REVIEW Validated questionnaires for assessing sexual dysfunction and BPH/LUTS: solidifying the common pathophysiologic link

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1 (2008) 20, S27 S32 & 2008 Nature Publishing Group All rights reserved /08 $ REVIEW Validated questionnaires for assessing sexual dysfunction and BPH/LUTS: solidifying the common pathophysiologic link RC Rosen 1 and AD Seftel 2,3 1 New England Research Institutes, Watertown, MA, USA; 2 Case Medical Center/University Hospitals of Cleveland, Cleveland, OH, USA and 3 Section of Urology, Louis Stokes Cleveland VA Medical Center, Cleveland, OH, USA Erectile dysfunction (ED) and benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS) share many epidemiologic and clinical similarities. First-line therapy for both conditions include oral medications (a blockers, phosphodiesterase inhibitors). The impetus to develop and use questionnaires to characterize these two conditions is based on the trend away from invasive diagnostic testing to the use of patient-reported outcomes or validated selfadministered questionnaires. The International Prostate Symptom Score, the International Index of Erectile Function, the Male Sexual Health Questionnaire (MSHQ) and the MSHQ short form are similar patient-reported assessment questionnaires used for research or clinical evaluation of BPH/LUTS, ED and ejaculatory dysfunction. These patient-based self-administered questionnaires are likely to assume an ever increasing important role in the future, as oral BPH therapies are considered for the treatment of ED and oral ED therapies are considered for the treatment of BPH/LUTS. (2008) 20, S27 S32; doi: /ijir Use of self-administered questionnaires (IPSS, MSHQ, IIEF) in the assessment of male urological disorders (BPH/LUTS, ED) Evidence from recent large-scale epidemiological studies confirms the prevalence and adverse effects on the quality of life of the common urological conditions in men, such as lower urinary tract symptoms (LUTS) and erectile dysfunction (ED). A major trend in recent years has been toward the use of patient self-administered questionnaires or patient-reported outcomes for clinical assessment of urological symptoms in men and women, such as sexual dysfunction or voiding disorders. These questionnaires, including the well-known International Prostate Symptom Score (IPSS) measure of voiding symptoms in men and the International Index of Erectile Function (IIEF) questionnaire for assessment of ED, have revolutionized the clinical and research evaluation of common urological symptoms in men. A large volume clinical research has also been based on the use of these measures. This paper considers the specific impact of current Correspondence: Dr RC Rosen, New England Research Institutes, 9 Galen Street, Watertown, MA 02472, USA. rrosen@neriscience.com questionnaire measures in the urologic assessment of ED and benign prostatic hyperplasia (BPH)/LUTS, in addition to the development of a validated new measure, the Male Sexual Health Questionnaire (MSHQ), for assessment of ejaculatory dysfunction (EjD), a common but neglected sexual problem in men with BPH/LUTS. ED and the IIEF ED is a prevalent age-related condition in men. ED is the inability to attain or maintain an erection for satisfactory sexual performance. 1 The pivotal phase 3 studies showing efficacy and safety for the oral erectogenic agents, the phosphodiesterase inhibitors (PDE5i, sildenafil, vardenafil and tadalafil), showed an average age of approximately 57 years for men participating in the sildenafil trial, 52 years for men participating in the vardenafil trials and 56 years for the men participating in the tadalafil trials. 2 4 These results indicated that ED was most common in men in their 5th and 6th decades. Historically, the diagnosis of male ED was made using a variety of invasive tests, such as the nocturnal penile tumescence monitor, penile duplex ultrasound, dynamic infusion cavernosometry and cavernosography. Thus far, there was no reliable, objective and

