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Background: Male patients with COVID-19 have been found with reduced serum total testosterone (tT) levels and with more severe clinical outcomes., Objectives: To assess total testosterone (tT) levels and the probability of recovering eugonadal tT levels during a minimum 12-month timespan in a cohort of men who have been followed over time after the recovery from laboratory-confirmed COVID-19., Materials and Methods: Demographic, clinical and hormonal values were collected for the overall cohort. Hypogonadism was defined as tT ≤9.2 nmol/l. The Charlson Comorbidity Index was used to score health-significant comorbidities. Descriptive statistics was used to compare hormonal levels at baseline versus 7-month (FU1) versus 12-month (FU2) follow-up, respectively. Multivariate cox proportional hazards regression model was used to identify the potential predictors of eugonadism recovery over time among patients with hypogonadism at the time of infection., Results: Of the original cohort of 286 patients, follow-up data were available for 121 (42.3%) at FU1 and 63 (22%) patients at FU2, respectively. Higher median interquartile range (IQR) tT levels were detected at FU2 (13.8 (12.3-15.3) nmol/L) versus FU1 (10.2 [9.3-10.9] nmol/L) and versus baseline (3.6 [3.02-4.02] nmol/L) (all p < 0.0001), whilst both LH and E 2 levels significantly decreased over the same time frame (all p ≤ 0.01). Circulating IL-6 levels further decreased at FU2 compared to FU1 levels (19.3 vs. 72.8 pg/ml) (p = 0.02). At multivariable cox regression analyses, baseline tT level (HR 1.19; p = 0.03 [1.02-1.4]) was independently associated with the probability of tT level normalization over time, after adjusting for potential confounders., Conclusions: Circulating tT levels keep increasing over time in men after COVID-19. Still, almost 30% of men who recovered from COVID-19 had low circulating T levels suggestive for a condition of hypogonadism at a minimum 12-month follow-up., (© 2022 American Society of Andrology and European Academy of Andrology.)

Purpose: Priapism is a debilitating condition that affects sexual function. As a majority of cases are idiopathic, investigators have hypothesized underlying vascular dysfunction which may predispose men to priapism. We sought to determine if men are at risk for other sequelae of vascular dysfunction such as cardiovascular and thromboembolic disease after a priapism event., Materials and Methods: Using a large commercial insurance claims data warehouse, we evaluated all men (age ≥20) with a diagnosis of priapism from 2003-2020 and matched them to a cohort of men with other urological disorders of sexual dysfunction (erectile dysfunction, Peyronie's disease, and premature ejaculation). We identified incident disease (cardiovascular disease, heart disease, embolism, thrombosis, cerebrovascular disease) for all cohorts., Results: A total of 10,459 men with priapism were identified and were matched to men with erectile dysfunction, Peyronie's disease, or premature ejaculation. The mean age was 51.1 years old. Men with priapism showed increased incidence of heart disease, both ischemic (HR 1.24, 95% CI 1.09-1.42) and other heart disease (HR 1.24, 95% CI 1.12-1.38) in the years following the priapism diagnosis. Incident cerebrovascular disease was also more likely in men with a history of priapism (HR 1.33, 95% CI 1.15-1.55). Men requiring treatment for ischemic priapism had a higher hazard of cardiovascular and cerebrovascular disease. In addition, men with more priapism episodes had a higher rate of cardiovascular disease and thromboembolic events., Conclusions: Men with priapism are at increased risk for cardiovascular and cerebrovascular events in the years following a priapism.

Background: The current standard of care for the systemic treatment of metastatic hormone sensitive prostate cancer (mHSPC) includes androgen deprivation therapy (ADT) with either docetaxel or advanced androgen blockage (AAB). Recently, two studies have tested the combination of ADT, docetaxel and AAB (triplet therapy) relative to docetaxel and ADT in this setting. Herein, we aimed to compare the effect on survival outcomes of available systemic treatments for mHSPC., Methods: A comprehensive search for all published phase III randomized control trials on first line mHSPC that evaluated AAB (TITAN, ARCHES, STAMPEDE, LATITUDE, ENZAMET) or docetaxel (GETUG-AFU15, CHAARTED, STAMPEDE) or their combination (ARASENS, PEACE-1) was conducted PubMed, EMBASE, Web of Science, and Scopus databases up to 15/04/2022. We reconstructed survival data from published Kaplan-Meier curves on overall survival (OS) and progression free survival (PFS) and meta-analyzed docetaxel versus AAB versus triplet therapy (grouping together abiraterone/darolutamide and docetaxel). The outcomes of interest were assessed using differences in restricted mean survival time (ΔRMST) at different time points and Cox regression., Results: Ten trials were included involving 5,544 patients for assessing OS and 5,725 for PFS. Triplet therapy was associated with longer OS when compared to docetaxel (48-month ΔRMST: 2.6; 95 %CI: 1.8,3.4; p < 0.001) but yielded similar OS when compared to AAB (48-month ΔRMST: -0.8; 95 % CI: -1.8, 0.2; p = 0.1). Similarly, triplet therapy was associated with longer PFS when compared to docetaxel (48-month ΔRMST: 10.3; 95 %CI: 9.0,11.6; p < 0.001) but yielded similar PFS when compared to AAB (48-month ΔRMST: 1.1; 95 %CI: -0.2,2.3; p = 0.1)., Conclusions: Overall, we found no OS nor PFS benefit for patients with mHSPC treated with triplet therapy compared to AAB alone, while an advantage emerged for both AAB or triplet therapy relative to docetaxel., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose of Review: This review aims to report the latest discoveries regarding the relationship between BMI, obesity, and cancer development and treatment., Recent Findings: Obesity and metabolic syndrome relationships with cancer have been deeply investigated in the literature but their association is still debated. Currently, it has been recorded an association between BMI and endometrial, colorectal, gastric, liver, bladder, and prostate cancer. The mechanisms behind this association have also been investigated. It has been hypothesized that chronic inflammation determined by obesity may concur to the development of tumors and that Insulin Resistance may enhance cell proliferation directly or indirectly. Moreover, different studies suggest that the relationship between higher BMI and cancer may include metabolic disturbances comparable to those linked to metabolic syndrome. However, greater weight has been linked to a better overall prognosis in patients with advanced disease, a concept called the obesity paradox. This paradox has been recently investigated in the context of urological malignancies, such as bladder, prostate, and kidney cancer., Summary: Patients' metabolic and morphological status may impact their risk of developing different types of tumors and the response to systemic therapy. However, further research is necessary to better delineate the mechanisms behind these associations and how they could or should affect medical decision., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The KEYNOTE-564 trial showed improved disease-free survival (DFS) for patients with high-risk renal cell carcinoma (RCC) receiving adjuvant pembrolizumab as compared to placebo. However, if systematically administered to all high-risk patients, it might lead to the overtreatment in a non-negligible proportion of patient. Therefore, we aimed to determine the optimal candidate for adjuvant pembrolizumab., Methods: Within a prospectively maintained database we selected patients who fulfilled the inclusion criteria of the KEYNOTE-564. We compared baseline characteristics and oncologic outcomes in this cohort with those of the placebo arm of the KEYNOTE-564. Regression tree analyses was used to generate a risk stratification tool to predict 1-year DFS after surgery., Results: In the off-trial setting, patients had worse tumor characteristics then in the KEYNOTE-564 placebo arm, i.e. there were more pT4 (5.4 vs. 2.7%, p = 0.046) and pN1 (15 vs. 6.3%, p < 0.001) cases. Median DFS was 29 (95% CI 21-35) months as compared to value not reached in KEYNOTE-564 and 1-year DFS was 64.2% (95% CI 59.6-69.2) as compared to 76.2% (95% CI 72.2-79.7), respectively. Patients with pN1 were at the highest risk of 1-year recurrence (1-year DFS 28.6% [95% CI 20.2-40.3]); patients without LNI, but necrosis were at intermediate risk (1-year DFS 62.5% [95% CI 56.9-68.8]); those without LNI and necrosis were at the lowest risk (1-year DFS 83.8% [95% CI 79.1-88.9]). LVI substratification furtherly improved the accuracy in the prediction of early recurrence., Conclusions: Patients potentially eligible for adjuvant pembrolizumab have worse characteristics and DFS in the off-trial setting as compared to the placebo arm of the KEYNOTE-564. Patients with either LNI or necrosis were at the highest risk of early-recurrence, which make them the ideal candidate to adjuvant pembrolizumab., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Despite recent advances in the treatments of metastatic castration resistant prostate cancer (mCRPC), patients' prognosis remains suboptimal and novel treatment combinations are under scrutiny. On this matter, the recent ACIS trial tested the role of abiraterone plus apalutamide (androgen annihilation) in addition to androgen deprivation therapy, versus abiraterone plus androgen deprivation therapy. Herein, we performed a meta-analysis to compare overall survival (OS) and progression free survival (PFS) among patients who received androgen annihilation versus advanced androgen blockage (abiraterone or enzalutamide), in addition to conventional androgen deprivation therapy., Methods: A comprehensive search for all published phase III randomized control trials on first line mCRPC that evaluated advanced androgen blockage (COU-AA-302, PREVAIL) or androgen annihilation (ACIS) was conducted PubMed, EMBASE, Web of Science, and Scopus databases up to 31/12/2021. We reconstructed survival data from published Kaplan-Meier curves on overall survival (OS) and progression free survival (PFS) and meta-analyzed androgen annihilation versus advanced androgen blockage (grouping together abiraterone and enzalutamide) versus androgen deprivation therapy. The outcomes of interest were assessed using difference in restricted mean survival time (ΔRMST) at different time points., Results: Three trials were included involving 3787 patients. Overall, patients receiving androgen annihilation exhibited similar OS compared to advanced androgen blockage: ΔRMST at 36 months of - 0.2 (95%CI: -1.1, 0.8, p = 0.8). At 36 months, relatively to ADT alone, patients receiving androgen annihilation or advanced androgen blockage exhibited longer OS: ΔRMST of 1.6 (95%CI: 0.6, 2.7, p = 0.002) and 1.8 months (95%CI: 1.1, 2.5, p < 0.001), respectively. Patients receiving androgen annihilation exhibited better PFS compared to advanced androgen blockage: ΔRMST at 36 months of 2.4 months (95%CI: 1.0, 3.8, p = 0.001)., Conclusion: We found no OS benefit for patients with mCRPC treated with androgen annihilation compared to advanced androgen blockage. This might be ascribed to an increased rate of other cause mortality that might determine the absence of an OS benefit or to the efficacy of second line therapies. Optimal treatment sequence and patient selection for androgen annihilation remain open points. However, a PFS benefit was found in case of combination therapy, whose clinical meaning is not yet clear., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Erectile dysfunction aetiology has been historically identified as organic, psychogenic and mixed., Objectives: To stratify and compare a cohort of patients seeking medical help for erectile dysfunction for the first time according to the newly proposed binary classification of the European Association of Urology guidelines: 'primary organic' versus 'primary psychogenic'., Materials and Methods: Complete data from 2009 consecutive patients presenting for erectile dysfunction were analysed. All patients completed the International Index of Erectile Function at baseline. According to the presence of erectile dysfunction-related risk factors indexed by the European Association of Urology Guidelines on Sexual and Reproductive Health, patients were categorised as having primary organic (≥1 risk factor) or primary psychogenic (0 risk factor) erectile dysfunction. Descriptive statistics compared the two groups. Linear regression analysis tested the association between the number of risk factors and erectile dysfunction severity. Locally estimated scatterplot smoothing method graphically explored the relationship between the number of risk factors for erectile dysfunction and the International Index of Erectile Function domain scores., Results: Median (interquartile range) age at first presentation was 50 (39-61) years. Of all, 1632 (86.2%) and 377 (13.8%) were identified as having primary organic and primary psychogenic erectile dysfunction, respectively. Overall, 1488 (74.1%) patients were >40 years of age; in this subgroup, the most frequent risk factors were age, hypertension (29%), active smoking (42%) and alcohol intake (25.1%). Median (interquartile range) International Index of Erectile Function-erectile function score was 15 (7-22). Primary organic erectile dysfunction patients depicted lower International Index of Erectile Function-sexual desire and International Index of Erectile Function-orgasmic function scores (all p ≤ 0.02), whilst groups did not differ in terms of International Index of Erectile Function-erectile function, International Index of Erectile Function-intercourse satisfaction and International Index of Erectile Function-overall satisfaction scores., Discussion: One out of nine patients complaining of erectile dysfunction depict criteria for primary psychogenic erectile dysfunction. Erectile function severity could be as severe as patients with organic erectile dysfunction. The single-centre-based cross-sectional nature of the study, raising the possibility of selection biases, is our main limitation., Conclusions: One out of nine patients presenting for erectile dysfunction depict criteria suggestive for primary psychogenic erectile dysfunction in the real-life setting. Patients with primary psychogenic and primary organic erectile dysfunction have comparable erectile dysfunction severity, thus outlining the importance of a comprehensive and tailored management work-up in every patient seeking medical help for the first time., (© 2022 American Society of Andrology and European Academy of Andrology.)

