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BACKGROUND. Several studies have already investigated the relationship between IGF1 and semen parameters. However, clinical studies rarely concluded on the existence of a relationship between IGF1 and the sperm number, and whether the IGF1 serum levels have a practical value in the diagnostic work-up of patients with oligozoospermia is still unclear. OBJECTIVE. Molecular evidence reported that IGF1 and FSH belongs to the same molecular pathway. The aim of this study is to assess whether insulin-like growth factor-1 (IGF1)/follicle-stimulating hormone (FSH) ratio has an impact on testicular function and, specifically, on sperm number and testicular volume in a cohort of unselected men. METHODS. This is a cross-sectional study on 59 patients who attended the Seminology laboratory of the Division of Endocrinology of the University of Catania (Catania, Italy) for semen analysis. Data were analyzed to evaluate the relationships between IGF1 or IGF1/FSH ratio and sperm concentration, total sperm count (TSC), and testicular volume (TV). We also evaluated the occurrence of any difference in IGF1 and FSH serum levels and the IGF1/FSH ratio in patients with oligozoospermia and those with a TSC > 39 million/ejaculate. MAIN RESULTS AND ROLE OF CHANGE. Patients had a mean age of 31.0 ± 8.5 years. The mean FSH and IGF1 levels were 3.95 ± 2.55 mIU/mL and 232.59 ± 65.13 ng/mL, respectively. IGF1 serum levels did not correlate with sperm concentration, TSC, and TV. The IGF1/FSH ratio showed a positive correlation with sperm concentration (r = 0.408; p = 0.004), TSC (r = 0.468; p = 0.001), and TV (0.463; p = 0.002). Patients with oligozoospermia (Group 1, 23.7%, n = 14) had a significant lower IGF1/FSH ratio (57.9 ± 9.5 vs. 94.1 ± 8.7; p = 0.03) compared to those with TSC > 39 million/ejaculate (Group 2, 76.3%, n = 45). They did not differ significantly for neither IGF1 nor FSH serum levels. CONCLUSION. We found a positive correlation between the IGF1/FSH ratio and sperm concentration, TSC and TV. Furthermore, patients with oligozoospermia showed a significantly lower ratio compared to those with a normal TSC, while neither IGF1 nor FSH differed significantly in the two groups. Our results may reflect the existence of a molecular pathway to which IGF1 and FSH belongs. However, further studies are needed.

The spread of severe acute respiratory syndrome—Coronavirus 2 (SARS-CoV-2) around the world has rapidly sparked the interest of the scientific community to discover its implications in human health. Many studies have suggested that SARS-CoV-2 is directly or indirectly involved in the male reproductive tract impairment. Some evidence supports the possible role of the virus in male infertility. Therefore, this review aims to summarize the relationship between the male urogenital tract, male fertility, and the gonadal hormone profile. The testis is one of the organs with the highest expression of the angiotensin-converting enzyme (ACE) 2-receptor that allows the virus to penetrate human cells. Orchitis is a possible clinical manifestation of COVID-19 and testicular damage has been found on autopsy in the testes of patients who died from the disease. SARS-CoV-2 infection can compromise the blood-testis barrier, favoring testicular damage and the production of anti-sperm autoantibodies. Some studies have detected the presence of SARS-CoV-2 in semen and a high percentage of patients with COVID-19 have altered sperm parameters compared to controls. Finally, lower testosterone levels, higher luteinizing hormone (LH) levels, and decreased follicle-stimulating (FSH)/LH and testosterone/LH ratios suggest primary testicular damage. In conclusion, further studies are needed to evaluate the exact mechanisms by which SARS-CoV-2 affects the male reproductive system and fertility and to evaluate the reversibility of its long-term effects.

Diabetes mellitus (DM) is a widespread chronic disease with a prevalence that is expected to further increase in the near future. The classical management of DM includes the normalization of the glycometabolic profile and the evaluation of cardiac and cerebral vascular health by the intervention of an array of different specialists. However, so far, sexual dysfunctions are still a neglected complication in patients with DM, although there is an elevated prevalence of this long-term complication in male and female patients. Furthermore, some of them may represent a sign of vascular alteration and/or hypogonadism and require timely management to prevent the onset of major adverse cardiac events. This narrative review briefly summarizes the current evidence on epidemiology, pathogenesis, diagnosis, and therapy of erectile dysfunction in male patients with DM to support diabetologists in clinical practice.

