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

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

[Clinical guidelines for male infertility: controversial issues and the need to reach interdisciplinary consensus].

A review of controversial issues about the terminology on male infertility and reproductive function, which is currently used, as well as proposals for updating clinical guidelines for the diagnosis and treatment of male infertility and men in infertile couples are presented in the article. An algorithm is described, the elements of which ensure referral of patients based on the possibility and timing of restoration of reproductive function, taking into account the reproductive health of a woman, as well as increasing the likelihood of successful treatment aimed at the birth of a healthy child.

Dual-Activated H2O2-Responsive AIE Probes for Oocyte Quality Assessment.

Nonobstructive azoospermia (NOA) is an important cause of infertility, and intracytoplasmic sperm injection (ICSI) is the mainstay of treatment for these patients. In cases where a sufficient number of sperm (usually 1-2) is not available, the selection of oocytes for ICSI is a difficult problem that must be solved. Here, we constructed a dual-activated oxidative stress-responsive AIE probe, b-PyTPA. The strong donor-acceptor configuration of b-PyTPA leads to twisted intramolecular charge transfer (TICT) effect that quenches the fluorescence of the probe, however, H2O2 would specifically remove the boronatebenzyl unit and release a much weaker acceptor, which inhibits TICT and restores the fluorescence. In addition, the presence of a pyridine salt makes b-PyTPA more hydrophilic, whereas removal of the pyridine salt increases the hydrophobicity of PyTPA, which triggers aggregation and further enhances fluorescence. Thus, the higher the intracellular level of oxidative stress, the stronger the fluorescence. In vitro, this dual-activated fluorescent probe is capable of accurately detecting senescent cells (high oxidative stress). More importantly, b-PyTPA was able to characterize senescent oocytes, as assessed by the level of oxidative stress. It is also possible to identify high quality oocytes from those obtained for subsequent ICSI. In conclusion, this dual-activated oxidative stress-assessment probe enables the quality assessment of oocytes and has potential application in ICSI.

Prevalence of Abnormal Semen Parameters among the Infertile Couples Seeking Infertility Treatment.

Infertility, affecting 60 to 80 million couples globally, is clinically defined as the inability to conceive after 12 months of unprotected sexual contact. Male factors contribute significantly, comprising 40.0% to 50.0% of infertility cases. While the prevalence ranges from 5.0% to 30.0% in developing countries, the exact global prevalence remains unknown. The study, conducted at CMH and Ibn Sina Hospital, Jashore from October 2020 to September 2023, utilized a cross-sectional approach; examining 4173 samples aged 21 to 41. Exclusion criteria considered known female reproductive abnormalities or medications impacting male fertility. Standardized procedures, in-depth questionnaires and SPSS software version 15.0 were employed, adhering to World Health Organization Guidelines. In a study of 4173 seeking infertility treatment, 63.0% had abnormal semen parameters, with 45.0% aged 31-40 years. Addiction patterns: 76.0% used tobacco, 14.0% reported alcohol and tobacco. Occupations: 43.0% government workers, 41.0% private workers. Marriage duration: 44.0% married 5-10 years, infertility duration: 64.0% less than 6 years. Semen analysis showed 40% with sperm count above 65 million, 46.0% with 60.0-90.0% motile sperm, and 78.0% with sperm morphology below 15.0%. The most prevalent abnormality is asthenozoospermia 59%, with oligozoospermia and azoospermia observed in 31% and 3% of cases, respectively. This study highlights the global complexity of male infertility, emphasizing genetic factors in infertile couples. Addressing sample bias and the lack of national epidemiological data underscores the ongoing need for comprehensive research to advance global infertility diagnosis and treatment.

Reproductive outcomes in patients with high levels of sperm DNA fragmentation using testicular sperm for intracytoplasmic injection: a retrospective analysis.

