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Background: In 1999, 1 year after the approval of the first oral phosphodiesterase type 5 (PDE5) inhibitor for the treatment of erectile dysfunction (ED), the first Princeton Consensus Conference was held to address the clinical management of men with ED who also had cardiovascular disease. These issues were readdressed in the second and third conferences. In the 13 years since the last Princeton Consensus Conference, the experience with PDE5 inhibitors is more robust, and recent new data have emerged regarding not only safety and drug-drug interactions, but also a potential cardioprotective effect of these drugs., Aim: In March 2023, an interdisciplinary group of scientists and practitioners met for the fourth Princeton Consensus Guidelines at the Huntington Medical Research Institutes in Pasadena, California, to readdress the cardiovascular workup of men presenting with ED as well as the approach to treatment of ED in men with known cardiovascular disease., Method: A series of lectures from experts in the field followed by Delphi-type discussions were developed to reach consensus., Outcomes: Consensus was reached regarding a number of issues related to erectile dysfunction and the interaction with cardiovascular health and phosphodiesterase-5 inhibitors., Results: An algorithm based on recent recommendations of the American College of Cardiology and American Heart Association, including the use of computed tomography coronary artery calcium scoring, was integrated into the evaluation of men presenting with ED. Additionally, the issue of nitrate use was further considered in an algorithm regarding the treatment of ED patients with coronary artery disease. Other topics included the psychological effect of ED and the benefits of treating it; the mechanism of action of the PDE5 inhibitors; drug-drug interactions; optimizing use of a PDE5 inhibitors; rare adverse events; potential cardiovascular benefits observed in recent retrospective studies; adulteration of dietary supplements with PDE5 inhibitors; the pros and cons of over-the-counter PDE5 inhibitors; non-PDE5 inhibitor therapy for ED including restorative therapies such as stem cells, platelet-rich plasma, and shock therapy; other non-PDE5 inhibitor therapies, including injection therapy and penile prostheses; the issue of safety and effectiveness of PDE5 inhibitors in women; and recommendations for future studies in the field of sexual dysfunction and PDE5 inhibitor use were discussed., Clinical Implications: Algorithms and tables were developed to help guide the clinician in dealing with the interaction of ED and cardiovascular risk and disease., Strengths and Limitations: Strengths include the expertise of the participants and consensus recommendations. Limitations included that participants were from the United States only for this particular meeting., Conclusion: The issue of the intersection between cardiovascular health and sexual health remains an important topic with new studies suggesting the cardiovascular safety of PDE5 inhibitors., (© The Author(s) 2023. Published by Oxford University Press on behalf of The International Society of Sexual Medicine.)

Background: Treatment of "adult-onset hypogonadism" (AOH) with exogenous testosterone therapy (TTh) to raise serum testosterone (T) levels may influence cardiovascular (CV) risk factors in patients with AOH, whereas low endogenous T levels are associated with an increased CV risk and mortality., Aim: To critically evaluate studies reporting increased CV risk associated with TTh and to provide an overview of the risks and benefits of restoring T levels through exogenous TTh., Methods: A review of publications focusing on the association between TTh and increased CV risk was conducted, and the study methodologies and conclusions of each were critically evaluated. Further, recent clinical and epidemiological studies associating AOH or TTh with a change in CV risk, and pertinent hematologic and vascular effects noted in animal studies and in vitro, as well as in clinical practice were also reviewed., Outcomes: A review of the literature shows that untreated testosterone deficiency and/or low T is associated with an increase in CV risk and adverse outcomes, with numerous studies and meta-analyses to support a positive association between exogenous TTh and an improvement in CV risk factors in men with AOH., Results: Numerous studies in the literature demonstrate the positive benefits of using TTh; however, since 2013, some publications have suggested a link to increased CV risk associated with TTh. A number of these studies retrospectively analyzed insurance claims databases using diagnosis codes, procedures codes, and prescription information. Many reviews published since have pointed out the methodological flaws and debatable conclusions of these studies., Clinical Implications: A careful assessment of the patient's current health status and CV risk factors should be weighed against the benefits and possible risks resulting from TTh, and consideration should be given to deferring treatment pending resolution or stabilization of CV disease or risk factors., Strengths & Limitations: In this review, we provide an in-depth analysis of studies reporting increased CV risk with TTh. Many of the studies were not well-designed, randomized, double-blind, prospective clinical trials but rather post hoc analyses of cohort data. These studies may reflect bias in how treatment and nontreatment decisions are made or reflect conclusions based on widely cited methodological flaws., Conclusion: Appropriate patient selection supported by low pre-treatment T levels and monitoring T levels during treatment with the goal of achieving and maintaining physiologic levels all contribute to the safe and effective use of TTh in men with AOH. Khera M, Miner M, Jaffe J, et al. Testosterone Therapy and Cardiovascular Risk: A Critical Analysis of Studies Reporting Increased Risk. J Sex med 2021;18:83-98., (Copyright © 2020. Published by Elsevier Inc.)

