PDE5is-naïve versus non-naïve patients at first investigation for erectile dysfunction-findings from a long-term, real-life cross-sectional study.

BACKGROUND: Phosphodiesterase 5 inhibitors (PDE5is) represent a first-line pharmacological therapy for erectile dysfunction (ED). Men could obtain PDE5is for recreational purposes without any proper medical prescription. OBJECTIVE: We aimed to analyze clinical characteristics of patients who already used any PDE5i for ED without previous formal medical prescription. MATERIALS AND METHODS: Data from 2012 heterosexual, sexually active men seeking first medical help for ED at our outpatient clinic between 2005 and 2022 were analyzed. All patients were assessed with a comprehensive sexual and medical history and completed the International Index of Erectile Function (IIEF) at baseline. Comorbidities were scored with the Charlson comorbidity index (CCI). Thereof, according to exposure to any PDE5i before their first visit, patients were subdivided into: PDE5i-naïve and non-PDE5i-naïve patients. Descriptive statistics tested the sociodemographic and clinical characteristics of both groups. A logistic regression model predicted the likelihood of being PDE5i-naïve at the baseline. Linear regression analysis (LRA) estimated the likelihood of being PDE5i-naïve versus non-PDE5i-naïve over the analyzed timeframe. Lastly, local polynomial regression models graphically explored the likelihood of being PDE5i-naïve at the first clinical assessment over the analyzed timeframe, and the sensitivity analyses tested the probability of being PDE5i-naïve at baseline. RESULTS: Overall, 1,491 (70.9%) patients were PDE5i-naïve and 611 (29.1%) were non-PDE5i-naïve at the first assessment. PDE5is-naïve patients were younger, with a lower prevalence of CCI ≥ 1 and of normal erectile function (EF) than non-PDE5i-naïve men (all p < 0.05). Multivariable logistic regression found that patients with lower BMI (OR: 0.99), higher IIEF-EF scores (OR: 1.02), lower rates of severe ED (OR: 0.94), and who had been assessed earlier throughout the study timeframe (OR: 1.27) were less likely to be PDE5i-naïve at baseline. Univariate LRA revealed that younger patients (Coeff: -0.02), with lower CCI (Coeff: -0.29) and higher alcohol intake per week (Coeff: 0.52) were more likely to be PDE5i-naïve over the analyzed timeframe. Moreover, for the same IIEF-EF score, patients with higher CCI had lower probability of being PDE5i-naïve. CONCLUSIONS: Self-prescription of PDE5is is an attitude presents in the general population, despite this phenomenon has decreased overtime. Current data outline the importance to keep promoting educational campaigns to promote PDE5is as effective and safe medicinal products, while avoiding their improper use.

Testicular Cancer Treatments and Sexuality: A Narrative Review.

The incidence of testicular cancer (TC) has been rapidly increasing over the past years. Diagnosis and early treatment have shown good oncological control, guaranteeing the patient different treatment approaches according to histology and tumor stage. Currently, physicians usually prioritize oncological outcomes over sexual outcomes and quality of life, considering as a first aim the overall survival of the patients; however, differently from other neoplasms, quality of life is still strongly affected among TC patients, and sexual outcomes are frequently compromised after each TC treatment. Several studies have suggested that each treatment approach may be associated with sexual dysfunctions, including erectile dysfunction, ejaculatory disorders, fertility issues, and hormonal changes. Since testicular cancer patients are more frequently young men, the subject of this work is substantial and should be analyzed in detail to help specialists in the management of this disease. The aim of the current narrative review is to generally describe every treatment for TC, including surgery, chemotherapy, radiotherapy, and retroperitoneal lymph node dissection, and to establish which sexual dysfunction may be specifically associated with each therapy.

The Importance of Discordant Follicle Stimulating Hormone and Inhibin B Levels in Primary Infertile Men: Findings from a Cross-Sectional Study.

