A Proposal for the Comprehensive Care of Men on Androgen Deprivation Therapy: Recommendations From the Multidisciplinary Prostate Cancer 360 Working Group.

INTRODUCTION: To promote comprehensive care of patients throughout the androgen deprivation therapy (ADT) prescribing process, the Prostate Cancer 360 (PC360) Working Group developed monitoring and management recommendations intended to mitigate or prevent ADT-associated adverse events. METHODS: The PC360 Working Group included 14 interdisciplinary experts with a dedicated clinical interest in prostate cancer and ADT management. The working group defined challenges associated with ADT adverse event management and then collaboratively developed comprehensive care recommendations intended to be practical for ADT prescribers. RESULTS: The PC360 Working Group developed both overarching recommendations for ADT adverse event management and specific recommendations across 5 domains (cardiometabolic, bone, sexual, psychological, and lifestyle). The working group recommends an interdisciplinary, team-based approach wherein the ADT prescriber retains an oversight role for ADT management while empowering patients and their primary and specialty care providers to manage risk factors. The PC360 recommendations also emphasize the importance of proactive patient education that involves partners or other support providers. Recommended monitoring and assessment tools, risk factor management, and patient counseling points are also included for the 5 identified domains, with an emphasis on lifestyle and behavioral interventions that can improve quality of life and reduce the risk for ADT-associated complications. CONCLUSIONS: Comprehensive care of patients receiving ADT requires early and ongoing coordinated management of a variety of health domains, including cardiometabolic, bone, sexual, psychological health. Patient education and primary care provider involvement should begin prior to ADT initiation and continue throughout treatment to improve patient and partner quality of life.

Pharmacokinetics of testosterone therapies in relation to diurnal variation of serum testosterone levels as men age.

BACKGROUND: To improve symptoms associated with testosterone deficiency, many testosterone therapies are available that aim to restore serum testosterone (T) levels to the normal physiologic range. The magnitude, frequency, and duration between peak and trough T concentrations vary with route of administration, and none reflect normal endogenous daily diurnal T variations. OBJECTIVE: To compare pharmacokinetic profiles of serum T from approved T formulations with endogenous diurnal T variations in young and older men, and to consider whether there may be value in mimicking the diurnal T rhythmicity with exogenous testosterone therapies as men age. MATERIALS AND METHODS: A literature search of studies examining the diurnal variation of endogenous T in healthy men and men with testosterone deficiency was performed using PubMed in January 2020. Additional searches for serum T pharmacokinetic profiles of various testosterone therapy formulations were also conducted. Prescribing information for various T formulations was also reviewed. DISCUSSION AND CONCLUSION: Endogenous diurnal T variation is well described and appears to be blunted naturally as men age. Men with testosterone deficiency lack diurnal T variation and exhibit a flatter T profile compared with eugonadal men. Some T replacement options provide intraday T level variations similar to normal circadian secretion, and others provide a flatter exposure profile reflective of depot release. Others provide profiles that exceed the frequency and physiologic range of the natural diurnal variation of T. All exogenous T replacement dosing targets an increase in average T levels to within the normal physiologic range and improves symptoms associated with low T, but no single testosterone therapy can exactly mimic the normal diurnal T patterns seen in younger men and the blunted circadian T secretion of older men.

Over-the-counter medication availability could augment self-management of male lower urinary tract symptoms.

