Management Of Male Infertility Research Articles

Sperm DNA fragmentation and infertility: a narrative review.

The purpose of this narrative review is to provide a practical understanding of sperm DNA fragmentation (SDF) in the management of male infertility. A search for systematic reviews and meta-analyses (SRMA) on SDF between April 1st, 2018 and April 1st, 2023 was performed using PubMed and articles were selected as per their relevance to the topic. Guidelines from major societies were also reviewed. Three clinical cases are reported and discussed. The search initially identified 80 articles. We selected 13 SRMAs based on their relevance to the topic. Of the 13 SRMAs, 7 evaluated the effect of SDF on assisted reproductive technology (ART) outcomes and recurrent pregnancy loss, 3 studied the effect of varicocele repair on SDF, and 3 evaluated the role of SDF involving lifestyle and environmental health factors including body mass index and male factor treatment strategies. Evidence suggests that increased SDF has a negative impact on natural pregnancy and ART outcomes. SDF testing may be particularly important in the infertility evaluation of men with varicoceles, idiopathic or unexplained infertility, recurrent pregnancy loss, or previous ART failure. Further studies are needed on SDF testing and the implications it can have on male factor infertility and pregnancy outcomes as well as its implementation in the setting of ART.

Medical & Surgical Management of Male Infertility

Medical & Surgical Management of Male Infertility

New Insights beyond Established Norms: A Scoping Review of Genetic Testing for Infertile Men.

From a diagnostic standpoint, certain approaches to genetic screening in clinical practice remain ambiguous in the era of assisted reproduction. Even the most current guidelines do not provide definite guidance on testing protocols, leaving clinicians to carefully determine which tests best serve patients struggling with infertility. The lack of uniformity in the current practice of male fertility evaluation can prove to be quite costly, thus necessitating healthcare practitioners to carefully appraise the necessity and weigh the advantages against potential economic and psychological detriments. The objective of this review is to map the existing literature on the general topic of the clinical indications of routine karyotyping and/or AZF screening in infertile men, identify key concepts, determine where the gaps are, and lastly, provide an overview of the conclusions drawn from a body of knowledge that varies widely in terms of methodologies or disciplines. A thorough search was conducted for the published findings up until July 2023, utilizing PubMed (MEDLINE). This comprehensive search involved the use of specific search keywords, either individually or in combination. The search terms employed were as follows: "Karyotype", "Klinefelter" or "KS" or "47,XXY", "AZF" or "Azoospermi*" and/or "microdeletion*" in the title or abstract. Once the titles and abstracts of selected articles were obtained, the complete texts of linked papers were meticulously scrutinized. A total of 191 records were identified from PubMed. During screening, 161 records (84.3%) were eliminated. Finally, 30 papers were included in this scoping review, which was conducted in 18 countries. The number of sequence tag sites (STSs) used in the studies varied from 5 to 59. The rate of AZF deletions among patients with NOA ranged from 1.3% to 53%. The mean frequency was estimated to be 5.6%. The rate of YCM among patients with XXY karyotype was nil in 19 out of 30 studies (63%), whilst, in the remaining studies, the rate varied from 0.8% to 67%. This review provides insights into managing male infertility. The presence of spermatozoa in ejaculation and successful surgical retrieval cannot be excluded for individuals with AZFb/AZFbc microdeletions. Screening for Y chromosome microdeletions is not needed for mosaic or classic KS. Only 1% of individuals with sperm concentration exceeding 1×106 sperm/mL and less than 5×106 sperm/mL exhibit AZF microdeletions; therefore, testing referral for such populations may need reassessment. Individuals with mosaic monosomy X karyotype and certain chromosomal anomalies should be referred for AZF deletion screening. These findings have implications for male infertility management and future research.

