Tighter Blood Pressure Control Is Associated with Lower Incidence of Erectile Dysfunction in Hypertensive Men.

INTRODUCTION: Tighter blood pressure control is widely thought to be associated with better erectile function, although the preponderance of data is limited to dichotomous representations of hypertension without an attempt to look at degree of blood pressure control. AIM: To determine the association between optimal blood pressure control over time and the development of erectile dysfunction (ED) in a cohort of potent men. METHODS: We performed a retrospective cohort study of newly diagnosed hypertensive men without major medical comorbidities in an integrated healthcare system. Patients were stratified by exposure to hypertension, with varying levels of blood pressure control, as measured by ordinal categories of systolic blood pressure and deviation from the mean systolic pressure. MAIN OUTCOME MEASURES: Incidence of ED was defined by at least 2 primary care or urology diagnoses of ED in our electronic health records within 2 years, at least 2 filled prescriptions for ED medications within 2 years, or 1 diagnosis of ED and 2 filled prescriptions for ED medications. RESULTS: We identified 39,320 newly diagnosed hypertensive men. The overall incidence for ED was 13.9%, with a mean follow-up of 55.1 ± 28.7 months. Higher average systolic blood pressure was associated with a higher risk of ED in a dose-dependent manner (trend test, P < .001). Wide variation in blood pressure control was associated with a higher incidence of ED (OR [95% CI]; 1.359 [1.258-1.469]) and a shorter time to the development of ED (log rank, P < .0001). CLINICAL IMPLICATIONS: We believe these data may serve as a motivator for hypertensive men to better adhere to their hypertension treatment regimen. STRENGTH & LIMITATIONS: The retrospective nature of our study precludes us from drawing more than an association between tighter blood pressure control and ED. Strengths of our study include the large sample size, community cohort, and completeness of follow-up. CONCLUSION: Among adults diagnosed with hypertension, tighter blood pressure control, as measured by average systolic blood pressure and deviation from the average, is associated with a lower incidence and a longer time to the development of ED. Hsiao W, Bertsch RA, Hung Y-Y, et al. Tighter Blood Pressure Control Is Associated with Lower Incidence of Erectile Dysfunction in Hypertensive Men. J Sex Med 2019;16:410-417.

Testicular endothelial cells are a critical population in the germline stem cell niche.

Maintenance of adult tissues depends on stem cell self-renewal in local niches. Spermatogonial stem cells (SSC) are germline adult stem cells necessary for spermatogenesis and fertility. We show that testicular endothelial cells (TECs) are part of the SSC niche producing glial cell line-derived neurotrophic factor (GDNF) and other factors to support human and mouse SSCs in long-term culture. We demonstrate that FGF-2 binding to FGFR1 on TECs activates the calcineurin pathway to produce GDNF. Comparison of the TEC secretome to lung and liver endothelial cells identified 5 factors sufficient for long-term maintenance of human and mouse SSC colonies in feeder-free cultures. Male cancer survivors after chemotherapy are often infertile since SSCs are highly susceptible to cytotoxic injury. Transplantation of TECs alone restores spermatogenesis in mice after chemotherapy-induced depletion of SSCs. Identifying TECs as a niche population necessary for SSC self-renewal may facilitate fertility preservation for prepubertal boys diagnosed with cancer.

Update on male reproductive endocrinology.

Practitioners of male reproductive and sexual medicine must have an intimate understanding of the physiology of male reproductive endocrinology, as such a knowledge is the cornerstone on which hormonal treatments are based. In this review, we highlight what is known about male reproductive endocrine physiology and the various control mechanisms for the system. We also discuss the limitations of our current understanding of the reproductive physiology. We hope that this review is helpful for male reproductive medicine practitioners in understanding the principles on which hormonal treatments are based.

Outcomes of microsurgical vasovasostomy for vasectomy reversal: a meta-analysis and systematic review.

