Princeton IV consensus guidelines: PDE5 inhibitors and cardiac health.

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.

Diagnosis and Treatment of Infertility in Men: AUA/ASRM Guideline PART II.

PURPOSE: The summary presented herein represents Part II of the two-part series dedicated to the Diagnosis and Treatment of Infertility in Men: AUA/ASRM Guideline. Part II outlines the appropriate management of the male in an infertile couple. Medical therapies, surgical techniques, as well as use of intrauterine insemination (IUI)/in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) are covered to allow for optimal patient management. Please refer to Part I for discussion on evaluation of the infertile male and discussion of relevant health conditions that are associated with male infertility. MATERIALS/METHODS: The Emergency Care Research Institute Evidence-based Practice Center team searched PubMed®, Embase®, and Medline from January 2000 through May 2019. When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B (moderate), or C (low) for support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient evidence, additional information is provided as Clinical Principles and Expert Opinions (table[Table: see text]). This summary is being simultaneously published in Fertility and Sterility and The Journal of Urology. RESULTS: This Guideline provides updated, evidence-based recommendations regarding management of male infertility. Such recommendations are summarized in the associated algorithm (figure[Figure: see text]). CONCLUSION: Male contributions to infertility are prevalent, and specific treatment as well as assisted reproductive techniques are effective at managing male infertility. This document will undergo additional literature reviews and updating as the knowledge regarding current treatments and future treatment options continues to expand.

An Evaluation of a Clinical Care Pathway for the Management of Men With Nonorganic Erectile Dysfunction.

INTRODUCTION: There exists little literature on the outcomes of the medical management of men with erectile dysfunction (ED) with no overt organic etiology. AIM: This study was conducted to assess the outcomes of men with nonorganic ED treated medically. METHODS: All patients had normal hormone profiles and vascular assessment. All were given a trial of a phosphodiesterase type 5 inhibitor (PDE5i). If no improvement was experienced, intracavernosal injection (ICI) therapy was administered. All patients were encouraged to seek a consultation with a mental health professional. MAIN OUTCOME MEASURE: Patient demographics, medical comorbidities, hormone and hemodynamics assessments, and change in International Index of Erectile Function scores of patients were recorded. RESULTS: 116 men with a mean age or 38 ± 19 (range 16-57) years were studied. 21% had mild ED, 47% had moderate ED, and 32% had severe ED. 21% had seen a psychiatrist. 81% of patients responded to PDE5i with a penetration hardness erection on follow-up (mean duration of 7 ± 3 months postcommencement of PDE5i). However, only 68% of these were capable of a consistently good response. The mean Erectile Function domain score on PDE5i for the entire group improved from 18 ± 11 to 22 ± 6 (P = .01), and for PDE5i responders it was 27 ± 4 (P < .001). 28% of men (22 PDE5i failures and 10 with a mixed response to PDE5i) attempted ICI, all obtaining consistently functional erections. At a mean time point of 11 ± 5 months, 83% of those responding to PDE5i had ceased using PDE5i due to a lack of need. 11% of those using ICI continued to use them 6 months after starting ICI; the remainder had been transitioned back to PDE5i. Of the 29 patients in the latter subgroup, 66% were no longer using PDE5i consistently due to a lack of need. CLINICAL IMPLICATIONS: Not all men with nonorganic ED respond to PDE5i initially and many of those who respond do so only intermittently; such patients are potentially curable, using erectogenic pharmacotherapy for erectile confidence restoration, most men are capable of being weaned from drug therapy. STRENGTHS & LIMITATIONS: The strengths of the study are the large number of patients and the use of serial validated instruments to assess erectile function outcomes. As a weakness, despite normal hormone and vascular assessments, the diagnosis of nonorganic ED is still a presumptive one. CONCLUSION: Medical management of nonorganic ED utilizing the process of care model results in cure in a large proportion of such patients. The transient use of ICI in some patients permits successful PDE5i rechallenge. Jenkins LC, Hall M, Deveci S, et al. An Evaluation of a Clinical Care Pathway for the Management of Men With Nonorganic Erectile Dysfunction. J Sex Med 2019;16:1541-1546.

Recovery of erectile function after radical prostatectomy is quantitatively related to the response to intraoperative cavernous nerve stimulation.