Male infertility: an overview of etiology, diagnosis and management

Male infertility, a multifaceted condition characterized by the inability to achieve pregnancy within a partner after a year of unprotected intercourse, affects approximately 7% of men globally. The etiology of male infertility is diverse, including genetic abnormalities, hormonal imbalances, physical obstructions, and lifestyle factors. This review synthesizes current knowledge on the causes, diagnostic methods, and therapeutic interventions for male infertility, with an emphasis on recent advances in genetic and assisted reproductive technologies (ART). The diagnostic approach to male infertility involves a comprehensive evaluation, including semen analysis, hormonal profiling, genetic testing, and imaging techniques, to identify underlying causes. Management strategies range from lifestyle modifications and pharmacological treatments to surgical interventions and ART, such as in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Emerging technologies, including the use of artificial intelligence in semen analysis and the development of novel sperm retrieval techniques, promise to enhance diagnostic accuracy and treatment outcomes. Despite significant progress, challenges remain in improving access to care and addressing ethical considerations in the use of ART. This review highlights the importance of a multidisciplinary approach to the management of male infertility, integrating advances in medical science with considerations of patient well-being and ethical standards. Future research directions include elucidating the genetic basis of idiopathic male infertility, optimizing ART outcomes, and developing personalized treatment strategies. The ultimate goal is to improve the reproductive health and quality of life for affected individuals and couples.

Toward clinical exomes in diagnostics and management of male infertility

Infertility, affecting ∼10% of men, is predominantly caused by primary spermatogenic failure (SPGF). We screened likely pathogenic and pathogenic (LP/P) variants in 638 candidate genes for male infertility in 521 individuals presenting idiopathic SPGF and 323 normozoospermic men in the ESTAND cohort. Molecular diagnosis was reached for 64 men with SPGF (12%), with findings in 39 genes (6%). The yield did not differ significantly between the subgroups with azoospermia (20/185, 11%), oligozoospermia (18/181, 10%), and primary cryptorchidism with SPGF (26/155, 17%). Notably, 19 of 64 LP/P variants (30%) identified in 28 subjects represented recurrent findings in this study and/or with other male infertility cohorts. NR5A1 was the most frequently affected gene, with seven LP/P variants in six SPGF-affected men and two normozoospermic men. The link to SPGF was validated for recently proposed candidate genes ACTRT1, ASZ1, GLUD2, GREB1L, LEO1, RBM5, ROS1, and TGIF2LY. Heterozygous truncating variants in BNC1, reported in female infertility, emerged as plausible causes of severe oligozoospermia. Data suggested that several infertile men may present congenital conditions with less pronounced or pleiotropic phenotypes affecting the development and function of the reproductive system. Genes regulating the hypothalamic-pituitary-gonadal axis were affected in >30% of subjects with LP/P variants. Six individuals had more than one LP/P variant, including five with two findings from the gene panel. A 4-fold increased prevalence of cancer was observed in men with genetic infertility compared to the general male population (8% vs. 2%; p= 4.4×10-3). Expanding genetic testing in andrology will contribute to the multidisciplinary management of SPGF.

Use of empirical medical therapies for idiopathic male infertility in Australia and New Zealand.

Idiopathic male infertility is common, yet there is no approved treatment. This study aimed to understand practice patterns towards empirical medical therapy (EMT) for idiopathic male infertility in Australia and New Zealand (NZ). Clinical members of the Endocrine Society of Australia, Fertility Society of Australia & NZ, and Urological Society of Australia & NZ were invited to complete a survey. Questions included demographics, EMT practice habits, and thoughts regarding infertility case scenarios. Unadjusted group differences between specialists, those with and without additional training in male infertility, and frequency of managing it were evaluated. Overall, 147 of 2340 members participated (6.3%); majority were endocrinologists and gynaecologists. Participants were experienced; 35% had completed additional training in male infertility and 36.2% reported they frequently manage male infertility. Gynaecologists were more likely to manage male infertility and attend education courses than endocrinologists and urologists. Beliefs about the effect of EMT on sperm concentration and pregnancy did not differ between speciality types. Many respondents considered all patient scenarios suitable for EMT. Of medications, hCG and clomiphene were selected most. Two respondents indicated they would use testosterone to treat male infertility. This study demonstrates common use of EMT in Australia and NZ for idiopathic male infertility. The breadth of responses reflects a lack of consensus within the current literature, highlighting the need for further research to clarify their role in the management of idiopathic male infertility.

