Global Practice Patterns in the Evaluation of Non-Obstructive Azoospermia: Results of a World-Wide Survey and Expert Recommendations.

PURPOSE: Non-obstructive azoospermia (NOA) represents the persistent absence of sperm in ejaculate without obstruction, stemming from diverse disease processes. This survey explores global practices in NOA diagnosis, comparing them with guidelines and offering expert recommendations. MATERIALS AND METHODS: A 56-item questionnaire survey on NOA diagnosis and management was conducted globally from July to September 2022. This paper focuses on part 1, evaluating NOA diagnosis. Data from 367 participants across 49 countries were analyzed descriptively, with a Delphi process used for expert recommendations. RESULTS: Of 336 eligible responses, most participants were experienced attending physicians (70.93%). To diagnose azoospermia definitively, 81.7% requested two semen samples. Commonly ordered hormone tests included serum follicle-stimulating hormone (FSH) (97.0%), total testosterone (92.9%), and luteinizing hormone (86.9%). Genetic testing was requested by 66.6%, with karyotype analysis (86.2%) and Y chromosome microdeletions (88.3%) prevalent. Diagnostic testicular biopsy, distinguishing obstructive azoospermia (OA) from NOA, was not performed by 45.1%, while 34.6% did it selectively. Differentiation relied on physical examination (76.1%), serum hormone profiles (69.6%), and semen tests (68.1%). Expectations of finding sperm surgically were higher in men with normal FSH, larger testes, and a history of sperm in ejaculate. CONCLUSIONS: This expert survey, encompassing 367 participants from 49 countries, unveils congruence with recommended guidelines in NOA diagnosis. However, noteworthy disparities in practices suggest a need for evidence-based, international consensus guidelines to standardize NOA evaluation, addressing existing gaps in professional recommendations.

Artificial Intelligence in Andrology: From Semen Analysis to Image Diagnostics.

Artificial intelligence (AI) in medicine has gained a lot of momentum in the last decades and has been applied to various fields of medicine. Advances in computer science, medical informatics, robotics, and the need for personalized medicine have facilitated the role of AI in modern healthcare. Similarly, as in other fields, AI applications, such as machine learning, artificial neural networks, and deep learning, have shown great potential in andrology and reproductive medicine. AI-based tools are poised to become valuable assets with abilities to support and aid in diagnosing and treating male infertility, and in improving the accuracy of patient care. These automated, AI-based predictions may offer consistency and efficiency in terms of time and cost in infertility research and clinical management. In andrology and reproductive medicine, AI has been used for objective sperm, oocyte, and embryo selection, prediction of surgical outcomes, cost-effective assessment, development of robotic surgery, and clinical decision-making systems. In the future, better integration and implementation of AI into medicine will undoubtedly lead to pioneering evidence-based breakthroughs and the reshaping of andrology and reproductive medicine.

Lesional CD8+ T-Cell Number Predicts Surgical Outcomes of Melanocyte-Keratinocyte Transplantation Surgery for Vitiligo.

The melanocyte-keratinocyte transplantation procedure (MKTP) treats stable and recalcitrant vitiligo. Despite careful selection of candidates based on clinical stability, the success of the procedure is unpredictable. The aim of our study was to define the immunological profile of stable vitiligo lesions undergoing MKTP and correlate them with clinical outcomes. We included 20 MKTP candidates with vitiligo and a patient with piebaldism as a control. Prior to MKTP, T-cell subsets and chemokines in the recipient skin were measured by flow cytometry and ELISA. During MKTP, melanocytes in the donor skin were quantified by flow cytometry. After MKTP, patients were followed for 12 months and repigmentation was assessed clinically and by ImageJ analysis of clinical photographs. Baseline immunologic biomarkers, duration of clinical stability, and transplanted melanocyte number were correlated to postsurgical repigmentation scores. CD8+ T cells were elevated in 43% of the clinically stable vitiligo lesions. CD8+ T-cell number negatively correlated with postsurgical repigmentation scores (r = -0.635, P = 0.002). Duration of clinical stability, skin chemokines, and transplanted melanocyte number did not influence postsurgical repigmentation. This study demonstrates that CD8+ T-cell number correlates negatively with success of postsurgical repigmentation and can be a biomarker to identify ideal surgical candidates.

Oocytes evaluation and in-vitro fertilization/intra cytoplasmic sperm injection outcomes.