Diabetes mellitus (DM) is one of the most common chronic diseases worldwide and its prevalence is expected to increase in the coming years. Therefore, updated knowledge of all diabetic complications and their management is essential for the proper treatment of these patients. Sexual dysfunctions are one of the long-term complications of DM in both genders. However, female sexuality is still a taboo and sexual concerns are often overlooked, underdiagnosed, and untreated. The aim of this review is to summarize the current knowledge on the relationship between sexual function and DM in women. In particular, we evaluated the prevalence, etiology, diagnostic approaches, and current treatment options of female sexual dysfunction (FSD) in diabetic patients.

Congenital hypogonadotropic hypogonadism (cHH)/Kallmann syndrome (KS) is a rare genetic disorder with variable penetrance and a complex inheritance pattern. Consequently, it does not always follow Mendelian laws. More recently, digenic and oligogenic transmission has been recognized in 1.5–15% of cases. We report the results of a clinical and genetic investigation of five unrelated patients with cHH/KS analyzed using a customized gene panel. Patients were diagnosed according to the clinical, hormonal, and radiological criteria of the European Consensus Statement. DNA was analyzed using next-generation sequencing with a customized panel that included 31 genes. When available, first-degree relatives of the probands were also analyzed to assess genotype–phenotype segregation. The consequences of the identified variants on gene function were evaluated by analyzing the conservation of amino acids across species and by using molecular modeling. We found one new pathogenic variant of the CHD7 gene (c.576T>A, p.Tyr1928) and three new variants of unknown significance (VUSs) in IL17RD (c.960G>A, p.Met320Ile), FGF17 (c.208G>A, p.Gly70Arg), and DUSP6 (c.434T>G, p.Leu145Arg). All were present in the heterozygous state. Previously reported heterozygous variants were also found in the PROK2 (c.163del, p.Ile55*), CHD7 (c.c.2750C>T, p.Thr917Met and c.7891C>T, p.Arg2631*), FLRT3 (c.1106C>T, p.Ala369Val), and CCDC103 (c.461A>C, p.His154Pro) genes. Molecular modeling, molecular dynamics, and conservation analyses were performed on three out of the nine variants identified in our patients, namely, FGF17 (p.Gly70Arg), DUSP6 (p.Leu145Arg), and CHD7 p.(Thr917Met). Except for DUSP6, where the L145R variant was shown to disrupt the interaction between β6 and β3, needed for extracellular signal-regulated kinase 2 (ERK2) binding and recognition, no significant changes were identified between the wild-types and mutants of the other proteins. We found a new pathogenic variant of the CHD7 gene. The molecular modeling results suggest that the VUS of the DUSP6 (c.434T>G, p.Leu145Arg) gene may play a role in the pathogenesis of cHH. However, our analysis indicates that it is unlikely that the VUSs for the IL17RD (c.960G>A, p.Met320Ile) and FGF17 (c.208G>A, p.Gly70Arg) genes are involved in the pathogenesis of cHH. Functional studies are needed to confirm this hypothesis.

This systematic review and meta-analysis summarize the difference in the methylation of the H19 gene in patients with abnormal versus normal conventional sperm parameters. It also evaluates the effects of age and sperm concentration on H19 methylation in spermatozoa using meta-regression analysis. It was performed according to the MOOSE guidelines for meta-analyses and Systematic Reviews of Observational Studies and the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). The quality of the evidence reported in the studies included was assessed using the Cambridge Quality Checklists. A total of 11 articles met our inclusion criteria. Quantitative analysis showed that H19 methylation levels were significantly lower in the group of infertile patients than in fertile controls. The reduction in methylation was much more pronounced in patients with oligozoospermia (alone or associated with other sperm parameter abnormalities) and in those with recurrent pregnancy loss. Meta-regression analysis showed the results to be independent of both patient age and sperm concentration. Therefore, the H19 methylation pattern should be evaluated among couples accessing assisted reproductive techniques (ART), in order to gain prognostic information on ART outcome and offspring health.

