Hum. Reprod. [JOURNAL]
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200 papers
Changes in antral follicle dynamics following weight loss in women with polycystic ovary syndrome.
Carter FE, Jarrett BY, Lee ND … +6 more , Zaman N, Reich AM, Wilson KA, Oldfield AL, Vanden Brink H, Lujan ME
Hum Reprod · 2025 Nov · PMID 40929646 · Full text
STUDY QUESTION: Does weight loss from a hypocaloric dietary intervention improve antral follicle dynamics in women with PCOS? SUMMARY ANSWER: During a 3-month hypocaloric dietary intervention, women with PCOS who experie...
STUDY QUESTION: Does weight loss from a hypocaloric dietary intervention improve antral follicle dynamics in women with PCOS? SUMMARY ANSWER: During a 3-month hypocaloric dietary intervention, women with PCOS who experienced clinically meaningful weight loss showed more organized antral follicle development including fewer recruitment events, but no change in the overall frequency of selection, dominance, or ovulation. WHAT IS KNOWN ALREADY: There is a spectrum of disordered antral follicle development in women with PCOS including excessive follicle recruitment and turnover, decreased frequency of selection and dominance, and failure of ovulation. Lifestyle intervention aimed at weight loss is recommended to improve metabolic health in women with PCOS yet benefits on ovarian follicle development and ovulation are unclear. STUDY DESIGN, SIZE, DURATION: This was a prospective, single-arm lifestyle intervention study conducted over 4 months including a 1-month baseline assessment period and 3-month hypocaloric dietary intervention. Twenty women were allocated to the intervention with 0% attrition. PARTICIPANTS/MATERIALS, SETTING, METHODS: Females, ages 18-38 years, with PCOS and obesity (BMI > 30 kg/m2) underwent every-other-day transvaginal ultrasonography and venipuncture at an academic clinical research unit for 4 months. The number and size of all follicles were evaluated at each study visit, with individual growth profiles plotted retrospectively for follicles that grew to at least 7 mm. Gonadotropin and ovarian steroid hormone concentrations were measured every-other-day. Reproductive, anthropometric, and metabolic status markers were assessed at baseline and at the end of the intervention. MAIN RESULTS AND THE ROLE OF CHANCE: Hypocaloric dietary intervention resulted in an average weight loss of 8 ± 3% with significant reductions in all anthropometric markers assessed including BMI, waist circumference, total percent fat, and trunk fat mass (all P < 0.05). Of the glucoregulatory and cardiovascular risk markers assessed, only diastolic blood pressure (P = 0.040) and 2-h insulin concentrations following a glucose challenge (P = 0.029) were decreased post-intervention. Antral follicle development appeared more cyclic following the intervention with the frequency of recruitment (P = 0.043), and number of follicles recruited per cohort (P < 0.0001), decreasing with weight loss. By contrast, the frequency of selection, dominance, and ovulation did not change with weight loss (all P < 0.05). When ovulation occurred during the intervention, the size at selection for ovulatory follicles decreased with weight loss (P < 0.0001), whereas maximum luteal progesterone levels increased with weight loss (P = 0.036). Participants (35%) who responded to the intervention with a shortened inter-menstrual interval had lower baseline trunk fat mass (P = 0.048), fasting insulin (P = 0.022), and homeostatic model assessment for insulin resistance (P = 0.017) compared to non-responders. LIMITATIONS, REASONS FOR CAUTION: The duration of the intervention may not have been sufficient to capture an impact of weight loss on ovulatory cyclicity. Analyses were limited to the antral stages of follicle development and any impact of hypocaloric dietary intervention on pre-antral folliculogenesis was not evaluated. The small study sample limits statistical power and generalizability of the findings. WIDER IMPLICATIONS OF THE FINDINGS: Short-term hypocaloric dietary intervention did not consistently improve ovulation frequency in women with PCOS despite clinically meaningful weight loss. Counseling related to the benefits of short-term hypocaloric dietary intervention on reproductive health outcomes should be tempered as improvements in ovulation are likely only in those with a more favorable metabolic profile at the onset. Improvements in the early stages of antral follicle development with weight loss suggest potential for longer dietary interventions to improve ovulatory cyclicity in women with PCOS. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by funds from the President's Council of Cornell Women, United States Department of Agriculture (Grant No. 8106), and National Institutes of Health (R01-HD0937848, R56-HD089962). F.E.C., B.Y.J., and H.V.B. were supported by doctoral training awards from the National Institutes of Health (5 T32-HD087137, T32-DK007158) and Canadian Institutes of Health Research (Grant No. 146182), respectively. The authors have no competing interests. TRIAL REGISTRATION NUMBER: NCT01785719.
Mumps virus infection triggers early pro-inflammatory responses and impairs Leydig and Sertoli cell function in an ex vivo human testis model.
Franklin L, Kuassivi ON, Satie AP … +6 more , Abiven H, Mathieu R, Miaadi N, Plotton I, Le Tortorec A, Dejucq-Rainsford N
Hum Reprod · 2025 Dec · PMID 40925632 · Full text
STUDY QUESTION: What is the direct effect of mumps virus (MuV) replication within the human testis on the tissue innate immune responses and testicular cell functions? SUMMARY ANSWER: MuV induces an early pro-inflammator...
STUDY QUESTION: What is the direct effect of mumps virus (MuV) replication within the human testis on the tissue innate immune responses and testicular cell functions? SUMMARY ANSWER: MuV induces an early pro-inflammatory response in the human testis ex vivo and infects both Leydig cells and Sertoli cells, which drastically alters testosterone and inhibin B production. WHAT IS KNOWN ALREADY: Despite widespread vaccination efforts, orchitis remains a significant complication of MuV infection, especially in young men, which potentially results in infertility in up to 87% of patients with bilateral orchitis. Our understanding of MuV pathogenesis in the human testis has been limited by the lack of relevant animal models, impairing the development of effective treatments. STUDY DESIGN, SIZE, DURATION: Normal testes were collected from seven uninfected post-mortem donors (median age of 55 years, range 29-79). Organotypic cultures of human testis explants exposed or not to MuV ex vivo were undertaken for 10 days. Utilizing this original ex vivo model, we investigated the replication kinetics of MuV, identified its target cells, characterized the innate immune responses of the testis to the virus, and assessed the impact of the infection on testicular cell functions. PARTICIPANTS/MATERIALS, SETTING, METHODS: Human testis explants were exposed overnight to MuV at a multiplicity of infection of 1 and cultured on polyethylene terephthalate inserts at the air/medium interface for 10 days. MuV replication in human testis explants was evidenced by measuring the release of infectious viral particles in plaque-forming assay and viral RNA in RT-qPCR, as well as by in situ detection of replicative viral RNA in testicular cells all along the 10-day culture period. Infected cells were characterized by microscopy using specific cell markers and a probe against viral RNA. The innate immune response was assessed using RT-qPCR, in situ hybridization, and LegendPlex. Testosterone and its precursors were measured in the supernatants of MuV and mock-infected explants by mass spectrometry, while inhibin B was measured by ELISA. The impact of MuV infection on testis tissue and cells was further explored by lactate dehydrogenase viability assay, RT-qPCR, immunohistochemistry, and western blot. MAIN RESULTS AND THE ROLE OF CHANCE: MuV robustly replicated in human testicular explants all along the 10-day culture, progressing from the interstitial tissue, where it infected Leydig cells, macrophages, and peritubular cells, to the seminiferous tubules, where it targeted Sertoli cells. Unlike Zika virus, another testis-tropic virus, MuV triggered a pro-inflammatory response within 4 h in exposed human testis explants, characterized by transcriptional upregulation of interleukin 1 beta (IL1B) in sentinel cells. This was followed by the tissue release of inflammatory mediators (P = 0.02 for IL1B at 72 h and Day 7) and the dynamic regulation of interleukin 10 (IL10) upon viral replication. MuV replication inhibited testosterone production from Day 7 onwards (P < 0.03) by disrupting the steroidogenic activity of Leydig cells at the level of cytochrome P450 family 17 subfamily A member 1 (CYP17A1) and decreased inhibin B secretion from Sertoli cells from Day 4 onwards (P < 0.03), which exhibited features of pyroptosis. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: This ex vivo study, which demonstrates the direct impact of MuV replication in the human testis, does not assess the additional role of infiltrating peripheral immune cells in testicular lesions. WIDER IMPLICATIONS OF THE FINDINGS: These findings demonstrate that MuV infection of the human testis elicits a distinct early innate immune response in contrast to Zika virus, known for its silent persistence. This difference offers a potential explanation for the development of MuV-induced testis inflammation. Furthermore, our study provides evidence that MuV directly disrupts crucial testicular functions in the absence of leukocytic infiltrates. These data advance our understanding of the early events of MuV pathogenesis in the testis and provide a basis for further investigation into the mechanisms of orchitis versus silent infection. The ex vivo model of MuV-infected human testis developed in this study will serve as a valuable tool for evaluating antiviral strategies aimed at preserving testicular function in MuV-infected men. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by grants from the French National Research Agency (grant number ANR-21-CE15-0021-01) and from the Fondation pour la Recherche Médicale (FRM EQU202203014611), as well as by Institut National de la Santé et de la Recherche Médicale and the University of Rennes. The authors have no competing interests. TRIAL REGISTRATION NUMBER: N/A.
