Sexual Dysfunction and Dyspareunia in the Setting of the Genitourinary Syndrome of Menopause.

Sexual dysfunction is a common consequence of the genitourinary syndrome of menopause (GSM). In this book chapter, we discuss the pathophysiology, prevalence, evaluation, and evidence-based management of sexual dysfunction in patients affected by GSM. Additionally, we present an algorithm to guide clinicians in the management and treatment of sexual dysfunction in this setting based on available evidence and best practices.

Symptoms and associated impact in pre- and postmenopausal women with sexual arousal disorder: a concept elicitation study.

BACKGROUND: Approximately 26% of adult women in the United States suffer from female sexual arousal disorder (FSAD), yet little has been done to compare the experience of FSAD in pre- and postmenopausal women, which is critical to enhance the current understanding of FSAD and inform the development and assessment of treatment options for these patient populations. AIM: To explore the experience of condition-associated symptoms and the relative importance of FSAD symptoms, including their severity, bother, and impact, on participants' health-related quality of life (HRQoL) in pre- and postmenopausal women with FSAD. METHODS: In-depth, qualitative, semistructured concept elicitation interviews were conducted with premenopausal (n = 23) and postmenopausal (n = 13) women who were clinically diagnosed with FSAD by a trained sexual medicine clinician. All interviews were audio recorded and transcribed verbatim by a professional transcription company. Thematic analysis was performed with the assistance of NVivo qualitative analysis software. OUTCOMES: Outcomes included qualitative interview data about FSAD symptoms and HRQoL, as well as a comparison between pre- and postmenopausal populations. RESULTS: The most frequently reported symptom in both cohorts was "inability or difficulty with orgasm" (premenopausal, n = 21; postmenopausal, n = 13). The symptom that premenopausal women most desired to have treated was lubrication, and for postmenopausal women, it was a lack of lubrication or wetness and loss of feeling/sensation. In total, 21 of 23 premenopausal women and all 13 postmenopausal women reported a lack of feeling or sensation in the genitals. The most frequently reported HRQoL impact in both groups was decreased confidence. CLINICAL IMPLICATIONS: Results from this study suggest that the manifestation and experience of FSAD are similar in pre- and postmenopausal women and that the unmet need for an FSAD treatment in the postmenopausal population is just as great as that of the premenopausal population. STRENGTHS AND LIMITATIONS: This study involved in-depth qualitative interviews with a relatively small group of women (N = 36) recruited from only 5 study sites across the United States. CONCLUSION: The analysis of qualitative data from the concept elicitation interviews revealed a substantial physical and emotional burden of FSAD, underscoring the need for Food and Drug Administration-approved treatment options for pre- and postmenopausal women with FSAD.

Care after premenopausal risk-reducing salpingo-oophorectomy in high-risk women: Scoping review and international consensus recommendations.

Women at high inherited risk of ovarian cancer are offered risk-reducing salpingo-oophorectomy (RRSO) from age 35 to 45 years. Although potentially life-saving, RRSO may induce symptoms that negatively affect quality of life and impair long-term health. Clinical care following RRSO is often suboptimal. This scoping review describes how RRSO affects short- and long-term health and provides evidence-based international consensus recommendations for care from preoperative counselling to long-term disease prevention. This includes the efficacy and safety of hormonal and non-hormonal treatments for vasomotor symptoms, sleep disturbance and sexual dysfunction and effective approaches to prevent bone and cardiovascular disease.

Ethnic Minority Representation in Female Sexual Dysfunction Questionnaire Validation: A Scoping Review.

