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european urology 52 (2007) 321–323 available at www.sciencedirect.com journal homepage: www.europeanurology.com Editorial – referring to the article published on pp. 565–573 of this issue Ejaculatory Latency vs. Patient-Reported Outcomes (PROs) as Study End Points in Premature Ejaculation Clinical Trials Chris G. McMahon * Australian Centre for Sexual Health, Suite 2-4, Berry Road Medical Centre, 1a Berry Road, St Leonards, NSW, Australia 2071 Premature ejaculation (PE) is often reported, perhaps erroneously, as one of the most common male sexual disorders but remains poorly defined and inadequately characterised. As a result, a substantial disparity exists between the reported incidence of PE in many epidemiologic studies [1], which rely heavily on self-reported PE, and that suggested by community-based normative stopwatch intravaginal ejaculation latency time (IELT) studies [2]. Quantitative measures of intercourse, such as the IELT, and subjective patient-reported outcome (PRO) measures of voluntary control over ejaculation or self-efficacy, the extent of patient sexual satisfaction, and the level of bother or distress have been described and used as patient-related outcomes in clinical trials of PE. Each of the three criteria above has been operationalised, although not always with consistency. However, these dimensions may not be equally weighted, may vary in importance among patients, and may have differing meanings in different cultures where the attitude of the partner and culturally determined extent of emancipation may have an impact on the patient’s subjective diagnosis of PE. The medical literature contains several univariate and multivariate operational definitions of PE. The multivariate DSM-IV-TR definition of PE encompasses the main dimensions of PE, ejaculatory latency, control, and sexual satisfaction; however, it is vague, imprecise, subject to multiple interpretations, and a construct of authority-based opinions and not well-controlled clinical and epidemiologic studies [3]. Because the DSM-IV-TR definition of PE fails to nominate a quantified diagnostic IELT cut-off point, strict adherence may result in men with long IELT values of, for example, 10–20 min, being diagnosed with PE if they perceive themselves as suffering from PE [4]. The lack of consensus as to what constitutes PE continues to hamper clinical practice and basic and clinical research into the aetiology and management of this condition. The results of PE epidemiologic and drug treatment clinical trials are only reliable, interpretable, and capable of being generalised to patients with the disorder studied when consistent objective physiologic measures or sensitive, validated outcome assessment instruments are used as study end points [5] in well-defined and consistent populations where lifelong, acquired PE or PE with comorbid erectile dysfunction (ED) are treated as separate PE subgroups. Several validated PRO instruments using PROs of ejaculatory control, sexual satisfaction, and bother/distress have been reported and suggested as diagnostic tools and investigational end points in both epidemiologic and drug treatment clinical trials [6,7]. Treating physicians must interpret patient selfreports of PE and self-estimations of IELT with some caution because the estimation of ejaculatory latency by men and women may correlate poorly with stopwatch-recorded IELT. However, several authors have reported that patient self-estimation DOI of original article: 10.1016/j.eururo.2007.01.028 * Tel. + 61 2 94373906; Fax: + 61 2 99065900. E-mail address: [email protected]. 0302-2838/$ – see back matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2007.03.081 322 european urology 52 (2007) 321–323 of IELT correlates reasonably well with subsequent stopwatch IELT [8]. In the physician’s office, the diagnosis of PE is simple and can be achieved with a detailed medical and sexual history and a targeted physical examination. Stopwatch measurement of IELT and PRO inventories are not required. Investigations to determine the aetiology of PE are not indicated except in patients with ED, lower urinary tract symptoms (LUTS), or signs/symptoms of hyperthyroidism. However, patient self-estimation of IELT may be useful, especially when combined with a patient’s impression of change, in the assessment of response to treatment. Ejaculatory control is a subjective measure that is difficult to translate into quantifiable terms and is the most inconsistent dimension of PE. It has not been adequately operationalised to allow comparison across studies. Patrick et al reported that voluntary control differentiated men with PE from men without PE with 72% of men with PE describing ‘‘very poor’’ to ‘‘poor’’ compared to 5% in a group of normal controls [4]. However, diminished control is not exclusive to men with PE and some men with a brief IELT report adequate ejaculatory control [4]. Furthermore, there is a higher variability in changes in control compared to IELT in men treated with selective serotonin reuptake inhibitors (SSRIs) [9]. Men with PE report lower levels of sexual satisfaction than do men with normal ejaculatory latency. Patrick et al reported sexual satisfaction ratings of ‘‘very poor’’ or ‘‘poor’’ in 31% of men with PE, compared with 1% in a group of normal controls [4]. However, caution should be exercised in attributing improved satisfaction solely to the effect of drug treatment and contributions from other difficult-to-quantify issues such intimacy, friendship, sexual attraction, and communication should not be ignored. PE usually causes considerable distress among those men who seek treatment. Patrick et al reported that 64% of men with PE rated their extent of personal distress as ‘‘quite a bit’’ or ‘‘extremely’’ compared to 4% of the normal controls [4]. Men with PE may develop a pattern of sexual or relationship avoidance due to their fear, either assumed or actually based on previous criticism or actual ridicule from previous partners, that they will be unable to satisfy their partner. However, the word ‘‘distress’’ has negative social implications and its existence is denied by many men with PE. This dimension of PE is better captured by the word ‘‘bother.’’ The extent of psychological impact on patients, partners, and the overall relationship are perhaps the most important aspect of treatmentseeking behaviour and best define the severity of PE. Symonds et al [10] report the development and validation of brief self-administered five-item questionnaire to diagnose PE in clinical trials. A pilot development tool of nine questions was derived from qualitative research involving focus group and individual interviews of men with either physiciandiagnosed or self-reported PE and consultation with a panel of experts. Psychometric validation of this pilot development tool and development of a scoring system was achieved using men with either a stopwatch IELT < 2 min or a self-reported population of men with and without PE, and distilled this tool into a five-item, 0–25 score, one-dimensional measure that captures the essence of DSM-IV-TR and the dimensions of control, satisfaction, personal distress, and interpersonal distress. Sensitivity/specificity analysis suggests that a score 11 indicates PE. Although the methodology of the study is sound, it is complex and limited in several respects. The study population for the focus groups is relatively small (n = 40), has a higher mean age that that of a typical PE patient, and is derived from only the United States, Germany, and Spain. The self-reported population of men with and without PE was recruited from participants in a US Web-based survey system and, as such, represents a highly selected population of Internet users with an educational and socioeconomic profile that may substantially differ from the general population. Of particular interest is the report that the study group tended to complain more of lack of control and an inability to defer ejaculation as opposed to the typical PE patient’s primary complaint of brief latency. The authors fail to report whether younger men shared the same focus on control as the overall study group. These study design limitations suggest that the study population may not be truly representative of an international and multicultural population of men. The authors, in part, acknowledge these limitations and state that cross-cultural validity of this measure is required. Notwithstanding these comments, the tool represents a significant development towards simplifying the methodology of PE drug studies. Future development of this diagnostic tool would be incomplete without further validation to determine the potential relationships among scores, severity of PE, and response to treatment. Regulatory approval of new drug treatments for PE demands evaluation in large efficacy and safety trials, where clinical trial design and, in particular, the use of reliable, reproducible, and cost-effective study end points is paramount. The reliability of stopwatch IELT alone in assigning PE status, the use of PROs to replace stopwatch IELT, european urology 52 (2007) 321–323 or the predictive value of single-item PRO measures compared to multiple-item measures are incompletely understood issues. PRO measures, though providing important information, are at best subjective and relate to highly interpretable and imprecise dimensions of ejaculation, and their significance is weighted differently for different patients. On the other hand, IELT may not adequately categorise patients because some patients with a brief IELT report little or no bother and are therefore asymptomatic and not ‘‘suffering’’ from PE. Clearly, none of the dimensions of PE can universally distinguish men with PE from men without PE. The current consensus is that a combination of stopwatch IELT and a validated, patient-administered tool of PROs of control, satisfaction, personal distress, and interpersonal distress can adequately identify PE status in prevalence studies, in the screening phase of drug trials, and in measuring response to treatment. Conflicts of interest Associate Professor Chris G. McMahon is a paid consultant, member of a speaker’s panel and investigator for Pfizer, Bayer, Johnson & Johnson, and Solvay. References [1] Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors. JAMA 1999; 281:537–44. 323 [2] Waldinger MD, Quinn P, Dilleen M, et al. A multinational population survey of intravaginal ejaculation latency time. J Sex Med 2005;2:492–7. [3] American Psychiatric Association. Diagnostic and statistical manual of mental disorders, DSM-IV, ed. 4. Washington DC, 1994. p. 509–11. [4] Patrick DL, Althof SE, Pryor JL, et al. Premature ejaculation: an observational study of men and their partners. J Sex Med 2005;2:58–367. [5] McMahon CG, Meston C, Waldinger MD, et al. Disorders of orgasm in men and women, ejaculatory disorders in men. In: Lue TF, Basson R, Rosen R, Giuliano F, Khoury S, Montorsi F, editors. Sexual medicine: sexual dysfunctions in men and women. Health Publications; 2004. p. 409–68. [6] Althof S, Rosen R, Symonds T, et al. Development and validation of a new questionnaire to assess sexual satisfaction, control, and distress associated with premature ejaculation. J Sex Med 2006;3:465–75. [7] Yuan YM, Xin ZC, Jiang H, et al. Sexual function of premature ejaculation patients assayed with Chinese Index of Premature Ejaculation. Asian J Androl 2004;6: 121–6. [8] Pryor JL, Broderick GA, Ho KF, Jamieson C, Gagnon D. Comparison of estimated versus measured intravaginal ejaculatory latency time (IELT) in men with and without premature ejaculation (PE). J Sex Med 2005;3:54 (abstract no. 126). [9] Waldinger MD, Zwinderman AH, Schweitzer DH, Olivier B. Relevance of methodological design for the interpretation of efficacy of drug treatment of premature ejaculation: a systematic review and meta-analysis. Int J Impot Res 2004;16:369–81. [10] Symonds T, Perelman MA, Althof S, et al. Development and validation of a premature ejaculation diagnostic tool. Eur Urol 2007;52:565–73.