Assessment of artificial intelligence model and manual morphokinetic annotation system as embryo grading methods for successful live birth prediction: a retrospective monocentric study.

PURPOSE: The introduction of the time-lapse monitoring system (TMS) and the development of predictive algorithms could contribute to the optimal embryos selection for transfer. Therefore, the present study aims at investigating the efficiency of KIDScore and iDAScore systems for blastocyst stage embryos in predicting live birth events. METHODS: The present retrospective study was conducted in a private IVF Unit setting throughout a 10-month period from October 2021 to July 2022, and included the analysis of 429 embryos deriving from 91 IVF/ICSI cycles conducted due to infertility of various etiologies. Embryos incubated at the Embryoscope+ timelapse incubator were analyzed through the established scoring systems: KIDScore and iDAScore®. The main outcome measure was the comparison of the two scoring systems in terms of live birth prediction. Embryos with the higher scores at day 5 (KID5 score/iDA5 score) were transferred or cryopreserved for later use. RESULTS: Embryos with high KID5 and iDA5 scores positively correlated with the probability of successful live birth, with KID5 score yielding a higher efficiency in predicting a successful reproductive outcome compared to a proportionally high iDA5 score. KID5 demonstrated conservative performance in successfully predicting live birth compared to iDA5 score, indicating that an efficient prediction can be either provided by a relatively lower KID5 score or a relatively higher iDA5 score. CONCLUSION: The developed artificial intelligence tools should be implemented in clinical practice in conjunction with the conventional morphological assessment for the conduction of optimized embryo transfer in terms of a successful live birth.

Predictive value of seminal oxidation-reduction potential analysis for reproductive outcomes of ICSI.

RESEARCH QUESTION: Is seminal oxidation-reduction potential (ORP) clinically relevant to reproductive outcome? DESIGN: Prospective observational study including a total of 144 couples who had an intracytoplasmic sperm injection (ICSI) cycle between June 2018 and December 2020. The study included patients undergoing fresh ICSI cycles with autologous gametes. Cycles that had day 3 embryo transfers and cryopreservation cycles were excluded. There was no restriction on patients with severe male infertility; couples with unexplained infertility and unexplained male infertility were included, those with azoospermia were excluded. Semen analysis, seminal ORP as determined by means of the MiOXSYS system, sperm DNA fragmentation (SDF) and reproductive outcomes (fertilization, blastocyst development, clinical pregnancy and live birth) were determined. RESULTS: Seminal ORP was significantly negatively correlated with fertilization rate (r = -0.267; P = 0.0012), blastocyst development rate (r = -0.432; P < 0.0001), implantation/clinical pregnancy (r = -0.305; P = 0.0003) and live birth (r = -0.366; P < 0.0001). Receiver operating characteristic curve analysis showed significant predictive power for ORP for fertilization (≥80%; area under the curve [AUC] 0.652; P = 0.0012), blastocyst development rate (≥60%; AUC 0.794; P < 0.0001), implantation/clinical pregnancy (AUC 0.680; P = 0.0002) and live birth (AUC 0.728; P < 0.0001). Comparable results were obtained for SDF (fertilization: AUC 0.678; blastocyst development: AUC 0.777; implantation/clinical pregnancy: AUC 0.665; live birth: AUC 0.723). Normal sperm morphology showed the lowest predictive power for all reproductive outcome parameters. With male age as confounding factor, ORP (cut-off value of 0.51 mV/106 sperm/ml) has significant (P < 0.04667) effects on odds ratios for all reproductive outcome parameters. Multivariate logistic regression to investigate potential seminal and female confounding factors revealed that seminal ORP significantly (P < 0.0039; P < 0.0130) affects reproductive outcome. CONCLUSION: Seminal ORP is relevant for good fertilization, blastocyst development, implantation, clinical pregnancy and live birth.

Age at menarche and clinical outcomes following medically assisted reproduction (MAR): a cohort study.

Medically assisted reproduction (MAR) technologies have advanced rapidly, but in contrast to the specificity of modern approaches, they provide limited effectiveness in the management of the infertile couple. The purpose of this study was to assess the possible relationship between age at menarche and MAR outcomes of clinical pregnancy, live birth and the adverse incident of miscarriage, and to determine the offspring sex ratio according to age at menarche. In a cohort of 254 infertile couples who underwent 426 IVF/ICSI cycles, statistical analysis was performed by applying Student's t-test, chi-square test, and logistic regression models, adequately in the respective parameters and outcomes. The results indicated a strong association of age at menarche with the outcomes of clinical pregnancy (p = .0007) and live birth (p < .0001), especially by applying a threshold of 12 years in the first occurrence of menstruation (p = .0019 for clinical pregnancy, p < .0001 for live birth), also demonstrating a negative effect for earlier menarche that acts in parallel with the increasing age of the woman. Calculation of sex ratio demonstrated a tendency towards female offspring close to the age at menarche of 12 years. Age at menarche could serve as a surrogate parameter for reproductive potential towards personalized management of infertility.