BACKGROUND: Female sexual dysfunction (FSD) is a significant cause of distress for an estimated 12-24% of women, and over the past 5 decades several questionnaires have been developed for clinical practice. AIM: The purpose of this scoping review is to evaluate the ethnic representation of sample populations used in the studies to validate FSD questionnaires. METHODS: A scoping review was performed using electronic databases, including PubMed and Scopus, to identify FSD questionnaires validated between 1976 and 2021. Weighted averages from the combined ethnicity data were compared to population data from 2019 US census data and 2018 healthcare workforce reports to evaluate epidemiologic diversity. Ethnicity data from each questionnaire were also investigated longitudinally to evaluate trends in representation over the past 50 years. OUTCOMES: Our outcome of interest was comparison of the weighted averages for ethnicity categories from validation populations to the US female general population, US female health care workforce, and US census data. RESULTS: 48 validation studies were reviewed and showed that the average ethnic representation of the study populations relative to the US general population and US female health care workforce, respectively, was: Caucasian (83.7% vs 62.7% and 68.5%), Black (7.8% vs 13.3% and 8.3%), Hispanic (3.6% vs 16.0% and 9.6%), Native American (0.1% vs 0.8% and 0.3%), Asian (0.6% vs 6.4% and 6.2%), and Other (3.1% vs 0.7% and 1.4%). CLINICAL IMPLICATIONS: FSD questionnaires are relied upon in research and clinical settings, so lack of diversity in validation populations could lead to under recognition and undertreatment in ethnic minority women. STRENGTHS & LIMITATIONS: Our results are dependent on the quality of data available from previously published validation studies. We attempted to account for biases in lack of data and size of validation populations by using weighted averages for making comparisons. We chose the US general population and female healthcare workforce for comparison and analyzed validation populations across multiple decades and geographic locations. Many of the validation studies were performed at least 10 years ago and may not reflect the current state of FSD and potential of questionnaire responses of ethnic minority women. This manuscript raises critical awareness regarding the lack of validated instruments for FSD in ethnically diverse women. CONCLUSION: Study populations used to validate FSD questionnaires demonstrate a trend of ethnic minority underrepresentation relative to the US female general and healthcare workforce populations. Battle CR, Rubin RS, Kingsberg SA, et al. Ethnic Minority Representation in Female Sexual Dysfunction Questionnaire Validation: A Scoping Review. J Sex Med 2022;19:1824-1838.

International Society for the Study of Women's Sexual Health Clinical Practice Guideline for the Use of Systemic Testosterone for Hypoactive Sexual Desire Disorder in Women.

BACKGROUND: The Global Consensus Position Statement on the Use of Testosterone Therapy for Women (Global Position Statement) recommended testosterone therapy for postmenopausal women with hypoactive sexual desire disorder (HSDD). AIM: To provide a clinical practice guideline for the use of testosterone including identification of patients, laboratory testing, dosing, post-treatment monitoring, and follow-up care in women with HSDD. METHODS: The International Society for the Study of Women's Sexual Health appointed a multidisciplinary panel of experts who performed a literature review of original research, meta-analyses, review papers, and consensus guidelines regarding testosterone use in women. Consensus was reached using a modified Delphi method. OUTCOMES: A clinically useful guideline following a biopsychosocial assessment and treatment approach for the safe and efficacious use of testosterone in women with HSDD was developed including measurement, indications, formulations, prescribing, dosing, monitoring, and follow-up. RESULTS: Although the Global Position Statement endorses testosterone therapy for only postmenopausal women, limited data also support the use in late reproductive age premenopausal women, consistent with the International Society for the Study of Women's Sexual Health Process of Care for the Management of HSDD. Systemic transdermal testosterone is recommended for women with HSDD not primarily related to modifiable factors or comorbidities such as relationship or mental health problems. Current available research supports a moderate therapeutic benefit. Safety data show no serious adverse events with physiologic testosterone use, but long-term safety has not been established. Before initiation of therapy, clinicians should provide an informed consent. Shared decision-making involves a comprehensive discussion of off-label use, as well as benefits and risks. A total testosterone level should not be used to diagnose HSDD, but as a baseline for monitoring. Government-approved transdermal male formulations can be used cautiously with dosing appropriate for women. Patients should be assessed for signs of androgen excess and total testosterone levels monitored to maintain concentrations in the physiologic premenopausal range. Compounded products cannot be recommended because of the lack of efficacy and safety data. CLINICAL IMPLICATIONS: This clinical practice guideline provides standards for safely prescribing testosterone to women with HSDD, including identification of appropriate patients, dosing, and monitoring. STRENGTHS & LIMITATIONS: This evidence-based guideline builds on a recently published comprehensive meta-analysis and the Global Position Statement endorsed by numerous societies. The limitation is that testosterone therapy is not approved for women by most regulatory agencies, thereby making prescribing and proper dosing challenging. CONCLUSION: Despite substantial evidence regarding safety, efficacy, and clinical use, access to testosterone therapy for the treatment of HSDD in women remains a significant unmet need. Parish SJ, Simon JA, Davis SR, et al. International Society for the Study of Women's Sexual Health Clinical Practice Guideline for the Use of Systemic Testosterone for Hypoactive Sexual Desire Disorder in Women. J Sex Med 2021;18:849-867.