2 S28 noninvasive assessment of male ED available. Introduction of the new oral ED medicines mandated that a reliable clinical instrument be developed to quantitate erectile function and that this tool be made available to the clinician. The introduction of the IIEF ushered in a new era into sexual medicine, in which a new simple, reliable and reproducible method of quantitating erectile function was now widely available. 5 The rationale behind the IIEF was the need to develop a brief, reliable and self-administered measure of erectile function that was cross-culturally valid and psychometrically sound, with the sensitivity and specificity for detecting treatment-related changes in patients with ED. The IIEF addressed the relevant domains of male sexual function (that is, erectile function, orgasmic function, sexual desire, intercourse satisfaction and overall satisfaction), was psychometrically sound, and has been linguistically validated in 10 languages. The IIEF also showed the sensitivity and specificity for detecting treatment-related changes in patients with ED. BPH and IPSS BPH is similarly an age-related condition of middleaged and older men. The epidemiology, anatomy and pathophysiology of BPH are discussed in various papers throughout this issue. 6 9 BPH is an anatomical, age-related and hormonally dependent growth of the prostate. Benign prostate growth induces physiological changes in men that in some cases lead to bothersome LUTS. These LUTS exert their effects in an individual s life by disrupting their daily activities and can be associated with a diminishing quality of life. Although a benign prostatic obstruction is relatively common in those with LUTS in approximately one-third of men with significant LUTS, there is no evidence of prostatic obstruction. 10 Historically, BPH was diagnosed by a variety of office-based procedures, including cystoscopy and intravenous pyelography. To assess BPH symptoms noninvasively, an objective, validated measure of voiding symptoms was developed. A symptom index for BPH was developed and validated by a multidisciplinary measurement committee of the American Urological Association. Validation studies were conducted involving a total of 210 BPH patients and 108 control individuals. The final American Urological Association symptom index includes seven questions covering frequency, nocturia, weak urinary stream, hesitancy, intermittence, incomplete emptying and urgency. On testing, the index was found to be internally consistent (Cronbach s a ¼ 0.86) and the score generated had excellent test retest reliability (r ¼ 0.92). Scores were highly correlated with participants global ratings of the magnitude of their urinary problems (r ¼ ) and discriminated well between BPH and control individuals (receiver operating characteristic area 0.85). Finally, the index was sensitive to change with preoperative (surgical) scores decreasing from a mean of 17.6 to 7.1 by 4 weeks after prostatectomy (Po0.001). The American Urological Association symptom index is clinically meaningful, reliable, valid and responsive to treatment. It is useful both for clinical practice and for inclusion in research protocols. It is noted that the average age of the men enrolled in the pivotal treatment trials of BPH was 64 years. 11 Current and historical treatment of BPH/LUTS includes the use of oral a-antagonists, such as doxazosin, tamsulosin, terazosin and alfuzosin; oral 5a-reductase inhibitors such as finasteride and dutasteride; a variety of minimally invasive and more invasive surgical options, watchful waiting and phytotherapy. LUTS and sexual function Epidemiological studies have shown that ED and BPH coexist in a large percentage of middle-aged and older men. For example, this has been shown in the recent Cologne Male Survey. 12 An age-stratified population, reflecting the German male age structure between 30 and 80 years of age, of 8000 men in the Cologne district was approached by letter with a recently developed and validated questionnaire for male ED. A total of 4883 men replied (61.0% response rate), with 4489 questionnaires (56.1%) completed and evaluable. The authors found 72.2% prevalence of LUTS in patients with ED as compared with 37.7% prevalence of LUTS in non- ED patients. 12 Additional studies have shown a consistent association between LUTS and sexual function in men In particular, the multinational survey of the aging male (MSAM)-7 study 15 showed that middle-aged and older men in seven different countries had relatively high rates of LUTS, ED and ejaculatory problems, as measured by the Danish Prostate Symptom Scale. 16 Ejaculatory problems were almost equally prevalent compared with ED, and were associated with similarly high levels of bother. 15 The MSAM-7 analyzed the survey results from men aged years in the United States and in six European countries. 15 The overall prevalence of ED (difficulty in achieving an erection) in the MSAM-7 was 49%, with 10% reporting complete absence of erections. It is noted that the overall prevalence of EjD (defined as ejaculation with decreased amount of semen or loss of ejaculation) in men able to achieve erections was 46%, with 5% of the men reporting complete absence of ejaculation. Sexual activity, which was reported as a mean of 5.9 times each month for the total sample of

