APHRODITE criteria: addressing male patients with hypogonadism and/or infertility owing to altered idiopathic testicular function

In males, congenital adrenal hyperplasia due to 21 hydroxylase deficiency is associated to normal fertility or infertility caused by a hypogonadotrophic hypogonadism (HH) or gonadal damage caused by intratesticular adrenal remnants. We report a 29-year-old male with azoospermia, without any important personal or family background. Physical examination was normal, his height was 150 cm and his testicular volume was 10 ml (normal 15 to 25 ml). Laboratory showed a normal testosterone and FSH and LH in the low normal limit. These results discarded a HH, whose diagnostic requirements are a low testosterone and inadequately normal or low gonadotrophins. A testicular biopsy was informed as compatible with HH. A 21 hydroxylase deficiency was suspected and confirmed with extremely high levels of 17 hydroxyprogesterone at baseline and after stimulation with fast acting ACTH. Clomiphene citrate did not increase testosterone or gonatrophin levels. Testicular ultrasound discarded the presence of adrenal nodules. Betametasone therapy resulted in a normal testicular development, normalization of sperm count, reduction of 17 hydroxyprogesterone and testosterone levels with an ulterior rise of the latter. Spontaneous paternity was achieved twice. It must be remembered that in cases of azoospermia due to congenital adrenal hyperplasia, testosterone produced by adrenal glands hinders the laboratory diagnosis of HH.

The male factor is considered a major contributory factor to infertility. Apart from the conventional causes for male infertility such as varicocoele, cryptorchidism, infections, obstructive lesions, cystic fibrosis, trauma and tumours, a new and important cause has been identified as being responsible for the so-called idiopathic male infertility: oxidative stress. Oxidative Stress (OS) is a condition that occurs when the production of Reactive Oxygen Species (ROS) overwhelms the antioxidant defense produced against them. In male reproductive pathological conditions, the OS significantly impairs spermatogenesis and sperm function, which may lead to male infertility. Reactive Oxygen Species (ROS) known as free radicals are oxidizing agents generated as a result of metabolism of oxygen and have at least one unpaired electron that make them very reactive species. Spermatozoa generate Reactive Oxygen Species (ROS) in physiological amounts, which play a role in sperm functions during sperm capacitation, Acrosome Reaction (AR) and oocyte fusion, but they need to be controlled and their concentrations maintained at a level that is not deleterious to the cells. Administration of antioxidants in patients with 'male factor' infertility has begun to attract considerable interest. The main difficulty of such an approach is our incomplete understanding of the role of free radicals in normal and abnormal sperm function leading to male infertility. The purpose of the present review is to address the relationship between ROS and idiopathic male factor infertility.

Evaluation of the ovarian reserve in young low responders with normal basal levels of follicle-stimulating hormone using three-dimensional ultrasonography

The aim of this study was to determine the relationship between serum magnesium (Mg) concentrations in middle-aged and older men, and the occurrence of selected metabolic and hormonal disorders. The study involved a total of 313 men aged 50-75 years, and who underwent standard anthropometric measurements. Also determined were blood serum Mg, lipid parameters - total cholesterol (TCh), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglyceride (TG) and carbohydrate metabolism parameters - glucose, insulin (I). In men with a normal total testosterone (TT) concentration, serum Mg was significantly higher compared to patients with a total testosterone deficiency. The subjects with metabolic syndrome had lower serum Mg compared to patients without metabolic syndrome. Serum Mg concentration in type 2 diabetes mellitus was lower compared to men without diabetes. In patients with arterial hypertension, serum Mg concentration was lower than in patients without hypertension. Statistically significant negative correlations were found for the relationships between Mg concentration and body mass index, waist-to-hip ratio, abdominal circumference, arterial blood pressure. Statistically significant, positive correlations were found for the relationships between Mg concentration and TT, TCh, LDL concentrations. The lower serum Mg level may be conducive to the development of total testosterone deficiency, arterial hypertension, diabetes, and therefore metabolic syndrome.

