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.

Could the sperm epigenome become a diagnostic tool for evaluation of the infertile man?

Although male infertility is currently diagnosed when abnormal sperm parameters are found, the poor predictive ability of sperm parameters on natural fecundity and medically assisted reproduction outcome poses the need for improved diagnostic techniques for male infertility. The accumulating evidence about the role played by the sperm epigenome in modulation of the early phases of embryonic development has led researchers to focus on the epigenetic mechanisms within the sperm epigenome to find new molecular markers of male infertility. Indeed, sperm epigenome abnormalities could explain some cases of unexplained male infertility in men showing normal sperm parameters and were found to be associated with poor embryo development in IVF cycles. The present mini-review summarizes the current knowledge about this interesting topic, starting from a description of the epigenetic mechanisms of gene expression regulation (i.e. DNA methylation, histone modifications, and non-coding RNAs' activity). We also discuss possible mechanisms by which environmental factors might cause epigenetic changes in the human germline and affect embryonic development, as well as subsequent generations' phenotypes. Studies demonstrating sperm epigenome abnormalities in men with male infertility are reviewed, with particular emphasis on those with the more severe form of spermatogenic dysfunction. Observations demonstrate that the diagnostic and prognostic efficacy of sperm epigenome evaluation will help facilitate the management of men with male factor infertility.

Successful Bilateral Sperm Retrieval in a Hypogonadal Patient with Non-Obstructive Azoospermia Showing Normal Serum 17-Hydroxyprogesterone Levels Suggestive of Normal Intratesticular Testosterone Production: A Case Report.

The impact of hypogonadism on the probability of retrieving testicular sperm from patients with non-obstructive azoospermia (NOA) is still a matter of debate. Conflicting evidence in this field may be justified by the striking differences between serum and intratesticular testosterone (ITT) levels found in men with severe spermatogenic dysfunction, so that normal ITT levels may coexist with low serum testosterone levels. Here we report the case of a patient with NOA with a steadily reduced serum testosterone level irresponsive to hormonal stimulation with human chorionic gonadotropin. Supported by his normal serum 17-hydroxyprogesterone (17 OHP) levels, previously suggested to be marker of ITT levels, microdissection testicular sperm extraction was performed for both testes on two separate occasions, resulting in the retrieval of enough sperm for ICSI. Three ICSI cycles were then performed, one blastocyst was transferred, and five were cryopreserved. This case report suggests that normal serum 17 OHP levels, being suggestive of normal ITT levels, may support the decision to proceed with surgical sperm retrieval in hypogonadal patients with NOA, even for those irresponsive to hormonal treatment.

Male Infertility: A Review of Key Papers Appearing in the Reproductive Medicine and Andrology Section of the Journal of Clinical Medicine.

Male infertility accounts for 30% of infertility cases and its prevalence in the general population approximately ranges between 9 and 15%, according to the available surveys [...].

Follicle-stimulating hormone treatment for male factor infertility.

Follicle-stimulating hormone (FSH) treatment has been proven effective in stimulating spermatogenesis and improving the reproductive ability of men with hypogonadotropic hypogonadism, while the usefulness of such a treatment in infertile patients with normal pituitary function is restricted to a subgroup of responders that, however, cannot be identified by the current diagnostic tools before treatment. In this review we summarize the role played by FSH in the modulation of spermatogenesis, the effect of FSH treatment at a standard replacement dose and at higher dose on sperm parameters, spontaneous and in vitro fertilization pregnancy rates, and the efforts made to identify possible responders to FSH treatment.

A complete dissection of the whole testicular parenchyma is required in most patients with nonobstructive azoospermia to obtain enough good quality testicular spermatozoa for ICSI.