Objective: The aim of the current review is to summarize the available evidence to aid clinicians in the surveillance, treatment and follow-up of the different primary tumors developed by patients diagnosed with von Hippel-Lindau (VHL) syndrome., Methods: A non-systematic narrative review of original articles, meta-analyses, and randomized trials was conducted, including articles in the pre-clinical setting to support relevant findings., Results: VHL disease is the most common rare hereditary disorder associated with clear cell renal cell carcinoma. Affected individuals inherit a germline mutation in one VHL allele, and any somatic event that disrupt the other allele can trigger mutations, chromosomal rearrangements, or epigenetic regulations leading to oncogenesis. From a clinical perspective, patients continuously develop multiple primary tumors., Conclusion: Because VHL is considered a rare disease, very limited evidence is available for diagnosis, surveillance, active treatment with local or systemic therapy and follow-up., (© 2022 Editorial Office of Asian Journal of Urology. Production and hosting by Elsevier B.V.)

Background: With the advent of immuno-oncology compounds in randomized trials, we observe more and more survival curves crossing. From a statistical standpoint this corresponds to violation of the proportional hazard assumption. When this occurs, the hazard ratio from the Cox regression is not reliable as an estimate. Herein, we aimed to identify the most appropriate IO-based therapy for metastatic renal cell carcinoma applying an alternative method to overcome the issue of hazard assumption violation for meta-analyses., Methods: Pubmed, EMBASE, Web of Science and Scopus databases were searched. Only phase III randomized clinical trials on IO-IO (nivo-ipi) or IO-TKI combinations were included. An algorithm to obtain survival data from published Kaplan-Meier curves was used to reconstruct data on overall survival (OS), progression-free survival (PFS) and duration of response (DoR). Differences in restricted mean survival time (RMST) were used for comparisons., Results: individual survival data from 4,206 patients from five trials were reconciled. Patients who received nivo-ipi or IO-TKI had better OS, PFS and DoR relative to sunitinib (all p<0.001). Patients who received IO-TKI had similar OS and PFS relative to nivo-ipi, with a 36-month ΔRMST of -0.55 (95% CI: -1.71-0.60; p=0.3) and -1.5 (95% CI: -2.9-0.0; p=0.051) months, respectively. Regarding DoR, patients who received nivo-ipi had longer duration of response relative to IO-TKI, with a 24-month ΔRMST of 1.5 (95% CI: 0.2-2.8; p=0.02) months., Conclusion: Despite overall similar OS and PFS for patients receiving nivo-ipi and IO-TKI combinations, DoR was more favorable in patients who received nivo-ipi compared to IO-TKI. A meta-analysis based on differences in RMST is a useful alternative whenever the proportional hazard assumption is violated. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42021241421., Competing Interests: Author AN: Consulting: Merck, Astra Zeneca, Janssen, Incyte, Roche, Rainier Therapeutics, Clovis Oncology, Bayer, and Astellas/Seattle Genetics, Ferring, Immunomedics. Grant/Research support: Merck, Ipsen, and Astra Zeneca. Travel expenses/Honoraria: Roche, Merck, Astra Zeneca, and Janssen. Authors AM, GF, GP and BM own equities of Oltre Medical Consulting, Toulouse, France. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest, (Copyright © 2022 Nocera, Fallara, Raggi, Belladelli, Robesti, Montorsi, Karakiewicz, Malavaud, Ploussard, Necchi and Martini.)