PURPOSE: We aimed to investigate the relationship between follicle stimulating hormone (FSH) and inhibin B (InhB). MATERIALS AND METHODS: Data from 1,230 consecutive men presenting for primary couple's infertility were analyzed. Health-significant comorbidities were scored with Charlson comorbidity index. Quartiles of FSH and InhB were considered to determine threshold values. Descriptive statistics and logistic regression models tested association between FSH and InhB values. RESULTS: Overall, 1,080 (87.8%) men had concordant FSH and InhB values. Conversely, 150 patients (12.2%) had discrepancies in FSH and InhB, with 78 (6.3%) and 72 (5.9%) men reporting both low and high FSH and InhB values, respectively. Infertile men with discordant values were younger (median [interquartile range] 38.0 years [34-41 years] vs. 36.0 years [31-40 years]); had smaller testicular volume (TV) (12 mL [10-15 mL] vs. 15 mL [12-20 mL]); and, had more frequently a sperm DNA fragmentation test >30% (179 [59.1%] vs. 40 [78.4%]) than those with concordant values (all p<0.05). Moreover, a higher frequency of previous cryptorchidism (27.3% vs. 11.9%), lower sperm concentration (3.0 million/mL [0.9-11.0 million/mL] vs. 13.8 million/mL [3.1-36.0 million/mL]), lower progressive sperm motility rates (12.0% [5.0%-25.3%] vs. 20.0% [7.0%-36.0%]), and greater rates of non-obstructive azoospermia (36.4% vs. 23.9%) were found in men with discordant FSH and InhB values (all p≤0.005). At multivariable logistic regression analysis, higher body mass index (odds ratio [OR], 1.08; p=0.001), smaller TV (OR, 0.91; p<0.001), and a history of cryptorchidism (OR, 2.49; p<0.001) were associated with discordant FSH and InhB values. CONCLUSIONS: More than one out of ten infertile men had discordant FSH and InhB values in the real-life setting showing worse clinical profiles than those with concordant levels. Smaller TV and history of cryptorchidism could be used as clinical markers to better tailor the need to test InhB.

Unrecognised orgasmic phase disorders in men presenting with new-onset erectile dysfunction-Findings from a real-life, cross-sectional study.

BACKGROUND: Orgasmic phase disorders in men worsen the burden of erectile dysfunction on sexual satisfaction. OBJECTIVES: To investigate the prevalence of and predictors of unreported orgasmic phase disorder in a cohort of men looking for their first urological assessment for new-onset erectile dysfunction in a real-life setting. MATERIALS AND METHODS: Data from 1107 heterosexual, sexually active men consecutively assessed for new-onset erectile dysfunction were analysed. Throughout a comprehensive medical and sexual history, all patients were asked to self-report any orgasmic phase disorder and to complete the International Index of Erectile Function and the Beck's Inventory for Depression (depressive symptoms scored as Beck's Inventory for Depression ≥11). Men self-reporting orgasmic phase disorder during the interview were excluded from further analyses. The median value of the International Index of Erectile Function-orgasmic function domain was arbitrarily used to categorise men with (International Index of Erectile Function-orgasmic function ≤5) and without unreported orgasmic phase disorder (International Index of Erectile Function-orgasmic function >5). Circulating hormones were measured in every patient. Descriptive statistics and logistic regression models were used to test the association between clinical variables and unreported orgasmic phase disorder. RESULTS: Of 1098 patients with non-self-reporting orgasmic phase disorder, 314 (28.6%) had International Index of Erectile Function-orgasmic function ≤5. Patients with erectile dysfunction + unreported orgasmic phase disorder were older (median [interquartile range]: 58 [44-66] years vs. 51 [40-60] years), had higher body mass index [25.8 (23.7-28.1) kg/m2 vs. 25.2 (23.3-27.4) kg/m2 ], higher prevalence of type 2 diabetes (36 [11.5%] vs. 45 [5.7%]) and lower International Index of Erectile Function-erectile function scores (6 [2-10] vs. 18 [11-24]) than men with erectile dysfunction-only (all p < 0.05). Patients with erectile dysfunction + unreported orgasmic phase disorder depicted higher rates of severe erectile dysfunction (75.5% vs. 25%) and Beck's Inventory for Depression ≥11 (22.6% vs. 17.9%) (all p < 0.05). In the multivariable logistic regression analysis, older age (odds ratio: 1.02) and lower International Index of Erectile Function-erectile function scores (odds ratio: 0.83) were independently associated with unreported orgasmic phase disorder (all p < 0.05). CONCLUSIONS: Almost one in three men seeking first medical help for erectile dysfunction depicted criteria suggestive of unreported orgasmic phase disorder. Men with unreported orgasmic phase disorder were older and had higher rates of severe erectile dysfunction and concomitant depressive symptoms. These real-life findings outline the clinical relevance of a comprehensive investigation of concomitant sexual dysfunction in men only complaining of erectile dysfunction to more effectively tailor patient management.

