Human Reproduction (Oxford, England)[JOURNAL]
Sun
200 papers
Comparative analysis of the organization of endometriosis care in five high-income countries: implications for health systems and policy.
Leroy R, Abbott J, Benahmed N … +9 more , Camberlin C, De Jaeger M, Hartwell D, Kent A, Nap A, Ng C, Ombelet S, Schweppe KW, Desimpel F
Hum Reprod · 2025 Dec · PMID 41091783 · Publisher ↗
STUDY QUESTION: How is endometriosis care organized at the primary, secondary, and tertiary care levels in five high-income countries? SUMMARY ANSWER: In all countries under study, initiatives have been taken to provide...
STUDY QUESTION: How is endometriosis care organized at the primary, secondary, and tertiary care levels in five high-income countries? SUMMARY ANSWER: In all countries under study, initiatives have been taken to provide endometriosis care by experienced health care professionals in a multidisciplinary setting, but certification criteria for secondary and tertiary centres vary greatly across countries. WHAT IS KNOWN ALREADY: Endometriosis is a highly prevalent and complex disease with potentially significant physical, sexual, psychological, social, and economic impacts on those affected. Logically, a multidisciplinary approach by health care providers with expertise and experience has been recommended. STUDY DESIGN, SIZE, DURATION: This study included five high-income countries where endometriosis care was centralized to some extent or where a national action plan for endometriosis was developed. PARTICIPANTS/MATERIALS, SETTING, METHODS: Based on a review of the literature, five countries were selected: Australia, Denmark, Germany, the Netherlands, and the UK. Information was collected through a review of peer-reviewed and grey literature that was revised and amended by experts from each country. MAIN RESULTS AND THE ROLE OF CHANCE: In 2018, Australia launched a comprehensive government-led national action plan for endometriosis. In Germany, secondary and tertiary endometriosis care is organized at three levels, while in Denmark and the Netherlands, a two-level system has been installed, whereas in the UK, only tertiary referral centres have been initiated to date. Only in Denmark must secondary care centres refer patients with advanced endometriosis to tertiary care centres. In all countries studied, treatment for advanced endometriosis is also carried out in centres without certification, where the quality of care is not assessed. National endometriosis registries have commenced and are active in Australia and the UK. In the selected countries, various initiatives have been taken to enhance the training of health care professionals, to inform patients, and to increase awareness on endometriosis. In none of the studied countries is endometriosis (automatically) recognized and/or registered as a chronic condition. LIMITATIONS, REASONS FOR CAUTION: In the five countries evaluated, there are continuing efforts to further improve the organization of endometriosis care. With ongoing revisions of service provision, resourcing and health care structures for endometriosis are evolving considerably; therefore, this overview should be considered as a snapshot taken up to early 2025. Since this overview relies principally on scientific literature, policy documents, and expert opinions, and not on objective outcomes, there may be dyssynchrony between what is summarized here and actual clinical practice. WIDER IMPLICATIONS OF THE FINDINGS: This overview may provide advice and guidance for policy makers in the development of a framework for the organization of endometriosis care in their country. STUDY FUNDING/COMPETING INTEREST(S): The research was supported by the government-approved work program of the Belgian Health Care Knowledge Centre (KCE). C.N. is funded though the NECST Network grant (4-I66SNMA) from the Australian Government Department of Health and Aged Care, manages research grant funding from the MRFF, is Chair of the Australian Clinical Trials Alliance (ACTA) Special Interest Group for Network Managers (SIGNet) and was a previous employee with CSL Vifor (formerly Vifor Pharma Pty. Ltd). J.A. is on advisory boards and received consulting fees from Gedeon Richter, BD and Hologic, received honoraria for lectures from MSD and Hologic, and received support for attending meetings from Hologic. He is on the Endometriosis Advisory Group for the Australian Government, Chaired the first Australian Guidelines for Endometriosis Diagnosis and Management, and contributed to the Governments National Action Plan on Endometriosis. He is the Chair of the NECST Network, past-President of AGES, and past-Chair and Medical Director of Endometriosis Australia and holds multiple competitive grants in endometriosis research through Australian Government funding agencies (Commonwealth Department of Health and Aged Care, MRFF), AGES, Country Women's Association of NSW, MSD and Endometriosis Australia. R.L., N.B., C.C., F.D., M.D.J., D.H., A.K., A.N., S.O., and K.-W.S. have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.
In vitro system completely restores oogenesis in congenitally infertile mice.
Yoshida K, Kimura S, Taguchi M … +4 more , Morimoto H, Kanatsu-Shinohara M, Shinohara T, Obata Y
Hum Reprod · 2025 Dec · PMID 41057044 · Full text
STUDY QUESTION: Can in vitro systems, combined with transient gene expression or factor supplementation, completely restore fertility in congenitally infertile mice? SUMMARY ANSWER: Transient expression of Kitl via adeno...
STUDY QUESTION: Can in vitro systems, combined with transient gene expression or factor supplementation, completely restore fertility in congenitally infertile mice? SUMMARY ANSWER: Transient expression of Kitl via adeno-associated virus (AAV) vectors or supplementation with recombinant KITL in KitlSl-t/KitlSl-t mice-a model of congenital infertility caused by a mutation in the Kitl locus-resulted in the production of mature oocytes and the birth of healthy, fertile offspring. WHAT IS KNOWN ALREADY: Although in vivo gene delivery has enabled offspring production in infertile mouse models, low efficiency, unpredictability of parturition timing, inflammatory risk, possible viral genome integration, and lack of real-time oogenesis observation remain major concerns. Despite the potential of in vitro oogenesis as an alternative, complete functional restoration of gene deficiency has not been reported. STUDY DESIGN, SIZE, DURATION: AAV-mCherry was applied to wild-type mouse ovaries, and expression levels were compared across 15 serotypes (2.5 × 1011 viral genomes/ml; N = 4-12; 4-day infection, 20-day culture) to identify optimal AAV serotypes for ovarian gene delivery. The effects of AAV-Kitl infection (six doses; N = 3-5) and recombinant KITL supplementation (four doses; N = 5) on oocyte growth were evaluated in KitlSl-t/KitlSl-t mouse ovaries. On culture day 17 or 18, secondary follicles were isolated and cultured for an additional 16 days to evaluate oocyte competence for maturation, fertilization, and full-term development. Offspring were delivered 52-53 days after treatment initiation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Ovaries from KitlSl-t/KitlSl-t mice were dissociated into single cells and reaggregated in U-bottom wells with media containing AAV8-Kitl, AAV9-Kitl, or recombinant KITL. Reconstituted ovaries were cultured on insert membranes, thereby allowing primordial follicles to develop into secondary follicles. Isolated secondary follicles were further cultured to the antral stage, and cumulus-oocyte complexes were subjected to IVM and IVF. The resulting embryos were transferred to foster mothers. Finally, the offspring were subjected to PCR screening for AAV sequences and fertility tests. MAIN RESULTS AND THE ROLE OF CHANCE: AAV8, AAV9, AAVrh.10, and AAVrh.32.33 induced significantly higher levels of mCherry expression in wild-type mouse ovaries than 10 of the 15 AAV evaluated serotypes in vitro (P < 0.05). AAV8-Kitl promoted primordial follicle activation in a dose-dependent manner in KitlSl-t/KitlSl-t mouse ovaries, with the highest number of secondary follicles (80 per reconstituted ovary) obtained at 1.0 × 1011 vg/ml (P < 0.05). In contrast, AAV9-Kitl required 2.5- to 10-fold higher titers to achieve comparable levels of secondary follicle formation. Contrastingly, no secondary follicles were formed in KitlSl-t/KitlSl-t mouse ovaries following mock treatment. Furthermore, supplementation with 200 ng/ml recombinant KITL supported secondary follicle formation at levels comparable to those in the wild-type mouse ovaries. More than 10% of fertilized oocytes developed to full term, regardless of the treatment method. AAV DNA was not detected in the genomes of the 47 offspring, and all tested female mice exhibited normal fertility. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: To date, complete in vitro oogenesis has only been achieved in mice; its applicability to other species, including humans, remains unverified. WIDER IMPLICATIONS OF THE FINDINGS: This study establishes a novel and controllable in vitro platform to compensate for gene function through transient gene expression or factor supplementation, without permanent genomic modification. This approach provides a powerful framework for the dissection of gene functions during oogenesis, modeling of reproductive disorders, and development of fertility restoration strategies in both clinical and conservation contexts. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by KAKENHI (grant numbers 18H05547, 23K27088, and 25H01353). The authors declare no competing interests.
No anxiety or pain reduction by Virtual Reality during oocyte retrieval in IVF/ICSI treatment: results of a randomized controlled trial.
van Haaps AP, Schreurs AMF, Rosielle K … +3 more , Mijatovic V, Kallewaard JW, Dreyer K
Hum Reprod · 2026 Jan · PMID 41057042 · Full text
STUDY QUESTION: What is the effect of Virtual Reality (VR) on anxiety and pain during oocyte retrieval in IVF/ICSI treatment? SUMMARY ANSWER: There is no significant effect of VR on anxiety and pain during oocyte retriev...