OBJECTIVE: To perform a systematic review and meta-analysis of the published literature evaluating vasovasostomy for vasectomy reversal outcomes. METHODS: We conducted a review of English language articles describing results of microscopic vasovasostomy for vasectomy reversal. Two reviewers independently examined the studies for eligibility and evaluated data from each study. Meta-analysis was performed using a random effects model. RESULTS: Thirty-one studies with 6633 patients met inclusion criteria. Mean patient age at time of vasectomy reversal was 38.9 years with a mean obstructive interval of 7.2 years. The mean postprocedure patency and pregnancy rates weighted by sample size were 89.4% and 73.0%, respectively. A meta-analysis comparing an obstructive interval (OI) of <10 years to an OI of at least 10 years duration produced a pooled incidence ratios (IR; meta-IR) of 1.17 (95% confidence interval [CI], 1.09-1.25) for patency and 1.24 (95% CI, 1.12-1.38) for pregnancy. Incidence of patency for modified 1-layer technique was similar to that after a 2-layer procedure with a meta-IR of 1.04 (95% CI, 1.00-1.08). Because of a small number of relevant studies, a meta-analysis for other predictors of success such as sperm granuloma, quality of vasal fluid, and female factors was not feasible. CONCLUSION: We found no statistically significant difference in vasovasostomy outcomes when comparing the impact of single vs multilayer anastomoses. Patients with an OI <10 years showed higher patency and pregnancy rates compared with those with an OI ≥10 years. Uniform definitions of patency are necessary to characterize success and standardize outcome reporting.

Association between the presence of sperm in the vasal fluid during vasectomy reversal and postoperative patency: a systematic review and meta-analysis.

OBJECTIVE: To investigate the association between the presence of sperm in the vasal fluid during vasectomy reversal (VR) and postoperative patency. METHODS: We performed a systematic review and meta-analysis of the English-language literature reporting on the association between the presence of sperm in the intraoperative vasal fluid (ie, whole or parts vs none) and patency (ie, patent or not) after microsurgical vasovasostomy for men with obstructive azoospermia due to vasectomy. Odds ratios (OR) and 95% confidence intervals were calculated to quantify the strength of the association reported by each study. Meta-analysis was performed using a random-effects model. RESULTS: Four case series and 2 retrospective cohort studies of a total of 1293 eligible patients were identified. The mean age at VR was 37.8 years, and the mean obstructive interval was 7.1 years. The unadjusted OR of postoperative patency was 4.1 times higher (95% confidence interval, 2.3-7.3) given the presence of intravasal sperm or sperm parts as opposed to their absence at the time of VR (Q = 3.4; df = 5; P = .6; I(2) = 22%). The pooled OR should be interpreted with caution as only the 2 retrospective cohort studies reported meaningful data on this association. Because of inconsistent reporting, analysis of other vasal fluid characteristics (eg, consistency) and outcomes (eg, pregnancy) was not possible. CONCLUSION: The presence of whole sperm or sperm parts in the vasal fluid during VR is positively associated with postoperative patency. Our review highlights the poor methodological quality of existing evidence and underscores the need for more thorough follow up and higher standards of reporting in future studies.

Nomograms incorporating serum C-reactive protein effectively predict mortality before and after surgical treatment of renal cell carcinoma.

OBJECTIVES: To incorporate C-reactive protein into nomograms estimating survival in patients with renal cell carcinoma. METHODS: Patients undergoing surgery for renal cell carcinoma from 2005-2012 were studied retrospectively. Multivariable Cox proportional hazards regression and competing risks regression models including stage, grade, C-reactive protein levels and presence of metastatic disease were constructed. Outcomes analyzed include overall mortality overall mortality and renal cell carcinoma-specific mortality. RESULTS: The cohort included 516 patients with a mean follow up of 1.7 years (SD 1.4 years). One- and 3-year renal cell carcinoma-specific mortality was 8.8% and 13.5%, respectively. Four nomograms were generated using overall mortality and renal cell carcinoma-specific mortality as end-points, two each for pre- and postoperative counseling. The factor with the largest effect on all nomograms was preoperative C-reactive protein. Based on the internal validation with bootstrapping, the concordance indices for renal cell carcinoma-specific mortality in the preoperative nomogram, postoperative nomogram, and the Mayo Clinic stage, size, grade and necrosis score were 0.889, 0.893, and 0.832, respectively (P = 0.005 and 0.002 comparing with stage, size, grade and necrosis scores for preoperative or postoperative nomograms). For overall mortality, the preoperative nomogram, postoperative nomogram, and stage, size, grade and necrosis score showed concordance indices of 0.866, 0.897, and 0.828, respectively (P = 0.123 and 0.008 compared with stage, size, grade and necrosis score for preoperative or postoperative nomograms). CONCLUSIONS: We have generated nomograms incorporating serum C-reactive protein levels that effectively predict overall mortality and renal cell carcinoma specific mortality. Our findings warrant external validation.

