 95% CI ¼ 1.4-30.5) and age older than 60 years (odds ratio ¼ 4.6, 95% CI ¼ 1.3e17.3). Clinical Implications: In men infected with HTLV-1, neurologic dysfunction is a stronger predictor of ED than risk factors for atherosclerosis. Strengths and Limitations: The small number of patients limited the power of the statistical analysis, but clearly neurologic manifestations had a greater association with ED than risk factors for atherosclerosis, and there was no association between metabolic syndrome and severity of ED. Conclusion: Neurologic impairment is the major cause of ED in individuals infected with HTLV-1 and risk factors for atherosclerosis did not have a strong relation with ED in this population. de Oliveira CJV, Neto JAC, Andrade RCP, et al. Risk Factors for Erectile Dysfunction in Men With HTLV-1. J Sex Med 2017;14:1195e1200. Copyright 2017, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.
Key Words: Erectile Dysfunction; Human T-Lymphotropic Virus 1; Atherosclerosis; Neurologic Disease
INTRODUCTION Human T-cell lymphotropic virus type 1 (HTLV-1) was identified in 1980 and is the etiologic agent of HTLV-1e Received May 19, 2017. Accepted August 1, 2017.
associated myelopathy (HAM), also known as tropical spastic paraparesis (TSP), and of adult T-cell leukemia and lymphoma.1,2 It is estimated that approximately 5 to 10 million 4
Department of Medicine and Diagnostic Support, Federal University of Bahia School of Medicine, Salvador, Bahia, Brazil;
1
Postgraduate Program in Health Sciences, Federal University of Bahia School of Medicine, Salvador, Bahia, Brazil;
5
Instituto Gonçalo Moniz, Fiocruz, Salvador, Bahia, Brazil;
2
Immunology Service, University Hospital Professor Edgard Santos, Federal University of Bahia, Salvador, Bahia, Brazil;
6
3
Physical Therapy Department, University Hospital Professor Edgard Santos, Federal University of Bahia, Salvador, Bahia, Brazil;
Copyright ª 2017, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jsxm.2017.08.001
J Sex Med 2017;14:1195e1200
National Institute of Science and Technology in Tropical Diseases, CNPq/ MCT, Salvador, Bahia, Brazil
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people are infected by HTLV-1 worldwide, mainly in southwestern Japan, the Caribbean, Africa, and South and Central America.3 Only a minority of patients with HTLV-1 develop HAM/TSP, which is caused by an exaggerated inflammatory response and progressive demyelization of the spinal cord leading to low back pain, weakness of the lower limbs, hyperreflexia, and the Babinski sign.2,4,5 The disease typically progresses to the inability to walk because of a spastic paraparesis.2 However, a large percentage of infected patients who do not fulfill the diagnostic criteria for HAM/TSP can have neurologic symptoms, such as weakness of the inferior limbs, paresthesias, and sphincter disorders.6,7 Urinary symptoms, mainly of overactive bladder, occur in up to 100% of patients with HAM/TSP and is observed in approximately 20% of subjects with HTLV-1 who can be considered HTLV-1 carriers.6,8,9 Erectile dysfunction (ED) also has been observed in a large percentage of individuals infected with HTLV-1 with or without evidence of myelopathy. In a study evaluating the frequency of ED in HTLV-1 infection, it was found that ED was present in 35% of HTLV-1 carriers, in 79% of patients with probable HAM/TSP, and in 93.7% of patients with definitive HAM/TSP.9 Although there is a clear relation between ED and the degree of neurologic impairment in HTLV-1, ED also can occur in patients with HTLV-1 without neurologic disease.6,7,9 Actually ED is threefold higher in patients with HTLV-1 without HAM/TSP than in seronegative controls.6 Moreover, severe ED has been observed in young HTLV-1 carriers.9 In the general population, age, atherosclerosis, and diabetes mellitus (DM) are the most important risk factors for ED.10 Atherosclerosis leads to occlusive vessel phenomena that impair adequate blood flow to the penile arteries and microvessels of the cavernous bodies, resulting in ED.10e14 Atherosclerosis has been recognized as an inflammatory illness and HTLV-1 is associated with an exaggerated production of proinflammatory cytokines.15e19 Therefore, the exaggerated inflammatory response observed in HTLV-1 infection could contribute to atherosclerosis and, in consequence, ED. Because ED also is documented in individuals infected with HTLV-1 without evidence of neurologic damage, and atherosclerosis is the major cause of ED in the general population, we evaluated whether there was an association between ED and traditional risk factors for atherosclerosis, such as DM, high blood pressure (HBP), dyslipidemia, metabolic syndrome, and obesity in individuals infected with HTLV-1.