Patient distress and its negative impact on treatment continuation: do psychological interventions have a significant impact?
Awtrey S, Domar AD
Hum Reprod · 2025 Oct · PMID 40921707 · Publisher ↗
Recent studies have shown a high prevalence of psychological distress among fertility patients and how it correlates with decreases in IVF treatment continuation rates. In addition, research has demonstrated the efficacy...
Recent studies have shown a high prevalence of psychological distress among fertility patients and how it correlates with decreases in IVF treatment continuation rates. In addition, research has demonstrated the efficacy of psychological interventions, especially cognitive behavioral therapy and mind-body interventions, in reducing fertility patient distress and potentially increasing pregnancy rates. With the significant relationships between patient distress and dropout rates and between psychological interventions and decreased patient distress both established, the question that remains unaddressed is the impact of psychological interventions on IVF discontinuation rates. Specifically, if it is known that infertility patients are distressed, that the distress is associated with treatment termination, and that psychological interventions can lead to significant decreases in distress, can and do these interventions also increase treatment continuation rates? This mini-review examines the prevalence of negative psychological symptoms in individuals with infertility, why patients discontinue fertility treatment, the efficacy of psychological interventions on patient distress, and, ultimately, the efficacy of psychological interventions on fertility patient retention.
Identifying essential information for a valid informed consent of egg donors: an international Delphi study.
Jacxsens L, Pennings G, Lentacker L … +2 more , Stoop D, Provoost V
Hum Reprod · 2025 Nov · PMID 40912272 · Publisher ↗
STUDY QUESTION: What information does an international group of professionals and egg donors consider relevant and morally necessary for prospective egg donors to provide valid informed consent? SUMMARY ANSWER: Participa...
STUDY QUESTION: What information does an international group of professionals and egg donors consider relevant and morally necessary for prospective egg donors to provide valid informed consent? SUMMARY ANSWER: Participants considered 80% of all concrete information items (CIIs) to be relevant (e.g. all legal aspects) and 67% to be morally necessary. WHAT IS KNOWN ALREADY: Studies indicate that egg donors are not always adequately informed and have expressed a desire for more comprehensive information. This highlights the need for a comprehensive guideline of essential information for prospective egg donors. STUDY DESIGN, SIZE, DURATION: This modified Delphi study used a survey in an iterative process of three rounds to reach a consensus on what information items are relevant and morally necessary for a valid informed consent of candidate egg donors. Invitations to participate were sent out in November 2023 and the final round closed in November 2024. PARTICIPANTS/MATERIALS, SETTING, METHODS: The 35 participants were experienced egg donors and professionals from a range of disciplines (social and medical sciences, bioethics, psychology, fertility medicine and law) from 14 countries. The survey consisted of 13 categories and 133 CIIs, which participants scored for relevance via a 4-point Likert scale and moral necessity on a dichotomous scale (yes/no). Content Validity Index (CVI) was calculated for measuring relevance and percentage of agreement for moral necessity. A comment section was available. MAIN RESULTS AND THE ROLE OF CHANCE: Consensus was indicated as an I-CVI (CVI per item) of 0.78 or higher. The same cut-off was used to indicate consensus for moral necessity. For 27 out of 133 CIIs, the I-CVI was lower than 0.78. The percentage of moral necessity was below 0.78 for 44 CIIs. Four CIIs reached a I-CVI of 1: all experts thought it was relevant for a candidate donor to know (i) the need to undergo ovarian stimulation and (ii) a retrieval procedure, as well as (iii) her legal rights over the donated eggs after the retrieval procedure and (iv) her legal right to withdraw consent. The latter is the only CII that scored 100% on moral necessity. The CII with the lowest I-CVI is 'The family type and characteristics of the potential recipients of the donor eggs' (0.32). The CII with the lowest percentage of agreement for moral necessity was 'An egg donor's social circle might give negative feedback/opinions on the donation' (36.36%). In several categories (e.g. 'Physical side-effects and risks'), almost all CIIs reached a consensus among experienced egg donors, bioethicists, and humanities and social sciences experts, while hardly any CII reached a consensus among fertility experts, lawyers, and academic medical doctors. LIMITATIONS, REASONS FOR CAUTION: Despite our efforts, we were unable to obtain input from registered nurses and midwives. Not all participants remained engaged through all the iterative rounds, which may weaken the results of the study. However, the dropout rates between rounds in this study were within the acceptable 20-30% range. WIDER IMPLICATIONS OF THE FINDINGS: Our results give fertility professionals a standard of essential information to make sure that prospective egg donors are adequately informed and know what to expect when they decide to donate. It also gives researchers a potential standard to evaluate the quality of the information provision in fertility clinics. STUDY FUNDING/COMPETING INTEREST(S): This study is funded by the Special Research Fund, Bijzonder Onderzoeksfonds of Ghent University (BOFSTG2020000901). The authors declare that they have no competing interests. TRIAL REGISTRATION NUMBER: N/A.
Personalizing elective oocyte cryopreservation: a novel predictive model for oocyte yield across multiple stimulation cycles.
Tighe J, Theodorou E, Anson N … +5 more , Kasaven LS, Jones BP, Ahmed-Odia R, Cordero J, Ben Nagi J
Hum Reprod · 2025 Nov · PMID 40912270 · Publisher ↗
STUDY QUESTION: Can patient age and ovarian reserve tests predict the number of cryopreserved oocytes in patients undergoing one or more ovarian stimulation cycles for elective oocyte cryopreservation (EOC)? SUMMARY ANSW...
