The role of testosterone in men's health: is it time for a new approach?

PURPOSE: Because of many unanswered questions regarding men's health, a literature review was performed to better understand the role of testosterone and testosterone replacement therapy (TRT) in the management of hypogonadism and aging related prostate gland diseases (ARPGD) including prostate cancer (PCa) and benign prostatic hyperplasia (BPH) with lower urinary tract symptoms (LUTS). METHODS: The PubMed database was screened for pertinent peer reviewed articles published during the last four decades that culminated in the positions and recommendations in this paper. RESULTS: Hypogonadism seriously impacts men's health, and the diagnosis remains controversial. The incidence of ARPGD is projected to increase worldwide and treatment still has significant limitations. There is compelling evidence that lower, not higher, testosterone levels trigger the development of PCa and BPH through androgen receptor over-expression. TRT was found to be safe and effective in treating hypogonadism including in PCa survivors and those harboring PCa. There is also evidence that TRT might reduce the incidence and prevalence of ARPGD. CONCLUSIONS AND RECOMMENDATIONS: This review synthesizes a wide-ranging compendium of basic science and clinical research that strongly encourages altering the present approach to diagnosing and treating men with hypogonadism and ARPGD. These findings underscore the importance of avoiding significant testosterone decline and support the use of TRT. Ten recommendations are offered as a framework for the way forward. It is now time for clinicians, payers, researchers, funding agencies, professional associations, and patient advocacy groups to embrace this new paradigm to increase longevity and improve the quality of life.

Improved global response outcome after intradetrusor injection of adult muscle-derived cells for the treatment of underactive bladder.

We report on the first regulatory approved clinical trial of a prospective open-label physician-initiated study assessing the safety and efficacy of intradetrusor injected Autologous Muscle Derived Cells (AMDC) treatment for underactive bladder (UAB). 20 non-neurogenic UAB patients were treated. Approximately 50-250 mg of quadriceps femoris muscle was collected using a spirotome 8-gauge needle. The muscle biopsy samples were sent to Cook MyoSite (Pittsburgh, PA) for processing, isolation, and propagation of cells. Research patients received approximately 30 intradetrusor injections of 0.5 mL delivered to the bladder, for a total of 15 mL and 125 million AMDC, performed utilizing a flexible cystoscope under direct vision using topical local anesthesia. Follow-up assessments included adverse events and efficacy via voiding diary and urodynamic testing at 1, 3, 6 and 12 months post-injection. An optional second injection was offered at the end of the 6 months visit. 20 patients received the first injection and all 20 patients requested and received a second injection. Median patient age was 65 years old (range 41-82 years). There were 16 male (80%) and 4 female (20%) patients. Etiology included 7 men (35%) with persistent urinary retention after transurethral resection of the prostate for benign prostatic hyperplasia and 13 patients (65%) with idiopathic chronic urinary retention. At the primary outcome time point of 12 months, 11/19 patients (58%) reported a global response assessment (GRA) ≥ 5, showing slight to marked improvement in their UAB symptoms, compared to 6/20 (30%) patients at 3 months post-injection. No serious procedure or treatment-related adverse events occurred. Noted improvements included: decreased post void residual urine volume, increased voiding efficiency, and decreased catheter use. Intradetrusor-injected AMDC as a treatment for UAB was successfully completed in a 20-patient trial without serious adverse event and with signal of efficacy. Cellular therapy may be a promising novel treatment for catheter-dependent chronic urinary retention. A multicenter controlled trial is needed to further assess the promise of regenerative medicine in the treatment of lower urinary tract dysfunction.

Underactive Bladder; Review of Progress and Impact From the International CURE-UAB Initiative.

There is a significant need for research and understanding of underactive bladder (UAB). The International Congress of Urologic Research and Education on Aging UnderActive Bladder (CURE-UAB) was organized by Doctors Michael Chancellor and Ananias Diokno in order to address these concerns. CURE-UAB was supported, in part, by the US National Institute of Aging and National Institute of Diabetes Digestive and Kidney. Since 2014, there have been 5 successful CURE-UAB congresses. They have brought together diverse stakeholders in the UAB field to identify areas of major scientific challenge and initiated a call to action among the medical community. In this review, we will highlight current and novel treatments under development for UAB and the progress and impact from the CURE-UAB initiative.

Effect of Group-Administered Behavioral Treatment on Urinary Incontinence in Older Women: A Randomized Clinical Trial.