STUDY QUESTION: What is the effect of Virtual Reality (VR) on anxiety and pain during oocyte retrieval in IVF/ICSI treatment? SUMMARY ANSWER: There is no significant effect of VR on anxiety and pain during oocyte retrieval in IVF/ICSI treatment. WHAT IS KNOWN ALREADY: Patients undergoing oocyte retrieval in IVF/ICSI treatment often experience anxiety and pain, despite conscious sedation. VR might offer a solution since it has been successful in reducing procedural anxiety and pain during medical procedures, with the potential to replace standard analgesic care. STUDY DESIGN, SIZE, DURATION: A single-centre, open-label, randomized controlled trial was conducted between February 2023 and August 2024. Due to the nature of the intervention, the study was not blinded. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients undergoing oocyte retrieval as part of IVF/ICSI treatment were screened. After providing informed consent, participants were randomized between oocyte retrieval with VR added to conscious sedation and oocyte retrieval with conscious sedation only. When assigned to the intervention group, patients received the VR intervention through a head-mounted device, showing nature films and relaxation exercises. This was added to standard care which includes analgesia and sedatives. Sounds were delivered through the head-mounted device or headphones. The primary outcome was pre- and post-procedural anxiety, measured using the STAI questionnaire. Secondary outcomes included procedural pain (NRS, scale 0-10), satisfaction scores (NRS, scale 0-10), VR preferences, and side effects. MAIN RESULTS AND THE ROLE OF CHANCE: There were 113 participants included: 57 in the intervention group receiving VR and 56 in the control group not receiving VR. We observed no differences between the intervention and control groups in pre-procedural anxiety (mean difference (MD) 0.14 (95% CI -1.78, 2.05), P = 0.885), post-procedural anxiety (MD 0.45 (95% CI -1.21, 2.11), P = 0.589), overall pain (MD -0.12 (95% CI -0.97, 0.73), P = 0.779), and peak pain (MD 0.59 (-0.51, 1.68), P = 0.287). LIMITATIONS, REASONS FOR CAUTION: VR might only be effective for a certain group of patients undergoing retrieval, or might be more effective in reducing pre-procedural anxiety, which in turn might lead to a reduction in procedural pain. Furthermore, it might reduce pain up to a certain threshold, or be effective when the duration of the procedure is short. WIDER IMPLICATIONS OF THE FINDINGS: Since VR does not affect anxiety and pain for the general patient population undergoing oocyte retrieval, we do not advise incorporating VR to standard IVF/ICSI anxiety and pain management. For future studies, it is important to investigate which subgroup could benefit from VR and how it could be implemented to study interventions from a non-pharmacological approach. Patient preferences regarding anxiety and pain management during IVF/ICSI treatment should be considered. STUDY FUNDING/COMPETING INTEREST(S): External funding from ZonMw (Grant number 838002978), the Implementation and Scale-up Coaching, and the Eggcelent Change grant from Theramex have been received for this study to cover the costs of the VR devices. A.P.v.H. and K.R. report to have received a travel grant from Merck to visit ESHRE 2022. A.M.F.S. reports to have been an invited speaker at ESHRE where travel and hotel costs are covered. V.M. reports to have received institutional research grants from Guerbet, Merck, and Ferring. He has received travel and speaker's fees from Guerbet. J.W.K. reports to be on the Advisory board of Boston Scientific, Saluda, Nevro, Abbott, and Medtronic, and received consulting fees from these organizations. He is a board member of the BNS. KD reports to have received an institutional research grant from Guerbet, a speaker's fee from Guerbet, and financial support to attend meetings by Merck and Guerbet. TRIAL REGISTRATION NUMBER: NCT05555498. TRIAL REGISTRATION DATE: 26 September 2022. DATE OF FIRST PATIENT’S ENROLMENT: 7 February 2023.
Cumulative live birth rates in women with endometriosis undergoing ART treatment.
Paul RC, Deans R, Henry A … +5 more , Ng C, Rowlands I, Mishra GD, Abbott J, Chambers GM
Hum Reprod · 2025 Dec · PMID 41052783 · Full text
STUDY QUESTION: How do cumulative live birth rates (CLBRs) in women with endometriosis compare to those with other infertility diagnoses undergoing ART? SUMMARY ANSWER: Women with endometriosis as the sole cause of infer...
STUDY QUESTION: How do cumulative live birth rates (CLBRs) in women with endometriosis compare to those with other infertility diagnoses undergoing ART? SUMMARY ANSWER: Women with endometriosis as the sole cause of infertility achieved higher CLBRs compared to those with additional infertility diagnoses (endometriosis-plus) or other non-endometriosis causes of infertility. WHAT IS KNOWN ALREADY: Endometriosis affects approximately 10% of women of reproductive age and is a major cause of infertility, with many women resorting to ART treatments in the hope of achieving a pregnancy. However, the comparative success rates of ART for these women, compared to those with other causes of infertility is not well understood. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study included 79 318 women who initiated autologous ART between 2014 and 2019 in Australia and New Zealand, with follow-up through 2021 or the first live birth. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were categorized into three groups based on infertility diagnosis: endometriosis-only (n = 4311), endometriosis-plus (n = 6312; endometriosis with other infertility factors) and other-infertility (n = 68 695; no endometriosis). Conservative and optimal CLBRs were calculated based on assumptions made about the chance of live birth for women who discontinued treatment. MAIN RESULTS AND THE ROLE OF CHANCE: Endometriosis was reported as the sole cause of infertility in 5% of women (endometriosis-only), while 8% had endometriosis with other diagnoses (endometriosis-plus). The remaining women had either other causes of infertility (63%) or unexplained infertility (24%). Depending on assumptions made regarding patients who discontinued treatment, the CLBR by the sixth complete cycle for women diagnosed with endometriosis-only ranged from 64% to 83%; for women with an endometriosis-plus diagnoses, the CLBR ranged from 54.3% to 68.7%; and for women without endometriosis, the CLBR ranged from 57.3% to 76.5%. Compared to women without endometriosis, the live birth rate was 6% higher in endometriosis-only group (RR: 1.06; 95% CI: 1.04-1.08) and 5% lower in endometriosis-plus group (RR: 0.95; 95% CI: 0.93-0.97). Compared to the endometriosis-only group, pregnancy loss was 46% higher (RR: 1.46; 95% CI: 1.35-1.59) in endometriosis-plus group. LIMITATIONS, REASONS FOR CAUTION: The study did not assess endometriosis severity or phenotype, which may influence ART outcomes. WIDER IMPLICATIONS OF THE FINDINGS: These findings provide critical data for counselling women with endometriosis regarding ART success. The higher CLBR in the endometriosis-only group suggests that isolated endometriosis does not negatively impact ART outcomes and highlights the need for tailored management in women with additional infertility factors. STUDY FUNDING/COMPETING INTEREST(S): This study is funded through the Medical Research Future Fund (MRFF) Research Data Infrastructure grant (MRFRFD000065). The sponsors had no role in the design and conduct of the study; data collection, management, analysis and interpretation; manuscript preparation, review, or approval; or the decision to submit for publication. FSANZ contracts National Perinatal Epidemiology and Statistics Unit (NPESU) of the University of New South Wales (UNSW) to prepare annual reports and benchmarking reports from the Australian and New Zealand Assisted Reproductive Technology Database (ANZARD): one of those datasets is used in this study. R.C.P. is a Research Fellow of the NPESU, UNSW. G.M.C. is the Director of the NPESU, UNSW. J.A. reports support from the Medical Research Future Fund and the Australian Government Department of Health and Aged Care, consulting fees from Hologic and Gedeon Richter, honoraria from Hologic, and advisory board participation with Gedeon Richter. G.D.M. reports funding from the NHMRC and the Australian Government Department of Health and Aged Care and is lead editor of a book published by Oxford University Press. C.N. reports institutional funding, an unpaid leadership role with ACTA and is a former employee of CSL Vifor. R.D., A.H., and I.R. declare no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.
Identifying candidate genes for spermatogenic failure and predicting ICSI outcomes using single-cell RNA sequencing and protein-protein interaction networks.
Liu L, Huang S, Jiang F … +4 more , Liang G, Zhu X, Zhu H, Tian W
Hum Reprod · 2025 Nov · PMID 41033661 · Publisher ↗
STUDY QUESTION: How can integrating updated single-cell transcriptomics and protein-protein interactions (PPIs) with machine learning algorithms improve gene prioritization for spermatogenic failure and predict ICSI outc...