STUDY QUESTION: Can patient age and ovarian reserve tests predict the number of cryopreserved oocytes in patients undergoing one or more ovarian stimulation cycles for elective oocyte cryopreservation (EOC)? SUMMARY ANSWER: A predictive model incorporating patient age, antral follicle count (AFC), anti-Müllerian hormone (AMH), and FSH levels achieved the greatest predictive accuracy. WHAT IS KNOWN ALREADY: As a consequence of societal evolution, women are increasingly delaying starting a family. However, the natural decline in ovarian reserve and oocyte quality as age advances can increase the risk of age-related fertility decline (ARFD) and involuntary childlessness. EOC is a fertility preservation procedure designed to mitigate against the risk of ARFD. Multiple studies have evaluated the optimum number of cryopreserved oocytes to achieve one or more live births, with many women requiring more than one cycle. Previous studies have modelled oocyte yield in response to ovarian stimulation in single-cycle sub-fertile populations, which limits translatability to a population who are presumed fertile and electively cryopreserving their oocytes. Predictive models incorporating data from multiple cycles in an elective population could aid clinician-patient counselling in women undergoing EOC. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study was conducted using data from patients (N = 579) who underwent one or more ovarian stimulation cycles for EOC at the Centre for Reproductive and Genetic Health (CRGH) between 2016 and 2023 inclusive. Baseline characteristics at each cycle, including age, BMI, AFC, AMH, and FSH levels, were recorded. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Cryopreservation of ≥10 oocytes following an ovarian stimulation cycle was classified as a good response, while ≥5 oocytes indicated an adequate response. The following parameter combinations were subsequently evaluated in negative binomial regression models with generalized estimation equation: (i) age, AFC, AMH, and FSH; (ii) age, AFC, and AMH; (iii) age, AMH, and FSH; (iv) age and AMH; and (v) age and AFC. Receiver operating characteristic curves, with corresponding AUC, sensitivity, and specificity values, were generated for all models. R version 4.4 was used for all statistical analyses. MAIN RESULTS AND THE ROLE OF CHANCE: Model 1 achieved the highest AUC for predicting a good response, AUC: 0.7922 (95% CI: 0.7628-0.8217), with a corresponding sensitivity of 0.7631 (95% CI: 0.7190-0.8095), and a specificity of 0.694 (95% CI: 0.6580-0.7297). Model 2 achieved the second highest AUC of 0.7919 (95% CI: 0.7625-0.8213), followed by Model 3, AUC 0.7770 (95% CI: 0.7463-0.8078). Model 5 achieved an AUC of 0.7749 (95% CI: 0.7441-0.8056), and Model 4 achieved the lowest AUC of 0.7727 (95% CI: 0.7417-0.8038). Similarly, Model 1 achieved the highest AUC for predicting an adequate response, AUC: 0.7917 (95% CI: 0.7586-0.8249), with a corresponding sensitivity of 0.7255 (95% CI: 0.6940-0.7571), and a specificity of 0.7481 (95% CI: 0.6890-0.8036). Model 2 achieved the second highest AUC of 0.7837 (95% CI: 0.7504-0.8169), followed by Model 5, AUC 0.7729 (95% CI: 0.7391-0.8068). Model 3 achieved an AUC of 0.7723 (95% CI: 0.7376-0.8069), and Model 4 similarly achieved the lowest AUC of 0.7607 (95% CI: 0.7257-0.7958). LIMITATIONS, REASONS FOR CAUTION: This analysis, based on data from a single fertility centre, does not incorporate patient ethnicity or previous oocyte yield as model variables. Consequently, while we evaluate the impact of age and baseline ovarian reserve on predictive accuracy, model performance may vary across different patient cohorts. WIDER IMPLICATIONS OF THE FINDINGS: Predictive models incorporating patient age and baseline ovarian reserve tests across multiple cycles may aid clinician-patient discussions for women undergoing EOC. Model accuracy could be enhanced by the incorporation of ethnicity and prior EOC outcomes as model variables in large multicentre studies. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used for this study. None of the authors have any competing interests, nor have they received or are due to receive any payment for writing this article. TRIAL REGISTRATION NUMBER: This cohort study did not require registration. Following consultation with the Medical Advisory Committee at CRGH, ethical approval was not deemed necessary.
Optimizing IVF lab workflows through data-driven insights: associations between lab management, procedural timings, and workload with blastulation rates.
Innocenti F, Cermisoni GC, Taggi M … +10 more , Casciani V, Soscia DM, Dovere L, Stoppa M, Albricci L, Vaiarelli A, Coticchio G, Maggiulli R, Rienzi L, Cimadomo D
Hum Reprod · 2025 Nov · PMID 40912269 · Publisher ↗
STUDY QUESTION: Do IVF laboratory workflows influence the mean blastulation rate per cohort of inseminated metaphase II oocytes (m-BR)? SUMMARY ANSWER: Neither the total number of procedures nor the workload per operator...
STUDY QUESTION: Do IVF laboratory workflows influence the mean blastulation rate per cohort of inseminated metaphase II oocytes (m-BR)? SUMMARY ANSWER: Neither the total number of procedures nor the workload per operator affected m-BR; instead, each additional hour in the interval from ovulation trigger to oocyte denudation (range 36-44 h) was associated with a measurable decline, especially beyond the 40-h threshold. WHAT IS KNOWN ALREADY: Control of laboratory conditions and standardized protocols are essential for optimizing m-BR in IVF. While advancements in technology and culture systems have improved ART outcomes, the effect of laboratory managerial decisions and procedural timing on embryological outcomes remains unclear. Previous studies have suggested that factors, such as prolonged oocyte handling, suboptimal culture conditions, and organizational inefficiencies, may affect in vitro embryo development, but available data are still limited. STUDY DESIGN, SIZE, DURATION: This retrospective study analyzed 7986 ICSI cycles performed between 2015 and 2022 at a private IVF center. Data were automatically registered and then retrospectively extracted from an Electronic Witnessing System to evaluate workload distribution and procedural timings. The study aimed to assess whether variations in laboratory managerial decisions influence the m-BR. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study included all patients undergoing ICSI with fresh own oocytes. Metrics under investigation included the number of daily procedures overall and per operator and procedural timings, such as the interval between ovulation trigger and oocyte denudation. Results were adjusted for confounders, including maternal age, male factor infertility, and culture conditions. Multivariate linear regression and generalized estimating equations were used to assess associations with m-BR, accounting for repeated measures in couples undergoing multiple retrievals. MAIN RESULTS AND THE ROLE OF CHANCE: The overall m-BR was 35.7 ± 28.1% with 79% of the cycles resulting in at least one blastocyst obtained. No significant association was found between daily workload and m-BR, indicating that the number of daily procedures did not impact laboratory performance. After adjusting for confounders (maternal age, sperm factor, incubation conditions, and culture medium type), only the timing between ovulation trigger and oocyte denudation emerged as critical. A consistent and significant decline in m-BR was observed with each additional hour of delay between 36- and 44-h post-trigger (unstandardized coefficient B: -1.6%, 95% CI: -2.1 to -1.1%). The time between oocyte retrieval and denudation (range: 2-6 h) showed a significant association with a lower chance to obtain at least one blastocyst in each ICSI cycle (adjusted OR: 0.91, 95% CI: 0.86-0.96, P < 0.001). LIMITATIONS, REASONS FOR CAUTION: This was a retrospective single-center study. While the findings are robust and relevant for high-volume IVF laboratories, they may not be directly generalizable to smaller clinics with different workflows or lower caseloads. Additionally, only ICSI cycles were included; further studies are needed to confirm the findings for conventional IVF in different settings and patient populations. WIDER IMPLICATIONS OF THE FINDINGS: These findings suggest that even large workloads can be managed without compromising IVF performance, provided that lab schedules and personnel are carefully coordinated to meet ideal timing requirements. In the future, artificial intelligence models may support these lab management activities by predicting workloads and helping maintain timely schedules. STUDY FUNDING/COMPETING INTEREST(S): No funding. The authors declare no conflict of interest related with the content of this study. TRIAL REGISTRATION NUMBER: N/A.
A high proportion of immature oocytes in a cycle cohort does not compromise embryo development or live birth rates after ICSI.
Sripada V, Sakkas D, Vaughan D … +2 more , Morse B, Fouks Y
Hum Reprod · 2025 Dec · PMID 40912262 · Publisher ↗
STUDY QUESTION: Does a high proportion of immature oocytes impact embryo development and live birth rates in IVF-ICSI cycles? SUMMARY ANSWER: While a high proportion of immature oocytes is associated with lower blastocys...
