Purpose: The current randomized, double-blind, placebo-controlled clinical trial addressed the effects on penile erectile function of relatively high daily oral doses (6 g/day) of l-ARG for 3 months (N = 51) compared to placebo (N = 47), in patients with vasculogenic ED, with comparison between mild–moderate and severe vasculogenic ED. Methods: The outcome measures included IIEF-6 score and cavernous arteries peak systolic flow velocity (PSV) at dynamic penile duplex ultrasonography (PDU). Results: l-ARG supplementation for 3 months significantly increased IIEF-6 score in the overall cohort (p < 0.0001) and in subgroups of patients with mild–moderate (p < 0.0001) and severe (p = 0.007) vasculogenic ED; PSV was significantly increased in the overall cohort (p < 0.0001) and in patients with mild–moderate (p < 0.0001), but not severe vasculogenic ED. At study completion, 74% of patients improved ED degree category, although only 24% of patients, mainly belonging to the baseline category of mild ED, reached IIEF-6 scores compatible with absence of ED; moreover, 20% of patients, exclusively belonging to the baseline category of mild–moderate vasculogenic ED, reached PSV values compatible with absence of ED. Conclusion: The results of the current study demonstrated that supplementation with relatively high doses of l-ARG as a single compound for 3 months significantly improved penile erectile function, assessed by both IIEF-6 score and PSV at dynamic PDU in patients with mild–moderate, and improved IIEF-6 score, but not PSV, in patients with severe vasculogenic ED, therefore suggesting that l-ARG might be an alternative treatment in mild–moderate vasculogenic ED patients experiencing adverse effects or with contraindications for chronic treatment with PDE5i compounds.

The Disorders of Sex Development (DSDs) are congenital conditions characterized by inconsistency among chromosomal, gonadal, and anatomical sex development. The aim of this research is to report the clinical and cytogenetic findings of four DSD cases and 13 couples of heterosexual twins in sheep. To this purpose, C- and R-banding techniques were used, and the analyses of the SRY (Sex Determining Region Y) and AMEL (Amelogenin) genes were carried out. Moreover, morphopathological analyses were performed in one case. The four DSD sheep cases were registered as females at birth, and for none of them it was possible to establish whether the subjects were born from heterosexual multiple births. Three of the four cases were diagnosed as XX/XY blood lymphocyte chimaeras, while the fourth case was diagnosed as a 54, XY SRY-positive DSD sheep. None of the heterosexual twins showed XX/XY blood chimaerism. This finding suggests that the blood chimaeric cases detected could also be due to a zygote/embryo fusion. Moreover, no gene variants involved in sheep DSD are known, the identification of which would be very useful for the sheep industry.

Cadmium is a known human carcinogen, and has been shown to profoundly affect male reproductive function, at multiple levels, by exerting both endocrine and non-endocrine actions. Nevertheless, the potential role of cadmium in the etiology of testis cancer has been scantly investigated in humans, and, currently, available epidemiological observational studies are insufficient to draw definitive conclusions in this regard. On the contrary, experimental studies in laboratory animals demonstrated that cadmium is a strong inducer of testis tumors, mostly represented by benign Leydig cell adenoma; moreover, malignant transformation was also reported in few animals, following cadmium treatment. Early experimental studies in animals proposed an endocrine-dependent mechanism of cadmium-induced testis tumorigenesis; however, more recent findings from cell-free assays, in vitro studies, and short-term in vivo studies, highlighted that cadmium might also contribute to testis tumor development by early occurring endocrine-independent mechanisms, which include aberrant gene expression within the testis, and genotoxic effects, and take place well before the timing of testis tumorigenesis. These endocrine-independent mechanisms, however, have not been directly investigated on testis tumor samples retrieved from affected, cadmium-treated animals so far. The present review focuses on the relationship between cadmium exposure and testis cancer, by reporting the few epidemiological observational human studies available, and by providing animal-based experimental evidences of cadmium implication in the pathogenesis and progression of testis tumor. Moreover, the relevance of experimental animal studies to human cadmium exposure and the translational potential of experimental findings will be extensively discussed, by critically addressing strengths and weaknesses of available data.