This study aims to compare the embryological and clinical parameters of intracytoplasmic sperm injection (ICSI) cycles using testicular versus ejaculated sperm in male patients with elevated sperm DNA fragmentation (SDF). A total of 73 ICSI cycles were examined in couples where the male partner exhibited high levels of SDF. ICSI was performed using either ejaculated or testicular sperm. The primary outcomes were rates of blastocyst formation, high-quality embryo development, and clinical pregnancy. The DNA fragmentation index (DFI) for testicular sperm (16.81 ± 17.51) was significantly lower than that of ejaculated sperm (56.96 ± 17.56). While the blastocyst formation rate was significantly higher in the testicular sperm group compared to the ejaculated sperm group, no statistically significant differences were noted in fertilization rate (72.15% vs. 77.23%), rate of high-quality embryo formation (47.17% vs. 46.53%), clinical pregnancy (50% vs. 56.52%), Cumulative pregnancy (70.2% vs. 55.6%), or live birth rate (43.75% vs.43.48%). Testicular spermatozoa have no additional advantage over ejaculated spermatozoa except for blastocyst quality in patients with high SDF, the use of testicular spermatozoa for the first ICSI cycle in male infertility patients with high SDF should be undertaken after much consideration at present.

A systematic review of interventions to improve male knowledge of fertility and fertility-related risk factors.

Male infertility is a global health concern. The effectiveness of interventions developed to improve males' knowledge of fertility regulation and fertility-related risk factors remains unclear. This systematic review aimed to synthesize and evaluate the evidence for these interventions. Four databases were searched from inception to June 2023. Eligible studies examined interventions to increase fertility knowledge among presumed fertile males aged ≥16 years of age. Conference abstracts, protocols and studies without sex-disaggregated results for males were excluded. A narrative synthesis without meta-analysis was performed. A total of 4884 records were identified. Five studies (reported in six publications), all conducted in high-income countries, were included. Two were randomized control trials, and three were experimental studies. Interventions were delivered in person by a health professional (n = 3), online and via a mobile app. All studies showed a significant improvement in knowledge of fertility or fertility-related risk factors from baseline to follow-up. The largest improvement was observed for secondary and vocational students. A moderate, long-term retainment of knowledge was observed at two-year follow-up in one study. Available evidence suggests interventions to improve males' fertility knowledge are effective, particularly for younger, less educated males.

Aggressive sperm immobilization improves reproductive outcomes in patients with suboptimal semen parameters and previous ICSI fertilization failure.

Intracytoplasmic sperm injection (ICSI) is the most effective procedure to resolve male infertility, enhancing overall fertilization and pregnancy outcomes. However, it is important to note that fertilization failure (FF) can still occur in a few cases after ICSI. This study aims to introduce a specialized technique of aggressive sperm immobilization for ICSI and evaluate its impact on reproductive outcomes in cases involving prior fertilization failure. All infertile couples with male partners having suboptimal semen samples and previous ICSI fertilization failure were evaluated using retrospective data from National Taiwan tertiary university hospital (NTUH) between January 2016 and February 2022. Fertilization failure in our study was defined as less than 30% fertilization rate (FR, the number of normally fertilized oocytes divided by the total number of injected mature oocytes). Data involving both standard (routine procedure) and aggressive sperm immobilization (SI) techniques during different ICSI cycles were included in this study. Standard and aggressive SI methods were performed by compressing the distal half tail of the spermatozoa ≦ 5 and 15 times prior to ICSI respectively. Generalized estimating equations analysis were applied to compare the clinical outcomes between two procedures. Overall, data from 23 infertile couples who had undergone 65 ICSI cycles (31 standard SI with low fertilization rate and 34 aggressive SI) were included in the study. The average FR in the ICSI cycles with standard SI and aggressive SI were 23.6 ± 23.1% and 49.5 ± 31.8 respectively (P = 0.0002). The majority of embryos were transferred at the day 3 stage, with an average number transferred of 2.6 ± 0.9 in the aggressive SI group and 1.9 ± 0.9 in the standard group. The number of embryos transferred per transfer cycle was higher in the aggressive SI (P = 0.015), whereas the number of good-quality embryos was similar between the two procedures (P = 0.44). There were one and seven live births from the standard SI cycles and aggressive SI cycles respectively. In conclusion, aggressive SI was associated with a significantly higher FR, resulting in more available embryos for transfer without compromising embryo quality. Therefore, this specialized technique improved pregnancy outcome among infertile couples with a previous ICSI-FF. It can be a safe, economic, and effective method to improve the assisted reproductive technologies outcomes for infertile patients affected by previous ICSI-FF.