Background: In 2021, the World Health Organization (WHO) has provided the latest update on processing and evaluating semen analysis., Objectives: To assess (i) the rate of discordance in semen parameters categorization across three different WHO reference values (namely WHO21, 2010 and 1999) and (ii) the clinical differences among discordant semen analyses from a cohort of primary infertile men., Materials and Methods: Data from 788 infertile men were analyzed. Semen parameters were interpreted based on WHO21, WHO10, and WHO99 reference criteria. Pregnancy outcomes with assisted reproductive techniques (ART) were available for 110 (14%) patients. Descriptive statistics was applied to describe potential differences among the three consecutive WHO references criteria., Results: Semen parameters categorizations were highly different across the three groups (p < 0.001). Of all, 271 (42.2%) patients had normal semen parameters according to WHO10 but were pathologic when considered with WHO21 reference criteria (namely, men with increased semen abnormalities). Infertile men with increased semen abnormalities had lower testicular volume (p < 0.001) but higher FSH (p < 0.01) and LH (p < 0.001) values than those who had no change in terms of semen parameters categorization. Negative ART outcomes were more frequently reported in men with worsening semen parameters compared with those with confirmed semen parameters at WHO21 versus WHO10 (26.8% vs. 49%, p = 0.03). Conversely, infertile men with worsening semen parameters at WHO21 versus WHO99 were similar in terms of clinical and hormonal characteristics compared with those with the same rate of semen abnormalities., Conclusions: One out of three infertile men showed worsened semen categorization according to WHO21 versus WHO10. Infertile men with worsening of semen parameters had worse clinical and hormonal characteristics than those with confirmed numbers of semen abnormalities. Moreover, live birth rates were lower in men with worsening semen abnormalities as for WHO21., (© 2022 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)

Background: Male factor contributes to up to 50% of cases of couples experiencing infertility. Cannabis is one of the most commonly used recreational drugs, and its effects on the reproductive system have been largely debated in the literature., Objectives: The aim of this study is to evaluate the effect of recreational cannabis use on total T (tT) levels, gonadal status, and sperm parameters in a cohort of primary infertile non-Finnish, white-European men., Materials and Methods: Data of 2074 white-European men visited for primary couple's infertility were analyzed. Lifestyle factors and cannabis use were investigated in all participants. Semen analyses were based on the 2010 World Health Organization reference criteria. Serum hormones were evaluated, and patients were subdivided based on their gonadal status. Health-significant comorbidities were scored with the Charlson Comorbidity Index (CCI). Descriptive statistics and linear regression analyses were used to test the association between cannabis use, sperm parameters, and hormonal levels. Logistic regression analyses tested potential predictors for abnormal sperm parameters and gonadal status., Results: Of 2074, 225 (10.9%) patients reported cannabis use in their lifetime. Total Testosterone levels were lower in cannabis users compared to nonusers (p = 0.03). In a multivariable linear regression analysis, cannabis use was inversely associated with tT levels (ß = -0.372 ng/ml; p = 0.005) but not with follicle-stimulating hormone nor with luteinizing hormone levels. Conversely, at multivariable logistic regression model cannabis use was not associated with the type of hypogonadism. At multivariable linear regression analysis, cannabis use was inversely associated with sperm morphology (p = 0.007), while not with both sperm concentration and sperm motility. Similarly, at adjusted logistic regression analysis cannabis use resulted associated with teratozoospermia (p = 0.039) but not with oligo-, astheno-, and azoospermia., Conclusions: Infertile men using cannabis are at higher risk of having lower testosterone levels and altered sperm morphology as compared with nonusers., (© 2022 American Society of Andrology and European Academy of Andrology.)

Background: Organophosphate (OP) insecticides represent one of the largest classes of sprayed insecticides in the U.S., and their use has been associated with various adverse health outcomes, including disorders of blood pressure regulation such as hypertension (HTN)., Methods: In a study of 935 adults from the NHANES 2013-2014 cycle, we examined the relationship between systolic and diastolic blood pressure changes and urinary concentrations of three OP insecticides metabolites, including 3,5,6-trichloro-2-pyridinol (TCPy), oxypyrimidine, and para-nitrophenol. These metabolites correspond to the parent compounds chlorpyrifos, diazinon, and methyl parathion, respectively. Weighted, multivariable linear regression analysis while adjusting for potential confounders were used to model the relationship between OP metabolites and blood pressure. Weighted, multivariable logistic regression analysis was used to model the odds of HTN for quartile of metabolites., Results: We observed significant, inverse association between TCPy on systolic blood pressure (β-estimate = -0.16, p < 0.001) and diastolic blood pressure (β-estimate = -0.15, p < 0.001). Analysis with para-nitrophenol revealed a significant, positive association with systolic blood pressure (β-estimate = 0.03, p = 0.02), and an inverse association with diastolic blood pressure (β-estimate = -0.09, p < 0.001). For oxypyrimidine, we observed significant, positive associations between systolic blood pressure (β-estimate = 0.58, p = 0.03) and diastolic blood pressure (β-estimate = 0.31, p < 0.001). Furthermore, we observed significant interactions between TCPy and ethnicity on systolic blood pressure (β-estimate = 1.46, p = 0.0036). Significant interaction terms were observed between oxypyrimidine and ethnicity (β-estimate = -1.73, p < 0.001), as well as oxypyrimidine and BMI (β-estimate = 1.51 p < 0.001) on systolic blood pressure, and between oxypyrimidine and age (β-estimate = 1.96, p = 0.02), race (β-estimate = -3.81 p = 0.004), and BMI on diastolic blood pressure (β-estimate = 0.72, p = 0.02). A significant interaction was observed between para-nitrophenol and BMI for systolic blood pressure (β-estimate = 0.43, p = 0.01), and between para-nitrophenol and ethnicity on diastolic blood pressure (β-estimate = 2.19, p = 0.006). Lastly, we observed a significant association between the odds of HTN and TCPy quartiles (OR = 0.65, 95% CI [0.43,0.99])., Conclusion: Our findings support previous studies suggesting a role for organophosphate insecticides in the etiology of blood pressure dysregulation and HTN. Future studies are warranted to corroborate these findings, evaluate dose-response relationships between organophosphate insecticides and blood pressure, determine clinical significance, and elucidate biological mechanisms underlying this association., (© 2022. The Author(s).)

Background: Holmium laser enucleation of the prostate (HoLEP) is considered a challenging procedure with a non-negligible risk of complications limiting its widespread adoption. We investigated rates and preoperative predictors of complications in a high-volume center with long-time experience., Methods: Data from 284 patients treated with HoLEP between 2015 and 2017 were analyzed. Postoperative complications occurring up to 12 months after surgery were collected following the EAU guidelines recommendations. Procedure-specific complications were defined and graded by using the Clavien-Dindo (CD) system. Logistic regression analysis evaluated preoperative risk factors for postoperative complications., Results: Baseline prostate volume was (median, IQR) 87 (60, 120) ml. As a whole, in-hospital and after discharge complications were 19% and 11.6%, respectively, with a 28.6% overall rate at 12 months from surgery. Complications were graded as CD 1 (8% [22]), 2 (18.2% [52]) and 3 (1.8% [5]), respectively. Fever was the most frequently reported (11% of cases), followed by acute urinary retention (8%). At logistic regression analysis, older age (OR: 1.07; 95%CI: 1.01-1.12; P=0.01) and having an indwelling catheter before surgery (OR: 4.03; 95%CI 1.64-9.9; P=0.002) emerged as significant risk factors for post-HoLEP complications, after accounting for surgeon experience and baseline parameters., Conclusions: HoLEP is a safe procedure in a high-volume center with less than 2% high-grade complications. Older patients with indwelling catheter deserve to be carefully managed due to a higher risk of postoperative complications.

The recent introduction of immunotherapy in the first line setting of advanced renal cell carcinoma (aRCC) has dramatically improved patients' prognosis. The aim of the current meta-analysis was to provide level 1a evidence supporting the use of pembrolizumab plus tyrosine kinase inhibitors (TKI) as first-line treatment for advanced RCC. All published randomized prospective trials including patients with advanced RCC treated with pembrolizumab in combination with TKIs vs Sunitinib were included in this meta-analysis. An algorithm was used to reconstruct survival data from the published Kaplan-Meier curves of overall survival (OS), progression free survival (PFS) and duration of response (DoR) from the included trials. Restricted mean survival time (RMST) with 95% confidence interval (CI) for comparison among the different regimens was calculated. Main outcomes were differences in RMST for OS, PFS and DoR for pembrolizumab plus TKIs vs sunitinib arm. Reconstructed survival data from 1,573 patients were retrieved from 2 trials (KEYNOTE-581 and KEYNOTE-426) comparing pembrolizumab plus TKI (lenvatinib or axitinib, respectively) to sunitinib. Patients who received pembrolizumab-lenvatinib or pembrolizumab-axinitinib had better OS (24-month ΔRMST of 1.79 months [95% CI: 0.12-2.50; P < 0.001]), PFS (24-month ΔRMST of 3.83 months [95% CI: 2.93-4.74; P < 0.001]) and DoR (24-month ΔRMST of 2.32 months [95% CI: 0.97-3.67; P < 0.001]) relative to sunitinib. Pembrolizumab-lenvatinib combination gave a marginal benefit in terms of OS, PFS and DoR relative to pembrolizumab-axitinib group. By relying on individual survival data, we provided a level-1a evidence supporting the use of pembrolizumab plus TKI for first-line aRCC treatment., (Copyright © 2022. Published by Elsevier Inc.)