Importance: Urinary incontinence (UI) guidelines recommend behavioral interventions as first-line treatment using individualized approaches. A one-time, group-administered behavioral treatment (GBT) could enhance access to behavioral treatment. Objective: To compare the effectiveness, cost, and cost-effectiveness of GBT with no treatment for UI in older women. Design, Setting, and Participants: Multisite randomized clinical trial (the Group Learning Achieves Decreased Incidents of Lower Urinary Symptoms [GLADIOLUS] study), conducted from July 7, 2014, to December 31, 2016. The setting was outpatient practices at 3 academic medical centers. Community-dwelling women 55 years or older with UI were recruited by mail and screened for eligibility, including a score of 3 or higher on the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF), symptoms of at least 3 months' duration, and absence of medical conditions or treatments that could affect continence status. Of 2171 mail respondents, 1125 were invited for clinical screening; 463 were eligible and randomized; 398 completed the 12-month study. Interventions: The GBT group received a one-time 2-hour bladder health class, supported by written materials and an audio CD. Main Outcomes and Measures: Outcomes were measured at in-person visits (at 3 and 12 months) and by mail or telephone (at 6 and 9 months). The primary outcome was the change in the ICIQ-SF score. Secondary outcome measures assessed UI severity, quality of life, perceptions of improvement, pelvic floor muscle strength, and costs. Evaluators were masked to group assignment. Results: Participants (232 in the GBT group and 231 in the control group) were aged 55 to 91 years (mean [SD] age, 64 [7] years), and 46.2% (214 of 463) were African American. In intent-to-treat analyses, the ICIQ-SF scores for GBT were consistently lower than control across all time points but did not achieve the projected 3-point difference. At 3 months, the difference in differences was 0.96 points (95% CI, -1.51 to -0.41 points), which was statistically significant but clinically modest. The mean (SE) treatment effects at 6, 9, and 12 months were 1.36 (0.32), 2.13 (0.33), and 1.77 (0.31), respectively. Significant group differences were found at all time points in favor of GBT on all secondary outcomes except pelvic floor muscle strength. The incremental cost to achieve a treatment success was $723 at 3 months; GBT dominated at 12 months. Conclusions and Relevance: The GLADIOLUS study shows that a novel one-time GBT program is modestly effective and cost-effective for reducing UI frequency, severity, and bother and improving quality of life. Group-administered behavioral treatment is a promising first-line approach to enhancing access to noninvasive behavioral treatment for older women with UI. Trial Registration: ClinicalTrials.gov identifier: NCT02001714.

New technology assessment and current and upcoming therapies for underactive bladder.

BACKGROUND AND AIMS: Stakeholders from around the world came together to address the unmet needs of underactive bladder (UAB) at the 3rd International Congress for Underactive Bladder. METHODS: The main recommendation from the regulatory working group is a need for a meeting of UAB stakeholders and regulatory agencies including the FDA to discuss guidance for regulatory trial design for devices, drugs, and/or biologics for UAB. RESULTS: The following issues to be discussed and agreed upon for UAB trials: 1) Appropriate inclusion and exclusion criteria. 2) Should residual urine volume be the primary outcome parameter and how often should it be measured? 3) Are there secondary measures that should have a place in UAB trials, such as change in the number of catheterizations, quality of life measures, etc.? 4) Use and format of bladder voiding and catheterization diary for trials. 5) Define role and technique of urodynamics in UAB trials. Are urodynamics required to monitor, and possibly exclude, individuals with high pressure voiding induced by bladder prokinetic therapies? 6) Development and use of UAB questionnaires. DISCUSSION AND CONCLUSION: The UAB regulatory working group recognizes the path forward should include engaging the FDA and other regulatory organizations that may harmonize and formalize guidance for regulatory trial designs for therapeutics for UAB.

Costs and Sustainability of a Behavioral Intervention for Urinary Incontinence Prevention.

INTRODUCTION: Many women choose behavioral interventions as first line treatment for urinary incontinence. We developed a 20-minute abbreviated video, which proved to be similar to a 2-hour in-person class in a randomized trial. This study examines economic end points for the 20-minute video relative to the 2-hour class. METHODS: We randomized 332 participants to the 2-hour class and 315 to the 20-minute video. We estimated the cost for the 2-hour class, the 20-minute video and followup health care utilization. Participants were followed for 3, 12 and 24 months, and asked about health care utilization, quality of life and lost productivity. To measure perceived value, we queried each participant regarding willingness to pay. Regression analysis was used for statistical comparisons. RESULTS: The estimated per participant cost for a 2-hour class was $38, which was more than the marginal cost of the video ($0). We found no significant differences between the treatment groups at each followup for quality of life, lost productivity or health care utilization. Women were willing to pay $26, $21 and $30 for a copy of the DVD, video on the Web and in-person class, respectively, all of which were less than the average cost of the in-person class ($38). CONCLUSIONS: Poor adherence remains a challenge for many behavioral interventions designed to prevent urinary incontinence. The 20-minute video is less expensive than the 2-hour class and is equally effective. Distributing the video on the Internet will improve access and will be easier to sustain than in-person classes.

Addressing challenges in underactive bladder: recommendations and insights from the Congress on Underactive Bladder (CURE-UAB).

