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The standard FSH treatment is based on a 3 months period, after which both quantitative/qualitative improvement of sperm parameters and increased pregnancy rate were reported. In this prospective clinical trial, for the first time, we studied (i) Sperm hyaluronic acid binding capacity after highly purified FSH (hpFSH) treatment; (ii) the effect after short-term and standard treatment on this functional parameter. As secondary objective, we analyzed three SNPs on FSHβ and FSHR genes to define their potential predictive value for responsiveness. From a total of 210 consecutive patients, 40 oligo- and/or astheno- and/or teratozoospermic patients fulfilled the inclusion criteria. Treatment consisted in hpFSH 75 IU/L every other day for 3 months. To avoid potential biases derived from the lack of placebo, we analyzed each patient after 4-6 months of 'wash-out' period. After FSH treatment, we observed a statistically significant (p < 0.001) improvement of the percentage of hyaluronic acid bound spermatozoa from basal to T1 (after 1 month) and to T3 (after 3 months). Importantly, these values returned to near-baseline value after the wash-out. The same results were detected for total motile sperm count after 3 months with return to baseline after wash-out. Forty-two percent of patients responded to the therapy with increasing hyaluronic acid binding capacity above the double of the Intraindividual Variation (IV) while 24% of patients reached above the normal Sperm-Hyaluronan Binding Assay (HBA) value. Further increase in 'responders' was observed at T3. The responsiveness to treatment resulted independent from FSHR/FSHβ polymorphisms. The significant positive effect on sperm maturity after 1 month opens novel therapeutic perspectives. In view of both the high cost and the relative invasiveness of treatment, the short protocol (1 month) could represent a viable FSH treatment option prior Assisted Reproductive Techniques since FSH, by acting on sperm maturation, increases the proportion of functionally competent cells., (© 2017 American Society of Andrology and European Academy of Andrology.)

Study Question: Is sexual dysfunction associated with severity of semen quality impairment in men with couple infertility?, Summary Answer: In males of infertile couples the prevalence of erectile dysfunction (ED) increases as a function of semen quality impairment severity., What Is Known Already: Infertile men are at a higher risk for sexual dysfunction, psychopathological and general health disorders. However, it has never been systematically investigated if these problems are associated with severity of semen quality impairment., Study Design, Size, Duration: Cross-sectional analysis of a first-time evaluation of 448 males of infertile couples attending an outpatient clinic from September 2010 to November 2015. In addition, 74 age-matched healthy, fertile men from an ultrasound study on male fertility were studied for comparison., Participants/materials, Setting, Methods: All subjects underwent a complete physical, biochemical, scrotal and flaccid penile colour-Doppler ultrasound evaluation and semen analysis. Patients had already undergone at least one semen analysis; therefore, the majority were aware of their sperm quality before taking part in the study. Validated tools, such as the International Index of Sexual Function-15 (IIEF-15), Premature Ejaculation Diagnostic Tool (PEDT), Middlesex Hospital Questionnaire (MHQ), National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI), International Prostate Symptom Score and Chronic Disease Score (CDS), were used to evaluate, respectively, sexual dysfunction, premature ejaculation (PE), psychopathological traits, prostatitis-like symptoms, lower urinary tract symptoms and general health status., Main Results and the Role of Chance: Among men with couple infertility, 96 showed azoospermia (Group #1), 245 at least one sperm abnormality (Group #2) and 107 normozoospermia (Group #3). Fertile men were considered as a control group (Group #4). After adjusting for age, we observed a higher prevalence of ED (IIEF-15-erectile function domain score <26) (18.3% versus 0%; P = 0.006) and PE (PEDT score >8) (12.9% versus 4.1%; P = 0.036) in males of infertile couples compared with fertile men. The ED prevalence increases as a function of semen quality impairment severity (P < 0.0001), even after adjusting for confounders (age, CDS, MHQ and NIH-CPSI total score), despite similar hormonal, glyco-metabolic and penile vascular status. Compared to fertile men, all three groups of males with couple infertility showed a poorer erectile function, associated with an overall psychopathological burden (MHQ total score), particularly with somatized anxiety (MHQ-S). Azoospermic men showed the worst erectile function and general health: in this group, erectile function was negatively associated not only with psychopathological disturbances (MHQ total and MHQ-S scores; P < 0.0001) but also with a less healthy phenotype (higher CDS; P = 0.015). In addition, azoospermic men reported higher PE prevalence and lower sexual desire and orgasmic function when compared to fertile men (all P < 0.05), all of which were related to