An artificial neural network for the prediction of assisted reproduction outcome.

PURPOSE: To construct and validate an efficient artificial neural network (ANN) based on parameters with statistical correlation to live birth, to be used as a comprehensive tool for the prediction of the clinical outcome for patients undergoing ART. METHODS: Data from 257 infertile couples that underwent a total of 426 IVF/ICSI cycles from 2010 to 2017 was collected on an ensemble of 118 parameters for each cycle. Statistical correlation of the parameters with the outcome of live birth was performed, using either t test or χ2 test, and the parameters that demonstrated statistical significance were used to construct the ANN. Cross-validation was performed by random separation of data and repeating the training-testing procedure by 10 times. RESULTS: 12 statistically significant parameters out of the initial ensemble were used for the ANN construction, which exhibited a cumulative sensitivity and specificity of 76.7% and 73.4%, respectively. During cross-validation, the system exhibited the following: sensitivity 69.2% ± 2.36%, specificity 69.19% ± 2.8% (OR 5.21 ± 1.27), PPV 36.96 ± 3.44, NPV 89.61 ± 1.09, and OA 69.19% ± 2.69%. A rather small standard deviation in the performance indices between the training and test sets throughout the validation process indicated a stable performance of the constructed ANN. CONCLUSIONS: The constructed ANN is based on statistically significant variables with the outcome of live birth and represents a stable and efficient system with increased performance indices. Validation of the system allowed an insight of its clinical value as a supportive tool in medical decisions, and overall provides a reliable approach in the routine practice of IVF units in a user-friendly environment.

Mild versus conventional antagonist ovarian stimulation protocols in expected normal responders undergoing IVF/ICSI: a case-control study.

Mild controlled ovarian hyperstimulation (COH) protocols combining clomiphene citrate (CC) or letrozole with gonadotropins were introduced as an effective alternative of conventional COH in normal responders undergoing IVF/ICSI. In this case-control study, we compared 41 participants treated with a mild stimulation protocol receiving gonadotropins combined with either CC (n = 24) or letrozole (n = 17) with 71 subfertile participants with matching baseline characteristics, conforming with the same inclusion criteria and treated with a conventional antagonist protocol. Live birth was determined in reduced rates in the study group compared to the control group, reaching marginal statistical significance [4/41 versus 19/71, p = 0.050], as also in the respective number of clinical pregnancies [6/41 versus 22/71, p = 0.054], although the incidence of miscarriage was similar for both groups [2/41 versus 5/71, p = 0.714]. Most of the secondary parameters examined, favored the conventional antagonist protocol. There was no difference in any of the outcomes reported between the three different stimulation groups in post-hoc analysis. Mild stimulation regimens with the aid of either CC or letrozole employing GnRH antagonists do not seem to constitute an equally effective method as compared to the conventional antagonist protocol to be offered in good prognosis subfertile women seeking an induced cycle toward IVF/ICSI.

Aspirin for in vitro fertilisation.