Background: Previous studies supported the beneficial effects of a very short abstinence period on sperm quality. This systematic review and meta-analysis aimed to evaluate the effects of a very short abstinence period (within 4 h) on assisted reproductive technique (ART) outcomes. Methods: A literature search was performed using the Pubmed, Scopus, Web of Science, and Cochrane databases. A meta-analysis was performed according to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) for randomized controlled trials (RCTs). All eligible studies were selected following the PICOS (Population, Intervention, Comparison/Comparator, Outcomes, Study type) model. The following pregnancy outcomes after ART were considered: fertilization rate (FR), implantation rate (IR), clinical pregnancy rate (CPR), live birth rate (LBR), and miscarriage rate (MR). This study was registered on PROSPERO (CRD42023396429). Results: We evaluated 414 records for eligibility, and 7 studies were ultimately included. Our analysis showed that a very short abstinence period significantly increased the IR, CPR, and LBR after ART. No significant differences were found for the FR and MR. Conclusions: A second ejaculation collected very shortly after the first one could represent a simple strategy to improve the results of ART, especially in couples including patients with abnormal sperm parameters.

Purpose: To prospectively investigate the effects of treatment with liraglutide, a glucagon-like peptide 1 (GLP1) analog, on reproductive and sexual function in men with metabolic hypogonadism who are of childbearing age. Materials and Methods: To accomplish this purpose, 110 men of childbearing age (18–35 years) with metabolic hypogonadism were enrolled and divided into three groups, according to their desire to have children. Group A was made up of men actively seeking fatherhood, Group B, of men who did not seek fatherhood, and Group C, of men who had already fathered a child. Group A patients were treated with gonadotropins (urofollitropin at 150 IU, three times a week, and human chorionic gonadotropin at 2000 IU, twice a week), Group B patients with liraglutide (3 mg daily), and Group C patients with transdermal testosterone (60 mg per day). All patients were treated for 4 months. Results: Patients treated with liraglutide (Group B) showed significant improvement in conventional sperm parameters, compared to baseline and Group A patients, and in the quality of erectile function compared to baseline and patients of Groups A and C. In addition, they had significantly higher levels of total testosterone and sex hormone-binding globulin serum levels after 4 months of treatment with liraglutide than those achieved by patients in the other two groups at the end of the respective treatments. Finally, Group B patients also showed significantly higher serum gonadotropin levels than the other groups. Conclusions: The results of this study showed, for the first time, the efficacy of liraglutide, a GLP1 analog, for the pharmacological treatment of male patients with metabolic hypogonadism. Liraglutide has also shown advantages over traditional treatments on both reproductive and sexual function and appears to offer greater benefits in terms of metabolic protection. These findings suggest that liraglutide is a useful drug for the treatment of obese males with metabolic hypogonadism.

The protocols commonly used in assisted reproductive technology (ART) consist of long-term embryo culture up to the blastocyst stage after the insemination of all mature oocytes, the freezing of all the embryos produced, and their subsequent transfer one by one. These practices, along with preimplantation genetic testing, although developed to improve the live birth rate (LBR) and reduce the risk of multiple pregnancies, are drawing attention to the possible increase in obstetric and perinatal risks, and adverse epigenetic consequences in offspring. Furthermore, ethical–legal concerns are growing regarding the increase in cryopreservation and storage of frozen embryos. In an attempt to reduce the risk associated with prolonged embryo culture and avoid embryo storage, we have chosen to inseminate a limited number of oocytes not exceeding the number of embryos to be transferred, after two days or less of culture. We retrospectively analyzed 245 ICSI cycles performed in 184 infertile couples with a female partner aged ≥40 from January 2016 to July 2021. The results showed a fertilization rate of 95.7%, a miscarriage rate of 48.9%, and a LBR of 10% with twin pregnancies of 16.7%. The cumulative LBR in our group of couples was 13%. No embryos were frozen. In conclusion, these results suggest that oocyte selection and embryo transfer at the cleaving stage constitute a practice that has a LBR comparable to that of the more commonly used protocols in older women who have reduced ovarian reserve.

Introduction: Androgen insensitivity syndrome (AIS), an X-linked recessive disorder of sex development (DSD), is caused by variants of the androgen receptor (AR) gene, mapping in the long arm of the X chromosome, which cause a complete loss of function of the receptor. Case presentation: We report a patient diagnosed with complete AIS (CAIS) at birth due to swelling in the bilateral inguinal region. Transabdominal ultrasound revealed the absence of the uterus and ovaries and the presence of bilateral testes in the inguinal region. The karyotype was 46,XY. She underwent bilateral orchiectomy at 9 months and was given estrogen substitutive therapy at the age of 11 years. Genetic analysis of the AR gene variants was requested when, at the age of 20, the patient came to our observation. Methods: The genetic testing was performed by next-generation sequence (NGS) analysis. Results: The genetic analysis showed the presence of the c.2242T>A, p.(Phe748Ile) variant in the AR gene. To the best of our knowledge, this variant has not been published so far. Furthermore, the patient has a heterozygous c.317A>G, p.(Gln106Arg) variation of the gonadotropin-releasing hormone receptor (GNRHR) gene, a heterozygous c.2273G>A, p.Arg758His variation of the chromodomain helicase DNA binding protein 7 (CHD7) gene, and compound heterozygous c.875A>G, p.Tyr292Cys, and c.8023A>G, p.Ile2675Val variations of the Dynein Axonemal Heavy Chain 11 (DNAH11) gene. Conclusions: The case herein reported underlines the importance of an accurate genetic analysis that has to include karyotype and AR gene variant analysis. This is useful to confirm a clinical diagnosis and establish the proper management of patients with CAIS. Numerous variants of the AR gene have not yet been identified. Moreover, several pitfalls are still present in the management of these patients. More studies are needed to answer unresolved questions, and common protocols are required for the clinical follow-up of patients with CAIS.