Low Birth Weight is Associated with Sperm DNA Fragmentation and Assisted Reproductive Technology Outcomes in Primary Infertile Men: Results of a Cross-Sectional Study.

PURPOSE: To assess the relationship between clinical and semen characteristics and assisted reproductive technology (ART) outcomes with different birth weight (BW) categories in a cohort of infertile men. MATERIALS AND METHODS: Data from 1,063 infertile men were analyzed. Patients with BW ≤2,500, 2,500-4,000, and ≥4,000 g were considered as having low BW (LBW), normal BW (NBW), and high BW (HBW), respectively. Testicular volume (TV) was assessed with a Prader orchidometer. Serum hormones were measured in all cases. Semen analyses were categorized based on 2021 World Health Organization reference criteria. Sperm DNA fragmentation (SDF) was tested in every patient and considered pathological for SDF >30%. ART outcomes were available for 282 (26.5%) patients. Descriptive statistics and logistic regression analyses detailed the association between semen parameters and clinical characteristics and the defined BW categories. RESULTS: Of all, LBW, NBW, and HBW categories were found in 79 (7.5%), 807 (76.0%), and 177 (16.5%) men, respectively. LBW men had smaller TV, presented higher follicle-stimulating hormone (FSH) but lower total testosterone levels compared to other groups (all p<0.01). Sperm progressive motility (p=0.01) and normal morphology (p<0.01) were lower and SDF values were higher (all p<0.01) in LBW compared to other groups. ART pregnancy outcomes were lower in LBW compared to both NBW and HBW categories (26.1% vs. 34.5% vs. 34.5%, p=0.01). At multivariable logistic regression analysis, LBW was associated with SDF >30% (odd ratio [OR] 3.7; p<0.001), after accounting for age, Charlson Comorbidity Index (CCI), FSH, and TV. Similarly, LBW (OR 2.2; p<0.001), SDF >30% (OR 2.9; p<0.001) and partner's age (OR 1.3; p=0.001) were associated with negative ART outcomes, after accounting for the same predictors. CONCLUSIONS: LBW was associated with impaired clinical and semen characteristics in infertile men compared to both NBW and HBW. SDF and ART outcomes were significantly worse in the LBW group.

Anti-Müllerian hormone predicts positive sperm retrieval in men with idiopathic non-obstructive azoospermia-findings from a multi-centric cross-sectional study.