In this review, we focus on current trends in the management of male lower urinary tract symptoms (LUTS), defined here as LUTS, namely, storage, voiding, and post-micturition symptoms presumed secondary to benign prostatic hyperplasia (BPH), and discuss possible novel approaches toward better care. According to results of a PubMed database search covering the last 10 years and using keywords pertaining to male LUTS, this condition continues to be globally undiagnosed or diagnosed late, partly because of men's hesitation to seek help for perceived embarrassing problems or problems considered a normal part of aging. In addition, the prevalence of male LUTS is continually increasing because of a constantly aging population. Male LUTS can be bothersome and affect the quality of life (QoL) and sexual function. Additional effective alternatives for managing this condition need to be identified and incorporated into the current care model. Considering that most male LUTS such as frequency, hesitancy, urgency, and intermittency are easy to self-identify, a self-management approach toward male LUTS is proposed. Limited evidence supports the efficacy of phytotherapies and herbals as self-management options for male LUTS. However, introducing over-the-counter (OTC) medication with proven efficacy, accompanied by lifestyle and behavioral modifications, may be a promising approach that will encourage more men to treat their symptoms in a timely manner. Formal guidelines, along with appropriate education programs for patients and support from the healthcare community, will be needed to ensure that the promise of this approach is fully materialized.

Erectile Dysfunction: AUA Guideline.

PURPOSE: The purpose of this guideline is to provide a clinical strategy for the diagnosis and treatment of erectile dysfunction. MATERIALS AND METHODS: A systematic review of the literature using the Pubmed, Embase, and Cochrane databases (search dates 1/1/1965 to 7/29/17) was conducted to identify peer-reviewed publications relevant to the diagnosis and treatment of erectile dysfunction. Evidence-based statements were based on body of evidence strength Grade A, B, or C and were designated as Strong, Moderate, and Conditional Recommendations with additional statements presented in the form of Clinical Principles or Expert Opinions. RESULTS: The American Urological Association has developed an evidence-based guideline on the management of erectile dysfunction. This document is designed to be used in conjunction with the associated treatment algorithm. CONCLUSIONS: Using the shared decision-making process as a cornerstone for care, all patients should be informed of all treatment modalities that are not contraindicated, regardless of invasiveness or irreversibility, as potential first-line treatments. For each treatment, the clinician should ensure that the man and his partner have a full understanding of the benefits and risk/burdens associated with that choice.

Evaluation and Management of Testosterone Deficiency: AUA Guideline.

PURPOSE: There has been a marked increase in testosterone prescriptions in the past decade resulting in a growing need to give practicing clinicians proper guidance on the evaluation and management of the testosterone deficient patient. MATERIALS AND METHODS: A systematic review utilized research from the Mayo Clinic Evidence Based Practice Center and additional supplementation by the authors. Evidence-based statements were based on body of evidence strength Grade A, B, or C and were designated as Strong, Moderate, and Conditional Recommendations with additional statements presented in the form of Clinical Principles or Expert Opinions (table 1 in supplementary unabridged guideline, http://jurology.com/). RESULTS: This guideline was developed by a multi-disciplinary panel to inform clinicians on the proper assessment of patients with testosterone deficiency and the safe and effective management of men on testosterone therapy. Additional statements were developed to guide the clinician on the appropriate care of patients who are at risk for or have cardiovascular disease or prostate cancer as well as patients who are interested in preserving fertility. CONCLUSIONS: The care of testosterone deficient patients should focus on accurate assessment of total testosterone levels, symptoms, and signs as well as proper on-treatment monitoring to ensure therapeutic testosterone levels are reached and symptoms are ameliorated. Future longitudinal observational studies and clinical trials of significant duration in this space will improve diagnostic techniques and treatment of men with testosterone deficiency as well as provide more data on the adverse events that may be associated with testosterone therapy.

The Intersection of Medicine and Urology: An Emerging Paradigm of Sexual Function, Cardiometabolic Risk, Bone Health, and Men's Health Centers.

Men's mental health and how they think about their health are critical to the future of men's health. Poor health choice patterns are established under age 50, when men are twice as likely to die than women. As the future of medicine focuses on quality and value, a better understanding of the social determinants of men's health will identify areas for improvement. The presentation of a man to a clinician's office with a sexual health complaint presents an opportunity for more complete evaluation. The future of men's health will be well served by integrated men's health centers that focus on the entire man.