BACKGROUND: Aspirin is used with the aim of optimising the chance of live birth in women undergoing assisted reproductive technology (ART), despite inconsistent evidence of its efficacy and safety (in terms of intraoperative bleeding during oocyte retrieval and risk of miscarriage). The most appropriate time to commence aspirin therapy and the length of treatment required are also still to be determined. This is the second update of the review first published in 2007. OBJECTIVES: To evaluate the effectiveness and safety of aspirin in women undergoing ART. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 4) in the Cochrane Library (searched 9 May 2016); the databases MEDLINE (1946 to 9 May 2016) and Embase (1974 to 9 May 2016); and trial registers (ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform search portal). We also examined the reference lists of all known primary studies and review articles, citation lists of relevant publications and abstracts of major scientific meetings, combined with the Cochrane Gynaecology and Fertility Group's search strategy. SELECTION CRITERIA: Randomised controlled trials on aspirin for women undergoing ART. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and risk of bias and extracted the data. The primary review outcome was live birth. Secondary outcomes included clinical pregnancy, ongoing pregnancy, multiple pregnancy, miscarriage, and other complications associated with IVF/ICSI or with pregnancy and birth. We combined data to calculate risk ratios (RRs) (for dichotomous data) and mean differences (MDs) (for continuous data) and 95% confidence intervals (CIs). Statistical heterogeneity was assessed using the I² statistic. We assessed the overall quality of the evidence for the main comparisons using GRADE methods. MAIN RESULTS: The search identified 13 trials as eligible for inclusion in the review, including a total of 2653 participants with a mean age of 35 years. Ten studies used a dose of 100 mg and three used 80 mg of aspirin per day. In most of them, aspirin was commenced immediately at the start of down-regulation, while the duration of treatment varied widely. Eight studies provided a placebo for the control group.There was no evidence of a difference between the aspirin group and the group receiving no treatment or placebo in rates of live birth (RR 0.91, 95% CI 0.72 to 1.15, 3 RCTs, n = 1053, I² = 15%, moderate-quality evidence). In addition, clinical pregnancy rates were also similar for the two groups (RR 1.03, 95% CI 0.91 to 1.17, 10 RCTs, n = 2142, I² = 27%, moderate-quality evidence); sensitivity analysis, excluding studies at high risk of bias, did not change the effect estimate. There was no evidence of a difference between groups in terms of multiple pregnancy as confirmed by ultrasound (RR 0.67, 95% CI 0.37 to 1.25, 2 RCTs, n = 656, I² = 0%, low-quality evidence), miscarriage (RR 1.10, 95% CI 0.68 to 1.77, 5 RCTs, n = 1497, I² = 0%, low-quality evidence), ectopic pregnancy (RR 1.86, 95% CI 0.75 to 4.63, 3 RCTs, n = 1135, I² = 0%, very low quality evidence) or vaginal bleeding (RR 1.01, 95% CI 0.14 to 7.13, 1 RCT, n = 487, very low quality evidence). Data were lacking on other adverse effects.The overall quality of the evidence ranged from very low to moderate; limitations were poor reporting of study methods and suspected publication bias. AUTHORS' CONCLUSIONS: Currently there is no evidence in favour of routine use of aspirin in order to improve pregnancy rates for a general IVF population. This is based on available data from randomised controlled trials, where there is currently no evidence of an effect of aspirin on women undergoing ART, as there is no single outcome measure demonstrating a benefit with its use. Furthermore, current evidence does not exclude the possibility of adverse effects.

STAT5A/B gene locus undergoes amplification during human prostate cancer progression.

The molecular mechanisms underlying progression of prostate cancer (PCa) to castrate-resistant (CR) and metastatic disease are poorly understood. Our previous mechanistic work shows that inhibition of transcription factor Stat5 by multiple alternative methods induces extensive rapid apoptotic death of Stat5-positive PCa cells in vitro and inhibits PCa xenograft tumor growth in nude mice. Furthermore, STAT5A/B induces invasive behavior of PCa cells in vitro and in vivo, suggesting involvement of STAT5A/B in PCa progression. Nuclear STAT5A/B protein levels are increased in high-grade PCas, CR PCas, and distant metastases, and high nuclear STAT5A/B expression predicts early disease recurrence and PCa-specific death in clinical PCas. Based on these findings, STAT5A/B represents a therapeutic target protein for advanced PCa. The mechanisms underlying increased Stat5 protein levels in PCa are unclear. Herein, we demonstrate amplification at the STAT5A/B gene locus in a significant fraction of clinical PCa specimens. STAT5A/B gene amplification was more frequently found in PCas of high histologic grades and in CR distant metastases. Quantitative in situ analysis revealed that STAT5A/B gene amplification was associated with increased STAT5A/B protein expression in PCa. Functional studies showed that increased STAT5A/B copy numbers conferred growth advantage in PCa cells in vitro and as xenograft tumors in vivo. The work presented herein provides the first evidence of somatic STAT5A/B gene amplification in clinical PCas.

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

PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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%. CONCLUSION: 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.

Technical Aspects and Clinical Limitations of Sperm DNA Fragmentation Testing in Male Infertility: A Global Survey, Current Guidelines, and Expert Recommendations.