The identification of markers capable of evaluating oocyte quality, its maturation, function, and embryo progression and implantation potential has frequently initiated research interest. However, to date, univocal criteria of oocyte competence do not exist. A major cause of low oocyte quality is evidently advanced maternal age. However, other factors may influence oocyte competence. Among these are obesity, lifestyle factors, genetic and systematic pathologies, ovarian stimulation protocols, laboratory procedures, culture, and environmental conditions. The morphological and maturational evaluation of oocytes is probably the most widely used. Several morphological features, both cytoplasmic (cytoplasmic pattern and hue, presence of vacuoles, refractile bodies, granulation, and smooth endoplasmic reticulum clusters) and extra-cytoplasmic (perivitelline space, zona pellucida thickness, oocyte shape, and polar bodies), have been proposed to distinguish oocytes with the best reproductive potential among a cohort. No single abnormality seems to be sufficiently predictive of the developmental capacity of the oocyte. Some abnormalities such as cumulus cells dysmorphisms, central granulation, vacuoles, and smooth endoplasmic reticulum clusters, however, seem to be associated with poor developmental potential of the embryo, although oocyte dysmorphisms are very common and the data in the literature is limited and provide conflicting views. Other criteria involving gene expression of cumulus cells as well as the metabolomic analysis of spent culture media have been explored. Also, sophisticated technologies such as polar bodies biopsy, meiotic spindle visualization, mitochondrial activity, oxygen consumption, and measurement of glucose-6-phosphate dehydrogenase activity have been proposed. Many of these approaches, however, remain largely research-based and have not found widespread application in clinical service. Due to the lack of consistent data for the assessment of oocyte quality and competence, probably oocyte morphology and oocyte maturity remain important indicators to determine oocyte quality. The aim of this review was to provide spherical attributes and evidence on recent and present research on the topic by analyzing the current methods for evaluation of the oocyte quality, and the impact of oocyte quality on reproductive outcomes. Additionally, current limitations of oocyte quality evaluation are highlighted and insights on future research are provided to optimize the selection techniques of oocytes to improve ART outcomes.

Controversy and Consensus on Indications for Sperm DNA Fragmentation Testing in Male Infertility: A Global Survey, Current Guidelines, and Expert Recommendations.

PURPOSE: Sperm DNA fragmentation (SDF) testing was recently added to the sixth edition of the World Health Organization laboratory manual for the examination and processing of human semen. Many conditions and risk factors have been associated with elevated SDF; therefore, it is important to identify the population of infertile men who might benefit from this test. The purpose of this study was to investigate global practices related to indications for SDF testing, compare the relevant professional society guideline recommendations, and provide expert recommendations. MATERIALS AND METHODS: Clinicians managing male infertility were invited to take part in a global online survey on SDF clinical practices. This was conducted following the CHERRIES checklist criteria. The responses were compared to professional society guideline recommendations related to SDF and the appropriate available evidence. Expert recommendations on indications for SDF testing were then formulated, and the Delphi method was used to reach consensus. RESULTS: The survey was completed by 436 experts from 55 countries. Almost 75% of respondents test for SDF in all or some men with unexplained or idiopathic infertility, 39% order it routinely in the work-up of recurrent pregnancy loss (RPL), and 62.2% investigate SDF in smokers. While 47% of reproductive urologists test SDF to support the decision for varicocele repair surgery when conventional semen parameters are normal, significantly fewer general urologists (23%; p=0.008) do the same. Nearly 70% would assess SDF before assisted reproductive technologies (ART), either always or for certain conditions. Recurrent ART failure is a common indication for SDF testing. Very few society recommendations were found regarding SDF testing. CONCLUSIONS: This article presents the largest global survey on the indications for SDF testing in infertile men, and demonstrates diverse practices. Furthermore, it highlights the paucity of professional society guideline recommendations. Expert recommendations are proposed to help guide clinicians.

The Renaissance of Male Infertility Management in the Golden Age of Andrology.

