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Purpose: The continuous improvement and development of fertility care, internationally, requires ongoing monitoring of current delivery processes and outcomes in clinical practice. This descriptive and exploratory mixed-methods study was conducted in eight countries (Brazil, China, France, Germany, Italy, Mexico, Spain and the United Kingdom) to assess the unmet needs of fertility patients (male and female), and existing challenges, barriers and educational gaps of physicians and laboratory specialists involved in human fertility care during the COVID-19 pandemic., Materials and Methods: The study was deployed sequentially in two phases: 1) in-depth 45-minute semi-structured interviews (n=76), transcribed, coded and thematically analysed using an inductive reasoning approach, 2) an online survey (n=303) informed by the findings of the qualitative interviews, face validated by experts in reproductive medicine, and analysed using descriptive and inferential statistical methods., Results: The integrated results of both phases indicated numerous areas of challenges, including: 1) investigating male-related infertility; 2) deciding appropriate treatment for men and selective use of assisted reproductive technology; and 3) maintaining access to high-quality fertility care during a pandemic., Conclusions: The paper presents a reflective piece on knowledge and skills that warrant ongoing monitoring and improvement amongst reproductive medicine healthcare professionals amidst future pandemics and unanticipated health system disruptions. Moreover, these findings suggest that there is an additional need to better understand the required changes in policies and organizational processes that would facilitate access to andrology services for male infertility and specialized care, as needed., Competing Interests: None declared., (Copyright® by the International Brazilian Journal of Urology.)

Varicocele can reduce male fertility potential through various oxidative stress mechanisms. Excessive production of reactive oxygen species may overwhelm the sperm's defenses against oxidative stress, damaging the sperm chromatin. Sperm DNA fragmentation, in the form of DNA strand breaks, is recognized as a consequence of the oxidative stress cascade and is commonly found in the ejaculates of men with varicocele and fertility issues. This paper reviews the current knowledge regarding the association between varicocele, oxidative stress, sperm DNA fragmentation, and male infertility, and examines the role of varicocele repair in alleviating oxidative-sperm DNA fragmentation in these patients. Additionally, we highlight areas for further research to address knowledge gaps relevant to clinical practice., Competing Interests: None declared., (Copyright® by the International Brazilian Journal of Urology.)

Non-obstructive azoospermia (NOA) is found in up to 15% of infertile men. While several causes for NOA have been identified, the exact etiology remains unknown in many patients. Advances in assisted reproductive technology, including intracytoplasmic sperm injection (ICSI) and testicular sperm retrieval, have provided hope for these patients. This review summarizes the chances of success with ICSI for NOA patients and examines preoperative factors and laboratory techniques associated with positive outcomes. Furthermore, we reviewed possible consequences for offspring by the use of ICSI with testicular sperm retrieved from NOA patients and the interventions that could potentially mitigate risks. Testicular sperm retrieved from NOA patients may exhibit increased chromosomal abnormalities, and although lower fertilization and pregnancy rates are reported in NOA patients compared to other forms of infertility, the available evidence does not suggest a significant increase in miscarriage rate, congenital malformation, or developmental delay in their offspring compared to the offspring of patients with less severe forms of infertility or the offspring of fertile men. However, due to limited data, NOA patients should receive specialized reproductive care and personalized management. Counseling of NOA patients is essential before initiating any fertility enhancement treatment not only to mitigate health risks associated with NOA but also to enhance the chances of successful outcomes and minimize possible risks to the offspring.

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Research Question: What clinical factors are associated with 'unexpected' poor or suboptimal responses to IVF ovarian stimulation per POSEIDON's criteria, and which AMH and AFC threshold values distinguish this population?, Design: Tri-centre retrospective cohort study (2015-2017) involving first-time IVF and ICSI cycles with conventional ovarian stimulation (≥150 IU/day of FSH). Eligibility criteria included sufficient ovarian reserve markers according to POSEIDON's classification (AMH ≥1.2 ng/ml; AFC ≥5). Ovarian response categories were poor (<4 oocytes), suboptimal (4-9 oocytes) and normal (≥9 oocytes). Primary outcomes included clinical factors associated with an unexpected poor or suboptimal response to conventional ovarian stimulation using logistic regression analyses, and the threshold values of AMH and AFC predicting increased risk of such responses using ROC curves., Results: A total of 7625 patients met the inclusion criteria: 204 (9.3%) were poor and 1998 (90.7%) were suboptimal responders. Logistic regression identified significant clinical predictors for a poor or suboptimal response, including AFC, AMH, total gonadotrophin dose, gonadotrophin type and trigger type (P ≤ 0.02). The ROC curves indicated that AMH 2.87 ng/ml (AUC 0.740) and AFC 12 (AUC 0.826) were the threshold values predicting a poor or suboptimal response; AMH 2.17 ng/ml (AUC 0.741) and AFC 9 (AUC 0.835) predicted a poor response; and AMH 2.97 ng/ml (AUC 0.722) and AFC 12 (AUC 0.801) predicted a suboptimal response., Conclusions: The threshold values of AMH and AFC predicting 'unexpected' poor or suboptimal response were higher than expected. These findings have critical implications for tailoring IVF stimulation regimens and dosages., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: To explore factors influencing microdissection testicular sperm extraction (micro-TESE) success in hypogonadal men with nonobstructive azoospermia (NOA)., Design: A cohort study., Setting: University-affiliated male reproductive health center., Patient(s): A total of 616 consecutive patients with NOA and hypogonadism (total testosterone [T] levels <350 ng/dL) underwent micro-TESE between 2014 and 2021. All patients had no prior sperm retrieval (SR) history., Intervention(s): Patients aged 23-55 years underwent comprehensive clinical, laboratory, and histopathological diagnostic evaluation for NOA and were further categorized into two cohorts on the basis of pre-SR hormonal stimulation., Main Outcome Measure(s): A multivariable logistic regression analysis explored the associations between patient variables and micro-TESE success, defined as the presence of viable spermatozoa in extracted specimens. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were computed to assess the relationship between SR success and relevant predictors. Sperm retrieval rates were compared between patients receiving or not hormonal stimulation, and logistic regression analysis evaluated the effect of baseline follicle-stimulating hormone levels (i.e., normogonadotropic vs. hypergonadotropic classes) on SR success., Result(s): The overall micro-TESE success rate was 56.6%. Baseline follicle-stimulating hormone levels (aOR, 0.97; 95% CI, 0.94-0.99), pre-SR hormonal stimulation (aOR, 2.54; 95% CI, 1.64-3.93), presence of clinical varicocele (aOR, 0.05; 95% CI, 0.01-0.51), history of previous varicocelectomy (aOR, 2.55; 95% CI, 1.26-5.16), and testicular histopathology were independent predictors of SR success. Among hormone-pretreated patients, pre-micro-TESE T levels and delta T (an absolute increase in T levels from baseline) were associated with SR success. A pre-micro-TESE T level of 418.5 ng/dL (area under the curve value: 0.78) and a delta T of 258 ng/dL (area under the value: 0.76) distinguished patients with positive and negative SR outcomes. Subgroup analysis showed that pre-SR hormonal stimulation yielded a greater benefit for normogonadotropic patients than for those who were hypergonadotropic., Conclusion(s): This study underscores the association between clinical factors and micro-TESE success in hypogonadal men with NOA. Although causality is not established, our findings suggest that these patients may benefit from pre-SR interventions, particularly hormonal stimulation and varicocele repair., Clinical Trial Registration Number: NCT05110391., Competing Interests: Declaration of Interests S.C.E reports receipt of lecture fees from Med.E.A. (Italy), Sanitanova (Italy), and Merck KGaA (Germany); unrestricted research grants from Merck KGaA, Germany; WHO (Switzerland) - Chair, Male Infertility Group, WHO Infertility Guidelines (in preparation) – unpaid; Brazilian Society of Urology (Brazil) - Member, Department of Education and Research – unpaid; Med.E.A. - Member, Andrology and Reproductive Medicine Committees - unpaid. A.P.P.A. reports funding from ANDROFERT (Brazil) - Institutional support: provision of study materials, funding for statistical analysis as part of a Thesis Project for the submitted work. R.M. has nothing to disclose. S.V. has nothing to disclose. A.F. has nothing to disclose. C.L.Z.R. has nothing to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Male infertility is a great matter of concern as out of 15% of infertile couples in the reproductive age, about 40% are contributed by male factors alone. For DNA condensation during spermatogenesis, constrained DNA nicking is required, which if increased beyond certain level results in infertility in men. High sperm DNA Fragmentation (SDF) majorly contributes to male infertility and its association with regards to poor natural conception and assisted reproductive technology (ART) outcomes is equivocal. Apoptosis, protamination failure and the excess of reactive oxygen species (ROS) are considered to be the main causes of SDF. It's testing came into existence because of the limitations of the conventional methods in explaining infertility in normozoospermic infertile individuals. Over the past 25 years, SDF's several testing strategies have been proposed to diagnose the aetiology of infertility. Various treatments combined with sperm selection techniques are being used alone or in combination to reduce DNA fragmentation index (DFI) and obtain spermatozoa with high quality chromatin for assisted reproduction. This review summarises SDF's main causes, its impact on fertility and clinical outcomes in assisted reproduction, the need to perform test, testing procedures, and the treatment strategies.