PURPOSE: Sperm DNA fragmentation (SDF) is a functional sperm abnormality that can impact reproductive potential, for which four assays have been described in the recently published sixth edition of the WHO laboratory manual for the examination and processing of human semen. The purpose of this study was to examine the global practices related to the use of SDF assays and investigate the barriers and limitations that clinicians face in incorporating these tests into their practice. MATERIALS AND METHODS: Clinicians managing male infertility were invited to complete an online survey on practices related to SDF diagnostic and treatment approaches. Their responses related to the technical aspects of SDF testing, current professional society guidelines, and the literature were used to generate expert recommendations via the Delphi method. Finally, challenges related to SDF that the clinicians encounter in their daily practice were captured. RESULTS: The survey was completed by 436 reproductive clinicians. Overall, terminal deoxynucleotidyl transferase deoxyuridine triphosphate Nick-End Labeling (TUNEL) is the most commonly used assay chosen by 28.6%, followed by the sperm chromatin structure assay (24.1%), and the sperm chromatin dispersion (19.1%). The choice of the assay was largely influenced by availability (70% of respondents). A threshold of 30% was the most selected cut-off value for elevated SDF by 33.7% of clinicians. Of respondents, 53.6% recommend SDF testing after 3 to 5 days of abstinence. Although 75.3% believe SDF testing can provide an explanation for many unknown causes of infertility, the main limiting factors selected by respondents are a lack of professional society guideline recommendations (62.7%) and an absence of globally accepted references for SDF interpretation (50.3%). CONCLUSIONS: This study represents the largest global survey on the technical aspects of SDF testing as well as the barriers encountered by clinicians. Unified global recommendations regarding clinician implementation and standard laboratory interpretation of SDF testing are crucial.

A family with Hoyeraal-Hreidarsson syndrome and four variants in two genes of the telomerase core complex.

We describe an African American family with Hoyeraal-Hreidarrson syndrome (HHS) in which 2 TERT mutations (causing P530L and A880T amino acid changes) and two in the DKC1 variants (G486R and A487A) were segregating. Both genes are associated with dyskeratosis congenita and HHS. It was important to determine the importance of these mutations in disease pathogenesis to counsel family members. From genetic analysis of family members, telomere length and X-inactivation studies we concluded that compound heterozygosity for the TERT mutations was the major cause of HHS and the DKC1 G486R variant is a rare African variant unlikely to cause disease.

Bridging the Gap between AZF Microdeletions and Karyotype: Twelve Years' Experience of an Infertility Center.

PURPOSE: Despite all past efforts, the current guidelines are not explicit enough regarding the indications for performing azoospermia factor (AZF) screening and karyotype, burdening clinicians with the decision to assess whether such tests are meaningful for the infertile male patient. These assessments can be costly and it is up to the healthcare practitioner to decide which are necessary and to weigh the benefits against economic/psychological harm. The aim of this study is to address such gaps and provide update on current management options for this group of patients. MATERIALS AND METHODS: To address such gaps in male infertility management and to elucidate whether AZF screening is indicated in individuals who concomitantly harbor chromosomal abnormalities we conducted a retrospective cohort analysis of 10,388 consecutive patients with non-obstructive azoospermia (NOA) and severe oligozoospermia. RESULTS: Previously, it has been suggested that all NOA cases with chromosomal defects, except males with 46,XY/45,X karyotype, have no indication for AZF screening. Our findings revealed that cases carrying the following chromosomal abnormalities inv(Y)(p11.2q12); idic(Y)(q11.2); 46,XY,r(Y); idic(Y)(p11.2) and der(Y;Autosome) (76/169; 44.9%; 95% CI, 37.7-52.5) should also be referred for AZF deletion screening. Here, we also report the correlation between sperm count and AZF deletions as a secondary outcome. In accordance with previously reported data from North America and Europe, our data revealed that only 1% of cases with >1×106 sperm/mL had Y chromosome microdeletions (YCMs). CONCLUSIONS: In the era of assisted reproduction, finding cost-minimization strategies in infertility clinics without affecting the quality of diagnosis is becoming one of the top prioritized topics for future research. From a diagnostic viewpoint, the results reflect a need to reconsider the different karyotype presentations and the sperm count thresholds in male infertility guidelines as indicators for YCM screening during an infertility evaluation.

How to select healthy sperm for intracytoplasmic sperm injection in samples with high sperm DNA fragmentation?