Awareness of and attitudes towards infertility and its treatment: a cross-sectional survey of men in a United States primary care population.

Previous studies have described racial and socioeconomic disparities in the treatment of infertility. Patient factors such as attitudes and awareness may be contributing factors. Since primary care is often the setting that serves as an entry into other areas of medicine, we sought to evaluate men's attitudes and awareness of male infertility in the primary care setting. To do this, we performed a cross-sectional survey of men's attitudes toward men's health issues in 210 men from two primary care clinic waiting rooms in Atlanta, Georgia. The survey was self-administered with closed-ended question items and was approximately 20 min in length. Of the 310 men approached, 210 agreed to participate and returned completed surveys. Overall, 52% of men said they were "very" or "somewhat" familiar with infertility and 25% were familiar with treatments for infertility. Some men had heard of surgery (21%) and medication (35%) as treatments for male infertility. Awareness and familiarity with the condition was greater in high socioeconomic status men (i.e. college graduates or those with income >$100 k per year) but did not differ by race on multivariate analysis. Attitudes toward infertility varied by race with non-Caucasian men being more likely to indicate that infertility is a serious condition, to be concerned about infertility, and to believe it decreases a man's quality-of-life. Therefore, a lack of awareness, but not negative attitudes, may contribute to previously-described disparities in the treatment of infertility.

Ejaculatory physiology and pathophysiology: assessment and treatment in male infertility.

Azoospermia is a heterogeneous condition with multiple etiologies and a variety of treatments. In this chapter we present a summary of retrograde ejaculation and anejaculation, both of which are characterized by an absence of antegrade semen propulsion through the male reproductive tract. Each of these affects fertility, but is pathophysiologically distinct disorders with differing evaluation and treatment. Retrograde ejaculation has a myriad of well-characterized causes, from pharmacologic disruption to interference of neural mechanisms by surgical intervention for a variety of diseases. Medication is the mainstay of treatment, although only a minority responds and develops antegrade ejaculation. For the men who are not responders to medical therapy, but still have fertility goals, there are a variety of sperm retrieval techniques to assist their reproductive abilities. Failure of emission is characterized by an absence of the emission phase and no antegrade or retrograde expulsion of ejaculatory products. If fertility is desired, these men must rely on assisted ejaculatory procedures, and treatment choice is guided by etiology and response. Ultimately, retrograde ejaculation and failure of emission are in a spectrum of ejaculatory disorders which impair male fertility.

Updates on sperm retrieval techniques.

In the most extreme form of male infertility, the male partner is azoospermic. The advent of in vitro fertilization (IVF)-intracytoplasmic sperm injection (ICSI) has revolutionized our ability to treat azoospermia in both obstructive and non-obstructive cases. In obstructive azoospermia, it allows paternity without microsurgical reproductive tract reconstruction and also in cases where the reproductive tract is unreconstructable. In men with non-obstructive azoospermia, microdissection testicular sperm extraction (mTESE) has allowed us to retrieve sperm in men with exceedingly low sperm production. The introduction of microsurgery in sperm retrieval improves sperm yields and quality while minimizing the chance of surgical morbidity.

A guide for inflatable penile prosthesis reservoir placement: pertinent anatomical measurements of the retropubic space.