Background/Objectives: The “Land of Fires” (LF) in the Campania Region has attracted considerable attention due to massive environmental contamination deriving from decades of illegal disposal, burial, and burning of urban, industrial, and toxic waste. Cadmium (Cd) has been repeatedly proven to affect male reproductive function by a plethora of endocrine and non-endocrine mechanisms. The scientific literature is almost devoid of large studies addressing semen quality in this area, particularly by directly correlating seminal parameters to objectively measured pollutant burden in biological samples. Therefore, the aim of the current study was to comprehensively evaluate semen quality of males of reproductive age living in the LF, by correlating seminal parameters to cumulative local male reproductive tract Cd burden objectively quantified in whole semen samples. Methods: The current single-center, observational, cross-sectional study evaluated semen quality in 493 males aged 14–50 (29.07 ± 7.17) years living in three LF municipalities. Moreover, the association of semen quality with whole semen Cd (sCd) levels measured by inductively coupled plasma mass spectrometry (ICP-MS) was addressed in a subgroup of participants; semen samples suitable for semen Cd measurements were available from 383/493 (77.7%) participants of the total cohort, and all analyses involving semen Cd were performed within the measured subset. Results: In the total cohort, seminal parameters were as follows: semen pH 8.32 ± 0.3, semen volume 3.13 ± 1.67 mL, sperm concentration 37.58 ± 30.18 × 10⁶/mL, total count 111.2 ± 104 × 10⁶/ejaculate, total motility 56.83 ± 16.09%, progressive motility 50.22 ± 16.63%, in situ motility 6.72 ± 3.43%, immotile spermatozoa 43.07 ± 15.88%, normal morphology 7.97 ± 4.02%, and viability 64.75 ± 15.34%. Prevalence of normozoospermia and pathological seminal parameters was as follows: normozoospermia 66.5% (328/493), pathological seminal parameters 33.5% (165/493), specifically, oligozoospermia 14% (69/493), cryptozoospermia 0.8% (4/493), azoospermia 2.2% (11/493), asthenozoospermia 3% (15/493), teratozoospermia 0.6% (3/493), oligo-astheno-teratozoospermia 6.1% (30/493), necrozoospermia 5.7% (28/493), and different combined seminal parameters alterations 7.1% (35/493). Whole semen Cd was below (undetectable) or above (detectable) the limit of detection (LoD) (0.2 μg/L) in 66.6% (255/383) and 33.4% (128/383) whole semen samples, respectively. In samples with detectable sCd, sCd level was below or above the median value (0.76 μg/L; min–max 0.1–5.95 μg/L) in 23.4% (30/128) and 76.6% (98/128) whole semen samples, respectively. Participants with detectable sCd levels had a significantly reduced sperm total count (93.28 ± 84.88 × 10⁶/ejaculate vs. 113.2 ± 101.5 × 10⁶/ejaculate; p = 0.037), and normal morphology (7.29 ± 3.71% vs. 8.23 ± 3.91%; p = 0.034), and a significantly lower prevalence of normozoospermia (60.2% vs. 72.2%; p = 0.02) and significantly higher prevalence of pathological seminal parameters (39.8% vs. 27.8%; p = 0.02), specifically, a significantly higher prevalence of oligozoospermia (21.1% vs. 12.6%; p = 0.036) than those with undetectable sCd levels. Whole semen Cd levels were significantly higher in participants with pathological seminal parameters (1.08 ± 0.84 μg/L vs. 0.93 ± 0.74 μg/L; p = 0.037) than those with normozoospermia. Participants with sCd levels above the median value (N = 98) had a significantly reduced sperm concentration (29.12 ± 24.84 × 10⁶/mL vs. 43.62 ± 29.55 × 10⁶/mL; p = 0.015) and displayed a trend towards reduced sperm normal morphology (6.92 ± 3.38% vs. 8.55 ± 4.49%; p = 0.057) than those with sCd levels below the median value (N = 30). Moreover, participants with sCd levels above the median value (N = 98) had a significantly reduced sperm concentration (29.12 ± 24.84 × 10⁶/mL vs. 35.3 ± 26.29 × 10⁶/mL; p = 0.03), total count (85.77 ± 80.52 × 10⁶/ejaculate vs. 113.2 ± 101.5 × 10⁶/ejaculate; p = 0.008) and normal morphology (6.92 ± 3.38% vs. 8.23 ± 3.91%; p = 0.006), and a significantly lower prevalence of normozoospermia (57.1% vs. 72.2%; p = 0.008) and significantly higher prevalence of pathological seminal (42.9% vs. 27.8%; p = 0.008), specifically, a significantly higher prevalence of oligozoospermia (23.5% vs. 12.6%; p = 0.014) than those with undetectable sCd levels. Conclusions: The results of the current study demonstrate an association between the environmental Cd exposure and the impairment of seminal parameters, with a significantly poorer semen quality in participants with detectable sCd, and, more markedly, in those with sCd level above the median value, compared to participants with undetectable sCd, although subgroups comparisons highlighted a homogeneous profile in major confounders including age, BMI, and smoking habits among subgroups of participants with different sCd burden.

