Non-invasive biomarkers for sperm retrieval in non-obstructive patients: a comprehensive review.

Recent advancements in reproductive medicine have guided novel strategies for addressing male infertility, particularly in cases of non-obstructive azoospermia (NOA). Two prominent invasive interventions, namely testicular sperm extraction (TESE) and microdissection TESE (micro-TESE), have emerged as key techniques to retrieve gametes for assisted reproduction technologies (ART). Both heterogeneity and complexity of NOA pose a multifaceted challenge to clinicians, as the invasiveness of these procedures and their unpredictable success underscore the need for more precise guidance. Seminal plasma can be aptly regarded as a liquid biopsy of the male reproductive tract, encompassing secretions from the testes, epididymides, seminal vesicles, bulbourethral glands, and prostate. This fluid harbors a variety of cell-free nucleic acids, microvesicles, proteins, and metabolites intricately linked to gonadal activity. However, despite numerous investigations exploring potential biomarkers from seminal fluid, their widespread inclusion into the clinical practice remains limited. This could be partially due to the complex interplay of diverse clinical and genetic factors inherent to NOA that likely contributes to the absence of definitive biomarkers for residual spermatogenesis. It is conceivable that the integration of clinical data with biomarkers could increase the potential in predicting surgical procedure outcomes and their choice in NOA cases. This comprehensive review addresses the challenge of sperm retrieval in NOA through non-invasive biomarkers. Moreover, we delve into promising perspectives, elucidating innovative approaches grounded in multi-omics methodologies, including genomics, transcriptomics and proteomics. These cutting-edge techniques, combined with the clinical and genetics features of patients, could improve the use of biomarkers in personalized medical approaches, patient counseling, and the decision-making continuum. Finally, Artificial intelligence (AI) holds significant potential in the realm of combining biomarkers and clinical data, also in the context of identifying non-invasive biomarkers for sperm retrieval.

Undiagnosed RASopathies in infertile men.

RASopathies are syndromes caused by congenital defects in the Ras/mitogen-activated protein kinase (MAPK) pathway genes, with a population prevalence of 1 in 1,000. Patients are typically identified in childhood based on diverse characteristic features, including cryptorchidism (CR) in >50% of affected men. As CR predisposes to spermatogenic failure (SPGF; total sperm count per ejaculate 0-39 million), we hypothesized that men seeking infertility management include cases with undiagnosed RASopathies. Likely pathogenic or pathogenic (LP/P) variants in 22 RASopathy-linked genes were screened in 521 idiopathic SPGF patients (including 155 CR cases) and 323 normozoospermic controls using exome sequencing. All 844 men were recruited to the ESTonian ANDrology (ESTAND) cohort and underwent identical andrological phenotyping. RASopathy-specific variant interpretation guidelines were used for pathogenicity assessment. LP/P variants were identified in PTPN11 (two), SOS1 (three), SOS2 (one), LZTR1 (one), SPRED1 (one), NF1 (one), and MAP2K1 (one). The findings affected six of 155 cases with CR and SPGF, three of 366 men with SPGF only, and one (of 323) normozoospermic subfertile man. The subgroup "CR and SPGF" had over 13-fold enrichment of findings compared to controls (3.9% vs. 0.3%; Fisher's exact test, p = 5.5 × 10-3). All ESTAND subjects with LP/P variants in the Ras/MAPK pathway genes presented congenital genitourinary anomalies, skeletal and joint conditions, and other RASopathy-linked health concerns. Rare forms of malignancies (schwannomatosis and pancreatic and testicular cancer) were reported on four occasions. The Genetics of Male Infertility Initiative (GEMINI) cohort (1,416 SPGF cases and 317 fertile men) was used to validate the outcome. LP/P variants in PTPN11 (three), LZTR1 (three), and MRAS (one) were identified in six SPGF cases (including 4/31 GEMINI cases with CR) and one normozoospermic man. Undiagnosed RASopathies were detected in total for 17 ESTAND and GEMINI subjects, 15 SPGF patients (10 with CR), and two fertile men. Affected RASopathy genes showed high expression in spermatogenic and testicular somatic cells. In conclusion, congenital defects in the Ras/MAPK pathway genes represent a new congenital etiology of syndromic male infertility. Undiagnosed RASopathies were especially enriched among patients with a history of cryptorchidism. Given the relationship between RASopathies and other conditions, infertile men found to have this molecular diagnosis should be evaluated for known RASopathy-linked health concerns, including specific rare malignancies.