STUDY QUESTION: How can integrating updated single-cell transcriptomics and protein-protein interactions (PPIs) with machine learning algorithms improve gene prioritization for spermatogenic failure and predict ICSI outcomes? SUMMARY ANSWER: A machine learning framework integrating single-cell RNA sequencing (scRNA-seq) and PPI networks efficiently identified 320 candidate genes for spermatogenic failure and achieved high precision in predicting ICSI outcomes (precision-recall (PRC)-AUC=0.96, 95% CI: 0.89-1.00; receiver operating characteristic (ROC)-AUC = 0.82, 95% CI: 0.63-0.97). WHAT IS KNOWN ALREADY: Over 100 genes are implicated in spermatogenic failure, yet patients with distinct genetic backgrounds exhibit highly variable ICSI outcomes. While machine learning-based gene prioritization offers potential for novel gene discovery, the existing methods rely on bulk RNA sequencing or lack multi-omics integration, limiting their ability to leverage single-cell resolution or predict clinical outcomes. STUDY DESIGN, SIZE, DURATION: This study combined scRNA-seq data (capturing cell type- and developmental stage-specific expression) from healthy human tissues with PPI networks to train predictive models. Validation included 5-fold cross-validation, functional enrichment analyses, and clinical data from whole-exome sequencing (WES) and ICSI outcomes in 34 patients with spermatogenic failure subtypes (azoospermia, asthenozoospermia, teratozoospermia). PARTICIPANTS/MATERIALS, SETTING, METHODS: Public datasets (Human Protein Atlas, STRING, Gene Expression Omnibus) provided scRNA-seq and PPI data. Node2Vec-derived PPI network embeddings and cell type- and developmental stage-specific expression features were used to train random forest classifiers. Gene Ontology, Mammalian Phenotype Ontology enrichment analyses, and WES of patient blood samples validated candidate genes and ICSI outcomes. MAIN RESULTS AND THE ROLE OF CHANCE: Our models demonstrated robust performance in spermatogenic failure gene prediction (PRC-AUC = 0.88, 95% CI: 0.83-0.93; ROC-AUC = 0.98, 95% CI: 0.96-0.99), subtype classification (e.g. teratozoospermia, PRC-AUC = 0.96, 95% CI: 0.91-0.99; ROC-AUC = 0.94, 95% CI: 0.87-0.98), and ICSI outcome prediction (PRC-AUC = 0.96, 95% CI: 0.89-1.00; ROC-AUC = 0.82, 95% CI: 0.63-0.97). WES of patient samples revealed an increased detection rate of likely causative variants among a subset of model-predicted genes, rising from 11.8% to 29.4%, with clinical outcomes aligning with model predictions. LIMITATIONS, REASONS FOR CAUTION: Model limitations include training on literature-curated or database-annotated gene labels, which may introduce misclassification or annotation bias. Additionally, the absence of experimental validation and the limited size and diversity of external cohorts necessitate further verification. WIDER IMPLICATIONS OF THE FINDINGS: This integrative machine learning framework provides a powerful tool for uncovering genetic contributors to male infertility and predicting treatment outcomes, paving the way for improved diagnostic strategies and more informed clinical decision-making in reproductive medicine. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Natural Science Foundation of China (32370719, 32170667), the Shanghai Municipal Science and Technology Major Project (2017SHZDZX01), and the National Key Research and Development Program of China (2021YFC2301503). The authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.
Livebirth among 5940 Danish women diagnosed with breast cancer at age 18-40 years between 1968 and 2016: a register-based cohort study.
Yde AM, Colmorn LB, Pinborg A … +5 more , Schmidt L, Kroman N, Kyhl FN, Vassard D, Macklon KT
Hum Reprod · 2025 Dec · PMID 41032889 · Publisher ↗
STUDY QUESTION: Does livebirth probability differ between women diagnosed with breast cancer and unaffected women and is it impacted by age at diagnosis, time trends, parity, partnership status, and the presence of lymph...
STUDY QUESTION: Does livebirth probability differ between women diagnosed with breast cancer and unaffected women and is it impacted by age at diagnosis, time trends, parity, partnership status, and the presence of lymph node metastases and distant metastases? SUMMARY ANSWER: Livebirth probability was significantly reduced in 5940 women diagnosed with breast cancer aged 18-40 years during 1968-2016 compared to 1 126 478 age-matched unaffected women, particularly among women with higher diagnosis age, parity ≥ 1, marriage, and the presence of nodal involvement and distant metastases. WHAT IS KNOWN ALREADY: The survival rate for women diagnosed with breast cancer has increased over the recent decades, and in Denmark, the 5-year survival rate for women diagnosed <50 years of age was 92.2% in 2022. Chemotherapy can damage the ovarian reserve, resulting in premature ovarian insufficiency and infertility. The age of first-time mothers is increasing, and many women have not yet completed family building at the time of diagnosis. Consequently, greater focus is now placed on quality-of-life following breast cancer, including the possibility of survivors to have children. Studies have shown a decreased fertility rate in women diagnosed with cancer during their reproductive lifespan, however, studies specifically focusing on the probability of livebirth in women previously diagnosed with breast cancer are scarce. STUDY DESIGN, SIZE, DURATION: This is a national, register-based cohort study including women diagnosed with breast cancer from the Danish Cancer Register between 1968 and 2016, aged 18-40 years at time of diagnosis (n = 5940). Each woman was randomly matched with ∼190 unaffected women from the background population according to the age at diagnosis (n = 1 126 478). The women were followed in medical and sociodemographic national population registers until childbirth, death, immigration, or end of study (31 December 2018). PARTICIPANTS/MATERIALS, SETTING, METHODS: In all analyses, we compared the probability of livebirth between women diagnosed with breast cancer and the age-matched comparison group. Analyses were stratified by parity- and partnership status at diagnosis, age-group at diagnosis, and year of diagnosis. Stratified analyses on the probability of livebirth were conducted for women with lymph-node metastases and distant metastases at the time of diagnosis. Analyses were adjusted for age, year of diagnosis, parity, educational level, and migration status. MAIN RESULTS AND THE ROLE OF CHANCE: The study population consisted of 5940 women aged 18-40 years at diagnosis of breast cancer between 1968 and 2016 and 1 126 478 women in the age-matched comparison group. Breast cancer survivors had a significantly lower probability of livebirth than the age-matched comparison group (aHR 0.38 [95% CI 0.35-0.41]); negatively impacted by increasing age at diagnosis (35-40 years: aHR 0.34 [95% CI 0.28-0.40], 18-24 years: 0.66 [95% CI 0.46-0.95]), parity ≥1 (parous: aHR 0.31 [95% CI 0.27-0.35], nulliparous: 0.51 [95% CI 0.45-0.59]), and marriage (married: aHR 0.31 [95% CI 0.27-0.36], single 0.53 [95% CI 0.45-0.63]). Being diagnosed in recent decades increased the probability of livebirth in nulliparous women; however, the same association was not found for parous women. Among women with nodal involvement (48%) and distant metastases (3%), the probability of livebirth compared to unaffected women was aHR 0.30 [95% CI 0.26-0.35] and 0.18 [95% CI 0.08-0.42], respectively. LIMITATIONS, REASONS FOR CAUTION: We did not have information on whether the women desired children or whether they underwent fertility preservation (FP) prior to receiving gonadotoxic treatment. For women diagnosed in the most recent decades, the follow-up time was limited. Information on tamoxifen treatment for estrogen receptor-positive tumors could have been relevant, as it likely delays pregnancy and consequently reduces conception probability. WIDER IMPLICATIONS OF THE FINDINGS: Our results highlight the continued importance of onco-fertility counseling and FP in young women diagnosed with breast cancer, particularly among women diagnosed toward the end of their reproductive lifespan and those with the presence of lymph node metastases and distant metastases. STUDY FUNDING/COMPETING INTEREST(S): The study is funded by the Independent Research Fund Denmark (Grant ID 10.46540/4308-00130B). Anja Pinborg has received grants (payment to institution) and consultancy fees from Gedeon Richter, Ferring Pharmaceuticals, Merck A/S, and Cryos; honoraria from Gedeon Richter, Ferring Pharmaceuticals, Merck A/S, and Organon; and support for attending meetings and/or travel (payment to institution) from Gideon Richter. These companies had no role in the study. The remaining authors have no conflicts or interests to declare. TRIAL REGISTRATION NUMBER: N/A.
Managing obesity-related male infertility: insights from weight loss intervention.
Pereira TA, Thaker N, Rubez AC … +3 more , Lima VFN, Bernie HL, Esteves SC
Hum Reprod · 2025 Nov · PMID 41024420 · Publisher ↗
Obesity is a global health concern with major implications for male reproductive function. It disrupts endocrine and metabolic homeostasis, impairs semen quality, and is associated with reduced pregnancy and live birth r...