We thank our French colleagues for commenting [...]

Background: Selenium (Se) is an essential component of selenoenzymes, which have catalytic and antioxidant functions. A low Se status has been reported in patients with chronic autoimmune thyroiditis (AT) who benefit from Se supplementation. The role of Se in male reproduction is still a matter of debate. Although Se and selenoenzymes ensure sperm viability and protect against increased oxidative stress, only a few studies have assessed the effects of the administration of Se alone on sperm parameters, providing contrasting results. Aim: The aim of this study was to assess the effects of oral Se supplementation on conventional sperm parameters and DNA fragmentation (SDF) in patients with AT of reproductive age with normal thyroid function. Patients and Methods: Only patients with AT and normal thyroid function were selected for this study. All included patients underwent oral Se supplementation at the dose of 83 µg once daily (Syrel®, IBSA) for six months. Sperm conventional parameters, SDF, and thyroid function were assessed before and at the end of the treatment. Results: Twenty AT patients with normal weight were enrolled. After Se supplementation, they showed a higher sperm concentration, a higher percentage of sperm with progressive motility, and a higher percentage with normal morphology. They also had lower semen leukocyte concentration, and a lower percentage of spermatozoa with DNA fragmentation compared with pre-treatment values. Free-thyroxine serum levels increased significantly, whereas free triiodothyronine showed an upward trend. The thyroid-stimulating hormone did not change significantly. Conclusion: Se supplementation may represent a possible non-hormonal therapeutic choice for the treatment of male infertility, although further studies are needed to confirm this evidence. The possible thyroid hormone dependency of these findings needs to be clarified.

Objective: To evaluate the changes of conventional sperm parameters in men who referred to an andrology reference center in Catania (Eastern Sicily, Italy) in the decade 2011–2020. Methods: For this purpose, we selected–retrospectively and randomly–the reports of 1409 semen analyses performed according to the 2010 WHO criteria. Data on sperm concentration, total sperm count, progressive sperm motility, and percentage of normal forms were analyzed using linear regression of the raw and logarithmic-transformed data. The sperm parameters were subsequently pooled in two five-year periods (2011–2015 and 2016–2020) and compared with each other. Finally, the influence of the city of residence was assessed on five-year pooled data. Main results: A slight but non-significant decline of total sperm count (−2.26 million/year, p = 0.065) and the percentage of spermatozoa with normal morphology (−0.08%/year, p = 0.057) was observed. In contrast, a significant increase of progressive sperm motility (+0.28%/year, p = 0.008) over time was found. The total sperm count of the quinquennium 2016–2020 was significantly lower. and an upward trend of progressive sperm motility was found. compared to the years 2011–2015. No changes in sperm concentration and morphology occurred in the years 2011–2015 vs. 2016–2020. Sperm conventional parameters did not differ when the five-year pooled data were analyzed according to the town of residence. Conclusions: Divergent trends of total sperm count and progressive sperm motility over time were found in patients from Eastern Sicily. This may point out the need of assessing whether a time-dependent change of biofunctional sperm parameters occurs to really understand the trend of sperm quality over time.