A Systemic Review on Use of Medicinal Plant for Management of Male Infertility

A recent issue with current society is the fall in male infertility. In 50% of instances, couple infertility is caused by the failure in spermatogenesis of the male partner. The male reproductive system is impacted by a variety of factors that lead to infertility, including genitourinary tract infections, endocrine abnormalities, immunological factors, lifestyle, stress, and drug-related damage. There are medications and therapies for male infertility, but they are not very effective, have harmful side effects, and are contraindicated. Plants are among the greatest natural cures for illnesses since they have very few side effects and include a variety of phytoconstituents from different chemical classes. Depending on their concentration, plant bioactive such as flavonoids, polyphenols, glycosides, alkaloids, and terpenoids might have a variable effect on sperm quality - either positively or adversely. These compounds have been suggested as organic reactive oxygen species scavengers for the treatment of male infertility. This review makes an effort to compile the available information and offer perspectives for upcoming investigations on how plants affect male gonads. This review summarizes the most recent research on the use of phytoconstituents to increase testosterone production, support healthy spermatogenesis, and prevent age-related degenerative illnesses linked to low levels of testosterone. This review includes information on about 45 herbal plants that have been published in several papers. The articles have several headings, including plant taxonomy, bioactive components, impacts on fertility, and medical applications. This review provides information on the applications of natural sources for male fertility enhancement and their potential mechanisms of action.

(302) Intertest Reliability of Seminal Round Cells and Leukocytes Without Treatment in Men Presenting for Infertility

Abstract Introduction Pyospermia may be due to infection or inflammation along the male reproductive tract. Semen round cells and leukocytes can have a major impact on the management of infertility yet we have a poor understanding of the natural history of patients with seminal round cells or pyospermia. Objective We aimed to assess the intertest reliability of seminal leukocytes and round cells within serial semen analyses in patients without treatment. Methods We conducted a retrospective review of men presenting to a high-volume fertility center for evaluation who had multiple semen analyses assessed for leukocytes between 2/1/2022 and 1/1/2023. Men with azoospermia or who received treatment for pyospermia including antibiotics or surgery in the interval between the tests were excluded. We recorded round cells, the presence of leukocytes, and days between tests. The presence of leukocytes was detected using QwikCheck™ Test Strips which report a positive result if the concentration of leukocytes was greater or equal to 1 million/ml. A Bland-Altman assessment of agreement was conducted to assess the agreement of the number of round cells between the first and second semen analysis. The limits of agreement (LoA) represent the 95% confidence intervals between which we expect most of the differences between measurements. The number of round cells was log-transformed prior to analysis as they were positively skewed. A Cohen Kappa test was used to assess the agreement between the presence of leukocytes in the first sample and the second sample. Results One hundred patients were included in the analysis. The mean time between tests was 75 days (SD: 68.3 days) ranging from 1 to 285 days. There was a median of 2.95 million round cells in the initial semen analysis and 2.45 million round cells in the follow-up semen analysis. Nineteen patients had positive leukocytes on the initial sample and fifteen on the second sample. Eight patients had persistently positive leukocytes. The assessment of agreement for the round cells in the initial and follow-up semen analysis shows a lower LoA of 22% and an upper LoA of 582% meaning that most measurements of round cells in the follow-up tests are estimated to be between 22% and 582% of the initial measurement. The wide range of LoAs suggests poor agreement between tests. The kappa for the presence of leukocytes in the first and second sample was 0.36 (CI 0.13-0.60) which would be considered a fair agreement. Conclusions Round cells and semen leukocytes are poorly understood but are used to aid in the diagnosis and management of male infertility. The number of round cells and the presence of pyospermia between samples varies greatly in patients even without treatment. Providers should consider these discrepancies prior to initiating treatment of pyospermia in men presenting for infertility. Further study is needed to gain a better understanding of how round cells and semen leukocytes should influence management of men with infertility. Providers should be cautious when using the presence of round cells or pyospermia to influence treatment as there is poor consistency between tests even without pyospermia treatment. Disclosure No.