Obesity is a global health concern with major implications for male reproductive function. It disrupts endocrine and metabolic homeostasis, impairs semen quality, and is associated with reduced pregnancy and live birth rates. Hormonal imbalances, inflammation, and lipid stress are key contributors to these impairments. This mini-review summarizes current evidence on the impact of therapeutic interventions, including lifestyle modification, bariatric surgery, and pharmacological approaches such as glucagon-like peptide-1 (GLP-1) receptor agonists, on male fertility outcomes. Lifestyle interventions, particularly moderate-intensity exercise and dietary improvements, are first-line therapies and should be routinely encouraged. Caloric restriction and Mediterranean-style diets rich in antioxidants have been associated with improved semen quality and hormonal balance. Bariatric surgery raises testosterone levels and may improve sperm quality and assisted reproduction outcomes in some men, but declines in sperm concentration and cases of postoperative azoospermia have also been reported. These findings underscore the importance of preoperative fertility counselling and consideration of sperm cryopreservation. GLP-1 receptor agonists promote weight loss and may improve sperm motility and hormonal markers; however, isolated cases of reversible impairment in sperm quality have been reported. Despite growing clinical use of these interventions, it remains unclear whether the observed benefits stem from weight loss itself or the specific treatment modalities. Longitudinal studies are needed to determine whether fertility improvements translate into higher conception rates. The reproductive safety of GLP-1 agonists in the preconception period also warrants further investigation. We recommend prioritizing pragmatic clinical trials with functional fertility endpoints, as well as mechanistic studies in well-characterized male obesity phenotypes and evaluation of offspring health. Ultimately, a shift is necessary from a narrow focus on weight loss to a broader emphasis on enhancing metabolic health. Personalized approaches tailored towards hormonal profiles, comorbidities, and fertility goals, supported by behavioural counselling and multidisciplinary care, are essential for advancing the treatment of obesity-related male infertility.
Exploring geographical differences in semen quality of young men using spatial dependence analysis.
Rahban R, Santa-Ramírez HA, Senn A … +4 more , Stettler E, Guessous I, Joost S, Nef S
Hum Reprod · 2025 Dec · PMID 41022404 · Full text
STUDY QUESTION: Are semen quality parameters randomly distributed across space, or do they exhibit spatial patterns that may reflect underlying environmental influences? SUMMARY ANSWER: Semen quality parameters are not r...
STUDY QUESTION: Are semen quality parameters randomly distributed across space, or do they exhibit spatial patterns that may reflect underlying environmental influences? SUMMARY ANSWER: Semen quality parameters are not randomly distributed in Switzerland but exhibit distinct spatial clustering, with identifiable hotspots indicating areas of comparatively higher values and coldspots indicating areas of comparatively lower values. WHAT IS KNOWN ALREADY: Regional differences in semen quality across Europe suggest environmental influences, but most studies are limited to urban areas with small samples and low geographic precision, leaving gaps in understanding precise geographical patterns at a national level. STUDY DESIGN, SIZE, DURATION: This is a cross-sectional study, including 2677 men aged 18-22 from the general Swiss population who were recruited between 2005 and 2018 during military conscription. PARTICIPANTS/MATERIALS, SETTING, METHODS: Each participant provided a semen sample and completed a questionnaire on health and lifestyle, including demographic details on their residence. Georeferenced data were used to compute the level of spatial dependence using the local Getis-Ord Gi* statistic with a 25 km spatial lag to identify clusters of high versus low semen parameter values across Switzerland. The parameters assessed included semen volume, sperm concentration, total sperm count, and sperm morphology. Participants belonging to the same Getis-Ord Gi* class for each semen parameter formed a persistent cluster. To assess differences in environmental exposure between high- and low-persistent clusters, land use data within a 500 m radius of each participant's place of residence were extracted from national registries for the periods of 1992-1997 and 2004-2009. MAIN RESULTS AND THE ROLE OF CHANCE: Semen quality parameters are not randomly distributed across Switzerland, with distinct local clusters of high values (hotspots) and low values (coldspots) identified. A persistent low-value cluster was observed in central western Switzerland. Analysis of national land use data revealed significant differences in agricultural land types between clusters: fodder and field crops accounted for 52.0% of the land use in the coldspot, compared to 28.3% in the hotspot and 30.1% in the non-significant cluster. Additionally, the mean proportion of built areas (housing and infrastructure) near participants' residences was significantly lower in the coldspot (32.6%) compared to the hotspots (53.3%). LIMITATIONS, REASONS FOR CAUTION: Although the study population is nationwide and broadly representative, the sample size used for individual-level spatial analyses limits statistical power. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge, this is the first study to apply spatial dependence methods to investigate semen quality parameters using individual-level data at a national scale. This approach can be extended to larger datasets to further explore the relationship between environmental factors and reproductive health. The insights gained may inform public health policy by supporting more targeted environmental monitoring and preventive strategies. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by funding from the Swiss Centre for Applied Human Toxicology-SCAHT to R.R. and to S.N. and from the Département de l'Instruction Publique (DIP) of the state of Geneva to S.N. The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.
Rethinking decision-making support in elective egg freezing: complementing counselling with decision aids.
Ribeiro S, Anastasi A, Kalaitzopoulos DR … +9 more , Fraire-Zamora JJ, Ammar OF, Liperis G, Ali ZE, Massarotti C, Ehrbar V, Parmegiani L, Salmeri N, Horta F
Hum Reprod · 2025 Nov · PMID 41005756 · Publisher ↗
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Increased AIF-1-mediated p38 MAPK phosphorylation in the mid-secretory endometrium impairs endometrial receptivity in women with recurrent implantation failure.
Zhou M, Duan J, Zhou X … +4 more , Zhu H, Zhang D, Xu B, Zhang A
Hum Reprod · 2025 Nov · PMID 41003697 · Publisher ↗
STUDY QUESTION: How does allograft inflammatory factor-1 (AIF-1) affect endometrial receptivity in women with recurrent implantation failure (RIF)? SUMMARY ANSWER: Significant upregulation of AIF-1 in the endometrial str...
STUDY QUESTION: How does allograft inflammatory factor-1 (AIF-1) affect endometrial receptivity in women with recurrent implantation failure (RIF)? SUMMARY ANSWER: Significant upregulation of AIF-1 in the endometrial stromal cells of women with RIF inhibits cell proliferation and decidualization via the p38 mitogen-activated protein kinase (MAPK) phosphorylation, thereby reducing endometrial receptivity. WHAT IS KNOWN ALREADY: RIF is a challenging clinical issue, with AIF-1, a cytokine-inducible protein linked to allograft rejection, potentially contributing to its pathogenesis. However, the precise mechanisms remain elusive. STUDY DESIGN, SIZE, DURATION: This study analyzed endometrial tissue samples from women diagnosed with RIF and a control group of fertile women from December 2018 to December 2023. Single-cell RNA sequencing (scRNA-seq) data from public datasets (GSE111976, GSE250130, GSE183837) were integrated to characterize AIF-1 expression patterns in endometrium. Isolated human endometrial stromal cells (HESCs) from the human endometrium and an endometrial stromal cell line were used for in vitro analysis, and an in vivo mouse model with AIF-1 overexpression in the uterus was employed to evaluate implantation outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS: Mid-secretory endometrial samples were collected from the 18 patients with RIF and 18 control patients; endometrial samples from another five different phases during the menstrual cycle were collected from 30 additional control patients. Quantitative PCR, western blot, immunohistochemical and immunofluorescence analyses, and RNA sequencing were conducted to determine the expression levels of AIF-1 and various markers. Cell proliferation, decidualization, and trophoblast outgrowth were measured. AIF-1 overexpression and gene silencing were achieved by plasmid injection and short hairpin RNA, respectively. For in vivo experiments, CD-1 mice with intrauterine injection of an AIF-1 plasmid were used. Phosphorylation of p38 was inhibited by PD169316. MAIN RESULTS AND THE ROLE OF CHANCE: Based on scRNA-seq analysis and our own endometrial tissue detection, AIF-1 was significantly increased in HESCs in patients with RIF compared with their control group during the mid-secretory phase. AIF-1 overexpression resulted in reduced cell proliferation, inadequate cell decidualization, and diminished embryo outgrowth in in vitro experiments, and it reduced the number of embryo implantation sites in CD-1 mice; these effects were mitigated by PD169316, an inhibitor of p38 MAPK. LIMITATIONS, REASONS FOR CAUTION: Although the study establishes a link between increased AIF-1 expression in endometrial stromal cells and reduced endometrial receptivity, the role of AIF-1 in endometrial macrophages during embryo implantation remains unclear. WIDER IMPLICATIONS OF THE FINDINGS: The findings suggest that targeting the AIF-1 and p38 MAPK pathway could serve as a promising therapeutic strategy to improve endometrial receptivity in RIF patients. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Key R&D Program of China (No. 2022YFC2703800) and the National Natural Science Foundation of China [Nos. 82271703; 82371704; 82071596; 82071712; 82101800; 81701513]. The authors declare that they have no conflict of interests with the contents of this manuscript. TRIAL REGISTRATION NUMBER: N/A.
