Introduction. E Zonana Farca 1, V Francolugo-Vélez 2, C Moy-Eransus 3, A Orozco Bravo 4 L-J Tseng 5 and VJ Stecher 5

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1 (2008) 20, & 2008 Nature Publishing Group All rights reserved /08 $ ORIGINAL ARTICLE Self-esteem, confidence and relationship satisfaction in men with erectile dysfunction: a randomized, parallel-group, double-blind, placebo-controlled study of sildenafil in Mexico E Zonana Farca 1, V Francolugo-Vélez 2, C Moy-Eransus 3, A Orozco Bravo 4 L-J Tseng 5 and VJ Stecher 5 1 Angeles Mocel Hospital, Mexico City, Mexico; 2 Henri Dunant Hospital, Cuernavaca Morelos, Mexico; 3 Angeles del Pedregal Hospital, Mexico City, Mexico; 4 Angel Leaño Hospital, Zapopan, Jalisco, Mexico and 5 Pfizer Inc, New York, NY, USA Erectile dysfunction (ED) negatively impacts self-esteem and relationship satisfaction. The Self-Esteem and Relationship (SEAR) questionnaire is a validated, ED-specific, patient-reported instrument that specifically addresses self-esteem and relationship issues within the context of ED. Effective ED treatment with sildenafil in a double-blind, placebo-controlled clinical trial conducted in Brazil, Mexico, Australia and Japan showed pooled cross-cultural improvements in self-esteem, confidence and relationship satisfaction. This report focuses on the results from the subgroup of men from nine Mexican centers who participated in the multinational study. A total of 95 men aged X18 years with clinically diagnosed ED and currently in a stable relationship were randomized to placebo (n ¼ 47) or sildenafil (n ¼ 48). The SEAR results for Mexican men showed that sildenafil treatment led to significant improvements in self-esteem, confidence and relationship satisfaction. These data support an earlier study showing that Latin American men taking sildenafil have similar safety and efficacy profiles compared to non-latin counterparts. (2008) 20, ; doi: /ijir ; published online 5 June 2008 Keywords: erectile dysfunction; self-esteem; Mexico; relationship satisfaction Introduction Erectile dysfunction (ED) is a common problem for men throughout the world. The Global Study of Sexual Attitudes and Behaviors (GSSAB) survey, which included 29 countries, found a 13 28% prevalence of ED in men years of age. 1 In the United States, the Massachusetts Male Aging Study reported a 52% prevalence of ED of any degree in men years of age. In addition, after the age of 40 years there was an increasing prevalence of 5% per decade for complete (severe) ED. 2 Recent data indicate that 22% of men over age 40 years have moderate to severe ED. 3 In agreement with data from the United States, a cross-national epidemiological study conducted in Brazil, Italy, Japan and Malaysia found that Correspondence: Dr VJ Stecher, Global Sexual Health Team, Pfizer Inc, 235 East 42nd Street, New York, NY 10017, USA. vera.stecher@pfizer.com Received 5 February 2008; revised 14 April 2008; accepted 3 May 2008; published online 5 June % of men between the ages of 40 and 70 years hadsomedegreeofed. 4 Few epidemiological investigations specific to the incidence of ED in Mexico are published, but a 26.1% overall prevalence of ED was determined by Hernandez Moreno et al. 5 in a survey of a Mexican male population that was 18 years of age or older, with an active sex life. In this report, the incidence of psychogenic ED was the predominant etiology at an estimated 67.8%. The major risk factors associated with ED in Mexican men were age440 years, diabetes mellitus, obesity and the use of antihypertensive drugs. In the Men s Attitudes to Life Events and Sexuality (MALES) study, which aimed to identify the prevalence of ED and related health issues in male populations in Europe and North and South America, the prevalence of ED in Mexico was lower, at 14%, than that reported in the Hernandez study. 6 However, the differences in ED prevalence between the Hernandez and MALES studies may reflect the age differences of participants in the two studies. The majority of Mexican men in the MALES study were younger than 40 years, with only 37.9% of