Underactive bladder (UAB) is an expanding troublesome health issue, exerting a major influence on the health and independence of older people with a disproportionally low level of attention received. The 2nd International Congress on Underactive Bladder (CURE-UAB 2) convened in Denver, CO on December 3 and 4, 2015, and comprised of top clinicians, scientists, and other stakeholders to address the challenges in UAB. A series of workshops aimed to define UAB and its phenotype, define detrusor underactivity (DU) and create a subtyping of DU, evaluate existing animal models for DU, and lastly to establish research priorities for UAB.

A Randomized Controlled Trial to Compare 2 Scalable Interventions for Lower Urinary Tract Symptom Prevention: Main Outcomes of the TULIP Study.

PURPOSE: We compared 2-year urinary incontinence and urgency scores of older women who attended a 2-hour bladder health class vs those who viewed a 20-minute abbreviated class video for the purpose of urinary incontinence prevention. MATERIALS AND METHODS: A randomized, 2-arm, parallel design study was done to test the superiority of the 20-minute video over the 2-hour class. Outcomes at baseline, and 3, 12 and 24 months were the scores on questions 1 to 3 of ICIQ-SF (International Consultation on Incontinence Short Form) as the primary outcome and on IUSS (Indevus Urgency Severity Scale). Intent to treat analysis was done to compare the change from baseline in each intervention group across time and also with each other. Multiple imputation was used for missing data. RESULTS: A total of 647 women participated in the study. Mean age was 63 years and approximately 28% of the participants were African American, primarily from an urban setting. The 2 arms were balanced on body mass index at baseline, age, race/ethnicity, education, employment status, income and marital status. No differences in primary or secondary outcomes were demonstrated between the 2 groups from baseline to the 3, 12 or 24-month visits. CONCLUSIONS: The absence of significant differences in the outcome measures of ICIQ-SF and IUSS between the 2-hour class and the 20-minute video groups demonstrates that the 2 interventions were comparable. As urinary incontinence and urgency tend to rise annually in older women, instruction in bladder health self-care provided through either the 2-hour class or the 20-minute video format is a useful intervention to prevent urinary incontinence in older women.

Continence Index: a new screening questionnaire to predict the probability of future incontinence in older women in the community.

PURPOSE: Urinary incontinence (UI) is a chronic, costly condition that impairs quality of life. To identify older women most at risk, the Medical Epidemiologic and Social Aspects of Aging (MESA) datasets were mined to create a set of questions that can reliably predict future UI. METHODS: MESA data were collected during four household interviews at approximately 1 year intervals. Factors associated with becoming incontinent at the second interview (HH2) were identified using logistic regression (construction datasets). Based on p values and odds ratios, eight potential predictive factors with their 256 combinations and corresponding prediction probabilities formed the Continence Index. Its predictive and discriminatory capability was tested against the same cohort's outcome in the fourth survey (HH4 validation datasets). Sensitivity analysis, area under receiver operating characteristic (ROC) curve, predicted probabilities and confidence intervals were used to statistically validate the Continence Index. RESULTS: Body mass index, sneezing, post-partum UI, urinary frequency, mild UI, belief of developing UI in the future, difficulty stopping urinary stream and remembering names emerged as the strongest predictors of UI. The confidence intervals for prediction probabilities strongly agreed between construction and validation datasets. Calculated sensitivity, specificity, false-positive and false-negative values revealed that the areas under the ROCs (0.802 and 0.799) for the construction and validation datasets, respectively, indicated good discriminatory capabilities of the index as a predictor. CONCLUSION: The Continence Index will help identify older women most at risk of UI in order to apply targeted prevention strategies in women that are most likely to benefit.

Intradetrusor injection of adult muscle-derived cells for the treatment of underactive bladder: pilot study.

We conducted the first-regenerative medicine cellular therapy for underactive bladder (UAB) in an FDA-approved, compassionate-use IND trial to evaluate treatment safety and potential clinical efficacy of autologous muscle-derived stem cells (AMDC) on a patient with UAB. No study-related adverse events or side effects were reported. In the 1-year follow-up period, the subject denied any gross hematuria, urgency, frequency or infection. A reduction in maximum cystometric capacity from 844 to 663 mL was observed, and the patient was able to void small amounts but continues to require self-catheterization 1 year after AMDC injection. Intradetrusor injection of AMDC is safe, minimally invasive and a promising treatment option for the UAB.

Exploring factors associated with sexual activity in community-dwelling older adults.