Introduction: Cligosiban is an orally administered oxytocin receptor antagonist being developed to treat premature ejaculation (PE)., Aim: To determine the safety and efficacy of cligosiban capsules (dose range 400-800 mg) to improve intravaginal ejaculation latency time (IELT) and patient-reported outcomes in men with severe lifelong PE., Methods: Patients recorded details of at least 4 sexual intercourse events during a 4-week run-in period, after which they underwent baseline assessments. Patients were eligible for the study if they rated their control of ejaculation as poor/very poor and their stopwatch-assessed IELT was ≤1 minute in ≥75% of intercourse attempts. Eligible patients were randomized to an 8-week treatment period with double-blind cligosiban or placebo (to be taken 1 to 6 hours prior to sexual activity). The starting dose was 400 mg (not more than 1 dose per day) which could be increased to 800 mg after 2 and/or 4 weeks of treatment. Assessments were conducted at 2, 4, and 8 weeks., Main Outcome Measure: Efficacy measures were comprised of IELT, self-rating of ejaculation control and ejaculation-related distress (recorded in an electronic diary after each intercourse attempt), premature ejaculation profile, and the Clinical Global Impression of Change., Results: The mean ratio of fold change from baseline in IELT to the last 4 weeks of treatment (cligosiban/placebo) was 1.9 compared to a baseline of 1.0 (P = .0079). The mean increase in IELT from baseline to the last 4 weeks of treatment was 61.0 seconds for cligosiban, which was significantly different from (and 3.6-fold greater than) the mean increase of 16.4 seconds for placebo (P = .0086). Statistically significant improvements in ejaculation control and ejaculation-related personal distress scores were also observed for cligosiban compared to little or no change with placebo. Cligosiban was generally well tolerated, with no serious or severe adverse events or other safety parameters., Clinical Implications: This proof-of-concept study demonstrated the potential for cligosiban, an oxytocin antagonist, to successfully treat symptoms of severe lifelong PE., Strengths and Limitations: This was a Phase II, randomized, double-blind, placebo-controlled study that was adequately powered to detect a clinically meaningful difference in change in IELT between cligosiban and placebo. Larger studies will be needed to confirm these findings, determine the optimal dose of cligosiban and assess efficacy in men with acquired PE., Conclusions: Cligosiban was well tolerated, and resulted in significant benefits in both objective and subjective measures of ejaculatory control in men with lifelong PE and therefore offers significant potential as an on-demand, orally administered agent for the treatment of PE. McMahon C, Althof S, Rosen R, et al. The Oxytocin Antagonist Cligosiban Prolongs Intravaginal Ejaculatory Latency and Improves Patient-Reported Outcomes in Men with Lifelong Premature Ejaculation: Results of a Randomized, Double-Blind, Placebo-Controlled Proof-of-Concept Trial (PEPIX). J Sex Med 2019; 16:1178-1187., (Copyright © 2019 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: Female sexual function is dependent, in part, upon normal endothelial function within the genital arterial (hypogastric-cavernosal) vascular bed. The first two Princeton Consensus Conferences were focused on relationships between male sexual function and cardiovascular health, and development of contemporary clinical guidelines for dysfunction management., Aim: The third Princeton Consensus Conference updated recommendations and assessed, for the first time, the association between female sexual dysfunction (FSD) and presence of systemic vascular endothelial dysfunction and its consequences in women. This report focuses on the association between cardiometabolic risk factors and female sexual health., Methods: A panel of experts reviewed multinational data concerning associations between several cardiometabolic risks in women (hypertension, dyslipidemia and/or hyperlipemia, cigarette smoking, diabetes mellitus, and metabolic syndrome/obesity) and sexual health. Literature was reviewed concerning associations between FSD and presence or absence of cardiovascular disease, predictive association of FSD with cardiovascular events, and the possibility of vascular risk factor treatment modifying FSD., Main Outcome Measure: Main outcome measures used were cardiometabolic risk factors and female sexual health, specifically genital arousal., Results: Women treated for hypertension have more FSD than normotensives. Women with hyperlipidemia but without cardiovascular disease have more FSD than women without hyperlipidemia. Women with metabolic syndrome/obesity have more FSD than those without. Cardiometabolic risk factors, diabetes, and coronary heart disease are associated with more FSD. Data support that treatment of metabolic syndrome/obesity is associated with less FSD. Currently, there are no data to support that FSD is a predictor of future cardiovascular events., Conclusion: Female sexual health is complex: there is relative independence between subjective and objective aspects of arousal and desire, with numerous contributing factors (hormonal, psychological, interpersonal, and social). Based on limited current data, there appears to be an association between female sexual health and vascular risk factors (hypertension, hyperlipidemia, metabolic syndrome/obesity, diabetes, and coronary heart disease). More research is needed., (© 2012 International Society for Sexual Medicine.)

Introduction: Erectile dysfunction (ED) is common and considered to be predominantly of vascular origin., Aim: To evaluate the link between ED and coronary artery disease (CAD) and provide a consensus report regarding evaluation and management., Methods: A committee of eight experts from six countries was convened to review the worldwide literature concerning ED and CAD and provide a guideline for management., Main Outcome Measure: Expert opinion was based on grading the evidence-based medical literature, widespread internal committee discussion, public presentation, and debate., Results: ED and CAD frequently coexist. Between 50-70% of men with CAD have ED. ED can arise before CAD is symptomatic with a time window of 3-5 years. ED and CAD share the same risk factors, and endothelial dysfunction is the common denominator. Treating ED in cardiac patients is safe, provided that their risks are properly evaluated., Conclusion: ED is a marker for silent CAD that needs to be excluded. Men with CAD frequently have ED that can be treated safely following guidelines.

Introduction: Phosphodiesterase type-5 (PDE-5) inhibitors have previously been evaluated for their efficacy and safety in various clinical trials in men with erectile dysfunction (ED) with or without associated comorbidities., Aim: This is the first prospective, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of a PDE-5 inhibitor (i.e., vardenafil) in an exclusive population of men with ED and dyslipidemia., Main Outcome Measures: Three coprimary efficacy measurements (Sexual Encounter Performance [SEP]2, SEP3, International Index of Erectile Function-Erectile Function [IIEF-EF] domain scores) were used to assess the differential effect of vardenafil vs. placebo in this patient population. Adverse events (AEs) safety data were obtained to compare safety outcomes., Methods: This 12-week of randomized, double-blind, placebo-controlled study was conducted in 59 U.S. centers. Patients received either on-demand, flexible-dose vardenafil 10 mg (titrated to 5 mg or 20 mg based upon efficacy and safety) or placebo., Results: Of the 712 patients screened and entered into the study, 395 were randomized. Baseline demographics for the intent-to-treat population included: mean age, 54.4 years (+/-7.5 standard deviation [SD]); 76% Caucasian; mean body mass index (BMI), 31.7 kg/m(2) (+/-12.7 SD); 47% past/present smoker; and 42% severe ED. Aside from dyslipidemia, other comorbidities included hypertension, 61%; obesity (i.e., BMI >/= 30), 51%; and type 1 or 2 diabetes, 40%. During the 12-week treatment period, the least squares (LS) adjusted mean success rates in patients on vardenafil vs. placebo were: SEP2, 79.09% vs. 51.92%; and SEP3, 66.69% vs. 33.83% (P < 0.001). The LS adjusted mean IIEF-EF domain score for week 12 using LOCF was 21.99 in patients on vardenafil therapy vs. 14.83 in those on placebo (P < 0.001). The most commonly encountered AEs were headache and nasal congestion., Conclusions: Vardenafil was demonstrated to be safe and effective for managing ED in men with ED and associated dyslipidemia. The results of this study support the role of expanded research on outcomes related to effective ED treatment and aggressive lipid control.