2 Mexican participants in this study aged 40 years or older, whereas more than 50% of the participants in the Hernandez survey were older than 40 years. Clinical trials show that ED has a negative impact on self-esteem and relationship satisfaction. 2,7,8 The Self-Esteem and Relationship (SEAR) questionnaire is a validated, ED-specific, patient-reported instrument developed specifically to address self-esteem and relationship issues within the context of ED. 8 Since its development, the treatment responsiveness of the SEAR questionnaire has been demonstrated in two clinical trials, based in the United States, of sildenafil citrate in men with ED Since the development and validation of the English version, the SEAR questionnaire has been linguistically translated into other languages, including Spanish. 12 The SEAR questionnaire consists of 14 questions divided into two domains: the sexual relationship domain (eight items) and the confidence domain (six items). The confidence domain is further divided into two subscales: the self-esteem subscale (four items) and the overall relationship subscale (two items). Responses to questions are summed and the summed score for each component (domain, subscale and overall scores) is transformed onto a 100-point scale with higher scores inversely correlated with ED severity. Numerous placebo-controlled, double-blind and open-label clinical trials investigating sildenafil, a phosphodiesterase type-5 inhibitor, suggest that the drug is well tolerated and effective for the treatment of ED. 13,14 In multicultural, worldwide studies, depression, anxiety and loss of self-esteem associated with ED show improvement upon effective ED treatment. 2,7 Cultural attitudes about sex can vary. Thus, an evaluation of distinct cultural responses to ED can be useful for understanding treatment responses within different cultural groups and aid in the development of treatment strategies and the allocation of resources. Mexican men reportedly have lower cytochrome 450 3A4 (CYP3A4) activity, the major liver enzyme responsible for sildenafil metabolism. Twofold higher peak levels of sildenafil were found in the serum of Mexican men, although the drug half-life of about 4 h was similar to that of historical controls. Therefore, the safety and tolerability of sildenafil in Mexican men is of interest. In addition, few studies of ED or its treatment in this population are available. A double-blind, placebo-controlled clinical trial conducted in Brazil, Mexico, Australia and Japan showed that effective ED treatment is associated with pooled cross-cultural improvements in selfesteem, confidence and relationship satisfaction. 15 This report focuses on the results on the SEAR questionnaire in the subgroup of Mexican men with ED who participated in the multinational study of sildenafil as a treatment for ED. Methods Patients Men aged 18 years or older with a clinical diagnosis of ED, documented by a score of p21 on the Sexual Health Inventory for Men, 16 and currently in a stable relationship with a partner were eligible for the study. Because the effect of ED treatment on self-esteem was an endpoint, a score of p75 on the self-esteem subscale of the SEAR questionnaire was required for eligibility. All patients gave written informed consent. The relevant, local institutional review boards approved the study. Major exclusion criteria included resting hypotension or hypertension, significant cardiovascular disease, patients prescribed or currently taking nitrates or ritonavir, clinically significant laboratory results and prior use of sildenafil (46 tablets). In addition, men with a psychological condition or social circumstances that impaired their ability to participate reliably in the study were excluded. Study design The study was designed as a randomized, doubleblind, placebo-controlled trial, and was conducted in compliance with the ethical principles according to the current revision of the Declaration of Helsinki (revised Edinburgh, October 2000). 14 Data for this analysis were reported from nine centers in Mexico. The study included a 2-week screening phase that was followed by a 12-week treatment phase in which patients were randomized to receive 50 mg of sildenafil (adjustable to 25 or 100 mg based on patient response) or matching placebo as needed for satisfactory erections for sexual activity, but not to exceed one dose per day. Assessments The primary endpoint was change from baseline on the self-esteem subscale of the SEAR questionnaire. Secondary endpoints included the mean change from baseline in the other SEAR components: sexual relationship domain, confidence domain, overall relationship subscale and the overall score; mean change from baseline in the domains of the International Index of Erectile Function (IIEF; erectile function, orgasmic function, sexual desire, intercourse satisfaction and overall satisfaction domains); the mean change from baseline in intercourse success rates derived from patient sexual activity event logs; and the mean score for the Global Efficacy Question (GEQ): When you took a dose of study drug and had sexual stimulation, how often did you get an erection that allowed you to engage in satisfactory sexual intercourse? Statistical analysis An analysis of covariance model with treatment group as the key explanatory variable and further 403