BACKGROUND: Due to the heterogeneous distribution of seminiferous tubules (STs) in patients with nonobstructive azoospermia (NOA), retrieving enough good quality spermatozoa for ICSI may require a complete testicular dissection. According to the only available study in this field, spermatozoa may be found in the testis surface in 34.2% of patients, while a deeper testicular dissection is able to provide spermatozoa for ICSI in 28% of those without spermatozoa in the testis surface. OBJECTIVES: To determine the probability of finding enough spermatozoa for ICSI at the initial wide incision of the testis in a cohort of men with NOA undergoing microdissection testicular spermatozoa extraction (mTESE). MATERIALS AND METHODS: We evaluated 276 patients, aged 37 (20-62) years, who underwent unilateral (86, 31.15%) or bilateral (190, 68.8%) mTESE from January 2018 through December 2021. During mTESE, the entire surface of the testicular parenchyma was explored first in search for dilated STs: if no/ not enough spermatozoa were retrieved, the deeper portion of the parenchyma was explored. RESULTS: Spermatozoa were retrieved in 137 patients (49.6%). Histopathology demonstrated Sertoli-cell only syndrome in 65.6% of operated testes, while maturation arrest was found in 19.5%, hypospermatogenesis (HS) in 12.7%, and hyalinosis in 2%. Spermatozoa were obtained from the testis surface in 46 of 276 patients (16.6%), and after a complete dissection in 91 subjects (32.9%). On multivariate logistic regression, only the histopathological subcategory HS was predictive of the chance of retrieving spermatozoa from the surface of the testis (OR 3.24, 95% CI 1.37-7.69, p = 0.007). DISCUSSION: Most patients with NOA, particularly those with unfavorable histopathological patterns, require a complete dissection of the testicular parenchyma to obtain enough good quality for ICSI. CONCLUSIONS: By enabling the complete exploration of the testicular parenchyma, mTESE is to be preferred to cTESE to retrieve spermatozoa in patients with NOA.

Protocol for developing a core outcome set for male infertility research: an international consensus development study.

STUDY QUESTION: We aim to develop, disseminate and implement a minimum data set, known as a core outcome set, for future male infertility research. WHAT IS KNOWN ALREADY: Research into male infertility can be challenging to design, conduct and report. Evidence from randomized trials can be difficult to interpret and of limited ability to inform clinical practice for numerous reasons. These may include complex issues, such as variation in outcome measures and outcome reporting bias, as well as failure to consider the perspectives of men and their partners with lived experience of fertility problems. Previously, the Core Outcome Measure for Infertility Trials (COMMIT) initiative, an international consortium of researchers, healthcare professionals and people with fertility problems, has developed a core outcome set for general infertility research. Now, a bespoke core outcome set for male infertility is required to address the unique challenges pertinent to male infertility research. STUDY DESIGN SIZE DURATION: Stakeholders, including healthcare professionals, allied healthcare professionals, scientists, researchers and people with fertility problems, will be invited to participate. Formal consensus science methods will be used, including the modified Delphi method, modified Nominal Group Technique and the National Institutes of Health's consensus development conference. PARTICIPANTS/MATERIALS SETTING METHODS: An international steering group, including the relevant stakeholders outlined above, has been established to guide the development of this core outcome set. Possible core outcomes will be identified by undertaking a systematic review of randomized controlled trials evaluating potential treatments for male factor infertility. These outcomes will be entered into a modified Delphi method. Repeated reflection and re-scoring should promote convergence towards consensus outcomes, which will be prioritized during a consensus development meeting to identify a final core outcome set. We will establish standardized definitions and recommend high-quality measurement instruments for individual core outcomes. STUDY FUNDING/COMPETING INTERESTS: This work has been supported by the Urology Foundation small project award, 2021. C.L.R.B. is the recipient of a BMGF grant and received consultancy fees from Exscentia and Exceed sperm testing, paid to the University of Dundee and speaking fees or honoraria paid personally by Ferring, Copper Surgical and RBMO. S.B. received royalties from Cambridge University Press, Speaker honoraria for Obstetrical and Gynaecological Society of Singapore, Merk SMART Masterclass and Merk FERRING Forum, paid to the University of Aberdeen. Payment for leadership roles within NHS Grampian, previously paid to self, now paid to University of Aberdeen. An Honorarium is received as Editor in Chief of Human Reproduction Open. M.L.E. is an advisor to the companies Hannah and Ro. B.W.M. received an investigator grant from the NHMRC, No: GNT1176437 is a paid consultant for ObsEva and has received research funding from Ferring and Merck. R.R.H. received royalties from Elsevier for a book, consultancy fees from Glyciome, and presentation fees from GryNumber Health and Aytu Bioscience. Aytu Bioscience also funded MiOXYS systems and sensors. Attendance at Fertility 2020 and Roadshow South Africa by Ralf Henkel was funded by LogixX Pharma Ltd. R.R.H. is also Editor in Chief of Andrologia and has been an employee of LogixX Pharma Ltd. since 2020. M.S.K. is an associate editor with Human Reproduction Open. K.Mc.E. received an honoraria for lectures from Bayer and Pharmasure in 2019 and payment for an ESHRE grant review in 2019. His attendance at ESHRE 2019 and AUA 2019 was sponsored by Pharmasure and Bayer, respectively. The remaining authors declare no competing interests. TRIAL REGISTRATION NUMBER: Core Outcome Measures in Effectiveness Trials (COMET) initiative registration No: 1586. Available at www.comet-initiative.org/Studies/Details/1586. TRIAL REGISTRATION DATE: N/A. DATE OF FIRST PATIENT'S ENROLMENT: N/A.