Cancer risk and male Infertility: Unravelling predictive biomarkers and prognostic indicators.

In recent years, there has been a global increase in cases of male infertility. There are about 30 million cases of male infertility worldwide and male reproductive health is showing rapid decline in last few decades. It is now recognized as a potential risk factor for developing certain types of cancer, particularly genitourinary malignancies like testicular and prostate cancer. Male infertility is considered a potential indicator of overall health and an early biomarker for cancer. Cases of unexplained male factor infertility have high levels of oxidative stress and oxidative DNA damage and this induces both denovo germ line mutations and epimutations due to build up of 8-hydroxy 2 deoxygunaosine abase which is highly mutagenic and also induces hypomethylation and genomic instability. Consequently, there is growing evidence to explore the various factors contributing to an increased cancer risk. Currently, the available prognostic and predictive biomarkers associated with semen characteristics and cancer risk are limited but gaining significant attention in clinical research for the diagnosis and treatment of elevated cancer risk in the individual and in offspring. The male germ cell being transcriptionally and translationally inert has a highly truncated repair mechanism and has minimal antioxidants and thus most vulnerable to oxidative injury due to environmental factors and unhealthy lifestyle and social habits. Therefore, advancing our understanding requires a thorough evaluation of the pathophysiologic mechanisms at the DNA, RNA, protein, and metabolite levels to identify key biomarkers that may underlie the pathogenesis of male infertility and associated cancer. Advanced methodologies such as genomics, epigenetics, proteomics, transcriptomics, and metabolomics stand at the forefront of cutting-edge approaches for discovering novel biomarkers, spanning from infertility to associated cancer types. Henceforth, in this review, we aim to assess the role and potential of recently identified predictive and prognostic biomarkers, offering insights into the success of assisted reproductive technologies, causes of azoospermia and idiopathic infertility, the impact of integrated holistic approach and lifestyle modifications, and the monitoring of cancer susceptibility, initiation and progression. Comprehending these biomarkers is crucial for providing comprehensive counselling to infertile men and cancer patients, along with their families.

Improved phenotypic classification of male infertility to promote discovery of genetic causes.

An increasing number of genes are being described in the context of non-syndromic male infertility. Linking the underlying genetic causes of non-syndromic male infertility with clinical data from patients is important to establish new genotype-phenotype correlations. This process can be facilitated by using universal nomenclature, but no standardized vocabulary is available in the field of non-syndromic male infertility. The International Male Infertility Genomics Consortium aimed at filling this gap, providing a standardized vocabulary containing nomenclature based on the Human Phenotype Ontology (HPO). The "HPO tree" was substantially revised compared with the previous version and is based on the clinical work-up of infertile men, including physical examination and hormonal assessment. Some causes of male infertility can already be suspected based on the patient's clinical history, whereas in other instances, a testicular biopsy is needed for diagnosis. We assembled 49 HPO terms that are linked in a logical hierarchy and showed examples of morphological features of spermatozoa and testicular histology of infertile men with identified genetic diagnoses to describe the phenotypes. This work will help to record patients' phenotypes systematically and facilitate communication between geneticists and andrologists. Collaboration across institutions will improve the identification of patients with the same phenotypes, which will promote the discovery of novel genetic causes for non-syndromic male infertility.

EAA/EMQN best practice guidelines for molecular diagnosis of Y-chromosomal microdeletions: State of the art 2023.

