Noel N. Kim

Introduction: Sexual function is a critical issue for human health and impacts the quality of life of patients and their partners. In this ICSM report, basic science and translational perspectives have been examined from the past decade of literature since the last ICSM report, and have been integrated to produce a state of the art summary of the physiology and molecular biology of sexual function/dysfunction and development of novel nanotechnology-based vehicles and treatments to aid regeneration and clinical translation in men and women. Objectives: Examine, critically assess, and curate the most important and impactful basic and translational research findings on male and female sexual dysfunction since 2015. Methods: Literature reviews were performed by a multidisciplinary committee of sexual medicine experts between June 2023 through May 2024. Findings were presented at the ICSM meeting in Madrid (June 2024), and comments from the consultation were incorporated to develop this consensus report. Results: Erectile dysfunction (ED), which accompanies prostatectomy, diabetes, aging, and vascular disease in men, develops through both common and distinct mechanisms that involve neural injury, penile remodeling (smooth muscle (SM) apoptosis and increased collagen/fibrosis), dysregulated SM contractility, increased oxidative stress, immune response, and genomic instability. In women, disorders of genital pain, arousal, sexual desire, and orgasm involve multiple, overlapping neurological and endocrine mechanisms. Research on ED has been more extensive and the underlying molecular mechanisms have been better characterized than female sexual dysfunction. Future research directions should focus on pathways that underlie penile tissue remodeling and fibrosis associated with cavernous nerve injury in prostatectomy and diabetes, since this leads to irreversible ED. Particular emphasis should be placed on therapeutic targets to improve/enhance nerve regeneration, neuroprotection, “on demand” sexual function, SM contractility/relaxation, oxidative stress, immune response, and hormone function. In women, despite the existence of approved and off-label treatments for disorders of sexual desire and orgasm, the greater influence of psychosocial factors for these aspects of sexual function demands a multidisciplinary approach, along with predictive animal models. Genome-wide association studies have great potential in advancing the field but require replication and functional validation of findings from bioinformatic analyses. Progress in nanotechnology and regenerative therapies offers an exciting frontier in the targeted delivery of ameliorative/restorative treatments. Conclusions: Research in sexual medicine has expanded through accelerated rates of discovery and increased breadth and diversity. However, much work remains in translating preclinical findings into biomarkers and clinical therapies that can improve patient outcomes.

Background: Electrohydraulic shockwave devices have been Food and Drug Administration-cleared for improved blood flow and connective tissue activation and have been used to treat erectile dysfunction (ED). In this study, the main focus was to evaluate improvement in erectile tissue quality after low intensity shockwave therapy (LiSWT). Methods: A single-blind, sham-controlled, randomized, prospective study, was performed in men with ED naïve to shockwave or radial ballistic pressure wave therapy. Participants were randomized 1:2 to simulated (sham) or active LiSWT treatment. After simulated treatments, participants in the Sham Arm were converted to active LiSWT, while participants initially in the Active Treatment Arm received no further treatment. Assessments were performed at baseline and two follow-up visits. Subjective parameters of erectile function (EF) were assessed by total and EF domain scores of the International Index of Erectile Function (IIEF) and sexual encounter profile (SEP). Objective parameters of penile erection were measurements of hypoechoic areas in images obtained by grayscale ultrasound (GUS) with high resolution 15.4 MHz probe and cavernosal artery peak systolic velocity (PSV) and end diastolic velocity (EDV) by color duplex Doppler ultrasound (DUS). Outcome measures for erectile and urinary function were also obtained. Results: Simulated LiSWT did not significantly change any assessment parameter. Sham Arm participants who converted to active LiSWT had significantly increased mean IIEF total (P=0.02) and IIEF-EF scores that approached statistical significance (P=0.06), relative to baseline. Similarly, at the end of the study, Active Treatment Arm participants had significantly increased mean IIEF total (P=0.02) and IIEF-EF scores that approached statistical significance (P=0.07), relative to baseline. Additionally, at the end of the study, SEP3 success rates (erection lasting long enough for successful intercourse) approached statistical significance when Sham Arm participants were converted to active LiSWT (P=0.08) and reached statistical significance in the Active Treatment Arm (P=0.049). GUS assessments by visual grading were significantly correlated to IIEF-EF score (P=0.002) and were significantly increased relative to baseline in the Active Treatment Arm at follow-up Assessment 1 (P=0.03) and Assessment 2 (P=0.04). The greatest reduction in hypoechoic area after LiSWT occurred in the proximal penile shaft. EDV was also significantly reduced in the Active Treatment Arm at follow-up Assessment 1 (P=0.04) and Assessment 2 (P=0.04). LiSWT also resulted in improved prostate symptom scores, approaching significance in the Active Treatment Arm (P=0.055) with no changes in prostate-specific antigen. Treatment-related adverse events were limited and transient. Conclusions: In this prospective trial, LiSWT was safe and efficacious for erectile symptoms using GUS imaging as a novel, non-invasive method to assess improvements in corporal veno-occlusive function. Improved veno-occlusion and reduced hypoechoic area demonstrated by GUS imaging suggest that LiSWT decreases connective tissue content in penile erectile tissue. Lower urinary tract symptoms also improved with LiSWT. Trial Registration: NCT06600893 on clinicaltrials.gov.