Infertility affects nearly 186 million people worldwide and the male partner is the cause in about half of the cases. Meta-regression data indicate an unexplained decline in sperm concentration and total sperm count over the last four decades, with an increasing prevalence of male infertility. This suggests an urgent need to implement further basic and clinical research in Andrology. Andrology developed as a branch of urology, gynecology, endocrinology, and, dermatology. The first scientific journal devoted to andrological sciences was founded in 1969. Since then, despite great advancements, andrology has encountered several obstacles in its growth. In fact, for cultural reasons, the male partner has often been neglected in the diagnostic and therapeutic workup of the infertile couple. Furthermore, the development of assisted reproductive techniques (ART) has driven a strong impression that this biotechnology can overcome all forms of infertility, with a common belief that having a spermatozoon from a male partner (a sort of sperm donor) is all that is needed to achieve pregnancy. However, clinical practice has shown that the quality of the male gamete is important for a successful ART outcome. Furthermore, the safety of ART has been questioned because of the high prevalence of comorbidities in the offspring of ART conceptions compared to spontaneous conceptions. These issues have paved the way for more research and a greater understanding of the mechanisms of spermatogenesis and male infertility. Consequently, numerous discoveries have been made in the field of andrology, ranging from genetics to several "omics" technologies, oxidative stress and sperm DNA fragmentation, the sixth edition of the WHO manual, artificial intelligence, management of azoospermia, fertility in cancers survivors, artificial testis, 3D printing, gene engineering, stem cells therapy for spermatogenesis, and reconstructive microsurgery and seminal microbiome. Nevertheless, as many cases of male infertility remain idiopathic, further studies are required to improve the clinical management of infertile males. A multidisciplinary strategy involving both clinicians and scientists in basic, translational, and clinical research is the core principle that will allow andrology to overcome its limits and reach further goals. This state-of-the-art article aims to present a historical review of andrology, and, particularly, male infertility, from its "Middle Ages" to its "Renaissance", a golden age of andrology.

Vulnerability of The Male Reproductive System to SARS-CoV-2 Invasion: Potential Role for The Endoplasmic Reticulum Chaperone Grp78/HSPA5/BiP.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may adversely affect male reproductive tissues and male
fertility. This concern is elicited by the higher susceptibility and mortality rate of men to the SARS-CoV-2 mediated coronavirus disease-19 (COVID-19), compared to the women. SARS-CoV-2 enters host cells after binding to a functional receptor named angiotensin-converting enzyme-2 (ACE2) and then replicates in the host cells and gets released into the plasma. SARS-CoVs use the endoplasmic reticulum (ER) as a site for viral protein synthesis and processing, as well as glucose-regulated protein 78 (Grp78) is a key ER chaperone involved in protein folding by preventing newly synthesized proteins from aggregation.
Therefore, we analyzed Grp78 expression in various human organs, particularly male reproductive organs, using Broad
Institute Cancer Cell Line Encyclopedia (CCLE), the Genotype-Tissue Expression (GTEx), and Human Protein Atlas online
datasets. Grp78 is expressed in male reproductive tissues such as the testis, epididymis, prostate, and seminal vesicle. It can facilitate the coronavirus entry into the male reproductive tract, providing an opportunity for its replication. This link between the SARS-CoV-2 and the Grp78 protein could become a therapeutic target to mitigate its harmful effects on male fertility.

Comprehensive Analysis of Global Research on Human Varicocele: A Scientometric Approach.

PURPOSE: This study provides a comprehensive analysis of research trends on the etiology, mechanisms, potential risk factors, diagnosis, prognosis, surgical and non-surgical treatment of varicocele, and clinical outcomes before and after varicocele repair. MATERIALS AND METHODS: Varicocele studies published between 1988 and 2020 were retrieved from the Scopus database on April 5, 2021. Original studies on human varicocele were included, irrespective of language. Retrieved articles were manually screened for inclusion in various sub-categories. Bibliometric data was subjected to scientometric analysis using descriptive statistics. Network, heat and geographic mapping were generated using relevant software. RESULTS: In total, 1,943 original human studies on varicocele were published. These were predominantly from the northern hemisphere and developed countries, and published in journals from the United States and Germany. Network map analysis for countries showed several interconnected nodal points, with the USA being the largest, and Agarwal A. from Cleveland Clinic, USA, being a center point of worldwide varicocele research collaborations. Studies of adolescents were underrepresented compared with studies of adults. Studies on diagnostic and prognostic aspects of varicocele were more numerous than studies on varicocele prevalence, mechanistic studies and studies focusing on etiological and risk factors. Varicocele surgery was more investigated than non-surgical approaches. To evaluate the impact of varicocele and its treatment, researchers mainly analyzed basic semen parameters, although markers of seminal oxidative stress are being increasingly investigated in the last decade, while reproductive outcomes such as live birth rate were under-reported in the literature. CONCLUSIONS: This study analyzes the publication trends in original research on human varicocele spanning over the last three decades. Our analysis emphasizes areas for further exploration to better understand varicocele's impact on men's health and male fertility.

Evaluation of pubertal onset and characteristics in Egyptian boys: A cross-sectional study.