Partial Epididymal Obstruction as a Cause of Idiopathic Oligozoospermia: A Reproductive Urologist's Perspective following 35 Years of Surgical and Clinical Experience.

The role of partial epididymal obstruction as contributing to the development of oligozoospermia has been neglected for decades. In the early 1970s, however, Robert Schoysman, a gynecological surgeon devoted to the surgical and medical management of male factor infertility, dedicated many efforts to study such a pathology and its possible effects on male fertility. Following the studies of this pioneer in the field, we concentrated our attention to the patterns of partial and complete epididymal obstruction during surgical scrotal exploration, once made possible even in oligozoospermic men by diagnostic and therapeutic interventions, such as vasovesciculography or seminal tract washout test, at present considered obsolete and no longer feasible in light of the current guidelines. Interestingly, we found signs of partial epididymal obstruction in about 30% of oligozoospermic men with normal testicular volume and serum FSH level as well as normal spermatogenesis at testis biopsy. We, then, compared the findings of scrotal ultrasound with those of scrotal exploration and found that the ultrasound abnormalities of the epididymis were highly predictive of anatomic alteration of the gland. In the present study, we report our experience, together with a historical review of the literature, on this topic.

Male Infertility: New Developments, Current Challenges, and Future Directions.

There have been many significant scientific advances in the diagnostics and treatment modalities in the field of male infertility in recent decades. Examples of these include assisted reproductive technologies, sperm selection techniques for intracytoplasmic sperm injection, surgical procedures for sperm retrieval, and novel tests of sperm function. However, there is certainly a need for new developments in this field. In this review, we discuss advances in the management of male infertility, such as seminal oxidative stress testing, sperm DNA fragmentation testing, genetic and epigenetic tests, genetic manipulations, artificial intelligence, personalized medicine, and telemedicine. The role of the reproductive urologist will continue to expand in future years to address different topzics related to diverse questions and controversies of pathophysiology, diagnosis, and therapy of male infertility, training researchers and physicians in medical and scientific research in reproductive urology/andrology, and further development of andrology as an independent specialty.

Impact of depression and the potential effect of its treatment on semen parameters

BackgroundUp to 30% of male infertility may be idiopathic. Researchers are looking into psychological problems, particularly depression, as possible risk factors for such idiopathic etiology. We aimed to assess how depression affects Egyptian patients’ semen parameters and its indicators for male fertility and to evaluate the potential positive influence of improving the score of depression on these parameters. A prospective observational pilot clinical study included twenty-one male patients with moderate, severe, or very severe depression. They were subjected to baseline semen analysis. All patients were treated by serotonin and norepinephrine reuptake inhibitors (SNRIs). Those who showed improvement in their depression, within the following 6 months, were eligible for a second evaluation of their semen. We compared baseline semen parameters of all patients to 2021-WHO lower normal limit as well as post-improvement values.ResultsOnly 16 patients showed improvement in their depression after treatment with SNRIs and were candidates for the 2nd assessment of semen analysis. No significant improvements could be detected except for volume. Yet, on repeating the comparisons including only patients with abnormal baseline semen parameters, significant improvements were observed in most semen parameters, including semen volume, sperm count per ejaculate, and percentage of sperm motility either progressive or total.ConclusionThe results addressed the potential impact of depression on male fertility in a sample of Egyptian patients through a negative effect on semen parameters. This effect is neither sole nor direct and may require either predisposed individuals or the existence of other co-factors to be manifested. However, the appropriate treatment of depression may reverse such effects and help in the management of male infertility.