International Society for the Study of Women's Sexual Health Clinical Practice Guideline for the Use of Systemic Testosterone for Hypoactive Sexual Desire Disorder in Women.

AIM: To provide a clinical practice guideline for the use of testosterone including identification of patients, laboratory testing, dosing, post-treatment monitoring, and follow-up care in women with hypoactive sexual desire disorder (HSDD). METHODS: The International Society for the Study of Women's Sexual Health appointed a multidisciplinary panel of experts who performed a literature review of original research, meta-analyses, review papers, and consensus guidelines regarding testosterone use in women. Consensus was reached using a modified Delphi method. OUTCOMES: A clinically useful guideline following a biopsychosocial assessment and treatment approach for the safe and efficacious use of testosterone in women with HSDD was developed including measurement, indications, formulations, prescribing, dosing, monitoring, and follow-up. RESULTS: Although the Global Position Statement endorses testosterone therapy for only postmenopausal women, limited data also support the use in late reproductive age premenopausal women, consistent with the International Society for the Study of Women's Sexual Health Process of Care for the Management of HSDD. Systemic transdermal testosterone is recommended for women with HSDD not primarily related to modifiable factors or comorbidities such as relationship or mental health problems. Current available research supports a moderate therapeutic benefit. Safety data show no serious adverse events with physiologic testosterone use, but long-term safety has not been established. Before initiation of therapy, clinicians should provide an informed consent. Shared decision-making involves a comprehensive discussion of off-label use, as well as benefits and risks. A total testosterone level should not be used to diagnose HSDD, but as a baseline for monitoring. Government-approved transdermal male formulations can be used cautiously with dosing appropriate for women. Patients should be assessed for signs of androgen excess and total testosterone levels monitored to maintain concentrations in the physiologic premenopausal range. Compounded products cannot be recommended because of the lack of efficacy and safety data. CLINICAL IMPLICATIONS: This clinical practice guideline provides standards for safely prescribing testosterone to women with HSDD, including identification of appropriate patients, dosing, and monitoring. STRENGTHS AND LIMITATIONS: This evidence-based guideline builds on a recently published comprehensive meta-analysis and the Global Position Statement endorsed by numerous societies. The limitation is that testosterone therapy is not approved for women by most regulatory agencies, thereby making prescribing and proper dosing challenging. CONCLUSION: Despite substantial evidence regarding safety, efficacy, and clinical use, access to testosterone therapy for the treatment of HSDD in women remains a significant unmet need.

Effects of Timing of Flibanserin Administration Relative to Alcohol Intake in Healthy Premenopausal Women: A Randomized, Double-Blind, Crossover Study.