Association of subcutaneous testosterone pellet therapy with developing secondary polycythemia.

A variety of methods for testosterone replacement therapy (TRT) exist, and the major potential risks of TRT have been well established. The risk of developing polycythemia secondary to exogenous testosterone (T) has been reported to range from 0.4% to 40%. Implantable T pellets have been used since 1972, and secondary polycythemia has been reported to be as low as 0.4% with this administration modality. However, our experience has suggested a higher rate. We conducted an institutional review board-approved, single-institution, retrospective chart review (2009-2013) to determine the rate of secondary polycythemia in 228 men treated with subcutaneously implanted testosterone pellets. Kaplan-Meyer failure curves were used to estimate time until the development of polycythemia (hematocrit >50%). The mean number of pellets administered was 12 (range: 6-16). The mean follow-up was 566 days. The median time to development of polycythemia whereby 50% of patients developed polycythemia was 50 months. The estimated rate of polycythemia at 6 months was 10.4%, 12 months was 17.3%, and 24 months was 30.2%. We concluded that the incidence of secondary polycythemia while on T pellet therapy may be higher than previously established.

Role of Genetic Testing for Inherited Prostate Cancer Risk: Philadelphia Prostate Cancer Consensus Conference 2017.

Purpose Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-driven working framework for comprehensive genetic evaluation of inherited PCA in the multigene testing era addressing genetic counseling, testing, and genetically informed management. Methods An expert consensus conference was convened including key stakeholders to address genetic counseling and testing, PCA screening, and management informed by evidence review. Results Consensus was strong that patients should engage in shared decision making for genetic testing. There was strong consensus to test HOXB13 for suspected hereditary PCA, BRCA1/2 for suspected hereditary breast and ovarian cancer, and DNA mismatch repair genes for suspected Lynch syndrome. There was strong consensus to factor BRCA2 mutations into PCA screening discussions. BRCA2 achieved moderate consensus for factoring into early-stage management discussion, with stronger consensus in high-risk/advanced and metastatic setting. Agreement was moderate to test all men with metastatic castration-resistant PCA, regardless of family history, with stronger agreement to test BRCA1/2 and moderate agreement to test ATM to inform prognosis and targeted therapy. Conclusion To our knowledge, this is the first comprehensive, multidisciplinary consensus statement to address a genetic evaluation framework for inherited PCA in the multigene testing era. Future research should focus on developing a working definition of familial PCA for clinical genetic testing, expanding understanding of genetic contribution to aggressive PCA, exploring clinical use of genetic testing for PCA management, genetic testing of African American males, and addressing the value framework of genetic evaluation and testing men at risk for PCA-a clinically heterogeneous disease.

Erectile dysfunction and lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH) combined responders to tadalafil after 12 weeks of treatment.

OBJECTIVE: To analyse the proportion of men taking tadalafil 5 mg once daily who experience a combined improvement in symptoms of both erectile dysfunction (ED) and lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH). MATERIALS AND METHODS: The data from men aged ≥45 years randomized to tadalafil 5 mg once daily or placebo enrolled in one of four randomized, placebo-controlled LUTS/BPH clinical trials were analysed (N = 927). A novel classification of 'combined responders' to ED and LUTS/BPH treatment was defined, based on published criteria for men who showed improvement in both International Index of Erectile Function - Erectile Function domain (IIEF-EF) score and total International Prostate Symptom Score (IPSS). Descriptive analyses assessed the covariate distribution by responder status. Unadjusted and adjusted logistic regressions provided odds ratios with 95% confidence intervals comparing combined responders with all others (partial and non-responders). RESULTS: Among men randomized to tadalafil 5 mg, 40.5% were combined responders (n = 189). Among placebo randomized men, 18.3% were combined responders (n = 84). Combined responders, in the total population, had the highest baseline IPSS and lowest baseline IIEF-EF scores, corresponding to the highest level of dysfunction. The majority of men were aged ≤65 years, white, non-obese, non-smokers, and regular alcohol consumers. Only treatment, baseline IPSS, baseline IIEF-EF, obesity and psychoactive medication use were significantly associated with responder status (P ≤ 0.05). Tadalafil-treated men had 2.8 times significantly increased adjusted odds of being combined responders vs non-responders (P < 0.001). For each unit decrease in baseline IIEF-EF or alcoholic drink consumption per week there was a 4% significant increase in the adjusted odds of being a combined responder to tadalafil therapy. CONCLUSIONS: This novel measure of combined response is useful in differentiating patients with clinically relevant symptom improvement for both ED and LUTS/BPH after treatment with tadalafil 5 mg once daily vs placebo. This combined responder measure may be useful in future assessment of treatment benefits across patient groups after various types of treatment intervention (e.g. surgical vs pharmacotherapy vs non-pharmacological intervention).