OBJECTIVE: To correlate the results of intraoperative cavernous nerve stimulation (CaNS) at radical prostatectomy (RP), with preoperative erectile function (EF) and to determine the significance of the results of stimulation after RP in predicting the recovery of EF. PATIENTS AND METHODS: The study included 183 potent men who had not received neoadjuvant therapy, and who had RP without nerve grafting, with intraoperative CaNS, between July 1998 and April 2002. Follow-up International Index of Erectile Function (IIEF) questionnaires were returned at a median (range) of 25 (1-51) months. Age, preoperative EF, neurovascular bundle (NVB) status, pathological stage and CaNS results were evaluated as independent predictors of the recovery of EF, as assessed by the IIEF, using Cox proportional hazards analysis. RESULTS: CaNS strength before RP correlated with the level of preoperative potency (P = 0.023). CaNS strength after RP correlated with that before RP (P < 0.001) and the degree of NVB preservation (P = 0.007). Only age and maximum percentage change in penile girth after RP were significant independent predictors of the recovery of EF. For each 1-year increase in age, men were 4%, 6% and 5% less likely to achieve erections, defined as an IIEF EF domain score of >or=17, >or=22 and >or=26, respectively. For each 1% increase in maximum percentage change in penile girth after RP with CaNS, men were 26% (95% confidence interval 7-48%), 22% (0-49%), and 47% (17-83%) more likely to achieve erections, with an IIEF EF score of >or=17, >or=22 and >or=26, respectively. There was a significant false-negative rate, with 15% of patients with a minimal CaNS response normalizing their EF score and 35% recovering scores of >or/=22. CONCLUSIONS: While CaNS results after RP correlated strongly with the degree of NVB preservation, the degree of penile girth change, rather than degree of surgeon-documented NVB preservation, was independently predictive of the recovery of EF.

The effect of hyperbaric oxygen therapy on erectile function recovery in a rat cavernous nerve injury model.

INTRODUCTION: Cavernosal oxygenation appears to be important for preservation of erectile tissue health. Hyperbaric oxygen therapy (HBOT) has been shown to improve tissue oxygenation and has neuromodulatory effects. AIM: This study was designed to define the effects of HBOT on erectile function (EF) and cavernosal tissue in the rat cavernous nerve (CN) injury model. METHODS: Four groups of Sprague-Dawley rats were studied: rats with bilateral CN crush, HBOT treated (Crush+/HBOT+); bilateral CN-crush/no HBOT (C+/H-); no crush/no HBOT (C-/H-); and no crush/HBOT (C-/H+). HBOT was delivered daily for 90 minutes at three atmospheres for 10 days commencing the day of CN crush. MAIN OUTCOME MEASURES: Ten days after CN injury, the animals underwent CN stimulation measuring the maximal intracavernosal pressure/mean arterial pressure (ICP/MAP) ratios. Corporal tissue was harvested pre-sacrifice, and immunohistochemically stained for nerve growth factor (NGF), endothelial nitric oxide synthase (eNOS), and cluster of differentiation molecule (CD31). Histologic analysis was performed for Masson's trichrome to assess the smooth muscle-collagen ratio. Terminal deoxynucleotidyl transferase Biotin-dUTP Nick End Labeling assay was used to define apoptotic indices (AIs). RESULTS: The C+/H- group had significantly lower ICP/MAP ratios compared with C-/H- rats, (31% vs. 70%, P < 0.001). C+/H+ rats had significantly higher ICP/MAP ratio recovery compared with the C+/H- group (55% vs. 31%, P = 0.005). NGF and eNOS staining densities were higher in C+/H+ rats compared with C+/H- rats (P < 0.05 and P < 0.001, respectively). No difference was seen in CD31 expression. Staining density for MT displayed a trend toward higher smooth muscle preservation after HBOT. AIs were significantly increased by HBOT (P < 0.05). CONCLUSION: HBOT following a CN injury improved EF preservation in this model, supporting the cavernosal oxygenation concept as protective mechanism for EF. The effects appear to be mediated via preservation of neurotrophic and endothelial factor expression.

The impact of shock wave therapy at varied energy and dose levels on functional and structural changes in erectile tissue.