STUDY QUESTION: Does a high proportion of immature oocytes impact embryo development and live birth rates in IVF-ICSI cycles? SUMMARY ANSWER: While a high proportion of immature oocytes is associated with lower blastocyst formation and reduced preimplantation genetic testing for aneuploidy (PGT-A) utilization, live birth rates remain comparable when key confounders-such as age, BMI, gonadotropin dosage, and metaphase-II (MII) count-are balanced, but cycles with a very low MII proportion resulted in fewer embryo transfers, which is quantitatively limiting, even if embryo quality appears unaffected. WHAT IS KNOWN ALREADY: Previous studies have linked a lower proportion of mature oocytes (MII) to decreased fertilization rates, abnormal embryo development, and lower pregnancy and live birth rates. However, it remains unclear whether these outcomes are due to quantitative limitations (fewer mature oocytes available) or qualitative deficiencies (intrinsic oocyte quality issues). The impact of high proportions of immature oocytes on downstream IVF outcomes remains controversial. STUDY DESIGN, SIZE, DURATION: Retrospective cohort study at a single academically affiliated fertility clinic between December 2014 and December 2023. PARTICIPANTS/MATERIALS, SETTING, METHODS: 22 117 patients undergoing IVF-ICSI cycles were categorized into three groups based on the proportion of mature (MII) oocytes: very low MII proportion (≤0.25), low MII proportion (≤0.5), and 100% MII oocytes. Propensity score matching (PSM) was applied in two phases: first, adjusting for age, BMI, gonadotropin dosage, and anti-Müllerian hormone levels; second, adjusting for age, BMI, gonadotropin dosage, and MII count. MAIN RESULTS AND THE ROLE OF CHANCE: Cycles with a very low MII proportion (≤0.25) had significantly lower blastocyst formation-mean 1.32 (SD 2.77; 95% CI: 1.03-1.61) versus 3.10 (SD 3.22; 95% CI: 2.77-3.43; P < 0.001)-and reduced PGT-A utilization-mean percent PGT-A normal 34% (95% CI: 30-38%) versus 40% (95% CI: 36-44%; P < 0.001). However, after PSM, live birth rates per an embryo transfer did not differ significantly between very low MII and perfect MII groups for both cryopreserved transfers (41.6% versus 30%, P = 0.68) and fresh embryo transfers (46.1% versus 38%, P = 0.69). The low MII proportion group (≤0.5) showed a trend toward lower cryopreserved transfer rates (44% versus 53%, P = 0.05), while fresh transfer rates remained comparable (30% versus 26.6%, P = 0.55). LIMITATIONS, REASONS FOR CAUTION: This study is limited by its retrospective nature and reliance on electronic medical records. While PSM effectively reduced confounding, inherent oocyte quality markers (e.g. mitochondrial function) were not directly measured. Additionally, the non-uniform distribution of MII proportions across groups may have influenced statistical power. WIDER IMPLICATIONS OF THE FINDINGS: These results underscore the importance of personalized ovarian stimulation protocols to optimize mature oocyte (MII) yield and support successful outcomes, even in patients with high proportions of immature oocytes. STUDY FUNDING/COMPETING INTEREST(S): The study was not funded. No competing interests. TRIAL REGISTRATION NUMBER: N/A.
Fine particulate matter exposure and sperm DNA fragmentation in US men: a spatial cross-sectional study.
Fouks Y, Vaughan DA, Bortoletto P … +6 more , Chang JC, Lantsberg D, Datta VX, McSweeney B, Schwartz JD, Sakkas D
Hum Reprod · 2025 Oct · PMID 40897385 · Full text
STUDY QUESTION: Does exposure to fine particulate matter (PM2.5) impact sperm DNA fragmentation? SUMMARY ANSWER: Higher PM2.5 exposure was associated with increased sperm DNA fragmentation, with greater effects observed...
STUDY QUESTION: Does exposure to fine particulate matter (PM2.5) impact sperm DNA fragmentation? SUMMARY ANSWER: Higher PM2.5 exposure was associated with increased sperm DNA fragmentation, with greater effects observed in men of lower socioeconomic status (SES). WHAT IS KNOWN ALREADY: Environmental air pollutants such as PM2.5 have been linked to adverse reproductive and perinatal outcomes. However, their impact on sperm chromatin integrity remains underexplored, particularly in the context of geographic and sociodemographic modifiers. STUDY DESIGN, SIZE, DURATION: This was a cross-sectional study including 21 851 semen samples collected between 2005 and 2022 from men undergoing fertility evaluation across multiple US regions. PARTICIPANTS/MATERIALS, SETTING, METHODS: Semen samples were obtained from men older than 18 years, with testing performed in a single reference laboratory. Exposure to PM2.5 was estimated using validated satellite-derived models and aligned with the 70-80 day spermatogenic window prior to sample collection. Spatial linear mixed-effects models incorporating natural splines and geographic correlation structures were used to assess nonlinear associations between PM2.5 and sperm DNA fragmentation index (DFI), while adjusting for age, SES, population density, and racial composition. Interaction terms were used to evaluate effect modification. MAIN RESULTS AND THE ROLE OF CHANCE: Higher PM2.5 exposure was associated with increased DFI (estimate = 0.45; P = 0.0025), with a clear nonlinear dose-response pattern peaking at ∼11 µg/m³. A significant interaction was observed between PM2.5 and SES (estimate = 0.45; P = 0.0148), indicating that men from lower SES areas experienced stronger pollution-related DNA damage. Age remained a strong independent predictor: men ≥50 years showed markedly elevated DFI (estimate = 14.36; P < 0.0001). LIMITATIONS, REASONS FOR CAUTION: The sample was derived from men seeking fertility evaluation and may not represent the general population. ZIP-code level SES and exposure proxies may not reflect to the full extent an individual-level exposures, and residual confounding is possible. WIDER IMPLICATIONS OF THE FINDINGS: These results underscore the reproductive health consequences of environmental air pollution and its intersection with social inequality. PM2.5 exposure may disproportionately affect sperm chromatin quality in disadvantaged populations; this finding supports targeted environmental and reproductive health interventions. Sperm DNA fragmentation may serve as a biomarker of environmental and social stress. STUDY FUNDING/COMPETING INTEREST(S): This study was internally funded. V.X.D. and B.M. are employees of ReproSource, which provided laboratory testing, and Quest Diagnostics. No other conflicts of interest were reported. TRIAL REGISTRATION NUMBER: N/A.
Posthumous sperm retrieval in the context of armed conflict.
Barda S, Dekalo S, Mendelson T … +5 more , Marom R, Veredgorn Y, Bashi T, Azem F, Weizman NF
Hum Reprod · 2025 Nov · PMID 40897384 · Publisher ↗
STUDY QUESTION: What are the clinical and logistical predictors of sperm viability in posthumous sperm retrieval (PHSR), and how do post-mortem interval (PMI), body refrigeration, and mechanism of death affect outcomes?...
STUDY QUESTION: What are the clinical and logistical predictors of sperm viability in posthumous sperm retrieval (PHSR), and how do post-mortem interval (PMI), body refrigeration, and mechanism of death affect outcomes? SUMMARY ANSWER: Shorter PMI and body refrigeration significantly enhance post-mortem sperm viability, with the mechanism of death modulating viability patterns in a time-dependent manner. WHAT IS KNOWN ALREADY: PHSR has gained increasing prominence in reproductive medicine, yet technical aspects remain under-researched. Key questions regarding optimal timing, storage conditions, and cause of death effects on sperm quality lack systematic investigation. STUDY DESIGN, SIZE, DURATION: Retrospective observational study of 28 PHSR procedures performed between October 2023 and December 2024 at a tertiary academic medical center. PARTICIPANTS/MATERIALS, SETTING, METHODS: Twenty-eight deceased men aged 19-37 years whose families requested PHSR. Unilateral testicular biopsy was performed, followed by sperm viability assessment and cryopreservation. Fresh and post-thaw sperm viability were analyzed as functions of PMI, body refrigeration, and mechanism of death using linear regression and multivariate analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Viable sperm were successfully retrieved in 25 of 28 cases (89%) up to 37 h post-mortem under optimal conditions. Median fresh sperm viability was 42.0% (quartile 1-quartile 3 [Q1-Q3] 38.0-52.0%), declining to 27.0% (Q1-Q3: 20.0-32.0%) following cryopreservation, representing a median reduction of 39% (Q1-Q3: 32-48%). Linear regression showed a time-dependent viability decline of ∼2% per hour post-mortem. Refrigeration was associated with preserved viability at extended PMIs, with all successful retrievals beyond 14 h occurring in refrigerated bodies. Blast injuries showed higher initial viability than gunshot wounds but a more rapid decline over time. A multivariate model incorporating PMI, refrigeration, and mechanism of death explained 59.2% of the variance in sperm viability. LIMITATIONS, REASONS FOR CAUTION: Limited sample size (n = 28) and unique wartime circumstances may limit generalizability. Documentation of intermediate storage conditions was challenging under combat conditions. Long-term outcomes and fertilization success require further investigation. WIDER IMPLICATIONS OF THE FINDINGS: These findings provide evidence-based benchmarks for PHSR protocols and practical guidance for clinical decision-making and family counseling. The quantitative relationships identified can inform timing decisions and optimize retrieval success rates. STUDY FUNDING/COMPETING INTEREST(S): This study received no external funding. All authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.
Recurrent implantation failure: when study design fails before the embryos.
Ata B, Kalafat E, Pirtea P
Hum Reprod · 2025 Oct · PMID 40897383 · Publisher ↗
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Validating the current duration approach for measuring infertility prevalence using novel app data from the USA.