Background: Existing literature does not provide accurate epidemiological data regarding the true prevalence of men with non-obstructive azoospermia (NOA) who would be eligible for hormonal optimization therapy, according to specific pre-treatment criteria., Objectives: To investigate the characteristics of those men with NOA who would qualify for the medical therapy prior to any SR procedure in a large multi-centric cross-sectional study., Materials and Methods: Complete data from 1644 NOA patients seeking medical help for primary infertility at three tertiary referral centers from USA, Brazil, and Italy were analyzed. Baseline serum hormone levels were collected for all patients. NOA was confirmed after two consecutive semen analyses. Genetic tests, including karyotype analysis and Y microdeletions, were performed on all patients. Patients with secondary hypogonadism (total testosterone (T) levels less than 300 ng/dL and luteinizing hormone (LH) levels less than 8 mIU/mL) were earmarked as potential candidates for receiving clomiphene citrate (CC) and/or human chorionic gonadotropin (hCG). Patients with a T to 17β-estradiol (E2) ratio < 10 were classified as eligible for aromatase inhibitors (AIs) therapy (e.g., anastrazole). A third sub-cohort was created by combining the criteria of the first two sub-cohorts. Descriptive statistics was used to detail overall characteristics and differences between the different sub-cohorts., Results: Among the 1,644 men, 28% (n = 460) had T < 300 ng/dL and LH < 8 mIU/mL, thereby being potentially suitable for CC and/or hCG, while 37% (n = 607) had a T to E2 ratio < 10 thus potentially suitable for AIs. Lastly, 17.7% (n = 280) met the criteria for potential eligibility for both CC and/or hCG and AIs., Conclusions: Findings from this multicentric cross-sectional study reveal that about 30% of men with NOA were eligible for hormonal treatment with CC and/or hCG while 37% were found to be potential candidates for AIs, and 17% for both therapies. Therefore, these findings show that a only a small subset of NOA patients can benefit from medical therapy prior to considering any SR procedures., (© 2024 American Society of Andrology and European Academy of Andrology.)

Objective: Planned oocyte cryopreservation (OC) is being increasingly utilized worldwide. However, some women cannot accumulate sufficient oocytes because of poor response to stimulation. The POSEIDON classification is a novel system to classify patients with 'expected' or 'unexpected' inappropriate ovarian response to exogenous gonadotropins. Our study aimed to examine the prevalence of POSEIDON patients among women undergoing planned OC., Study Design: We retrospectively reviewed the first cycles of 160 consecutive patients undergoing planned OC. Patients were classified into the four POSEIDON groups or as 'non-POSEIDON' based on age, AMH level and the number of oocytes retrieved. The primary outcome measure was the prevalence of POSEIDON patients., Results: Overall, 63 patients (39.4 %) were classified as POSEIDON patients, 12 in group 1, 12 in group 2, 8 in group 3, and 31 in group 4. Compared to non-POSEIDON patients, POSEIDON patients had increased basal FSH levels and reduced serum AMH levels and antral follicle counts, required higher FSH starting doses and increased gonadotropin requirements and reached lower peak serum estradiol levels. Additionally, POSEIDON patients had a lower number of oocytes retrieved (7.6 ± 3.1 vs.20.2 ± 9.9, p < 0.001) and vitrified (5.8 ± 2.9 vs.14.7 ± 6.8, p < 0.001) than non-POSEIDON counterparts, respectively., Conclusion: We found a high prevalence of patients being classified as low prognosis according to the POSEIDON criteria among patients seeking planned OC. POSEIDON patients had increased gonadotropin requirements and a significantly lower number of oocytes retrieved and vitrified. This novel, unexpected finding adds clinically relevant information for counselling and management of patients undergoing planned OC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Research Question: Can a novel classification system of the infertile male - 'APHRODITE' (Addressing male Patients with Hypogonadism and/or infeRtility Owing to altereD, Idiopathic TEsticular function) - stratify different subgroups of male infertility to help scientists to design clinical trials on the hormonal treatment of male infertility, and clinicians to counsel and treat the endocrinological imbalances in men and, ultimately, increase the chances of natural and assisted conception?, Design: A collaboration between andrologists, reproductive urologists and gynaecologists, with specialization in reproductive medicine and expertise in male infertility, led to the development of the APHRODITE criteria through an iterative consensus process based on clinical patient descriptions and the results of routine laboratory tests, including semen analysis and hormonal testing., Results: Five patient groups were delineated according to the APHRODITE criteria; (1) Hypogonadotrophic hypogonadism (acquired and congenital); (2) Idiopathic male infertility with lowered semen analysis parameters, normal serum FSH and normal serum total testosterone concentrations; (3) A hypogonadal state with lowered semen analysis parameters, normal FSH and reduced total testosterone concentrations; (4) Lowered semen analysis parameters, elevated FSH concentrations and reduced or normal total testosterone concentrations; and (5) Unexplained male infertility in the context of unexplained couple infertility., Conclusion: The APHRODITE criteria offer a novel and standardized patient stratification system for male infertility independent of aetiology and/or altered spermatogenesis, facilitating communication among clinicians, researchers and patients to improve reproductive outcomes following hormonal therapy. APHRODITE is proposed as a basis for future trials of the hormonal treatment of male infertility., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: SCE reports speaker's fees from Merck and MedEA, and research grants from Merck KGaA, outside of the submitted work. PH reports speaker's fees from Merck, Institut Biochimique, and Gedeon-Richter, outside of the submitted work.