Oxidative stress in male infertility and therapeutic approach: A mini-review

Growing evidence suggests that oxidative stress is a major cause of male infertility. Spermatozoa are highly sensitive cells due to the vulnerability of their membrane fatty acids and the diminished antioxidant defense. Reactive oxygen species (ROS) impact multiple signaling pathways involved in mitochondrial dysfunction, hormonal unbalance and semen quality decline. The origin of ROS is diverse, including generated normal cellular metabolism, environmental exposure, advanced paternal age and inflammation. Research has indicated that antioxidant supplementation can improve oxidative stress and reduce the risk of chronic diseases. Moreover, it is widely known that antioxidant supplementation can enhance sperm quality and increase the pregnancy rate in couples undergoing fertility treatments. The current study highlights the deleterious effect of ROS and its impact on semen function. In addition, it contributes to the development of a clinical approach for the use of antioxidants in the management of male infertility.

Homoeopathic Management of Male Infertility—A Case Series

Abstract Background and Objectives Male infertility means a man is not able to start a pregnancy with his female partner. Infertility affects 10 to 15% of the couples globally. Male factor infertility contributes to about 20 to 30% of the cases. Low sperm concentration, poor sperm motility and abnormal sperm morphology are the main etiological factors for male infertility. For some patients, high cost of conventional treatment can be a deterrent while some fail to respond to it. Therefore, there is a need to explore the role of homoeopathy as an alternative. Methods Five male patients with infertility were treated with homoeopathic medicine based on the totality of symptoms after consulting repertory and Materia Medica. Further studies with suitable sample size are the cases were followed up with laboratory investigations are reported according to the HOM-CASE guidelines. Results Improvement was guaged by sperm analysis of all five men during treatment and all five cases resulted in pregnancy. Conclusion Further studies with suitable sample size are Warranted for further validation of the results.

Proteomic approach towards identification of seminal fluid biomarkers from individuals with severe oligozoospermia, cryptozoospermia and non-obstructive azoospermia: a pilot study.

Infertility becomes a global problem that affects to the same extent females and males. As reasons of male infertility can differ among individuals, the accurate diagnostics is essential for effective treatment. The most problematic both in diagnostics and in treatment are disturbances of spermatogenesis. Seminal fluid is rich in proteins that potentially can serve as markers for male infertility and among them, markers of spermatogenesis which are highly desired. To find biomarkers of spermatogenesis, we applied comparative proteomics using nano ultra performance liquid chromatography and tandem mass spectrometry (nanoUPLC-MS/MS) followed by single-sample Western blotting (WB) using seminal fluid samples from males with different types of infertility including non-obstructive azoospermia (NOA), cryptozoospermia (C) and severe oligozoospermia (SO). Then, the extensive survey on the identified proteins and their function in male reproductive system has been done. The proteomic approach has enabled to identified five seminal fluid proteins being potential markers of spermatogenesis disorders: ADGRG2, RAB3B, LTF, SLC2A3 and spermine synthase (SMS). Among them ADGRG2 seems to be strongly involved in male infertility. In addition, WB indicated that the distribution of LTF, SLC2A3 and SMS was not coherent among the individuals, especially in a group with NOA. Functional annotation analysis and search in proteomics databases revealed that vast majority of the proteins originated from extracellular environment. The presented data point out several proteins that potentially can become biomarkers of male infertility. The data suggest, however, different mechanisms behind the male infertility indicating that the etiology is more complex. We assume that recognition of these mechanisms may lead to the creation of specific protein panel helpful in the management of male infertility and therefore, further studies are required.

Evaluating the Predictive Value of Diagnostic Testicular Biopsy for Sperm Retrieval Outcomes in Men with Non-Obstructive Azoospermia.