Bell SO, Hwang S, Malloy S … +1 more , Nobles J
Hum Reprod · 2025 Nov · PMID 40897382 · Full text
STUDY QUESTION: Are the assumptions required by the current duration (CD) approach to estimating population infertility met, and does the CD approach produce similar infertility estimates to those from the 'gold standard...
STUDY QUESTION: Are the assumptions required by the current duration (CD) approach to estimating population infertility met, and does the CD approach produce similar infertility estimates to those from the 'gold standard' incident prospective cohort approach within the same sample using fertility app data? SUMMARY ANSWER: While we find evidence of CD assumption violation, once addressed, the CD approach produces comparable infertility prevalence estimates and patterns to those from an incident prospective cohort design when selecting from the same sample of women. WHAT IS KNOWN ALREADY: The CD approach to documenting population and subgroup infertility is a promising, more feasible, and cost-effective alternative method to the incident prospective cohort design. However, as a field, we do not have sufficient evidence to use the CD approach for the study of population infertility because method assumptions have not been rigorously tested using population-based samples. STUDY DESIGN, SIZE, DURATION: We use prospective cohort data provided by users of smartphone applications in which they record fertility and pregnancy information. The total prospective cohort sample included 167 451 people using the applications between 1 January 2015 and 28 February 2022. To generate valid comparisons, we drew six CD samples from the same data source. The samples contained between 17 196 and 26 259 people measured in designated months. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants are users of a fertility and pregnancy smartphone application aged 18-44 years who were trying to become pregnant and began using the smartphone application during the study period. We first tested the three assumptions required by the CD approach. We then estimated 12-month infertility prevalence separately using prospective and CD approaches, first for all users, and then for subpopulations stratified by age, education, parity, and level of poverty. We assessed whether estimates of population infertility using prospective and CD approaches were statistically different, overall and for each subpopulation. MAIN RESULTS AND THE ROLE OF CHANCE: We demonstrate clear violation of one CD assumption, and suggestive evidence of one other assumption violation. The prospective survival function resulted in a 12-month infertility prevalence of 36.1% (95% CI 35.8-36.3) while the CD estimate adjusted for assumption violation was 37.0% (95% CI 36.2-37.7). Infertility patterns by user characteristics were similar for prospective and CD estimates, with greater levels of infertility for those 35 years old or greater, those with no children, those with less education, and those residing in areas with greater levels of poverty. LIMITATIONS, REASONS FOR CAUTION: Potential sample selection and censoring do not affect the internal validity of within-sample comparison tests, which answer the study's primary research questions. However, selection and censoring may contribute to sample non-representativeness and the higher than expected levels of infertility relative to the US population. WIDER IMPLICATIONS OF THE FINDINGS: Researchers can potentially learn about patterns of infertility with cross-sectional data alone, provided they statistically address CD assumption violations. This finding facilitates the study of infertility in populations, subpopulations, places, and periods for which infertility estimates do not exist. Although we weighted the samples to reflect the US population sociodemographic characteristics, users of this app may underreport pregnancy and/or may be subfertile, thus, the infertility prevalence estimates reported here should not be interpreted as population-level estimates for the USA. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by grants from the National Institute of Child Health and Human Development (R01HD102207, K01HD107172, P2CHD047873, P2CHD042854). The funders were not involved in the study design, analyses, manuscript writing, or decision to publish. S.M. is an employee of Ovia Health by Labcorp, and owns stock in Labcorp Holdings. Ovia Health created the fertility app from which the data for the analysis were sourced. Other authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: N/A.
Reply: Recurrent implantation failure: when study design fails before the embryos.
Wang Q, Zhang X, Wang C
Hum Reprod · 2025 Oct · PMID 40897380 · Publisher ↗
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Forecasting Outcomes of Assisted Reproductive Treatments Using Artificial Networks (FORTUNE) classification system: a new prognostic model to predict euploid blastocyst yield in patients undergoing IVF.
Seli E, Kalafat E, Reig A … +3 more , Whitehead C, Ata B, Garcia-Velasco J
Hum Reprod · 2025 Nov · PMID 40889782 · Publisher ↗
STUDY QUESTION: Can a prediction model classify IVF patients into distinct prognostic groups based on their expected yield of euploid blastocysts? SUMMARY ANSWER: Five distinct prognostic groups were identified, with cha...
STUDY QUESTION: Can a prediction model classify IVF patients into distinct prognostic groups based on their expected yield of euploid blastocysts? SUMMARY ANSWER: Five distinct prognostic groups were identified, with chance of obtaining at least one euploid blastocyst ranging from <1% to 2% in very poor to ∼95% in very good prognosis groups. WHAT IS KNOWN ALREADY: Euploid blastocyst yield is a critical determinant of IVF success. While female age strongly influences embryo euploidy, other factors like ovarian reserve markers, partner age, and BMI may also contribute. Current approaches rely on basic and somewhat arbitrary classification of ovarian reserve markers and patient age, which are unable to represent the granular multidimensional relationship between them. A systematic approach to classify patients based on their expected euploid yield would enable better treatment planning and patient counseling. STUDY DESIGN, SIZE, DURATION: A retrospective analysis of 10 774 IVF cycles from 8256 couples undergoing pre-implantation genetic testing for aneuploidy (PGT-A) of all available blastocysts from years 2020 to 2023 and a temporal validation cohort of 2089 cycles of 2089 patients from year 2024. The prediction model was developed using generalized additive models for location, scale, and shape using a development cohort from 2020 to 2023, and cross-validated through exhaustive 5-fold cross-validation. Temporal validation was performed using an entirely separate cohort from 2024. Model performance was assessed through calibration plots and discrimination metrics. PARTICIPANTS/MATERIALS, SETTING, METHODS: Couples undergoing IVF with PGT-A of all their available blastocysts were included. Model included female age, partner age, anti-Müllerian hormone (AMH), antral follicle count, and BMI as predictors. Non-linear associations were captured using neural networks and restricted cubic splines. Missing data were handled using multivariate imputation by chained equations. MAIN RESULTS AND THE ROLE OF CHANCE: The median female age was 36.3 years (IQR: 33.3-39.5) and AMH was 2.0 ng/ml (IQR: 1.0-3.8). Models for predicting ≥1, ≥2, and ≥3 euploid blastocysts yield achieved very good discrimination performance in 5-fold cross-validation samples with mean AUCs of 0.834, 0.849, and 0.861, respectively. Models showed negligible shrinkage (<1%) between training and cross-validation sets with near-perfect calibration slopes (mean: 1.00, IQR: 0.99-1.01) and intercepts (mean: 0.015, IQR: 0.00-0.03). Using predicted absolute counts of euploid blastocysts, five distinct prognostic groups were created based on predicted euploid blastocyst yield. Patients in the very poor prognosis group had 98.3% probability of obtaining no euploid blastocysts after stimulation while the probabilities were 80.2%, 47.5%, 15.8%, and 4.7% in poor, borderline, good, and very good prognosis groups. The chances of obtaining ≥3 euploid blastocysts were 79.8%, 43.7%, 8.9%, 0.2%, and 0% in very good, good, borderline, poor, and very poor prognosis groups. In the temporal validation set (n = 2089), which constituted the first cycles of patients that were treated, the rates of no euploid blastocysts obtained at the end of stimulation were 100.0%, 82.6%, 47.4%, 13.1%, and 4.4% in the very poor, poor, borderline, good, and very good prognosis groups. The rates of three or more euploid blastocysts obtained at the end of stimulation in the temporal validation set were 83.5%, 51.0%, 10.7%, 0.6%, and 0.0% for very good, good, borderline, poor, and very poor prognosis groups. The FORTUNE (Forecasting Outcomes of Reproductive Treatments Using artificial Networks) model is available for use and further validation at https://epsilonkappa-analytics.shinyapps.io/FORTUNE and App Store for iOS mobile devices https://apps.apple.com/en/app/fortune-ivf/id6747190429. LIMITATIONS, REASONS FOR CAUTION: Single-center study design may limit generalizability. The model does not account for laboratory-specific factors or stimulation protocols. WIDER IMPLICATIONS OF THE FINDINGS: This novel classification system provides objective, personalized counseling for IVF patients regarding expected euploid yield, enabling better-informed decision-making about treatment options and number of planned stimulation cycles. STUDY FUNDING/COMPETING INTEREST(S): There was no funding needed for this study. 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. TRIAL REGISTRATION NUMBER: N/A.