Purpose: To determine the risk of not being a poor responder in ovarian stimulation (OS) for in vitro fertilization (IVF) when ovarian reserve markers are discordant-one falling within Poseidon's criteria normal range (e.g., anti-Müllerian hormone (AMH) ≥ 1.2 ng/mL or antral follicle count (AFC) ≥ 5), and the other in the poor ovarian reserve range., Methods: A tri-center retrospective cohort study (2015-2017) involving women with discordant AMH and AFC values undergoing their first IVF/ICSI cycle using conventional OS (cOS, ≥ 150 IU/day of follicle-stimulating hormone). Discordant serum AMH and AFC values were defined according to Poseidon's criteria (AMH < 1.2 ng/mL and AFC ≥ 5 or AMH ≥ 1.2 ng/mL and AFC < 5). Poor ovarian response (POR) was < 4 retrieved oocytes. Receiver operating characteristic (ROC) curves were used to determine AMH and AFC cut-offs for non-POR. Logistic regression analysis evaluated factors associated with non-POR., Results: Out of 8797 patients who underwent assessment with both AMH and AFC, 1172 (13.3%) exhibited discordant values. Of these, 854 (72.9%) had ≥ 4 oocytes retrieved. Within this group, 726 (85.0%) had "low" AMH values, whereas 128 (15.0%) had "low" AFCs. An AFC of 6 had 77% sensitivity and 52% specificity (AUC = 0.700), while AMH of 1.19 ng/mL had 31% sensitivity and 85% specificity (AUC = 0.492) for non-POR. AFC and the use of recombinant gonadotropins were positive predictors of non-POR., Conclusions: When serum AMH is < 1.19 ng/mL, but AFC is ≥ 6, there is a moderate likelihood of a non-POR during stimulation. Conversely, if AFC is < 5 but serum AMH is ≥ 1.19 ng/mL, the chances of non-POR are low. Among patients with discordant markers, AFC emerges as the primary predictor of oocyte yield., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: This review provides a comprehensive overview of the existing research on the seminal microbiome and its association with male infertility, while also highlighting areas that warrant further investigation., Methods: A narrative review was conducted, encompassing all relevant studies published between 1980-2023 on the male reproductive tract microbiome in humans. This review considered studies utilizing culture-based, polymerase chain reaction (PCR)-based, and next-generation sequencing (NGS)-based methodologies to analyze the microbiome. Data extraction encompassed sample types (semen or testicular tissue), study designs, participant characteristics, employed techniques, and critical findings., Results: We included 37 studies comprising 9,310 participants. Among these, 16 studies used culture-based methods, 16 utilized NGS, and five employed a combination of methods for microorganism identification. Notably, none of the studies assessed fungi or viruses. All NGS-based studies identified the presence of bacteria in all semen samples. Two notable characteristics of the seminal microbiome were observed: substantial variability in species composition among individuals and the formation of microbial communities with a dominant species. Studies examining the testicular microbiome revealed that the testicular compartment is not sterile. Interestingly, sexually active couples shared 56% of predominant genera, and among couples with positive cultures in both partners, 61% of them shared at least one genital pathogen. In couples with infertility of known causes, there was an overlap in bacterial composition between the seminal and vaginal microbiomes, featuring an increased prevalence of Staphylococcus and Streptococcus genera. Furthermore, the seminal microbiome had discernible effects on reproductive outcomes. However, bacteria in IVF culture media did not seem to impact pregnancy rates., Conclusion: Existing literature underscores that various genera of bacteria colonize the male reproductive tract. These organisms do not exist independently; instead, they play a pivotal role in regulating functions and maintaining hemostasis. Future research should prioritize longitudinal and prospective studies and investigations into the influence of infertility causes and commonly prescribed medication to enhance our understanding of the seminal microbiota's role in reproductive health., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer AG declared a shared affiliation with the author(s) FC, AC, CA to the handling editor at the time of review. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision, (Copyright © 2024 Neto, Viana, Cariati, Conforti, Alviggi and Esteves.)

Varicocele is the leading cause of male infertility. It can affect sperm quantity and quality through various non-mutually exclusive pathophysiological mechanisms, mainly oxidative stress. Excessive production of reactive oxygen species may overwhelm the sperm's defenses against oxidative stress and harm the sperm's DNA. Excessive sperm DNA breaks, so-called sperm DNA fragmentation, result from the oxidative stress cascade and are commonly found in the ejaculates of men with varicocele and fertility-related issues. Measuring sperm DNA fragmentation can provide valuable information on the extent of harm and might help select candidates for surgical treatment. Varicocelectomy is beneficial for alleviating oxidative stress-associated infertility and improving sperm DNA integrity. However, reproductive outcomes of infertile men with elevated sperm DNA fragmentation rates and surgically treated varicoceles remain poorly studied, and there is a need for well-designed trials to determine the impact of sperm DNA fragmentation reduction on natural and medically assisted reproduction.

Objective: To investigate the prevalence and clinical implications of biochemical hypogonadism in infertile men with nonobstructive azoospermia (NOA)., Design: Cohort study., Setting: University-affiliated tertiary center for male reproductive health., Patients: 767 consecutive normogonadotropic or hypergonadotropic patients with NOA undergoing infertility evaluation from 2014 to 2021., Intervention: Patients aged 23-55 years underwent comprehensive clinical, hormonal, genetic, semen analysis, and histopathology evaluations and were classified on the basis of predefined baseline follicle-stimulating hormone (12 IU/L) and total testosterone (350 ng/dL) serum levels cutpoints into four groups: hypergonadotropic hypogonadal, hypergonadotropic eugonadal, normogonadotropic hypogonadal, and normogonadotropic eugonadal. All patients were naïve regarding previous sperm retrieval (SR) or hormonal therapy use., Main Outcome Measures: The period prevalence of biochemical hypogonadism, defined as testosterone levels of <350 ng/dL, and the distribution of patients per group were computed. The associations between hypogonadism, clinical factors, and SR success were evaluated using multivariable logistic regression analyses. Adjusted relative risks (aRRs) and 95% confidence intervals (CIs) were estimated to assess the association between SR and patient classification., Results: The overall period prevalence of biochemical hypogonadism was 80.8% (95% CI 77.9%-83.4%). The prevalence of patients by group was hypergonadotropic hypogonadal (42.4%, 38.9%-45.9%), normogonadotropic hypogonadal (38.5%; 35.1%-41.9%), hypergonadotropic eugonadal (8.3%; 6.6%-10.5%), and normogonadotropic eugonadal (10.8%; 8.8%-13.2%). Reduced testicular volume and lower estradiol levels were associated with an increased likelihood of hypogonadism. Paternal age was also an independent predictor, with higher age linked to an increased likelihood of hypogonadism. Hypogonadism was less likely in patients with germ cell maturation arrest and more likely in those with Sertoli cell-only. Patients with hypergonadotropic hypogonadism had lower SR success than normogonadotropic eugonadal counterparts (aRR 0.611; 95% CI 0.398-0.855). In the subset of hypogonadal men, hypergonadotropic patients had lower SR success than normogonadotropic participants (aRR 0.632; 0.469-0.811)., Conclusion: The prevalence of biochemical hypogonadism among men with NOA is substantial. Hypogonadism is associated with testicular volume, estradiol levels, age, and histopathology patterns. This condition impacts SR success and emphasizes the need for improved care for men with NOA., Competing Interests: A.P.P.A. reports funding from Androfert (provision of study materials, funding for statistical analysis) as part of a Thesis Project for the submitted work. S.C.E. reports receipt of lecture fees from Merck KGa and Medea (Medical Education Academy, Italy); and leadership roles: WHO - Chair, Male Infertility Group, WHO Infertility Guidelines, Brazilian Society of Urology - Member, Department of Education and Research, Medea - Member, Reproductive Medicine Committee outside the submitted work., (© 2023 The Author(s).)

