Therapeutic management in women with a diminished ovarian reserve: a systematic review and meta-analysis of randomized controlled trials.

IMPORTANCE: The clinical management of women with diminished ovarian reserve (DOR) is a challenge in the field of medically assisted reproduction. Several therapeutic strategies have been proposed, but with mixed results, mainly because the definition of DOR used was inconsistent among trials. OBJECTIVE: To investigate adjuvant treatments and protocols involving only women with DOR according to POSEIDON criteria. DATA SOURCES: We conducted a systematic search using the MEDLINE (PubMed), EMBASE, and ISI Web of Knowledge databases to identify relevant studies published up to June 2024. The review protocol was registered at http://www.crd.york.ac.uk/PROSPERO/ (registration number CRD42022346117). STUDY SELECTION AND SYNTHESIS: After duplication removal, the titles and abstracts of 4,806 articles were scrutinized, and 124 full-text articles were assessed for eligibility. In total, 38 randomized controlled trials were included in the qualitative/quantitative analysis. The following interventions were evaluated: dehydroepiandrosterone (n = 1,336), testosterone (n = 418), high- versus low-dose gonadotropin (n = 957), delayed-start protocol with GnRH antagonist (n = 398), letrozole (n = 612), clomiphene citrate (1,113), growth hormone (311), luteal phase stimulation (n = 57), dual triggering (n = 139), dual stimulation (168), luteinizing hormone (979), oestradiol pre-treatment (n = 552), and corifollitropin alfa (n = 561). RESULTS: Testosterone supplementation is associated with higher live birth rates compared with non-supplemented women among all interventions evaluated (OR 2.19, 95% CI 1.11-4.32, 4 studies, 368 patients; p = 0.02). Testosterone (WMD 0.88, 95% CI 0.03-1.72; 4 studies, n = 368 patients; p = 0.04), DHEA (WMD 0.60, 95% CI 0.07-1.13; 4 studies, n = 418 patients; p = 0.03), high-dose gonadotropin regimen (WMD -1.57, 95% CI -2.12 to -1.17; 2 studies, n = 905 patients; p < 0.0001) and delayed started protocol (WMD 1.32, 95% CI 0.74 to 1.89; 3 studies, n = 398 patients; p < 0.00001) significantly improved the total number of eggs collected. The other interventions did not produce significant improvements. CONCLUSION AND RELEVANCE: Specific interventions such as testosterone seem to correlate with a better live birth rate in women with diminished ovarian reserve; these findings should be further explored in randomized trials.

From pathophysiology to practice: addressing oxidative stress and sperm DNA fragmentation in Varicocele-affected subfertile men.

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.

Non-Obstructive Azoospermia and Intracytoplasmic Sperm Injection: Unveiling the Chances of Success and Possible Consequences for Offspring.

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.

A multi-faceted exploration of unmet needs in the continuing improvement and development of fertility care amidst a pandemic.

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.

Clinical factors impacting microdissection testicular sperm extraction success in hypogonadal men with nonobstructive azoospermia.

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.

Eligibility for the medical therapy among men with non-obstructive azoospermia-Findings from a multi-centric cross-sectional study.

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 17ß-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.

Clinical factors associated with unexpected poor or suboptimal response in Poseidon criteria patients.

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.

Prevalence and clinical implications of biochemical hypogonadism in patients with nonobstructive azoospermia undergoing infertility evaluation.

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.

Effect of environmental factors on seminal microbiome and impact on sperm quality.

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.

Significance of serum AMH and antral follicle count discrepancy for the prediction of ovarian stimulation response in Poseidon criteria patients.

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.

High prevalence of low prognosis by the POSEIDON criteria in women undergoing planned oocyte cryopreservation.

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.

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.