OBJECTIVES: Only minimal literature exists on consequences of shock wave therapy (SWT) on erectile function in treatment of Peyronie's disease (PD). This study was undertaken to define SWT impact at varied energy/dose levels at different time points on functional and structural changes in erectile tissue. METHODS: In 45 rats 2000 shock waves (sw) at 2 BAR were applied to the penis weekly sorted by one, two, and three sessions (high-dose/energy level, HD-1, HD-2, HD-3). Each group was followed for 1, 7, or 28 d before measuring intracavernosal pressure (ICP) and mean arterial pressure (MAP). Fifteen control animals (C1, C7, C28) underwent anesthesia alone. Another 15 animals were exposed to three SWT sessions applying 1000 sw at 1 BAR and analyzed identically (low-dose/energy level, LD-3-1, -7, -28). Terminal deoxynucleotidyl transferase biotin-dUTP nick-end labeling assay was used to define the apoptotic index (AI) and Masson's trichrome (MT) staining was prepared to evaluate smooth muscle-to-collagen ratios. RESULTS: ICP/MAP ratios for all C groups displayed a mean of 64%. All SWT groups demonstrated significantly reduced ICP/MAP ratios compared to their corresponding C groups (p<0.05). The LD-3 groups showed a trend toward improved ICP/MAP ratios. LD-3-28 demonstrated significant recovery compared to HD-3-28 (55+/-8% vs. 41+/-10%, p=0.004), but remained reduced compared to C28 (63+/-5%, p=0.03). No statistical differences were seen for MT staining in SWT groups compared to C (p>0.05). AIs for the LD-3 groups were significantly lower compared to the HD-3 groups (p<0.001), but all AIs were significantly increased compared to C groups (p<0.01). CONCLUSIONS: Overall, at both energy/dose levels, SWT resulted in a time- and treatment-dependent reduction of ICP/MAP ratios, which might be mediated partly through apoptosis and collagenization of corporal smooth muscle.

Neuroprotective strategies in radical prostatectomy.

In this section, authors from New York give their views on the various neuroprotective strategies for patients having a radical prostatectomy, such as the use of nerve grafts and other approaches. A joint study from Korea, the USA, Canada and the UK is presented in a paper on the importance of patient perception in the clinical assessment and management of BPH. There is also a review of robotic urological surgery. Finally, authors from New York give a review on the life of Isaac Newton. This is a new historical review in the journal, but one that will be of general interest.

Prevention and treatment of erectile dysfunction using lifestyle changes and dietary supplements: what works and what is worthless, part I.

Clinicians working in urology should adhere to the same guidelines that are observed in cardiovascular medicine when dealing with a patient with ED. A golden opportunity exists to discuss lifestyle changes with any man with or concerned about ED. Providing heart-healthy recommendations to men with minimal to extensive ED may produce a twofold impact: (1) patients may be able to affect the future extent of their disease, and (2) patients may become healthier overall. Patients following a heart-healthy lifestyle after a diagnosis of ED or to prevent ED should enjoy increased quality or quantity of life. The time is more than ripe for patients to understand that heart health is tantamount to erectile health.

Prevention and treatment of erectile dysfunction using lifestyle changes and dietary supplements: what works and what is worthless, part II.

It seems naïve to believe that some plants or herbs do not contain specific compounds that could benefit patients with ED. Many supplements have not been investigated in a laboratory or clinical research setting before commercial sale, however,which creates a complex situation. If efficacy is or is not demonstrated through adequate research, then the benefit or lack thereof cannot be mentioned on the label. Furthermore, clinicians and the public cannot be made aware of which compounds or supplements are effective because no general standards for sale exist under the current guidelines. Dietary supplements have received a tremendous amount of publicity. The large and growing market for ED treatment seems to have contributed partly to the promotion of numerous supplements and their apparent benefits. Whether these dietary supplements have merit is questionable. Some supplements may produce results opposite to those advertised. Other supplements may be enjoying the benefits of the placebo effect. Because a placebo response of 25% to 50% has been recorded in clinical trials with effective agents, it is understandable that some supplements enjoy financial success despite the limited research espousing their use. If one to two of four individuals or one of three individuals who try a dietary supplement gain some benefit for their ED, the market for these supplements will remain extraordinary. On a larger scale, of 100,000 men who try a supplement, approximately 25,000 to 50,000 will claim some success. The challenge for clinicians is to discuss the placebo response properly and the need for good research before any intervention, especially supplements, can be advocated for general use. Table 2 summarizes some popular ED supplements and general conclusions that can be drawn from clinical investigations. Some dietary supplements may have an active ingredient that benefits patients with certain types of ED. An exciting area of future dietary supplement research is the ability of certain agents to have a synergistic effect with prescription agents for ED, thereby improving response rates in men that have failed approved ED therapy initially, especially with oral agents. Randomized clinical trials are the best method of determining which dietary supplements will become a part of conventional medicine. Therefore, more randomized trials for dietary supplements are needed so that they may have the opportunity to become a part of the mainstream milieu, which means that more funding needs to be made available for ED research. The coming years of research should bring enormous excitement and objectivity to this area of medicine.