Responder Analyses from a Phase 2b Dose-Ranging Study of Bremelanotide.

BACKGROUND: Responder analyses are used to determine whether changes that occur during a clinical trial are clinically meaningful; for subjective endpoints such as those based on patient-reported outcomes (PROs), responder analyses are particularly useful. AIM: To identify the minimal clinically important difference (MCID) for selected scores on questionnaires assessing female sexual functioning and to use these differences to analyze the response in a large, controlled, phase 2b, dose-finding study of bremelanotide in premenopausal women with hypoactive sexual desire disorder (HSDD) and mixed HSDD/female sexual arousal disorder (FSAD). METHODS: The responder analyses were performed for the change from baseline to end of study for a total of 7 endpoints. Each PRO endpoint was assessed using at least 1 of 4 types of responder analyses: a planned analysis anchored to MCIDs based on expert estimates (historical anchors); post hoc analyses based on self-reported global benefit; receiver operating characteristic (ROC) curves; and cumulative distribution function. The prespecified analysis groups were all female sexual dysfunction (FSD)-based diagnoses (all study participants), those with HSDD alone, and a combined group of those with FSAD alone plus those with mixed HSDD/FSAD. Post hoc analyses were also performed for subjects with mixed HSDD/FSAD with a primary diagnosis of HSDD. OUTCOMES: MCIDs based on the ROC curves for changes in Female Sexual Function Index-desire domain, Female Sexual Distress Scale-Desire/Arousal/Orgasm (FSDS-DAO) total score, FSDS-DAO item 13 and 14 scores, and number of satisfying sexual events. RESULTS: Outcomes matched those based on input from clinical experts. For all 7 endpoints, responder rates at the 1.75 mg dose in the overall modified intention-to-treat population achieved statistical significance compared with placebo (P ≤ .03). CLINICAL IMPLICATIONS: These responder definitions were subsequently used in the bremelanotide phase 3 registration studies (RECONNECT) that evaluated the safety and efficacy of the bremelanotide 1.75 mg subcutaneous dose in premenopausal women with HSDD. STRENGTHS & LIMITATIONS: MCIDs for this study were based on changes from a single-blind phase to account for changes due to the placebo effect. These analyses were restricted to a study population composed only of premenopausal women with a clinical diagnosis of HSDD and/or FSAD and were based on data from the same clinical trial. CONCLUSION: Bremelanotide was safe and well tolerated and demonstrated significant improvement in efficacy vs placebo in the phase 2b trial. The multiple responder analyses offer a valuable approach for determining clinically important effects of bremelanotide for HSDD and FSAD. Althof S, Derogatis LR, Greenberg S, et al. Responder Analyses from a Phase 2b Dose-Ranging Study of Bremelanotide. J Sex Med 2019;16:1226-1235.

Flibanserin for Hypoactive Sexual Desire Disorder: An Open-Label Safety Study.

BACKGROUND: To evaluate the safety of flibanserin in premenopausal and naturally postmenopausal women with hypoactive sexual desire disorder (HSDD) in an open-label extension (OLE) study. AIM: To examine the safety and tolerability of flibanserin 100 mg once daily at bedtime in the treatment of premenopausal and naturally postmenopausal women with HSDD in a multicenter 28-week OLE study. METHODS: Patients entering this study received flibanserin or placebo in the double-blinded, placebo-controlled trials of premenopausal and postmenopausal women and in a pharmacokinetic study of postmenopausal women. OUTCOMES: The primary end point of this OLE study was the incidence of adverse events (AEs). Secondary exploratory efficacy measures included the Female Sexual Distress Scale-Revised (FSDS-R) total score and FSDS-R item 13 (distress owing to low desire) score and the Female Sexual Function Index (FSFI) total score. Because the sponsor terminated the study early at discontinuation of the development of flibanserin, only descriptive statistics were calculated. RESULTS: Of the 595 patients receiving study medication, 346 and 249 patients were premenopausal and postmenopausal, respectively. The mean number of days of exposure to flibanserin was 72.8 (SD = 41.6). AEs were reported by 352 patients (59.2%), and most AEs (93.8%) were mild or moderate. The most common AEs (≥5%) were dizziness (9.6%), somnolence (8.6%), insomnia (6.2%), and nausea (5.7%). There were no flibanserin-related serious AEs and no instances of suicidal ideation. The safety profile of flibanserin was similar for premenopausal and postmenopausal women. The FSDS-R total scores and FSDS-R item 13 scores were numerically lower at weeks 4, 12, and 20 than at baseline (decrease in distress owing to low desire) for premenopausal and postmenopausal women. Mean FSFI total scores were numerically higher at weeks 4, 12, and 20 than at baseline, irrespective of menopausal status of the patients. CLINICAL IMPLICATIONS: The results of this study support the safety and tolerability of flibanserin for the treatment of HSDD in premenopausal and naturally postmenopausal women. STRENGTHS AND LIMITATIONS: Although this open-label study was designed to be 28 weeks long, it was discontinued early by the sponsor, and patients' maximum duration of exposure to flibanserin was 23.9 weeks. The open-label design and lack of a placebo-controlled arm are other study limitations. CONCLUSION: In this open-label study, flibanserin 100 mg once daily at bedtime was generally safe and well tolerated by premenopausal and naturally postmenopausal women with HSDD. Simon JA, Derogatis L, Portman D, et al. Flibanserin for Hypoactive Sexual Desire Disorder: An Open-Label Safety Study. J Sex Med 2018;15:387-395.