Reliability of self-reported endometriosis and adenomyosis data in online surveys: results from the ComPaRe-Endometriosis e-cohort.
Gouesbet S, du Cheyron J, Amazouz H … +5 more , Breton Z, Pane I, Toko-Kamga L, Tran VT, Kvaskoff M
Hum Reprod · 2025 Nov · PMID 40882977 · Publisher ↗
STUDY QUESTION: How reliable are self-reported endometriosis or adenomyosis data compared with medical reports in online patient surveys? SUMMARY ANSWER: In our sample, reliability was strong to excellent for diagnosis,...
STUDY QUESTION: How reliable are self-reported endometriosis or adenomyosis data compared with medical reports in online patient surveys? SUMMARY ANSWER: In our sample, reliability was strong to excellent for diagnosis, age at diagnosis, and stage at diagnosis, while reliability for macro-phenotype of endometriosis ranged from fair to substantial. WHAT IS KNOWN ALREADY: Many online surveys rely on self-reported endometriosis data. Previous research has shown validation rates ranging from 72% to 95% for self-reported endometriosis diagnosis in population cohorts, but this rate is unknown in the context of online surveys among patient populations or patient e-cohorts. STUDY DESIGN, SIZE, DURATION: We conducted a specific study within ComPaRe-Endometriosis, a French e-cohort launched in 2018 and following up several thousands of women with endometriosis and/or adenomyosis. Within this study, a total of 215 participants sent their medical reports. We compared participants' self-reported diagnosis and disease characteristics, as collected in self-reported questionnaires at baseline in the ComPaRe-Endometriosis cohort, with data from contemporaneous medical reports. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were asked to send their medical reports mentioning diagnosis and its date, and type(s) and stage of endometriosis. We assessed the reliability between baseline self-reported data and medical report data using descriptive statistics, intraclass correlation coefficient (ICC), Cohen's Kappa, and weighted Kappa. MAIN RESULTS AND THE ROLE OF CHANCE: The study included 215 participants with a mean age of 33.8 years (SD = 7.0). Over half (52.1%) reported endometriosis alone, 8.4% adenomyosis alone, and 39.5% reported both diseases. Endometriosis and adenomyosis diagnoses were correctly reported among 95.9% and 90.3% of participants, respectively. Self-reported age at diagnosis showed excellent reliability with ICC = 0.96 for endometriosis and ICC = 0.91 for adenomyosis. Regarding self-reported disease stage, substantial-to-almost perfect agreement (κw = 0.86-0.78) and excellent reliability (ICC = 0.91-0.94) were observed. For self-reported macro-phenotype of endometriosis, agreement varied: substantial for endometrioma (K = 0.62-0.74), moderate-to-substantial for deep endometriosis (K = 0.40-0.61), and fair-to-moderate for superficial peritoneal endometriosis (K = 0.35-0.43). LIMITATIONS, REASONS FOR CAUTION: The most motivated participants may have a particular profile in terms of involvement in their care, which constitutes a limitation to the generalizability of the findings. WIDER IMPLICATIONS OF THE FINDINGS: Several studies assessed the reliability of self-reported endometriosis data in population cohorts and found validation rates ranging from 72% to 95% with medical reports. This figure could vary greatly depending on several criteria (study population, clarity of the question about diagnosis, tool used to confirm diagnosis…). In this work, we found a striking heterogeneity in the way macro-phenotype of disease was described in medical reports. Since many studies rely on self-reported data, this work underscores the importance of harmonizing the report of diagnosis and endometriosis/adenomyosis characteristics in medical reports in order to ease continuity of care and ensure high-quality research on these conditions. STUDY FUNDING/COMPETING INTEREST(S): The ComPaRe cohort was supported by the Assistance Publique-Hôpitaux de Paris (APHP) and the Université Paris Cité. ComPaRe-Endometriosis was funded through grants from the Fondation de France (#00132975/WB-2022-44780) and the Agence Nationale de la Recherche (#ANR-22-CE36-0016-01) and received donations from patient societies and initiatives (EndoMind, EndoFrance, EndoAction, Les Joyeux Boulomanes Farlédois, La Belle et L'endo, Les Chroniques Endométriques). S.G. was supported by a PhD scholarship from the French Ministry of Research and a grant from the Crédit Agricole Ile-de-France Mécénat. Z.B. was supported by the French National Association for Research and Technology (ANRT) and Lyv Healthcare during their PhD. The funders had no role in the design, interpretation, or decision to publish the study. The other authors report no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.
Fertility status and risk of pediatric cardiovascular diseases: a population-based nested case-control study.
Weng SS, Huang YT, Huang YT … +1 more , Chien LY
Hum Reprod · 2025 Oct · PMID 40839769 · Publisher ↗
STUDY QUESTION: Is parental fertility status and use of IVF associated with the risk of pediatric cardiovascular diseases among offspring aged 0-13 years, and is this association mediated by perinatal factors? SUMMARY AN...
STUDY QUESTION: Is parental fertility status and use of IVF associated with the risk of pediatric cardiovascular diseases among offspring aged 0-13 years, and is this association mediated by perinatal factors? SUMMARY ANSWER: Children conceived through IVF and those born to parents with subfertility (defined as one partner with an infertility diagnosis and not using ART for the study pregnancy) have an increased risk for congenital heart defects, partly explained by multiple gestations. WHAT IS KNOWN ALREADY: Evidence indicates that children born following IVF have an increased risk of premature vascular aging. However, the risk of developing cardiovascular diseases during childhood and the extent to which such risks are associated with adverse perinatal outcomes remains uncertain. STUDY DESIGN, SIZE, DURATION: This nationwide, population-based, nested case-control study included registry data from 2 228 073 parents-child triads in Taiwan from 1 January 2004 to 31 December 2017. Offspring were categorized into three groups based on their parents' fertility status (fertile [achieved spontaneous conception, no infertility diagnosis], subfertility, and IVF [conception via IVF, including ICSI]). The three groups were followed from birth (between 1 January 2004 and 31 December 2017) until they developed the outcomes of interest, met any exclusion criteria, died, or until the end of the study period (31 December 2017), whichever came first. PARTICIPANTS/MATERIALS, SETTING, METHODS: In the study cohort, we identified 41 113 children with newly diagnosed pediatric cardiovascular diseases and used incidence density sampling to match each case to four controls (n = 169 850), based on age, sex, mother's residential township at delivery, and the calendar date of the pediatric cardiovascular disease diagnosis. Pediatric cardiovascular diseases included diagnoses of congenital heart defects, hypertensive diseases, cardiomyopathy, and arrhythmia. Conditional logistic regression was performed to examine the association between fertility status and pediatric cardiovascular diseases. Causal mediation analysis was used to test for mediation by multiple gestations, preterm birth, and low birth weight. MAIN RESULTS AND THE ROLE OF CHANCE: During 11.5 million person-years of follow-up (median [interquartile range, IQR], 6 years [2-10]), IVF conception was associated with an increased risk of congenital heart defects compared with subfertility (odds ratio [OR], 1.47; 95% CI, 1.36-1.60; incidence rate difference [IRD], 375.1 per 100 000 person-years [95% CI, 331.8-418.3]) and fertile group (OR, 1.72; 95% CI, 1.60-1.85; IRD, 445.7 per 100 000 person-years [95% CI, 403.0-488.3]). Subfertility was associated with a 1.19-fold higher risk of congenital heart defects (95% CI, 1.16-1.23; IRD, 70.6 per 100 000 person-years [95% CI, 61.9-79.4]) than fertile group. Multiple gestations accounted for 31.16% of the association between IVF and congenital heart defects compared with subfertility and for 54.26% of the association compared with fertile group. No significant associations were found between fertility status and hypertensive diseases, cardiomyopathy, or arrhythmias. LIMITATIONS, REASONS FOR CAUTION: Although the national data with a long follow-up period were used, the duration may still be insufficient to detect potential risks for hypertensive diseases, cardiomyopathy, and arrhythmia. Lack of data on pregnancy terminations could lead to underestimation of congenital heart defects risk. WIDER IMPLICATIONS OF THE FINDINGS: These findings suggest that a reduction in the occurrence of multiple gestations may help reduce the risk of congenital heart defects related to IVF conception. IVF conception should prompt consideration of fetal echocardiography, particularly in mothers with multiple gestations. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by grants from Shin Kong Wu Ho-Su Memorial Hospital (No. 109GB006-1). The funders had no role in the study design, data collection, analysis, interpretation, report writing, or the decision to submit the article for publication. The authors have no competing interests to disclose. TRIAL REGISTRATION NUMBER: N/A.