APHRODITE criteria: addressing male patients with hypogonadism and/or infertility owing to altered idiopathic testicular function.

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.

Intracytoplasmic sperm injection versus conventional in-vitro fertilisation for couples with infertility with non-severe male factor: a multicentre, open-label, randomised controlled trial.

BACKGROUND: Introduced in 1992, intracytoplasmic sperm injection (ICSI) was initially indicated for severe male infertility; however, its use has since been expanded to non-severe male infertility. We aimed to compare the efficacy and safety of ICSI versus conventional in-vitro fertilisation (IVF) in couples with infertility with non-severe male factor. METHODS: We conducted an investigator-initiated, multicentre, open-label, randomised controlled trial in ten reproductive medicine centres across China. Couples with infertility with non-severe male factor without a history of poor fertilisation were randomly assigned (1:1) to undergo either ICSI or conventional IVF. The primary outcome was live birth after first embryo transfer. We performed the primary analysis in the intention-to-treat population using log-binomial regression models for categorical outcomes or linear regression models for continuous outcomes, adjusting for centre. This trial is registered with Clinicaltrials.gov, NCT03298633, and is completed. FINDINGS: Between April 4, 2018, and Nov 15, 2021, 3879 couples were screened, of whom 2387 (61·5%) couples were randomly assigned (1184 [49·6%] to the ICSI group and 1203 [50·4%] to the conventional IVF group). After excluding couples who were ineligible, randomised twice, or withdrew consent, 1154 (97·5%) in the ICSI group and 1175 (97·7%) in the conventional IVF group were included in the primary analysis. Live birth after first embryo transfer occurred in 390 (33·8%) couples in the ICSI group and in 430 (36·6%) couples in the conventional IVF group (adjusted risk ratio [RR] 0·92 [95% CI 0·83-1·03]; p=0·16). Two (0·2%) neonatal deaths were reported in the ICSI group and one (0·1%) in the conventional IVF group. INTERPRETATION: In couples with infertility with non-severe male factor, ICSI did not improve live birth rate compared with conventional IVF. Given that ICSI is an invasive procedure associated with additional costs and potential increased risks to offspring health, routine use is not recommended in this population. FUNDING: National Natural Science Foundation of China, National Key Research and Development Program, Beijing Municipal Science & Technology Commission, and Peking University Third Hospital.

'Intracytoplasmic sperm injection (ICSI) paradox' and 'andrological ignorance': AI in the era of fourth industrial revolution to navigate the blind spots.

The quandary known as the Intracytoplasmic Sperm Injection (ICSI) paradox is found at the juncture of Assisted Reproductive Technology (ART) and 'andrological ignorance' - a term coined to denote the undervalued treatment and comprehension of male infertility. The prevalent use of ICSI as a solution for severe male infertility, despite its potential to propagate genetically defective sperm, consequently posing a threat to progeny health, illuminates this paradox. We posit that the meteoric rise in Industrial Revolution 4.0 (IR 4.0) and Artificial Intelligence (AI) technologies holds the potential for a transformative shift in addressing male infertility, specifically by mitigating the limitations engendered by 'andrological ignorance.' We advocate for the urgent need to transcend andrological ignorance, envisaging AI as a cornerstone in the precise diagnosis and treatment of the root causes of male infertility. This approach also incorporates the identification of potential genetic defects in descendants, the establishment of knowledge platforms dedicated to male reproductive health, and the optimization of therapeutic outcomes. Our hypothesis suggests that the assimilation of AI could streamline ICSI implementation, leading to an overall enhancement in the realm of male fertility treatments. However, it is essential to conduct further investigations to substantiate the efficacy of AI applications in a clinical setting. This article emphasizes the significance of harnessing AI technologies to optimize patient outcomes in the fast-paced domain of reproductive medicine, thereby fostering the well-being of upcoming generations.