METHODS Study Design and Population This is a cross-sectional study conducted in the multidisciplinary HTLV-1 clinic of the Federal University of Bahia University Hospital (Bahia, Brazil). Patients were enrolled from January 2013 through June 2015. The inclusion criterion was a
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positive enzyme-linked immunoassay result for HTLV-1 confirmed by western blot. Exclusion criteria were age younger than 18 or older than 70 years, history of cancer, use of penile prosthesis, psychiatric disorders, and a motor deficit caused by other neurologic disorders. Patients were not using ED medications at the time of the study.
Evaluation of Neurologic Impairment and Clinical Forms of HTLV-1 Infection The degree of neurologic impairment of participants was evaluated by the Osame’s Disability Motor Scale (ODMS) and the Expanded Disability Status Scale (EDSS).2,20 Individuals with an ODMS score equal to 0 and an EDSS score equal to 0 were considered HTLV-1 carriers, or asymptomatic from a neurologic standpoint. Probable HAM/TSP was defined according to the Castro-Costa classification.21 These patients had an ODMS score equal to 0 and an EDSS score higher than 2. Patients with HAM/TSP had an ODMS score of at least 1 and an EDSS score of at least 3. Patients with probable or definitive HAM/TSP were considered to have neurologic disease associated with HTLV-1 infection. The five-item International Index of Erectile Function (IIEF-5) was used to evaluate the degree of ED.22 It is a self-applied questionnaire with scores ranging from 5 to 25. Individuals with an IIEF-5 score higher than 21 are considered to have normal erectile function (scores 5e7 ¼ severe ED, scores 8e11 ¼ moderate ED, scores 11e16 ¼ moderate to light ED, scores 17e21 ¼ light ED).
Definition of Atherosclerosis Risk Factors DM and HBP were defined by clinical history or documentation of a fasting blood sugar level higher than 125 mg/dL or higher than 175 mg/dL after a meal and blood pressure higher than 140 and 85 mm Hg, respectively.23,24 Hypercholesterolemia was defined as a total cholesterol level higher than 200 mg/dL, low high-density lipoprotein (HDL) cholesterol was defined as a level lower than 40 mg/dL, and high lowdensity lipoprotein (LDL) cholesterol was defined as a level higher than 150 mg/dL.25,26 Hypertriglyceridemia was defined as a triglyceride level higher than 150 mg/dL in blood collected after 10 to 12 hours of fasting.25,26 Overweight and obesity were determined by body mass index (BMI) and waist circumference.26,27 Waist circumference was measured between the iliac crest and the bottom-most rib with the individual in the standing position. Increased waist circumference was defined as larger than 102 cm.26 BMI was calculated by dividing the patient’s weight (kilograms) by the square of height (meters). Values from 18.5 to 24.9 kg/m2 were considered normal, those from 25.0 to 29.9 kg/m2 were considered overweight, and those above 30 kg/m2 were considered obesity.26 Metabolic syndrome was defined by the presence of three of the following five criteria: HBP; increased abdominal fat (abdominal circumference > 102 cm in men); serum HDL cholesterol level lower than 40 mg/dL; serum fasting glucose J Sex Med 2017;14:1195e1200
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Table 1. Demographic, clinical, and laboratory data from 84 subjects with HTLV-1 infection stratified by presence or absence of ED
Table 2. Risk factors for ED in 84 subjects with HTLV-1 infection by univariate logistic regression 95% CI
ED, n (%) Variables
Yes (n ¼ 43)
No (n ¼ 41)
P value
Age (y) .003 <60 23 (53.5) 35 (85.4) 60 20 (46.5) 6 (14.6) Clinic forms of HTLV-1 infection <.001 Asymptomatic 18 (41.9) 37 (90.2) Probable HAM/TSP 11 (25.6) 2 (4.9) HAM/TSP 14 (32.6) 2 (4.9) Risk factors for atherosclerosis DM 8 (18.6) 1 (2.4) .03 HBP 16 (37.2) 8 (19.5) .12 High LDL cholesterol 10 (23.3) 8 (19.5) .87 Low HDL cholesterol 17 (39.5) 12 (29.3) .44 High triglycerides 15 (34.9) 10 (24.4) .41 Metabolic syndrome 11 (25.5) 4 (9.7) .08 Abdominal circumference 15 (34.9) 11 (26.8) .57 BMI .51 Low weight 2 (4.7) 0 (0.0) Normal 18 (41.9) 16 (39) Overweight 14 (32.6) 14 (34.1) Obesity 9 (20.9) 11 (26.8) BMI ¼ body mass index; DM ¼ diabetes mellitus; ED ¼ erectile dysfunction; HAM ¼ human T-cell lymphotropic virus type 1eassociated myelopathy; HBP ¼ high blood pressure; HDL ¼ high-density lipoprotein; HTLV-1 ¼ human T-cell lymphotropic virus type 1; LDL ¼ low-density lipoprotein; TSP ¼ tropical spastic paraparesis.