Testing for AZoospermia Factor (AZF) deletions of the Y chromosome is a key component of the diagnostic workup of azoospermic and severely oligozoospermic men. This revision of the 2013 European Academy of Andrology (EAA) and EMQN CIC (previously known as the European Molecular Genetics Quality Network) laboratory guidelines summarizes recent clinically relevant advances and provides an update on the results of the external quality assessment program jointly offered by both organizations. A basic multiplex PCR reaction followed by a deletion extension analysis remains the gold-standard methodology to detect and correctly interpret AZF deletions. Recent data have led to an update of the sY84 reverse primer sequence, as well as to a refinement of what were previously considered as interchangeable border markers for AZFa and AZFb deletion breakpoints. More specifically, sY83 and sY143 are no longer recommended for the deletion extension analysis, leaving sY1064 and sY1192, respectively, as first-choice markers. Despite the transition, currently underway in several countries, toward a diagnosis based on certified kits, it should be noted that many of these commercial products are not recommended due to an unnecessarily high number of tested markers, and none of those currently available are, to the best of our knowledge, in accordance with the new first-choice markers for the deletion extension analysis. The gr/gr partial AZFc deletion remains a population-specific risk factor for impaired sperm production and a predisposing factor for testicular germ cell tumors. Testing for this deletion type is, as before, left at the discretion of the diagnostic labs and referring clinicians. Annual participation in an external quality control program is strongly encouraged, as the 22-year experience of the EMQN/EAA scheme clearly demonstrates a steep decline in diagnostic errors and an improvement in reporting practice.

Frozen embryo transfer outcomes decline with increasing female body mass index in female but not male factor infertility: analysis of 56,564 euploid blastocyst transfers.

OBJECTIVE: To evaluate the association of body mass index (BMI) with cycle outcomes after euploid frozen blastocyst transfer. DESIGN: Retrospective cohort study. SETTING: Not applicable. PATIENT(S): A total of 56,564 first single autologous euploid frozen embryo transfers from the 2016-2019 Society for Assisted Reproductive Technology database were analyzed using BMI and using World Health Organization BMI cohorts. Subanalyses were performed on cycles among patients with a sole diagnosis of polycystic ovary syndrome (PCOS) (n = 4,626) and among patients with only a male factor (n = 10,854). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Clinical pregnancy, pregnancy loss, and live birth (LB). RESULT(S): Success rates and adjusted odds ratios (aORs) with 95% confidence intervals (CIs) for all outcomes were most favorable among those with normal BMI and progressively worsened with increasing BMI. These trends persisted among patients with PCOS for clinical pregnancy (aOR, 0.99; 95% CI, 0.98-0.997), pregnancy loss (aOR, 1.02; 95% CI, 1.01-1.04), and LB (aOR, 0.98; 95% CI, 0.97-0.99), but not among patients with a male factor only for clinical pregnancy (aOR, 1.00; 95% CI, 0.99-1.01), pregnancy loss (aOR, 1.01; 95% CI, 0.99-1.03), or LB (aOR, 0.99; 95% CI, 0.98-1.00). CONCLUSION(S): In the largest cohort to date, increasing BMI was associated with decreased pregnancy and LB and increased pregnancy loss after euploid frozen embryo transfers among the entire cohort and among patients with a sole diagnosis of PCOS; however, these results were attenuated among patients with a sole diagnosis of male factor infertility, suggesting that associated female infertility diagnoses and not BMI alone may underlie this trend.

The Role of Circular RNAs in Male Infertility and Reproductive Cancers: A Narrative Review.

Infertility is a global health problem affecting about 15% of all couples, of which 50% are due to male infertility. Although the etiology of infertility is known in most infertile men, idiopathic male infertility remains a challenge. Therefore, there is a need for novel diagnostic methods to detect the underlying mechanisms and develop appropriate therapies. Recent studies have focused on the role of non-coding RNAs (ncRNAs) in male infertility. Circular RNAs (CircRNAs), a type of ncRNAs, are found to play a key role in the development of some pathological conditions, including cardiovascular diseases, diabetes, cancers, autoimmune diseases, etc. Several studies have reported the presence of CircRNAs and their target genes in the human reproductive system. In addition, their expression in testicular tissues, sperm cells, and seminal fluid has been identified. Abnormal expression of CircRNAs has been associated with azoospermia and asthenozoospermia in infertile men. The present narrative review provides a brief description of the role of CircRNAs in spermatogenic cells, male infertility, and reproductive cancers. In addition, some CircRNAs have been identified as potential biomarkers for disease detection and treatment.