Psychometric Properties of the Sexual Event Diary in a Sample of Dutch Women With Female Sexual Interest/Arousal Disorder.

BACKGROUND: Efficacy of on-demand drugs for women with hypoactive sexual desire disorder or female sexual interest/arousal disorder (FSIAD) should be assessed using a validated instrument that assesses the discrete sexual events during which the on-demand drug is taken, because this type of assessment is more proximate to an on-demand drug's efficacy compared to instruments that assess sexual function over longer periods of time. AIM: The aim of this study was to assess the psychometric properties of the Dutch translation of the previously validated 11-item Sexual Event Diary (SED) for measuring sexual satisfaction and sexual functioning during discrete sexual events. METHODS: Psychometric assessment was performed on data of 1,840 SEDs from 139 women with hypoactive sexual desire disorder/FSIAD, collected during a randomized clinical cross-over trial conducted in the Netherlands. OUTCOMES: Item scores of the SED at the event level, and at subject level, summarized item scores during the placebo run-in period (PRI) and active treatment period, and score changes from PRI to active treatment period. RESULTS: Reliability and convergent validity were confirmed. All item scores showed the ability to discriminate between known groups. Larger mean score changes from PRI were observed in groups with known benefit from the medication, as compared to those with no benefit. Guyatt effect sizes ranged from 0.51-1.02, thereby demonstrating ability to detect change. CLINICAL TRANSLATION: The Dutch version of the SED is an excellent instrument for assessing female sexual functioning and sexual satisfaction during discrete sexual events and for assessing these concepts over longer periods of time. CONCLUSIONS: Data were collected in a randomized, well-controlled trial. The large number of data points gave high statistical power, and the results confirmed previous findings. However, care is needed when generalizing the SED's validity to other areas of research, eg, recreational drug use and sexual risky behaviors, since the current validation study has not used such data. Consistent with the US-English version, the Dutch version of the SED is a reliable, valid, and responsive instrument, and suitable for use in evaluating effects of on-demand drugs in women with FSIAD. van Nes Y, Bloemers J, Kessels R, et al. Psychometric Properties of the Sexual Event Diary in a Sample of Dutch Women With Female Sexual Interest/Arousal Disorder. J Sex Med 2018;15:722-731.

Validity and Clinically Meaningful Changes in the Psychosexual Daily Questionnaire and Derogatis Interview for Sexual Function Assessment: Results From the Testosterone Trials.

BACKGROUND: Limited information is available on the performance characteristics of 2 questionnaires commonly used in clinical research, the Psychosexual Daily Questionnaire (PDQ) and the Derogatis Interview for Sexual Function (DISF)-II Assessment, especially in older men with low testosterone (T) and impaired sexual function. AIM: To determine reliability of PDQ and DISF-II by assessing the correlation within and between domains in the questionnaires and to define clinically meaningful changes in sexual activity (PDQ question 4 [Q4]) and desire (DISF-II sexual desire domain [SDD]) domains. METHODS: Data from 470 men participating in the T Trials were used to calculate Spearman correlation coefficients of individual items and total score among questionnaires to determine convergent and construct validity. Clinically meaningful changes for sexual desire and activity were determined by randomly dividing the sample into training and validation sets. Anchor- and distribution-based clinically meaningful change criteria were defined in the training set, and selected changes were evaluated in the validation set. OUTCOMES: Validity of the PDQ and DISF-II and clinically meaningful changes in sexual desire and activity were determined in older men in T Trials. RESULTS: Moderate to strong correlations were shown within and between domains from different questionnaires. Using Patient Global Impression of Change as an anchor, clinically meaningful change in PDQ sexual activity was ≥0.6, and in DISF-SDD was ≥5.0. Applying these change cut-points to the validation set, a greater proportion of T-treated men achieved clinically meaningful improvement in their sexual desire and activity compared to placebo-treated men. CLINICAL IMPLICATIONS: The PDQ-Q4 and DISF-II-SDD can be used to reliably assess clinically meaningful changes in sexual activity and sexual desire in hypogonadal men treated with T. STRENGTHS & LIMITATIONS: Strengths of this study include a large sample size, long trial duration, and inclusion of men with low libido and unequivocally low T levels. Limitations include using data from a single study that enrolled only older hypogonadal men, and only 1 anchor for both sexual desire and activity. CONCLUSION: Moderate to strong correlations were demonstrated within and between different sexual domains of the PDQ and DISF-II confirming construct and convergent validity. Clinically meaningful improvement in elderly hypogonadal men was change of ≥0.6 score in the PDQ-Q4 and ≥5.0 in the DISF-SDD. Improvements in sexual activity and desire in the T Trials were modest but clinically meaningful. Wang C, Stephens-Shields AJ, DeRogatis LR, et al. Validity and Clinically Meaningful Changes in the Psychosexual Daily Questionnaire and Derogatis Interview for Sexual Function Assessment: Results From the Testosterone Trials. J Sex Med 2018;15:997-1009.