Various medications, surgeries, and assisted reproductive techniques are used to treat male infertility, but the high cost and low effectiveness have made these methods unpopular. The use of herbal medicines such as Withania somnifera, Ceratonia siliqua, Nigella sativa and Alpinia officinarum for the treatment of male infertility has become highly popular in recent years. We conducted this systematic review to evaluate the recent scientific evidence regarding herbal medicines used to treat idiopathic male infertility (IMI). Online literature resources were checked using different search engines, including ISI, Web of Knowledge, Medline, PubMed, Scopus, and Google Scholar. Date restrictions were applied to 2020, and the publication language was restricted to English and Persian. The risk of bias was evaluated using the Cochrane method. Out of 851 articles, 14 trials with 1218 participants were included. Of the 15 plants and medicinal products introduced in the selected studies, 12 cases were effective in treating male infertility. Each of these plants or products affects specific components of male fertility for which various mechanisms were mentioned, but most of them had antioxidant effects. No serious side effects were reported. Whitania somnifera roots, Alpinia officinarum, Nigella sativa seeds, Tomato, and Ceratonia siliqua and the formulation of Xperm, PHF, Churna Ratnam, Svaguptadi Churna, Y virilin capsule, manix capsule, and Tradafertil tablet revealed successful outcomes in treatment of idiopathic male infertility.

Infertility is a significant global health issue, affecting 8–12% of couples of reproductive age, with male factor infertility contributing to 30–50% of cases. Despite advances in assisted reproductive technologies, particularly intra-cytoplasmic sperm injection, male infertility remains understudied compared to female infertility. This review aims to explore the genetic underpinnings of male factor infertility, including identified genetic mutations, chromosomal abnormalities, and epigenetic factors, and to investigate the broader health implications for affected men. The emerging data suggest that male infertility is not only a reproductive issue but also a potential predictor of chronic diseases, including autoimmune disorders, cancer, and premature death. Additionally, the inheritance of male factor infertility and its potential effects on offspring health remains indeterminate. Studies have shown conflicting results regarding the impact of parental infertility and fertility treatments on the semen quality and reproductive health of offspring. This review summarizes the current understanding of the genetic causes of male infertility, highlights the impact of chromosomal disorders, reviews the spectrum of sperm quality and hormonal profiles, and discourses on the need for further research to clarify the relationships between parental subfertility, male infertility, and offspring health. By investigating these complex interrelationships, future research can help shape more effective diagnostic and treatment strategies for male infertility and its broader implications for men’s health and future generations.

Infertility is on the rise, but the underlying causes still remain mostly unknown. In fact, for about one third of infertile men, semen parameters are within reference limits. This so called ‘unexplained male infertility’ seems to rest on elusive functional defects of the sperm undetectable by semen analysis, precluding early diagnosis of the infertility and evidence-based treatment by medically assisted reproduction (MAR). As a result, affected couples often experience failed MAR attempts, subjecting the ‘healthy’ female to recurring medical risks. We set out to gain insight into the pathomechanisms underlying unexplained male infertility. To this end, we systematically assessed the function of the sperm-specific multisubunit CatSper-channel complex in sperm of 2,300 men undergoing a fertility workup at our center, using a simple motility-based ‘CatSper-Test’ combined with [Ca2+]i fluorimetric and electrophysiological recordings. Thereby, we identified a group of men with normal semen parameters, but defective CatSper function. These men or couples failed to conceive naturally and upon MAR via intrauterine insemination and in vitro fertilization. Intracytoplasmic sperm injection (ICSI) was, ultimately, required to conceive a child. We revealed that the defective CatSper function was caused by variations in CATSPER genes. Moreover, we unveiled that CatSper-deficient human sperm were unable to undergo hyperactive motility and, therefore, failed to penetrate the egg coat. Thus, we provide the experimental evidence that sperm hyperactivation is required for human fertilization, explaining the infertility of CatSper-deficient men and need of ICSI for medically assisted reproduction. Finally, our study also revealed that defective CatSper function and ensuing failure to hyperactivate represents the most common cause of unexplained male infertility known thus far and that this sperm channelopathy can readily be diagnosed, enabling future evidence-based treatment of affected couples.