Non-obstructive azoospermia (NOA) presents a challenge in male infertility management. This study aimed to assess the efficacy of diagnostic testicular biopsy (DTB) in predicting sperm retrieval success via therapeutic testicular biopsy (TTB) and to understand the role of systemic inflammation in microdissection testicular sperm extraction (mTESE) outcomes. A retrospective analysis was conducted on 50 NOA males who underwent mTESE at the University of Ioannina's Department of Urology from January 2017 to December 2019. All participants underwent thorough medical evaluations, including semen analyses and endocrinological assessments. DTB did not detect spermatozoa in half of the patients who later showed positive sperm findings in TTB. Preoperative variables, such as age, plasma levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), total testosterone (TT), prolactin (PRL), estradiol (E2), and inflammation biomarkers (neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), monocyte-eosinophil ratio (MER)), were not consistently predictive of sperm retrieval success. Notably, TTB-negative patients had elevated NLR and PLR values, suggesting a possible link between systemic inflammation and reduced sperm retrieval during mTESE. The findings question the necessity of an initial DTB, which might provide misleading results. A negative DTB should not deter further TTB or intracytoplasmic sperm injection (ICSI) attempts. The study emphasizes the need for further research to refine diagnostic approaches and deepen the understanding of factors influencing sperm retrieval in NOA patients, ultimately enhancing their prospects of biological parenthood.

Effects of the aqueous extract of Anthocleista liebrechtsiana leaves (Longamiceae) on ethanol-induced spermatic disorders in rats

Anthocleista liebrechtsiana is a plant used in traditional medicine in Cameroon to treat sexual asthenia and male infertility. In order to evaluate the effects of Anthocleista. liebrechtsiana hydroalcoholic extract leaves on ethanol-induced sperm disorders in rats, adult male rats were divided into 4 groups of five rats each. The experimental period lasted 75 days. It was divided into two phases: an oligospermia or azoospermia induction phase (21 days) during which all the animals were intoxicated with 40 ° ethanol at a dose of 6 g/kg except the normal control group, and the treatment phase which lasted 54 days. During the latter phase, the animals of the negative control group received ethanol and distilled water per os; those of test groups A and B received ethanol and hydroalcoholic extract at doses of 150 and 300 mg/kg, respectively. At the end of this period, the animals were anesthetized and then sacrificed. Reproductive organs and annex glands were removed and weighed; arteriovenous blood was collected in tubes for testosterone assay. Sperm count, motility, sperm vitality was determined, and histopathological analysis of the testis, epididymis and prostate was performed. The results of the study showed that treatment of rats with 40° ethanol has significantly reduced body weight, relative weight of reproductive organs and the annex glands, the number of spermatozoa, their mobility and vitality, and the level of testosterone compared to the normal group. The treatment with the hydroalcoholic extract of Anthocleista liebrechtsiana significantly corrected the weight of the reproductive organs and annexed glands, and the number, mobility and vitality of spermatozoa. These results indicate the ability of the hydroalcoholic extract of Anthocleista. liebrechtsiana to correct the deleterious effects of ethanol on sperm parameters. These results thereby justify the use of Anthocleista. liebrechtsiana leaves in the management of male infertility in the traditional pharmacopoeia.

Combined evaluation of prolactin-induced peptide (PIP) and extracellular signal-regulated kinase (ERK) as new sperm biomarkers of FSH treatment efficacy in normogonadotropic idiopathic infertile men.