INTRODUCTION: Flibanserin is approved in the United States and Canada for the treatment of acquired, generalized, hypoactive sexual desire disorder in premenopausal women. Sedation-related side effects are among the most prevalent adverse events. Although infrequent, hypotension and syncope remain safety concerns because of possible interaction of flibanserin with alcohol. AIM: To evaluate the impact of the timing of alcohol consumption on flibanserin safety and tolerability. METHODS: In this single-center, randomized, double-blind, placebo-controlled, 4-treatment crossover study, 64 healthy premenopausal women (mean age 32.5 ± 8.7 years; range 20‒52 years) received once-daily flibanserin 100 mg or placebo during each of two 10-day treatment periods. Study medication was administered on days 1-3 to achieve steady state. On days 4, 6, 8, and 10, after a standard breakfast, participants consumed 0.4 g/kg ethanol (approximately equivalent to two 5-oz glasses of wine) administered with orange juice 2, 4, or 6 hours before taking study medication or orange juice alone (no ethanol) 2 hours before taking study medication. OUTCOMES: The primary endpoint was percentage of participants experiencing syncope or orthostatic hypotension-associated adverse events requiring medical intervention. Secondary endpoints included the incidence of hypotension, the incidence of orthostatic hypotension, and rates of adverse events of special interest (syncope, orthostatic hypotension, dizziness, and somnolence). RESULTS: 1 participant experienced a primary endpoint event (syncope) during treatment with placebo taken 4 hours after ethanol consumption. Within each ethanol dose-timing treatment, there were no statistically significant differences for flibanserin compared with placebo. Rates of hypotension were 53.3-66.7% after flibanserin dosing and 57.4-63.3% after placebo dosing. Rates for orthostatic hypotension were 0.0-5.0% after flibanserin dosing and 1.7-6.6% after placebo dosing. CLINICAL IMPLICATIONS: Ethanol interaction with flibanserin was not observed in this study. STRENGTHS & LIMITATIONS: This study provides information regarding the use of flibanserin after the consumption of moderate amounts of ethanol (0.4 g/kg). However, daytime administration of flibanserin is not consistent with the drug's indicated bedtime dosing. CONCLUSION: Flibanserin, at steady state taken 2, 4, or 6 hours after 0.4 g/kg of ethanol intake did not increase the incidence of hypotension, orthostatic hypotension, or syncope compared with either flibanserin alone or ethanol alone. Simon JA, Clayton AH, Kingsberg SA, et al. Effects of Timing of Flibanserin Administration Relative to Alcohol Intake in Healthy Premenopausal Women: A Randomized, Double-Blind, Crossover Study. J Sex Med 2019;16:1779-1786.

Global Consensus Position Statement on the Use of Testosterone Therapy for Women.

This Statement is being simultaneously published in the journals Climacteric, Maturitas, Journal of Sexual Medicine, and Journal of Clinical Endocrinology and Metabolism on behalf of the International Menopause Society, The European Menopause and Andropause Society, The International Society for Sexual Medicine, and The Endocrine Society, respectively. This Position Statement has been endorsed by the International Menopause Society, The Endocrine Society, The European Menopause and Andropause Society, The International Society for Sexual Medicine, The International Society for the Study of Women's Sexual Health, The North American Menopause Society, The Federacion Latinoamericana de Sociedades de Climaterio y Menopausia, The Royal College of Obstetricians and Gynaecologists, The International Society of Endocrinology, The Endocrine Society of Australia, and The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.

An international Urogynecological association (IUGA)/international continence society (ICS) joint report on the terminology for the assessment of sexual health of women with pelvic floor dysfunction.

INTRODUCTION AND HYPOTHESIS: The terminology in current use for sexual function and dysfunction in women with pelvic floor disorders lacks uniformity, which leads to uncertainty, confusion, and unintended ambiguity. The terminology for the sexual health of women with pelvic floor dysfunction needs to be collated in a clinically-based consensus report. METHODS: This report combines the input of members of the Standardization and Terminology Committees of two International Organizations, the International Urogynecological Association (IUGA), and the International Continence Society (ICS), assisted at intervals by many external referees. Internal and external review was developed to exhaustively examine each definition, with decision-making by collective opinion (consensus). Importantly, this report is not meant to replace, but rather complement current terminology used in other fields for female sexual health and to clarify terms specific to women with pelvic floor dysfunction. RESULTS: A clinically based terminology report for sexual health in women with pelvic floor dysfunction encompassing over 100 separate definitions, has been developed. Key aims have been to make the terminology interpretable by practitioners, trainees, and researchers in female pelvic floor dysfunction. Interval review (5-10 years) is anticipated to keep the document updated and as widely acceptable as possible. CONCLUSIONS: A consensus-based terminology report for female sexual health in women with pelvic floor dysfunction has been produced aimed at being a significant aid to clinical practice and a stimulus for research.

The Women's EMPOWER Survey: Identifying Women's Perceptions on Vulvar and Vaginal Atrophy and Its Treatment.