STUDY QUESTION: Is it possible to identify a reliable marker of successful sperm retrieval (+SR) in men with idiopathic non-obstructive azoospermia (iNOA) undergoing microdissection testicular sperm extraction (mTESE)? SUMMARY ANSWER: A higher likelihood of +SR during mTESE is observed in men with iNOA and lower preoperative serum anti-Müllerian hormone (AMH) levels, with good predictive accuracy achieved using an AMH threshold of <4 ng/ml. WHAT IS KNOWN ALREADY: AMH has been previously linked to +SR in men with iNOA undergoing mTESE prior to ART. STUDY DESIGN, SIZE, DURATION: A multi-centre cross-sectional study was carried out with a cohort of 117 men with iNOA undergoing mTESE at three tertiary-referral centres. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data from 117 consecutive white-European men with iNOA presenting for primary couple's infertility associated with a pure male factor at three centres were analysed. Descriptive statistics was applied to compare patients with negative (-SR) versus +SR at mTESE. Multivariate logistic regression models were fitted to predict +SR at mTESE, after adjusting for possible confounders. Diagnostic accuracy of the factors associated with +SR was assessed. Decision curve analyses were used to display the clinical benefit. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, 60 (51.3%) men had an -SR and 57 (48.7%) had a +SR at mTESE. Patients with +SR had lower levels of baseline AMH (P = 0.005) and higher levels of estradiol (E2) (P = 0.01). At multivariate logistic regression analysis, lower levels of AMH (odds ratio: 0.79; 95% CI: 0.64-0.93, P = 0.03) were associated with +SR at mTESE, after adjusting for possible confounders (e.g. age, mean testicular volume, FSH, and E2). A threshold of AMH <4 ng/ml achieved the highest accuracy for +SR at mTESE, with an AUC of 70.3% (95% CI: 59.8-80.7). Decision curve analysis displayed the net clinical benefit of using an AMH <4 ng/ml threshold. LIMITATIONS, REASONS FOR CAUTION: There is a need for external validation in even larger cohorts, across different centres and ethnicities. Systematic reviews and meta-analysis to provide high level of evidence are lacking in the context of AMH and SR rates in men with iNOA. WIDER IMPLICATIONS OF THE FINDINGS: Current findings suggest that slightly more than one in two men with iNOA had -SR at mTESE. Overall, men with iNOA with lower levels of AMH had a significantly higher percentage of successful SR at surgery. A threshold of <4 ng/ml for circulating AMH ensured satisfactory sensitivity, specificity, and positive predictive values in the context of +SR at mTESE. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by voluntary donations from the Urological Research Institute (URI). All authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Kidney function impairment in men with primary infertility: A case-control analysis.

BACKGROUND: Infertile men have a worse overall health status than their fertile counterparts. OBJECTIVE: We aimed to (1) compare kidney function in men presenting for primary couple's infertility with that of fertile men and (2) assess kidney function impairment toward sperm quality in infertile men. MATERIALS AND METHODS: In this case-control study, 387 consecutive white-European infertile men were matched by age with 134 same-ethnicity fertile men. Complete clinical and laboratory data were available for each patient. The Chronic Kidney Disease Epidemiology Collaboration function was used for estimated glomerular filtration rate calculation. Kidney functional impairment was defined as an estimated glomerular filtration rate <90 mL/min per 1.73 m2 , according to the Kidney Disease Improving Global Outcomes criteria. Multivariable logistic regression analysis was used to (1) assess the association between kidney function impairment and infertility status and (2) investigate the association between kidney function and semen analysis abnormalities in infertile men. RESULTS: After matching, 34 (8.8%) infertile men depicted at least a mild unknown impairment of kidney function compared to only four (3%) fertile men, with four (3%) of the infertile presenting with an overt kidney function impairment (estimated glomerular filtration rate <60 mL/min per 1.73 m2 ). There were no differences in terms of age, body mass index and rate of comorbidities between the two groups (all p > 0.05). After adjusting for major confounders, infertility status was associated with a higher risk of reduced estimated glomerular filtration rate (odds ratio 3.20; 95% confidence interval 1.21-5.2; p = 0.002). Conversely, estimated glomerular filtration rate was not associated with sperm abnormalities in infertile men. CONCLUSIONS: Mild kidney function impairment was found in 9% of asymptomatic and unaware men presenting for primary couple's infertility investigation. This novel finding corroborates growing data on a significant association of male infertility with a poorer overall male health status and the need for tailored preventive strategies.

Clinical parameters associated with altered sperm DNA fragmentation index among primary infertile men: Findings from a real-life cross-sectional study.