Nearly, 40% of the causes of male infertility remain idiopathic. The only suggested treatment in idiopathic oligo- and/or asthenozoospermia in normogonadotropic patients is the FSH. In the current clinical practice, efficacy is exclusively assessable through semen analysis after 3months of treatment. No molecular markers of treatment efficacy are appliable in clinical practice. The aim of the present work is to evaluate the combination of extracellular signal regulated kinase (ERK) 1 and 2 and prolactin inducible peptide (PIP) as potential markers of idiopathic infertility and FSH treatment efficacy. Western blot and confocal microscopy were performed to analyze the modulation of PIP and ERK1/2 in idiopathic infertile patients (IIP) sperm cells. Taking advantage of mass spectrometry analysis, we identified these proteins unequivocally in sperm cells. We demonstrated a significant decrease of both PIP protein and of ERK1/2 levels in spermatozoa obtained from IIP in comparison to healthy fertile patients (HFP). Conversely, we reported a significant increase of these markers comparing infertile patientsbefore and after 3months of FSH treatment. Importantly, this correlated with an increase in total number of sperm and sperm motility after FSH treatment. Finally, we identified of PIP and ERK2 proteins in sperm samples by proteomic analysis. The combined evaluation of ERK1/2 and PIP proteins might represent a useful molecular marker to tailor FSH treatment in the management of male normogonadotropic idiopathic infertility.

P-082 Estradiol levels in idiopathic male infertility

Abstract Study question Investigating estradiol in relation with other sperm parameters might reveal new correlations which would help our understanding of male idiopathic infertility Summary answer Statistical significance was found in a series of correlations of E2 levels and sperm, hormonal and health parameters What is known already Male infertility is a rising major health concern, with sperm counts decreasing by 50-60% in the recent decades. The causes for male infertility are very different (genetic, systemic, neurological, infections, trauma, etc.), but at least 44% of cases are idiopathic. Estradiol (E2) regulates spermatogenesis by binding to classical intracellular estrogen receptors or membrane estrogen receptors to trigger genomic and nongenomic signal transduction pathways. Although E2 doesn’t carry any prognostic value by itself, as its levels don’t vary significantly between infertile and fertile men, its association with other parameters may lead to a better understanding of male infertility Study design, size, duration the design of cross-sectional study comprising 111 subjects- 87 infertile patients (median: 34 years, range 20–55 years) and 24 control (median: 33 years, range 20–45 years). The subjects were included in this study during 3 years (between October 2019- September2022). Inclusion criteria: spermatic parameters according to WHO 2010 Standards Exclusion criteria: Radiotherapy and/or pelvic chemotherapy (over the last 6 months), known genetic aberrations, endocrine diseases, urogenital infections, bilateral orchiectomy, vasectomy and occupational exposure. Participants/materials, setting, methods Infertile men were grouped in azoospermia (AZOO), oligoasthenoteratozoospermia (OATS/OATSS) and oligoasthenozoospermia (OAS/OASS). Blood and semen samples were collected and E2 levels were measured in both seminal and blood samples, along with sperm parameters (sperm count, motility, morphology) and other factors (BMI, hormone and vitamin D levels, BsmI polymorphism in the vitamin D receptor gene) were evaluated. E2 levels were assayed using the electrochemiluminescence method with the RocheCobas E601 autoanalyzer. Main results and the role of chance E2 varies slightly between the different patients’ groups, the highest values being found in the OAT/OATSS group. BMI is higher in the infertile group; significant higher values were found for the OAS/OASS (p = 0.002) and OATS/OATS (p = 0.017) groups. Statistical analysis has revealed a significant difference between serum and seminal E2 levels in each group (AZOO p = 0.0355; OATS/OATSS p = 0.0156; control p = 0.0009), but also between OATS/OATSS seminal group and control seminal group (p = 0.0366). The E2/Inhibin ratio presented higher values in patients with OATS/OATSS (p = 0.0031) and azoospermia (p = 0.0059). The lowest values of E2/Vitamin D ratio were detected in the OAS/OASS and OATS/OATSS groups (p = 0.0254), A significant increase of E2 serum level was observed in patients from the OATS/OATSS group in the case of homozygous for mutant allele of BsmI polymorphism (p = 0.0419). The results bring new evidence regarding the role of E2 in male infertility. The obtained data indicates an interplay between E2 and Inhibin B and vitamin D serum levels, highlighting it’s the role in male infertility. Limitations, reasons for caution The study could be extended to a larger population sample, in order to further validate the obtained results Wider implications of the findings Estradiol activity plays an important role in male fertility and along with the investigated parameters could serve as potential markers in the diagnosis and management of male infertility. Trial registration number PN-III-P2-2.1-PED-2019-4402

A Machine Learning Approach for the Prediction of Testicular Sperm Extraction in Nonobstructive Azoospermia: Algorithm Development and Validation Study.