HSPA1L and HSPA1B gene polymorphisms and haplotypes are associated with idiopathic male infertility in Iranian population

This comparative cross-sectional study aimed to evaluate the relationship between serum leptin and testosterone, FSH, LH, PRL and semen quality in fertile and idiopathic infertile Yemeni men. A total of 30 infertile males with unknown causes and 30 age-matched healthy fertile males were enrolled in this study. The body mass index (BMI) and waist circumference (WC) were measured. Semen samples were analyzed according to the WHO manual for semen analysis. Serum samples were tested for hormones. Subjects were then divided into subgroups and compared based on their main seminal findings. The WC, serum leptin, PRL, FSH and LH levels were significantly higher (p < 0.05) in the infertile subjects than in the fertile group. Serum leptin demonstrated a significant positive correlation (p < 0.01) with body weight, BMI and WC in fertile males and a significant negative correlation (p < 0.01) with testosterone in fertile and infertile males. Similarly, a significant positive correlation was found between serum leptin and FSH (p < 0.01) and LH (p < 0.05) levels in the infertile subjects. The findings showed that non-obstructive azoospermic (NOA) patients have significant (p < 0.05) high levels of serum leptin, FSH, and LH. These findings may support the possibility of a direct peripheral negative effect of leptin on testicular steroidogenesis independent of the suggested indirect effect, and it could directly impact spermatogenesis without inhibiting testosterone production. This effect was accompanied by increasing serum PRL levels. Furthermore, serum leptin and gonadotropins were found to be increased in the idiopathic NOA group. The present study provided valuable insights into the fertile and idiopathic infertile Yemeni males and could establish an important foundation for future andrological-related studies such as investigating the relationship between leptin and other hormones; and infertility-related genetic and epigenetic factors.

Infertility is a widespread global issue that affects approximately 15% of sexually active and active couples, which contributes to about 50% of cases. Currently, the condition remains prevalent and often inadequately treated. This systematic review aims to evaluate existing studies investigating the effects of probiotic supplementation in men. A comprehensive search was conducted across major databases, including PubMed, Cochrane, Science Direct, and Scielo, using relevant keywords such as 'probiotic' OR 'Lactobacillus' OR 'Bifidobacterium' AND 'Male infertility' OR 'male fertility' OR 'sperm quality' OR 'sperm motility' OR 'oligoasthenoteratozoospermia' and their Portuguese equivalents. Four randomized clinical studies met the inclusion criteria, focusing on men diagnosed with idiopathic male infertility (oligozoospermia, teratozoospermia, and asthenozoospermia). The findings revealed that probiotic administration exhibited promising antioxidant properties by combating reactive oxygen species (ROS), consequently protecting sperm DNA from damage that correlates with declining sperm quality. Significant improvements were observed across all sperm parameters, with notable enhancement in motility. Consequently, probiotic supplementation emerges as a potential therapeutic alternative for men diagnosed with idiopathic infertility, demonstrating positive effects on sperm quality.