Purpose: To provide agreed-upon guidelines on the management of a hyper-responsive patient undergoing ovarian stimulation (OS) METHODS: A literature search was performed regarding the management of hyper-response to OS for assisted reproductive technology. A scientific committee consisting of 4 experts discussed, amended, and selected the final statements. A priori, it was decided that consensus would be reached when ≥66% of the participants agreed, and ≤3 rounds would be used to obtain this consensus. A total of 28/31 experts responded (selected for global coverage), anonymous to each other., Results: A total of 26/28 statements reached consensus. The most relevant are summarized here. The target number of oocytes to be collected in a stimulation cycle for IVF in an anticipated hyper-responder is 15-19 (89.3% consensus). For a potential hyper-responder, it is preferable to achieve a hyper-response and freeze all than aim for a fresh transfer (71.4% consensus). GnRH agonists should be avoided for pituitary suppression in anticipated hyper-responders performing IVF (96.4% consensus). The preferred starting dose in the first IVF stimulation cycle of an anticipated hyper-responder of average weight is 150 IU/day (82.1% consensus). ICoasting in order to decrease the risk of OHSS should not be used (89.7% consensus). Metformin should be added before/during ovarian stimulation to anticipated hyper-responders only if the patient has PCOS and is insulin resistant (82.1% consensus). In the case of a hyper-response, a dopaminergic agent should be used only if hCG will be used as a trigger (including dual/double trigger) with or without a fresh transfer (67.9% consensus). After using a GnRH agonist trigger due to a perceived risk of OHSS, luteal phase rescue with hCG and an attempt of a fresh transfer is discouraged regardless of the number of oocytes collected (72.4% consensus). The choice of the FET protocol is not influenced by the fact that the patient is a hyper-responder (82.8% consensus). In the cases of freeze all due to OHSS risk, a FET cycle can be performed in the immediate first menstrual cycle (92.9% consensus)., Conclusion: These guidelines for the management of hyper-response can be useful for tailoring patient care and for harmonizing future research., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Intracytoplasmic sperm injection (ICSI) using surgically retrieved spermatozoa outside the classic context of azoospermia has been increasingly used to overcome infertility. The primary indications include high levels of sperm DNA damage in ejaculated spermatozoa and severe oligozoospermia or cryptozoospermia, particularly in couples with ICSI failure for no apparent reason. Current evidence suggests that surgically retrieved spermatozoa for ICSI in the above context improves  outcomes, mainly concerning pregnancy and miscarriage rates. The reasons are not fully understood but may be related to the lower levels of DNA damage in spermatozoa retrieved from the testis compared with ejaculated counterparts. These findings are consistent with the notion that excessive sperm DNA damage  can be a limiting factor responsible for the failure to conceive. Using testicular in preference of low-quality ejaculated spermatozoa bypasses post-testicular sperm DNA damage caused primarily by oxidative stress, thus increasing the likelihood of oocyte fertilization by genomically intact spermatozoa. Despite the overall favorable results, data remain limited, and mainly concern males with confirmed sperm DNA damage in the ejaculate. Additionally, information regarding the health of ICSI offspring resulting from the use of surgically retrieved spermatoa of non-azoospermic males is still lacking. Efforts should be made to improve the male partner's reproductive health for safer ICSI utilization. A comprehensive andrological evaluation aiming to identify and treat the underlying male infertility factor contributing to sperm DNA damage is essential for achieving this goal., (© 2023 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)

The purpose of this article is to provide an explanation of the background behind a checklist that declares the laboratory methods used in a scientific study. It focuses primarily on implementing laboratory procedures to yield reliable results in basic semen examinations. While the World Health Organization (WHO) and international standards provide recommendations for basic semen examination, manuscripts submitted to Andrology frequently lack transparency regarding the specific techniques used. In addition, the terminology used for semen examination results often fails to provide a clear definition of the groups under study. Furthermore, the WHO's reference limits are often misinterpreted as strict boundaries between fertility and infertility. It is important to note that valid clinical andrological diagnoses and treatments cannot rely solely on semen examination results; they require proper laboratory procedures as a foundation for diagnosing and treating male patients. Therefore, scientific journals should promote the adoption of robust laboratory practices and an accurate definition of patient groups. A checklist can facilitate the design of high-quality studies and the creation of informative publications. Further, it can help journals assess submitted manuscripts and improve the overall quality of their publications., (© 2023 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)

Background: In a true-natural cycle (t-NC), optimal progesterone (P 4 ) output from the corpus luteum is crucial for establishing and maintaining an intrauterine pregnancy. In a previous retrospective study, low P 4 levels (< 10 ng/mL) measured one day before warmed blastocyst transfer in t-NC were associated with significantly lower live-birth rates. In the current study, we aim to examine the relationship between patient, follicular-phase endocrine and ultrasonographic characteristics, and serum P 4 levels one day prior to warmed blastocyst transfer in t-NC., Method: 178 consecutive women undergoing their first t-NC frozen embryo transfer (FET) between July 2017-August 2022 were included. Following serial ultrasonographic and endocrine monitoring, ovulation was documented by follicular collapse. Luteinized unruptured follicle (LUF) was diagnosed when there was no follicular collapse despite luteinizing-hormone surge (> 17 IU/L) and increased serum P 4 (> 1.5 ng/mL). FET was scheduled on follicular collapse + 5 or LH surge + 6 in LUF cycles. Primary outcome was serum P 4 on FET - 1., Results: Among the 178 patients, 86% (n = 153) experienced follicular collapse, while 14% (n = 25) had LUF. On FET-1, the median serum luteal P 4 level was 12.9 ng/mL (IQR: 9.3-17.2), ranging from 1.8 to 34.4 ng/mL. Linear stepwise regression revealed a negative correlation between body mass index (BMI) and LUF, and a positive correlation between follicular phase peak-E 2 and peak-P 4 levels with P 4 levels on FET-1. The ROC curve analyses to predict < 9.3 ng/mL (< 25th percentile) P 4 levels on FET-1 day showed AUC of 0.70 (95%CI 0.61-0.79) for BMI (cut-off: 23.85 kg/m 2 ), 0.71 (95%CI 0.61-0.80) for follicular phase peak-P 4 levels (cut-off: 0.87 ng/mL), and 0.68 (95%CI 0.59-0.77) for follicular phase peak-E 2 levels (cut-off: 290.5 pg/mL). Combining all four independent parameters yielded an AUC of 0.80 (95%CI 0.72-0.88). The adjusted-odds ratio for having < 9.3 ng/mL P 4 levels on FET-1 day for patients with LUF compared to those with follicle collapse was 4.97 (95%CI 1.66-14.94)., Conclusion: The BMI, LUF, peak-E 2, and peak-P 4 levels are independent predictors of low serum P 4 levels on FET-1 (< 25th percentile; <9.3 ng/ml) in t-NC FET cycles. Recognition of risk factors for low serum P 4 on FET-1 may permit a personalized approach for LPS in t-NC FET to maximize reproductive outcomes., (© 2023. BioMed Central Ltd., part of Springer Nature.)

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., (© 2023. Springer Nature Limited.)