3 men, decreased significantly with increasing age and severity of LUTS. Both ED and EjD were also significantly associated with the severity of LUTS (Po0.001). Furthermore, age and LUTS were stronger risk factors for ED and EjD than was diabetes, hypertension, heart disease or hyperlipidemia. 15 On the basis of this evidence of an association between common symptoms of LUTS in aging and middle-aged men and both erectile and ejaculatory problems, a new self-administered patient questionnaire was developed for assessing both erection and ejaculation problems and other core domains of sexual function in aging men the MSHQ. 17 This questionnaire was developed with 19 items in three core function domains (erection, ejaculation and satisfaction). An optional sexual desire domain was developed for additional potential use in studies of hypoactive sexual desire in men. The questionnaire has been validated in two separate studies, and has recently been administered in both patient registry and clinical trial designs. 18,19 Other self-administered questionnaires or patientreported outcome measures, 20 which are used in the assessment of sexual function, include the IIEF (15 items; five domains of male sexual function: erectile function, orgasmic function, sexual desire, intercourse satisfaction and overall satisfaction). 5,21 Brief Sexual Function Inventory includes 11 items that focus on sexual drive, erection, ejaculation, perceptions of problems in each of these areas and overall satisfaction, 22 and the International Continence Society Sex Questionnaire includes four items assessing erectile function, ejaculatory function, pain/discomfort during ejaculation and the extent to which urinary symptoms interfere with sexual function. 23 The Danish Prostate Symptom Score Sex questionnaire has also been used to assess erection, ejaculation, pain/discomfort during ejaculation and the bothersomeness of each of these items. 16 Anew self-administered questionnaire, the 25-item MSHQ, was developed in 2003 and was subjected to both qualitative and quantitative validation studies. 17 An abbreviated version of the MSHQ has recently been published. 24 Intended to replace the long-form seven-item domain of ejaculatory function in the original long-form MSHQ, the MSHQ-EjD Short Form questionnaire has only four items on ejaculation, one of which addresses bother or satisfaction: if you have had any ejaculation difficulties or have been unable to ejaculate, have you been bothered by this? The responses to this question range from not at all bothered to extremely bothered. The other three items on the scale address aspects of ejaculatory function, such as ejaculatory delay or loss of force or volume of ejaculation. The original questionnaire items for the MSHQ were developed, according to published Food and Drug Administration guidelines, 20 on the basis of selected focus groups conducted in men with and without ejaculatory and erection problems, and from a comprehensive literature review and evidencebased opinion from expert advisors. A conceptual model of the four major domains (erection, ejaculation, satisfaction and desire) was developed, which was subsequently modified in individual interviews and focus group discussion with middle-aged and older men. 17 Individual questionnaire items were developed on the basis of qualitative interviewing techniques and cognitive debriefing methodology, following closely on recent Food and Drug Administration guidelines. 20 The MSHQ includes domains for erection, ejaculation and sexual satisfaction, and provides a more in-depth assessment of ejaculatory function and sexual satisfaction than the IIEF. The full MSHQ includes additional domains for erectile function (three items) and sexual satisfaction (six items). These domains were captured in the IIEF also. The MSHQ-EjD Short Form 24 does not address erectile function (which can be captured in the short-form IIEF 25 or long form of the MSHQ. 17 The MSHQ-EjD Short Form provides a brief (4-item), easily administered short questionnaire for assessing ejaculatory function and related distress or bother in middle-aged or older men with BPH and/ or other urinary disorders. The MSHQ has been used in both clinical trials and observational studies 18,26 in middle-aged and older men. In the recently published BPH Registry, 26 for example, a high rate of both ED and EjD was observed in 6900 men with BPH/LUTS. For men in the BPH Registry database, MSHQ erection and ejaculation domain scores have been shown to correlate significantly with LUTS severity and LUTS bother, with the severity of ED and EjD increasing as LUTS severity increases. 