Driving change: aligning reproductive medicine research funding with disease impact.
Barratt CLR
Hum Reprod · 2025 Oct · PMID 40833376 · Publisher ↗
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Paracetamol (N-acetyl-para-aminophenol) disrupts early embryogenesis by cell cycle inhibition.
Nielsen BS, Petersen MR, Martin-Gonzalez J … +24 more , Holmberg C, Mjoseng HK, Frederiksen H, Rosenthal C, Jørgensen EM, Serup P, Christensen SL, Petersen KB, Kristiansen K, Jørgensen NR, Kari J, Hay-Schmidt A, Heurte M, Pedersen PA, Juul A, Pinborg A, Ziebe S, Lindenberg S, Elers J, David A, Lindenberg F, Zedeler A, Christensen ST, Kristensen DM
Hum Reprod · 2025 Oct · PMID 40819833 · Publisher ↗
STUDY QUESTION: Does paracetamol (N-acetyl-para-aminophenol (APAP) also known as acetaminophen) interfere with cell division and thereby disrupt pre-implantation embryonic development? SUMMARY ANSWER: Our findings sugges...
STUDY QUESTION: Does paracetamol (N-acetyl-para-aminophenol (APAP) also known as acetaminophen) interfere with cell division and thereby disrupt pre-implantation embryonic development? SUMMARY ANSWER: Our findings suggest that APAP exposure inhibits cell cycling during pre-implantation development (PID) through the reduction of DNA synthesis, potentially resulting in early embryonic loss. WHAT IS KNOWN ALREADY: It is estimated that 10-40% of all human conceptions fail around the time of implantation. Genetic factors explain ∼50% of early embryonic loss, leaving a substantial portion of early losses without a known cause. Smoking and alcohol are established risk factors for spontaneous abortion, underscoring the importance of the chemical environment during embryonic development. STUDY DESIGN, SIZE, DURATION: To address the challenges in determining the mechanism of action and the effects of APAP during PID, we utilized a range of approaches, including in vitro, ex vivo, and in vivo methods across various models ranging from yeasts to human embryos and women of fertile age. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 90 human embryos were exposed in vitro (22 cleavage stage and 68 blastocyst-stage embryos). Endometrial tissue and uterine fluid were collected from seven women as part of an endometrial scratching procedure. Follicular fluid was collected from 26 women during transvaginal ultrasound guided aspiration of the pre-ovulatory follicles. All human material was sampled in accordance with relevant guidelines and regulations with consent from the regional scientific ethical committee of the Capital Region of Denmark and signed informed patient consent given prior to donation. All mouse experiments were approved by the Danish Animal Experiments Inspectorate and under EU directive 2010/63/EU on the protection of animals used for scientific purposes. The cultivation of the human embryonic stem cell lines H1 and HUES4 was conducted in compliance with relevant guidelines and regulations, following approval from the regional scientific ethical committee of the Capital Region of Denmark. MAIN RESULTS AND THE ROLE OF CHANCE: After exposure to APAP, we found an unequivocal repression of cell division across all used model systems. APAP exposure hindered cell cycle progression, likely by inhibiting ribonucleotide reductase, leading to reduced DNA synthesis and accumulation in the S-phase. At concentrations found in the reproductive system of women after standard dosing, APAP exposure decreased cell numbers in mouse and human cleavage-stage embryos or caused direct embryonic death. Similar exposure to mouse and human blastocyst-stage embryos resulted in a reduced inner cell mass and decreased DNA synthesis, respectively. LIMITATIONS, REASONS FOR CAUTION: A limitation of the study is the low number of available human cleavage-stage embryos. However, the high number of human blastocysts and our translational approach, which demonstrated reproducibility across various model systems, partly addressed this limitation. Further studies are needed to confirm the potential association between APAP use and pregnancy loss in prospective cohorts. WIDER IMPLICATIONS OF THE FINDINGS: Our findings indicate that the widely used mild analgesic APAP could contribute to early embryonic loss by impairing initial cell divisions. These results suggest that APAP should be used with caution by women attempting to conceive. Given that cell division is fundamental to all development, further investigation is now warranted to substantiate these findings and to elucidate possible implications for other developmental processes, such as gonadal and brain differentiation. STUDY FUNDING/COMPETING INTEREST(S): The research was funded by the Lundbeck Foundation (R324-2019-1881). Authors P.S. and H.K.M. were affiliated with the Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW; NNF21CC0073729). H.K.M. received a fellowship from the Novo Nordisk Foundation as part of the Copenhagen Bioscience PhD Program, supported by grant NNF19SA003544. M.H and A.D. are part of the National French Research Infrastructure France Exposome and have received funding from the European Regional Development Fund and Britanny region (Contrat Plan Etat Region, project Exposome, AIDEN 106201). TRIAL REGISTRATION NUMBER: N/A.
Stratifying IVF population endometria using a prognosis gradient independent of endometrial timing†.
Sanchez-Reyes JM, Parraga-Leo A, Sebastian-Leon P … +10 more , Vidal MDC, Marti-Garcia D, Spath K, Sanchez-Ribas I, Sanz FJ, Pellicer N, Remohi J, Wells D, Pellicer A, Diaz-Gimeno P
Hum Reprod · 2025 Oct · PMID 40796355 · Full text
STUDY QUESTION: Can the disrupted window of implantation (WOI) be stratified according to transcriptomic patterns associated with reproductive success in IVF patients undergoing HRT? SUMMARY ANSWER: There are four transc...