Research Question: Does administration of subcutaneous (s.c.) progesterone support ongoing pregnancy rates (OPR) similar to vaginal progesterone using a rescue protocol in hormone replacement therapy frozen embryo transfer cycles?, Design: Retrospective cohort study. Two sequential cohorts - vaginal progesterone gel (December 2019-October 2021; n=474) and s.c. progesterone (November 2021-November 2022; n=249) -were compared. Following oestrogen priming, s.c. progesterone 25 mg twice daily (b.d.) or vaginal progesterone gel 90 mg b.d. was administered. Serum progesterone was measured 1 day prior to warmed blastocyst transfer (i.e. day 5 of progesterone administration). In patients with serum progesterone concentrations <8.75 ng/ml, additional s.c. progesterone (rescue protocol; 25 mg) was provided., Results: In the vaginal progesterone gel group, 15.8% of patients had serum progesterone <8.75 ng/ml and received the rescue protocol, whereas no patients in the s.c. progesterone group received the rescue protocol. OPR, along with positive pregnancy and clinical pregnancy rates, were comparable between the s.c. progesterone group without the rescue protocol and the vaginal progesterone gel group with the rescue protocol. After the rescue protocol, the route of progesterone administration was not a significant predictor of ongoing pregnancy. The impact of different serum progesterone concentrations on reproductive outcomes was evaluated by percentile (<10 th , 10-49 th , 50-90 th and >90 th percentiles), taking the >90 th percentile as the reference subgroup. In both the vaginal progesterone gel group and the s.c. progesterone group, all serum progesterone percentile subgroups had similar OPR., Conclusions: Subcutaneous progesterone 25 mg b.d. secures serum progesterone >8.75 ng/ml, whereas additional exogenous progesterone (rescue protocol) was needed in 15.8% of patients who received vaginal progesterone. The s.c. and vaginal progesterone routes, with the rescue protocol if needed, yield comparable OPR., (Copyright © 2023 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Background: Total fertilization failure (TFF) is the failure of all metaphase II oocytes to fertilize in ART cycles. The phenomenon represents a known cause of infertility, affecting 1-3% of ICSI cycles. Oocyte activation deficiency (OAD) is the leading cause of fertilization failure, attributed to sperm- or oocyte-related issues, although until recently little attention has been given to oocyte-related deficiencies. Different strategies for overcoming TFF have been proposed in clinical settings, mainly using artificial oocyte activation (AOA) by calcium ionophores. Typically, AOA has been blindly applied with no previous diagnosis testing and, therefore, not considering the origin of the deficiency. The scarcity of data available and the heterogeneous population subjected to AOA make it challenging to draw firm conclusions about the efficacy and safety of AOA treatments., Objective and Rationale: TFF leads to an unexpected, premature termination of ART, which inflicts a substantial psychological and financial burden on patients. This review aims to provide a substantial update on: the pathophysiology of fertilization failure, focusing both on sperm- and oocyte-related factors; the relevance of diagnostic testing to determine the cause of OAD; and the effectiveness and safety of AOA treatments to overcome fertilization failure., Search Methods: Relevant studies were identified in the English-language literature using PubMed search terms, including fertilization failure, AOA, phospholipase C zeta (PLCζ), PLCZ1 mutations, oocyte-related factors, wee1-like protein kinase 2 (WEE2) mutations, PAT1 homolog 2 (PATL2) mutations, tubulin beta-8 chain (TUBB8) mutations, and transducin-like enhancer protein 6 (TLE6) mutations. All relevant publications until November 2022 were critically evaluated and discussed., Outcomes: Fertilization failure after ART has been predominantly associated with PLCζ deficiencies in sperm. The reason relates to the well-established inability of defective PLCζ to trigger the characteristic pattern of intracellular Ca2+ oscillations responsible for activating specific molecular pathways in the oocyte that lead to meiosis resumption and completion. However, oocyte deficiencies have recently emerged to play critical roles in fertilization failure. Specifically, mutations have been identified in genes such as WEE2, PATL2, TUBB8, and TLE6. Such mutations translate into altered protein synthesis that results in defective transduction of the physiological Ca2+ signal needed for maturation-promoting factor (MPF) inactivation, which is indispensable for oocyte activation. The effectiveness of AOA treatments is closely related to identifying the causal factor of fertilization failure. Various diagnostic tests have been developed to determine the cause of OAD, including heterologous and homologous tests, particle image velocimetry, immunostaining, and genetic tests. On this basis, it has been shown that conventional AOA strategies, based on inducing the calcium oscillations, are highly effective in overcoming fertilization failure caused by PLCζ-sperm deficiencies. In contrast, oocyte-related deficiencies might be successfully managed using alternative AOA promoters that induce MPF inactivation and meiosis resumption. Such agents include cycloheximide, N,N,N',N'-tetrakis(2-pyridylmethyl)ethane-1,2-diamine (TPEN), roscovitine, and WEE2 complementary RNA. In addition, when OAD is caused by oocyte dysmaturity, applying a modified ovarian stimulation protocol and trigger could improve fertilization., Wider Implications: AOA treatments represent a promising therapy to overcome fertilization failure caused by sperm- and oocyte-related factors. Diagnosing the cause of fertilization failure will be essential to improve the effectiveness and safe utilization of AOA treatments. Even though most data have not shown adverse effects of AOA on pre- and post-implantation embryo development, the literature is scarce on the matter concerned and recent studies, mainly using mice, suggest that AOA might cause epigenetic alterations in the resulting embryos and offspring. Until more robust data are available, and despite the encouraging results obtained, AOA should be applied clinically judiciously and only after appropriate patient counseling. Currently, AOA should be considered an innovative treatment, not an established one., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Competing Interests: None declared.

Male infertility is a disease that deserves greater clinical attention and research. A universally accepted definition that emphasizes the modulatory impact of age, lifestyle and environmental factors and includes comprehensive diagnostic and treatment guidelines is needed to ensure accurate evaluation and effective care. Accordingly, male infertility should be defined as a disease of the male reproductive system, caused primarily by congenital and genetic conditions, anatomical, endocrine, functional or immunological abnormalities of the reproductive system, genital tract infections, cancer and its related treatments, and sexual disorders incompatible with intercourse. Inadequate lifestyle, exposure to toxicants and advanced paternal age are critical factors acting alone or exacerbating the impact of known causative factors. The focus on male infertility must be balanced with that on female infertility to ensure the best possible outcome for the couple. Fertility clinics are encouraged to prioritize collaboration with reproductive urologists and andrologists to provide the best possible care for male infertility patients., (Copyright © 2023 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

High rates of multiple implantation after assisted reproductive technology (ART) treatment represent one of the major problems for both mothers and their fetuses. Given the availability of techniques intended to identify embryos with the highest chance for development to term, such as comprehensive chromosome screening (CCS) and blastocyst transfer, the decision on the number of embryos to transfer deserves careful consideration. This report presents real-life data from two clinics using the Fischer protocol for cycle programming in patients undergoing ART. Our data indicate that ovarian stimulation using the Fischer protocol provides consistent and optimal ART outcomes in centers following strict quality management standards. However, high multiple implantation rates were observed in fresh and frozen transfer cycles after transferring two embryos - even in patients aged over 39 years. The live birth rates after CCS were superior to those using untested embryos. These findings were held for the three age groups irrespective of the CCS culture day (D1 = PN stages, or D5 = blastocysts). Our results support a single embryo transfer policy, particularly in women under 34 years of age with favorable conditions during ART treatment, i.e., a high number of available fertilized oocytes., Competing Interests: Declaration of competing interest S.C.E. declares receipt of unrestricted research grants from Merck and lecture fees from Merck, and Med.E.A. R.F. declares receipt of payment for lectures from Merck and Med.E.A. The remaining authors have nothing to disclose., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Human papillomavirus (HPV) is a common sexually transmitted disease that has been linked to both cancer and reproductive health issues. While its impact on fertility and pregnancy success has been studied, there is still too little evidence about the influence of HPV on assisted reproductive technology (ART). Therefore, there exists a need for HPV testing in couples undergoing infertility treatments. Infertile men have been found to have a higher prevalence of seminal HPV infection, which can compromise sperm quality and reproductive function. As such, it could be important to investigate the correlation between HPV and ART outcomes in order to improve the quality of evidence. Understanding the potentially detrimental effects of HPV on ART outcomes may have promising important implications for the management of infertility. This minireview summarizes the so far limited developments in this area and highlights the major need for further well-designed studies to address this issue., Competing Interests: Competing interests We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted., (Copyright © 2023 Society for Biology of Reproduction & the Institute of Animal Reproduction and Food Research of Polish Academy of Sciences in Olsztyn. Published by Elsevier B.V. All rights reserved.)