Cardiovascular diseases are the main cause of mortality in the Western population, so the attempt to find a marker capable of predicting their early onset is not surprising. It is known that arteriogenic erectile dysfunction (ED) precedes the onset of a major coronary event by several years. However, a marker that is able to early identify those patients who should undergo further diagnostic investigations is, to date, missing. Recent research on this topic has focused on the role of the mean platelet volume (MPV), a marker of platelet activity that is high in most vascular diseases, such as coronary artery disease (CAD), stroke, peripheral artery disease (PAD), and ED. The basic pathophysiological mechanism of all these clinical conditions is atherosclerosis. Platelets play a central role in amplifying this process both indirectly by stimulating endothelial cells to produce inflammatory cytokines and chemokines, and directly through the expression of membrane receptors and the release of molecules that contribute to the formation of atherosclerotic plaque. The objective of this review is to critically analyze the evidence on the role of MPV in predicting the diagnosis and severity of vasculogenic ED and the possibility of using this simple marker as a first step to start a diagnostic process aimed at assessing the cardiovascular risk in these patients.

Erectile dysfunction (ED) is found very frequently in the male population, in particular in its arteriogenic form, which also represents an important predictor of cardiovascular diseases (CVDs). Some evidence suggests that vitamin D could play a role in cardiovascular risk prevention thanks to its ability to reduce endothelial damage, oxidative stress, the production of inflammatory cytokines, and dyslipidemia. Since ED and CVDs have pathogenic mechanisms in common, numerous studies have evaluated a possible association between vitamin D deficiency (blood concentrations of 25-hydroxyvitamin D < 20 ng/mL) and ED, but with conflicting results. This meta-analysis was therefore performed to clarify the discrepancy of the data so far published. To achieve this, articles have been searched extensively in the Pubmed, MEDLINE, Cochrane, Academic One Files, Google Scholar, and Scopus databases from the first day they were created until January 2020. The search strategy included pertinent Medical Subjects Headings (MeSH) terms. Of the 431 items retrieved, only eight observational studies were included, resulting in a total sample size of 4055 patients. It was found that 25-hydroxyvitaminD (25(OH)D) levels did not show any significant difference between patients with and without ED. However, when patients with vitamin D deficiency only were taken into account, the international index of erectile function (IIEF) score for erectile dysfunction was significantly worse than in controls. This association remained significant even when eugonadal-only patients were considered. Finally, we found that eugonadal patients with severe ED have lower 25(OH)D3 levels than patients with mild ED. In conclusion, this meta-analysis suggests an association between vitamin D deficiency and the presence of severe forms of ED, independent of testicular function.

The use of inositols in endocrinological clinical practice is increasingly widespread. Most of the existing evidence concerns myoinositol (MYO), the most abundant form in nature, especially in women with polycystic ovarian syndrome. We have previously shown that MYO increases sperm motility in patients with asthenozoospermia by the increase of sperm mitochondrial membrane potential (MMP), a biofunctional sperm parameter closely associated to sperm motility. The aim of this study was to evaluate the effects of D-chiro-inositol (DCI), another biologically active isoform of inositols, on sperm MMP, as data on this matter has never been released so far. To accomplish this, semen samples from 15 patients with asthenozoospermia and 15 healthy normozoospermic men were incubated with increasing concentrations of DCI (0, 75, and 750 µg/mL) or phosphate buffer saline for 30 min. Incubation with DCI significantly improved sperm MMP at lower concentrations, and with shorter incubation length than those used in our similar MYO studies. In conclusion, these findings indicate that DCI positively impacts on sperm mitochondrial function in vitro. Studies aimed at assessing the role of DCI in the treatment of asthenozoospermia in-vivo are warranted.

Obesity is a major current public health problem of global significance. A progressive sperm quality decline, and a decline in male fertility, have been reported in recent decades. Several studies have reported a strict relationship between obesity and male reproductive dysfunction. Among the many mechanisms by which obesity impairs male gonadal function, sirtuins (SIRTs) have an emerging role. SIRTs are highly conserved nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases that play a role in gene regulation, metabolism, aging, and cancer. SIRTs regulate the energy balance, the lipid balance, glucose metabolism, and adipogenesis, but current evidence also indicates a role for SIRTs in male reproduction. However, the majority of the studies have been conducted in animal models and very few have been conducted with humans. This review shows that SIRTs play an important role among the molecular mechanisms by which obesity interferes with male fertility. This highlights the need to deepen this relationship. It will be of particular interest to evaluate whether synthetic and/or natural compounds capable of modifying the activity of SIRTs may also be useful for the treatment of obesity and its effects on gonadal function. Although few studies have explored the role of SIRT activators in obesity-induced male infertility, some molecules, such as resveratrol, appear to be effective in modulating SIRT activity, as well as counteracting the negative effects of obesity on male fertility. The search for strategies to improve male reproductive function in overweight/obese patients is a challenge and understanding the role of SIRTs and their activators may open new interesting scenarios in the coming years.

