Psychometric validation of the Female Sexual Distress Scale-Desire/Arousal/Orgasm.

BACKGROUND: For the treatment of female sexual dysfunction, the most relevant outcome measures are patient-reported treatment effects and changes in symptoms, underscoring the need for reliable, validated patient-reported outcome (PRO) instruments. The aim of this study was to evaluate the psychometric characteristics (validity and reliability) of the Female Sexual Distress Scale-Desire/Arousal/Orgasm (FSDS-DAO) PRO measure, which was adapted from the validated FSDS-Revised (FSDS-R) questionnaire and added 2 questions involving arousal and orgasm. METHODS: Psychometric analyses were based on the data from a multicenter phase 2b dose-finding study that compared the safety and efficacy of bremelanotide versus placebo and were conducted in the evaluable modified intent-to-treat population (N = 325) from that study. Psychometric evaluation of the new items in the FSDS-DAO included confirmatory factor analyses, tests of internal consistency and test-retest reliability, examinations of convergent and discriminant validity, and determination of responsiveness. The validity of the FSDS-DAO was evaluated based on previously developed instruments, including the Female Sexual Function Index (FSFI), General Assessment Questionnaire (GAQ), Women's Inventory of Treatment Satisfaction (WITS-9), and Female Sexual Encounter Profile-Revised (FSEP-R). RESULTS: Confirmatory factor analyses demonstrated that the FSDS-DAO items fit very well (Bentler's comparative fit index of 0.929). Cronbach's α for the FSDS-DAO total score was ≥ 0.91 at Visits 1, 2, 5, and 12, demonstrating adequate internal consistency reliability. Test-retest reliability was acceptable with an intra-class coefficient of 0.61 and a Spearman's correlation coefficient score of 0.62 between Visits 1 and 2 (4 weeks). Acceptable construct validity was demonstrated by significant correlations with related PRO scales in the expected directions and magnitude. For example, participants reporting the worst levels of sexual function on the FSFI also showed the worst FSDS-DAO scores at Visits 5 and 12. The FSDS-DAO total score was responsive to change. CONCLUSIONS: Evidence supports the validity and reliability of the FSDS-DAO for assessing sexually related distress in women with female sexual arousal disorder and/or hypoactive sexual desire disorder; the addition of the arousal and orgasm items did not impact the validity and reliability of the measure. Clinical Trial Registration ClinicalTrials.gov NCT01382719.

Reliability and validity of the elements of desire questionnaire in premenopausal women with hypoactive sexual desire disorder.

BACKGROUND: The Elements of Desire Questionnaire (EDQ) is a patient-reported outcome (PRO) measure developed to evaluate sexual desire and was included in two identically designed phase 3 clinical trials (RECONNECT) as an exploratory endpoint. The EDQ was developed based on a literature review, qualitative research with patients with hypoactive sexual desire disorder (HSDD), and input from clinical experts. This instrument is intended to be used to collect efficacy data in clinical trials evaluating potential treatments for HSDD. The objective of this study was to evaluate the measurement properties of both the monthly and daily recall versions of the EDQ during the RECONNECT trials. METHODS: Participants completed the EDQ daily version for 7 consecutive days prior to selected monthly clinic visits. The monthly recall version was completed at each monthly clinic visit. The analysis population consisted of all subjects with Female Sexual Function Index (FSFI) data at baseline and ≥ 1 follow-up visit. RESULTS: At baseline, 1144 and 676 subjects completed the monthly and daily recall EDQs, respectively. The EDQ scores had good internal consistency and test-retest reliability. Monthly and daily recall EDQ scores were correlated with FSFI-desire domain scores at baseline and month 3. Scores from the monthly and daily recall versions were also correlated. After 6 months, there was a significantly greater improvement for bremelanotide versus placebo in both the monthly and daily recall versions (both P < 0.0001). CONCLUSIONS: The results demonstrated that EDQ exhibited good reliability, validity, and sensitivity to change. Consistent with other validated PRO measures of sexual desire, the EDQ provides additional insights into sexual desire. TRIAL REGISTRATION: NCT02338960 and NCT02333071 (RECONNECT studies).

Instruments for Screening, Diagnosis, and Management of Patients with Generalized Acquired Hypoactive Sexual Desire Disorder.