INTRODUCTION: Vulvar and vaginal atrophy (VVA) affects up to two thirds of postmenopausal women, but most symptomatic women do not receive prescription therapy. AIM: To evaluate postmenopausal women's perceptions of VVA and treatment options for symptoms in the Women's EMPOWER survey. METHODS: The Rose Research firm conducted an internet survey of female consumers provided by Lightspeed Global Market Insite. Women at least 45 years of age who reported symptoms of VVA and residing in the United States were recruited. MAIN OUTCOME MEASURES: Survey results were compiled and analyzed by all women and by treatment subgroups. RESULTS: Respondents (N = 1,858) had a median age of 58 years (range = 45-90). Only 7% currently used prescribed VVA therapies (local estrogen therapies or oral selective estrogen receptor modulators), whereas 18% were former users of prescribed VVA therapies, 25% used over-the-counter treatments, and 50% had never used any treatment. Many women (81%) were not aware of VVA or that it is a medical condition. Most never users (72%) had never discussed their symptoms with a health care professional (HCP). The main reason for women not to discuss their symptoms with an HCP was that they believed that VVA was just a natural part of aging and something to live with. When women spoke to an HCP about their symptoms, most (85%) initiated the discussion. Preferred sources of information were written material from the HCP's office (46%) or questionnaires to fill out before seeing the HCP (41%).The most negative attributes of hormonal products were perceived risk of systemic absorption, messiness of local creams, and the need to reuse an applicator. Overall, HCPs only recommended vaginal estrogen therapy to 23% and oral hormone therapies to 18% of women. When using vaginal estrogen therapy, less than half of women adhered to and complied with posology; only 33% to 51% of women were very to extremely satisfied with their efficacy. CONCLUSION: The Women's EMPOWER survey showed that VVA continues to be an under-recognized and under-treated condition, despite recent educational initiatives. A disconnect in education, communication, and information between HCPs and their menopausal patients remains prevalent. Kingsberg S, Krychman M, Graham S, et al. The Women's EMPOWER Survey: Identifying Women's Perceptions on Vulvar and Vaginal Atrophy and Its Treatment. J Sex Med 2017;14:413-424.

The Women's EMPOWER Survey: Women's Knowledge and Awareness of Treatment Options for Vulvar and Vaginal Atrophy Remains Inadequate.

INTRODUCTION: Postmenopausal women's knowledge about vulvar and vaginal atrophy (VVA) and available treatment options has historically been inadequate. Recent direct-to-consumer marketing and educational efforts would have been expected to increase awareness and treatment options. AIM: To compare results of the Women's EMPOWER survey with other available VVA surveys to assess progress in women's understanding and approaches to treatment of VVA. METHODS: The Women's EMPOWER survey, an internet-based survey of US women with VVA symptoms, assessed women's awareness of VVA and their behaviors and attitudes associated with symptom treatment. MAIN OUTCOME MEASURES: These survey results were compared with previously published results of the Revealing Vaginal Effects at Mid-Life (REVEAL), Women's Voices in Menopause (WVM), Vaginal Health: Insight, Views, & Attitudes (VIVA), Clarifying Vaginal Atrophy's Impact on Sex and Relationship (CLOSER), and Real Women's Views of Treatment Options for Menopausal Vaginal Changes (REVIVE) surveys. RESULTS: Results of the Women's EMPOWER survey were consistent with those of past VVA surveys and showed that postmenopausal women generally failed to recognize VVA and its chronic, progressive process and that they were reluctant to discuss vaginal or sexual symptoms with their health care professionals (HCPs). However, women indicated a strong desire for accurate medical information about VVA from their health care professionals and a willingness to learn if HCPs would initiate the conversation. Most women believed that vaginal symptoms are a normal part of aging and they just need to cope with the symptoms. In the United States, women were most concerned with safety-related issues, including increased risk of breast cancer, side effects, and systemic absorption. CONCLUSION: The Women's EMPOWER survey demonstrates and reinforces that even with multimedia marketing and educational strategies in the years after other major VVA surveys, minimal progress has been made toward increasing women's awareness of, knowledge about, or understanding of VVA. Based on these data, a focus on initiating discussions and education with postmenopausal women so that they better comprehend VVA as a chronic progressive medical condition (not just aging), the symptoms associated with VVA, and the benefit-risk profile regarding treatment options is warranted. Krychman M, Graham S, Bernick B, et al. The Women's EMPOWER Survey: Women's Knowledge and Awareness of Treatment Options for Vulvar and Vaginal Atrophy Remains Inadequate. J Sex Med 2017;14:425-433.