Study question Are the novel mutations of TSPY1 gene associated with idiopathic male infertility in men? Summary answer Sporadic TSPY1 gene mutation is one of the major causes of idiopathic male infertility among men. What is known already As per the published research, there are several studies including AZF micro-deletion, sex chromosome copy number variation but surprisingly studies on Y chromosome genes are not that much available. Due to the genetic cross-talks of different regulatory mechanisms involved in the spermatogenesis process, male infertility still remains idiopathic. Contradictory outcome of the analyses intrigues the association of the variations of TSPY1 gene with male infertility. Previous analyses did not reveal implication of TSPY1 gene as etiologic factor of male infertility. Study design, size, duration This was a population-based case-control study that includes 184 cases of spermatogenic failure and 197 age-matched fertile men as controls and the study was conducted between March, 2018 and February, 2021 to infer whether the genetic mutations are significantly associated with spermatogenic failure. Participants/materials, setting, methods The samples were collected from the Institute of Reproductive Medicine (IRM) and Genome-the fertility centre. All the selected individuals agreed to participate in the study and provided blood samples. We isolated DNA from the blood samples, designed specific primers and went for PCR. We performed Sanger’s dideoxy sequencing of TSPY1 gene reading frame followed by in silico analyses of detected variations to interpret their intuitive effects on transcript and protein level of TSPY1 gene. Main results and the role of chance We found one novel deletion namely MN734578 (NC_000024.10:g.9468830del) and one novel insertion MN719944 (NC_000024.10:g.9468815_9468816insA). Both these mutations exhibited strong association with male infertility. MN734578 showed compelling confederacy with male infertility increasing the risk factor against the odd 19.023 (P value 0.0027). Here the mutation was found in 8 out of 184 case individuals. MN719944 was found to be extremely correlated with male infertility increasing the risk factor by 14.547 folds (P value 0.0117). This mutation is found in 6 out of 184 case individuals. Both the mutations were not not found in the control individuals. In silico analyses using different software SIFT, PROVEAN, REGULATIONSPOTTER, HSF and SpliceAid suggest prospective disruption in splice sites and alteration in different isoforms of TSPY1 transcripts and amino acid sequence in TSPY1 protein. We calculated Odds ratios with respective 95% confidence interval (CI) by performing Fisher’s exact test. After Bonferroni's correction, a two-tailed P-value of less than 0.02 was considered statistically significant. Limitations, reasons for caution The origin of the novel mutations is unknown and the outcome does not provide mechanistic details how do de novo mutations imperil the process of spermatogenesis. Wider implications of the findings The study provides evidence in favour of implication of TSPY1 gene in male fertility. The outcome sheds light to get insight into the issue of unexplained male infertility in Bengali will help to manage fertility problem in men. Trial registration number Not applicable

Excessive generation of seminal reactive oxygen species (ROS) by immature spermatozoa and white blood cells, especially granulocytes, in the ejaculate is detrimental to spermatozoa. The cellular antioxidant defense mitigates the impact of elevated ROS production. The imbalance between ROS and available antioxidants results in oxidative stress (OS), leads to lipids peroxidation, alters proteins expression, and results in DNA fragmentation and male infertility. Accurate assessment of ROS is important as it provides information about oxidative stress as an underlying cause of male infertility. Different direct and indirect methods and instruments are available for the laboratory measurement of oxidative stress in seminal plasma and spermatozoa. The measurement of ROS by the chemiluminescence assay is a direct method that can measure both extracellular and intracellular (global) ROS in real-time using luminol as probe. This assay provides reference values that can help differentiate infertile men from fertile men. Total antioxidant capacity measurement in seminal plasma is indicative of the antioxidant reserves. DNA fragmentation is determined by several assays, including the TUNEL assay. The TUNEL assay measures single- and double-strand damage in spermatozoa as a result of oxidative stress. Measurement of oxidation reduction potential (ORP) in semen and seminal plasma is a measure of the redox potential or the oxidative stress status in a given sample. These tests can be included as advanced andrology screening diagnostic approaches that can complement routine semen analysis and can help explain the underlying cause of idiopathic or unexplained male infertility. This chapter outlines the importance of oxidative stress and its measurement in semen and seminal plasma.

<strong><em>Background & aim</em></strong><strong><em>:</em></strong> Idiopathic male infertility refers to the condition in which there is no clear cause for the diagnosis of infertility. Human menopausal gonadotropin (HMG) containing the follicle-stimulating hormone and luteinizing hormone is a medication that causes ovarian follicles to grow in women. This medication can also induce spermatogenesis in men. The present study was conducted to investigate and compare the rates of pregnancy and live birth in partners of men with unexplained infertility after the injection of 8 and 12 ampules of HMG.<br /> <strong><em>Methods</em></strong><strong><em>:</em></strong> This clinical trial study was carried out on 22 men with unexplained infertility who referred to the Urology Clinic of Rafsanjan University of Medical Sciences, Rafsanjan, Iran, during March 2016 and December 2018. The patients were randomly divided into two groups each of which included 11 cases. For one group 8 HMG injections and for the other group 12 HMG injections were administered (two injections per week). Afterward, the results of clinical pregnancy were assessed, and the cases were followed up to live birth after the clinical pregnancy. Data analysis was carried out using the Chi-square test. <strong><em>Results:</em></strong> In this study, the rate of positive pregnancy was reported as 62.5% in the group with 12 HMG injections in comparison to 37.5% in the group with 8 HMG injections. Although the pregnancy rate was higher in the 12-injection group, statistically there was no significant difference (P=0.7).<br /> <strong><em>Conclusion: </em></strong>According to the results of the present study, it can be concluded that for couples with unexplained male infertility, the administration of 8 to 12 HMG injections can increase the chance of pregnancy and live birth. Since this study was the first attempt to evaluate the pregnancy rate after treatment with HMG, it is suggested to perform further studies for the assessment of HMG effect on hormonal profile and chromatin quality.