Cardiovascular Disease Prevention in Men with Vascular Erectile Dysfunction: The View of the Preventive Cardiologist.

Vascular erectile dysfunction is a powerful marker of increased cardiovascular risk. However, current guidelines lack specific recommendations on the role that the evaluation of vascular erectile dysfunction should play in cardiovascular risk assessment, as well on the risk stratification strategy that men with vascular erectile dysfunction should undergo. In the last 3 years, erectile dysfunction experts have made a call for more specific guidance and have proposed the selective use of several prognostic tests for further cardiovascular risk assessment in these patients. Among them, stress testing has been prioritized, whereas other tests are considered second-line tools. In this review, we provide additional perspective from the viewpoint of the preventive cardiologist. We discuss the limitations of current risk scores and the potential interplay between erectile dysfunction assessment and the use of personalized prognostic tools, such as the coronary artery calcium score, in the cardiovascular risk stratification and management of men with vascular erectile dysfunction. Finally, we present an algorithm for primary care physicians, urologists, and cardiologists to aid clinical decision-making.

Peyronie's Disease: AUA Guideline.

PURPOSE: The purpose of this guideline is to provide a clinical framework for the diagnosis and treatment of Peyronie's disease. MATERIALS AND METHODS: A systematic review of the literature using the PubMed®, EMBASE® and Cochrane databases (search dates 1/1/1965 to 1/26/15) was conducted to identify peer-reviewed publications relevant to the diagnosis and treatment of PD. The review yielded an evidence base of 303 articles after application of inclusion/exclusion criteria. RESULTS: The systematic review was used to create guideline statements regarding treatment of PD. When sufficient evidence existed, the body of evidence for a particular treatment was assigned a strength rating of A (high quality evidence; high certainty), B (moderate quality evidence; moderate certainty), or C (low quality evidence; low certainty). Evidence-based statements of Strong, Moderate, or Conditional Recommendation were developed based on benefits and risks/burdens to patients. Additional consensus statements related to the diagnosis of PD are provided as Clinical Principles and Expert Opinions due to insufficient published evidence. CONCLUSIONS: There is a continually expanding literature on PD; the Panel notes that this document constitutes a clinical strategy and is not intended to be interpreted rigidly. The most effective approach for a particular patient is best determined by the individual clinician and patient in the context of that patient's history, values, and goals for treatment. As the science relevant to PD evolves and improves, the strategies presented here will be amended to remain consistent with the highest standards of clinical care.

Testosterone therapy and cardiovascular risk: advances and controversies.