Efficacy and Safety of On-Demand Use of 2 Treatments Designed for Different Etiologies of Female Sexual Interest/Arousal Disorder: 3 Randomized Clinical Trials.

BACKGROUND: In women, low sexual desire and/or sexual arousal can lead to sexual dissatisfaction and emotional distress, collectively defined as female sexual interest/arousal disorder (FSIAD). Few pharmaceutical treatment options are currently available. AIM: To investigate the efficacy and safety of 2 novel on-demand pharmacologic treatments that have been designed to treat 2 FSIAD subgroups (women with low sensitivity for sexual cues and women with dysfunctional over-activation of sexual inhibition) using a personalized medicine approach using an allocation formula based on genetic, hormonal, and psychological variables developed to predict drug efficacy in the subgroups. METHODS: 497 women (21-70 years old) with FSIAD were randomized to 1 of 12 8-week treatment regimens in 3 double-blinded, randomized, placebo-controlled, dose-finding studies conducted at 16 research sites in the United States. Efficacy and safety of the following on-demand treatments was tested: placebo, testosterone (T; 0.5 mg), sildenafil (S; 50 mg), buspirone (B; 10 mg) and combination therapies (T 0.25 mg + S 25 mg, T 0.25 mg + S 50 mg, T 0.5 mg + S 25 mg, T 0.5 mg + S 50 mg, and T 0.25 mg + B 5 mg, T 0.25 mg + B 10 mg, T 0.5 mg + B 5 mg, T 0.5 mg + B 10 mg). OUTCOMES: The primary efficacy measure was the change in satisfying sexual events (SSEs) from the 4-week baseline to the 4-week average of the 8-week active treatment period after medication intake. For the primary end points, the combination treatments were compared with placebo and the respective monotherapies on this measure. RESULTS: In women with low sensitivity for sexual cues, 0.5 mg T + 50 mg S increased the number of SSEs from baseline compared with placebo (difference in change [Δ] = 1.70, 95% CI = 0.57-2.84, P = .004) and monotherapies (S: Δ = 1.95, 95% CI = 0.44-3.45, P = .012; T: Δ = 1.69, 95% CI = 0.58-2.80, P = .003). In women with overactive inhibition, 0.5 mg T + 10 mg B increased the number of SSEs from baseline compared with placebo (Δ = 0.99, 95% CI = 0.17-1.82, P = .019) and monotherapies (B: Δ = 1.52, 95% CI = 0.57-2.46, P = .002; T: Δ = 0.98, 95% CI = 0.17-1.78, P = .018). Secondary end points followed this pattern of results. The most common drug-related side effects were flushing (T + S treatment, 3%; T + B treatment, 2%), headache (placebo treatment, 2%; T + S treatment, 9%), dizziness (T + B treatment, 3%), and nausea (T + S treatment, 3%; T + B treatment, 2%). CLINICAL IMPLICATIONS: T + S and T + B are promising treatments for women with FSIAD. STRENGTHS AND LIMITATIONS: The data were collected in 3 well-designed randomized clinical trials that tested multiple doses in a substantial number of women. The influence of T + S and T + B on distress and the potentially sustained improvements after medication cessation were not investigated. CONCLUSIONS: T + S and T + B are well tolerated and safe and significantly increase the number of SSEs in different FSIAD subgroups. Tuiten A, van Rooij K, Bloemers J, et al. Efficacy and Safety of On-Demand Use of 2 Treatments Designed for Different Etiologies of Female Sexual Interest/Arousal Disorder: 3 Randomized Clinical Trials. J Sex Med 2018;15:201-216.

Effect of Single-Treatment, Surface-Cooled Radiofrequency Therapy on Vaginal Laxity and Female Sexual Function: The VIVEVE I Randomized Controlled Trial.

INTRODUCTION: Vaginal laxity is a highly prevalent and undertreated medical condition. AIM: To evaluate the efficacy and safety of surface-cooled, monopolar radiofrequency (RFc) therapy for the treatment of vaginal laxity in the VIVEVE I trial. METHODS: The VIVEVE I trial was a prospective, randomized, single-blinded, and sham-controlled study. Nine study centers in Canada, Italy, Spain, and Japan participated. Women presenting with vaginal laxity were screened and informed consent was obtained. Major study inclusion criteria were premenopausal status, age at least 18 years, at least one full-term vaginal delivery, and normal genito-pelvic examination results. Enrolled subjects were randomized (2:1) to receive RFc therapy (Active [90 J/cm2] vs Sham [1 J/cm2], respectively) delivered to the vaginal tissue. MAIN OUTCOME MEASURES: The primary efficacy outcome was the proportion of randomized subjects reporting "no vaginal laxity" (Active vs Sham) at 6 months postintervention, which was assessed using the Vaginal Laxity Questionnaire. Treatment-emergent adverse events were evaluated in all treated subjects. Secondary efficacy end points included change on the Female Sexual Function Index (FSFI) and the revised Female Sexual Distress Scale (FSDS-R). RESULTS: No vaginal laxity was achieved by 43.5% and 19.6% (P = .002) in the Active and Sham groups, respectively. Differences in FSFI and FSDS-R total scores (Active vs Sham) were 1.8 (P = .031) and -2.42 (P = .056), respectively, in favor of Active treatment. Treatment-emergent adverse events were reported by 11.1% and 12.3% of subjects in the Active and Sham arms, respectively. CONCLUSION: The VIVEVE I trial is the first randomized, controlled, blinded, clinical study of RFc for the treatment of vaginal laxity. A single treatment of RFc therapy was found to be safe and associated with both improved vaginal laxity and improved sexual function. The results from this trial support the use of a novel non-surgical therapy for vaginal laxity, a prevalent and undertreated condition.