Male infertility is a widespread condition among western countries. Meta-regression data show that sperm concentration and total sperm count have halved in the last decades. The reasons of this decline are still unclear. The evaluation of testicular function in pre-pubertal children may be effective in the timely detection of Sertoli cell (SC) disfunction, which anticipates the diagnosis of male infertility. The aim of this Special Issue is to gather together in vitro evidence on SC physiology, causes of SC dysfunction, and to suggest a practical approach to be adopted in children.

Male infertility affects half of infertile couples and, currently, a relevant percentage of cases of male infertility is considered as idiopathic. Although the male contribution to human fertilization has traditionally been restricted to sperm DNA, current evidence suggest that a relevant number of sperm transcripts and proteins are involved in acrosome reactions, sperm‒oocyte fusion and, once released into the oocyte, embryo growth and development. The aim of this review is to provide updated and comprehensive insight into the molecular biology of spermatogenesis, including evidence on spermatogenetic failure and underlining the role of the sperm-carried molecular factors involved in oocyte fertilization and embryo growth. This represents the first step in the identification of new possible diagnostic and, possibly, therapeutic markers in the field of apparently idiopathic male infertility.

Introduction: Osteoporosis is increasingly prevalent in the elderly, with fractures mostly occurring in women and men who are older than 55 and 65 years of age, respectively. The aim of this review was to examine the evidence regarding the influence of hormones on bone metabolism, followed by clinical data of hormonal changes in the elderly, in the attempt to provide possible poorly explored diagnostic and therapeutic candidate targets for the management of primary osteoporosis in the aging population. Material and methods: An extensive Medline search using PubMed, Embase, and Cochrane Library was performed. Results: While the rise in Thyroid-stimulating hormone (TSH) levels has a protective role on bone mass, the decline of estrogen, testosterone, Insulin-like growth factor 1 (IGF1), and vitamin D and the rise of cortisol, parathyroid hormone, and follicle-stimulating hormone (FSH) favor bone loss in the elderly. Particularly, the AA rs6166 FSH receptor (FSHR) genotype, encoding for a more sensitive FSHR than that encoded by the GG one, is associated with low total body mass density (BMD), independently of circulating estrogen. A polyclonal antibody with a FSHR-binding sequence against the β-subunit of murine FSH seems to be effective in ameliorating bone loss in ovariectomized mice. Conclusions: A complete hormonal assessment should be completed for both women and men during bone loss evaluation. Novel possible diagnostic and therapeutic tools might be developed for the management of male and female osteoporosis.

Pediatric varicocele has an overall prevalence of 15%, being more frequent as puberty begins. It can damage testicular function, interfering with Sertoli cell proliferation and hormone secretion, testicular growth and spermatogenesis. Proper management has a pivotal role for future fertility preservation. The aim of this review was to discuss the diagnosis, management and treatment of childhood and adolescent varicocele from an endocrinologic perspective, illustrating the current evidence of the European Society of Pediatric Urology (ESPU), the European Association of Urology (EAU), the American Urological Association (AUA) and the American Society for Reproductive Medicine (ASRM) scientific societies. According to the ASRM/ESPU/AUA practice committee, the treatment of adolescent varicocele is indicated in the case of decreased testicular volume or sperm abnormalities, while it is contraindicated in subclinical varicocele. The recent EAS/ESPU meta-analysis reports that moderate evidence exists on the benefits of varicocele treatment in children and adolescents in terms of testicular volume and sperm concentration increase. No specific phenotype in terms of testicular volume cut-off or peak retrograde flow (PRF) is indicated. Based on current evidence, we suggest that conservative management may be suggested in patients with PRF < 30 cm/s, testicular asymmetry < 10% and no evidence of sperm and hormonal abnormalities. In patients with 10−20% testicular volume asymmetry or 30 < PRF ≤ 38 cm/s or sperm abnormalities, careful follow-up may ensue. In the case of absent catch-up growth or sperm recovery, varicocele repair should be suggested. Finally, treatment can be proposed at the initial consultation in painful varicocele, testicular volume asymmetry ≥ 20%, PRF > 38 cm/s, infertility and failure of testicular development.