Prasterone, an intravaginal dyspareunia treatment in menopausal women, improves vaginal health through intracellular conversion of dehydroepiandrosterone into androgens and estrogens. Phase 3 trials for prasterone showed significant improvement in vaginal tissue health and reduction of pain. To assess vestibular changes with daily use of intravaginal prasterone in menopausal women with moderate to severe dyspareunia. This open-label prospective pilot study was conducted over 20 weeks. It included 11 menopausal women (median age, 56 years) who were treated daily with intravaginal inserts of 6.5-mg prasterone and assessed monthly. During vulvoscopy, vestibular pain was assessed by cotton-tipped swab testing, and vestibular and vaginal health was independently assessed with the Visual Scale (VS). In addition, vulvoscopic photographs were obtained and assessed via the Vulvoscopic Genital Tissue Appearance (VGTA) scale to evaluate overall genital tissue health. Mean changes from baseline for genital tissue health and pain assessments were analyzed by repeated measures 1-way analysis of variance, followed by a Dunnett post hoc test. Sexual event diaries were completed and adverse events recorded. Outcomes included indices of genital tissue health: pain assessment by cotton-tipped swab testing, VS of the vestibule and vagina, VGTA, and sexual event diary. Aggregate scores from the cotton-tipped swab test progressively improved, reaching statistical significance at week 16, which was maintained through week 20 (−7.27, P = .019). VS scores significantly improved from baseline by week 4 and were maintained through week 20 for the vestibule (−3.00, P = .004) and vagina (−4.00, P = .002). An overall 1607 vulvoscopic photographs were examined; all showed reduction in vestibular erythema and pallor at the end of the study. The mean change from baseline at week 20 for the VGTA score was −7.9 (P = .0016). Intercourse associated with pain was reduced from 81.3% of initiated events during the first month of the study to 8.3% during the last month. Sexual activities that were discontinued due to discomfort were reduced from 45.8% to 6.3%. No prasterone-related serious adverse events were reported. Prasterone, a safe and effective intravaginal hormone treatment, significantly improves vestibular health parameters. Strengths are the prospective study design and the use of multiple outcome measures to assess vestibular tissue health and pain associated with sexual activity. Limitations are the small study cohort and use of nonvalidated outcome measures. Our findings suggest that intravaginal prasterone exerts biologic activity on the androgenic endodermal vestibule, as the medication passes from vagina to vestibule, resulting in amelioration of pain associated with sexual activity.

Flibanserin was approved by the US FDA in 2015 and by Health Canada in 2018 for the treatment of acquired, generalized hypoactive sexual desire disorder (HSDD)

Introduction Flibanserin treatment increases sexual desire and satisfying sexual events while decreasing distress in certain women diagnosed with acquired, generalized hypoactive sexual desire disorder (HSDD). Additional aspects of sexual function and the time course of response have not been fully characterized. Aim To evaluate changes in sexual function assessed by the subdomains of the Female Sexual Function Index (FSFI) in women with HSDD treated with flibanserin. Methods FSFI data pooled from 3 pivotal flibanserin trials in premenopausal women (flibanserin = 1,165; placebo = 1,203) and FSFI data from one complete flibanserin trial in postmenopausal women (flibanserin = 432; placebo = 463) were subjected to post-hoc analyses. For each FSFI subdomain, least squares mean change from baseline was calculated at each assessment visit (treatment weeks 4, 8, 16, 24) and treatment groups were compared using analysis of covariance. Standardized effect size (Cohen's d) was also determined for each FSFI subdomain. Main Outcome Measure Changes from baseline in FSFI subdomains. Results Compared to placebo, both premenopausal (P < .02) and postmenopausal (P < .045) patients in the flibanserin group reported significantly greater increases over baseline in the FSFI subdomain scores of desire, arousal, lubrication, orgasm, and satisfaction. In premenopausal patients, significant improvements were observed at the first assessment of response (week 4) and were maintained through week 24. In postmenopausal patients, significant improvements were observed at week 4 for desire and arousal, while significant improvements in lubrication, orgasm, and satisfaction were observed at week 8. At week 24, excluding the pain subdomain, standardized effect sizes ranged from 0.18 to 0.28 in the premenopausal cohort and 0.12 to 0.29 in the postmenopausal cohort. In both pre- and postmenopausal patients, improvements in pain were smaller and largely undifferentiated between treatment groups. Clinical Implications While variations in time to response should be taken into consideration, on average, the beneficial impact of flibanserin on overall sexual function occurs within the first month of treatment. The data also suggest that the response to flibanserin is sustained for the duration of treatment. Strengths and Limitations Sexual function assessments were performed in a large cohort of 2,368 premenopausal women and 895 postmenopausal women. However, the FSFI assesses changes over a 1-month period and time points earlier than 4 weeks could not be assessed. Conclusion These analyses suggest that assessment of benefit of flibanserin in HSDD should include improvements across all domains of sexual function, not only desire. Simon JA, Clayton AH, Goldstein I, et al. Effects of Flibanserin on Subdomain Scores of the Female Sexual Function Index in Women With Hypoactive Sexual Desire Disorder. Sex Med 2022;XX:XXXXXX.