Psychometric Evaluation of the Hypogonadism Impact of Symptoms Questionnaire Short Form (HIS-Q-SF).

BACKGROUND: The Hypogonadism Impact of Symptoms Questionnaire Short Form (HIS-Q-SF) is a patient-reported outcome measurement designed to evaluate the symptoms of hypogonadism. The HIS-Q-SF is an abbreviated version including17 items from the original 28-item HIS-Q. AIM: To conduct item analyses and reduction, evaluate the psychometric properties of the HIS-Q-SF, and provide guidance on score interpretation. METHODS: A 12-week observational longitudinal study of hypogonadal men was conducted as part of the original HIS-Q psychometric evaluation. Participants completed the original HIS-Q every 2 weeks. Blood samples were collected to evaluate testosterone levels. Participants completed the Aging Male's Symptoms Scale, the International Index of Erectile Function, the Short Form-12, and the PROMIS Sexual Activity, Satisfaction with Sex Life, Sleep Disturbance, and Applied Cognition Scales (baseline and weeks 6 and 12). Clinicians completed the Clinical Global Impression of Severity and Change scales and a clinical form. MAIN OUTCOME MEASURES: Item performance was evaluated using descriptive statistics and Rasch analyses. Reliability (internal consistency and test-retest), validity (concurrent and know groups), and responsiveness were assessed. RESULTS: One hundred seventy-seven men participated (mean age = 54.1 years, range = 23-83). Similar to the full HIS-Q, the final abbreviated HIS-Q-SF instrument includes five domains (sexual, energy, sleep, cognition, and mood) with two sexual subdomains (libido and sexual function). For key domains, test-retest reliability was very good, and construct validity was good for all domains. Known-groups validity was demonstrated for all domain scores, subdomain scores, and total score based on the Clinical Global Impression-Severity. All domains and subdomains were responsive to change based on patient-rated anchor questions. CLINICAL IMPLICATIONS: The HIS-Q-SF could be a useful tool in clinical practice, epidemiologic studies, and other academic research settings. STRENGTHS AND LIMITATIONS: Careful consideration was given to the selection of the final HIS-Q-SF items based on quantitative data and clinical expert feedback. Overall, the reduced set of items demonstrated strong psychometric properties. Testosterone levels for the participating men were not as low as anticipated, which could have limited the ability to examine the relations between the HIS-Q-SF and testosterone levels. Further, the analyses used data collected through administration of the full HIS-Q, and future studies should administer the standalone HIS-Q-SF to replicate the psychometric analyses reported in the present study. CONCLUSION: Similar to the original HIS-Q, the HIS-Q-SF has evidence supporting reliability, validity, and responsiveness. The short form includes a smaller set of items that might be more suitable for use in clinical practice or academic research settings. Gelhorn HL, Roberts LJ, Khandelwal N, et al. Psychometric Evaluation of the Hypogonadism Impact of Symptoms Questionnaire Short Form (HIS-Q-SF). J Sex Med 2017;14:1046-1058.

The Sexual Event Diary (SED): Development and Validation of a Standardized Questionnaire for Assessing Female Sexual Functioning During Discrete Sexual Events.

BACKGROUND: The efficacy of on-demand drugs for hypoactive sexual desire disorder (HSDD) or female sexual interest/arousal disorder (FSIAD) should be assessed using a validated instrument that assesses the discrete sexual events during which the on-demand drug is taken. AIM: To develop and validate an event log for measuring sexual satisfaction and sexual functioning of discrete sexual events. METHODS: Psychometric assessment was carried out on data of 10,959 Sexual Event Diaries (SEDs) collected during three clinical trials in a total of 421 women with HSDD. Cognitive debriefing interviews were held with 16 women with HSDD. OUTCOMES: Item scores of the SED at the event level and at the subject level, summarized item scores of women during the baseline establishment and active treatment periods, and score changes in women from baseline establishment to active treatment. RESULTS: Several items of the initial 16-item SED items showed weak validity. The 16-item SED was refined to the 11-item SED. The reliability, content, and convergent validity of the 11-item SED were confirmed. For most 11-item SED item scores, the ability to discriminate between known groups was confirmed. Larger mean score changes from the baseline establishment period were found in those with than in those without known benefit from the medication, and Guyatt effect sizes ranged from 0.73 to 1.58, thereby demonstrating the ability to detect change. CLINICAL TRANSLATION: The SED is a good tool for assessing sexual function during a discrete sexual event and for assessing the sexual function of women over longer periods. STRENGTHS AND LIMITATIONS: The validation of the SED was performed on data from nearly 11,000 sexual events, gathered as part of a drug development program for HSDD and FSIAD. This amount of data provides very robust results when related to drug use for HSDD and FSIAD, but caution is advised when generalizing the validity of the SED directly to other areas of research (eg, recreational drug use and sexual risky behaviors), because such data were not used in this validation. CONCLUSIONS: The 11-item SED is a reliable, valid, and responsive instrument and suitable for use in evaluating the effects of on-demand drugs in women with HSDD or FSIAD. van Nes Y, Bloemers J, van der Heijden PGM, et al. The Sexual Event Diary (SED): Development and Validation of a Standardized Questionnaire for Assessing Female Sexual Functioning During Discrete Sexual Events. J Sex Med 2017;14:1438-1450.