INTRODUCTION: The primary concern for many prosthetic urologic surgeons in placing the three-piece inflatable penile prosthesis (IPP) is the concept of "blind reservoir placement." Extensive reports permeate the literature regarding bladder, bowel, vascular, and various hernial complications occurring while attempting to place the reservoir into the retropubic space. However, despite these widely documented complications, there is a paucity of published literature on surgically pertinent anatomical measurements of the retropubic space relating to reservoir placement. The focus of this project was to evaluate the special relationships and anatomical measurements of the retropubic space to better aid the surgeon in the safe placement of the reservoir. AIM: Analyses of the spatial measurements of reservoir placement into the retropubic space with a focus on utilizing a penoscrotal approach were conducted. In addition, we reviewed and evaluated the published literature for important contributions surrounding the various surgical techniques during placement of a penile prosthesis reservoir. METHODS: Cadaveric pelvic specimens were dissected to determine the distance and angulation (in degrees) from the inguinal ring to several critical anatomic structures in the pelvis. This format was utilized to simulate the basic features of reservoir placement into the classic retropubic space. We also reviewed and evaluated the published literature for important contributions describing the various surgical techniques in the placement of penile prosthesis reservoirs into the retropubic space. MAIN OUTCOME MEASURES: Anatomic measurements were obtained from the inguinal ring to the bladder, external iliac vein, and superior origin of the dorsal suspensory ligament at the anterior apex of the pendulous penis. The angle was measured from the inguinal ring to these structures and recorded. We also reviewed the published literature for various penoscrotal IPP surgical techniques involving placement of the reservoir into the retropubic space to further supplement the pertinent spatial relationships data acquired in this study. RESULTS: Of the 28 cadavers, 3 were excluded because of signs of major pelvic surgery, and an additional 6 sides were excluded because of unilateral fibrosis/surgery or difficulty in exposure. Distance to the decompressed bladder was 5-8 cm (average 6.45 cm) at a 15-30 (22.8) degrees medial measurement from the inguinal ring. The filled bladder was 2-4 cm (average 2.61 cm) from the inguinal ring. The external iliac vein distance from the inguinal ring was 2.5-4 cm (average 3.23 cm) at a 20-60 (36.4) degrees lateral measurement from the inguinal ring. Heretofore, the published literature does not appear to have detailed measurements that are provided in this study. CONCLUSIONS: These anatomical measurements of the retropubic space demonstrate the importance of decompressing the bladder and avoiding deep dissection lateral to the inguinal ring, as the external iliac vein is much closer than currently espoused. We feel that these data are significant to the surgeon proceeding with reservoir placement during IPP surgery.

Microsurgical subinguinal varicocelectomy with testicular delivery.

OBJECTIVE: To demonstrate our approach to the microsurgical subinguinal varicocelectomy with testicular delivery. DESIGN: An instructional video demonstrating the surgical procedure in a step-by-step manner, highlighting useful surgical techniques. SETTING: Not applicable. PATIENT(S): Patients with male factor infertility. INTERVENTION(S): After appropriate patient selection and counseling, varicocelectomy is performed with a subinguinal approach utilizing the surgical microscope. The patient is under general anesthesia and we employ an operating microscope. The patient is positioned supine. MAIN OUTCOME MEASURE(S): Not applicable. RESULTS: A 2.5-cm subinguinal incision was made and the testicle was then delivered. Through the operating microscope at 10-20X magnification, internal spermatic veins were identified and ligated. Smaller veins were taken with electrocautery. The testicular artery was identified using the microdoppler probe. We employ hydrodissection in identifying and isolating the testicular artery. The spermatic cord is then repeatedly examined until no veins other than deferential veins remain. The gubernaculum is also thinned sufficiently so that veins on both sides can be identified and ligated. Testicular delivery was performed and external spermatic veins as well as gubernacular veins ligated. CONCLUSION(S): Varicoceles are found in up to 15% of all men, and in up to 40% of infertile men. Varicoceles have negative effects on testicular function. Varicocelectomy improves testicular function and may halt the accelerated rate of decline in testicular function associated with varicoceles. Sperm parameters, serum testosterone levels, and pregnancy rates have all been shown to improve following varicocelectomy. Use of the operating microscope, the microdoppler probe, and black and white sutures aid in efficiency. Testicular delivery is useful to ligate external spermatic veins as well as gubernacular veins.

Injection anxiety and pain in men using intracavernosal injection therapy after radical pelvic surgery.