Optimizing the number of cryopreserved donor oocytes to fertilize with a focus on minimizing excess embryos.
Tsai S, Ma X, Spring S … +1 more , Spandorfer S
Hum Reprod · 2025 Dec · PMID 40998380 · Publisher ↗
STUDY QUESTION: What is the optimal number of frozen donor oocytes to thaw and fertilize to achieve one live birth while minimizing supernumerary embryos? SUMMARY ANSWER: For patients who want only one child, fertilizing...
STUDY QUESTION: What is the optimal number of frozen donor oocytes to thaw and fertilize to achieve one live birth while minimizing supernumerary embryos? SUMMARY ANSWER: For patients who want only one child, fertilizing 6-7 frozen donor oocytes would result in approximately one supernumerary embryo while maintaining the live birth rate. WHAT IS ALREADY KNOWN: Studies on frozen donor oocyte outcomes focus on live birth rate, but little is known about the resulting number of supernumerary embryos. STUDY DESIGN, SIZE, DURATION: This is a retrospective cohort study using data from the 2016-2020 Society for Assisted Reproductive Technology Clinic Outcomes Reporting System. A total of 11,554 frozen donor oocyte recipients undergoing their first cycle with frozen donor oocytes were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: The 11,554 frozen donor oocyte recipients were stratified into quartiles based on the number of frozen donor oocytes thawed (<6, 6, 7, and >7). The primary outcome was the number of supernumerary blastocysts, defined as the number of blastocysts remaining after the first live birth, or at the final transfer cycle if the patient did not have a live birth. MAIN RESULTS AND THE ROLE OF CHANCE: On average, patients thawed 6.74 ± 1.96 oocytes, resulting in 4.77 ± 2.07 2PNs (2 pronuclei), 2.44 ± 1.59 usable embryos, and 1.02 ± 1.47 supernumerary blastocysts. The average number of cryopreserved supernumerary blastocysts increased as the number of frozen donor oocytes thawed increased (0.50 vs. 0.90 vs. 0.99 vs. 1.49 blastocysts in each quartile, respectively, P<0.01). However, live birth rates were only significantly lower when less than six frozen donor oocytes were thawed and fertilized (37.6% vs. 48.5% vs. 50.3% vs. 51.3%, P<0.01). LIMITATIONS, REASONS FOR CAUTION: There are limitations to utilizing national databases, including missing data and the inability to extrapolate additional nuanced information not originally collected. WIDER IMPLICATIONS OF THE FINDINGS: The number of supernumerary blastocysts increases even with small increases in the number of frozen donor oocytes exposed to sperm. While thawing 6-7 frozen donor oocytes aligns with most practices, almost a quarter of patients thawed more than 7 frozen donor oocytes, which led to a significant increase in the number of supernumerary embryos to 1.49 without a significant increase in live birth rate. STUDY FUNDING/COMPETING INTEREST(S): Xiaoyue Ma, MSc is partially supported by the following grant: Clinical and Translational Science Center at Weill Cornell Medical College (1-UL1-TR002384-01). Steven Spandorfer is a former President of the Society for Assisted Reproductive Technology. TRIAL REGISTRATION NUMBER: Not applicable.
SWS1-complex in premature ovarian insufficiency: SWSAP1 as a new POI gene.
Lokchine A, Zhang F, Cluzeau L … +22 more , Le Page L, Belaud-Rotureau MA, Planes M, Mary L, Esvant A, Launay E, Fergus-Mackie J, Nouyou B, Metayer-Amelot L, Akloul L, Marijon P, Carré W, Cuny A, Dybal E, Duros S, Domin-Bernhard M, Christin-Maitre S, Odent S, Vialard F, Tucker EJ, Jasin M, Jaillard S
Hum Reprod · 2025 Nov · PMID 40991243 · Publisher ↗
STUDY QUESTION: What other zinc finger SWIM domain-containing protein 7 (SWS1/ZSWIM7) partners are involved in premature ovarian insufficiency (POI)? SUMMARY ANSWER: This study identifies novel pathogenic variants in zin...
STUDY QUESTION: What other zinc finger SWIM domain-containing protein 7 (SWS1/ZSWIM7) partners are involved in premature ovarian insufficiency (POI)? SUMMARY ANSWER: This study identifies novel pathogenic variants in zinc finger SWIM domain-containing protein 7 (SWS1/ZSWIM7) and its partner, SWSAP1, which impair interhomolog homologous recombination (IH-HR) and lead to isolated POI. WHAT IS KNOWN ALREADY: Knockout mice models of the SWS1-complex (also known as the SWS1-SWSAP1-SPIDR complex or Shu complex) are infertile due to meiotic arrest. Variants of both SWS1/ZSWIM7 and SPIDR are described in POI, but so far, no SWSAP1 variants have been described in female infertility. STUDY DESIGN, SIZE, DURATION: Screening for SWS1-complex variants was performed using exome or genome sequencing data from women with POI as ongoing patient care. In silico modelling, IH-HR assays, and western-blot analysis were performed to test the impact of novel variants identified in genes of the SWS1-complex (SWSAP1 and SWS1/ZSWIM7) on homologous recombination, protein expression, and protein interactions. PARTICIPANTS/MATERIALS, SETTING, METHODS: Five unrelated patients from France were enrolled based on their exome or genome sequencing result as part of ongoing patient care. All the patients were diagnosed with POI and met the European Society of Human Reproduction and Embryology (ESHRE) diagnostic criteria for POI. Functional validation was performed using mouse embryonic stem cells to study the impact of two novel variants found in two patients. MAIN RESULTS AND THE ROLE OF CHANCE: We report five different pathogenic or likely pathogenic variants in five patients. We report the previously described c.231_232del and c.176C>T variants in SWS1/ZSWIM7, as well as two novel variants, c.22del and c.151C>T. Additionally, we report a homozygous frameshift deletion in SWSAP1 (c.353del). All the patients display a similar phenotype of severe isolated POI, associated with primary or early secondary amenorrhea and signs of puberty delay. In silico modelling and IH-HR assays of both SWS1/ZSWIM7 c.176C>T and SWSAP1 c.353del indicated a partial decrease or absence of IH-HR activity in Sws1-/- or Swsap1-/- cells, respectively, and destabilization of the SWSAP1 truncation mutant. LIMITATIONS, REASONS FOR CAUTION: Identification of other patients carrying SWSAP1 variants is needed to evaluate in-depth phenotype to genotype correlations. Future studies should evaluate the role of other genes in the SWS1-complex and explore the potential for therapeutic interventions targeting homologous recombination. WIDER IMPLICATIONS OF THE FINDINGS: These findings provide direct clinical and functional evidence that all three members of the SWS1-complex are implicated in female fertility and recapitulate the observed mouse phenotypes. IH-HR assays provide a relevant functional approach to validate novel variants in homologous recombination genes for POI patients, given the importance of IH-HR for meiotic progression. STUDY FUNDING/COMPETING INTEREST(S): The French Genomic Medicine Initiative PFMG2025 is supported by grants from the French government, notably by the French National Research Agency under the Programme d'Investissments d'Avenir for the CAD (ANR-21-ESRE0001) and the CRefIX (ANR-10-INBS-09-01). M.J. was supported by R01 HD112624 and R35CA253174 grants. E.J.T. was supported by a Norman Beischer Fellowship and a Centre for Research Excellence for Women's Health in Reproductive Life (CRE-WHiRL) fellowship from the National Health and Medical Research Council (NHMRC). J.F.M. was supported by a Research Training Program scholarship from the Australian Government. The authors declare no competing interests. TRIAL REGISTRATION NUMBER: This manuscript included genomic analysis performed in clinical practice in patients with RD/CGP and cancers in France. Consequently, a clinical trial NCT number was not required as we reported in this manuscript results obtained in clinical practice. In compliance with the French law on bioethics (2004-800, 06/08/2004), patients had signed written informed consent forms for clinical practice and had been informed of the research use of what remained of their samples after establishing the molecular diagnosis.
ART in Europe, 2020: results generated from European registries by ESHRE†.
European IVF Monitoring Consortium (EIM) for the European Society of Human Reproduction and Embryology (ESHRE) , Smeenk J, Wyns C … +9 more , De Geyter C, Kupka MS, Bergh C, Cuevas Saiz I, De Neubourg D, Rezabek K, Tandler-Schneider A, Rugescu I, Goossens V
Hum Reprod · 2025 Nov · PMID 40985526 · Publisher ↗
STUDY QUESTION: What are the data and trends of ART and IUI cycle numbers and their outcomes, and of fertility preservation (FP) interventions, reported in 2020 as compared to previous years? SUMMARY ANSWER: This 24th ES...