Toward a More Evidence-Based Nosology and Nomenclature for Female Sexual Dysfunctions-Part I.

INTRODUCTION: A nomenclature is defined as a classification system for assigning names or terms in a scientific discipline. A nosology more specifically provides a scientific classification system for diseases or disorders. Historically, the nosologic system informing female sexual dysfunction (FSD) has been the system developed by the American Psychiatric Association in its Diagnostic and Statistical Manual of Mental Disorders (DSM-III through DSM-5). Experts have recognized limitations of its use in clinical practice, including concerns that the DSM-5 system does not adequately reflect the spectrum and presentation of FSD. AIM: To review the central considerations and issues that underlie the development of a new evidence-based nomenclature that reliably and validly defines the categories of FSD and will effectively function in clinical and research settings, serve as a basis for International Classification of Diseases (ICD) codes, and provide regulatory guidance for interventions designed as FSD treatments. METHODS: The International Society for the Study of Women's Sexual Health conducted a 2-day conference on nomenclature for FSD in December 2013. Key opinion leaders representing diverse areas of expertise discussed ideal characteristics, existing DSM definitions, and current and future ICD coding to develop consensus for this new nomenclature. MAIN OUTCOME MEASURE: A comprehensive appreciation of the parameters and characteristics essential to a new FSD nomenclature and terminology that will serve as the principal nosology for the description and diagnosis of FSD. RESULTS: A critical appraisal of the essential elements of a classification system for diagnosing FSD was accomplished. The applicability of DSM-5 FSD definitions was challenged; and the considerations for developing a new nomenclature were discussed, including comorbidities, clinical thresholds, alternative etiologies, and validity. CONCLUSION: The essential elements for developing a valid, reliable, credible, and clinically applicable nosology for FSD were enumerated as a preamble to constructing the actual nosologic system (Part II).

TX-004HR Improves Sexual Function as Measured by the Female Sexual Function Index in Postmenopausal Women With Vulvar and Vaginal Atrophy: The REJOICE Trial.

INTRODUCTION: TX-004HR is an investigational, applicator-free, vaginal soft gel capsule containing low-dose solubilized 17ß-estradiol. The phase 3, randomized, double-blinded, placebo-controlled, multicenter REJOICE trial has shown TX-004HR to be safe and effective for the treatment of moderate to severe dyspareunia in postmenopausal women with vulvar and vaginal atrophy (VVA). AIM: To evaluate the effect of TX-004HR on female sexual dysfunction in postmenopausal women with VVA. METHODS: The REJOICE study compared the effects of 12-week treatment with TX-004HR (4, 10, or 25 µg) with placebo in postmenopausal women (40-75 years old) with VVA and a most bothersome symptom of moderate to severe dyspareunia. Changes in the percentage of superficial and parabasal cells, vaginal pH, and dyspareunia were measured as co-primary end points. Female sexual dysfunction was evaluated as a secondary end point using the Female Sexual Function Index (FSFI) patient self-report inventory. MAIN OUTCOME MEASURES: Changes from baseline to week 12 in total and individual domain FSFI scores for each TX-004HR dose were compared with those for placebo. RESULTS: All three TX-004HR doses increased the baseline total FSFI score after 12 weeks, with 10 µg (P < .05) and 25 µg (P = .0019) having a significantly greater effect than placebo. A similar trend was observed for the individual FSFI domains, with 10 and 25 µg significantly improving baselines scores for pain and lubrication at 12 weeks (P ≤ .015 for all vs placebo). Changes from baseline to week 12 in arousal (P = .0085) and satisfaction (P = .0073) were significantly greater for TX-004HR 25 µg vs placebo. All three TX-004HR doses were comparable to placebo in their effect on desire and orgasm. CONCLUSION: TX-004HR improved FSFI scores in a dose-dependent manner. The observed improvements in sexual function suggest that TX-004HR is a promising treatment option for postmenopausal VVA with a potential added beneficial effect on female sexual dysfunction.

Psychometric Evaluation of the Hypogonadism Impact of Symptoms Questionnaire.

