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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.

Male infertility is a major public health concern globally with unknown etiology in approximately half of cases. The decline in total sperm count over the past four decades and the parallel increase in childhood obesity may suggest an association between these two conditions. Here, we review the molecular mechanisms through which obesity during childhood and adolescence may impair future testicular function. Several mechanisms occurring in obesity can interfere with the delicate metabolic processes taking place at the testicular level during childhood and adolescence, providing the molecular substrate to hypothesize a causal relationship between childhood obesity and the risk of low sperm counts in adulthood. Pediatric obesity is increasing worldwide and its contribution to the decline is sperm count has been questioned. By comprehensively reviewing the literature, the authors herein report molecular mechanisms that may suggest the causality of this association.

Obesity is a widespread disease that is associated with numerous and serious comorbidities. These include metabolic syndrome, diabetes mellitus, cardiovascular-cerebrovascular disease, hypertension, obstructive sleep apnea syndrome, cancer, and sexual and hormonal disorders. The treatment of obesity has therefore become a goal of great clinical and social relevance. Among the therapeutic strategies against obesity, resveratrol has aroused great interest. This polyphenol has anticancer and antioxidant properties and cytoprotective and anti-inflammatory effects. Other favorable effects attributed to resveratrol are anti-lipid, anti-aging, anti-bacterial, anti-viral, and neuroprotective actions. Administration of resveratrol appears to improve the metabolic profile in obese and/or insulin-resistant patients. This article aims to review the main results of clinical studies evaluating the effects of administering resveratrol alone in overweight/obese patients.

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 Tirzepatide (TZP), a dual agonist of glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, has recently been introduced in Italy for the treatment of obesity. Obesity is frequently associated with metabolic hypogonadism, which is characterized by low testosterone levels and normal low levels of gonadotropin. This condition exacerbates metabolic dysfunction and increases the risk of type 2 diabetes mellitus (DM). This study aims to evaluate the effects of TZP on metabolic hypogonadism in patients with obesity. Methods Male patients with obesity and metabolic hypogonadism were enrolled. Exclusion criteria included recent use of medications for hypertension, dyslipidemia, DM, anti-androgens, or hyperprolactinemia. All participants followed a hypocaloric diet and engaged in 20 min of daily brisk walking. Patients were allocated to one of the following treatment groups: Group A received 2.5 mg of TZP weekly for the first month, with the dose increased to 5 mg from the second month; Group B received no pharmacological treatment: Group C received transdermal testosterone. Clinical evaluations were conducted at 2 months including assessment of body composition, the Binge Eating Scale (BES), 5-item International Index of Erectile Function (IIEF-5) questionnaire to evaluate erectile dysfunction (ED), and serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), sex hormone-binding globulin (SHBG), total testosterone (TT), and 17β-estradiol (E 2 ). Free (fT) and bioavailable testosterone (bioT) were calculated using the Vermeulen formula. Results A total of 83 patients with obesity (mean age 55.3 ± 5.5 years) were included in the study, divided into three groups: Group A (28 patients, mean age 56.3 ± 4.7 years), Group B (30 patients, mean age 55.1 ± 5.2 years), and Group C (25 patients, mean age 54.0 ± 6.5 years). At baseline, significant differences were observed in waist circumference (WC), which was higher in Group B, as well as in the BES score, lean mass (LM), and serum LH levels, all of which were higher in Group A. After 2 months, Group A showed significantly greater reductions in body weight, WC, BES score, and fat mass, along with a notable increase in LM and IIEF-5 score compared to Groups B and C. Additionally, Group A exhibited significantly higher serum levels of LH, FSH, SHBG, TT, fT, and bioT, while E 2 levels were significantly lower than both Groups B and C. Conclusion The results of this study suggest that TZP is effective in improving both metabolic parameters, ED, and gonadal hormone levels in patients with obesity and metabolic hypogonadism. These findings position TZP as a promising treatment for obese patients with functional hypogonadism arising from metabolic-related alterations.

Follicle-stimulating hormone (FSH) represents a therapeutic option in normogonadotropic patients with idiopathic oligozoospermia. The aim of this review was to evaluate the possible dose- and drug-dependent efficacy of FSH treatment on conventional sperm parameters. We performed a comprehensive systematic review via a meta-analysis of all available randomized controlled trials, in which FSH administration was compared with placebo or no treatment when administered to normogonadotropic patients with idiopathic oligozoospermia. Of the 971 articles that were retrieved, 5 were finally included, including a total of 372 patients and 294 controls. Overall, FSH treatment was effective in ameliorating the sperm concentration, total count, progressive motility, but not normal forms. On the basis of the weekly dosage, the studies were classified into those using low (175-262.5 IU per week), intermediate (350-525 IU per week), and high (700-1050 IU per week) doses. At low doses, FSH improved only sperm motility. At intermediate doses, FSH ameliorated sperm concentration and morphology. Total sperm count and progressive motility showed a trend toward the increase. At high doses, FSH increased sperm concentration, total sperm count, and progressive motility. Sperm morphology showed a trend toward the increase. Finally, both highly purified FSH (hpFSH) and recombinant human FSH (rhFSH) improved sperm concentration, total sperm count, progressive motility, but not morphology. No different efficacy was observed between these two preparations. This meta-analysis provides evidence in favor of high FSH doses. The FSH efficacy was not related to the preparation type (recombinant vs highly purified). Further studies are needed to evaluate the effectiveness of long-standing treatment regimes.