level higher than 100 mg/dL; and triglyceride level higher than 150 mg/dL.23,24
Ethical Issues This study was approved by the research ethics committee of the Federal University of Bahia University Hospital, and all patients provided a written informed consent.
Statistical Analysis Continuous variables were expressed as mean and SD and categorical variables were presented as absolute and relative frequencies. Patients were stratified into one of two groups according to the presence or absence of ED. The Student t-test was used to compare means and the c2 or Fisher exact test, as indicated, was used to compare proportions between groups. The Spearman correlation technique was used to evaluate the correlation between ED and the degree of neurologic impairment measured by the EDSS and between ED and obesity determined by the BMI. A binary logistic regression analysis was conducted to identify independent predictors of ED. The results were considered statistically significant at a P value less than 0.05 in the final analyses. All statistical analyses were performed using SPSS 17 (SPSS, Inc, Chicago, IL, USA). J Sex Med 2017;14:1195e1200
Independent variables
OR
Lower
Upper
P value
Age > 60 y DM HBP Metabolic syndrome Neurologic disease
5.07 9.14 2.44 3.18 12.84
1.76 1.08 0.90 0.92 3.88
14.54 76.76 6.57 10.96 42.49
.003 .042 .077 .067 .001
ED ¼ erectile dysfunction; DM ¼ diabetes mellitus; HBP ¼ high blood pressure; HTLV-1 ¼ human T-cell lymphotropic virus type 1; OR ¼ odds ratio.
RESULTS One hundred two men were evaluated and 18 were excluded; reasons for exclusion were age older than 70 years (n ¼ 11), cancer (n ¼ 2), inability to stay standing (n ¼ 2), penile prosthesis (n ¼ 2), and neurologic impairment from poliomyelitis (n ¼ 1). The mean age ± SD of the 84 participants was 54 ± 10.5 years, and the overall frequency of ED was 51.2%. Table 1 lists the demographic, clinical, and laboratory data of 84 subjects with HTLV-1 stratified by the presence or absence of ED. ED was associated with age older than 60 years, degree of neurologic involvement, and DM but not with HBP, high LDL cholesterol, low HDL cholesterol, high triglycerides, metabolic syndrome, or BMI. There also was no association between metabolic syndrome and severity of ED. Metabolic syndrome was observed in 34% of patients with light and moderate to light ED and in 25% of patients with severe ED. To further explore the risk factors for ED in subjects with HTLV-1, we conducted univariate and multivariate logistic regression analyses. On univariate analysis (Table 2), symptomatic HTLV-1 infection (patients with HAM/TSP or probable HAM/TSP) showed the greatest association with ED, followed by DM and age older than 60 years. Metabolic syndrome and HBP showed a trend but were not statistically significantly associated with ED. In multivariate analysis, symptomatic HTLV-1 infection remained the most important risk factor for ED (adjusted odds ratio ¼ 22.1, 95% ¼ CI 5.3e92.3), followed distantly by HBP (adjusted odds ratio ¼ 6.3, 95% CI ¼ 1.4e30.5), and age older than 60 years (adjusted odds ratio ¼ 4.6, 95% CI ¼ 1.3e17.3; Table 3). Because of the strong association between ED and neurologic manifestations of HTLV-1, we evaluated the risk factors for ED in 18 patients who did not have probable or definitive HAM/ TSP. Most (55.5%) were younger than 60 years, DM was documented in only three subjects (16.7%), metabolic syndrome and/or increased abdominal circumference were noted in five (27.8%), and obesity was noted in four (22.2%). In 9 of the 18 patients, there were no risk factors for atherosclerosis and no psychiatric or hormonal disorders that could explain the ED. Of these individuals, six had moderate ED and three had moderate to severe or severe ED.