Background: In the context of established male hypogonadism, testosterone therapy (TTh) has been employed to regain physiologic levels of circulating testosterone and improve sexual function and overall quality of life., Aim: To assess the risk of cardiovascular disease and mortality as time-dependent outcomes in treated vs TTh untreated hypogonadal men., Methods: A meta-analysis using weighted time-related measure of risk (hazard ratios (HRs)) for each of the outcome for all included studies was performed. Studies investigating male adults (≥18 years old) diagnosed with hypogonadism and divided into 2 arms (a treatment arm [any TTh] and a control arm [observation or placebo]) and assessing the risk of death and/or cardiovascular events were included. Single arm, non-comparative studies were excluded as well as studies that did not report the HRs for the chosen outcomes. This systemic review was registered on PROSPERO (CRD42022301592) and performed according to MOOSE and PRISMA guidelines., Outcomes: Overall mortality and cardiovascular events of any type., Results: Overall, 10 studies were included in the meta-analysis, involving 179,631 hypogonadal men. Hypogonadal men treated with TTh were found to be at lower mortality risk from all causes relative to the control (observation or palcebo) arm (HR: 0.70; 95% Confidence Interval [CI]: 0.54-0.90; P < .01), whilst any unfavorable effect of TTh in hypogonadal men in terms of cardiovascular events compared to untreated/observed hypogonadal men was found (HR: 0.98; 95% CI 0.73-1.33; P = .89)., Clinical Implications: TTh in hypogonadal men might play a role in reducing the overall risk of death without increasing cardiovascular events risk., Strengths & Limitation: Main limitations are represented by the high heterogeneity among the studies in terms of included population, definition for hypogonadism, type of TTh, definition of cardio-vascular event used, and the length of follow-up., Conclusion: According to time-related measures of risk only, an increased risk of long-term morbidity and early mortality for untreated hypogonadal men was depicted, further outlining the clinical importance and safety of TTh in true hypogonadal men, with the urgent need of collecting long-term follow-up data. Fallara G, Pozzi E, Belladelli F, et al. Cardiovascular Morbidity and Mortality in Men - Findings From a Meta-analysis on the Time-related Measure of Risk of Exogenous Testosterone. J Sex Med 2022;19:1243-1254., (Copyright © 2022 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Some studies suggest a relationship between semen quality and pregnancy rates of assisted reproduction technologies (ART). Others have questioned the utility of semen quality as proxy for fertility in couples attempting to conceive with or without assistance. We aimed to investigate the current body of evidence which correlates semen parameters and clinical pregnancy among couples utilizing ART (i.e. in vitro fertilization [IVF], intracytoplasmic sperm injection [ICSI]) through a systematic review and meta-analysis of cross-sectional and retrospective cohort studies. Pooled Odd Ratio (OR) for oligo-, astheno- and teratospermic compared to normospermic number of ART cycles were calculated among. Meta-regression and sub-group analysis were implemented to model the contribution of clinical/demographic and laboratory standards differences among the studies. Overall, 17 studies were analysed representing 17,348 cycles were analysed. Pooled OR for impaired sperm concentration, motility and morphology was 1 (95%Confidence Interval [CI]: 0.97-1.03), 0.88 (95%CI: 0.73-1.03) and 0.88 (95%CI: 0.75-1) respectively. Further analysis on sperm morphology showed no differences with regard of IVF versus ICSI (p = 0.14) nor a significant correlation with rising reference thresholds (Coeff: -0.02, p = 0.38). A temporal trend towards a null association between semen parameters and clinical pregnancy was observed over the 20-year observation period (Coeff: 0.01, p = 0.014). The current analysis found no association between semen quality (as measured by concentration, motility or morphology) and clinical pregnancy rates utilizing ART. Future investigations are necessary to explore the association between semen parameters and other ART outcomes (e.g. fertilization, implantation, birth and perinatal health)., (© 2022 The Authors. Andrologia published by Wiley-VCH GmbH.)

In this narrative review we provide an overview of the current literature on male hypogonadism and related comorbidities, also depicting the role of testosterone therapy (TTh) in the various settings. Male hypogonadism has been associated with major comorbidities such as type 2 diabetes mellitus, obesity and cardiovascular diseases, promoting a vicious cycle that may lead to further hypogonadism. The biological underpinnings of this association are currently under investigations, but clearly emerges the relevance of the hypothalamic-pituitary-gonadal axis. Hypogonadism has also been associated with increased risk of mortality. As such, TTh has the potential to oppose these patterns and improve cardiovascular and metabolic health in hypogonadal men. Clinical and observational data suggest that in males with hypogonadism, TTh, together with lifestyle changes and diabetes medications, may improve glycemia, reduce risk of progression to diabetes and provides positive effects on cardiovascular risk. Conversely, available data does not fully support any increased risk of prostate cancer in men under TTh. Of clinical relevance, a possible harmful role of hypogonadal status in men with COVID-19 eventually emerged., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Caffeine is one of the most commonly used psychoactive drugs in the world, and provides many health benefits including alertness, improved memory, and reducing inflammation. Despite these benefits, caffeine has been implicated in a number of adverse health outcomes possibly due to effects within the endocrine system, effects that may contribute to impaired reproductive function and low testosterone in men. Previous studies have investigated associations between caffeine consumption and testosterone levels in men, although the quantity and generalizability of these studies is lacking, and the results between studies are conflicting and inconclusive., Methods: Using data from a cross-sectional study of 372 adult men in the 2013-2014 NHANES survey cycle, the researchers set out to characterize the association between serum testosterone levels, caffeine, and 14 caffeine metabolites., Results: Multivariable, weighted linear regression revealed a significant inverse association between caffeine and testosterone. Multivariable, linear regression revealed significant, inverse associations between 6 xanthine metabolic products of caffeine and testosterone. Inverse associations were observed between 5-methyluric acid products and testosterone, as well as between 5-acetlyamino-6-amino-3-methyluracil and testosterone. A significant, positive association was observed for 7-methyl xanthine, 3,7-dimethyluric acid, and 7-methyluric acid. Logistic regression models to characterize the association between 2 biologically active metabolites of caffeine (theobromine and theophylline) and odds of low testosterone (< 300 ng/dL) were non-significant., Conclusions: These findings suggest a potential role for caffeine's contribution to the etiology of low testosterone and biochemical androgen deficiency. Future studies are warranted to corroborate these findings and elucidate biological mechanisms underlying this association., (© 2022. The Author(s).)

Background: Previous studies have investigated associations between herbicides such as 2,4-Dichlorophenoxyacetic acid (2,4-D) and dyshormonogenesis, specifically low testosterone, in human, rodent, and cell models, but results have been conflicting and inconclusive., Methods: Using data from a cross-sectional study of 456 adult men in the 2013-2014 NHANES survey cycle, we examined the relationship between urinary concentrations of 2,4-D and serum testosterone levels., Results: Multivariable regression models adjusting for potential confounders revealed a significant, negative association between urinary 2,4-D and mean serum testosterone among U.S. adult males (β =  - 11.4 ng/dL, p = 0.02). Multivariable logistic regression models using a cutoff defining abnormally low testosterone (i.e., serum testosterone < 300 ng/dL) revealed no significant associations between 2,4-D and the odds of low testosterone., Conclusion: These findings expand on previous literature implicating a role for 2,4-D in the etiology of low testosterone and dyshormonogenesis. Future studies are warranted to corroborate these findings, determine clinical significance, and to investigate the proposed potential biological mechanisms underlying this association., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Background: Pembrolizumab and atezolizumab have recently been approved for the first-line treatment of patients with advanced urothelial carcinoma (aUC) who are not eligible for cisplatin-based chemotherapy and whose tumors have high PD-L1 expression; however, the use of these immunotherapeutic agents relative to standard of care chemotherapy has ongoing concerns. The aim of this present study is to compare the effectiveness of single-agent immune-oncology (IO) compounds versus platinum-based chemotherapy in the first-line setting of aUC., Methods: A comprehensive search for phase III trials on IO versus chemotherapy was conducted in PubMed, EMBASE, Web of Science, and Scopus databases from 01/2016 to 05/2021. An algorithm to obtain survival data from published Kaplan-Meier curves was used to reconstruct overall survival (OS) data. After demonstrating violation of the proportional hazard assumption, we used the difference in restricted mean survival time (ΔRMST) to compare OS., Results: OS data from 2,068 individuals from 3 phase III trials investigating the role of IO vs chemotherapy were reconciled. Overall, patients receiving IO [n = 1,013 (49%)] or chemotherapy [n = 1,055 (51%)] had similar OS with a 24-month ΔRMST of -0.4 (95% CI: -1.1, 0.4; p = 0.2) months. In the cisplatin-ineligible population, patients receiving IO [n = 509 (49%)] or chemotherapy [n = 530 (51%)] had similar OS with a 24-month ΔRMST of 0.1 (95% CI: -0.9, 1.2; p = 0.7) months. In the cisplatin-ineligible population with PD-L1-high tumors, patients receiving IO [n = 226 (50%)] or chemotherapy [n = 226 (50%)] had similar OS with a 24-month ΔRMST of 1.1 (95% CI: -0.5, 2.7; p = 0.1) months., Conclusion: We found no OS benefit for patients treated with first-line immune checkpoint inhibition compared to chemotherapy among the overall population, cisplatin-ineligible patients, and PD-L1-high patients., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Study Question: we aimed to investigate the relationship between the tyg index and both semen and hormonal characteristics in a cohort of primary infertile men. Summary answer: almost one in two primary infertile men presented with a triglycerides/glucose index (tyg) suggestive of insulin resistance (ir). overall, patients with tyg suggestive of ir showed worse clinical, hormonal, and semen parameters. What is already known: male factor infertility (MFI) is often associated with metabolic disorders such as diabetes mellitus and metabolic syndrome, where insulin resistance (IR) plays a relevant pathological role. Recently, TyG has been suggested as a user-friendly IR marker., Study Design: serum hormones and the sperm DNA fragmentation index (SDF) were measured in every patient. The semen analysis was based on 2010 WHO reference criteria. Glucose and insulin levels were measured for every man after a 12-h overnight fast, and the homeostatic model assessment index (HOMA-IR) was then calculated and categorized using a 2.6 threshold. Similarly, fasting glucose and triglycerides levels were measured and the TyG index was calculated and categorized using an 8.1 threshold. Descriptive statistics and logistic regression models tested the association between the TyG and semen and hormonal characteristics., Participants: complete demographic, clinical, and laboratory data from 726 consecutive white European primary infertile men were considered for this analysis. Main results and the role of chance: the median (IQR) age was 39 (35-43) years. A TyG and HOMA suggestive for IR was found in 339 (46.6%) and 154 (21.2%) men, respectively. During the Spearman's test, the TyG index was highly correlated with HOMA-IR (rho = 0.46, p < 0.001). Compared to men with a normal TyG, men with TyG > 8.1 were older, had greater BMI and CCI scores, and lower total testosterone and sperm concentration, but higher DFI, and presented a greater proportion of NOA (all p < 0.01). The multivariable logistic regression analysis showed that men with TyG > 8.1 were at higher risk of SDF > 30 (OR 1.92 (CI: 1.2-2.9)) and NOA (OR 1.78 (CI: 1.1-2.8)). Wider implications of the findings: the Tyng index may act as a reliable marker of IR in the clinical work-up of primary infertile men in real-life settings.