BACKGROUND: Recurrent pregnancy loss and unexplained infertility are the current indications to test sperm DNA fragmentation according to the European Association of Urology Guidelines on sexual and reproductive health. OBJECTIVE: To identify a novel and better performing model to diagnose primary infertile men presenting with altered sperm DNA fragmentation and to outline its predictive ability in respect to current European Association of Urology Guidelines' recommendations. MATERIALS AND METHODS: Data from the latest 515 consecutive primary infertile men as for World Health Organization criteria were analyzed. Semen analysis, sperm DNA fragmentation (according to sperm chromatin structure assay), and serum hormones were considered in every patient. Altered sperm DNA fragmentation was defined with levels greater than 30%. Descriptive statistics was applied to compare patients with normal versus SDF > 30%. The new predicting model was identified through logistic regression analysis exploring potential predictors of SDF > 30% at first clinical presentation. Diagnostic accuracy between the two predictive models (European Association of Urology Guidelines vs. new) was assessed, and decision curve analyses tested their clinical benefit. RESULTS: Of 515, 268 (51.9%) patients had SDF > 30% at clinical presentation. Patients with SDF > 30% were older (median [interquartile range] 39 [35-43] vs. 37 [34-41] years), had lower mean testicular volume (Prader 15 [12-20] vs. 17.5 [13.5-20] and lower total motile sperm count (1.80 [0.7-13.2] vs. 11.82 [4.2-44.5] × 106 ), all p < 0.001. No other clinical differences were depicted. The two groups showed similar rates of history of recurrent pregnancy loss and unexplained infertility. At multivariable logistic regression analysis, age more than 38 years (odds ratio: 2.43) and baseline total motile sperm count less than 20 × 106 (odds ratio: 3.72) were associated with SDF > 30%, after adjusting for Prader < 15, history of miscarriages and unexplained infertility, all p < 0.0001. The newly identified model (unexplained infertility + history of poli-abortions + Prader < 15 + age ≥38 years + total motile sperm count <20 × 106 ) showed higher accuracy to identify SDF > 30% at baseline in respect to European Association of Urology Guidelines (area under the curve: 72.1 vs. 52.7), with superior clinical net benefit use. CONCLUSIONS: The application of the European Association of Urology sexual and reproductive health guidelines does not ensure proper identification of primary infertile men with pathological sperm DNA fragmentation. We propose a novel and better performing predictive model to identify the infertile men with altered sperm DNA fragmentation at first clinical assessment. DISCUSSION: As altered sperm DNA fragmentation has been widely linked with the inability to conceive, this second-level test could be further implemented over the diagnostic workup of a broader subset of patients presenting for male factor infertility. We propose a better performing model to identify this specific category of patients.

The symptomatic burden of Peyronie's disease at presentation according to patient age: A critical analysis of the Peyronie's disease questionnaire (PDQ) domains.

BACKGROUND: Peyronie's disease (PD) has a huge impact on patients' physical and psychological wellbeing. OBJECTIVES: To investigate whether patients' age has an impact on PD symptomatic burden at first presentation. MATERIALS AND METHODS: Data from 129 consecutive heterosexual patients seeking first medical attention for PD at a single andrological tertiary-referral centre were collected. All patients completed the International Index for Erectile Function (IIEF) and the PD questionnaire (PDQ). Descriptive statistics were used to compare clinical features between younger (≤40years) and older (>40 years) patients. Multivariable linear model assessed the impact of age, the degree of penile curvature and their impact on PDQ (total scores and its domains), after adjusting for PD duration and IIEF-erectile function domain scores. RESULTS: Of 129, 24 (18.6%) patients were ≤40 years old. Young patients presented with a less severe curvature than older patients (median [interquartile ranges] 20° [15-36] vs. 50° [40-80]; p = 0.04). However, younger age was associated with higher psychological and physical symptoms, PDQ-penile pain and PDQ-symptom bother scores (Coeff -0.11, -0.21 and -0.17, respectively) (all p < 0.05). Moreover, the greater the degree of curvature, the higher the PDQ-psychological and physical symptoms and the PDQ-symptom bother scores (Coeff. 0.21 and 0.22, respectively; all p < 0.05). CONCLUSION: Around one in five men seeking first medical help for PD is younger than 40 years at presentation in the real-life setting. PD-related distress varies according to patients' age, with younger men presenting with a greater risk of penile pain and symptom bother despite lower curvature.

Haemospermia in the Real- Life Setting: A New High-Risk Stratification.