The objective of this study was to evaluate pubertal onset and characteristics in Egyptian boys. Examination of schoolboys (9-18 years) included height (cm), penile length (cm) and testicular volume (ml). Pubertal onset was considered at gonadal (G) stage 2 (G2 indicated testicular volume from 4-8 ml). Out of 1,078 boys, 270 (25%) were residents in urban areas, 414 (38.4%) in suburban areas and 394 (36.5%) in rural areas. The mean (±SD) age of G2 was 11.1 ± 1.2 years (5th and 95th percentiles were 10 and 13 years respectively). The age of 10.5 years was predictive of G2 with 89.9% sensitivity and 86.2% specificity (95% confidence interval; p < 0.001). The changes in testicular volumes and penile lengths, at the age interval from 16 to 18 years, were not significant. Pubertal onset was earlier among Egyptian boys in urban areas, with smaller family size, less crowding conditions, adequate illumination and good ventilation, although the difference was not statistically significant (p > 0.05). In conclusion, the mean age of pubertal onset among Egyptian boys was 11.1 years. A tendency towards earlier pubertal onset was observed in Egyptian boys who lived in urban areas and had better socio-demographic conditions.

A rational approach to the management of varicocele-associated nonobstructive azoospermia.

A consensus needs to be reached on a rational approach to infertile men with varicocele-associated nonobstructive azoospermia. Future studies are warranted to understand the mechanism behind the variable influence of varicocele on testicular function, which causes partial or complete damage of spermatogenesis in some cases and leaves it unaltered in others.

Histopathologic patterns of testicular biopsies in infertile azoospermic men with varicocele.

In azoospermic infertile men with varicocele, testicular biopsy revealed histopathologic patterns that varied from disorganized spermatogenesis with low or moderate sperm scores to early (primary spermatocytes stage) or late (spermatid stage) arrested spermatogenesis or germ cell aplasia and Sertoli cells only. Diagnostic testicular biopsy can be helpful for accurate management of azoospermic infertile men with varicoceles before surgical repair.

Phenotypical characteristics of the immune cells in allergic contact dermatitis, atopic dermatitis and pityriasis rosea.

Allergic contact dermatitis (ACD) is a cell-mediated, delayed type IV immunologic reaction. Atopic dermatitis (AD) is a chronic inflammatory skin disease that results from a complex interaction between immunologic, genetic, and environmental factors. Pityriasis rosea (PR) is a self-limited eruption of unknown etiology. Immune cell infiltrate is a constant feature in the inflammatory skin diseases. Here, we performed phenotypical characterization of the immune cells in ACD, AD and PR (ten cases each). We performed immunohistochemical stains for B cells (CD20), T cells (CD3), histiocytes (CD68) and T cells with cytotoxic activity (granzyme-B). The data were compared with findings in 20 specimens of normal skin. The results were scored as mean values of positively stained immune cells. Immunohistochemistry showed significantly high counts of immune cells in lesional skin (ACD, AD and PR) compared to the normal one (p < 0.05). In the lesional skin, the immune cells were composed predominantly of CD3(+) T lymphocytes and CD68(+) cells (histiocytes). Some of the CD3(+) cells were granzyme B(+). The counts of some immune cells (CD3(+) and CD68(+)) were high in ACD compared to AD and PR. The counts of CD20(+) and granzyme B(+) cells were high in PR compared to ACD and AD. However, these differences did not reach the level of statistical significance. The present data describe the profile of the immune cell infiltrate in AD, ACD and PR. The cell-mediated immunity seems to have critical role in the development of these lesions.

Effect of cigarette smoking on levels of seminal oxidative stress in infertile men: a prospective study.

OBJECTIVE: To investigate levels of seminal oxidative stress (OS) and sperm quality in a group of infertile men with a history of cigarette smoking. DESIGN: A prospective clinical study. SETTING: Male infertility clinic, Urological Institute, the Cleveland Clinic Foundation, Cleveland, Ohio. PATIENT(S): Infertile men who smoked cigarettes (n = 20), infertile men who were nonsmokers (n = 32), and healthy nonsmoking donors (n = 13). INTERVENTION(S): Genital examination, standard semen analysis, sperm DNA damage. MAIN OUTCOME MEASURE(S): Levels of seminal reactive oxygen species (ROS) and total antioxidant capacity (TAC) measured by a chemiluminescence assay and seminal OS assessed by calculating a ROS-TAC score. Sperm DNA damage was measured by sperm chromatin structure assay. RESULT(S): Smoking was associated with a 48% increase in seminal leukocyte concentrations (P<.0001), a 107% increase in ROS levels (P=.001), and a 10-point decrease in ROS-TAC scores (P=.003). Differences in standard sperm variables and DNA damage indices between the infertile smokers and infertile nonsmokers were not statistically significant. CONCLUSION(S): Infertile men who smoke cigarettes have higher levels of seminal OS than infertile nonsmokers. Given the potential adverse effects of seminal OS on fertility, physicians should advise infertile men who smoke cigarettes to quit.