Testicular sperm extraction (TESE) is an essential therapeutic tool for the management of male infertility. However, it is an invasive procedure with a success rate up to 50%. To date, no model based on clinical and laboratory parameters is sufficiently powerful to accurately predict the success of sperm retrieval in TESE. The aim of this study is to compare a wide range of predictive models under similar conditions for TESE outcomes in patients with nonobstructive azoospermia (NOA) to identify the correct mathematical approach to apply, most appropriate study size, and relevance of the input biomarkers. We analyzed 201 patients who underwent TESE at Tenon Hospital (Assistance Publique-Hôpitaux de Paris, Sorbonne University, Paris), distributed in a retrospective training cohort of 175 patients (January 2012 to April 2021) and a prospective testing cohort (May 2021 to December 2021) of 26 patients. Preoperative data (according to the French standard exploration of male infertility, 16 variables) including urogenital history, hormonal data, genetic data, and TESE outcomes (representing the target variable) were collected. A TESE was considered positive if we obtained sufficient spermatozoa for intracytoplasmic sperm injection. After preprocessing the raw data, 8 machine learning (ML) models were trained and optimized on the retrospective training cohort data set: The hyperparameter tuning was performed by random search. Finally, the prospective testing cohort data set was used for the model evaluation. The metrics used to evaluate and compare the models were the following: sensitivity, specificity, area under the receiver operating characteristic curve (AUC-ROC), and accuracy. The importance of each variable in the model was assessed using the permutation feature importance technique, and the optimal number of patients to include in the study was assessed using the learning curve. The ensemble models, based on decision trees, showed the best performance, especially the random forest model, which yielded the following results: AUC=0.90, sensitivity=100%, and specificity=69.2%. Furthermore, a study size of 120 patients seemed sufficient to properly exploit the preoperative data in the modeling process, since increasing the number of patients beyond 120 during model training did not bring any performance improvement. Furthermore, inhibin B and a history of varicoceles exhibited the highest predictive capacity. An ML algorithm based on an appropriate approach can predict successful sperm retrieval in men with NOA undergoing TESE, with promising performance. However, although this study is consistent with the first step of this process, a subsequent formal prospective multicentric validation study should be undertaken before any clinical applications. As future work, we consider the use of recent and clinically relevant data sets (including seminal plasma biomarkers, especially noncoding RNAs, as markers of residual spermatogenesis in NOA patients) to improve our results even more.

Mitochondria Quality Control and Male Fertility.

Mitochondria are pivotal to cellular homeostasis, performing vital functions such as bioenergetics, biosynthesis, and cell signalling. Proper maintenance of these processes is crucial to prevent disease development and ensure optimal cell function. Mitochondrial dynamics, including fission, fusion, biogenesis, mitophagy, and apoptosis, maintain mitochondrial quality control, which is essential for overall cell health. In male reproduction, mitochondria play a pivotal role in germ cell development and any defects in mitochondrial quality can have serious consequences on male fertility. Reactive oxygen species (ROS) also play a crucial role in sperm capacitation, but excessive ROS levels can trigger oxidative damage. Any imbalance between ROS and sperm quality control, caused by non-communicable diseases or environmental factors, can lead to an increase in oxidative stress, cell damage, and apoptosis, which in turn affect sperm concentration, quality, and motility. Therefore, assessing mitochondrial functionality and quality control is essential to gain valuable insights into male infertility. In sum, proper mitochondrial functionality is essential for overall health, and particularly important for male fertility. The assessment of mitochondrial functionality and quality control can provide crucial information for the study and management of male infertility and may lead to the development of new strategies for its management.