INTRODUCTION: The Hypogonadism Impact of Symptoms Questionnaire (HIS-Q) is a patient-reported outcome measurement designed to comprehensively evaluate the symptoms of hypogonadism and to detect changes in these symptoms in response to treatment. AIM: To conduct item analysis and reduction, evaluate the psychometric properties of the HIS-Q, and provide guidance on interpreting the instrument score. METHODS: A 12-week observational, longitudinal study of hypogonadal men was conducted. Participants completed the HIS-Q every 2 weeks. Blood samples were collected to evaluate testosterone levels. Participants also completed the Aging Male's Symptoms Scale, the International Index of Erectile Function, the Short Form-12 Health Survey, and the Patient-Reported Outcomes Measurement Information System Sexual Activity, Satisfaction with Sex Life, Sleep Disturbance, and Applied Cognition Scales (at baseline and weeks 6 and 12). Clinicians completed the Clinical Global Impression of Severity and Change measurements and a clinical form. MAIN OUTCOME MEASURES: Individual item performance was evaluated using descriptive statistics and Rasch analyses. Reliability (internal consistency and test-retest), validity (concurrent and know groups), and responsiveness were assessed. RESULTS: In total, 177 men participated in the study (mean age = 54.1 years, range = 23-83). The original 53-item draft HIS-Q was reduced to 28 items; the final instrument included five domains (sexual, energy, sleep, cognition, and mood) with two sexual subdomains (libido and sexual function). For all domains, test-retest reliability was acceptable (intraclass correlation coefficients > 0.70), construct validity was good (|r > 0.30| for all comparisons). Known-groups validity was demonstrated for all HIS-Q domain scores, subdomain scores, and the total score as measured by the Clinical Global Impression of Severity, and total testosterone level at baseline (P < .05 for all comparisons). All domains and subdomains were responsive to change based on patient-rated anchor questions (P < .05 for all comparisons). CONCLUSION: The final 28-item HIS-Q is reliable, valid, and responsive. The HIS-Q is suitable for inclusion in future clinical trials to help characterize the effects of testosterone replacement therapy.

Development of the Hypogonadism Impact of Symptoms Questionnaire Short Form: Qualitative Research.

INTRODUCTION: Hypogonadism in men is often associated with poor libido, erectile dysfunction, irritability, fatigue, and psychological and relationship problems. Many of these symptoms can be best assessed through patient report. The 28-item Hypogonadism Impact of Symptoms Questionnaire (HIS-Q) was developed to evaluate hypogonadism symptoms in men with low testosterone in the context of clinical trials. AIM: To develop a briefer version of the HIS-Q that could be practical for use in treatment settings. METHODS: Participants with low testosterone levels and symptoms consistent with hypogonadism were recruited through clinical sites. Focus groups and interviews were conducted to elicit symptom concepts and identify those that were most relevant to patients, including changes as a consequence of treatment. MAIN OUTCOME MEASURES: Systematic analysis of the qualitative data and expert clinician input were used to develop the HIS-Q short form (HIS-Q-SF). One-on-one cognitive interviews were conducted to confirm the content validity of the HIS-Q-SF. RESULTS: Thirty-five men participated in this qualitative research. Concept elicitation was conducted through focus group discussions (n = 18) and telephone interviews (n = 2); then, the draft HIS-Q-SF was evaluated through cognitive interviews (n = 15). The mean age of total sample was 53.2 ± 6.8 years, and the mean serum total testosterone level was 184.9 ± 55.2 ng/dL. Results suggest that the HIS-Q-SF has demonstrated content validity, including the content coverage, comprehensibility, and the appropriateness of the response options and recall period. The final version of the HIS-Q-SF includes 17 items and is aligned with the original longer version of the instrument. CONCLUSION: The HIS-Q-SF is a comprehensive measurement of hypogonadism symptom severity in men. Content coverage and content validity were confirmed. The instrument will be evaluated further to establish the psychometric characteristics and to assess the utility of the measurement in clinical treatment settings.

Effect of Intravaginal Prasterone on Sexual Dysfunction in Postmenopausal Women with Vulvovaginal Atrophy.

INTRODUCTION: Previous data have shown that intravaginal dehydroepiandrosterone (DHEA, prasterone) improved all the domains of sexual function, an effect most likely related to the local formation of androgens from DHEA. AIMS: To confirm in a placebo-controlled, prospective, double-blind and randomized study the benefits of daily intravaginal DHEA for 12 weeks on sexual function using the Female Sexual Function Index (FSFI) questionnaire. METHODS: Placebo was administered daily to 157 women while 325 women received 0.50% (6.5 mg) DHEA daily for 12 weeks. All women were postmenopausal meeting the criteria of vulvovaginal atrophy (VVA), namely moderate to severe dyspareunia as their most bothersome symptom of VVA in addition to having ≤5% of vaginal superficial cells and vaginal pH > 5.0. The FSFI questionnaire was filled at baseline (screening and day 1), 6 weeks and 12 weeks. Comparison between DHEA and placebo of the changes from baseline to 12 weeks was made using the analysis of covariance test, with treatment group as the main factor and baseline value as the covariate. MAIN OUTCOME MEASURES: The six domains and total score of the FSFI questionnaire were evaluated. RESULTS: The FSFI domain desire increased over placebo by 0.24 unit (+49.0%, P = 0.0105), arousal by 0.42 unit (+56.8%, P = 0.0022), lubrication by 0.57 unit (+36.1%, P = 0.0005), orgasm by 0.32 unit (+33.0%, P = 0.047), satisfaction by 0.44 unit (+48.3%, P = 0.0012), and pain at sexual activity by 0.62 unit (+39.2%, P = 0.001). The total FSFI score, on the other hand, has shown a superiority of 2.59 units in the DHEA group over placebo or a 41.3% greater change than placebo (P = 0.0006 over placebo). CONCLUSION: The present data show that all the six domains of the FSFI are improved over placebo (from P = 0.047 to 0.0005), thus confirming the previously observed benefits of intravaginal DHEA on female sexual dysfunction by an action exerted exclusively at the level of the vagina, in the absence of biologically significant changes of serum steroids levels.