STUDY QUESTION: Can the disrupted window of implantation (WOI) be stratified according to transcriptomic patterns associated with reproductive success in IVF patients undergoing HRT? SUMMARY ANSWER: There are four transcriptomic patterns independent of endometrial timing associated with a gradient of reproductive prognosis underlying different molecular pathomechanisms. WHAT IS KNOWN ALREADY: A molecular heterogeneous profile independent of endometrial timing has been discovered as a cause of implantation failure that disrupt the endometrial transcriptome in the mid-secretory phase. However, the molecular heterogeneous patterns underlying the disruption remain poorly identify and understood. Characterizing the molecular heterogeneity of this endometrial disruption is crucial to develop personalized and more accurate diagnostic tools for preventive medicine, particularly for patients with a high risk of endometrial failure. STUDY DESIGN, SIZE, DURATION: In this multicenter prospective study, 195 IVF patients undergoing HRT with endometrial biopsy collection, during mid-secretory phase for endometrial progression evaluation, were recruited between January 2019 and August 2022. Out of 195 patients, 131 were finally included in the following analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Endometrial biopsies were processed for whole endometrial transcriptome analysis using RNA-Sequencing. To identify disruptions in the WOI, the transcriptomic variation due to cyclic endometrial tissue changes was removed. Out of 195 biopsies sequenced, 131 were derived from patients that met the clinical criteria to be classified as implantation failure group (≥3 implantation failures, n = 32) or control group (<3 implantation failures, n = 99). An artificial intelligence (AI) model, based on two supervised learning algorithms: support vector machine (SVM) and k-nearest neighbors (kNN), was performed with 131 patients that were randomly allocated to training (n = 105) and test (n = 26) sets for biomarker signature discovery and assessment of predictive performance, respectively. The reproductive outcomes of the single embryo transfer immediately after biopsy collection were analyzed. Differential expression and functional analyses were performed to characterize molecular profiles. Finally, a quantitative PCR (qPCR) assay was used to corroborate the differential expression of six potential biomarkers. MAIN RESULTS AND THE ROLE OF CHANCE: With the dichotomous clinical classification of poor or good reproductive prognosis, there was no transcriptomic distinction between patients with a history of implantation failures during HRT endometrial preparation. Alternatively, using an AI model to stratify IVF patients based on the probability of endometrial disruption revealed molecular and clinical differences between patterns. Patients were stratified into four reproductive prognosis-related profiles: p1 (n = 24), p2 (n = 14), c2 (n = 32) and c1 (n = 61). The highest pregnancy rate (PR) was associated with c1 (91%) and the highest ongoing pregnancy rate (OPR) was associated with c2 (78%), linking these profiles to good reproductive prognoses. On the other hand, p1 had the highest biochemical miscarriage rate (43%) while p2 had the highest clinical miscarriage rate (43%). Notably, both p1 and p2 were related to lower PR and OPR, supporting that these profiles were associated with poor prognoses. Regarding the functional characterization in the poor prognosis profiles that were linked to miscarriages, p1 was associated with an excessive immune response against the embryo during early pregnancy stages, while p2 was initially immune-tolerant but rejected the fetus in later stages due to the lack of metabolic response. LIMITATIONS, REASONS FOR CAUTION: Due to the heterogeneous character of the disrupted WOI and the limited sample size of the different stratified groups, the AI model has limited population inference. However, our significant promising findings provide strong leads for further clinical studies with larger sample sizes. WIDER IMPLICATIONS OF THE FINDINGS: This new transcriptomic taxonomy associated with distinct reproductive outcomes provides clues to design new and more accurate evaluation tools for endometrial-factor infertility. Furthermore, it enables tailoring therapeutic strategies to apply a personalized medicine to each patient suffering from endometrial-factor infertility, improving their odds of getting pregnant. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the IVI Foundation (1706-FIVI-048-PD); Instituto de Salud Carlos III (ISCIII) and co-funded by the European Regional Development Fund "A way to make Europe" (PI19/00537 [P.D.-G.]) as well as Instituto Carlos III (ISCIII) through project (PI23/00806 [P.D.-G.]) and co-funded by European Union. Patricia Diaz-Gimeno is supported by Instituto de Salud Carlos III (ISCIII) through the Miguel Servet program (CP20/00118) co-funded by the European Union. Patricia Sebastian-Leon and Francisco Jose Sanz are funded by Instituto de Salud Carlos III (ISCIII) through the Sara Borrell postdoctoral program (CD21/00132 [P.S.-L.] and CD23/00032 [F.J.S.]) co-financed by the European Union. Josefa Maria Sanchez-Reyes was supported by a predoctoral fellowship program of the Generalitat Valenciana (ACIF/2018/072 and BEFPI/2020/028). Antonio Parraga-Leo (FPU18/01777) and Diana Marti-Garcia (FPU19/03247) were supported by predoctoral fellowship programs of the Spanish Ministry of Science, Innovation and Universities. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: Not applicable.
Biallelic variants in DLGAP5 cause spindle assembly defects and human early embryonic arrest.
Hu H, Wan X, Sun J … +10 more , Zhang S, Guo J, Zhang Y, Meng F, Zhang S, Gu Y, Gong F, Liao H, Lin G, Zheng W
Hum Reprod · 2025 Oct · PMID 40796344 · Publisher ↗
STUDY QUESTION: What effects do DLGAP5 defects have on human early embryo development? SUMMARY ANSWER: DLGAP5 deficiency disrupts normal spindle assembly through its interaction with TACC3, leading to female infertility...
STUDY QUESTION: What effects do DLGAP5 defects have on human early embryo development? SUMMARY ANSWER: DLGAP5 deficiency disrupts normal spindle assembly through its interaction with TACC3, leading to female infertility characterized by recurrent early embryonic arrest (REEA). WHAT IS KNOWN ALREADY: REEA is a significant contributor to failures in assisted reproductive technology. While genetic factors play a crucial role, known gene variants account for only a small proportion of affected individuals, leaving many underlying genetic factors yet to be elucidated. The relationship between spindle assembly and early embryonic development has emerged as a key research focus, however, our understanding of bipolar spindles in human oocytes and early embryos remains limited, highlighting the need for further investigation into the essential molecular players involved. STUDY DESIGN, SIZE, DURATION: A total of 488 female patients experiencing infertility characterized as REEA were recruited from a university-affiliated center from November 2021 to December 2023. PARTICIPANTS/MATERIALS, SETTING, METHODS: Whole-exome sequencing was performed on the REEA cohort to identify candidate variants. HeLa cells were transiently transfected with wild-type and mutant plasmids to evaluate protein abundance and localization. Mutant mRNAs were expressed at the zygote stage to monitor subsequent embryonic development. Immunoprecipitation-mass spectrometry was employed to identify altered interacting molecules associated with the candidate variants. Additionally, a site-directed mutant mouse model was developed to investigate the pathogenic mechanisms in vivo, validated with patient oocytes and arrested embryos. MAIN RESULTS AND THE ROLE OF CHANCE: The study identified two nonsense variants, one frameshift variant, and one missense pathogenic variant in the DLGAP5 gene of three independent families from the cohort of 488 REEA patients through whole-exome sequencing. All affected individuals displayed a Mendelian recessive inheritance pattern. These variants significantly altered protein length, abundance, or localization, resulting in spindle abnormalities in HeLa cells and mouse zygotes. Furthermore, the microinjection of exogenous mutant DLGAP5 mRNA into mouse zygote and the construction of Dlgap5 site-directed mutant mice successfully replicated the patient phenotypes. Functional studies, both in vivo and in vitro, revealed that DLGAP5 deficiency disrupts normal spindle assembly through its interaction with TACC3. LIMITATIONS, REASONS FOR CAUTION: This study was unable to observe the dynamic changes in spindle assembly in oocytes from patients with DLGAP5 variants due to ethical restrictions. Additionally, a larger patient cohort is needed, particularly multi-center and multi-ethnic studies, to further establish the relationship between DLGAP5 variants and female infertility. WIDER IMPLICATIONS OF THE FINDINGS: These findings suggest that DLGAP5 is essential for spindle assembly in oocytes through its interaction with TACC3. This could position DLGAP5 as a novel molecular diagnostic marker and a potential target for interventions in female infertility related to REEA. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Natural Science Foundation of China (82371672 and 82371667), the National Key Research and Development Program of China (2023YFC2705504 and 2022YFC2702300), the Natural Science Foundation of Hunan Province (2024JJ2083), the Science and Technology Innovation Program of Hunan Province (2023RC3233) and the Scientific Research Foundation of Reproductive and Genetic Hospital of CITIC-XIANGYA (YNXM-202202 and YNXM-202402), and Hunan Provincial Grant for Innovative Province Construction (2019SK4012). The authors declare they have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.
Endometrial preparation protocols for frozen embryo transfer: risk assessment and individualized management.
Polyzos NP
Hum Reprod · 2025 Oct · PMID 40796314 · Publisher ↗
Frozen embryo transfer (FET) cycles have increased exponentially in the last decade. For many years, the most widely accepted protocol for endometrial preparation for FET cycles has been the artificial cycle (AC-FET), ma...
Frozen embryo transfer (FET) cycles have increased exponentially in the last decade. For many years, the most widely accepted protocol for endometrial preparation for FET cycles has been the artificial cycle (AC-FET), mainly due to the ease of coordinating the timing of embryo transfer with the operational needs of the IVF lab, the medical team and the patient. Accumulating data support that, due to the presence of corpus luteum, natural cycle frozen embryo transfer (NC-FET) is associated with better maternal and perinatal outcomes, especially lower preeclampsia risk, as compared with AC-FET. In this context, novel protocols for endometrial preparation in NC-FET are being tested, to allow better planning of NC-FET either through a flexible ovulation trigger or via initiation of progesterone administration independent of ovulation. Although several clinicians recommend a complete shift to NC-FET for all normo-ovulatory women to prevent pregnancy complications, reverting to a "back to nature" approach is not a comprehensive solution to the problem. Abandoning AC-FET, without any other action, will not solve the problem, simply because not all patients have the same risk. Preeclampsia is a multifactorial disease, and several factors, aside from AC-FET, may present a much higher risk of developing the condition. Therefore, a thorough assessment of preeclampsia risk before selecting a FET protocol, optimizing first-trimester screening algorithms and implementing primary prevention measures for truly at-risk patients-rather than stigmatizing and abandoning AC-FET-should be prioritized.
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