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Table 3. Independent predictors of ED in 84 subjects with HTLV-1 infection by multivariate logistic regression model* 95% CI Independent variables
OR
Lower
Upper
P value
Age > 60 y HBP Neurologic disease
4.64 6.31 22.13
1.25 1.39 5.31
17.25 28.69 92.25
.022 .017 <.001
ED ¼ erectile dysfunction; HBP ¼ high blood pressure; HTLV-1 ¼ human T-cell lymphotropic virus type 1; OR ¼ odds ratio. *Five variables were entered in the single-step multivariate logistic regression model: age older than 60 years, HBP, diabetes mellitus, metabolic syndrome, and neurologic disease. The table presents only variables that achieved statistical significance.
DISCUSSION HAM/TSP is a severe disease caused by HTLV-1 but it occurs only in a small percentage of infected individuals.5 However, evidence accumulated in the past 10 years has indicated that a large percentage of individuals with HTLV-1 have other clinical manifestations, including ED.6e8 Indeed, a large percentage of individuals with HTLV-1 have moderate or severe ED.9 In this study, although we found that age, atherosclerosis, and DM could contribute to the ED observed in HTLV-1, the main cause of ED in these individuals was neurologic disease. Moreover, in half the subjects with HTLV-1 and ED but without evidence of neurologic disease, no other risk factor except HTLV-1 infection was documented. In a Brazilian study of individuals without HTLV-1, 52% of men 40 to 70 years old had some degree of ED.28 The pathophysiology of ED can be vascular, neurogenic, psychogenic, and endocrine.29 Erection is a vascular event and atherosclerosis is the main cause of ED.30 The prevalence of ED increases with age and in men older than 70 years the prevalence of ED is up to 80%.31 Atherosclerosis also increases with age and the risk factors for atherosclerosis, such as dyslipidemia, metabolic syndrome, obesity, DM, and HBP, are strongly associated with ED.32,33 In the present study, when the entire sample of subjects with HTLV-1 was evaluated for ED and risk factors for atherosclerosis, only DM was associated with ED. However, this association was found in only 10% of subjects. There was no association of ED with high LDL cholesterol, low HDL cholesterol, high triglycerides, abdominal circumference, or obesity. In the multivariate logistic regression model, the association between DM and ED disappeared. In this analysis, the occurrence of neurologic disease increased the odds of ED by 22 times, whereas HBP and age older than 60 years increased those odds by 6.3 and 4.6 times, respectively. This reinforces the findings of a previous study linking ED with the degree of neurologic manifestations in HTLV-1.9 It has been estimated that in the general population only 10% to 19% of ED is neurogenic, but in HTLV-1 infection up to 95% of patients who have definitive or probable HAM/TSP have
ED.9,34 However, a large number of patients with HTLV-1 considered HTLV-1 carriers have ED.6 The main pathologic finding in patients with HAM/TSP is degeneration of the white matter in the lateral column of the thoracic spine. It is not clear why patients might only present ED or urologic manifestations of a neurogenic bladder, but it is known that only 1.7% of subjects with HTLV-1 who have these manifestations progress to HAM/TSP.5 These data emphasize the necessity of better understanding the pathogenesis of ED and other urologic manifestations in patients with HTLV-1 who do not fulfill the criteria for HAM/TSP. It is likely that the inflammatory response and damage of the spinal cord that cause neurogenic bladder or ED do not progress to induce more severe neurologic damage as observed in HAM/TSP. Studies using magnetic resonance imaging of the lumbar and sacral medullae and electromyography are in progress and could explain the occurrence of ED in HTLV-1 carriers in the absence of apparent neurologic disease, risk factors for atherosclerosis, psychiatric disease, or hormonal disorders. An important limitation of the present study is the small sample, which makes the estimates imprecise. However, the statistically significant associations reported are valid and emphasize the importance of neurologic disease as an important cause of ED in patients with HTLV-1. Although we found that age, atherosclerosis, and HBP can contribute to ED in this population, neurologic damage by the viral infection is the most important risk factor for ED in patients with HTLV-1. Moreover, we speculate that ED could be the unique or first manifestation of neurologic disease related to HTLV-1.