Psychometric properties of the Iranian version of the female sexual distress scale-revised in women.

INTRODUCTION: Several tools for the assessment of sexuality-related distress are now available. The Female Sexual Distress Scale (FSDS) and its revised version (FSDS-R) are extensively validated and among the most widely used tools to measure sexually related personal distress. AIM: The aim of the study was to determine the psychometric properties of the Iranian version of the FSDS-R in a population sample of Iranian women. METHODS: A total of 2,400 married and potentially sexually active women were recruited and categorized into three groups including (i) a healthy control group; (ii) a group of women with hypoactive sexual desire disorder (HSDD); and (iii) a group of women suffering from other female sexual dysfunction (FSD). Participants were asked to complete a set of questionnaires including the Iranian version of the Female Sexual Function Index (FSFI-IV), the FSDS-R, and the Hospital Anxiety and Depression Scale. MAIN OUTCOME MEASURES: Sexuality-related distress and FSD as assessed by the Iranian version of the FSDS-R and the FSFI-IV are the main outcome measures. RESULTS: Internal consistencies and test-retest reliability of the FSDS-R across the three assessments points for the three groups were >0.70. The FSDS-R correlated significantly with anxiety, depression, and the FSFI total score. Significant differences in the FSDS-R scores were found between healthy women, women with HSDD, and women with other types of FSD. Factor analysis of the FSDS-R yielded a single-factor model with an acceptable fit. CONCLUSIONS: The Persian version of the FSDS-R is a valid and reliable instrument for the assessment of sexuality-related distress in Iranian women and can be used to screen patients with HSDD.

Efficacy of flibanserin in women with hypoactive sexual desire disorder: results from the BEGONIA trial.

INTRODUCTION: Hypoactive Sexual Desire Disorder (HSDD) is characterized by low sexual desire that causes marked distress or interpersonal difficulty. AIM: The aim of this study was to assess the efficacy and safety of the 5-HT1A agonist/5-HT2A antagonist flibanserin in premenopausal women with HSDD. METHODS: This was a randomized, placebo-controlled trial in which premenopausal women with HSDD (mean age: 36.6 years) were treated with flibanserin 100 mg once daily at bedtime (qhs) (n = 542) or placebo (n = 545) for 24 weeks. MAIN OUTCOME MEASURES: Coprimary end points were the change from baseline to study end in Female Sexual Function Index (FSFI) desire domain score and in number of satisfying sexual events (SSE) over 28 days. Secondary end points included the change from baseline in FSFI total score, Female Sexual Distress Scale-Revised (FSDS-R) total score, and FSDS-R Item 13 score. RESULTS: Compared with placebo, flibanserin led to increases in mean (standard deviation) SSE of 2.5 (4.6) vs. 1.5 (4.5), mean (standard error [SE]) FSFI desire domain score of 1.0 (0.1) vs. 0.7 (0.1), and mean (SE) FSFI total score of 5.3 (0.3) vs. 3.5 (0.3); and decreases in mean (SE) FSDS-R Item 13 score of -1.0 (0.1) vs. -0.7 (0.1) and mean (SE) FSDS-R total score of -9.4 (0.6) vs. -6.1 (0.6); all P ≤ 0.0001. The most frequently reported adverse events in the flibanserin group were somnolence, dizziness, and nausea, with adverse events leading to discontinuation in 9.6% of women receiving flibanserin vs. 3.7% on placebo. CONCLUSION: In premenopausal women with HSDD, flibanserin 100 mg qhs resulted in significant improvements in the number of SSE and sexual desire (FSFI desire domain score) vs. placebo. Flibanserin was associated with significant reductions in distress associated with sexual dysfunction (FSDS-R total score) and distress associated with low sexual desire (FSDS-R Item 13) vs. placebo. There were no significant safety concerns associated with the use of flibanserin for 24 weeks.

Association of major depression with sexual dysfunction in men.

The effect of type and severity of depression on sexual functioning was examined before treatment in 591 men with Major Depression (MDD) or Atypical Depression, as determined by percentage of subjects meeting Diagnostic and Statistical Manual, 4th Edition (DSM-IV) sexual dysfunction criteria (A and B only), and percentage with Derogatis Inventory of Sexual Function (DISF) scores greater than 1 standard deviation below normal. Sexual dysfunction rates were higher for MDD than for Atypical Depression. Depression affected DISF domains differently: orgasm was most impaired, whereas sexual desire was preserved. More severe depression resulted in greater sexual dysfunction.

Validity of the decreased sexual desire screener for diagnosing hypoactive sexual desire disorder.