Purpose: To provide an agreed upon definition of hyper-response for women undergoing ovarian stimulation (OS)?, Methods: A literature search was performed regarding hyper-response to ovarian stimulation for assisted reproductive technology. A scientific committee consisting of 5 experts discussed, amended, and selected the final statements in the questionnaire for the first round of the Delphi consensus. The questionnaire was distributed to 31 experts, 22 of whom responded (with representation selected for global coverage), each anonymous to the others. A priori, it was decided that consensus would be reached when ≥ 66% of the participants agreed and ≤ 3 rounds would be used to obtain this consensus., Results: 17/18 statements reached consensus. The most relevant are summarized here. (I) Definition of a hyper-response: Collection of ≥ 15 oocytes is characterized as a hyper-response (72.7% agreement). OHSS is not relevant for the definition of hyper-response if the number of collected oocytes is above a threshold (≥ 15) (77.3% agreement). The most important factor in defining a hyper-response during stimulation is the number of follicles ≥ 10 mm in mean diameter (86.4% agreement). (II) Risk factors for hyper-response: AMH values (95.5% agreement), AFC (95.5% agreement), patient's age (77.3% agreement) but not ovarian volume (72.7% agreement). In a patient without previous ovarian stimulation, the most important risk factor for a hyper-response is the antral follicular count (AFC) (68.2% agreement). In a patient without previous ovarian stimulation, when AMH and AFC are discordant, one suggesting a hyper-response and the other not, AFC is the more reliable marker (68.2% agreement). The lowest serum AMH value that would place one at risk for a hyper-response is ≥ 2 ng/ml (14.3 pmol/L) (72.7% agreement). The lowest AFC that would place one at risk for a hyper-response is ≥ 18 (81.8% agreement). Women with polycystic ovarian syndrome (PCOS) as per Rotterdam criteria are at a higher risk of hyper-response than women without PCOS with equivalent follicle counts and gonadotropin doses during ovarian stimulation for IVF (86.4% agreement). No consensus was reached regarding the number of growing follicles ≥ 10 mm that would define a hyper-response., Conclusion: The definition of hyper-response and its risk factors can be useful for harmonizing research, improving understanding of the subject, and tailoring patient care., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Assisted reproductive technology may influence epigenetic signature as the procedures coincide with the extensive epigenetic modification occurring from fertilization to embryo implantation. However, it is still unclear to what extent ART alters the embryo epigenome. In vivo fertilization occurs in the fallopian tube, where a specific and natural environment enables the embryo's healthy development. During this dynamic period, major waves of epigenetic reprogramming, crucial for the normal fate of the embryo, take place. Over the past decade, concerns relating to the raised incidence of epigenetic anomalies and imprinting following ART have been raised by several authors. Epigenetic reprogramming is particularly susceptible to environmental conditions during the periconceptional period; therefore, unphysiological conditions, including ovarian stimulation, in vitro fertilization, embryo culture, cryopreservation of gametes and embryos, parental lifestyle, and underlying infertility, have the potential to contribute to epigenetic dysregulation independently or collectively. This review critically appraises the evidence relating to the association between ART and genetic and epigenetic modifications that may be transmitted to the offspring., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

A high ovarian response to conventional ovarian stimulation (OS) is characterized by an increased number of follicles and/or oocytes compared with a normal response (10-15 oocytes retrieved). According to current definitions, a high response can be diagnosed before oocyte pick-up when >18-20 follicles ≥11-12 mm are observed on the day of ovulation triggering; high response can be diagnosed after oocyte pick-up when >18-20 oocytes have been retrieved. Women with a high response are also at high risk of early ovarian hyper-stimulation syndrome (OHSS)/or late OHSS after fresh embryo transfers. Women at risk of high response can be diagnosed before stimulation based on several indices, including ovarian reserve markers (anti-Müllerian hormone [AMH] and antral follicle count [AFC], with cutoff values indicative of a high response in patients with PCOS of >3.4 ng/mL for AMH and >24 for AFC). Owing to the high proportion of high responders who are at the risk of developing OHSS (up to 30%), this educational article provides a framework for the identification and management of patients who fall into this category. The risk of high response can be greatly reduced through appropriate management, such as individualized choice of the gonadotropin starting dose, dose adjustment based on hormonal and ultrasound monitoring during OS, the choice of down-regulation protocol and ovulation trigger, and the choice between fresh or elective frozen embryo transfer. Appropriate management strategies still need to be defined for women who are predicted to have a high response and those who have an unexpected high response after starting treatment., Competing Interests: Declaration of competing interest PD declares research grants and honoraria from Merck KGaA, Darmstadt, Germany, MSD, Ferring Pharmaceuticals; and paid consultancy work from Merck KGaA, Darmstadt, Germany. YaK received lecture fees/honoraria/grants from MSD; Merck KGaA, Darmstadt, Germany; Besins Healthcare; Gedeon Richter; Abbott; Bayer; ISBA; LD Collins; Ferring and Sun Pharma. SCE declares the receipt of unrestricted research grants from Merck and lecture fees from Merck, Event Planet, and Med.E.A. NP declares research grants and honoraria from Merck KGaA, Darmstadt, Germany; MSD; Organon; Ferring Pharmaceuticals; Besins International; Roche Diagnostics; IBSA; Theramex; Gedeon Richter. SKS has received speaker fees for non-promotional educational symposia by Merck KGaA, Darmstadt, Germany; MSD; Ferring; Pharmasure. DS has participated in Speaker's bureaus for both Merck KGaA, Darmstadt, Germany and Organon. BR has no conflicts of interest to declare. HY has no conflicts of interest to declare. MC has declared past sponsorship from Merck KGaA, Darmstadt, Germany, for scientific conference presentations. YuK received speaker fees/honoraria/grants from MSD, Merck KGaA, Darmstadt, Germany; Besins Healthcare; Gedeon Richter; Abbott; Bayer; and Sun Pharma. BS received research grants and honoraria from Merck KGaA, Darmstadt, Germany and Gedeon Richter. ML and TDH are employees of Merck Healthcare KGaA, Darmstadt, Germany. ALM declares research grants and honoraria from Merck KGaA, Darmstadt, Germany; MSD; Ferring Pharmaceuticals; Gedeon Richter; ISBA; Theramex; Organon; Roche; Beckman Coulter., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: The SARS-CoV-2 pandemic has rapidly spread worldwide and, among the others, the male gender was quickly recognized as an independent risk factor for both the disease and its consequences. Since the possibility of long-term hormonal axis changes and male gamete impairment have been hypothesized but a relatively low levels of evidence has been reached, we focused this narrative mini-review on summarizing key state-of-the-art knowledge on male reproductive effects of COVID-19 as a quick reference for reproductive health specialists., Methods: A comprehensive Medline/PubMed and Embase search was performed selecting all relevant, peer-reviewed papers in English published from 2020. Other relevant papers were selected from the reference lists., Results: Available evidence indicates that the likelihood of direct testicular damage from SARS-CoV-2 is somewhat low, but there are many indirect ways (fever, cytokine imbalance, and drugs) through which the pituitary-gonadal axis and spermatogenesis may be disrupted. These alterations are probably transient, but as available evidence is low quality, it cannot be excluded that previous pathologies or comorbidities might modulate the risk of their persistence. On the other hand, available evidence shows high safety regarding andrological health for available vaccines, although studies are mainly focused on mRNA vaccines., Conclusion: A careful andrological evaluation of men recovering from COVID-19 is highly recommended. Since available evidence is relatively scarce, a careful andrological follow-up and counseling of these patients are mandatory., (© 2022. The Author(s).)