ACKNOWLEDGMENTS We thank Cristiano Franco, Glória Orge, Lúcia Passos, and the student Victor Hugo for their contribution in the preparation of this article. Corresponding Author: Edgar Marcelino de Carvalho Filho, MD, PhD, Immunology Service, University Hospital Professor Edgard Santos, Federal University of Bahia, 5o andar, Rua João das Botas, s/n, Canela, 40110060, Salvador, Bahia, Brazil. Tel: 55-71-3245-5493; Fax: 55-71-3245-7110; E-mail: imuno@ ufba.br Conflicts of Interest: The authors report no conflicts of interest. Funding: This study was funded by Brazilian National Research Council (CNPq).
STATEMENT OF AUTHORSHIP Category 1 (a) Conception and Design Cassius José Vitor de Oliveira; José Abraão Carneiro Neto; Rosana C. P. Andrade; Paulo Novis Rocha; Edgar Marcelino de Carvalho Filho J Sex Med 2017;14:1195e1200
Risk Factors for ED in HTLV-1 (b) Acquisition of Data Cassius José Vitor de Oliveira; José Abraão Carneiro Neto; Rosana C. P. Andrade; Paulo Novis Rocha; Edgar Marcelino de Carvalho Filho (c) Analysis and Interpretation of Data Cassius José Vitor de Oliveira; José Abraão Carneiro Neto; Rosana C. P. Andrade; Paulo Novis Rocha; Edgar Marcelino de Carvalho Filho Category 2 (a) Drafting the Article Cassius José Vitor de Oliveira; José Abraão Carneiro Neto; Rosana C. P. Andrade; Paulo Novis Rocha; Edgar Marcelino de Carvalho Filho (b) Revising It for Intellectual Content Cassius José Vitor de Oliveira; José Abraão Carneiro Neto; Rosana C. P. Andrade; Paulo Novis Rocha; Edgar Marcelino de Carvalho Filho Category 3 (a) Final Approval of the Completed Article Cassius José Vitor de Oliveira; José Abraão Carneiro Neto; Rosana C. P. Andrade; Paulo Novis Rocha; Edgar Marcelino de Carvalho Filho
REFERENCES 1. Poiesz BJ, Ruscetti FW, Gazdar AF, et al. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci U S A 1980;77:7415-7419. 2. Osame M, Usuku K, Izumo S, et al. HTLV-I associated myelopathy, a new clinical entity. Lancet 1986;1:1031-1032. 3. Gessain A, Cassar O. Epidemiological aspects and world distribution of HTLV-1 Infection. Front Microbiol 2012;3:388. 4. Araujo A, Lima MA, Silva MT. Human T-lymphotropic virus 1 neurologic disease. Curr Treat Options Neurol 2008;10: 193-200. 5. Tanajura D, Castro N, Oliveira P, et al. Neurological manifestations in human T-cell lymphotropic virus type 1 (HTLV-1)e infected individuals without HTLV-1eassociated myelopathy/ tropical spastic paraparesis: a longitudinal cohort study. Clin Infect Dis 2015;61:49-56. 6. Caskey MF, Morgan DJ, Porto AF, et al. Clinical manifestations associated with HTLV type I infection: a cross-sectional study. AIDS Res Hum Retroviruses 2007;23:365-371. 7. Poetker SK, Porto AF, Giozza SP, et al. Clinical manifestations in individuals with recent diagnosis of HTLV type I infection. J Clin Virol 2011;51:54-58.