STUDY QUESTION: What are the data and trends of ART and IUI cycle numbers and their outcomes, and of fertility preservation (FP) interventions, reported in 2020 as compared to previous years? SUMMARY ANSWER: This 24th ESHRE report highlights the number of ART treatment cycles and children born over the years, showing a decline in the total number of treatment cycles, when comparing 2020 with 2019, alongside a decline in twin deliveries owing to a decrease in transfers of multiple embryos; however, fresh IVF or ICSI cycles and frozen embryo transfers (FET) showed similar pregnancy rates, and the reported IUI cycle numbers decreased while maintaining stable outcomes. WHAT IS KNOWN ALREADY: ART aggregated data generated by national registries, clinics, or professional societies have been gathered and analyzed by the European IVF Monitoring (EIM) consortium since 1997 and reported in a total of 23 manuscripts published in Human Reproduction and Human Reproduction Open. STUDY DESIGN, SIZE, DURATION: Data on medically assisted reproduction (MAR) from European countries are collected by EIM for ESHRE each year. The data on treatment cycles performed between January 1 and December 31, 2020, were provided by either national registries or registries based on initiatives of medical associations and scientific organizations or committed persons in the 44 countries that are members of the EIM Consortium. PARTICIPANTS/MATERIALS, SETTING, METHODS: Overall, 1440 clinics offering ART services in 41 countries reported 923 318 treatment cycles (-14%; in 2019: 1 077 813), including 135 231 with IVF, 356 408 with ICSI, 305 373 with FET, 57 051 with preimplantation genetic testing (PGT), 64 007 with oocyte donation, 353 with IVM of oocytes, and 4895 cycles using frozen oocytes. A total of 1288 institutions reported data on IUI cycles using either husband/partner's semen (IUI-H; n = 112 663) or donor semen (IUI-D; n = 38 839) in 30 and 21 countries, respectively. Sixteen countries reported 29 566 interventions in pre-and post-pubertal patients for FP, including oocyte, ovarian tissue, semen, and testicular tissue banking. MAIN RESULTS AND THE ROLE OF CHANCE: In 24 countries (21 in 2019) in which all ART clinics reported to the registry, 356 427 treatment cycles were registered for a total population of approximately 268 million inhabitants in these countries, allowing the best estimate of a mean of 1330 cycles performed per million inhabitants (range: 142-3230). Among the reporting countries, for IVF, the clinical pregnancy rates (PR) per aspiration were similar to that in 2019 (22.1% versus 21.8% in 2019). For ICSI, the corresponding PRs showed similar trends (20.0% in 2020 versus 20.2% in 2019). When freeze-all cycles were excluded from the calculations, the clinical PRs per aspiration were 26.4% (28.5% in 2019) and 25.6% (26.2% in 2019) for IVF and ICSI, respectively. After oocyte donation, the PR per embryo transfer was 51.3% (50.5% in 2019) with freshly donated oocytes and 45.7% (44.8% in 2019) with thawed oocytes. After FET, the PR per thawing was 34.9% (versus 35.1% in 2019). In fresh cycles of both IVF and ICSI, the trend towards the transfer of fewer embryos continued with the transfer of 1, 2, 3, and ≥4 embryos in 57.2%, 37.8%, 4.8%, and 0.2%, of all treatments, respectively (corresponding to 55.4%, 39.9%, 2.6%, and 0.2% in 2019). This resulted in a reduced proportion of twin delivery rates (DRs) of 10.9% (11.9% in 2019) and a similar triplet DR of 0.2%. In FET cycles in 2020, the twin and triplet DRs were 7.9% and 0.1%, respectively (versus 8.9% and 0.1% in 2019). While the number of IUI cycles in 2020 decreased from 2019, the DRs remained stable at 8.8% after IUI-H (8.7% in 2019) and at 12.5% after IUI-D (12.1% in 2019). Twin and triplet DRs after IUI-H were 7.9% and 0.4% (in 2019: 8.7% and 0.4%) and 5.7% % and 0.1% after IUI-D (in 2019: 6.2% and 0.2%), respectively. Data on FP were provided by 16 countries (18 in 2019), reporting a total of 29 566 interventions (24 139 in 2019). Cryopreservation of ejaculated sperm (n = 21 864 versus n = 11 592 in 2019) and cryopreservation of oocytes (n = 6077 versus n = 10 784 in 2019) were the most frequently reported forms of FP. LIMITATIONS, REASONS FOR CAUTION: Caution with the interpretation of results should remain as data collection systems and completeness of reporting vary among European countries. Some countries were unable to deliver data about the number of initiated cycles and/or deliveries. WIDER IMPLICATIONS OF THE FINDINGS: The 24th ESHRE data collection on ART and IUI interventions shows a decrease of reported treatment cycles. A decline was observed when comparing 2020 with 2019, regarding the numbers of MAR treatments and births derived from these treatments in Europe. This break in the trend from prior years could be due to the effects of the COVID pandemic and/or due to the fact that some countries were not able to report. Although it is the largest data collection on MAR in Europe, further efforts to optimize both the collection and the reporting of data, from the perspective of improving surveillance and vigilance in the field of reproductive medicine, are awaited. STUDY FUNDING/COMPETING INTEREST(S): The study has received no external funding and all costs are covered by ESHRE. There are no competing interests.
Cumulative live birth rates under three consecutive IVF/ICSI treatment cycles are reduced in women with endometriosis and/or adenomyosis diagnosed by ultrasonography.
Alson S, Stenqvist A, Sladkevicius P
Hum Reprod · 2025 Dec · PMID 40974212 · Full text
STUDY QUESTION: Does endometriosis and/or adenomyosis, diagnosed using the International Deep Endometriosis Analysis (IDEA) group and the Morphological Uterus Sonographic Assessment (MUSA) group revised definitions, impa...
STUDY QUESTION: Does endometriosis and/or adenomyosis, diagnosed using the International Deep Endometriosis Analysis (IDEA) group and the Morphological Uterus Sonographic Assessment (MUSA) group revised definitions, impact cumulative live birth rates (CLBR) after three consecutive IVF or ICSI treatments? SUMMARY ANSWER: Women with endometriosis and/or adenomyosis, as diagnosed using transvaginal ultrasonography, had a 15% reduced chance of having a cumulative live birth after three consecutive IVF/ICSI treatments compared to women without these conditions. WHAT IS KNOWN ALREADY: Women with endometriosis or adenomyosis reportedly have lower live birth rates after their first IVF/ICSI treatment. However, most women undergo multiple cycles, and given their shared pathophysiology, the combined impact of both conditions over consecutive treatments remains unclear. STUDY DESIGN, SIZE, DURATION: This was a prospective cohort study of 1035 women undergoing up to three consecutive IVF/ICSI treatments at a university hospital between January 2019 and April 2024. Swedish regulations entitle women to up to three subsidized treatment cycles, including fresh and/or frozen embryo transfers, until the birth of a living child is achieved. PARTICIPANTS/MATERIALS, SETTING, METHODS: All 1035 included women underwent a transvaginal ultrasound examination prior to starting their first treatment. Using the IDEA and revised MUSA definitions, respectively, in total 293 (28.3%) women had endometriosis and/or direct features of adenomyosis on ultrasonography. All 1035 women underwent the first treatment cycle. In total, 818 (79.0%) women [595 (80.2%) of women without endometriosis and/or adenomyosis and 223 (76.1%) of women with either of the diseases] underwent all treatments they were eligible for. A total of 217 (21.0%) women dropped out after the first or second treatment even if they had not achieved a live birth. In total, 1725 fresh treatment cycles were initiated, leading to 1283 fresh and 622 frozen embryo transfers. Live births were recorded. The adjusted relative risk (aRR) for cumulative live birth after three consecutive IVF/ICSI treatment cycles was calculated on an intention-to-treat (ITT) as well as per-protocol (PP) basis, using a modified Poisson regression analysis, adjusting for age as a potential confounder. MAIN RESULTS AND THE ROLE OF CHANCE: The CLBR over three consecutive IVF/ICSI treatment cycles was 666/818 (81.4%) in the total cohort. In an ITT and PP analyses, respectively, women with endometriosis and/or adenomyosis had a lower CLBR of 156/293 (53.2%) or 156/223 (70.0%) compared to women without, CLBR of 510/742 (68.7%) or 510/595 (85.7%), P < 0.001. The aRR for cumulative live birth for women with endometriosis and/or adenomyosis was aRR (ITT) 0.80 (95% CI, 0.71-0.90), P < 0.001, and aRR (PP) 0.85 (95% CI, 0.77-0.93), P < 0.001 compared to women without the diseases. After stratifying the results per treatment cycle, the LBR after the first treatment for women with endometriosis and/or adenomyosis was 90/293 (30.7%), aRR 0.69 (95% CI 0.57-0.84), P < 0.001, after the second 44/154 (28.6%), aRR 0.72 (95% CI 0.54-0.96), P = 0.023, and after the third treatment 22/84 (26.2%), aRR 0.83 (95% CI 0.54-1.28), P = 0.183. For women without the diseases, the LBR was 335/742 (45.1%) in the first cycle, 132/319 (41.4%) in the second, and 43/133 (32.3%) in the third cycle. The largest differences were seen after fresh compared to frozen embryo transfers. LIMITATIONS, REASONS FOR CAUTION: The ultrasound examinations were performed at a tertiary care hospital by an examiner with expertise in endometriosis and adenomyosis. According to the revised MUSA definitions, direct features of adenomyosis are pathognomonic, whereas indirect features are only indicative of the disease. It is possible that some women with only indirect features, who were considered healthy in this study, in fact had the disease and therefore were wrongly classified. WIDER IMPLICATIONS OF THE FINDINGS: Despite a lower CLBR over three IVF/ICSI cycles, women with endometriosis and/or adenomyosis still have a reasonable chance of achieving a live birth with consecutive treatments. Negative results after the first treatment should not be an argument to withhold further attempts. Future research should explore strategies to enhance treatment success in this population, including the role of long-term suppression protocols, exogenous progesterone dosing, and personalized embryo transfer approaches. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by regional research grants from Region Skåne, Sweden. TRIAL REGISTRATION NUMBER: N/A.