Flibanserin in Postmenopausal Women With Hypoactive Sexual Desire Disorder: Results of the PLUMERIA Study.

BACKGROUND: Hypoactive sexual desire disorder (HSDD) is a common sexual disorder in younger and older women. Flibanserin is approved for the treatment of acquired generalized HSDD in premenopausal women only. The efficacy of flibanserin for postmenopausal women with HSDD was demonstrated in the first of two North American randomized, double-blinded, placebo-controlled trials (SNOWDROP). AIM: To evaluate the safety and efficacy of flibanserin in postmenopausal women with HSDD in a second randomized, double-blinded, placebo-controlled trial (PLUMERIA). METHODS: Naturally postmenopausal women were randomly assigned to receive flibanserin (100 mg/d) or placebo. Efficacy outcomes were assessed using the last-observation-carried-forward imputation method. OUTCOMES: Safety assessment included incidence of adverse events. Primary efficacy outcomes were the number of satisfying sexual events and the Female Sexual Function Index desire domain (FSFI-d) score. RESULTS: The study population (flibanserin, n = 376; placebo, n = 369) included primarily white women (84.7%), with a mean age of 56.1 years and a mean HSDD duration of 5.0 years. When the study was discontinued early by the sponsor, 45.3% of randomly assigned patients had completed week 16 (which served as the primary analysis time point). The most common adverse events in flibanserin-treated patients were insomnia (7.7%), somnolence (6.9%), and dizziness (6.4%). Improvement from baseline to week 16 (last-observation-carried-forward) in FSFI-d score was significantly greater for flibanserin compared with placebo (P = .011); however, the between-group comparison for satisfying sexual events did not reach statistical significance. CLINICAL IMPLICATIONS: Considered with the findings of the previous randomized controlled trial (SNOWDROP), the results of this study support the safety and efficacy of flibanserin in postmenopausal women. STRENGTHS AND LIMITATIONS: This was a well-designed randomized, placebo-controlled trial. A key limitation was early discontinuation by the study sponsor, which decreased the sample size. In addition, the validity of satisfying sexual events as a primary outcome measurement in HSDD studies has been called into question (but was required by the US Food and Drug Administration as a primary end point in studies of female sexual dysfunction at the time this study was conducted). CONCLUSION: Flibanserin was generally well tolerated in this population of naturally postmenopausal women. Despite the greatly decreased power to detect improvement compared with placebo on the efficacy measurements used, results suggest that flibanserin could be efficacious in postmenopausal women with HSDD. Portman DJ, Brown L, Yuan J, et al. Flibanserin in Postmenopausal Women With Hypoactive Sexual Desire Disorder: Results of the PLUMERIA Study. J Sex Med 2017;14:834-842.

Female Sexual Dysfunction-Medical and Psychological Treatments, Committee 14.

INTRODUCTION: Since the millennium we have witnessed significant strides in the science and treatment of female sexual dysfunction (FSD). This forward progress has included (i) the development of new theoretical models to describe healthy and dysfunctional sexual responses in women; (ii) alternative classification strategies of female sexual disorders; (iii) major advances in brain, hormonal, psychological, and interpersonal research focusing on etiologic factors and treatment approaches; (iv) strong and effective public advocacy for FSD; and (v) greater educational awareness of the impact of FSD on the woman and her partner. AIMS: To review the literature and describe the best practices for assessing and treating women with hypoactive sexual desire disorder, female sexual arousal disorder, and female orgasmic disorders. METHODS: The committee undertook a comprehensive review of the literature and discussion among themselves to determine the best assessment and treatment methods. RESULTS: Using a biopsychosocial lens, the committee presents recommendations (with levels of evidence) for assessment and treatment of hypoactive sexual desire disorder, female sexual arousal disorder, and female orgasmic disorders. CONCLUSION: The numerous significant strides in FSD that have occurred since the previous International Consultation of Sexual Medicine publications are reviewed in this article. Although evidence supports an integrated biopsychosocial approach to assessment and treatment of these disorders, the biological and psychological factors are artificially separated for review purposes. We recognize that best outcomes are achieved when all relevant factors are identified and addressed by the clinician and patient working together in concert (the sum is greater than the whole of its parts). Kingsberg SA, Althof S, Simon JA, et al. Female Sexual Dysfunction-Medical and Psychological Treatments, Committee 14. J Sex Med 2017;14:1463-1491.