Sexuality is an important, yet often overlooked, aspect of successful aging. The current article explores potential relationships between sexual activity in older adults and marital status, health, mobility, urinary incontinence, and caffeine and alcohol use, as well as sexual desire and erectile function in women and men, respectively. A survey was mailed to community-dwelling older adults 60 and older. Of 242 respondents (79% ages 60 to 74, 53% male), 159 (65.7%) were sexually active. A higher proportion of sexually active adults were married (p = 0.0005), had better health (p = 0.0003), and drank alcohol (p = 0.007). A lower proportion of sexually active adults had urinary incontinence (p = 0.006). Similar proportions of men and women were sexually active (62.8% and 68.2%, respectively; p = 0.38). Sexually active women had better sexual desire scores (p < 0.0001) and more drank alcohol (p = 0.0013). Sexually active men had better mobility (p = 0.012) and erectile function (p < 0.0001). Fewer sexually active men had incontinence (p < 0.0001). Only alcohol use and no urinary incontinence were predictors unique to women and men, respectively. Health care providers must be aware of factors that may impact sexual health in older adults.

Epidemiology and demographics of the underactive bladder: a cross-sectional survey.

The aim of this study was to evaluate the prevalence and awareness of symptoms suggestive of underactive bladder (UAB) in a heterogeneous, non-specific population to garner additional epidemiologic information about UAB. After IRB approval, an 18-item survey was mailed to 5,000 people living in metro Detroit to collect demographic data and questions regarding clinical urinary symptoms and familiarity with UAB. A total of 633 subjects (13; 54 % men, 46 % women) returned the survey. Nearly one quarter (23 %, n = 137) of respondents reported difficulty emptying his/her bladder, yet only 11 % (n = 70) had ever heard of UAB. The study results indicated that patient-reported bladder emptying symptoms are prevalent, as common in women as men, and significantly associated with comorbidity and poor self-reported health. The results suggest that the burden and impact of UAB might be significant and that a syndromic concept of UAB warrants research to determine the true burden of disease, increase awareness, and broaden efforts to investigate therapeutic directions.

Defining and advancing education and conservative therapies of underactive bladder.

In contrast to other forms of voiding dysfunction, underactive bladder (UAB) has traditionally received little research or educational attention. This is changing as our understanding of the underlying mechanisms of detrusor dysfunction and other forms of underactive bladder improves. In addition, the impact of UAB on patient symptoms, general and health-related quality of life, and caregiver burden are becoming more recognized. However, there remains a paucity of data on the subject, and an extensive need for additional research and education on the topic. This paper explores the current state of knowledge about UAB with an emphasis on education regarding the condition and conservative methods of assessment and treatment. Recommendations for future work in this area are considered.

Novel application of statistical methods to identify new urinary incontinence risk factors.

Longitudinal data for studying urinary incontinence (UI) risk factors are rare. Data from one study, the hallmark Medical, Epidemiological, and Social Aspects of Aging (MESA), have been analyzed in the past; however, repeated measures analyses that are crucial for analyzing longitudinal data have not been applied. We tested a novel application of statistical methods to identify UI risk factors in older women. MESA data were collected at baseline and yearly from a sample of 1955 men and women in the community. Only women responding to the 762 baseline and 559 follow-up questions at one year in each respective survey were examined. To test their utility in mining large data sets, and as a preliminary step to creating a predictive index for developing UI, logistic regression, generalized estimating equations (GEEs), and proportional hazard regression (PHREG) methods were used on the existing MESA data. The GEE and PHREG combination identified 15 significant risk factors associated with developing UI out of which six of them, namely, urinary frequency, urgency, any urine loss, urine loss after emptying, subject's anticipation, and doctor's proactivity, are found most highly significant by both methods. These six factors are potential candidates for constructing a future UI predictive index.

Outcomes of lumbar to sacral nerve rerouting for spina bifida.

PURPOSE: Restoring bladder and bowel function in spina bifida by creation of a skin-central nervous system-bladder reflex arc via lumbar to sacral nerve rerouting has a reported success rate of 87% in China. We report 1-year results of the first North American trial on nerve rerouting. MATERIALS AND METHODS: Nine subjects were enrolled in the study. Intradural lumbar to sacral nerve rerouting was performed. Subjects underwent urodynamic testing with stimulation of the cutaneous dermatome and careful neurological followup. Adverse events were closely monitored along with changes in bowel and bladder function. RESULTS: At 1 year 7 patients (78%) had a reproducible increase in bladder pressure with stimulation of the dermatome. Two patients were able to stop catheterization and all safely stopped antimuscarinics. No patient achieved complete urinary continence. The majority of subjects reported improved bowel function. One patient was continent of stool at baseline and 4 were continent at 1 year. Of the patients 89% had variable weakness of lower extremity muscle groups at 1 month. One child had persistent foot drop and the remainder returned to baseline by 12 months. CONCLUSIONS: At 1 year a novel reflex arc with stimulation of the appropriate dermatome was seen in the majority of subjects. Improvements in voiding and bowel function were noted. Lower extremity weakness was mostly self-limited, except in 1 subject with a persistent foot drop. More patients and longer followup are needed to assess the risk/benefit ratio of this novel procedure.