Male reproduction is a complex biological process, and male factor infertility is increasingly recognized as a biomarker for overall male health. Emerging data suggest associations between male reproduction and medical disease (genetic, infectious, chronic comorbid conditions), psychological disease, environmental exposures, dietary habits, medications and substances of abuse, and even socioeconomic factors. There is also evidence that a diagnosis of male fertility is associated with future disease risk including cancer, metabolic disease and mortality. As such, there is a growing view that the male fertility evaluation is an opportunity to improve a man's health beyond his immediate reproductive goals, and also highlights the necessity of a multidisciplinary approach., (Copyright © 2021 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Purpose of Review: While the molecular and genetic bases of Von Hippel-Lindau (VHL) disease have been extensively investigated, limited evidence is available to guide diagnosis, local or systemic therapy, and follow-up. The aim of the current review is to summarize the ongoing trials both in preclinical and clinical setting regarding VHL disease management., Recent Findings: Although genotype/phenotype correlations have been described, there is considerable inter and intra-familiar heterogeneity in VHL disease. Genetic anticipation has been reported in VHL disease. From a clinical point of view, expert-opinion-based protocols suggest testing those patients with any blood relative of an individual diagnosed with VHL disease, those with at least 1 or more suggestive neoplasms or patients presenting with clear cell renal cell carcinoma (ccRCC) diagnosed at a less than 40 years old, and/or multiple ccRCC. Clinical research is focused on safety and efficacy of systemic agents for patients with VHL-related ccRCC, with the aim to possibly preserve kidney function and improve patient survival., Summary: To date, preclinical and clinical research on the topic is scarce and clinical guidelines are not supported by strong validation studies., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The EAU guidelines on male sexual and reproductive health state that both partners of the infertile couple should undergo simultaneous investigation., Objectives: To assess the prevalence and the characteristics of infertile men who were referred for an andrological evaluation after failed attempts of Assisted Reproductive Technology (ART) with those who were evaluated at the beginning of their infertility pathway at a single academic centre over a 17-year period., Materials and Methods: Data of 3213 primary infertile couples assessed between 2003 and 2020 were analysed. Descriptive statistics compared the overall characteristics of male partners of couples with (+ART) or without (-ART) previous ART prior to andrological consultation. Logistic regression models analysed variables associated with +ART. Local polynomial regression models explored the probability of +ART over the analysed time frame., Results: Of all, 493 (15.3%) participants were +ART. Patients and female partners' age was higher in +ART couples (all p ≤ 0.04). Sperm concentration, progressive sperm motility and normal sperm morphology were lower in +ART than in -ART patients (all p < 0.001), along with a greater percentage of non-obstructive azoospermia in +ART compared to -ART men (p < 0.0001). At univariable analysis, patient age and partner age >35 years and a less recent assessment were associated with +ART status (all p ≤ 0.04). Male age and less recent years of assessment were also independent predictors of +ART, after accounting for partner's age >35 years (all p < 0.01). A not significant decrease of this pattern was observed throughout the last 7 years at local polynomial regression models., Discussion: Overall awareness towards the importance of a comprehensive evaluation for the male partner of every infertile couple should therefore be further strengthened., Conclusions: Approximately 15% of couples still undergo ART without any initial andrological evaluation in the real-life setting. A not significant decrease in this trend was observed over most recent years., (© 2021 American Society of Andrology and European Academy of Andrology.)

Testicular volume (TV) is considered a good clinical marker of hormonal and spermatogenic function. Accurate reference values for TV measures in infertile and fertile men are lacking. We aimed to assess references values for TV in white-European infertile men and fertile controls. We analyzed clinical and laboratory data from 1940 (95.0%) infertile men and 102 (5.0%) fertile controls. Groups were matched by age using propensity score weighting. TV was assessed using a Prader orchidometer (PO). Circulating hormones and semen parameters were investigated in every male. Descriptive statistics, Spearman's correlation, and logistic regression models tested potential associations between PO-estimated TV values and clinical variables. Receiver operating characteristic (ROC) curves were used to find TV value cutoffs for oligoasthenoteratozoospermia (OAT) and nonobstructive azoospermia (NOA) status in infertile men. The median testicular volume was smaller in infertile than that of fertile men (15.0 ml vs 22.5 ml; P < 0.001). TV positively correlated with total testosterone, sperm concentration, and progressive sperm motility (all P ≤ 0.001) in infertile men. At multivariable logistic regression analysis, infertile status (P < 0.001) and the presence of left varicocele (P < 0.001) were associated with TV < 15 ml. Testicular volume thresholds of 15 ml and 12 ml had a good predictive ability for detecting OAT and NOA status, respectively. In conclusion, infertile men have smaller testicular volume than fertile controls. TV positively correlated with total testosterone, sperm concentration, and progressive motility in infertile men, which was not the case in the age-matched fertile counterparts., Competing Interests: None

Substances of abuse (SoA), as well as smoking and alcohol consumption, are well known for their impact on male fertility status, erectile function, and ejaculation. We assessed SoA consumption habits in a cohort of men seeking medical attention for uro-andrological purposes. Data from 7447 men seeking medical attention for the first time for uro-andrological purposes were analyzed. A complete medical and sexual history was collected for each patient. Smoking, alcohol, and SoA consumption were investigated. Descriptive statistics was used to describe the whole cohort. The primary motivations for their evaluation were lower urinary tract symptoms (LUTS), erectile dysfunction (ED), and infertility in 1912 (25.7%), 2944 (39.5%), and 2591 (34.8%) men, respectively. Previous use of SoA was reported by 378 (5.1%) men, and 190 (2.6%) individuals were current users. Patients seeking medical attention for infertility were more frequently current SoA users (107; 4.1%) than men with ED (66; 2.2%) and LUTS (17; 0.9%) (both P < 0.001). Current users of SoA were younger than those with past or no SoA history (P < 0.001). Current SoA users were more frequently smokers (P < 0.001) and alcohol consumers (P < 0.001) than those with a previous history or those who had never tried SoA. In conclusion, approximately 3% of men seeking medical attention for uro-andrological purposes were current SoA consumers. Infertile men reported a higher use of SoA than those with ED or LUTS. Current SoA users were younger and more frequently concomitant smokers and alcohol consumers compared to those who did or had never used SoA., Competing Interests: None