Screening, diagnosis, and management of hypoactive sexual desire disorder (HSDD) and research into the condition have been challenging due to its biopsychosocial complexity and lack of consensus on relevant measures. Although physician interviews yield much clinically valid information, self-reported questionnaires appear more acceptable to patients and physicians. Consequently, validated patient-reported outcome (PRO) tools are essential for evaluation and management of HSDD, including any therapeutic intervention. The US Food and Drug Administration (FDA) has issued guidance on the use of appropriate endpoints and associated measures for female sexual dysfunction, including HSDD. Although many of the available measures were not designed specifically for HSDD assessment, as per FDA guidelines, most clinical studies have used individual domains or items from established tools, such as the Female Sexual Function Index-desire domain and Item 13 of the revised Female Sexual Distress Scale. For clinical practice, several professional societies recommend the Decreased Sexual Desire Screener and/or a sexual history as tools to diagnose HSDD. This review discusses frequently used PRO tools as well as the newly developed and validated Elements of Desire Questionnaire, which may be appropriate for clinical trials or clinical practice.

Prevalence of depression and anxiety in women newly diagnosed with vulvovaginal atrophy and dyspareunia.

OBJECTIVE: To quantify the association between vulvovaginal atrophy and depression, major depressive disorder, and anxiety. METHODS: Women with vulvovaginal atrophy from the Truven Health MarketScan Commercial and Medicare Supplemental Databases (01/2010-09/2016) with ≥365 days of continuous insurance coverage before and after the first vulvovaginal atrophy/dyspareunia diagnosis (index date) were selected. Women with vulvovaginal atrophy were matched 1:3 to women without (controls) according to age, calendar year, health plan, and region. The study period spanned from 12 months before to 12 months after index date. The ratios of diagnosed depression, major depressive disorder, and anxiety among women with vulvovaginal atrophy and the controls were calculated. Logistic regressions adjusting for proxies of menopause were used to compare prevalence. RESULTS: In all, 125,889 women with vulvovaginal atrophy and 376,057 controls were included (mean age 60.7 [45-101]). The prevalence of depression, major depressive disorder, and anxiety was higher among women with vulvovaginal atrophy compared with controls (23.9% vs 18.9%, 6.3% vs 4.7%, 16.6% vs 11.3%), with prevalence ratios of 1.26, 1.33, and 1.47, respectively (all P < 0.0001). Highest prevalences and differences were observed in younger women. Findings were consistent when analyzing newly diagnosed conditions. When adjusting for proxies of menopause (insomnia, vasomotor symptoms, dysuria, and estrogen therapy), vulvovaginal atrophy remained significant (prevalence odds ratios; depression 1.23, major depressive disorder 1.22, anxiety 1.39; all P < 0.0001). CONCLUSIONS: Vulvovaginal atrophy is associated with a significantly higher prevalence/incidence of depression, major depressive disorder, and anxiety. The higher prevalence/incidence and greater differences in younger women highlight the need for a multidisciplinary approach and early diagnosis/management of vulvovaginal atrophy.

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.

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.

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.

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.

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.

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.

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.

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.

Phase I Randomized Placebo-controlled, Double-blind Study of the Safety and Tolerability of Bremelanotide Coadministered With Ethanol in Healthy Male and Female Participants.