psychopathological symptoms., Limitations, Reasons for Caution: The cross-sectional nature of the study represents its main limitation. A possible selection bias concerning the control group of healthy, fertile men recruited into an ultrasound study might have occurred. Finally, causality cannot be inferred in this type of study design and hence there should be some caution in interpreting the results., Wider Implications of the Findings: Investigation of male sexual function, general health and psychological status in infertile couples, especially if azoospermic, is advisable, in order to improve not only reproductive but also general and sexual health., Study Funding/competing Interests: Grants were received from the Ministry of University and Scientific Research (SIR project to F.L., protocol number: RBSI14LFMQ). There are no conflicts of interest., Trial Registration Number: None., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The aim of this study was to provide a comprehensive genetic/phenotypic characterization of subjects suffering infertility owing to sperm macrocephaly (n = 3) or globozoospermia (n = 9) and to investigate whether the patients' genetic status was correlated with the alteration of various sperm parameters. AURKC was sequenced in case of sperm macrocephaly while the DPY19L2 status has been analyzed by multiple approaches including a novel qPCR-based copy number assay in case of globozoospermia. Globozoospermic patients were also analyzed for SPACA1, a novel candidate gene herein tested for the first time in humans. The effect of the patients' genetic status was interrogated by implementing the molecular screening with the characterization of several sperm parameters: (i) routine sperm analysis, integrated with transmission electron microscopy; (ii) sperm fluorescent in situ hybridization (FISH) analysis; (iii) sperm DNA fragmentation (DF) analysis. Moreover, for the first time, we performed microsatellite instability analysis as a marker of genome instability in men with sperm macrocephaly and globozoospermia. Finally, artificial reproductive technology (ART) history has been reported for those patients who underwent the treatment. Macrocephalic patients had an AURKC mutation and >89% tetraploid, highly fragmented spermatozoa. DPY19L2 was mutated in all patients with >80% globozoospermia: the two homozygous deleted men and the compound heterozygous showed the severest phenotype (90-100%). The newly developed qPCR method was fully validated and has the potential of detecting also yet undiscovered deletions. DPY19L2 status is unlikely related to FISH anomalies and DF, although globozoospermic men showed a higher disomy rate and DF compared with internal reference values. No patient was mutated for SPACA1. Our data support the general agreement on the negative correlation between macro/globozoospermia and conventional intracytoplasmic sperm injection outcomes. Microsatellites were stable in all patients analyzed. The comprehensive picture provided on these severe phenotypes causing infertility is of relevance in the management of patients undergoing ART., (© 2015 American Society of andrology and European Academy of andrology.)

Study Question: What is the impact of smoking behaviour on seminal, hormonal and male genital tract ultrasound parameters in subjects seeking medical care for couple infertility?, Study Answer: In males of infertile couples, current smokers (CS), when compared with non-smokers, show lower ejaculate and ultrasound-derived seminal vesicles (SV) volume, despite higher testosterone levels., What Is Known Already: Data on the effects of smoking on male fertility are conflicting. A correlation between smoking and reduced semen parameters has been reported, however, with a high heterogeneity among studies. An association between smoking behaviour and higher testosterone levels in men has been described in several, but not all, the previous studies. No study has systematically evaluated the impact of smoking on the male genital tract ultrasound characteristics., Study Design, Size and Duration: Retrospective cross-sectional analysis of a consecutive series of 426 subjects seeking medical care for couple infertility from January 2010 to July 2013., Participants/materials, Setting, Methods: From the entire cohort, 394 men (age 36.0 ± 8.0 years) free of genetic abnormalities were selected. All subjects underwent a complete andrological and physical examination, biochemical and hormonal assessment, scrotal and transrectal colour-Doppler ultrasound and semen analysis (including seminal interleukin-8 levels, sIL-8) within the same day., Main Results and the Role of Chance: Among the patients evaluated, 229 were never smokers (NS), 56 past smokers (PS) and 109 CS. When CS were compared with the rest of the sample (non-smokers, NS + PS), in a multivariate model (analysis of covariance, ANCOVA) adjusted for age, lifestyle (including alcohol, cannabis and physical activity), BMI and sex hormone-binding globulin, significantly higher androgen (total testosterone, P = 0.001; calculated free testosterone, P < 0.005) and lower FSH (P < 0.05) levels were observed in CS. However, when total testosterone was also included in the multivariate model as a further