Lifestyle, cigarette smoking and environmental pollution have a negative impact on male fertility. Therefore, the aim of this study was to evaluate the in-vitro effects of benzo-&alpha, pyrene (BaP) and aryl hydrocarbon receptor (AHR) agonists on motility and bio-functional sperm parameters. We further assessed whether resveratrol (RES), an AHR antagonist and antioxidant molecule, had any protective effect. To accomplish this, 30 normozoospermic, healthy, non-smoker men not exposed to BaP were enrolled. Spermatozoa of 15 men were incubated with increasing concentrations of BaP to evaluate its effect and to establish its dose response. Then, spermatozoa of the 15 other men were incubated with BaP (15 &micro, M/mL), chosen according to the dose-response and/or RES to evaluate its antagonistic effects. The effects of both substances were evaluated after 3 h of incubation on total and progressive sperm motility and on the following bio-functional sperm parameters evaluated by flow cytometry: Degree of chromatin compactness, viability, phosphatidylserine externalization (PS), late apoptosis, mitochondrial membrane potential (MMP), DNA fragmentation, degree of lipoperoxidation (LP), and concentrations of mitochondrial superoxide anion. Benzo-&alpha, pyrene decreased total and progressive sperm motility, impaired chromatin compactness, and increased sperm lipoperoxidation and mitochondrial superoxide anion levels. All these effects were statistically significant at the lowest concentration tested (15 &micro, M/mL) and they were confirmed at the concentration of 45 &micro, M/mL. In turn, RES was able to counteract the detrimental effects of BaP on sperm motility, abnormal chromatin compactness, lipid peroxidation, and mitochondrial superoxide. This study showed that BaP alters sperm motility and bio-functional sperm parameters and that RES exerts a protective effect on BaP-induced sperm damage.

Experimental evidence has shown that the IGF1 receptor (IGF1R) is involved in testicular development during embryogenesis. More recently, data gathered from mice granulosa cells and zebrafish spermatogonia suggest that IGF1R has a role in Follicle-stimulating hormone (FSH) signaling. No evidence has been reported on this matter in Sertoli cells (SCs) so far. The aim of the study was to evaluate the role, if any, of the IGF1R in FSH signaling in SCs. The effects of FSH exposure on myosin-phosphatase 1 (MYPT1), ERK 1/2, AKT308, AKT473, c-Jun N-terminal kinase (JNK) phosphorylation and on anti-M&uuml, llerian hormone (AMH), inhibin B and FSH receptor (FSHR) mRNA levels were assessed with and without the IGF1R inhibitor NVP-AEW541 in purified and functional porcine neonatal SCs. Pre-treatment with NVP-AEW541 inhibited the FSH-induced MYPT1 and ERK 1/2 phosphorylation, decreased the FSH-dependent Protein kinase B (AKT)308 phosphorylation, but did not affect the FSH-induced AKT473 and JNK phosphorylation rate. It also interfered with the FSH-induced AMH and FSHR down-regulation. No influence was observed on the FSH-stimulated Inhibin B gene expression. Conclusion. These findings support the role of theIGF1R in FSH signaling in porcine SCs. The possible influence of IGF1 stimulation on the FSH-mediated effects on SCs should be further explored.

In recent years, a growing number of studies seem to support the beneficial effects of a very short abstinence period on sperm parameters, especially in patients with oligo-asthenozoospermia (OA). On this basis, the aim of this study was to evaluate the effects of a short period of abstinence (1 h) on intracytoplasmic sperm injection (ICSI) outcomes in infertile patients with severe OA. We performed a retrospective study on 313 ICSI cycles in which couples were divided into two different groups based on sperm parameters of the male partners. Group 1 included normozoospermic men or male partners with a mild OA (n = 223). Group 2 included male partners with severe OA (n = 90). They were asked to provide a second consecutive ejaculation after 1 h from the first one. The best ejaculate was used to perform ICSI. We found a significant increase of total (p &lt, 0.001) and progressive motility (p &lt, 0.001) in the second ejaculate of patients of Group 2 compared with those of the first one. Spermatozoa of the second ejaculate were chosen for ICSI for all patients in Group 2. We found statistically significant improvement of clinical pregnancy rate (p = 0.001) and embryo quality (p = 0.003) in couples in Group 2 compared to those of Group 1. No statistically significant difference was found in fertilization, implantation, live birth delivery, and miscarriage rates between the two groups. Therefore, a second semen sample collected after a very short time-interval in patients with severe OA allowed us to obtain significantly higher clinical pregnancy rate with improved embryo quality compared to normozoospermic men or patients with mild OA. Fertilization, implantation, live birth delivery, and miscarriage rates were similar between the two groups. The present study shows that a second consecutive ejaculate could represent a simple strategy to obtain better sperm parameters and assisted reproductive technology (ART) outcomes in infertile patients with mild-severe OA.