The impact of obesity and metabolic health on male fertility: a systematic review.

The impact of paternal obesity and metabolic disease on semen quality and fertility outcomes is not fully appreciated. With increasing obesity rates, researchers have studied the intricate relationship between paternal body mass index, metabolic health, and male fertility. This systematic review identified 112 articles in the MEDLINE database between 2013 and 2023 that investigated the effects of body mass index, diabetes, metabolic syndrome, exercise, weight loss medication, or bariatric surgery on semen parameters, sperm quality, or fertility outcomes. This review suggests that obesity, diabetes, and metabolic syndrome have a negative impact on various parameters of male fertility, from semen quality to sperm deoxyribonucleic acid integrity. There is also mounting evidence that male obesity is correlated negatively with live births via both natural conception and assisted reproductive technologies. Lifestyle interventions, such as physical exercise, generally appear to improve male fertility markers; however, the type and intensity of exercise may play a crucial role. Pharmacologic treatments for weight loss, such as metformin and glucagon-like peptide 1 agonists, present a more complex picture, with studies suggesting both beneficial and detrimental effects on male reproductive health. Similarly, surgical interventions, such as gastric bypass surgery, show promise in improving hormonal imbalances but have mixed effects on semen parameters. Future research is needed to clarify these associations and inform clinical guidelines. In the interim, health practitioners should incorporate these insights into clinical practices, encouraging proactive lifestyle changes and providing targeted treatments to improve male reproductive health.

Male infertility.

Clinical infertility is the inability of a couple to conceive after 12 months of trying. Male factors are estimated to contribute to 30-50% of cases of infertility. Infertility or reduced fertility can result from testicular dysfunction, endocrinopathies, lifestyle factors (such as tobacco and obesity), congenital anatomical factors, gonadotoxic exposures and ageing, among others. The evaluation of male infertility includes detailed history taking, focused physical examination and selective laboratory testing, including semen analysis. Treatments include lifestyle optimization, empirical or targeted medical therapy as well as surgical therapies that lead to measurable improvement in fertility. Although male infertility is recognized as a disease with effects on quality of life for both members of the infertile couple, fewer data exist on specific quantification and impact compared with other health-related conditions.

Infertility: Evaluation and Management.

Infertility is the inability to achieve a pregnancy after 12 months of regular, unprotected sexual intercourse. Evaluation and treatment are recommended earlier than 12 months when risk factors for infertility exist, if the female partner is 35 years or older, and in the setting of nonheterosexual partnerships. A comprehensive medical history and physical examination emphasizing the thyroid, breast, and pelvic areas should be performed to help direct diagnosis and treatment. Causes of infertility in females include uterine and tubal factors, ovarian reserve, ovulatory dysfunction, obesity, and hormone-related disorders. Common male factor infertility issues include abnormal semen, hormonal disorders, and genetic abnormalities. Semen analysis is recommended for the initial assessment of the male partner. Evaluation of the female should include assessment of the uterus and fallopian tubes with ultrasonography or hysterosalpingography when indicated. Laparoscopy, hysteroscopy, or magnetic resonance imaging may be needed to evaluate for endometriosis, leiomyomas, or evidence of a previous pelvic infection. Treatment with ovulation induction agents, intrauterine insemination, in vitro fertilization, donor sperm or eggs, or surgery may be necessary. Unexplained male and female infertility can be treated with intrauterine insemination or in vitro fertilization. Limiting alcohol intake, avoiding tobacco and illicit drug use, consuming a profertility diet, and losing weight (if obese) may improve pregnancy success rates.

An Update on Male Canine Infertility.

Infertility in the dog is a common reason for presentation of stud dogs for assessment with veterinarians. This article aims to discuss and outline some of the tests that can be done to try to ascertain the underlying cause of abnormalities found in a semen assessment. Topics discussed are semen alkaline phosphatase measurement, retrograde ejaculation assessment, ultrasound of the male reproductive tract, semen culture, human chorionic gonadotropin response testing, dietary assessment for phytoestrogens, environmental impacts on spermatogenesis, testicular biopsy, supplements to improve semen quality and quantity, and when to expect an improvement in semen quality after starting treatment.