Study Question: Do early- and mid-luteal serum progesterone (P4) levels impact ongoing pregnancy rates (OPRs) in fresh blastocyst transfer cycles using standard luteal phase support (LPS)?, Summary Answer: A drop in serum P4 level from oocyte pick-up (OPU) + 3 days to OPU + 5 days (negative ΔP4) is associated with a ∼2-fold decrease in OPRs., What Is Known Already: In fresh embryo transfer cycles, significant inter-individual variation occurs in serum P4 levels during the luteal phase, possibly due to differences in endogenous P4 production after hCG trigger and/or differences in bioavailability of exogenously administered progesterone (P) via different routes. Although exogenous P may alleviate this drop in serum P4 in fresh transfer cycles, there is a paucity of data exploring the possible impact on reproductive outcomes of a reduction in serum P4 levels., Study Design, Size, Duration: Using a prospective cohort study design, following the initial enrollment of 558 consecutive patients, 340 fulfilled the inclusion and exclusion criteria and were included in the final analysis. The inclusion criteria were: (i) female age ≤40 years, (ii) BMI ≤35 kg/m2, (iii) retrieval of ≥3 oocytes irrespective of ovarian reserve, (iv) the use of a GnRH-agonist or GnRH-antagonist protocol with recombinant hCG triggering (6500 IU), (v) standard LPS and (vi) fresh blastocyst transfer. The exclusion criteria were: (i) triggering with GnRH-agonist or GnRH-agonist plus recombinant hCG (dual trigger), (ii) circulating P4 >1.5 ng/ml on the day of trigger and (iii) cleavage stage embryo transfer. Each patient was included only once. The primary outcome was ongoing pregnancy (OP), as defined by pregnancy ≥12 weeks of gestational age., Participants/materials, Setting, Methods: A GnRH-agonist (n = 53) or GnRH-antagonist (n = 287) protocol was used for ovarian stimulation. Vaginal progesterone gel (Crinone, 90 mg, 8%, Merck) once daily was used for LPS. Serum P4 levels were measured in all patients on five occasions: on the day of ovulation trigger, the day of OPU, OPU + 3 days, OPU + 5 days and OPU + 14 days; timing of blood sampling was standardized to be 3-5 h after the morning administration of vaginal progesterone gel. The delta P4 (ΔP4) level was calculated by subtracting the P4 level on the OPU + 3 days from the P4 level on the OPU + 5 days, resulting in either a positive or negative ΔP4., Main Results and the Role of Chance: The median P4 (min-max) on the day of triggering, day of OPU, OPU + 3 days, OPU + 5 days and OPU + 14 days were 0.83 ng/ml (0.18-1.42), 5.81 ng/ml (0.80-22.72), 80.00 ng/ml (22.91-161.05), 85.91 ng/ml (15.66-171.78) and 13.46 ng/ml (0.18-185.00), respectively. Serum P4 levels uniformly increased from the day of OPU to OPU + 3 days in all patients; however, from OPU + 3 days to OPU + 5 days, some patients had a decrease (negative ΔP4; n = 116; 34.1%), whereas others had an increase (positive ΔP4; n = 220; 64.7%), in circulating P4 levels. Although the median (min-max) P4 levels on the day of triggering, the day of OPU, and OPU + 3 days were comparable between the negative ΔP4 and positive ΔP4 groups, patients in the former group had significantly lower P4 levels on OPU + 5 days [69.67 ng/ml (15.66-150.02) versus 100.51 ng/ml (26.41-171.78); P < 0.001] and OPU + 14 days [8.28 ng/ml (0.28-157.00) versus 19.01 ng/ml (0.18-185.00), respectively; P < 0.001]. A drop in P4 level from OPU + 3 days to OPU + 5 days (negative ΔP4) was seen in approximately one-third of patients and was associated with a significantly lower OPR when compared with positive ΔP4 counterparts [33.6% versus 49.1%, odds ratio (OR); 0.53, 95% CI; 0.33-0.84; P = 0.008]; this decrease in OPR was due to lower initial pregnancy rates rather than increased overall pregnancy loss rates. For negative ΔP4 patients, the magnitude of ΔP4 was a significant predictor of OP (adjusted AUC = 0.65; 95% CI; 0.59-0.71), with an optimum threshold of -8.73 ng/ml, sensitivity and specificity were 48.7% and 79.2%, respectively. BMI (OR; 1.128, 95% CI; 1.064-1.197) was the only significant predictor of having a negative ΔP4; the higher the BMI, the higher the risk of having a negative ΔP4. Among positive ΔP4 patients, the magnitude of ΔP4 was a weak predictor of OP (AUC = 0.56, 95% CI; 0.48-0.64). Logistic regression analysis showed that blastocyst morphology (OR; 5.686, 95% CI; 1.433-22.565; P = 0.013) and ΔP4 (OR; 1.013, 95% CI; 0.1001-1.024; P = 0.031), but not the serum P4 level on OPU + 5 days, were the independent predictors of OP., Limitations, Reasons for Caution: The physiological circadian pulsatile secretion of P4 during the mid-luteal phase is a limitation; however, blood sampling was standardized to reduce the impact of timing., Wider Implications of the Findings: Two measurements (OPU + 3 days and OPU + 5 days) of serum P4 may identify those patients with a drop in P4 (approximately one-third of patients) associated with ∼2-fold lower OPRs. Rescuing these IVF cycles with additional P supplementation or adopting a blastocyst freeze-all policy should be tested in future randomized controlled trials., Study Funding/competing Interest(s): None. S.C.E. declares receipt of unrestricted research grants from Merck and lecture fees from Merck and Med.E.A. P.H. has received unrestricted research grants from MSD and Merck, as well as honoraria for lectures from MSD, Merck, Gedeon-Richter, Theramex, and IBSA. H.Y. declares receipt of honorarium for lectures from Merck, IBSA and research grants from Merck and Ferring. The remaining authors declare that they have no conflict of interest., Trial Registration Number: The study was registered at clinical trials.gov (NCT04128436)., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Gonadotropin therapy to treat specific male infertility disorders associated with hypogonadotropic hypogonadism is evidence-based and effective in restoring spermatogenesis and fertility. In contrast, its use to improve fertility in men with idiopathic oligozoospermia or nonobstructive azoospermia remains controversial, despite being widely practiced. The existence of two major inter-related pathways for spermatogenesis, including FSH and intratesticular testosterone, provides a rationale for empiric hormone stimulation therapy in both eugonadal and hypogonadal males with idiopathic oligozoospermia or nonobstructive azoospermia. Real-world data (RWD) on gonadotropin stimulating for these patient subsets, mainly using human chorionic gonadotropin and follicle-stimulating hormone, accumulated gradually, showing a positive therapeutic effect in some patients, translated by increased sperm production, sperm quality, and sperm retrieval rates. Although more evidence is needed, current insights from RWD research indicate that selected male infertility patients might be managed more effectively using gonadotropin therapy, with potential gains for all parties involved., Competing Interests: Declaration of competing interest SCE and LC declare receipt of unrestricted research grants from Merck and lecture fees from Merck and Med. E.A and Event Planet. Other authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The aim of this study was to assess mitochondrial DNA analysis as a predictor of the pregnancy potential of biopsied preimplantation embryos. The study included 78 blastomeres biopsied from day 4 cleavage stage euploid embryos. The embryo karyotype was confirmed by 24-chromosome preimplantation genetic testing for aneuploidies using the Illumina Next-Generation Sequencing (NGS) system. Mitochondria viability ratios (mtV) were determined from BAM files subjected to the web-based genome-analysis tool Galaxy. From this cohort of patients, 30.4% of patients ( n = 34) failed to establish pregnancy. The mean mtV ratio [mean = 1.51 ± 1.25-1.77 (95% CI)] for this group was significantly ( P < 0.01) lower compared with the embryo population that resulted in established pregnancies [mean = 2.5 ± 1.82-2.68 (95% CI)]. mtV multiple of mean (MoM) values were similarly significantly ( P < 0.01) lower in blastocysts failing to establish pregnancy. At a 0.5 MoM cut-off, the sensitivity of mtV quantitation was 35.3% and specificity was 78.2%. The positive predictive value for an mtV value > 0.5 MoM was 41.4%. This study demonstrates the clinical utility of preimplantation quantification of viable mitochondrial DNA in biopsied blastomeres as a prognosticator of pregnancy potential.