The body of evidence supports the negative impact of increased sperm DNA fragmentation (SDF) on natural fertility as well as assisted reproduction conditions. High SDF has been correlated with low pregnancy and delivery rates following intrauterine insemination. Also, high SDF is accused of reducing the rates of fertilization, implantation, pregnancy, and live birth following in-vitro fertilization (IVF). Despite no impact of high SDF on fertilization or pregnancy rates following intracytoplasmic sperm injection (ICSI), it has been correlated with poor embryo quality and a higher risk of miscarriage. Several methods have been introduced to help select sperm with the best DNA quality to be used in assisted reproductive technology procedures. These include magnetic-activated cell sorting, intracytoplasmic morphologically selected sperm injection, physiologic ICSI, and microfluidic sperm sorters, among others. This article aimed to discuss the impact of high SDF in infertile men on the reproductive outcome of couples undergoing IVF/ICSI. Additionally, this review highlights the principles, advantages, and limitations of different techniques that are currently used for the selection of sperm with intact DNA to be utilized for ICSI.

Sperm DNA fragmentation test: usefulness in assessing male fertility and assisted reproductive technology outcomes.

Male infertility is attributed to multiple factors including high levels of sperm DNA fragmentation (SDF). Conventional semen analysis continues to be the gold standard for diagnosis of male factor infertility around the world. However, the limitations of basic semen analysis have prompted the search for complementary assessments of sperm function and integrity. Sperm DNA fragmentation assays (direct or indirect) are emerging as important diagnostic tools in male infertility workups, and have been advocated for use in infertile couples for a variety of reasons. While a controlled degree of DNA nicking is required for appropriate DNA compaction, excessive fragmentation of sperm DNA is linked to impaired male fertility potential, decreased fertilization, poor embryo quality, recurrent pregnancy loss, and failure of assisted reproductive technology procedures. However, there is an ongoing debate regarding whether or not to employ SDF as a routine test for male infertility. This review compiles up-to-date information regarding the pathophysiology of SDF, the currently available SDF tests, and the role of SDF tests in natural and assisted conception conditions.

Time-lapse embryo monitoring: does it add to standard in-vitro fertilization/intra cytoplasmic sperm injection?

Since the first pioneering studies on time-lapse systems (TLSs) for embryo incubation, many things have changed. Two main factors influence the development of modern time-lapse incubators for human in-vitro fertilization (IVF): 1) the switch from traditional cell culture incubators to benchtops incubators, more suitable for human IVF; and 2) the improvement of imaging technology. Another major factor for the increase in the utilization of TLSs in IVF labs over the last decade was the advances in computer/wireless and smartphone/tablet technology, which allowed patients to see the footage of their growing embryos. Hence, more user-friendly features have allowed their introduction and routine use in IVF labs while image-capturing software has enabled storage and providing additional information to the patients concerning the development of their embryos. This review aims to describe the history and the different TLSs available in the market, to summarize the research and clinical results obtained by using this technology, and to reflect on how this technology is changing the modern IVF laboratory. The current limitations of TLSs will be also reviewed.

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.

Sperm DNA integrity and male infertility: a narrative review and guide for the reproductive physicians.

Background and Objective: Conventional semen analysis (SA) remains an essential tool in the initial male fertility evaluation and subsequent follow-up. However, it neither provides information about the functional status of spermatozoa nor addresses disorders such as idiopathic or unexplained infertility (UI). Recently, assessment of sperm DNA fragmentation (SDF) has been proposed as an extended sperm test that may help overcome these inherent limitations of basic SA. In this review, we aim to: (I) discuss the pathophysiological aspects of SDF, including natural repair mechanisms, causes, and impact on reproductive outcomes; (II) explain different assessment tools of SDF, and describe potential therapeutic options to manage infertile men with high SDF; and (III) analyse the strengths, weaknesses, opportunities and threats (SWOT) of current research on the topic. Methods: This review was constructed from original studies, systematic reviews and meta-analyses that were published over the years up until August 2021, related to the various aspects of SDF. Key Content and Findings: Different mechanisms lead to high SDF, including defective chromatin packaging, apoptosis, and seminal oxidative stress. The relevance of sperm DNA integrity to male fertility/infertility has been supported by the frequent observation of high levels of SDF in infertile men, and in association with risk factors for infertility. Additionally, high SDF levels have been inversely correlated with the outcomes of natural pregnancy and assisted reproduction. Terminal deoxynucleotidyl transferase dUTP nick end labelling, sperm chromatin structure assay, sperm chromatin dispersion, and Comet assay are four commonly used assays for measurement of SDF. Addressing lifestyle risks and underlying conditions, antioxidants, hormonal therapy, and advanced sperm selection techniques have all been proposed as potential therapeutic options to lower SDF. Conclusions: The sum of literature provides evidence of detrimental effects of high SDF on both natural and assisted fertility outcomes. Standardization of the techniques used for assessment of SDF and their incorporation into the work up of infertile couples may have significant implications on the future management of a selected category of infertile men with high SDF.