Post-Vasectomy Semen Analysis: Optimizing Laboratory Procedures and Test Interpretation through a Clinical Audit and Global Survey of Practices.

PURPOSE: The success of vasectomy is determined by the outcome of a post-vasectomy semen analysis (PVSA). This article describes a step-by-step procedure to perform PVSA accurately, report data from patients who underwent post vasectomy semen analysis between 2015 and 2021 experience, along with results from an international online survey on clinical practice. MATERIALS AND METHODS: We present a detailed step-by-step protocol for performing and interpretating PVSA testing, along with recommendations for proficiency testing, competency assessment for performing PVSA, and clinical and laboratory scenarios. Moreover, we conducted an analysis of 1,114 PVSA performed at the Cleveland Clinic's Andrology Laboratory and an online survey to understand clinician responses to the PVSA results in various countries. RESULTS: Results from our clinical experience showed that 92.1% of patients passed PVSA, with 7.9% being further tested. A total of 78 experts from 19 countries participated in the survey, and the majority reported to use time from vasectomy rather than the number of ejaculations as criterion to request PVSA. A high percentage of responders reported permitting unprotected intercourse only if PVSA samples show azoospermia while, in the presence of few non-motile sperm, the majority of responders suggested using alternative contraception, followed by another PVSA. In the presence of motile sperm, the majority of participants asked for further PVSA testing. Repeat vasectomy was mainly recommended if motile sperm were observed after multiple PVSA's. A large percentage reported to recommend a second PVSA due to the possibility of legal actions. CONCLUSIONS: Our results highlighted varying clinical practices around the globe, with controversy over the significance of non-motile sperm in the PVSA sample. Our data suggest that less stringent AUA guidelines would help improve test compliance. A large longitudinal multi-center study would clarify various doubts related to timing and interpretation of PVSA and would also help us to understand, and perhaps predict, recanalization and the potential for future failure of a vasectomy.

Sperm Vitality and Necrozoospermia: Diagnosis, Management, and Results of a Global Survey of Clinical Practice.

Sperm vitality testing is a basic semen examination that has been described in the World Health Organization (WHO) Laboratory Manual for the Examination and Processing of Human Semen from its primary edition, 40 years ago. Several methods can be used to test sperm vitality, such as the eosin-nigrosin (E-N) stain or the hypoosmotic swelling (HOS) test. In the 6th (2021) edition of the WHO Laboratory Manual, sperm vitality assessment is mainly recommended if the total motility is less than 40%. Hence, a motile spermatozoon is considered alive, however, in certain conditions an immotile spermatozoon can also be alive. Therefore, the differentiation between asthenozoospermia (pathological decrease in sperm motility) and necrozoospermia (pathological decrease in sperm vitality) is important in directing further investigation and management of infertile patients. The causes leading to necrozoospermia are diverse and can either be local or general, testicular or extra-testicular. The andrological management of necrozoospermia depends on its etiology. However, there is no standardized treatment available presently and practice varies among clinicians. In this study, we report the results of a global survey to understand current practices regarding the physician order of sperm vitality tests as well as the management practices for necrozoospermia. Laboratory and clinical scenarios are presented to guide the reader in the management of necrozoospermia with the overall objective of establishing a benchmark ranging from the diagnosis of necrozoospermia by sperm vitality testing to its clinical management.

Prediction Models for Successful Sperm Retrieval in Patients with Non-Obstructive Azoospermia Undergoing Microdissection Testicular Sperm Extraction: Is There Any Room for Further Studies?