The Patient-Oriented Strategies Encompassing IndividualizeDOocyte Number (POSEIDON) criteria identify and classify the so-called 'low-prognosis' patients undergoing assisted reproductive technology (ART). Recent large-scale studies using real-world data (RWD) have shown that patients classified under this system have distinct reproductive outcomes. Moreover, these studies also confirm that POSEIDON patients are commonly found in fertility centers. RWD has substantiated the validity of the POSEIDON biomarkers' thresholds (antral follicle count [AFC] and/or anti-Müllerian hormone [AMH]) for patient classification. Lastly, a predictive model has been developed and validated to estimate the POSEIDON metric of success (i.e., number of oocytes needed to achieve at least one euploid blastocyst). Although more evidence is needed in this area, current insights from RWD research indicate that infertility patients can be counseled and managed more effectively under the POSEIDON scope, with potential gains for all parties involved., Competing Interests: Declaration of competing interest S.C.E. declares receipt of unrestricted research grants from Merck and lecture fees from Merck and Med.E.A. H.Y. declares receipt of payment for lectures from Merck and Ferring. L.N.V. receives speaker fees and conferences from Merck, Merck Sharp, and Dohme (MSD), Ferring, and research grants from MSD and Ferring. PH declares receipt of unrestricted research grants from Merck, Ferring, Gedeon Richter, and IBSA and lecture fees from Merck, Gedeon Richter, and Med.E.A. AC and CA declare receipt of unrestricted research grants from Merck and lecture fees from Merck., (Copyright © 2022. Published by Elsevier Ltd.)

Biomedical science is rapidly developing in terms of more transparency, openness and reproducibility of scientific publications. This is even more important for all studies that are based on results from basic semen examination. Recently two concordant documents have been published: the 6th edition of the WHO Laboratory Manual for the Examination and Processing of Human Semen, and the International Standard ISO 23162:2021. With these tools, we propose that authors should be instructed to follow these laboratory methods in order to publish studies in peer-reviewed journals, preferable by using a checklist as suggested in an Appendix to this article., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Research Question: Does the timing of warmed blastocyst transfer in true natural cycle (tNC) differ according to six different commonly used definitions of LH surge, and do differences in timing have any impact on ongoing pregnancy rate (OPR)?, Design: Prospective monitoring, including repeated blood sampling and ultrasound analyses of 115 warmed blastocyst transfer cycles performed using tNC between January 2017 and October 2021., Results: The reference timing of follicular collapse +5 days would be equivalent to LH surge +6 days in only 5.2-41.2% of the cycles employing the six different definitions of the LH surge. In contrast, the reference timing was equivalent to LH surge +7 days in the majority of cycles (46.1-69.5%) and less commonly to LH surge +8 days (1.8-38.3%) and +9 days (0-10.4%). For each definition of the LH surge, the OPR were comparable among the different warmed blastocyst transfer timings related to the LH surge (LH surge +6/+7/+8/+9 days). When logistic regression analysis was performed to evaluate the independent effect of variation of warmed blastocyst transfer timing (LH surge +6/+7/+8/+9 days) on OPR and taking LH surge +6 days as the reference, change in timing was not an independent predictor of OPR for any of the definitions of the LH surge., Conclusions: Employing a policy of performing warmed blastocyst transfer on follicular collapse +5 days and using six different definitions of the LH surge, vitrified-warmed embryo transfer timing is indeed equivalent to LH surge +7/+8 and even +9 days in a significant proportion of tNC with comparable reproductive outcomes., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Efficient and safe embryo vitrification techniques have contributed to a marked worldwide increase in the use of elective frozen embryo transfer (FET). Pinpointing the day of ovulation, more commonly by documentation of the LH surge and less commonly by ultrasonography, is crucial for timing of FET in a true natural cycle (t-NC) to maximize the reproductive outcome., Objective and Rationale: The definition of the onset of the LH surge should be standardized in t-NC FET cycles; however, a clear definition is lacking in the available literature. The first search question concerns the definition of the onset of the LH surge in a natural cycle. The second search question relates to the duration between the onset of the LH surge and ovulation., Search Methods: We searched PubMed, Web of Science and Cochrane Library databases for two search questions from inception until 31 August 2021. 'Luteinizing hormone'[MeSH] OR 'LH' AND 'surge' terms were used to identify eligible articles to answer the first question, whereas 'Luteinizing hormone'[MeSH] OR 'LH' AND 'surge' OR 'rise' AND 'ovulation'[MeSH] OR 'follicular rupture' OR 'follicular collapse' were the terms used regarding the second question. The included publications were all written in the English language, conducted in women of reproductive age with regular ovulatory cycles and in whom serial serum or urine LH measurement was performed. For the quality and risk of bias assessment of the included studies, the Strengthening the Reporting of Observational Studies in Epidemiology and modified Newcastle Ottawa Scale were used., Outcomes: A total of 10 and 8 studies were included for search Questions 1 and 2, respectively. Over the years, through different studies and set-ups, testing in either serum or urine, different definitions for the onset of the LH surge have been developed without a consensus. An increase in LH level varying from 1.8- to 6-fold above the baseline LH level was used in seven studies and an increase of at least two or three standard deviations above the mean of the preceding LH measurements was used in two studies. An LH level exceeding the 30% of the amplitude (peak-baseline LH level) of the LH surge was defined as the onset day by one study. A marked inter-personal variation in the time interval between the onset of the LH surge and ovulation was seen, ranging from 22 to 56 h. When meta-analysis was performed, the mean duration in hours between the onset of the LH surge and ovulation was 33.91 (95% CI = 30.79-37.03: six studies, 187 cycles)., Wider Implications: The definition of the onset of the LH surge should be precisely defined in future well-designed studies employing state-of-art laboratory and ultrasonographic equipment. The window of implantation in a natural cycle is still a black box, and future research is warranted to delineate the optimal interval to time the embryo transfer in t-NC FET cycles. Randomized controlled trials employing different precise endocrine and/or ultrasonographic criteria for timing of FET in a t-NC are urgently required., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Increasing evidence has demonstrated that obesity impairs female fertility and negatively affects human reproductive outcome following medically assisted reproduction (MAR) treatment. In the United States, 36.5% of women of reproductive age are obese. Obesity results not only in metabolic disorders including type II diabetes and cardiovascular disease, but might also be responsible for chronic inflammation and oxidative stress. Several studies have demonstrated that inflammation and reactive oxygen species (ROS) in the ovary modify steroidogenesis and might induce anovulation, as well as affecting oocyte meiotic maturation, leading to impaired oocyte quality and embryo developmental competence. Although the adverse effect of female obesity on human reproduction has been an object of debate in the past, there is growing evidence showing a link between female obesity and increased risk of infertility. However, further studies need to clarify some gaps in knowledge. We reviewed the recent evidence on the association between female obesity and infertility. In particular, we highlight the association between fat distribution and reproductive outcome, and how the inflammation and oxidative stress mechanisms might reduce ovarian function and oocyte quality. Finally, we evaluate the connection between female obesity and endometrial receptivity.

The WHO (World Health Organization) manuals provide state-of-the-art guidance on how a semen analysis should be carried out. The much anticipated sixth edition of the WHO semen analysis manual has been released 10 years after its previous version and includes essential updates, such as new reference standards for semen volume and microscopic sperm characteristics of recent fathers. A well-conducted semen analysis remains an essential foundation of the infertility evaluation process and affects patient referral, diagnosis and treatment. However, a male infertility work-up primarily based on routine semen analysis does not provide men with an optimal fertility pathway; the primary reasons for routine semen analysis inadequacy in this context include its low predictive value for natural and assisted conception success, its inability to detect sperm DNA and epigenetic deficiencies that might negatively affect embryo development, implantation and offspring well-being, and the substantial overlap between semen parameters of fertile and subfertile individuals. Ideally, a full andrological assessment should be carried out by reproductive urologists in all men dealing with couple infertility and should include a detailed history analysis, physical examination, semen analysis, endocrine assessment and other tests as needed. Only through a complete male infertility work-up will relevant underlying medical and infertility conditions be revealed and potentially treated or alleviated. The ultimate goals of a comprehensive andrological assessment are to positively influence overall male health, pregnancy prospects and offspring well-being., (© 2022. Springer Nature Limited.)