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.

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

INTRODUCTION: Current Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) definitions of sexual dysfunction do not identify all sexual problems experienced clinically by women and are not necessarily applicable for biologic or biopsychosocial management of female sexual dysfunction. A unified nomenclature system enables clinicians, researchers, and regulatory agencies to use the same language and criteria for determining clinical end points, assessing research results, and managing patients. AIM: To develop nomenclature with classification systems for female sexual desire, arousal, and orgasm disorders with definitions pertinent to clinicians and researchers from multiple specialties who contribute to the field of sexual medicine. METHODS: Key national and international opinion leaders diverse in gender, geography, and areas of expertise met for 2 days to discuss and agree to definitions of female sexual desire, arousal, and orgasm disorders and persistent genital arousal disorder. The attendees consisted of 10 psychiatrists and psychologists; 12 health care providers in specialties such as gynecology, internal medicine, and sexual medicine; three basic scientists; and one sexuality educator, representing an array of societies working within the various areas of sexual function and dysfunction. MAIN OUTCOME MEASURE: A unified set of definitions was developed and accepted for use by the International Society for the Study of Women's Sexual Health (ISSWSH) and members of other stakeholder societies participating in the consensus meeting. RESULTS: Current DSM-5 definitions, in particular elimination of desire and arousal disorders as separate diagnoses and lack of definitions of other specific disorders, were adapted to create ISSWSH consensus nomenclature for distressing sexual dysfunctions. The ISSWSH definitions include hypoactive sexual desire disorder, female genital arousal disorder, persistent genital arousal disorder, female orgasmic disorder, pleasure dissociative orgasm disorder, and female orgasmic illness syndrome. CONCLUSION: Definitions for female sexual dysfunctions that reflect current science provide useful nomenclature for current and future management of women with sexual disorders and development of new therapies.

The Validation of the Female Sexual Function Index, Male Sexual Function Index, and Profile of Female Sexual Function for Use in Healthy Young Adults.

Past research has typically used clinical samples to evaluate the validity of sexual function measures. As normal variations in sexually healthy individuals are of important research and clinical interest, evaluating the applicability of common sexual function measures to these populations is important. Factor structures of the Female Sexual Function Index (FSFI), Male Sexual Function Index (MSFI) (adapted for this investigation), and Profile of Female Sexual Function (PFSF) were examined in young, healthy men and women. We predicted the factor structures to be consistent with past evaluations. In a cross-sectional study, 1,258 participants (M age = 19.56 years; 59 % women) completed these measures. Confirmatory factor analyses did not initially support the factor structures. However, factor loadings showed marked differences between positively and negatively worded items. As such, each measure's factor structure was tested using multi-trait multi-method confirmatory factor analysis which accounted for variance due to item valence. These models supported the predicted structures of the FSFI and MSFI, whereas the PFSF's Responsiveness scale required modification, resulting in an Avoidance scale for both genders. This study was one of few to validate the FSFI in young, healthy adults and the first to examine the MSFI and PFSF in these populations. Additionally, this investigation was the first to propose a reconceptualization of the PFSF Responsiveness scale into an Avoidance scale. Lastly, our study highlights the significant impact of item valence on how individuals respond to questions regarding their sexual functioning.

The Transaction Between Depression and Anxiety Symptoms and Sexual Functioning: A Prospective Study of Premenopausal, Healthy Women.

A number of studies have called attention to the problematic interplay between depression and anxiety symptoms and sexual difficulties. However, despite the bidirectional conceptualization of the association between affective and sexual problems, few studies have adequately examined temporal precedence or state-level fluctuations between these two constructs. Using Clark and Watson's (1991) tripartite model of anxiety and depression, the current study employed a repeated measures design to examine how weekly changes in affective symptoms were related to weekly changes in sexual functioning in a non-clinical sample of premenopausal women. First, we examined how general distress, anxious arousal, and anhedonia were concurrently related to various indices of sexual functioning. Next, we examined lagged effects of mood and anxiety symptoms predicting later levels of sexual functioning. Finally, we tested sexual functioning's influence on later reports of affective symptoms. Hierarchical linear modeling analyses revealed that, of the three symptom types tested, anhedonic depression was the most consistently related to sexual problems, and that these relations were more proximal than distal. The preponderance of data suggested temporal precedence of mood on sexual symptoms. These findings emphasize the importance of prospective studies in the investigation of mental and sexual health.