19 MSHQ ejaculation domain scores and MSHQ-EjD Short Form scores also varied significantly among specific BPH medical therapies, particularly in men with mild/moderate LUTS. 14 Further studies to determine the optimal MSHQ-EjD Short Form cutoff scores for diagnosing EjD and classifying its severity are ongoing. Overall, the MSHQ offers a brief, validated questionnaire for use in both research and clinical settings in the diagnosis and assessment of EjD. In this way, the MSHQ provides complementary data to the IIEF 5 and other validated questionnaire measures of male sexual function. It is of particular value in identifying ejaculatory problems associated with BPH/LUTS a neglected aspect of sexual health in middle-aged and aging men. What is next on the horizon? The well-known association between BPH/LUTS and sexual dysfunction has led to ongoing trials of single pharmacologic agents being used to treat both the conditions simultaneously. Questionnaire S29

4 S30 measures such as those described above have played a key role in delineating the effects of treatment on both symptoms of BPH/LUTS and sexual dysfunction. a-adrenergic blockers, longstanding first-line therapy for BPH/LUTS, produce a modest improvement in sexual function while having a more marked effect on BPH/LUTS symptoms. 27 Rosen et al. 27 evaluated the effects of extended-release alfuzosin HCl 10 mg once daily on sexual function in men with LUTS associated with BPH. In a randomized, double-blind, placebo-controlled study of men aged X50 years, after a 28-day placebo run-in period, patients were randomized to receive alfuzosin 10 mg once daily or matching placebo for 28 days. The mean change from baseline (day 1) in sexual function on day 29 was assessed using the Danish Prostate Symptom Score Sex questionnaire. A total of 372 patients were randomized to receive alfuzosin (n ¼ 186) or placebo (n ¼ 186), with 355 completing the study. At baseline, 64% of the patients reported ED and 63% reported EjD. For the 320 patients who completed the Danish Prostate Symptom Scale Sex, alfuzosin treatment was associated with a significant improvement in the mean change from baseline in erectile function on day 29 compared with placebo (P ¼ 0.02). No significant difference was observed between the two treatment groups in the mean change from baseline in ejaculatory function on day 29. For patients with ED at baseline, a marginal improvement in erectile function was shown with alfuzosin treatment (P ¼ 0.09 vs placebo). For patients with EjD at baseline, the mean change from baseline in ejaculatory function with alfuzosin was comparable to that with placebo. Others have used oral PDE5i to treat both ED and BPH/LUTS McVary et al. 30 reported on the effects of sildenafil in treating both ED and BPH/ LUTS in a recent study. These authors conducted a 12-week, double-blind, placebo-controlled study of sildenafil in men aged 45 years or older, who scored 25 or less on the erectile function domain of the IIEF and 12 or greater on the IPSS. End points were changes in IIEF domain scores, IPSS (irritative, obstructive and quality of life), the BPH Impact Index, the Self-Esteem And Relationship questionnaire and ED Inventory of Treatment Satisfaction Index Score. The 189 men receiving sildenafil had significant improvements in erectile function domain score vs the 180 on placebo (9.17 vs 1.86, Po0.0001) and on other domains of the IIEF. Similarly, in men receiving sildenafil vs placebo, significant improvements were observed in IPSS ( 6.32 vs 1.93, Po0.0001), BPH Impact Index ( 2.0 vs 0.9, Po0.0001), mean IPSS quality of life score ( 0.97 vs 0.29, Po0.0001) and total Self-Esteem and Relationship questionnaire scores (24.6 vs 4.3, Po0.0001). There was no difference in urinary flow between the groups (P ¼ 0.08). Using tadalafil, McVary et al. 30 assessed the efficacy and safety of tadalafil dose once daily for LUTS