1199 11. Katsiki N, Wierzbicki AS, Mikhailidis DP. Erectile dysfunction and coronary heart disease. Curr Opin Cardiol 2015;30: 416-421. 12. Junuzovic D, Mehmedbasic S. [Erectile dysfunction—incidence, causes and risk factors]. Med Arh 2004;58:35-38 [in Bosnian]. 13. Golijanin D, Singer E, Davis R, et al. Doppler evaluation of erectile dysfunction—part 1. Int J Impot Res 2007;19:37-42. 14. Golijanin D, Singer E, Davis R, et al. Doppler evaluation of erectile dysfunction—part 2. Int J Impot Res 2007;19:43-48. 15. Yudkin JS, Stehouwer CD, Emeis JJ, et al. C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arterioscler Thromb Vasc Biol 1999;19:972-978. 16. Ziccardi P, Nappo F, Giugliano G, et al. Reduction of inflammatory cytokine concentrations and improvement of endothelial functions in obese women after weight loss over one year. Circulation 2002;105:804-809. 17. Starling AL, Coelho-Dos-Reis JG, Peruhype-Magalhaes V, et al. Immunological signature of the different clinical stages of the HTLV-1 infection: establishing serum biomarkers for HTLV-1eassociated disease morbidity. Biomarkers 2015; 20:502-512. 18. Nascimento MC, Primo J, Bittencourt A, et al. Infective dermatitis has similar immunological features to human T lymphotropic virus-type 1eassociated myelopathy/tropical spastic paraparesis. Clin Exp Immunol 2009;156:455-462. 19. Santos SB, Oliveira P, Luna T, et al. Immunological and viral features in patients with overactive bladder associated with human T-cell lymphotropic virus type 1 infection. J Med Virol 2012;84:1809-1817. 20. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983; 33:1444-1452. 21. De Castro-Costa CM, Araujo AQ, Barreto MM, et al. Proposal for diagnostic criteria of tropical spastic paraparesis/HTLV-Ie associated myelopathy (TSP/HAM). AIDS Res Hum Retroviruses 2006;22:931-935. 22. Rosen RC, Cappelleri JC, Smith MD, et al. Development and evaluation of an abridged, 5-item version of the International Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction. Int J Impot Res 1999;11:319-326. 23. Genuth S, Alberti KG, Bennett P, et al. Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care 2003;26: 3160-3167.
8. Castro NM, Rodrigues W Jr, Freitas DM, et al. Urinary symptoms associated with human T-cell lymphotropic virus type I infection: evidence of urinary manifestations in large group of HTLV-I carriers. Urology 2007;69:813-818.
24. Mancia G, De Backer G, Dominiczak A, et al. 2007 Guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007;25:1105-1187.
9. Oliveira P, Castro NM, Muniz AL, et al. Prevalence of erectile dysfunction in HTLV-1einfected patients and its association with overactive bladder. Urology 2010;75:1100-1103.
25. Sanjay S, Bharti GS, Manish G, et al. Metabolic syndrome: an independent risk factor for erectile dysfunction. Indian J Endocrinol Metab 2015;19:277-282.
10. Sullivan ME, Keoghane SR, Miller MA. Vascular risk factors and erectile dysfunction. BJU Int 2001;87:838-845.
26. Alberti KG, Zimmet P, Shaw J. Metabolic syndrome—a new world-wide definition. A consensus statement from the
J Sex Med 2017;14:1195e1200
1200
de Oliveira et al
International Diabetes Federation. Diabet Med 2006;23: 469-480.
31. Kubin M, Wagner G, Fugl-Meyer AR. Epidemiology of erectile dysfunction. Int J Impot Res 2003;15:63-71.
27. World Health Organization (WHO). Global Health Observatory (GHO). Available at: http://www.who.int/gho/ncd/risk_factors/ overweight/en/. Published 2014. Accessed August 14, 2017.
32. El-Sakka AI, Morsy AM, Fagih BI, et al. Coronary artery risk factors in patients with erectile dysfunction. J Urol 2004; 172:251-254.
28. Moreira ED Jr, Abdo CH, Torres EB, et al. Prevalence and correlates of erectile dysfunction: results of the Brazilian Study of Sexual Behavior. Urology 2001;58:583-588. 29. Melman A, Gingell JC. The epidemiology and pathophysiology of erectile dysfunction. J Urol 1999;161:5-11.
33. Feldman HA, Johannes CB, Derby CA, et al. Erectile dysfunction and coronary risk factors: prospective results from the Massachusetts Male Aging Study. Prev Med 2000; 30:328-338.
30. Pastuszak AW. Current diagnosis and management of erectile dysfunction. Curr Sex Health Rep 2014;6:164-176.
34. Nehra A, Moreland RB. Neurologic erectile dysfunction. Urol Clin North Am 2001;28:289-308.
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