Two recent studies raised new concerns regarding cardiovascular (CV) risks with testosterone (T) therapy. This article reviews those studies as well as the extensive literature on T and CV risks. A MEDLINE search was performed for the years 1940 to August 2014 using the following key words: testosterone, androgens, human, male, cardiovascular, stroke, cerebrovascular accident, myocardial infarction, heart attack, death, and mortality. The weight and direction of evidence was evaluated and level of evidence (LOE) assigned. Only 4 articles were identified that suggested increased CV risks with T prescriptions: 2 retrospective analyses with serious methodological limitations, 1 placebo-controlled trial with few major adverse cardiac events, and 1 meta-analysis that included questionable studies and events. In contrast, several dozen studies have reported a beneficial effect of normal T levels on CV risks and mortality. Mortality and incident coronary artery disease are inversely associated with serum T concentrations (LOE IIa), as is severity of coronary artery disease (LOE IIa). Testosterone therapy is associated with reduced obesity, fat mass, and waist circumference (LOE Ib) and also improves glycemic control (LOE IIa). Mortality was reduced with T therapy in 2 retrospective studies. Several RCTs in men with coronary artery disease or heart failure reported improved function in men who received T compared with placebo. The largest meta-analysis to date revealed no increase in CV risks in men who received T and reduced CV risk among those with metabolic disease. In summary, there is no convincing evidence of increased CV risks with T therapy. On the contrary, there appears to be a strong beneficial relationship between normal T and CV health that has not yet been widely appreciated.

Erectile Dysfunction and Essential Hypertension: The Same Aging-related Disorder?

An erection is a mechanical event dependent primarily on corporeal vascular dynamics wherein arterial inflow and storage of blood within the corpora is greater than the egress of blood from the corpora. The most common cause of erectile dysfunction (ED) is the inability of the corporal tissue to store the blood within the corporal sinusoids once inflow into the corpora begins. This failure to store is primarily due to a corporal smooth muscle dysfunction and, in most men, is most likely an aging-related occurrence. Because the corporal smooth muscle is embryologically and physiologically indistinguishable from the smooth muscle within our arterial system, the authors hypothesize that the aging-related dysfunction that occurs within the penis also occurs within the arterial system, and that this smooth muscle dysfunction within the arterial media is most likely the cause of what is called essential hypertension. This panvascular smooth muscle myopathy could explain why hypertension is the most common comorbidity associated with ED and appears to indicate that both ED and essential hypertension are the same disorder, albeit in two different organ systems.

Peyronie's disease: epidemiology, diagnosis, and management.

OBJECTIVE: Peyronie's disease (PD) is a progressive fibrotic disorder of the penis that is characterized by formation of collagen plaques on the tunica albuginea of the penis that may result in penile deformity, pain (typically early in the disease course), and often occurs in conjunction with erectile dysfunction. This review's purpose is to raise awareness of PD among primary care physicians, who are likely to provide the initial diagnosis and information to patients. METHODS: PubMed was searched for articles related to epidemiology, diagnosis, and management of PD. Reference lists of relevant articles were also examined for further pertinent research. Following the goals of this review, references were selected based on their appropriateness for a primary care audience. RESULTS: The symptoms of PD may physically limit intercourse and impose a severe physical and psychological burden. The course of PD includes an early 'inflammatory' phase that may last 1-18 months and a subsequent 'stable' phase. In the early phase, patients may experience penile pain as the tunical plaque develops. During the stable phase, the plaque becomes more organized, penile curvature stabilizes, and the pain usually subsides. Currently, there are no US Food and Drug Administration approved therapies that have shown significant efficacy for PD. Nonsurgical treatment options are often used to manage PD with variable success. Most studies of nonsurgical management of PD are small, poorly controlled, and include patients in variable disease stages. Surgical treatment of PD is reserved for stable patients with erectile dysfunction and penile deformity that impairs sexual function. CONCLUSION: PD is frequently undiagnosed. Even when PD is correctly identified, choice of treatment is problematic, based on the limited currently available clinical data demonstrating clinical benefits associated with treatment. Newer medications in clinical testing seem to offer some potential benefit for men with PD, though further research is necessary.

12-month observation of testosterone replacement effectiveness in a general population of men.