Dopamine has been found in both semen and oviductal fluid and dopamine receptors (DRs) have been detected in male genital tract and spermatozoa, suggesting that dopamine system may control important reproductive functions in humans. Dopamine improves sperm motility and viability in animal models, although the underlying molecular mechanisms have not been fully elucidated. The aims of this study were to investigate DRs expression in human spermatozoa and to evaluate the in vitro effects of DRs agonists and antagonists on human sperm motility, kinetics and viability. DRs expression was assessed by immunofluorescence and western blot in spermatozoa from healthy volunteers and the effects of D2DR-like agonist cabergoline, D2DR-selective antagonist L-sulpiride, D4DR-selective agonist PD168,077 and D4DR-selective antagonist U-101958 on sperm motility, kinetics and viability were tested after 1 hour of treatment with serial doses of compounds. Sperm motility and kinetics were analyzed by Sperm Class Analyzer [SCA] 5.0, sperm viability was assessed by Vital Stain Dye. D2DR and D4DR are both expressed in human spermatozoa. Cabergoline significantly increased rapid progressive motile spermatozoa (RPMS) and decreased non motile spermatozoa (NMS). L-sulpiride showed opposite, although not significant, effects on sperm motility. PD168,077 and U-101958 did not significantly change sperm motility. Moreover, L-sulpiride significantly decreased curvilinear velocity (VCL) and increased wobble (WOB). All tested compounds did not affect sperm viability. Both cabergoline and PD168,077 induced Akt phosphorylation, compared to untreated spermatozoa. The results of the current study demonstrated that dopamine pathway may be involved in the modulation of human sperm motility and kinetic parameters, without affecting sperm viability, and that Akt could be regarded as a putative mediator; however, further experiments are being performed to identify the molecular mechanisms driving these effects.

Purpose: The current single-center, retrospective, observational cohort study with a cross-sectional design was conducted to evaluate the association between androgenic profile and metabolic cardiovascular risk (mCVR) factors and to explore whether testosterone deficiency was associated with an unfavourable cardiometabolic profile in a large community-recruited cohort of 659 young men aged 18–35 years. Methods: Participants underwent comprehensive assessment of anthropometric, biochemical, clinical, and hormonal parameters. Results: Body mass index (BMI), expression of generalized obesity, waist circumference (WC), expression of abdominal/visceral obesity, diastolic blood pressure (DBP) and triglycerides (TG) significantly and progressively decreased and high-density lipoprotein (HDL)-cholesterol significantly increased across total testosterone (TT) tertiles. Similarly, weight, BMI, WC, systolic blood pressure (SBP), DBP and TG significantly decreased and HDL-cholesterol significantly increased across SHBG tertiles. Weight and adiposity-related anthropometric parameters, namely BMI and WC, significantly and progressively decreased across calculated free testosterone (cFT) tertiles. Spearman correlation analysis showed that TT and SHBG were significantly and negatively correlated with weight ( r =-0.149, r =-0.154), BMI ( r =-0.204, r =-0.165), WC ( r =-0.234, r =-0.225), SBP ( r =-0.112, r =-0.142) and TG ( r =-0.117, r =-0.204), and significantly and positively correlated with HDL-cholesterol ( r = 0.167, r = 0.251). Additionally, SHBG was significantly and negatively correlated with DBP ( r =-0.173). cFT was significantly and negatively correlated with age ( r =-0.108) and BMI ( r =-0.132). In a multiple linear regression analysis in models adjusted for age, BMI and WC, TT and SHBG were independently associated with HDL-cholesterol (β = 0.151, β = 0.186), and SHBG was independently associated with SBP (β=-0.177) and DBP (β=-0.204). Men with testosterone below the normal range (Hypo-T group) showed a significantly higher prevalence of generalized obesity and abdominal obesity than men with testosterone within the normal range (Normal-T group). Conversely, Overweight/Obese men exhibited significantly lower TT and a significantly higher prevalence of testosterone deficiency than Normal-Weight men. Conclusion: In young adult men, androgenic profile was found to be robustly associated with mCVR factors; however, causality and temporal directionality cannot be inferred because of the cross-sectional design of the study.