Introduction: There is a close link between hyperlipidemia/dyslipidemia and erectile dysfunction (ED), with endothelial dysfunction as a common mechanism. Both ED and hyperlipidemia/dyslipidemia are rising in prevalence with mounting evidence that these conditions are harbingers of cardiovascular disease., Aim: This review was conducted to provide an update on the epidemiology and oral therapy of both dyslipidemia and ED, the connection between these two conditions, and clinical outcomes relating to the use of statins and phosphodiesterase type-5 (PDE5) inhibitors in men with ED who have associated dyslipidemia., Methods: A systematic search was performed of MEDLINE and EMBASE research databases to obtain articles pertaining to the epidemiology, mechanism, and clinical outcomes of statins and PDE5 inhibitors in men with ED and associated dyslipidemia., Main Outcome Measures: The clinical and preclinical studies related to ED and dyslipidemia are analyzed and their findings are assessed and summarized. Results. Hyperlipidemia/Dyslipidemia constitute a vascular risk factor having a considerable impact on erectile function. Furthermore, the role of endothelial dysfunction in the pathophysiology of both ED and dyslipidemia is paramount suggesting the importance of comanaging these conditions. Therefore, hyperlipidemia/dyslipidemia when present in patients with ED should prompt management with diet/exercise as well as appropriate pharmacotherapy. With ED being often associated with comorbidities, the use of concomitant pharmacotherapies enhances opportunities for managing the overall global cardiometabolic risk. Newer studies assessing the effect of PDE5 inhibitors in men with dyslipidemia will shed more light on the clinical profile of these agents when used in this patient population., Conclusions: While dyslipidemia and ED are important concerns for clinicians, there exists a gap that needs to be closed between the number of individuals who have either or both conditions and those who are receiving appropriate therapy based on evidence and patient-driven goals regarding clinical outcomes.

Introduction: As prescription drug expenditures increase, third-party payors are increasingly scrutinizing costs and reimbursement guidelines, such as for medications that treat chronic conditions that are not necessarily directly life threatening (i.e., obesity, nicotine addiction, and erectile dysfunction)., Aim: To review the costs and consequences of pharmacy benefit reimbursement policies related to erectile dysfunction therapies, using sildenafil citrate as the case study., Methods: Data and references were found through searches of PubMed and Google., Results and Conclusions: To meet the varied health needs of a defined population under reasonable resource constraints requires analysis of cost and of the economic and non-economic consequences of a treatment. Based on analysis of sildenafil data, oral therapy of erectile dysfunction provides substantial cost savings when compared with other treatment options and contributes insignificant overall costs to health plans. Regardless, health plans impose controls to limit reimbursement. Because erectile dysfunction is often a precursor to other conditions, such limitations could compromise detection and management of underlying disease (e.g., depressive, cardiovascular, and urogenital). Reimbursement restrictions may also decrease membership satisfaction and re-enrollment rates.