[First-line management of infertile couple. Guidelines for clinical practice of the French College of Obstetricians and Gynecologists 2022]. / Prise en charge de première intention du couple infertile : mise à jour des RPC 2010 du CNGOF.

OBJECTIVE: To update the 2010 CNGOF clinical practice guidelines for the first-line management of infertile couples. MATERIALS AND METHODS: Five major themes (first-line assessment of the infertile woman, first-line assessment of the infertile man, prevention of exposure to environmental factors, initial management using ovulation induction regimens, first-line reproductive surgery) were identified, enabling 28 questions to be formulated using the Patients, Intervention, Comparison, Outcome (PICO) format. Each question was addressed by a working group that had carried out a systematic review of the literature since 2010, and followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE®) methodology to assess the quality of the scientific data on which the recommendations were based. These recommendations were then validated during a national review by 40 national experts. RESULTS: The fertility work-up is recommended to be prescribed according to the woman's age: after one year of infertility before the age of 35 and after 6months after the age of 35. A couple's initial infertility work-up includes a single 3D ultrasound scan with antral follicle count, assessment of tubal permeability by hysterography or HyFOSy, anti-Mullerian hormone assay prior to assisted reproduction, and vaginal swabbing for vaginosis. If the 3D ultrasound is normal, hysterosonography and diagnostic hysteroscopy are not recommended as first-line procedures. Chlamydia trachomatis serology does not have the necessary performance to predict tubal patency. Post-coital testing is no longer recommended. In men, spermogram, spermocytogram and spermoculture are recommended as first-line tests. If the spermogram is normal, it is not recommended to check the spermogram. If the spermogram is abnormal, an examination by an andrologist, an ultrasound scan of the testicles and hormonal test are recommended. Based on the data in the literature, we are unable to recommend a BMI threshold for women that would contraindicate medical management of infertility. A well-balanced Mediterranean-style diet, physical activity and the cessation of smoking and cannabis are recommended for infertile couples. For fertility concern, it is recommended to limit alcohol consumption to less than 5 glasses a week. If the infertility work-up reveals no abnormalities, ovulation induction is not recommended for normo-ovulatory women. If intrauterine insemination is indicated based on an abnormal infertility work-up, gonadotropin stimulation and ovulation monitoring are recommended to avoid multiple pregnancies. If the infertility work-up reveals no abnormality, laparoscopy is probably recommended before the age of 30 to increase natural pregnancy rates. In the case of hydrosalpinx, surgical management is recommended prior to ART, with either salpingotomy or salpingectomy depending on the tubal score. It is recommended to operate on polyps>10mm, myomas 0, 1, 2 and synechiae prior to ART. The data in the literature do not allow us to systematically recommend asymptomatic uterine septa and isthmoceles as first-line surgery. CONCLUSION: Based on strong agreement between experts, we have been able to formulate updated recommendations in 28 areas concerning the initial management of infertile couples.

The psychosocial impact of male infertility on men undergoing ICSI treatment: a qualitative study.