3 404 controlling for severity of ED, etiology of ED, age and baseline score was used to assess changes in scores from baseline to week 12 on the SEAR, IIEF and percentage of successful intercourse attempts. 14 Partial Pearson s correlations (controlling for treatment) were obtained for changes in SEAR scores with changes in IIEF scores, changes in the percentage of intercourse attempts that were successful and GEQ responses at end of treatment. Ninety-five percent confidence intervals (95% CIs) of mean scores covered within-group changes and between-group comparisons. Effect sizes (ESs), determined for individual SEAR questionnaire components, were measured in standard deviation (s.d.) units and calculated as the difference in the mean change scores between treatment groups, divided by the s.d. of the baseline scores on that SEAR component. By convention, ESs of 0.20 s.d. units were considered as small, 0.50 as medium and 0.80 as large. 17 All statistical tests were two-sided, with a value of Po0.05 considered to be significant, using Statistical Analysis System software, version The intent-to-treat (ITT) population, defined as all randomized patients who took at least one dose of study medication and who presented efficacy data that could contribute to at least one posttreatment efficacy analysis, was used for the efficacy analysis. For patients who discontinued early, the last observation carried-forward value was used for the end of treatment analysis. A safety analysis was conducted on all randomized patients who took at least one dose of study medication. Table 1 Patient characteristics Placebo (n ¼ 47) Sildenafil (n ¼ 48) Age, mean±s.d. (years) 55±12 57±12 Weight, mean±s.d. (kg) 77.0± ±8.7 Height, mean±s.d. (cm) 168.9± ±6.5 ED duration, mean (range) 4.0 (0.1 35) 4.2 (0.3 27) (years) Etiology organic/mixed/ psychogenic (n/n/n) 15/20/12 24/18/6 Baseline SEAR scores (mean±s.e.) Sexual relationship domain 43.75± ±2.61 Confidence domain 38.41± ±2.45 Self-esteem subscale 39.13± ±2.39 Overall relationship 36.96± ±3.28 subscale Overall score 41.46± ±2.33 Abbreviations: ED, erectile dysfunction; SEAR, Self-Esteem and Relationship questionnaire. SEAR component score, range ¼ 0 100; higher scores indicate better outcomes. Safety and tolerability All treatment-emergent adverse events (AEs) and their suspected causality were recorded, along with details of severity and investigator s opinion of their relationship to study treatment, at each posttreatment visit. 14 Blood pressure and heart rate were measured at each study visit. Results A total of 95 patients from nine Mexican centers were randomized and received study medication (47 ¼ placebo, 48 ¼ sildenafil). Patient characteristics were similar among the two treatment groups (Table 1), although the ED etiology differed between groups, with more men having organic ED in the sildenafil group and more men having psychogenic ED in the placebo group. Four patients discontinued while receiving placebo. Three withdrew due to lack of efficacy and one defaulted from the study. Two patients discontinued while receiving sildenafil. One withdrew due to lack of efficacy and one defaulted from the study. Figure 1 Mean change from baseline in the Self-Esteem and Relationship (SEAR) questionnaire Self-esteem subscale score at the end of treatment (intent-to-treat group, week 12). The week 12 value is the last postbaseline value recorded on or before the week 12 visit. SEAR questionnaire Mexican patients who received sildenafil had significantly greater improvement on the self-esteem subscale compared to patients who received placebo (Figure 1). The patients taking sildenafil also had significantly greater improvement on the other SEAR components compared to patients on placebo (Figure 2). The ESs were large (X0.8) for all individual SEAR components: self-esteem subscale (ES ¼ 1.20), sexual relationship domain (ES ¼ 1.11), confidence domain (ES ¼ 1.23), overall relationship subscale (ES ¼ 0.87) and overall score (ES ¼ 1.33).