INTRODUCTION: Intracavernosal injection (ICI) therapy is a well-recognized treatment strategy with high success rates for men with erectile dysfunction. Despite this, injection anxiety and pain related to injection are significant barriers to its use. AIMS: This study aims to examine injection anxiety and injection pain in patients using ICI. METHODS: Men starting ICI therapy post radical pelvic surgery completed questionnaires at initial visit, at each of the two ICI training sessions and at a 4-month follow-up visit. MAIN OUTCOME MEASURES: Injection Anxiety Scale, Injection Pain Scale, Injection Reaction Inventory, and the Erectile Function Domain of the International Index of Erectile Function. RESULTS: Average age of the 68 men was 60±8 years. At 4 months, the self-reported frequency of ICI use was: 29%<1/week, 26% 1/week, 40% 2/week, and 5% 3/week. Mean injection anxiety score at first injection was 5.7±2.8 (range 0-10) and significantly decreased to a 4.1±3 at 4 months (P<0.001). At first injection, 65% reported high injection anxiety (≥5) and this significantly decreased to 42% (P=0.003) at 4 months. Anxiety at first injection was negatively related to ICI frequency at 4 months (r=-0.23, P=0.08). Mean injection pain score at first injection was low (2.2±1.8, range 0-10) and 59% rated injection pain≤2. Injection pain remained consistent across time periods. At first injection, injection anxiety (assessed prior to injection) was related to injection pain (r=0.21, P=0.04) and subjects (n=21) who reported high injection anxiety (≥5) across time points, reported an increase in injection pain scores from first injection to 4 months (2.7 vs. 3.7, P=0.05). CONCLUSIONS: Although injection anxiety decreased with ICI use, mean injection anxiety remained at a moderate level (4.4) and 42% of men continued to report "high" injection anxiety at 4 months. While injection pain was low, injection anxiety and pain were related. These data suggest the need for a psychological intervention to help lower injection anxiety related to ICI.

Breakage of Needle during Intracavernosal Injection and Use of Portable Ultrasound Guidance for Removal.

Purpose. Intracavernosal self-injection (ICI) was first described in 1982, and remains a viable therapy for erectile dysfunction. However, intracorporal needle breakage can be a rare complication of therapy. We report a rare complication of intracorporal needle breakage and a retention of a 30-gauge needle in a 42-year-old paraplegic man. We discuss our experience in using portable high-frequency ultrasound intraoperatively to visualize and guide removal of a retained ICI needle. Materials and Methods. Review of case and ultrasound technique are presented. Results. Using intraoperative ultrasound imaging, the retained intracorporal needle was successfully removed from the patient's penis without any complications. Follow-up ultrasonography and X-ray confirmed complete removal of the needle. Conclusions. We report on the successful implementation and use of a portable high-frequency ultrasound probe to visualize a retained intracorporal needle inside the penis and its use to guide removal. Given the rapid proliferation of portable ultrasound machines in the operating room and out in the field, we expect these imaging techniques to become routine, especially in urological emergencies.

Influence of vascular comorbidities and race on erectile dysfunction after prostate cancer radiotherapy.

INTRODUCTION: Vascular comorbidities (VC) (hypertension, diabetes, and hyperlipidemia) are known factors related to erectile dysfunction (ED) in men. However, no data are yet available for the effects of VC on ED incidence after prostate cancer radiotherapy (XRT). AIM: To investigate the influence of VC on post-XRT ED incidence and to further characterize ED incidence by racial groups. MAIN OUTCOME MEASURES: ED incidence. METHODS: We reviewed 732 charts of patients (267 Caucasian and 465 African American [AA]) who received prostate XRT (external beam radiotherapy and/or brachytherapy) with or without hormone therapy between 1999 and 2010. The number of pre-XRT VC (0, 1, 2, or 3) was determined by medical history and medication list. ED (defined by use of erectile aids or by documentation of moderate or high sexual dysfunction on patient history) was determined pre-XRT as well as 1, 2, and 4 years post-XRT. RESULTS: ED incidence progressively increased from 22% pre-XRT to 58% 4 years post-XRT (P < 0.01). Additionally, ED incidence significantly increased with number of VC-4-year incidence between patients with 1 vs. 0 (P = 0.02), 2 vs. 0 (P < 0.01), 3 vs. 0 (P < 0.01), 3 vs. 1 (P < 0.01), and 3 vs. 2 (P = 0.04) VC (2 vs. 1 VC was nonsignificant). Compared with the Caucasian patients, ED incidences were slightly higher for the AA group with 0, 1, 2, and 3 comorbidities at 4 years follow-up (but statistically nonsignificant). CONCLUSIONS: The number of VCs have a significant effect on development of post-XRT ED. Pre- and post-XRT ED appear to be independent of race when number of VCs are considered. Our results can be used to guide physicians in counseling patients on the incidence of ED by number of VC and as preliminary data for prospective efforts aimed at reducing post-XRT ED.