In the 2019 global consensus position statement on testosterone, ¹ Davis SR Baber R Panay N et al. Global consensus position statement on the use of testosterone therapy for women. J Sex Med. 2019; 16 : 1331-1337 Abstract Full Text Full Text PDF PubMed Google Scholar the expert panel stated that the only evidence-based indication for testosterone use in women was for the treatment of hypoactive sexual desire disorder (HSDD) in naturally or surgically postmenopausal women. This recommendation was largely based upon a systematic review and meta-analysis of randomized, placebo-controlled trial data assessing the efficacy and safety of testosterone on sexual function in women. ² Islam RM Bell RJ Green S et al. Safety and efficacy of testosterone for women: a systematic review and meta-analysis of randomised controlled trial data. Lancet Diabetes Endocrinol. 2019; 7 : 754-766 Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar Testosterone, when administered to achieve doses that approximate physiological levels in premenopausal women, was determined to have beneficial effects on sexual function in postmenopausal women, including increases in frequency of satisfactory sexual events, pleasure, arousal, orgasm, and responsiveness with concomitant decrease in distress. ² Islam RM Bell RJ Green S et al. Safety and efficacy of testosterone for women: a systematic review and meta-analysis of randomised controlled trial data. Lancet Diabetes Endocrinol. 2019; 7 : 754-766 Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar In a subsequently published clinical practice guideline, the International Society for the Study of Women's Sexual Health supported the use of testosterone therapy to treat HSDD in late reproductive age premenopausal women in addition to postmenopausal women. ³ 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 Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar Despite this global consensus, testosterone products for HSDD in women have not been approved for marketing by any government agency with the exception of Australia. ³ 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 Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar ^,4 Androfeme® (1% testosterone) cream, transdermal delivery. Lawley Pharmaceuticals, West Leederville, Western Australia, Australia 2020 Google Scholar

Flibanserin, a multifunctional serotonin receptor agonist and antagonist, is currently approved in the United States and Canada for the treatment of acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. A post hoc analysis of HSDD clinical trial data found that flibanserin treatment was associated with statistically significant weight loss relative to placebo, even though study patients were not selected for being overweight/obese and were provided no expectation for weight reduction or interventions intended to promote weight loss. To understand possible mechanisms by which flibanserin may produce weight loss. A literature review was performed using Medline database for relevant publications on the mechanisms of action by which flibanserin may provide weight loss and the links between sexual function and weight management. Examination of (i) biopsychosocial factors regulating sexual desire, food intake, and weight regulation; (ii) clinical pharmacology of flibanserin; (iii) neurobiology of brain reward circuitry; and (iv) identification of possible mechanisms common to flibanserin and weight loss. Based on flibanserin clinical trial data, there was no consistent correlation between weight loss and improvement in sexual function, as assessed by HSDD outcome measures. Nausea, a common adverse event associated with flibanserin use, also did not appear to be a contributing factor to weight loss. Hypothetical links between flibanserin treatment and weight loss include modulation of peripheral 5-HT_2A receptors and factors such as improved mood and improved sleep. Mechanisms of flibanserin-induced weight loss have not been well characterized but may involve indirect beneficial effects on peripheral 5-HT_2A receptors and central regulation of mood and sleep. Future research may better elucidate the links between sexual function and weight management and the mechanism(s) by which flibanserin use may result in weight loss. Simon JA, Kingsberg SA, Goldstein I, et al. Weight Loss in Women Taking Flibanserin for Hypoactive Sexual Desire Disorder (HSDD): Insights into Potential Mechanisms. Sex Med Rev 2019;7:575-586.

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.