Several prediction models for successful sperm retrieval (SSR) in patients with azoospermia due to spermatogenic dysfunction (also termed non-obstructive azoospermia-NOA) have been developed and published in the past years, however their resulting prediction accuracy has never been strong enough to translate their results in the clinical practice. This notwithstanding, the number of prediction models being proposed in this field is growing. We have reviewed the available evidence and found that, although patients with complete AZFc deletion or a history of cryptorchidism may have better probability of SSR compared to those with idiopathic NOA, no clinical or laboratory marker is able to determine whether a patient with NOA should or should not undergo microdissection testicular sperm extraction (mTESE) to have his testicular sperm retrieved. Further research is warranted to confirm the utility of evaluating the expression of noncoding RNAs in the seminal plasma, to individuate patients with NOA with higher probability of SSR.

Performing Microdissection Testicular Sperm Extraction: Surgical Pearls from a High-Volume Infertility Center.

Microdissection testicular sperm extraction (mTESE) has been demonstrated to be the gold-standard surgical technique for retrieving testicular sperm in patients with non-obstructive azoospermia (NOA) as it enables the exploration of the whole testicular parenchyma at a high magnification, allowing the identification of the rare dilated seminipherous tubules that may contain sperm, usually surrounded by thinner or atrophic tubules. MTESE requires a skilled and experienced surgeon whose learning curve may greatly affect the sperm retrieval rate, as demonstrated in previous reports. The present review is intended to offer a precise and detailed description of the mTESE surgical procedure, accompanied by an extensive iconography, to provide urologists with valuable information to be translated into clinical practice. Advice about the pre-surgical and post-surgical management of patients is also offered.

Intrasurgical parameters associated with successful sperm retrieval in patients with non-obstructive azoospermia undergoing salvage microdissection testicular sperm extraction.

BACKGROUND: Patients with non-obstructive azoospermia with a previously failed conventional testicular sperm extraction may undergo a salvage microdissection testicular sperm extraction with the probability of successful sperm retrieval being almost dependent upon the number of previous surgical attempts and to different histopathologic categories. OBJECTIVES: To determine whether the seminiferous tubules pattern and the histological categories could affect the sperm retrieval rate in patients with non-obstructive azoospermia undergoing salvage microdissection testicular sperm extraction after failed conventional testicular sperm extraction. MATERIALS AND METHODS: Seventy-nine patients undergoing unilateral or bilateral salvage microdissection testicular sperm extraction were evaluated. During microdissection testicular sperm extraction, if present, dilated tubules were retrieved, otherwise, tubules with slightly larger caliber than that of the surroundings were removed. When no dilated tubule or tubule with slightly larger caliber was found, not dilated tubules were excised. A prediction model was built with seminiferous tubules pattern and testis histology as covariates. RESULTS: Sperm retrieval was successful in 30 out of 79 patients. The prediction model correctly classified 88.3% of cases, explained the 29.7% variability of the outcome, and significantly predicted the microdissection testicular sperm extraction outcome with a sensitivity of 67.7% and a specificity of 90.2%, Both tubules with slightly larger caliber and not dilated tubules were negatively associated with the chance of retrieving spermatozoa. Among the histological categories, only early maturation arrest was significant to the model (log(SSR) = 0.57 - 1.9SDT - 3.3NDT - 1.76EMA) (where SSR is sperm retrieval rate, SDT is tubule with slightly larger caliber, NDT is not dilated tubule, and EMA is early maturation arrest). The model had a clearly useful discrimination (area under the curve = 0.814), the estimated performance was 0.8105, and internal calibration was acceptable (p > 0.05). DISCUSSION: Seminiferous tubules pattern and testis histology may reliably explain the salvage microdissection testicular sperm extraction outcome in all patients with non-obstructive azoospermia apart from those with early maturation arrest, where the homogeneous apparent seminiferous tubules pattern may be misleading. CONCLUSION: The outcome of salvage microdissection testicular sperm extraction can be predicted by the same intrasurgical parameters that have been demonstrated to predict the outcome of microdissection testicular sperm extraction in naïve patients with non-obstructive azoospermia.

Hormonal Treatment of Men with Nonobstructive Azoospermia: What Does the Evidence Suggest?

Hormonal stimulation of spermatogenesis prior to surgery has been tested by some authors to maximize the sperm retrieval yield in patients with nonobstructive azoospermia. Although the rationale of such an approach is theoretically sound, studies have provided conflicting results, and there are unmet questions that need to be addressed. In the present narrative review, we reviewed the current knowledge about the hormonal control of spermatogenesis, the relationship between presurgical serum hormones levels and sperm retrieval rates, and the results of studies investigating the effect of hormonal treatments prior to microdissection testicular sperm extraction. We pooled the available data about sperm retrieval rate in patients with low vs. normal testosterone levels, and found that patients with normal testosterone levels had a significantly higher chance of successful sperm retrieval compared to those with subnormal T levels (OR 1.63, 95% CI 1.08-2.45, p = 0.02). These data suggest that hormonal treatment may be justified in patients with hypogonadism; on the other hand, the available evidence is insufficient to recommend hormonal therapy as standard clinical practice to improve the sperm retrieval rate in patients with nonobstructive azoospermia.