Study question Can next generation sequencing (NGS) contribute to diagnoses male idiopathic infertility? Summary answer A male factor gene panel identifies pathogenic variants associated to spermatogenic failure in oligozoospermia and cryptozoospermia patients. What is known already In 50% of cases, infertility is due to a male factor problem. Although the causes of male infertility are heterogeneous, genetic causes account for approximately 30% of cases. Some phenotypes have been associated with specific genetic disorders such as chromosomal abnormalities and chromosome Y microdeletions. However, current genetic studies explain only 4% of cases, whilst most cases of male factor infertility remain without a clear diagnosis. Therefore, new techniques that explain the cause of male infertility are needed. Advances in NGS allowed us to study a large number of genes involved in spermatogenesis process in patients with idiopathic infertility. Study design, size, duration A retrospective study was performed from July 2020 until May 2021. A total of 30 patients with abnormal seminal count parameters (oligozoospermic and cryptozoospermic) were included in the male factor gene panel study. Patients carrying Y-chromosome microdeletions or abnormal karyotype were excluded. The control group included 20 normozoospermic healthy donors selected on the basis of normal semen parameters according to the WHO criteria (2010). Participants/materials, setting, methods Genomic DNA extraction from blood-EDTA of the patients was performed using the commercial MagMax DNA MultiSample Ultra kit and the King-Fisher automated extractor (ThermoFisher®). Next Generation Sequencing (NGS) was done using a panel with 426 genes involved in the spermatogenesis process. Panel sequencing for identification of genetic variants was performed using Nextera Enrichment technology (Illumina®). FASTAQ data were processed using BWA and GATK algorithms. VCF files were analyzed using Variant Interpreter software. Main results and the role of chance After data analysis, we observed that eight of the thirty patients studied were carriers of mutations in least one of the genes included in the panel (8/30, 26.7%). We identified the following pathogenic variants: a missense mutation (Phe1052Val) and a deletion (Phe508del) of CFTR gene (2/30, 6.6%), two frameshifts (Asp128GlufsTer34 and Lys1299Ter) of CEP290 (2/30, 6.6%), a missense mutation (Tyr284Cys) of GNRHR gene (1/30, 3.3%), a missense mutation (Tyr416Cys) of SCN5A gene (1/30, 3.3%), a deletion (Ser83del) of NANOS1 gene (1/30, 3.3%), a stop gained in splice region Arg341Ter of TEX14 gene (1/30, 3.3%), a splicing donor c.362 + 2T&amp;gt;C of ESR2 gene (1/30, 3.3%) and a missense mutation (Ser321Leu) of DNAH5 gene (1/30, 3.3%), which are related to spermatogenesis failure. Additionally, some variants classified as benign have been identified, which are not associated with pathogenicity. All the variants identified are related with male infertility, affecting spermatogenesis process, such as congenital bilateral absence of the vas deferens (CFTR), reproductive system syndrome (CEP190), endocrine disorder (GNRHR, hypogonadotropic hypogonadism), testis expressed (SCN5A), spermatogenic failure (NANOS1, TEX14 and ESR2) and syndromic infertility (DNAH5). Nevertheless, no pathogenic mutations associated to spermatogenic failure were observed in the control group. Limitations, reasons for caution The main limitation of this study is the small number of patients included. Further studies including a higher number of males with idiopathic infertility are warranted to confidently link the genetic variants included in our gene panel to spermatogenic failure. Wider implications of the findings The gene list included in our panel represents a step-forward in the diagnosis screening of males with altered sperm parameters. Our results may add in the knowledge of male factor infertility in order to provide etiologic factors towards a personalized treatment and adequate genetic counselling. Trial registration number Not applicable

FSH receptor gene polymorphisms in fertile and infertile Han-Chinese males