secondary to BPH. Following a 4-week, single-blind, placebo run-in, 281 men were randomly assigned (1:1) to 5 mg tadalafil for 6 weeks, followed by dose escalation to 20 mg for 6 weeks or 12 weeks of placebo. Tadalafil significantly improved the mean change from baseline in IPSS at 6 weeks (5 mg tadalafil 2.8 vs placebo 1.2) and at 12 weeks (5/20 mg tadalafil 3.8 vs placebo 1.7). Significant improvements were also seen in the IPSS irritative and obstructive domains, the IPSS quality of life index, a question about urinary symptom improvement and the BPH Impact Index (significant at 12 weeks) vs placebo. IPSS and IIEF erectile function domain scores improved significantly in 56% of men with LUTS/BPH who were sexually active and had ED. Changes in uroflowmetry parameters were similar in the placebo and tadalafil groups. Mechanism of PDE5i efficacy on BPH/LUTS 3 0,5 0 -cyclic nucleotide PDE11 is the most recently discovered family of human 3 0,5 0 -cyclic nucleotide PDEs. This family contains one gene, PDE11A, with four splice variants (PDE11A1 PDE11A4). The physiological role of PDE11A has not been determined. Tadalafil (Cialis), a PDE5A inhibitor used for the treatment of male ED, has been reported to partially inhibit PDE11. Therefore, it was of interest to consider the pattern of expression of PDE11 in human tissues. Although four PDE11A mrna transcripts have been reported, Loughney et al. 31 detected protein corresponding to only one of them, PDE11A4, in the human prostate, pituitary, heart and liver. Using immunohistochemistry, there was strong PDE11A antibody staining in the glandular epithelium of the prostate and weak staining of neuronal cells within parasympathetic ganglia in the heart. No PDE11A protein was detected in the blood vessels or cardiac myocytes. Another recent study has provided interesting results from an in vitro study. 32 Using the organ bath technique, the effects of increasing concentrations (1 nm10 mm) of the PDE5i s sildenafil, tadalafil and vardenafil, and the PDE4i s rolipram and RP on the tension induced by norepinephrine (40 mm) of prostate strip preparations were investigated. The accumulation of cyclic guanosine monophosphate and cyclic adenosine monophosphate in response to drug exposure was determined by radioimmunoassays. The tension induced by norepinephrine was dose-dependently reversed by the drugs with the following rank order of efficacy: tadalafil4rp rolipramXvardenafil4sildenafil. The maximal reversion of tension values ranged from 52.3%

5 (tadalafil) to 17% (sildenafil). Of the PDEi s, only tadalafil induced a 50% reversion of the initial tension. The most prominent enhancement in tissue cyclic adenosine monophosphate was registered in response to RP (11-fold), and cyclic guanosine monophosphate levels were significantly elevated by tadalafil, vardenafil and sildenafil (28- fold, 12-fold and 3-fold, respectively). The results of this study provide further evidence of the direct effects of PDE5i s on smooth muscle function in the prostate. Conclusion Validated questionnaires (IPSS, IIEF and MSHQ) are a key component of clinical assessment of male voiding and sexual disorders. As noted in this paper, BPH/LUTS and sexual dysfunction share many epidemiologic similarities in middle-aged and older men. We have provided an overview of the most common self-administered questionnaires used for assessing sexual dysfunction, including the IIEF and MSHQ questionnaires. For evaluating the symptoms of LUTS, the IPSS questionnaire is currently preferred. Increasing use of these questionnaires has stimulated significant research into the co-occurrence of urinary and sexual symptoms in aging men, and in the potential use of single agents or new treatment approaches to these common and potentially distressing conditions. However, it should be noted that we currently lack a single brief instrument that can characterize both sexual dysfunction and symptoms of BPH/LUTS. However, as BPH monotherapy is contemplated for ED treatment, and PDE5i therapy is now under investigation for BPH/LUTS, the impetus to develop a single instrument is present. Disclosure Raymond Rosen has received consulting fees from sanofi-aventis, Eli Lilly, and Bayer Schering. Allen Seftel has received consulting fees, lecture fees and grant support from Eli Lilly. Allen Seftel has also received consulting fees from sanofi-aventis. References 1 NIH Consensus Conference. Impotence. 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