Unlocking the mystery associated with infertility and prostate cancer: an update.

Male-specific reproductive disorders and cancers have increased intensely in recent years, making them a significant public health problem. Prostate cancer (PC) is the most often diagnosed cancer in men and is one of the leading causes of cancer-related mortality. Both genetic and epigenetic modifications contribute to the development and progression of PC, even though the exact underlying processes causing this disease have yet to be identified. Male infertility is also a complex and poorly understood phenomenon believed to afflict a significant portion of the male population. Chromosomal abnormalities, compromised DNA repair systems, and Y chromosome alterations are just a few of the proposed explanations. It is becoming widely accepted that infertility shares a link with PC. Much of the link between infertility and PC is probably attributable to common genetic defects. This article provides an overview of PC and spermatogenic abnormalities. This study also investigates the link between male infertility and PC and uncovers the underlying reasons, risk factors, and biological mechanisms contributing to this association.

Serum interleukin-38 and -41 levels as candidate biomarkers in male infertility.

BACKGROUND: Interleukin (IL)-38 and IL-41 are novel cytokines, but their role in male infertility (MI) is unknown. The purpose of this study was to measure the levels of serum IL-38 and IL-41 in patients with MI and correlate these levels with semen indexes. METHODS: Eighty-two patients with MI and 45 healthy controls (HC) were recruited for this study. Semen parameters were detected using computer-aided sperm analysis, Papanicolaou staining, ELISA, flow cytometry, peroxidase staining and enzyme methods. Serum IL-38 and IL-41 levels were determined by ELISA. RESULTS: Serum IL-38 levels were decreased (P < 0.01) in patients with MI compared with HC. Serum IL-41 levels were significantly higher in patients with MI than in HC (P < 0.0001). In patients with MI, serum IL-38 levels were positively correlated with semen white blood cell counts (r = 0.29, P = 0.009), and there was a positive correlation between semen white blood cell counts and sperm concentration (r = 0.28, P = 0.0100) and seminal plasma elastase (r = 0.67, P < 0.0001). Receiver operating characteristic curve analysis showed that the area under the curve of IL-38 for diagnosing MI was 0.5637 (P > 0.05), and the area under the curve of IL-41 for diagnosing MI was 0.7646 (P < 0.0001). CONCLUSIONS: Serum IL-38 levels were significantly lower, and serum IL-41 levels were higher in patients with MI. These results suggest that IL-38 and IL-41 may be novel biomarkers for the diagnosis of MI.

Evaluation and management of male genital tract infections in the setting of male infertility: an updated review.

PURPOSE OF REVIEW: Male infertility may be secondary to male genital tract infection (MGTI) in an estimated 15% of cases. In the absence of overt clinical signs, evaluation for MGTI beyond semen analysis is not well established. Therefore, we review the literature on the evaluation and management of MGTI in the setting of male infertility. RECENT FINDINGS: A set of international guidelines recommends semen culture and PCR testing, but the significance of positive results remains unclear. Clinical trials evaluating anti-inflammatory or antibiotic treatment report improvements in sperm parameters and leukocytospermia, but data on the effect on conception rates are lacking. Human papillomavirus (HPV) and the novel coronavirus (SARS-CoV-2) have been associated with poor semen parameters and decreased conception rates. SUMMARY: The finding of leukocytospermia on semen analysis prompts further evaluation for MGTI, including focused physical examination. The role of routine semen culture is controversial. Treatment options include anti-inflammatories; frequent ejaculation; and antibiotics, which should not be used in the absence of symptoms or microbiological infection. SARS-CoV-2 represents a subacute threat to fertility that should be screened for in the reproductive history along with HPV and other viruses.

Steroid Hormones in Seminal Plasma: the Relationship with Sperm Quality.