Reply to Pallotti et al. Comment on "Boitrelle et al. The Sixth Edition of the WHO Manual for Human Semen Analysis: A Critical Review and SWOT Analysis. Life 2021, 11, 1368".

We would like to thank F. Pallotti and his colleagues for their positive comments [...].

Male Age and Progressive Sperm Motility Are Critical Factors Affecting Embryological and Clinical Outcomes in Oocyte Donor ICSI Cycles.

This retrospective cohort study aimed to explore whether paternal age and semen quality parameters affect the embryological and clinical outcomes of ICSI with oocyte donation. A total of 339 oocyte donation (OD)-ICSI cycles were categorized into four groups according to the semen parameter profiles of the male counterparts: normozoospermia (NS, n = 184), oligozoospermia (OS, n = 41), asthenozoospermia (AS, n = 50), and oligoasthenozoospermia (OAS, n = 64). The effect of age, total sperm count, and progressive motility was separately analyzed for reproductive outcomes and compared between the study groups: fertilization, blastulation, and top-quality embryo rate, biochemical and clinical pregnancy, live birth, and miscarriage. A negative correlation between male age and fertilization rate was observed (rs = - 0.23, p < 0.0001), while male age was a significant factor for biochemical pregnancy (p = 0.0002), clinical pregnancy (p = 0.0017), and live birth (p = 0.0038). Reduced total sperm count and lowered progressive motility led to poorer fertilization rates (rs = 0.19 and 0.35, respectively, p < 0.0001) and affected embryo quality (rs = 0.13, p = 0.02, and rs = 0.22, p < 0.0001, respectively). OD-ICSI cycles with asthenozoospermia had significantly lowered success rates in biochemical pregnancy, clinical pregnancy, and live birth (p < 0.05). Our study demonstrated that both advanced male age and reduced progressive motility of spermatozoa exert a significant negative influence on the outcome of assisted reproduction, even in controlled procedures with gamete selection and optimization such as in OD-ICSI. Improvement in treatment strategies and male fertility evaluation requires incorporation of such evidence to obtain better prognosis towards personalized management.

Commercially Available Molecular Approaches to Evaluate Endometrial Receptivity: A Systematic Review and Critical Analysis of the Literature.

Despite the advances in the field of reproductive medicine, implantation failure represents a challenging condition affecting 10-30% of patients subjected to in vitro fertilization (IVF). Research has focused on the identification of molecules playing crucial roles in endometrial receptivity, with the aim of designing predictive tools for efficient detection of the implantation window. To that end, novel molecular genomic and transcriptomic approaches have been introduced as promising tools to enable personalized approaches with the aim of optimizing embryo transfer dating. However, the clinical value of these approaches remains unclear. The aim of this study is to provide a systematic review and critical analysis of the existing evidence regarding the employment of commercially available novel approaches to evaluate endometrial receptivity. An Embase and PubMed/Medline search was performed on 1 February 2022. From the 475 articles yielded, only 27 were included and analyzed. The considerable heterogeneity of the included articles indicates the uniqueness of the implantation window, showcasing that the optimal time for embryo transfer varies significantly between women. Moreover, this study provides information regarding the technical aspects of these advanced molecular tools, as well as an analysis of novel possible biomarkers for endometrial receptivity, providing a basis for future research in the field.

Sperm Morphology Assessment in the Era of Intracytoplasmic Sperm Injection: Reliable Results Require Focus on Standardization, Quality Control, and Training.

Semen analysis is the first, and frequently, the only step in the evaluation of male fertility. Although the laboratory procedures are conducted according to the World Health Organization (WHO) guidelines, semen analysis and especially sperm morphology assessment is very difficult to standardize and obtain reproducible results. This is mainly due to the highly subjective nature of their evaluation. ICSI is the choice of treatment when sperm morphology is severely abnormal (teratozoospermic). Hence, the standardization of laboratory protocols for sperm morphology evaluation represents a fundamental step to ensure reliable, accurate and consistent laboratory results that avoid misdiagnoses and inadequate treatment of the infertile patient. This article aims to promote standardized laboratory procedures for an accurate evaluation of sperm morphology, including the establishment of quality control and quality assurance policies. Additionally, the clinical importance of sperm morphology results in assisted reproductive outcomes is discussed, along with the clinical management of teratozoospermic patients.