How changes in depression and anxiety symptoms correspond to variations in female sexual response in a nonclinical sample of young women: a daily diary study.

INTRODUCTION: A large body of literature supports the co-occurrence of depression, anxiety, and sexual dysfunction. However, the manner in which affective symptoms map onto specific female sexual response indices is not well understood. AIMS: The present study aimed to examine changes in depression and anxiety symptoms and their correspondence to fluctuations in desire, subjective arousal, genital response, orgasmic function, and vaginal pain. METHODS: The study used a 2-week daily diary approach to examine same-day and temporal relations between affective symptoms and sexual function. MAIN OUTCOME MEASURES: The unique relations between shared and disorder-specific symptoms of depression and anxiety (i.e., general distress, anhedonia, and anxious arousal) and female sexual response (i.e., desire, subjective arousal, vaginal lubrication, orgasmic function, and sexual pain) were examined, controlling for baseline levels of sexual distress, depression, and anxiety, as well as age effects and menstruation. RESULTS: Analyses revealed that changes in depression and anxiety severity corresponded to same-day variations in sexual response. Specifically, anhedonia (depression-specific symptom) was related to poorer same-day sexual desire, whereas greater anxious arousal (anxiety-specific symptom) was independently related to simultaneous increases in subjective sexual arousal, vaginal lubrication, and sexual pain. Increases in general distress (i.e., shared symptoms) were associated with greater same-day difficulties achieving orgasm. Notably, only one temporal relation was found; it indicated that higher levels of anhedonia predicted a next-day decrease in sexual desire. CONCLUSIONS: It is proposed that the simultaneous changes in affective symptoms and sexual function may indicate that they are products of shared underlying mechanisms. That is, in response to stress, the processes manifesting as feelings of weak positive affect and amotivation are the very same processes responsible for diminished capacity for sexual desire. In contrast, the physiological hyperarousal associated with anxiety also gives rise to sexual arousal difficulties and vaginal pain.

Assessment of ospemifene or lubricants on clinical signs of VVA.

INTRODUCTION: Ospemifene is a new oral estrogen receptor agonist/antagonist with tissue-selective effects approved for the treatment of moderate to severe dyspareunia, a symptom of postmenopausal vulvar and vaginal atrophy (VVA). AIM: The aim of the study is to assess ospemifene or lubricant use on the clinical signs of VVA. METHODS: Subjects in three double-blind, placebo-controlled clinical trials were randomized to ospemifene or placebo. In two of the trials, women were provided nonhormonal lubricants for use as needed, and a preplanned evaluation of the frequency of lubricant use was performed. Additionally, a post hoc placebo group analysis for impact of lubricant use or nonuse on physiologic effects of the percentage of superficial and parabasal cells (maturation index) and vaginal pH was conducted. A secondary preplanned end point included visual examination of the vagina (clinical signs of vaginal dryness, petechiae, pallor, friability, and redness of the mucosa) comparing change from baseline to end of treatment for the ospemifene 60-mg/day group and vs. placebo. MAIN OUTCOME MEASURES: The primary end points in the phase 3 clinical trials included the percentage of superficial cells, parabasal cells, vaginal pH, and most bothersome symptoms compared with placebo. RESULTS: There was no significant difference in physiologic effects between placebo lubricant users vs. nonusers in either 12-week study. Compared with baseline, substantially more subjects receiving ospemifene 60 mg/day than placebo showed complete resolution of clinical signs of VVA after 12 and 52 weeks of treatment. CONCLUSIONS: Ospemifene substantially improved clinical signs of VVA. Within the placebo group, there was no difference in physiologic effects in lubricant users vs. nonusers. Based on gynecologic evaluation of the vagina, benefits were apparent at 12 weeks and sustained for 52 weeks in the ospemifene-treated subjects with significant improvement over placebo. In these three clinical trials, in contrast to ospemifene-treated women, placebo subjects who utilized lubricants had no improvement in their underlying vaginal physiology.