The purpose of this study was to find out whether the seminal testosterone and/or estradiol levels could serve as prognostic criteria for normal spermatogenesis and whether they are able to characterize the sperm pathology. The study involved healthy young male volunteers (n=269); serum and seminal steroid hormones were measured; the sperm concentration, mobility, and morphology were evaluated. The results indicate that the seminal testosterone concentration is lower (p<0.05) and the seminal estradiol is higher than the corresponding parameters in the serum (p<0.05). The seminal testosterone and estradiol concentrations negatively correlated with the sperm concentration, and the seminal estradiol concentration was higher in pathozoospermic than in normospermic men (p<0.05). It is assumed that the seminal estradiol level can be an indicator of sperm quality and serve as a biological predictor of normal spermatogenesis; in addition, this parameter can be used for diagnostic purposes in patients with impaired spermatogenesis induced by excess of estrogens.

Reproduction as a window for health in men.

Male factor infertility is widely considered a harbinger for a man's general health. Failure of reproduction often accompanies other underlying processes, with growing evidence suggesting that a diagnosis of infertility increases the likelihood of developing future cardiac, metabolic, and oncologic diseases. The goal of this review is to provide a comprehensive overview of the research on male fertility as a marker for current and future health. A multidisciplinary approach is essential, and there is growing consensus that the male fertility evaluation offers an opportunity to better men's wellness beyond their immediate reproductive ambitions.

Evolution of the basic semen analysis and processing sperm.

PURPOSE OF REVIEW: The sixth edition of the World Health Organization (WHO) laboratory manual for the examination and processing of human semen was recently published with specific step-by-step instructions for semen evaluation and sperm processing. Point-of-care (POC) testing for semen evaluation and microfluidics for sperm processing are rapidly evolving technologies that could impact how we evaluate and process sperm. Understanding the updated manual in the context of these novel technologies is important. RECENT FINDINGS: Proper standardization of semen evaluation and sperm processing will allow for consistent high-quality results among laboratories worldwide. POC testing could improve access to semen evaluations that generate referrals to male infertility specialists for further assessment. Microfluidics can select functional sperm with decreased DNA fragmentation in semen and testicular biopsy samples for assisted reproductive technology (ART). Clinical outcomes, such as pregnancy rates and live birth rates, have not been shown to be consistently improved with these technologies compared to conventional techniques, although high level evidence research in this area is limited. SUMMARY: POC testing and microfluidics have the potential to be combined with machine learning technologies to improve fertility care. If these technologies are appropriately optimized, they could change how we evaluate and process sperm, and potentially lead to improved ART outcomes.

Male reproductive health after 3 months from SARS-CoV-2 infection: a multicentric study.

PURPOSE: While SARS-CoV-2 infection appears not to be clinically evident in the testes, indirect inflammatory effects and fever may impair testicular function. To date, few long-term data of semen parameters impairment after recovery and comprehensive andrological evaluation of recovered patients has been published. The purpose of this study was to investigate whether SARS-CoV-2 infection affect male reproductive health. METHODS: Eighty patients were recruited three months after COVID-19 recovery. They performed physical examination, testicular ultrasound, semen analysis, sperm DNA integrity evaluation (TUNEL), anti-sperm antibodies (ASA) testing, sex hormone profile evaluation (Total testosterone, LH, FSH). In addition, all patients were administered International Index of Erectile Function questionnaire (IIEF-15). Sperm parameters were compared with two age-matched healthy pre-COVID-19 control groups of normozoospermic (CTR1) and primary infertile (CTR2) subjects. RESULTS: Median values of semen parameters from recovered SARS-CoV-2 subjects were within WHO 2010 fifth percentile. Mean percentage of sperm DNA fragmentation (%SDF) was 14.1 ± 7.0%. Gelatin Agglutination Test (GAT) was positive in 3.9% of blood serum samples, but no positive semen plasma sample was found. Only five subjects (6.2%) had total testosterone levels below the laboratory reference range. Mean bilateral testicular volume was 31.5 ± 9.6 ml. Erectile dysfunction was detected in 30% of subjects. CONCLUSION: Our data remark that COVID-19 does not seem to cause direct damage to the testicular function, while indirect damage appears to be transient. It is possible to counsel infertile couples to postpone the research of parenthood or ART procedures around three months after recovery from the infection.