In recent decades, the worldwide prevalence of obesity has risen dramatically and is currently estimated to be around 20%. Obesity is linked to an increased risk of comorbidities and premature mortality. Several studies have shown that obesity negatively impacts male fertility through various mechanisms. This review aims to investigate the molecular mechanisms through which obesity impairs male reproduction, including obesity-associated hypogonadism and its effects on spermatogenesis, chronic inflammation, and oxidative stress. Obesity negatively impacts both conventional and biofunctional sperm parameters, and it also induces epigenetic changes that can be transferred to offspring. Moreover, obesity-related diseases are linked to a dysregulation of adipocyte function and micro-environmental inflammatory processes. The dysregulated adipokines significantly influence insulin signaling, and they may also have a detrimental effect on testicular function. Sirtuins can also play an important role in inflammatory and metabolic responses in obese patients. Understanding the molecular mechanisms that are involved in obesity-induced male infertility could increase our ability to identify novel targets for the prevention and treatment of obesity and its related consequences.

Resveratrol (RSV) (3,4′,5 trihydroxystilbene) is a natural non-flavonoid polyphenol widely present in the Mediterranean diet. In particular, RSV is found in grapes, peanuts, berries, and red wine. Many beneficial effects of this molecule on human health have been reported. In fact, it improves some clinical aspects of various diseases, such as obesity, tumors, hypertension, Alzheimer’s disease, stroke, cardiovascular diseases, and diabetes mellitus. However, little is known about the relationship between this compound and male fertility and the few available results are often controversial. Therefore, this review evaluated the effects of RSV on human male fertility and the mechanisms through which this polyphenol could act on human spermatozoa.

A large proportion of patients with idiopathic spermatogenic failure (SPGF; oligozoospermia or nonobstructive azoospermia [NOA]) do not receive a diagnosis despite an extensive diagnostic workup. Recent evidence has shown that the etiology remains undefined in up to 75% of these patients. A number of genes involved in germ-cell proliferation, spermatocyte meiotic divisions, and spermatid development have been called into play in the pathogenesis of idiopathic oligozoospermia or NOA. However, this evidence mainly comes from case reports. Therefore, this study was undertaken to identify the molecular causes of SPGF. To accomplish this, 15 genes (USP9Y, NR5A1, KLHL10, ZMYND15, PLK4, TEX15, TEX11, MEIOB, SOHLH1, HSF2, SYCP3, TAF4B, NANOS1, SYCE1, and RHOXF2) involved in idiopathic SPGF were simultaneously analyzed in a cohort of 25 patients with idiopathic oligozoospermia or NOA, accurately selected after a thorough diagnostic workup. After next-generation sequencing (NGS) analysis, we identified the presence of rare variants in the NR5A1 and TEX11 genes with a pathogenic role in 3/25 (12.0%) patients. Seventeen other different variants were identified, and among them, 13 have never been reported before. Eleven out of 17 variants were likely pathogenic and deserve functional or segregation studies. The genes most frequently mutated were MEIOB, followed by USP9Y, KLHL10, NR5A1, and SOHLH1. No alterations were found in the SYCP3, TAF4B, NANOS1, SYCE1, or RHOXF2 genes. In conclusion, NGS technology, by screening a specific custom-made panel of genes, could help increase the diagnostic rate in patients with idiopathic oligozoospermia or NOA.

Hormonal and metabolic abnormalities have been reported in men with early-onset androgenetic alopecia (AGA). Although this has been ascribed to the existence of a male polycystic ovary syndrome (PCOS)-equivalent, data on this topic are inconsistent and this syndrome has not been already acknowledged. To evaluate if, already before the age of 35 years, any difference occurs in the glycolipid and hormonal profiles and in the body weight in men with AGA compared to age-matched controls, we performed a comprehensive meta-analysis of all the available observational case-control studies of literature, using MEDLINE, Google Schoolar and Scopus databases. Among 10596 papers retrieved, seven studies were finally included, enrolling a total of 1009 participants. Our findings demonstrate that young men with AGA have a slightly but significantly worse glycolipid profile compared to controls and a hormonal pattern resembling those of women with PCOS, already before the age of 35 years. Therefore, early-onset AGA might represent a phenotypic sign of the male PCOS-equivalent. The acknowledgement of this syndrome would be of importance to prevent the long-term consequences on health in the affected men. The glycolipid profile and the body weight should be monitored in men with AGA starting from the second decade of life.