Objective: To summarize the current body of evidence on the relationship between impaired male fertility and the risk of early death through a systematic review and meta-analysis of population-based retrospective cohort studies., Methods: PubMed, Web of Science, Embase, Cochrane Library, and Scopus databases were searched from inception to August 2020 according to the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines. Pooled Risk Ratio (RR), Risk Difference (Δr), Hazard Ratio (HR) and Standardized Mortality Ratio (SMR) differences among male factor infertility cohorts were compared to fertile/normospermic control populations or to national mortality data., Results: Six studies from 2006 to 2020 met inclusion criteria. Three studies examined male infertility and mortality (n tot  = 202,456; n deaths  = 1396), while four studies examined survival in relation to semen parameters (n tot  = 59,291; n deaths  = 643). Comparing infertile to fertile men, pooled HR for the risk of death was 1.26 (95%CI:1.01-1.59). Pooled RR and Δr of death for combined oligo- and azoospermic men vs normospermic men was 1.67 (95%CI:1.26-2.21) and 0.37% (95%CI:0.18-0.55%) respectively. When comparing oligo- and normospermic men to azoospermic men, the cumulative HR was 1.31 (95%CI:1.11-1.54) and 2.17 (95%CI:1.55-3.04) respectively. Infertile men had a lower overall risk of death compared to the overall population (SMR, 0.38, 95%CI:0.31-0.45)., Conclusion: Compared to fertile men, infertile men had a higher risk of death. Moreover, the risk of death increased with increasing severity of semen quality impairment. However, compared to men from the general population, infertile men have a lower risk of death suggesting that social determinants of health are also important., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aim: To assess the prevalence of isolated teratozoospermia (iTZS) in a cohort of infertile and fertile men; explore the relationship between iTZS, inflammatory parameters and sperm DNA fragmentation index (SDF) in the same cohort., Materials and Methods: 1824 infertile men and 103 fertile controls. Semen analysis, the neutrophil-to-lymphocyte ratio (NLR) and serum hormones were investigated. DFI was tested in infertile men only. According to 2010 WHO semen analysis, patients were categorized in 3 sub-groups of isolated sperm defects: isolated oligozoospermia (iOZS), isolated asthenozoospermia (iAZS) and iTZS. Descriptive statistics and linear regression models tested the association between clinical variables and inflammatory markers., Results: Among infertile men, iAZS, iTZS, and iOZS were found in 13.9%, 11.9% and 4.1% participants, respectively. iTZS was found in 37 (35.9%) fertile men. Infertile men with iTZS had higher NLR values than those with iOZS, iAZS and men with normal semen parameters (all p<0.001). FSH and LH were higher and inhibin B lower in iOZS infertile men compared to all other groups (p≤0.001). Hormonal characteristics were similar between iTZS infertile and fertile men. Similarly, iTZS infertile men had higher SDF than all other groups (all p<0.001). Infertile men with iTZS had higher NLR values than fertile men with iTZS (p<0.01). Linear regression analysis showed that, in infertile men, iTZS was associated with SDF and NLR (all p≤0.01)., Conclusions: iTZS was found in 11.9% of infertile men but it was even more prevalent in fertile controls. Infertile men with iTZS had higher NLR than fertile controls and increased SDF values than infertile participant with iAZS, iOZS, or normal semen parameters. No differences in hormonal characteristics were found between infertile and fertile men with iTZS., Competing Interests: The authors have declared that no competing interests exist.

Purpose: To describe the association between daily activity (i.e., daily step counts and accelerometer intensity measures) and serum TT levels in a representative sample of US adults aged 18 years or older., Methods: A retrospective cohort study was carried out utilizing the NHANES (National Health and Nutrition Examination Survey) 2003-2004 cycle. Physical activity was measured with a waist-worn uniaxial accelerometer (AM-7164; ActiGraph) for up to 7 days using a standardized protocol. Using linear and multivariable logistic regression controlling for relevant social, demographic, lifestyle, and comorbidity characteristics, we assessed the association between daily step counts and TT., Results: A total of 279 subjects with a median age 46 (IQR: 33-56) were included in the analysis. 23.3% of the cohort had a low serum TT level (TT < 350 ng/dl). Compared to men who took <4000 steps per day, men who took >4000 or >8000 steps/day had a lower odd of being hypogonadal (OR 0.14, 95% CI: 0.07-0.49 and 0.08, 95%CI: 0.02-0.44, respectively). While a threshold effect was noted on average, TT increased 7 ng/dL for each additional 1000 steps taken daily (β-estimate: 0.007, 95% CI: 0.002-0.013)., Conclusions: Patients with the lowest daily step counts had higher odds of being hypogonadal. The current work supports a possible association between daily steps, total testosterone, and hypogonadism for men in the US.

While studies have suggested that testosterone is associated with a man's health, the relationship with other sex steroids remains uncertain. The current study aimed to investigate the association between sex steroids (i.e. testosterone, estradiol and the testosterone:estradiol ratio) and mortality in a representative sample of 1,109 US men. Three NHANES continuous cycles (1999-2000, 2001-2002, 2003-2004) were included in our study. Serum testosterone and estradiol levels were evaluated along with sociodemographic, lifestyle and health factors. Cox proportional hazards models were used. The adjusted risk of death for men with low testosterone levels was 1.66 (95% CI = 1.00-2.74, p = .05). The adjusted risk of death for men with abnormal estradiol levels was 0.96 (95% CI = 0.48-1.91, p = .91). The adjusted risk of death for men with low testosterone to estradiol ratio was 1.27 (95% CI = 0.82-1.97, p = .88). Relevant lifestyle and health factors significantly attenuated the associations. The adjusted risk of CVD-related death for men with low testosterone levels was 2.43 (95% CI = 1.07-5.50, p = .03). In conclusion, a significant association between testosterone and mortality and testosterone to estradiol ratio and CVD-related mortality was identified., (© 2021 Wiley-VCH GmbH.)

Background: Scarce data are available about long-term follow-up (FU) in men undergoing holmium laser enucleation of the prostate (HoLEP)., Objective: To investigate the risk of being symptomatic at 10-yr FU after HoLEP., Design, Setting, and Participants: Perioperative data from 125 patients submitted to HoLEP in 2007-2010 by a single, highly experienced surgeon were analyzed. Patients were assessed by International Prostate Symptoms Score (IPSS), prostate-specific antigen (PSA), and uroflowmetry at 6-mo and 10-yr FU., Outcome Measurements and Statistical Analysis: Logistic regression models tested the association between clinically significant predictors and the risk of being symptomatic at long-term FU (defined as IPSS≥8 and/or peak flow rate [PFR]<15ml/s and/or postvoid residual volume [PVR]>20ml, need for symptomatic medical treatment, or redo surgery)., Results and Limitations: At surgery, median (interquartile range) age was 66 years (61, 69), prostate volume was 78ml (56, 105), and PFR was 9ml/s (7, 12). All patients showed favorable outcomes (ie, IPSS and uroflowmetry parameters) 6 months after surgery. At median 126-month FU, PFR was 16ml/s (13, 23), PVR was 10ml (5, 15), total IPSS was 5 (1-7), and PSA was 0.7 ng/ml (0.4, 1.3). Of all, 32 patients (26%) were symptomatic at long-term FU, seven (5.7%) reported urinary incontinence, and six (4.7%) underwent redo surgery throughout the FU period due to either bladder neck contracture or urethral stricture. Older patients at surgery (odds ratio [OR]: 1.12; 95% confidence interval [CI]: 1.03-1.22; p=0.006) and patients who never recovered full continence postoperatively (OR: 0.49; 95% CI: 0.01-0.27; p=0.001) were at a higher risk of being symptomatic at very long-term FU, after adjusting for baseline clinical characteristics., Conclusions: HoLEP ensures a durable relief of urinary symptoms in almost 75% of patients up to 10 years after surgery. Older patients and those who do not recover from incontinence after surgery should be counseled carefully regarding a higher risk of symptom recurrence at long-term assessment., Patient Summary: Consistent symptom relief is preserved even 10 years after holmium laser enucleation of the prostate in almost 75% of patients. Older age and incomplete continence recovery after surgery were the two most relevant risk factors for being symptomatic at long-term follow-up. Postoperative functional outcomes are kept in three out of four patients at 10-yr follow-up after holmium laser enucleation of the prostate. Conversely, the older the patient at surgery and the presence of incomplete continence recovery throughout the postoperative period, the greater the probability of being symptomatic at long-term follow-up., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Trends of male factor causes of couples' infertility over time have been poorly investigated., Objective: We investigated trends in the causes of pure male factor infertility (MFI) throughout the last 10 years in a tertiary-referral academic andrology center., Material and Methods: Baseline characteristics at first presentation from a cohort of 1647 consecutive male factor infertility patients belonging to primary infertile couples between 2008 and 2018 have been comprehensively collected over time. Seven major causes of male factor infertility were identified: varicocoele; history of cryptorchidism; hypogonadism (primary and secondary); obstructive azoospermia; genetic abnormalities; other causes (large group including the remnant conditions of known causes); and idiopathic infertility. Rates of different male factor infertility causes over the study period were analyzed. Multivariable logistic regression models tested the likelihood of male factor infertility causes over time. Estimated trends were explored graphically., Results: Of all, varicocoele was found in 615 (37.3%), cryptorchidism in 124 (7.5%), genetic abnormalities in 61 (3.7%), hypogonadism in 165 (10%), obstructive conditions in 55 (3.3%), other causes in 129 (7.8%) patients, and idiopathic infertility in 498 (30.3%) patients, respectively. Over time, a reduction in the proportions of cryptorchidism and varicocoele (all P < 0.001) cases was observed, along with an increase in the proportions of hypogonadism, other causes of MFI and idiopathic cases (all P ≤ 0.01). Rates of genetic and obstructive cases remained stable. The observed trends were confirmed at logistic regression models., Discussion and Conclusions: A decreasing trend in the proportions of varicocoele and cryptorchidism at first presentation was observed over the last 10 years; conversely, the proportions of idiopathic cases, hypogonadal patients, and infertile men presenting with other male factor infertility causes significantly increased over the same time frame at a single tertiary-referral academic andrology center., (© 2020 American Society of Andrology and European Academy of Andrology.)