4 405 Figure 2 Mean change from baseline in the Self-Esteem and Relationship (SEAR) overall, domain and subscale scores at the end of treatment (intent-to-treat group, week 12). The week 12 value is the last postbaseline value recorded on or before the week 12 visit. Measures of sexual function Patients receiving sildenafil had significantly greater improvements from baseline on the IIEF erectile function, orgasmic function, intercourse satisfaction and overall satisfaction domains compared to patients in the placebo group (Figure 3). The IIEF sexual desire domain was not significantly different between treatment groups. Patients receiving sildenafil also had significantly greater least squares (LSs) mean improvements in the percentage of successful intercourse attempts as recorded in the event log (73.7; 95% CI, ) compared to patients taking placebo (50.5; 95% CI, , P ¼ ). The mean score on the GEQ at the end of treatment (week 12) indicated significantly more frequent erections resulting in successful intercourse with sildenafil (LS mean 4.2; 95% CI, ) versus placebo (LS mean 3.5; 95% CI, ; P ¼ ). Correlations All mean changes from baseline SEAR scores correlated significantly (Po0.0001) with mean change from baseline in the IIEF domain scores and event log endpoints, as well as with GEQ responses at the end of treatment (Table 2). The SEAR overall score and self-esteem subscale had positive correlations of 0.83 and 0.72, respectively, with the IIEF erectile function domain (Po0.0001). SEAR component scores positively and significantly (Po0.0001) correlated with GEQ responses, with the strongest correlations observed with the SEAR sexual relationship domain (0.90) and the overall relationship subscale (0.90). SEAR component scores positively and significantly (Po0.0001) correlated with the percentage of successful intercourse attempts, with the strongest correlation observed with the SEAR overall score (0.67). Safety Sildenafil was well tolerated and the AEs were mild to moderate in severity. AEs affecting more than one patient in each treatment group that were considered related to treatment included headache (n ¼ 5), rhinitis (n ¼ 2) and dyspepsia (n ¼ 2). Treatmentrelated AEs in the placebo group included gastritis (n ¼ 1) and dizziness (n ¼ 1). There were no serious or severe AEs and no discontinuations or dose reductions due to AEs. Discussion The IIEF is considered the paradigm for measuring erectile function; however, more research on the psychosocial manifestations of ED in terms of how it affects mens relationships, confidence and selfesteem is needed. The SEAR questionnaire specifically assesses the impact of ED on psychosocial functioning and well-being as it is related to relationship satisfaction, confidence and particularly self-esteem. 8,9 Cultural attitudes about sex can vary and may result in deviations from predicted SEAR outcomes following sildenafil treatment in different societies. The SEAR results for Mexican men derived from a multinational trial involving Mexico and other countries (Brazil, Japan and Australia) showed that treatment with sildenafil resulted in significant improvements in self-esteem, confidence and relationship satisfaction in this subgroup. The associa-

5 406 Figure 3 Mean change from baseline in the International Index of Erectile Function (IIEF) domain scores at end of treatment (intent-to-treat group, week 12). The week 12 value is the last postbaseline value recorded on or before the week 12 visit. Table 2 Correlations between SEAR components and measures of sexual functioning SEAR components Pearson s partial correlation coefficient (r*) Erectile function Orgasmic function IIEF domains GEQ a Successful intercourse (%) Sexual desire Intercourse satisfaction Overall satisfaction 1. Sexual relationship Confidence a. Self-esteem b. Overall relationship 3. Overall score Abbreviations: GEQ, global efficacy question; IIEF, International Index of Erectile Function; SEAR, Self-Esteem and Relationship. a GEQ: When you took a dose of study drug and had sexual stimulation, how often did you get an erection that allowed you to engage in satisfactory sexual intercourse? *Po for all values. tion between improved erectile