The prevalence of idiopathic male infertility is high, up to 75% of patients with abnormal sperm parameters. Hence, the research of its causes is mandatory. Oxidative stress (OS) can be responsible for male infertility in 30–80% of cases. In recent years, seminal plasma (SP) proteomics has developed as a useful tool to provide biomarkers of specific diseases. This systematic review aims to collect the available evidence on the changes of SP proteome in patients exposed to OS to provide possible SP biomarkers of sperm OS. To accomplish this, the following keyterms “seminal fluid proteome”, “seminal plasma proteome”, “oxidative stress”, and “sperm oxidative stress” were used and 137 records were found. Among these, 17 were finally included. Nine proteins involved with OS were found overexpressed in patients with OS. Twenty-three proteins were found differentially expressed in patients with clinical conditions associated with OS, such as varicocele, male accessory gland infection/inflammation, cigarette smoke, and obesity. These proteins do not seem to overlap among the clinical conditions taken into account. We speculate that specific SP proteins may mediate OS in different clinical conditions. Altogether, these results suggest that proteomics could help to better understand some of the molecular mechanisms involved in the pathogenesis of infertility. However, further studies are needed to identify potential biomarkers of male infertility with valuable clinical significance.

As the “-omic” technology has largely developed, its application in the field of medical science seems a highly promising tool to clarify the etiology, at least in part, of the so-called idiopathic male infertility. The seminal plasma (SP) is made-up of secretions coming from the male accessory glands, namely epididymis, seminal vesicles, and prostate. It is not only a medium for sperm transport since it is able to modulate the female reproductive environment and immunity, to allow the acquisition of sperm competence, to influence the sperm RNA content, and even embryo development. The aim of this systematic review was to provide an updated and comprehensive description of the main transcripts and proteins reported by transcriptome and proteome studies performed in the human SP of patients with idiopathic infertility, in the attempt of identifying possible candidate molecular targets. We recurrently found that micro RNA (miR)-34, miR-122, and miR-509 are down-regulated in patients with non-obstructive azoospermia (NOA) and oligozoospermia compared with fertile controls. These molecules may represent interesting targets whose predictive role in testicular sperm extraction (TESE) or assisted reproductive techniques (ART) outcome deserves further investigation. Furthermore, according to the available proteomic studies, ECM1, TEX101, lectingalactoside-binding andsoluble 3 binding protein (LGALS3BP) have been reported as accurate predictors of TESE outcome. Interestingly, ECM1 is differently expressed in patients with different ART outcomes. Further prospective, ample-sized studies are needed to validate these molecular targets that will help in the counseling of patients with NOA or undergoing ART.

The evaluation of conventional and biofunctional sperm parameters is of fundamental importance for assessing male reproductive function. Among these, sperm motility is one of the most important parameters. Indeed, asthenozoospermia is a frequent cause of male infertility. Sperm motility depends on mitochondrial function and the measurement of mitochondrial membrane potential (MMP) better accounts for the function of this intracellular organelle. On the basis of these premises, the present study assessed whether the MMP predicts sperm motility at 4 h in patients with low or normal MMP. To accomplish this, 31 men were enrolled. Sperm analysis was conducted according to the WHO 2010 criteria. Particular attention was paid to the evaluation of MMP after liquefaction (T0) using JC-1 staining by flow cytometry. Sperm total and progressive motility were measured at T0 and after 4 h from seminal fluid collection (T4). Patients were divided into two groups based on their sperm mitochondrial function at T0. Group A (n = 18) was composed of men with normal mitochondrial function since they had a percentage of spermatozoa with low MMP (L-MMP) below the normal reference value of our laboratory (&lt, 36.5%). In contrast, group B (n = 13) was made up of men with impaired sperm mitochondrial function (L-MMP &gt, 36.5%). Group A had a slight but not significant reduction in total and progressive sperm motility at T4 compared with the values recorded at T0. In contrast, patients in group B showed a significant decline in both total and progressive sperm motility at T4 compared with T0 (p &lt, 0.05). The results of this study showed that worse mitochondrial function, assessed by staining with JC1, is associated with a significant decline in sperm motility over time. These findings may be of clinical relevance in programs of assisted reproduction techniques. Based on our knowledge, there is no other evidence in the literature that has shown this relationship in healthy men with low MMP of idiopathic etiology, but normozoospermics according to the WHO 2010 criteria.