Objective: To evaluate the association between cannabis use and testicular function (as assessed through semen quality and serum hormone levels) in different populations., Evidence Review: Systematic review and meta-analysis of population-based retrospective cohort studies. PRISMA guidelines were used for abstracting data and assessing data quality and validity. Data were pooled using a fixed-effects or random-effects model depending on the heterogeneity of studies included. Pooled risk ratio (RR) of having any sperm abnormality and testosterone, FSH, and LH standardized mean differences among male cannabis users and non-users, and meta-regression analysis according to age and year of publication., Results: Nine studies were evaluated which included 4014 men with semen data and 4787 with hormonal data. Overall among 1158 cannabis users, 44.9% had impaired semen parameters, compared with 24.5% of the 2856 non-users. The relative risk among cannabis users for any abnormal semen parameter was 1.159 (95% CI: 0.840; 1.599, P = 0.369). The standardized mean difference between user and non-user testosterone levels was -0.139 (95% CI: -0.413; 0.134, P = 0.318). For FSH, the standardized mean difference estimate was -0.142 (95% CI: -0.243; -0.0425, P = 0.005), while for LH the standardized mean difference estimate was -0.318 (95% CI: -0.810-0.175; P = 0.206)., Conclusions: The current evidence does not suggest clinically significant associations between cannabis use and testicular function. However, we cannot exclude an effect of cannabis because of the limited and heterogeneous studies. Additionally, well-designed studies will be needed to define the association between cannabis use and the male reproductive system., (© 2020 American Society of Andrology and European Academy of Andrology.)

We aimed to investigate clinical features potentially useful in primary bladder neck obstruction (PBNO) diagnosis in men presenting with lower urinary tract symptoms (LUTS). Data from 1229 men presenting for LUTS as their primary complaint at a single centre were retrospectively analysed. All patients underwent a comprehensive medical and physical assessment, and completed the International Prostate Symptoms Score. All patients were investigated with uroflowmetry, and trans-rectal ultrasound imaging to define prostate volume. Urodynamic evaluation was performed when the diagnosis of benign prostatic enlargement was not confirmed and the patient presented a significant chance of detrusor overactivity or underactivity. As per our internal protocol, patients < 60 years old with bothersome LUTS and > 60 years with a prostate volume (PV) < 40 mL were also investigated with urethrocystoscopy to rule out urethral stricture. Logistic regression analysis tested clinical predictors of possible PBNO. Of 1229 patients, 136 (11%) featured a clinical profile which was consistent with PBNO. Overall, these patients were younger (p < 0.0001), had lower BMI (p < 0.0001), less comorbidities (p = 0.004) and lower PSA values (p < 0.0001), but worse IPSS scores (p = 0.01) and lower PV values (p < 0.0001) compared to patients with other-aetiology LUTS. At multivariable analysis, younger age (OR 0.90; p = 0.003) and higher IPSS scores (OR 1.12; p = 0.01) were more likely to be associated with this subset of patients, after accounting for other clinical variables. One out of ten young/middle-aged men presenting for LUTS may be affected from PBNO. Younger patients with more severe LUTS systematically deserve an extensive assessment to rule out PBNO, thus including urethrocystoscopy and urodynamics with voiding-cysto-urethrogram.

A proportion of men are infertile despite having normal medical history/physical examination and normal semen analysis. We aimed to assess whether normal sperm parameters per se account for male factor fertility. 1,957 infertile men were compared with 103 age-comparable fertile controls. Semen analysis was based on 2010 World Health Organization reference criteria. Of all, 12.1% of infertile men and 40.8% of fertile men presented with normal sperm parameters. Among fertile men, 36.9% had isolated sperm abnormalities and 22.3% men showed two or more concomitant sperm abnormalities. Serum total testosterone was higher in infertile men with normal sperm parameters compared to those with ≥2 sperm abnormalities or azoospermia, but similar to those with isolated sperm abnormalities (p ≤ .001). Circulating hormones were similar among sperm parameters groups in fertile men. At multivariable analyses, testicular volume (OR 1.12, p ≤ .001) and FSH (OR 0.8, p ≤ .001) were associated with normal sperm parameters. Overall, the longer the infertility period, the greater the number of sperm parameters abnormalities (p < .01). In conclusion, we found that 12% of infertile men and only 41% of fertile men present with normal sperm parameters. Normal sperm parameters per se do not reliably account for fertility in the real-life setting., (© 2020 Wiley-VCH GmbH.)

Objective: To determine whether male infertility or impaired spermatogenesis is associated with mortality., Methods: The Optum de-identified Clinformatics Data Mart database was queried from 2003 to 2017. Infertile men were compared to subjects undergoing semen analysis (ie, infertility testing). Infertile men with oligozoospermia or azoospermia were included. Mortality was determined by data linkage to the Social Security Administration Death Master File. Results were adjusted for age, smoking, obesity, year of evaluation, and health care visits as well as for most prevalent comorbidities. We separately examined men with prevalent or incident cardiovascular disease and cancer diagnoses to determine associations with mortality., Results: A total of 134,796 infertile men and 242,282 controls were followed for a mean of 3.6 and 3.1 years respectively. Overall, infertile men had a higher risk of death (Hazard Ratio [HR]= 1.42, 95% CI: 1.27-1.60) The diagnosis of azoospermia was associated with a significantly increased risk of death (HR= 2.01, 95% CI: 1.60-2.53) with a higher trend among men with oligospermia (HR: 1.17, 95% CI: 0.92-1.49) compared to controls. Subanalysis was done excluding prevalent cardiovascular and malignant disease (alone and combined) showing similar hazard ratios., Conclusion: Male infertility is associated with a higher risk of mortality especially among azoospermic men. Prevalent disease (which is known to be higher among infertile men) did not explain the higher risk of death among infertile men. The implications for treatment and surveillance of infertile men require further study., (Published by Elsevier Inc.)