Update on the Management of Non-Obstructive Azoospermia: Current Evidence and Unmet Needs.

Azoospermia, defined as the absence of sperm in the ejaculate after examination of the centrifuged specimens, affects about 1% of the male population and 10-15% of infertile men [...].

Sperm source does not affect the ICSI outcome of patients with severely compromised spermatogenesis.

Patients with spermatogenic dysfunction may display sperm parameters ranging from extremely severe oligozoospermia (sperm count lower than 2 million/ml) to azoospermia. It has been proposed that, since these patients may have increased sperm DNA damage that could affect their ICSI outcome, the use of surgically retrieved testicular spermatozoa should be preferred to improve their chance of fathering their biological offspring. However, studies in this field have yielded conflicting results. The present study provides an updated assessment of this subject by comparing the ICSI outcome of 762 patients with nonobstructive azoospermia and 419 with sperm count lower than 2 million/ml (median sperm count 300,000/ml). Both groups were homogeneous for the number of retrieved and injected MII oocytes. No difference was seen in terms of fertilisation, clinical pregnancy and cumulative live birth rates. Only the number of injected MII oocytes was found to independently predict the live birth rate, even when adjusted for the number of transferred embryos (OR 1.10 (1.0-1.2, p = 0.038)). The results of the present study stand against the use of testicular spermatozoa in patients with extremely severe spermatogenic dysfunction with available spermatozoa in their ejaculate.

Sperm DNA Methylation Epimutation Biomarkers for Male Infertility and FSH Therapeutic Responsiveness.

Male factor infertility is increasing and recognized as playing a key role in reproductive health and disease. The current primary diagnostic approach is to assess sperm quality associated with reduced sperm number and motility, which has been historically of limited success in separating fertile from infertile males. The current study was designed to develop a molecular analysis to identify male idiopathic infertility using genome wide alterations in sperm DNA methylation. A signature of differential DNA methylation regions (DMRs) was identified to be associated with male idiopathic infertility patients. A promising therapeutic treatment of male infertility is the use of follicle stimulating hormone (FSH) analogs which improved sperm numbers and motility in a sub-population of infertility patients. The current study also identified genome-wide DMRs that were associated with the patients that were responsive to FSH therapy versus those that were non-responsive. This novel use of epigenetic biomarkers to identify responsive versus non-responsive patient populations is anticipated to dramatically improve clinical trials and facilitate therapeutic treatment of male infertility patients. The use of epigenetic biomarkers for disease and therapeutic responsiveness is anticipated to be applicable for other medical conditions.

Prediction model for testis histology in men with non-obstructive azoospermia: evidence for a limited predictive role of serum follicle-stimulating hormone.

PURPOSE: The present prediction model was intended to verify whether serum FSH level could be predictive of testis histology in patients with non-obstructive azoospermia (NOA). METHODS: We evaluated two datasets of patients with NOA: the first (San Paolo dataset) comprising 558 patients, 18-63 years old, the second (Procrea dataset) composed by 143 patients, 26-62 years old; bot datasets were combined to obtain a validation set. Multinomial logistic regression was first run with serum FSH and testis volume as independent predictors of testis histology, then, the correctly classified histological subcategories were set as outcome variables of a prediction model in both development and validation sets. RESULTS: Multinomial logistic regression showed that FSH was a significant predictor of testis histology in 58% of cases, although it was unable to correctly classify cases with focal SCO or maturation arrest (MA). A prediction model was then run with hypospermatogenesis (HYPO) and Sertoli-only syndrome (SCO) as outcome variables of a binary logistic regression. FSH significantly predicted both HYPO and SCO, with a sensitivity of 40.9 and 80.7 and a specificity of 84.3 and 46.8 respectively. The model showed a fair discriminative ability (ROC AUC 0.705 and 0.709 respectively) and was adequately calibrated. CONCLUSIONS: Supported by a robust statistical analysis, we conclude that serum FSH level cannot be considered a prognostic marker of spermatogenic dysfunction in patients with NOA.