BACKGROUND: Testosterone decline becomes more prevalent as men age and symptomatic testosterone deficiency is associated with potentially serious comorbidities. Despite limitations, registries can provide an opportunity to accumulate data regarding disease management in a typical patient population, including diagnosis, treatment, and outcomes. MATERIALS AND METHODS: The Testim Registry in the United States (TRiUS) was a prospective, 12-month, observational cohort registry of men prescribed Testim® (1% testosterone gel; Auxilium Pharmaceuticals, Inc.) for the first time; patients previously on other forms of testosterone replacement therapy (TRT) were eligible to participate in the study as well. The registry recorded total testosterone (TT) and free testosterone (FT) levels, prostate-specific antigen (PSA), sexual function, mood/depression, and cardiometabolic and anthropometric criteria before and after TRT. Changes over time were analyzed by analysis of variance, and linear regression and Pearson product-moment correlation coefficients were used to examine relationships between variables. RESULTS: At baseline, 849 patients from 72 sites were enrolled, with 743 of 849 started on 5 g gel/day (50 mg testosterone/day) and 106 of 849 started on 10 g gel/day (100 mg testosterone/day). Mean TT and FT levels increased significantly after 3 months of TRT (TT level, 16.8 ± 9.87 nmol/L [485 ± 284 ng/dL], P < 0.001; FT level, 286.3 ± 224.9 pmol/L [82.5 ± 64.8 pg/mL], P < 0.001) and were maintained at eugonadal levels. Mean PSA levels increased significantly (P = 0.004) from 1.12 ± 1.11 µg/L (1.12 ± 1.11 ng/mL) at baseline to 1.26 ± 1.22 µg/L (1.26 ± 1.22 ng/mL) after 12 months of TRT, although changes were well within guidelines (< 1.4 µg/L/year increase). Significant improvements were seen in sexual function and mood/depression at 3 months and in metabolic parameters at 12 months. CONCLUSION: Testosterone deficiency symptoms improved with TRT use in men; sexual function and mood/depression improvements were seen before metabolic improvements. Prostate-specific antigen levels increased, although increases were within guideline-determined safety limits.

Testosterone replacement therapy in men with hypogonadism and HIV/AIDS: results from the TRiUS registry.

BACKGROUND: Although hypogonadism is common in men with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), testosterone levels after testosterone replacement therapy (TRT) in this population have not been reported. METHODS: The Testim Registry in the United States (TRiUS) was the first prospective, observational registry of men with hypogonadism who were prescribed TRT. The TRiUS cohorts with (n = 82) and without (n = 767) HIV/AIDS were followed during 12 months of treatment with Testim® (1% testosterone gel; Auxilium Pharmaceuticals, Inc.). Total testosterone (TT) and free testosterone levels, symptoms of depression, sexual function, body composition profiles, and prostate-specific antigen levels were evaluated. RESULTS: The HIV/AIDS and non-HIV/AIDS cohorts differed at baseline in age (48.3 vs 52.5 years), TT level (13.0 vs 9.6 nmol/L), duration of hypogonadism (27.1 vs 14.6 months), prior TRT (36.6% vs 22.6%), body mass index (26.5 vs 32.0 kg/m2), and antidepressant (29% vs 15%) and opioid (20% vs 10%) use (P ≤ 0.01 for all comparisons). During the 12 months, both cohorts experienced significant elevations in TT and free testosterone levels to within normal ranges. Sexual function and depression scores improved and antidepressant medication use decreased in both cohorts. Body composition profiles improved significantly (P ≤ 0.05) in men without HIV/AIDS and remained stable in men with HIV/AIDS during the 12 months of follow-up. CONCLUSION: This 12-month, non-placebo-controlled, observational study of Testim® use in men with and without HIV/AIDS suggests that TRT may provide clinical benefits irrespective of the patient's HIV/AIDS status. This conclusion is supported by the higher testosterone levels, better sexual function, lower depression scores, and better body composition profiles found in both groups. However, given the loss of patients to follow-up, these results may reflect a bias toward drug responders.