We aimed to evaluate the relationship between serum testosterone (T) levels and penile curvature in a cohort of men presenting for chronic phase Peyronie's disease (PD). Clinical data from 149 patients assessed for chronic phase PD between 2016 and 2019 at a single academic center were analyzed. Deformity assessment was conducted during an intracavernosal injection-induced rigid erection. Both total T (tT) and calculated free T (cFT) were assessed in every patient and considered as continuous variables or according to quartiles of the normal range. Hypogonadism was defined for tT < 10.4 nmol/L. Descriptive statistics and linear regression models tested the association between T values and the severity of penile curvature. Overall, median tT value was 15.9 (11.4-20.8) nmol/L in the whole cohort; median curvature magnitude and plaque size were 45 (30-60) degrees and 1.5 (0.8-2.0) cm, respectively. Penile curvature (40.0 vs. 45.0 degree; p = 0.7) and plaque size (1.5 vs. 1.3 cm; p = 0.4) were similar between eugonadal and hypogonadal patients. The magnitude of penile curvature did not differ across tT quartiles (p = 0.31). Both at univariable (β 1.32; p < 0.01) and multivariable (β 1.34; p < 0.01) linear regression model, only duration of PD was associated with the severity of penile curvature magnitude. The results of this cross-sectional study confirmed that there is no association between serum T values and the severity of penile curvature in patients with chronic phase PD. Only PD duration is associated with penile deformity severity., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: To investigate the current evidence that correlates impaired male fertility with the risk of developing male-related malignancies., Design: Systematic review and meta-analysis of population-based retrospective cohort studies., Setting: Not applicable., Patient(s): Men diagnosed with impaired fertility status and subsequently observed to determine incidence risk in developing testicular cancer (TCa) or prostate cancer (PCa)., Intervention(s): Not applicable., Main Outcome Measure(s): Pooled risk ratio (RR) differences among male factor infertility subjects compared with a fertile control population, and meta-regression analysis according to age at baseline, mean follow-up, range of study time, and year of publication., Result(s): Six studies met the inclusion criteria and were critically examined. Four studies examined male infertility and TCa (n = 161,634; 174 TCa cases), and four examined infertility in relation to PCa (n = 183,950 men; 377 PCa cases) from 1963 to 2014. The pooled RR was 2.033 (95% confidence interval [CI], 1.66-2.48); heterogeneity: Q = 3.04 (degree of freedom [df] = 3); I 2 = 1.55% for TCa and 1.68 (95% CI, 1.17-2.4); Q = 23.3(df = 3); I 2 = 87.1% for PCa., Conclusion(s): Male infertility was associated with a subsequent risk of both TCa and PCa. Although the clinical significance of these findings remains uncertain, future studies should evaluate the underlying mechanisms to determine whether testis and prostate screening practices should be altered in men with male infertility., Clinical Trial Registration Number: PROSPERO 167277., (Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: A number of studies showed that obesity may negatively impact on sperm quality and consequently couple's fertility. Recently, specific attention was given to a clinical condition known as metabolically healthy obesity (MHO)., Objectives: To evaluate the effects of MHO on semen and hormonal parameters of men presenting for primary couple's infertility associated with pure male factor infertility (MFI)., Materials and Methods: Data from a homogenous cohort of 512 white-European primary infertile men belonging to couples with pure MFI have been cross-sectionally analyzed. Semen analysis was based on 2010 WHO reference criteria. Patients were segregated into eugonadal, secondary hypogonadal, primary hypogonadal, and compensated hypogonadal. The Harmonized International Diabetes Federation criteria were used to define metabolic syndrome (MetS). Based on BMI and MetS, patients were further segregated into the following: (a) metabolically healthy non-obese (MHNO); (b) metabolically unhealthy non-obese (MUNO) (c) metabolically healthy obesity (MHO); and, (d) metabolically unhealthy obesity (MUHO). Main outcome measures were the prevalence of MHO and the impact of MHO on semen and hormonal parameters in this cohort of MFI primary infertile men., Results: Overall, MHNO, MUNO, MHO, and MUHO were found in 462 (90%), 13 (2.5%), 27 (5.2%), and 10 (1.9%) men, respectively. MHO patients had lower total testosterone and SHBG levels (all P < .05) but higher E 2 values (P < .005) compared with MHNO men. Groups did not differ in terms of semen parameters. At multivariable logistic regression, analysis MHO was associated with an increased risk of primary and secondary hypogonadism (all P ≤ .02) compared with MHNO, after accounting for age and comorbid conditions., Discussion and Conclusions: Metabolically healthy obesity is threefold more prevalent than unhealthy obesity in primary infertile men. Despite semen parameters are comparable among groups, MHO patients show worse endocrine parameters and a higher risk of primary and secondary hypogonadism compared with metabolically healthy normal infertile men., (© 2020 American Society of Andrology and European Academy of Andrology.)

Background: Erectile dysfunction (ED) is widely considered as an early manifestation of cardiovascular diseases (CVDs), sharing similar risk factors., Aim: Assess rates and predictors of developing CVD and/or hypertension (HTN) over a long-term follow-up period using user-friendly and clinically reliable tools in men presenting with ED but without CVD/HTN or known vascular risk factors at baseline., Methods: Data from 108 patients presenting between 2005 and 2011 with ED were analyzed. All patients were free from CVD and/or HTN (CVD/HTN) at baseline. Patients completed the International Index of Erectile Function (IIEF) at baseline and were followed up every 6 months with clinical assessment or phone interview. Kaplan-Meier analyses estimated the probability of developing CVD/HTN over time. Cox-regression models tested the association between patient baseline characteristics (for example, age, Charlson Comorbidity Index, baseline IIEF-EF, ED severity, alcohol intake, smoking), response to phosphodiesterase type-5 inhibitors (PDE5is), and the risk of developing CVD/HTN., Results: Of all, 43 (40%) patients showed IIEF-EF scores suggestive of severe ED; 37 (39%) and 59 (61%) were nonresponders and responders to PDE5i, respectively. Median (interquartile range) age was 51 (41, 61) years. Median (interquartile range) follow-up was 95 (86-106) months. Overall, the estimated risk of developing CVD/HTN was 15% (95% confidence interval [CI]: 9-27) at 10-year assessment. Men with baseline severe ED had a higher risk of developing CVD/HTN (34%; 95% CI: 17-59, P = .03) at 10 years than patients with mild to moderate ED (5% [95% CI: 2-14]). At the Cox regression analysis, severe ED (Hazard ratio [HR], 4.62; 95% CI: 1.43, 8.89; P = .01) and baseline IIEF-EF score (HR, 0.92; 95% CI: 0.86, 0.99; P = .02) were associated to the risk of CVD/HTN overtime. Conversely, age and nonresponders to PDE5is (HR, 0.92; 95% CI: 0.32, 2.68; P = .9) were not associated to a risk of CVD/HTN over time., Clinical Implications: The use of an easy and user-friendly tool, as the IIEF-EF domain score, would allow to reliably assess which men with ED at first presentation may deserve a different, more specific and detailed cardiologic investigation to prevent inauspicious CV events., Strengths & Limitations: A single-center-based, observational longitudinal study, raising the possibility of selection biases are the main limits., Conclusions: Patients with severe ED and lower baseline IIEF-EF but no vascular risk factors at first presentation have more than 30% risk of developing CVD/HTN in 10-year time. Those patients may benefit from medical preventive strategies to lowering the risk of CV events and HTN. Pozzi E, Capogrosso P, Boeri L, et al. Longitudinal Risk of Developing Cardiovascular Diseases in Patients With Erectile Dysfunction-Which Patients Deserve More Attention?. J Sex Med 2020;17:1489-1494., (Copyright © 2020. Published by Elsevier Inc.)

Objective: We aimed to test the association between age, BMI and sex-hormone-binding globulin (SHBG) in a homogenous cohort of white-European men presenting for primary couple's infertility., Design: Retrospective study., Methods: Data from 1547 infertile men were analysed. Health-significant comorbidities were scored with the Charlson comorbidity index (CCI). Fasting serum hormones were measured in every patient. Age was considered according to quartile groups (<33, 33-41, >41 years) and BMI as normal weight (18.5-24.9 kg/m2), overweight (25.0-29.9 kg/m2) and obesity (>30 kg/m2). Descriptive statistics and linear regression analysis tested the associations between age, BMI and SHBG., Results: Median SHBG levels increased across quartiles of age and decreased along with BMI increases (all P < 0.001). For each year increase in age, SHBG increased 0.32 nmol/L; conversely, for each unit increase in BMI, SHBG decreased by 1.1 nmol/L (all P < 0.001). SHBG levels decline with increasing BMI was greater than SHBG progressive increase with age. Overall, BMI explained 3.0 times more of the variability in SHBG than did ageing. At multivariate linear model, age and BMI were the most significant factors influencing SHBG concentration (all P < 0.001), after accounting for CCI, albumin levels and smoking status., Conclusions: We found a wide distribution of SHBG concentrations across age and BMI values in primary infertile men. The association between BMI and lowered SHBG levels seems to be greater than the association of ageing with increased SHBG.

Purpose: Ongoing evidence has suggested the role of male factor infertility as a potential predictor of mortality and general health status. The aim of the present review is to update the current knowledge base regarding the association between male factor infertility and general health through a critical review of the literature., Materials and Methods: A systematic review of the literature was carried out from inception to November 2019 in order to evaluate significant associations between male infertility and adverse health outcomes such as cardiovascular, oncologic, metabolic and autoimmune diseases as well as overall mortality., Results: In all, 27 studies met inclusion criteria and were critically examined. Five studies examined male infertility and cardiovascular disease risk, 11 examined oncologic risk (e.g., overall cancer risk, testis and prostate cancer), 8 examined aggregate chronic medical diseases and 5 infertility related to incidence of mortality, for a total of 599,807 men diagnosed with any male factor infertility covering a period from 1916 to 2016., Conclusions: A man's fertility and overall health appear to be interconnected. Therefore, a diagnosis of male infertility may allow a window into future comorbidity and/or mortality which may help guide clinical decisions and counseling. Several possible etiologies such as genetic, epigenetic, developmental, and lifestyle-based factors need to be further evaluated in order to establish the underlying mechanisms between male infertility and health., Competing Interests: CONFLICTS OF INTEREST: The authors have nothing to disclose., (© The Korean Urological Association, 2020.)