Genetic Architecture of Azoospermia-Time to Advance the Standard of Care.

BACKGROUND: Crypto- and azoospermia (very few/no sperm in the semen) are main contributors to male factor infertility. Genetic causes for spermatogenic failure (SPGF) include Klinefelter syndrome and Y-chromosomal azoospermia factor microdeletions, and CFTR mutations for obstructive azoospermia (OA). However, the majority of cases remain unexplained because monogenic causes are not analysed. OBJECTIVE: To elucidate the monogenic contribution to azoospermia by prospective exome sequencing and strict application of recent clinical guidelines. DESIGN, SETTING, AND PARTICIPANTS: Since January 2017, we studied crypto- and azoospermic men without chromosomal aberrations and Y-chromosomal microdeletions attending the Centre of Reproductive Medicine and Andrology, Münster. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We performed exome sequencing in 647 men, analysed 60 genes having at least previous limited clinical validity, and strictly assessed variants according to clinical guidelines. RESULTS AND LIMITATIONS: Overall, 55 patients (8.5%) with diagnostic genetic variants were identified. Of these patients, 20 (3.1%) carried mutations in CFTR or ADGRG2, and were diagnosed with OA. In 35 patients (5.4%) with SPGF, mutations in 20 different genes were identified. According to ClinGen criteria, 19 of the SPGF genes now reach at least moderate clinical validity. As limitations, only one transcript per gene was considered, and the list of genes is increasing rapidly so cannot be exhaustive. CONCLUSIONS: The number of diagnostic genes in crypto-/azoospermia was almost doubled to 21 using exome-based analyses and clinical guidelines. Application of this procedure in routine diagnostics will significantly improve the diagnostic yield and clinical workup as the results indicate the success rate of testicular sperm extraction. PATIENT SUMMARY: When no sperm are found in the semen, a man cannot conceive naturally. The causes are often unknown, but genetics play a major role. We searched for genetic variants in a large group of patients and found causal mutations for one in 12 men; these predict the chances for fatherhood.

A bibliometric perspective with research trends and global productivity on the modernization of andrology from the founder of modern clinical andrology Edward Martin to the present.

OBJECTIVE: The number of studies in the field of andrology is increasing day by day, but a bibliometric study covering the entire literature on andrology has not yet been conducted. This bibliometric study aims to shed light on the question of where we came from and where we are going in andrology from past to present. It also aimed to summarize the intellectual structure of andrology to reveal global productivity and identify and map the latest trends of scientific articles published in the field of andrology. MATERIALS AND METHODS: 16,659 articles published between 1980 and 2022 were extracted from the Web of Science and analyzed using various statistical methods. Bibliometric network visualization maps revealed trending topics, global productivity, the most influential studies, and international collaborations. Spearman's correlation analysis was used for determining correlations. RESULTS: The top three productive countries were United States of America (3,452; 20.7%), China (2,300; 13.8%), and Germany (1,069; 6.4%). The top two most productive authors were Agarwal A. (n=130) and Nieschlag E. (n=130). The most productive institution was the Egyptian Knowledge Bank (n=422). From past to present, the most studied subjects were testis, male infertility, spermatozoa, testosterone, infertility, erectile dysfunction, spermatogenesis, sperm, prostate cancer (PCA)/neoplasms, oxidative stress, fertility/fertilization, semen, rat(s), apoptosis, azoospermia, sperm motility, human and varicocele. CONCLUSIONS: The trend topics that have been researched more in recent years include erectile dysfunction, oxidative stress, prostate cancer, sperm quality, sperm parameters, infertility, premature ejaculation, diabetes mellitus, obesity, prognosis, sperm DNA fragmentation/damage, antioxidant, asthenozoospermia, varicocelectomy, COVID-19, inflammation, prostatectomy, metabolic syndrome, hypogonadism, benign prostatic hyperplasia, lower urinary tract symptoms, meta-analysis, sexual dysfunction, peyronie's disease, and proliferation. We identified the research leadership of China, Japan, Turkey and India, in addition to Western countries, such as the USA and European countries.