The decreased sexual desire screener is a brief diagnostic instrument for generalized acquired hypoactive sexual desire disorder in women. During the screening visit of 2 clinical trials, the authors assessed sensitivity of the decreased sexual desire screener in premenopausal women presenting with decreased sexual desire. The authors compared diagnoses of generalized acquired hypoactive sexual desire disorder made by clinicians who were not trained or specialized in the diagnosis of female sexual dysfunction using the decreased sexual desire screener with diagnoses made by expert clinicians after an extensive diagnostic interview. The sensitivity of the decreased sexual desire screener was 0.946 in a North American trial and 0.960 in a European trial.

Effect of testosterone replacement on response to sildenafil citrate in men with erectile dysfunction: a parallel, randomized trial.

BACKGROUND: Erectile dysfunction and low testosterone levels frequently occur together. OBJECTIVE: To determine whether addition of testosterone to sildenafil therapy improves erectile response in men with erectile dysfunction and low testosterone levels. DESIGN: Randomized, double-blind, parallel, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00512707) SETTING: Outpatient academic research center. PARTICIPANTS: Men aged 40 to 70 years with scores of 25 or less for the erectile function domain (EFD) of the International Index of Erectile Function, total testosterone levels less than 11.45 nmol/L (<330 ng/dL), or free testosterone levels less than 173.35 pmol/L (<50 pg/mL). INTERVENTION: Sildenafil dose was optimized, and 140 participants were then randomly assigned to 14 weeks of daily transdermal gel that contained 10-g testosterone for 70 participants and placebo for the remaining 70 participants. All participants were included in the primary analysis, although 10 in the testosterone group and 12 in the placebo group did not complete the study. RESULTS: At baseline, the 2 groups had similar EFD scores. Administration of sildenafil alone was associated with a substantial increase in EFD score (mean, 7.7 [95% CI, 6.5 to 8.8]), but change in EFD score after randomization did not differ between the groups (difference, 2.2 [CI, -0.8 to 5.1]; P = 0.150). The findings were similar for other domains of sexual function in younger men, more obese men, and men with lower baseline testosterone levels or an inadequate response to sildenafil alone. Frequency of adverse events was similar for testosterone and placebo groups. LIMITATION: Whether testosterone could improve erectile function without sildenafil was not studied. CONCLUSION: Sildenafil plus testosterone was not superior to sildenafil plus placebo in improving erectile function in men with erectile dysfunction and low testosterone levels. PRIMARY FUNDING SOURCE: National Institute of Child Health and Human Development.

How to evaluate the efficacy of the phosphodiesterase type 5 inhibitors.

INTRODUCTION: Several methods have been so far proposed to compare the effectiveness of the three available phosphodiesterase type 5 inhibitors (PDE5Is). METHODS: Two urologists (E.C. and G.B.B.), together with the Controversy's Editor (E.A.J.), with expertise in the area of medical treatment of erectile dysfunction (ED) present the various perspectives on the evaluation of PDE5Is in ED. The use of the most popular psychometric tool, the International Index of Erectile Function, is presented by an expert psychologist (L.R.D.). MAIN OUTCOME MEASURES: Expert opinion supported by the critical review of the currently available literature. RESULTS: Trials have demonstrated that the PDE5Is are excellent drugs with a great specificity of action and an almost perfect tolerance profile. Some instruments for comparison of clinical efficacy have to be considered subjective (psychometry, patient's preference, changes in quality of general, or sexual life). Some others are more objective (hardness, hormonal levels, and local circulation). An evidence-based comparison of the three PDE5Is should in the future be rooted in both subjective and objective methods. This will be of paramount importance in the drug trial design of new, forthcoming PDE5Is. CONCLUSIONS: Comparison between PDE5Is using both subjective and objective parameters will permit to individuate, on the basis of the evidence, the subset of couples where one drug, or one dose, or dose regimen, is to be considered of first choice.

Intended or unintended consequences? The likely implications of raising the bar for sexual dysfunction diagnosis in the proposed DSM-V revisions: 2. For women with loss of subjective sexual arousal.

INTRODUCTION: Brotto proposes to combine female sexual desire and arousal disorders in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition. AIM: We provide evidence that the proposed criteria could potentially exclude from diagnosis or treatment a large number of women with distressing dysfunction in sexual arousal. METHODS: Rating scale data from nontreatment validation studies of patient-reported outcome measures including almost 500 women in North America and Europe, including 49 women diagnosed with arousal disorder only, were compared with the proposed criteria. MAIN OUTCOME MEASURES: The main measures were an early version of the eDiary (an electronic diary on sexual activity) and four previously validated measures of female sexual dysfunction (FSD), the clinician-rated Sexual Interest and Desire Inventory-Female and the self-rated Female Sexual Function Index, Changes in Sexual Functioning Questionnaire, and Female Sexual Distress Scale. Results. The women with female sexual arousal disorder (FSAD) scored as manifestly sexually dysfunctional and significantly sexually distressed. They had fewer satisfying sexual events (SSEs) vs. women with no FSD, with a lower proportion of SSEs, and significantly fewer orgasms. CONCLUSION: Despite evidence presented that women with FSAD have clinically disordered sexual function, our data also suggest that the majority of these women with FSAD would meet none of the six proposed "A" criteria for Sexual Interest/Arousal Disorder, raising new validity and utility concerns for the proposed diagnostic classification. Suggestions are made to modify the proposed new criteria so as to include such distressed women.