OBJECTIVE: To (i) identify a novel risk stratification for patients complaining of haemospermia; and, (ii) compare its predictive ability to select high-risk patients by retrospectively validating the EAU guidelines classification. METHODS: Data from 283 consecutive patients complaining of a single episode/recurrent haemospermia were retrospectively analyzed. Patients were stratified into low vs high-risk according to EAU guidelines, whose diagnostic performance was then validated. We identified a new risk stratification model based on clinical factors associated with (i) positive semen culture and (ii) prostate cancer (PCa) and bladder cancer (BC). Diagnostic accuracy of the two predictive models (EAU vs New) was assessed and decision curve analyses (DCA) tested their clinical benefit. RESULTS: Overall, 259 (91.5%) were high-risk and 24 (8.5%) low risk according to the EAU guidelines. Recurrent haemospermia was reported by 134 (47.4%) patients. 126 (44.5%) had baseline CCI score ≥ 1. At MVA logistic regression analysis, history of recurrent genito - urinary tract infections was identified as a predictor for positive semen culture (OR: 3.39, 95% CI: 1.77 - 6.57, P =.002). Likewise, baseline CCI ≥ 1 was identified as a predictor for PCa and BC (OR: 1.55, 95% CI: 1.17 - 2.04, P =.009). Sensitivity, specificity, and AUC of the EAU guidelines were 13.3%, 89.2% and 51% respectively, whereas the new model performed substantially better: 98.9%, 58% and 78% respectively. CONCLUSION: The application of the EAU guidelines risk stratification does not ensure proper identification of high-risk patients complaining of haemospermia. We propose a novel, better performing and easily implementable risk stratification tool.

"Stromal cells in prostate cancer pathobiology: friends or foes?"

The genomic, epigenetic and metabolic determinants of prostate cancer pathobiology have been extensively studied in epithelial cancer cells. However, malignant cells constantly interact with the surrounding environment-the so-called tumour microenvironment (TME)-which may influence tumour cells to proliferate and invade or to starve and die. In that regard, stromal cells-including fibroblasts, smooth muscle cells and vasculature-associated cells-constitute an essential fraction of the prostate cancer TME. However, they have been largely overlooked compared to other cell types (i.e. immune cells). Indeed, their importance in prostate physiology starts at organogenesis, as the soon-to-be prostate stroma determines embryonal epithelial cells to commit toward prostatic differentiation. Later in life, the appearance of a reactive stroma is linked to the malignant transformation of epithelial cells and cancer progression. In this Review, we discuss the main mesenchymal cell populations of the prostate stroma, highlighting their dynamic role in the transition of the healthy prostate epithelium to cancer. A thorough understanding of those populations, their phenotypes and their transcriptional programs may improve our understanding of prostate cancer pathobiology and may help to exploit prostate stroma as a biomarker of patient stratification and as a therapeutic target.

Does Air Pollution Impact on Semen Parameters? Findings from a Real-Life, Cross-Sectional Study in Italian Infertile Men.

PURPOSE: In industrialized countries, air pollutants levels have been monitored closely for environmental and research issues. Using Italian data, we aimed to investigate the association between air pollutants levels and semen parameters in a cohort of non-Finnish white-European men presenting for couple's infertility. MATERIALS AND METHODS: Complete demographic and laboratory data from 1,152 infertile men consecutively assessed between January 2015 and January 2018 were analyzed. Semen analyses were based on the 2010 World Health Organization reference criteria. Health-significant comorbidities were scored with the Charlson Comorbidity Index (CCI). We analyzed the annual average level of the three main markers of air pollution (Pm10, Pm2.5, and NO2) between 2014 and 2018. Descriptive statistics, linear and logistic regression analyses tested the association between air pollutants levels and semen parameters. RESULTS: Of 1,152 men, 87 (7.55%) had normal sperm parameters at first semen analysis. Of 1,065 patients with abnormal semen analyses, 237 (22.25%), 324 (30.42%), and 287 (26.95%) patients presented 1, 2 or 3 abnormalities, respectively, and 217 (20.38%) were azoospermic. At linear regression analysis, Pm10, Pm2.5, and NO2 were negatively associated with sperm morphology (Pm10: ß=-0.5288 µg/m3, p=0.001; Pm2.5: ß=-0.5240 µg/m3, p=0.019; NO2: ß=-0.4396 µg/m3, p<0.0001). Furthermore, the adjusted odds of normal sperm morphology <4% were 1.06 (95% confidence interval [CI], 1.03-1.09; p=0.007) for Pm10, 1.07 (95% CI, 1.03-1.11; p=0.007) for Pm 2.5, and 1.03 (95% CI, 1.02-1.05; p=0.001) for NO2, respectively. CONCLUSIONS: In a large homogenous cohort of infertile men, Pm10, Pm 2.5, and NO2 levels were negatively associated with sperm morphology. Conversely, no clear association was observed with other macroscopic sperm parameters.