Perioperative celecoxib decreases opioid use in patients undergoing testicular surgery: a randomized, double-blind, placebo controlled trial.

PURPOSE: We evaluated the effect of daily perioperative celecoxib on patient reported pain control and opioid use after testicular surgery. MATERIALS AND METHODS: Men scheduled to undergo elective outpatient microsurgical testicular sperm extraction were prospectively randomized to receive 200 mg celecoxib or placebo twice daily, which was initiated the night before surgery and continued for 6 days thereafter. Using an 11-point visual analog scale, participants self-reported the postoperative pain level and acetaminophen/hydrocodone use for supplemental pain control. We compared differences in pain scores and opioid use between the 2 patient groups using the Student t test with p<0.05 considered significant. RESULTS: At 1-year interim analysis 35 of 78 eligible participants (45%) had returned the study questionnaire, of whom 34 were included in the final analysis. Of the 34 patients the 16 who received celecoxib had significantly lower postoperative opioid use than those on placebo (6 vs 16 pills, p=0.02). We noted a statistically significant difference in postoperative day 1 and 2 patient reported pain scores (4 vs 6, p<0.05 and 3 vs 5, p=0.03) and opioid use (1 vs 5 pills, p<0.01 and 2 vs 4, p=0.02) seen between the celecoxib and placebo groups, respectively. No study complications were identified. The trial was terminated early based on the results of interim analysis. CONCLUSIONS: Twice daily celecoxib use started preoperatively significantly decreased patient reported postoperative pain and opioid use, especially in the early postoperative period. A short course of celecoxib is well tolerated and may be effective as part of multimodal postoperative analgesia in patients who undergo testicular surgery for sperm retrieval.

The TERE1 protein interacts with mitochondrial TBL2: regulation of trans-membrane potential, ROS/RNS and SXR target genes.

We originally discovered TERE1 as a potential tumor suppressor protein based upon reduced expression in bladder and prostate cancer specimens and growth inhibition of tumor cell lines/xenografts upon ectopic expression. Analysis of TERE1 (aka UBIAD1) has shown it is a prenyltransferase enzyme in the natural bio-synthetic pathways for both vitamin K-2 and COQ10 production and exhibits multiple subcellular localizations including mitochondria, endoplasmic reticulum, and golgi. Vitamin K-2 is involved in mitochondrial electron transport, SXR nuclear hormone receptor signaling and redox cycling: together these functions may form the basis for tumor suppressor function. To gain further insight into mechanisms of growth suppression and enzymatic regulation of TERE1 we isolated TERE1 associated proteins and identified the WD40 repeat, mitochondrial protein TBL2. We examined whether disease specific mutations in TERE1 affected interactions with TBL2 and the role of each protein in altering mitochondrial function, ROS/RNS production and SXR target gene regulation. Biochemical binding assays demonstrated a direct, high affinity interaction between TERE1 and TBL2 proteins; TERE1 was localized to both mitochondrial and non-mitochondrial membranes whereas TBL2 was predominantly mitochondrial; multiple independent single amino acid substitutions in TERE1 which cause a human hereditary corneal disease reduced binding to TBL2 strongly suggesting the relevance of this interaction. Ectopic TERE1 expression elevated mitochondrial trans-membrane potential, oxidative stress, NO production, and activated SXR targets. A TERE1-TBL2 complex likely functions in oxidative/nitrosative stress, lipid metabolism, and SXR signaling pathways in its role as a tumor suppressor.