Randomized controlled study on the use of virtual reality for pain relief in oocyte retrieval under transvaginal ultrasound guidance using paracervical block and conscious sedation.
Ng CSM, Tong PYW, Wong E … +4 more , Cheng HHY, Ko JKY, Li RHW, Ng EHY
Hum Reprod · 2025 Dec · PMID 40974211 · Full text
STUDY QUESTION: Does the use of virtual reality (VR) reduce pain levels experienced by women during transvaginal oocyte retrieval using paracervical block and conscious sedation? SUMMARY ANSWER: The use of VR did not red...
STUDY QUESTION: Does the use of virtual reality (VR) reduce pain levels experienced by women during transvaginal oocyte retrieval using paracervical block and conscious sedation? SUMMARY ANSWER: The use of VR did not reduce pain levels during oocyte retrieval using paracervical block and conscious sedation. WHAT IS KNOWN ALREADY: Conscious sedation is commonly used for pain relief during oocyte retrieval, and the concurrent use of more than one method of sedation and analgesia resulted in better pain relief than a single modality. Many studies have shown promising results in reducing anxiety and pain with the use of VR during medical procedures. STUDY DESIGN, SIZE, DURATION: This is a randomized controlled trial of 160 infertile women undergoing transvaginal oocyte retrieval using paracervical block and conscious sedation between December 2022 and October 2023. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was conducted in a university-affiliated assisted reproduction unit. Recruited women were randomly assigned into the VR group (n = 80) and the standard care group (n = 80). Pain levels upon vaginal puncture and oocyte retrieval were recorded using a 100-point visual analogue scale. MAIN RESULTS AND THE ROLE OF CHANCE: Both groups were comparable in terms of demographic parameters, ovarian stimulation responses, and the anxiety trait and state scores. There was no significant difference in maximal pain level at vaginal puncture (50.8 ± 23.6 vs. 54.8 ± 25.4; 95% CI -11.7, 3.7; P = 0.30) and oocyte retrieval (56.4 ± 24.6 vs. 60.3 ± 26.8; 95% CI -12.0, 4.2; P = 0.34) between the VR group and standard care group. The satisfaction score was similar in both groups. LIMITATIONS, REASONS FOR CAUTION: The small sample size of the study was a limitation. Blinding participants and researchers were not feasible due to the nature of the study. The degree of immersion was also affected when viewing the VR headset from a prone perspective, and the experience was also limited by the standardization of VR scenario and audio. The pain score recorded by the visual analogue scale was a subjective measurement. WIDER IMPLICATIONS OF THE FINDINGS: Although the use of VR was otherwise well tolerated without major side effect, its routine use for pain relief during oocyte retrieval cannot be supported. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by an internal grant (Professor P.C. Ho Research and Development Fund in Reproductive Medicine). None of the authors has conflicts of interest to declare. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov with identifier NCT05218382. TRIAL REGISTRATION DATE: 18 December 2021. DATE OF FIRST PATIENT’S ENROLMENT: 1 December 2022.
A prospective randomized controlled trial of antioxidants in human IVF and embryo culture media.
Kelley RL, Lee YSL, Agresta F … +12 more , Pehrsson NG, Stevens JM, Huang A, Sgroi J, Rozen G, Polyakov A, Hale L, Lew R, Stern C, Toledo M, Cattrall F, Gardner DK
Hum Reprod · 2025 Nov · PMID 40973967 · Publisher ↗
STUDY QUESTION: Does the addition of three antioxidants to culture media during gamete collection, insemination, and embryo culture increase the clinical pregnancy rate from fresh blastocyst transfers? SUMMARY ANSWER: Th...
STUDY QUESTION: Does the addition of three antioxidants to culture media during gamete collection, insemination, and embryo culture increase the clinical pregnancy rate from fresh blastocyst transfers? SUMMARY ANSWER: The clinical pregnancy rate from fresh blastocyst transfers was not increased by the addition of antioxidants to IVF and embryo culture media. WHAT IS KNOWN ALREADY: Addition of antioxidants to media is beneficial in mouse IVF, embryo culture, and cryopreservation. Prospective clinical trials of sibling human oocytes found an improvement in embryo quality and increased pregnancy rates from frozen blastocyst transfers in older patients. STUDY DESIGN, SIZE, DURATION: Single-centre, prospective randomized controlled trial, superiority study comparing media with or without the addition of antioxidants from January 2019 to November 2021. A total of 1482 patients were randomized before egg collection. Patients and their doctors were blinded to the treatment group. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients undergoing IVF/ICSI cycles and intending to undergo a fresh transfer of a single blastocyst were recruited. Exclusion criteria were previous participation in the study, use of cryopreserved oocytes/embryos, artificial oocyte activation, freeze-all cycle, or extraction of sperm from testicular biopsy. Seven hundred thirty-nine patients were randomized to control media and 743 patients to media containing the 'A3' antioxidant combination of acetyl-L-carnitine, α-lipoic acid, and N-acetyl-L-cysteine (treatment group). MAIN RESULTS AND THE ROLE OF CHANCE: The clinical pregnancy rate per randomized patient per cycle from fresh embryo transfer was not different between the control and antioxidant media (26.1% vs 22.9%; P > 0.05; RR 0.88 (95% CI 0.73-1.05)). In the Per Protocol population, which excludes patients with protocol violations or without a fresh transfer due to freeze-all or no embryo available, there was also no difference in between the control and antioxidant media in clinical pregnancy rate (36.7% vs 33.2%; P > 0.05; RR 0.90 (95% CI 0.76-1.07)) and live birth rate (32.4% vs 29.5%, P > 0.05). In the Intention-to-Treat population, antioxidant media produced a significant increase in the fertilization rate from 59.2 ± 26.3% to 64.5 ± 25.4% (P < 0.001) compared to control media. Blastocyst development rate per fertilized oocyte was not affected by antioxidant media, but the higher fertilization rate resulted in more fertilized oocytes per patient and therefore more blastocysts utilized per patient in the antioxidant group compared to the control (2.70 ± 2.59 vs 3.09 ± 2.96, P < 0.01). The increase in fertilization rate was observed in a subgroup analysis of ICSI cycles (57.9 ± 27.2% vs 68.3 ± 24.7%, P < 0.0001), and a decrease in the number of cycles with failed fertilization from 8.0 to 3.7% with antioxidant media (P < 0.01). In contrast, there was no effect of antioxidant media on fertilization rate in cycles with IVF insemination. LIMITATIONS, REASONS FOR CAUTION: This was a single-centre study, so the effects of antioxidant media in clinics with different protocols are unknown. Patient oxidative stress, which may be influenced by inflammation, diet, smoking status, antioxidant supplement consumption, and other lifestyle factors, was not accounted for. Any potential effect of renewing the antioxidants in the media during culture was not examined. WIDER IMPLICATIONS OF THE FINDINGS: Addition of antioxidants to culture media did not affect pregnancy rates from fresh single embryo transfers. An increase in fertilization rate was observed, which resulted in more blastocysts available for transfer and cryopreservation. There was no effect of antioxidants on blastocyst development rate or grade. Further studies are needed to validate the observed effect of antioxidants on fertilization rate following ICSI. STUDY FUNDING/COMPETING INTEREST(S): Culture media and an independent statistician were funded by Vitrolife AB. R.L.K has received travel funding and a speaker's honorarium from Vitrolife. D.K.G. has received research grants from Vitrolife at the University of Melbourne. N.-G.P. has received consulting fees from Vitrolife for work related to the study. All other authors have nothing to declare. TRIAL REGISTRATION NUMBER: ACTRN12618001479291. TRIAL REGISTRATION DATE: 4 September 2018. DATE OF FIRST PATIENT’S ENROLMENT: 28 January 2019.