covariate, the difference in FSH levels was not confirmed. In a similar model, a lower ejaculate volume (P < 0.01) and a higher prevalence of normal sperm morphology (P < 0.02) were also detected in CS in comparison with the rest of the sample. However, when total testosterone was also included in the multivariate model as a further covariate, only the difference in ejaculate volume between CS and non-smokers was confirmed (-0.61 ± 0.23 ml, P < 0.01). Finally, CS showed lower total SV volume, before and after ejaculation, even after adjusting for confounders (P = 0.02 and <0.01, respectively). Similar results were observed when the reported number of cigarettes smoked or the number of pack-years was considered separately., Limitations, Reasons for Caution: The present results are derived from patients consulting an Andrology Clinic for couple infertility, who could have different characteristics from the general male population or males consulting general practitioners for reasons other than couple infertility. In addition, we did not have a true control group composed of age-matched, apparently healthy, fertile men, and therefore true normative data of sonographic parameters cannot be inferred. Due to the cross-sectional nature of our study, neither a causality hypothesis nor mechanistic models can be drawn. Finally, this is a retrospective study, and further prospective studies are required., Wider Implications of the Findings: We report an apparent paradox in CS: lower SV volume despite higher testosterone levels. Our data suggest that smoking may negatively affect SV volume in an independent manner, as the difference between CS and non-smokers retained significance after adjusting for confounders including testosterone. This is the first study reporting such ultrasound evidence. How this new smoking-related alteration, along with low semen volume, impacts male fertility needs to be addressed by further studies., Study Funding/competing Interests: No funding was received for the study. None of the authors have any conflict of interest to declare., (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Study Question: What are the associations between semen apoptotic M540 bodies and other parameters of semen quality and sonographic alterations of the male genital tract in a cohort of infertile subjects?, Summary Answer: In infertile subjects, semen M450 bodies are highly correlated with ultrasound and clinical signs of testis abnormalities but not with alterations of other parts of the male genital tract, suggesting a testicular origin of M540 bodies., What Is Known Already: We have reported the presence in semen of round anucleate elements, named 'M540 bodies', resembling apoptotic bodies as they contain several apoptotic markers., Study Design and Size: A consecutive series of 130 males with couple infertility were evaluated, during the same day session, for clinical, scrotal and transrectal color-Doppler ultrasound characteristics, and hormonal and semen parameters, including interleukin 8 (sIL-8) and M540 body levels., Participants/materials, Setting Methods: Semen parameters were analyzed by WHO recommended procedures. CDU was performed using the ultrasonographic console Hitachi H21. sIL-8 and serum hormones were evaluated by ELISA methods., Main Results and the Role of Chance: The average percentage value of M540 bodies was 24.6 ± 18.3. After adjusting for possible confounders (age, waist, calculated free testosterone and smoking habit), M450 body levels negatively correlated with sperm number/ejaculate, progressive motility, normal morphology and sIL-8 levels (adj.r = -0.455, P < 0.0001; adj.r = -0.464, P < 0.0001; adj.r = -0.430, P < 0.001; adj.r = -0.236, P < 0.05, respectively). In a subset of patients with a history of cryptorchidism (n = 8), M540 bodies were higher than in non-cryptorchid men (40.5 ± 14.8 versus 23.6 ± 18.2%; P < 0.02). A negative correlation was found between M540 and ultrasound testis volume (adj.r = -0.241, P < 0.05), whereas a positive association was found with testis inhomogeneity [HR = 1.06 (1.02-1.09); P = 0.002], hypoechogenicity [HR = 1.05 (1.01-1.08); P < 0.02] and FSH levels (adj.r = 0.309, P < 0.01). No relationships were found with CDU characteristic of the prostate, seminal vesicles, epididymis and vas deferens. In a multivariate model, testis inhomogeneity and history of cryptorchidism were independently associated with M540 body levels (adj.r = 0.355, P < 0.01 and adj.r = 0.223, P < 0.05, respectively). Receiver operating characteristic analysis demonstrated that at the threshold of 27%, M540 bodies discriminate subjects with testis inhomogeneity with a sensitivity of 72% and specificity of 73%., Limitations, Reasons for Caution: The increased M540 body semen levels in men with a history of cryptorchidism should be confirmed in a larger number of patients., Wider Implications of the Findings: M540 bodies may be considered a semen marker of altered testis function and thus their evaluation may be helpful in the diagnosis of male infertility., Study Funding/competing Interest(s): This work was supported by grants from Ministry of University and Scientific Research (Prin project to E.B. and FIRB project to S.M.) and Regione Toscana (to G.F.).