BACKGROUND: Male infertility is in 20-70% of cases the cause of a couple's infertility. Severe forms of male infertility are best treated with Intracytoplasmic Sperm Injection (ICSI). The psychosocial impact of infertility and ICSI on men is unclear because the focus is socially, clinically, and scientifically on women. However, there is evidence that it can affect the psychological well-being of men, but these studies are mainly quantitative. Qualitative research needed to explore the experiences of infertile men in-depth is limited. Therefore, the objective of this study was to clarify the psychosocial consequences of male infertility on men undergoing ICSI to understand their experiences with reproduction problems more comprehensively. METHODS: In this generic qualitative study, men who were undergoing or had undergone ICSI after a male factor infertility diagnosis were included. A purposive sample with maximum variation was sought in a fertility clinic of one university medical centre in the Netherlands. Data were collected through individual face-to-face semi-structured interviews. Thematic analysis was used to identify themes from the data. RESULTS: Nineteen Dutch men were interviewed. The mean duration of the interviews was 90 min. An everyday contributing backpack was identified as the main theme, as men indicated that they always carried the psychosocial consequences of infertility and ICSI with them. Different world perspective, Turbulence of emotions, Changing relation, and Selective sharing were the psychosocial consequences that men were most affected by. Moreover, men indicated that they were Searching for contribution during ICSI because the focus was entirely on the woman. CONCLUSION: Men with male infertility experience psychosocial problems due to infertility and ICSI treatment. Healthcare professionals need to recognize the impact of infertility on men and create room for a role for them during ICSI.

Infertility, defined as not being able to get pregnant after at least 1 year of unprotected sex, is often caused by a male problem. ICSI (Intracytoplasmic Sperm Injection) is the suggested treatment for couples dealing with male infertility. During this treatment, in the laboratory, a single sperm is injected into an egg of the woman. This procedure can create an embryo that can be transferred into the woman's uterus. Women, unlike men, have to undergo many medical examinations and treatments during ICSI which can cause changes in their mental well-being. How and whether men's psychological and social well-being can be affected by infertility and ICSI is unclear. Therefore, by interviewing 19 Dutch men dealing with male infertility who were undergoing or had undergone ICSI, an attempt was made to better understand reproductive problems from their perspective. The interviews were all face-to-face and had a mean duration of 90 min. We found that men experienced various psychosocial consequences from infertility and ICSI: they started looking at the world differently, their relationship with their partner changed, emotions alternated, information sharing became selective and they were searching for contribution. The main theme: An everyday contributing backpack was identified, as men indicated that they always carried these psychosocial consequences with them in their daily lives. From this qualitative research, it has become clear that men dealing with male infertility experience psychosocial problems due to infertility and ICSI treatment. Healthcare professionals need to recognize the impact of infertility on men and create room for them.

Reproductive Outcomes of Conventional In Vitro Fertilization and Intracytoplasmic Sperm Injection in Patients with Non-Severe Male Infertility Across Poor and Different Sub-Optimal Ovarian Response Categories: A Cohort Study Based on 30,352 Fresh Cycles from 2009-2019.

Due to the influence of economic, social and many other factors, there are more and more reproductive problems. Originally introduced for managing male factor infertility, intracytoplasmic sperm injection had become the most commonly used fertilization treatment in the world, with broadened indications including low oocyte yield, prior fertilization failure with conventional in vitro fertilization etc. However, academic evidence for better live-birth outcomes of intracytoplasmic sperm injection over conventional in vitro fertilization is limited. Thus, we aimed to compare the reproductive outcomes of conventional in vitro fertilization and intracytoplasmic sperm injection in patients with non-severe male factor infertility across poor and different sub-optimal ovarian response categories. The fertility rate, implantation rate, clinical pregnancy rate, live birth rate and other obstetric outcomes were mainly compared. Our results showed that independent of the number of oocytes retrieved, intracytoplasmic sperm injection significantly increased the fertilization rate, while conventional in vitro fertilization cycles showed a higher implantation rate, clinical pregnancy rate, and live birth rate. No differences were observed in most obstetric outcomes. Our study indicates that poor ovarian response is not an indication for intracytoplasmic sperm injection in couples with non-severe male infertility.