Corpus luteum number and maternal circulatory adaptation from early pregnancy onwards: the Rotterdam Periconception Cohort (Predict Study).
Voskamp LW, Koerts JJ, Wiegel RE … +4 more , Verdonk K, Danser AHJ, Steegers-Theunissen RPM, Rousian M
Hum Reprod · 2025 Nov · PMID 40972010 · Full text
STUDY QUESTION: Is the number of corpora lutea (CL) associated with maternal circulatory adaptation to pregnancy, as assessed by blood pressure and uterine artery Doppler pulsatility and resistance indices? SUMMARY ANSWE...
STUDY QUESTION: Is the number of corpora lutea (CL) associated with maternal circulatory adaptation to pregnancy, as assessed by blood pressure and uterine artery Doppler pulsatility and resistance indices? SUMMARY ANSWER: Pregnancies without a corpus luteum have a higher mean arterial pressure throughout pregnancy and lower uterine artery pulsatility and resistance indices in the first and second trimesters, compared to pregnancies where one or more than one corpus luteum is present. WHAT IS KNOWN ALREADY: Different modes of conception result in varying numbers of corpus luteum in early pregnancy. Previous research has demonstrated significant differences in hypertensive disorders of pregnancy and birthweight in women with 0, 1, and multiple CL, as well as altered maternal cardiovascular adaptation. Although direct causal evidence is limited, these differences are thought to reflect the presence or absence of corpus luteum-derived hormones, suboptimal decidualization in programmed cycles, or both. STUDY DESIGN, SIZE, DURATION: This prospective study used data from the ongoing Rotterdam Periconception Cohort, including women with singleton pregnancies enrolled from 2010 to 2022 at the Erasmus MC, University Medical Center, a tertiary care facility. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study population for this research involved pregnancies in 1986 women: 1456 with one corpus luteum (1292 due to natural conception or insemination and 164 due to natural cycle frozen embryo transfer), 457 with more than one corpus luteum (due to fresh embryo transfer), and 73 with no corpus luteum (due to artificial cycle (AC)-FET). Linear mixed models were adjusted for maternal age, body mass index, nulliparity, smoking, pre-existing hypertension, and uterine artery Doppler outcomes, including mean arterial pressure. MAIN RESULTS AND THE ROLE OF CHANCE: Adjusted mean arterial pressure during pregnancy was significantly higher in women with 0 vs 1 CL (β + 2.19 mmHg, 95% CI [0.43-3.95], P = 0.015), but was not different between those with >1 and 1 CL (β -0.35 mmHg [-1.22 to 0.53], P = 0.438). This was also true for diastolic but not for systolic blood pressure. Uterine artery Doppler indices were available for 624 women. Adjusted uterine artery pulsatility index (PI) and resistance index (RI) were significantly lower in women with 0 CL compared to 1 CL, both at 11 weeks (PI: 1.53, 95% CI [1.38-1.69] vs 1.72 [1.65-1.79], P = 0.026; RI: 0.69, [0.66-0.73] vs 0.73 [0.72-0.75], P = 0.034) and at 22 weeks gestational age (PI: 0.64 [0.57-0.72] vs 0.81 [0.78-0.85], P < 0.001; RI: 0.44 [0.41-0.46] vs 0.51 [0.50-0.53], P < 0.001). In pregnancies with >1 CL, uterine artery indices were comparable to the 1 CL group, except for a slightly higher RI at 22 weeks (0.54 [0.52-0.55], P = 0.011). Restricting the analyses to only pregnancies conceived using ARTs did not change the observed directions of the effects. LIMITATIONS, REASONS FOR CAUTION: This study was conducted in a tertiary hospital setting, which may limit generalizability to other populations. Details on luteal support were incomplete, and the corpus luteum number was inferred based on the mode of conception, which could introduce confounding by indication. WIDER IMPLICATIONS OF THE FINDINGS: These results align with previous literature and provide robust evidence from a large cohort, adjusting for confounders. Notably, uterine artery models were additionally adjusted for the observed differences in mean arterial pressure. However, despite this adjustment, the differences in uterine artery indices between CL groups persisted, indicating that these cannot be explained by the higher mean arterial pressure and suggesting the involvement of distinct vascular mechanisms. The observed differences in circulatory adaptation to pregnancy between conceptions with corpus luteum numbers may underlie the higher incidence of hypertensive disorders of pregnancy after conception without a corpus luteum. Additionally, these insights further support the preference for certain ARTs, where feasible, to optimize maternal and neonatal outcomes. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the Departments of Obstetrics and Gynaecology and Internal Medicine of the Erasmus MC, University Medical Center, Rotterdam, the Netherlands. The authors declare no competing interests. TRIAL REGISTRATION NUMBER: This study is registered at the Dutch Trial Register (NTR6854).
Correction to: Ovarian stimulation with follitropin delta for in vitro fertilization: a multicentre, randomized, assessor-blind comparison with follitropin alfa using conventional dosing regimens (ADAPT-1 trial).
Hum Reprod · 2025 Nov · PMID 40971885 · Full text
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Uterus transplantation; first data on neurologic, neuropsychiatric, and physical examination follow-up of children up to 6 years of age.
Wentz E, Hagberg B, Hagberg H … +2 more , Bokström H, Brännström M
Hum Reprod · 2025 Dec · PMID 40971624 · Full text
STUDY QUESTION: What are the outcomes regarding cognition, development, physical, and psychiatric status of children born after uterus transplantation (UTx) up to 6 years after birth? SUMMARY ANSWER: The long-term and ve...
STUDY QUESTION: What are the outcomes regarding cognition, development, physical, and psychiatric status of children born after uterus transplantation (UTx) up to 6 years after birth? SUMMARY ANSWER: The long-term and very long-term outcomes of children born after UTx indicate normal cognitive, neuropsychiatric, and physical development. WHAT IS KNOWN ALREADY: Previous cohort studies of children born after UTx and followed up to 2-3 years indicate normal neurodevelopment and occasional cases of minor malformations. STUDY DESIGN, SIZE, DURATION: A prospective cohort study was performed on 11 offspring after UTx. All children (7 boys, 4 girls) were examined at age 2.5 years and eight children (5 boys, 3 girls) were examined at age 6 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: The cognitive evaluations, Bayley-III test and WPPSI-IV, were performed at age 2.5 years (n = 11) and age 6 years (n = 8), respectively. Parental questionnaires pertaining to neurodevelopmental and behavioural problems, including the Strengths and Difficulties questionnaire (SDQ) and the ESSENCE-Q, were administered. All children (age 2.5 years: n = 11; age: 6 years: n = 8) underwent physical examinations. MAIN RESULTS AND THE ROLE OF CHANCE: Cognitive skills showed results within the normal range at both age 2.5 years and age 6 years. According to the SDQ, emotional problems were the most common symptoms, affecting two children at age 2.5 years and two children at age 6 years. Three children scored above the cut off on the ESSENCE-Q at age 2.5 years, and one child continued to score 'high' at age 6 years. At the first examination, three children had asthma, and speech problems were observed in five children. Among those who were also assessed at age 6 years, these problems had abated. At age 6 years, one child was considered hyperactive, and another child exhibited vocal tics. Developmental and behavioural deviations were observed almost exclusively in the boys. LIMITATIONS, REASONS FOR CAUTION: Limitations of the study include the small sample size, and the lack of a comparison group. The small sample does not offer enough statistical power, and no firm conclusions can therefore be drawn based on the reported deviances. WIDER IMPLICATIONS OF THE FINDINGS: The long-term and very long-term outcomes of children born after UTx indicated normal cognitive development. A minority had minor physical and developmental problems, including asthma and speech problems at age 2.5 years, but most of these symptoms subsided by age 6 years. Boys seemed to be over-represented regarding developmental and behavioural deviations. The small sample size limits the ability to generalize the findings to all children born after UTx. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by The Swedish research council (Grant/Award Numbers: Dnr 2023-02035 (H.H.), 2024-03487 (M.B.)), the Swedish state under the agreement between the Swedish Government and the country councils, the ALF-agreement, grant/Award-Numbers: ALFGBG-1005108 (H.H.), ALFGBG-965535 (M.B.), Jane and Dan Olsson Foundation for Science (2020-09 (M.B.)), and Knut and Alice Wallenberg Foundation (2017.0363 (M.B.)). There are no conflicts of interest for any of the authors. TRIAL REGISTRATION NUMBER: NCT01844362, NCT02987023.
Correction to: A core outcome set for future male infertility research: development of an international consensus.
Hum Reprod · 2025 Oct · PMID 40929660 · Publisher ↗
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