High serum alpha-fetoprotein levels in primary infertile men.

BACKGROUND: Alfa-fetoprotein (AFP) is a serum glycoprotein highly produced during fetal development. While AFP synthesis drops dramatically after birth, AFP production only persists or returns under specific pathological condition. OBJECTIVE: We sought to investigate the rate of and the potential meaning of high AFP serum levels in men seeking first medical attention for couple's primary infertility. MATERIALS AND METHODS: Socio-demographic and clinical data from 1803 non-Finnish, White-European primary infertile men were retrospectively analysed. AFP was routinely measured in each patient (high AFP was defined as >7 ng/ml). Men with history of liver diseases, testicular cancer, or other known causes of increased AFP levels were excluded from the final analysis. Semen analyses were based on the 2010 World Health Organization reference criteria. Descriptive statistics and logistic regression models tested the association between serum AFP and clinical variables. Possible nonlinear relationships were graphically explored with locally estimated scatterplot smoothing method. RESULTS: Overall, high serum AFP level was found in 29 (1.7%) patients. Normal versus high AFP levels patients were comparable in terms of body mass index (BMI), Charlson Comorbidity Index, waist circumference, smoking habits, history of cryptorchidism, testicular volume, and serum hormones (i.e., follicle-stimulating hormone, luteinizing hormone, and total testosterone). Conversely, men with higher AFP levels were older (p = 0.02), had lower sperm concentration (p = 0.003), and were more frequently oligozoospermic and azoospermic (all p ≤ 0.03). At multivariate analysis, high AFP levels were independently associated with oligozoospermia (OR 3.79; p = 0.033) and azoospermia (OR 3.29; p = 0.006). Likewise, if AFP levels increase, patients were found to be older, with higher BMI and to have more comorbidities (all p < 0.05). DISCUSSION: Unexplained high AFP levels account for almost 2% of cases in primary infertile patients without a previous history of associated disorders. Higher serum AFP levels are linked with aberrant sperm counts, older age, obesity, and a greater amount of comorbid conditions. CONCLUSION: Despite the need for additional validation, these data suggest that serum AFP measurement might have a multifaceted role over the diagnostic work-up of males presenting for couple's infertility.

Circulating Cell-Free DNA in Renal Cell Carcinoma: The New Era of Precision Medicine.

Tumor biopsy is still the gold standard for diagnosing and prognosis renal cell carcinoma (RCC). However, its invasiveness, costs, and inability to accurately picture tumor heterogeneity represent major limitations to this procedure. Analysis of circulating cell-free DNA (cfDNA) is a non-invasive cost-effective technique that has the potential to ease cancer detection and prognosis. In particular, a growing body of evidence suggests that cfDNA could be a complementary tool to identify and prognosticate RCC while providing contemporary mutational profiling of the tumor. Further, recent research highlighted the role of cfDNA methylation profiling as a novel method for cancer detection and tissue-origin identification. This review synthesizes current knowledge on the diagnostic, prognostic, and predictive applications of cfDNA in RCC, with a specific focus on the potential role of cell-free methylated DNA (cfMeDNA).

Effects of recreational cannabis on testicular function in primary infertile men.

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.

The impact of different WHO reference criteria for semen analysis in clinical practice: Who will benefit from the new 2021 thresholds for normal semen parameters?

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.