PURPOSE: This was a Phase I study to evaluate the safety, tolerability, and hemodynamic and pharmacokinetic effects of bremelanotide (BMT) coadministered with ethanol to healthy male and female participants. METHODS: This was a randomized, placebo-controlled, double-blind, 3-period, 3-way crossover study. Individuals meeting the inclusion/exclusion criteria received BMT or placebo with or without ethanol at the research facility for 7 consecutive days. Participants were randomized to receive 1 of 6 treatment paths; each participant received single intranasal doses of BMT (20 mg) or placebo on days 1, 4, and 7, with or without oral ethanol (0.6 g/kg) while in a fasted state. The intranasal 20-mg dose of BMT has an exposure equivalent to ~1 to 2 times the subcutaneous dose currently being evaluated in Phase III studies. Vital signs, self-rated sedation scores, nursing and medical observations, and spontaneous reporting by participants provided the basis for evaluation of adverse events. A physical examination and a resting 12-lead electrocardiogram were performed at baseline and on study day 7. Blood and urine samples were obtained for clinical safety profile laboratory tests. FINDINGS: A total of 24 participants were enrolled (12 men; 12 women) and completed the study. Single doses of 20 mg intranasal BMT, administered with or without 0.6 g/kg ethanol, were found to be safe and generally well tolerated with mean maximum ethanol concentrations exceeding 80 mg/dL in women. No clinically significant pharmacokinetic interactions were found between ethanol and BMT either overall or by sex. No significant drug-related hypotensive or orthostatic hypotensive effects were noted. Treatment with BMT did not result in an increased frequency of treatment-emergent adverse events, and no participants discontinued the study because of adverse events. Physical examination, electrocardiography, and laboratory tests disclosed no clinically significant changes. IMPLICATIONS: Female sexual dysfunction is a multifactorial condition with anatomic, physiologic, medical, psychological, and social components. BMT is a synthetic peptide analogue of the naturally occurring hormone α-melanocyte-stimulating hormone and a melanocortin receptor agonist that is being developed for the treatment of hypoactive sexual desire disorder. Its mechanism of action involves activation of endogenous melanocortin hormone pathways involved in the sexual desire and arousal response. The results of this Phase I study found that BMT and ethanol can be safely coadministered and are generally well tolerated with no reports of drug-related serious adverse events. Phase III trials of subcutaneous BMT for the treatment of hypoactive sexual desire disorder in premenopausal women are in progress. ClinicalTrials.gov identifiers NCT02338960 and NCT02333071.

Hypoactive Sexual Desire Disorder: International Society for the Study of Women's Sexual Health (ISSWSH) Expert Consensus Panel Review.

The objective of the International Society for the Study of Women's Sexual Health expert consensus panel was to develop a concise, clinically relevant, evidence-based review of the epidemiology, physiology, pathogenesis, diagnosis, and treatment of hypoactive sexual desire disorder (HSDD), a sexual dysfunction affecting approximately 10% of adult women. Etiologic factors include conditions or drugs that decrease brain dopamine, melanocortin, oxytocin, and norepinephrine levels and augment brain serotonin, endocannabinoid, prolactin, and opioid levels. Symptoms include lack or loss of motivation to participate in sexual activity due to absent or decreased spontaneous desire, sexual desire in response to erotic cues or stimulation, or ability to maintain desire or interest through sexual activity for at least 6 months, with accompanying distress. Treatment follows a biopsychosocial model and is guided by history and assessment of symptoms. Sex therapy has been the standard treatment, although there is a paucity of studies assessing efficacy, except for mindfulness-based cognitive behavior therapy. Bupropion and buspirone may be considered off-label treatments for HSDD, despite limited safety and efficacy data. Menopausal women with HSDD may benefit from off-label testosterone treatment, as evidenced by multiple clinical trials reporting some efficacy and short-term safety. Currently, flibanserin is the only Food and Drug Administration-approved medication to treat premenopausal women with generalized acquired HSDD. Based on existing data, we hypothesize that all these therapies alter central inhibitory and excitatory pathways. In conclusion, HSDD significantly affects quality of life in women and can effectively be managed by health care providers with appropriate assessments and individualized treatments.

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).

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.

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.

Bremelanotide for female sexual dysfunctions in premenopausal women: a randomized, placebo-controlled dose-finding trial.

AIM: Evaluate efficacy/safety of bremelanotide (BMT), a melanocortin-receptor-4 agonist, to treat female sexual dysfunctions in premenopausal women. METHODS: Patients randomized to receive placebo or BMT 0.75, 1.25 or 1.75 mg self-administered subcutaneously, as desired, over 12 weeks. Primary end point was change in satisfying sexual events/month. Secondary end points included total score changes on female sexual function index and female sexual distress scale-desire/arousal/orgasm. RESULTS: Efficacy data, n = 327. For 1.25/1.75-mg pooled versus placebo, mean changes from baseline to study end were +0.7 versus +0.2 satisfying sexual events/month (p = 0.0180), +3.6 versus +1.9 female sexual function index total score (p = 0.0017), -11.1 versus -6.8 female sexual distress scale-desire/arousal/orgasm total score (p = 0.0014). Adverse events: nausea, flushing, headache. CONCLUSION: In premenopausal women with female sexual dysfunctions, self-administered, as desired, subcutaneous BMT was safe, effective, and well tolerated (NCT01382719).