function and enhanced self-esteem in Mexican men parallels the overall findings of other US and international double-blind, placebo-controlled clinical trials of sildenafil treatment in men with ED. 10,14,19 The erectile function domain of the IIEF had the strongest correlation with all SEAR components in all studies. Conversely, the sexual desire domain of the IIEF had the weakest correlation with all SEAR components in all studies. GEQ correlations for Mexico also paralleled the US and international studies, with the strongest correlation seen in the sexual relationship domain and overall scores. These results indicate that improved erectile function is strongly associated with improved psychosocial well-being across cultures. Cultural influences are not the only factors that can affect response to treatment. Genetic differences can influence disease incidence or drug metabolism and response to treatment. 20 An understanding of cultural influences, 21,22 as well as the genetic bases for disease prevalences and treatment responses in different populations 20 is important for optimizing treatment strategies. 26 The frequency of the endothelial cell nitric oxide synthase (enos) 894 G/T polymorphism that is associated with ED is similar among the healthy Mexican Mestizo, Huastec, Mayo and Mayan subpopulations, but differs from that of Caucasians. 27 In Mexican Mestizo men, the 894 G/T polymorphism was identified as an independent risk factor for ED along with hypertension and diabetes mellitus. 28 Although no study of sildenafil response in relationship to the 894 polymorphism is available in a Mexican population, the sildenafil response was decreased in German ED patients heterozygous for

6 the 894 T polymorphism, with a gene dosage effect evident in homozygous patients. 29 Interestingly, Mexican populations reportedly have lower CYP3A4 activity, the major enzyme in the liver responsible for sildenafil metabolism. 30,31 A comparison of sildenafil pharmacokinetics in young, healthy, Mexican men with historical pharmacokinetic data from Caucasian men taking the same 100 mg dose of sildenafil showed twofold higher peak levels of sildenafil in the serum of Mexican men, although the drug half-life of about 4 h was similar in both the groups. 32 These data suggest that the bioavailability of sildenafil could be higher in Mexican men than in Caucasians. However, in the current analysis of the Mexican subpopulation in the multinational trial, no serious or severe AEs, discontinuations due to AEs or other causes, or dose reductions were reported in this subgroup, and the occurrence of AEs was similar to that reported in other sildenafil trials. 13 Conclusions Despite putative genetic variables noted for Mexican men, the men in this study exhibited similar SEAR and IIEF scores compared to North American, Asian or European men. These data support an earlier study which shows Latin American men taking sildenafil have similar safety and efficacy profiles compared to their non-latino counterparts. 33,34 Treatment with sildenafil resulted in significant improvements in self-esteem, confidence and relationships as assessed by the SEAR questionnaire in Mexican men with ED. SEAR scores correlated significantly with efficacy, as determined by changes in the erectile function domain of the IIEF and percentage of successful intercourse attempts, as well as the frequency of erections satisfactory for intercourse. Acknowledgments This study was funded by Pfizer Inc. Editorial assistance was provided by Nancy Price and Janet E Matsuura, at Complete Healthcare Communications Inc., and was funded by Pfizer Inc., New York, NY. Study Investigators: Members of the Mexico SEAR study group are Angel Orozco Bravo, Zapopan, Jalisco; David Calvo Dominguez, Durango; Elias Zonana Farca, Mexico City; Victor Alfonzo Francolugo-Velez, Cuernavaca, Morelos; Carlos, Pacheco Gahbler, Mexico City; Luis Carlos Moy-Eransus, Mexico City; Jose Arturo Rodriguez Rivera, Zapopan, Jalisco; Ulises Perez Toriz, Puebla; Raymundo Alfonzo Ballesteros Villalobos, Aguascalientes. References 1 Laumann EO, Nicolosi A, Glasser DB, Paik A, Gingell C, Moreira E et al. 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