Human Reproduction (Oxford, England)[JOURNAL]
Sun
200 papers
Intracytoplasmic sperm injection: a paradigm shift in reproductive medicine.
Van Steirteghem A, Tournaye H
Hum Reprod · 2026 Mar · PMID 41782270 · Publisher ↗
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Investigating cycle-to-cycle variation and the impact of endometrial injury through differential gene expression analysis.
Teh WT, Chung J, Donoghue JF … +4 more , Holdsworth-Carson SJ, Rozen G, Stern C, Rogers PAW
Hum Reprod · 2026 May · PMID 41770874 · Full text
STUDY QUESTION: Does endometrial gene expression change across consecutive cycles and after endometrial injury? SUMMARY ANSWER: Although paired endometrial samples collected from the same woman across two consecutive cyc...
STUDY QUESTION: Does endometrial gene expression change across consecutive cycles and after endometrial injury? SUMMARY ANSWER: Although paired endometrial samples collected from the same woman across two consecutive cycles show greater similarity in molecular profile compared to samples from different women, endometrial injury in the preceding cycle did not result in any significant differential gene expression. WHAT IS KNOWN ALREADY: Uterine receptivity is a crucial factor influencing pregnancy rates in IVF. The potential benefits of endometrial injury in enhancing receptivity, as well as the effectiveness of genomic endometrial receptivity tests in predicting uterine receptivity are subjects of ongoing debate. STUDY DESIGN, SIZE, DURATION: This was a prospective study, involving endometrial biopsies from 20 women at mid-luteal phase over two consecutive menstrual cycles. PARTICIPANTS/MATERIALS, SETTING, METHODS: Differential gene expression analysis was conducted using a paired design and included estimated menstrual cycle time as a covariate. Pairwise distances of samples and principal component analysis were used to examine sample-to-sample variation. MAIN RESULTS AND THE ROLE OF CHANCE: Analysis of paired endometrial samples revealed no significant difference in differential gene expression before and after endometrial injury (P > 0.05). Sub-analyses of samples from infertile women and those with proven fertility also did not reveal significant changes in gene expression. Although the pairwise distance analysis indicated slightly more similarity between intra-patient samples when compared to inter-patient samples (P = 0.09), PCA did not show clear clustering of these pairs. LARGE SCALE DATA: The RNA-seq data generated in this study have been deposited in the Gene Expression Omnibus database under accession number GSE303049. LIMITATIONS, REASONS FOR CAUTION: The sample size for this study is relatively small. WIDER IMPLICATIONS OF THE FINDINGS: Our findings highlight the high degree of cycle-to-cycle variability in endometrial gene expression, even within the same individual. Importantly, the lack of significant changes in gene expression as a result of endometrial injury in the preceding cycle, indicates the molecular variability reflects inherent biological fluctuations rather than the effect of prior injury. This molecular variability may help explain why implantation does not always occur immediately, even with high-quality embryos, and why interventions such as endometrial injury or molecular receptivity tests have yielded inconsistent clinical outcomes. STUDY FUNDING/COMPETING INTEREST(S): This project was supported in part by National Health and Medical Research Council (NHMRC) Medical Postgraduate Scholarship No. 1055814 and The Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) Fellows' Clinical Research Scholarship 2013 (W.T.T.). W.T.T., J.C., and P.R. are named inventors on a patent on the molecular dating of endometrial samples with IP Australia, ID: AU2023287239A1-methods for determining menstrual cycle time point. The patent is held jointly by their employers: University of Melbourne and Royal Women's Hospital. No payments have been received for this patent to date. TRIAL REGISTRATION NUMBER: N/A.
AMH regulates ovary size by counteracting the positive influence of clustered ovarian follicle growth.
Lim C, Yiew L, Anderson NJ … +11 more , Smith P, Quirke L, Carne A, Sarma U, Rose R, Nicholson M, Jasoni CL, Liu P, Petrich S, Juengel J, Pankhurst MW
Hum Reprod · 2026 May · PMID 41742785 · Full text
STUDY QUESTION: Does anti-Müllerian hormone (AMH) influence preantral follicle development within a short range of AMH-secreting antral follicles? SUMMARY ANSWER: Immunization of sheep against AMH leads to increased foll...
STUDY QUESTION: Does anti-Müllerian hormone (AMH) influence preantral follicle development within a short range of AMH-secreting antral follicles? SUMMARY ANSWER: Immunization of sheep against AMH leads to increased follicle survival, specifically in regions close to small-medium antral follicles. WHAT IS KNOWN ALREADY: Serum AMH is known to inhibit the survival of immature ovarian follicles, but its biological role remains poorly understood. Mammalian ovaries contain many more developing ovarian follicles than are needed for ovulation, but how these systems operate remains unclear. STUDY DESIGN, SIZE, DURATION: Cross-sectional-control versus treatment studies examining the effects in the presence or absence of AMH. PARTICIPANTS/MATERIALS, SETTING, METHODS: Anti-AMH immunization experiments were conducted in sheep followed by histological 2D and 3D tissue analysis. Microdialysis was conducted on ex vivo human and sheep ovaries. Live-imaging of a fluorogenic enzyme-responsive reagent was conducted on ex vivo mouse ovaries. Organ/follicle culture was conducted on Amh+/+ and Amh-/- ovary tissues to measure follicle activation and growth rates. MAIN RESULTS AND THE ROLE OF CHANCE: The likely site of action of AMH was shown to be ovarian stroma adjacent to large follicles as microdialysis determined that receptor-activating concentrations of AMH were only observed within a short range of the follicle. The AMH-activating enzymes were also shown to be primarily located in stroma using live-imaging of a fluorogenic enzyme-responsive reagent. Sheep were immunized against AMH protein to inhibit extracellular signalling and the ovaries were examined using 3-dimensional reconstructions of ovarian follicle positions. This showed that inhibition of AMH signalling caused an increase in preantral follicle survival, but almost entirely in proximity to large developing follicles. LARGE SCALE DATA: None. LIMITATIONS, REASONS FOR CAUTION: Limited studies were conducted on human tissue but the results concur with the sheep experiments. Sheep ovaries provide a useful large-animal model for comparative anatomy with humans but there will be interspecies differences. WIDER IMPLICATIONS OF THE FINDINGS: These results add to the evidence that small growing follicle survival is influenced by the proximity of large follicles. This has relevance for conditions where large follicles are lacking (e.g. primary ovary insufficiency) or where follicle growth is excessive (e.g. PCOS). STUDY FUNDING/COMPETING INTEREST(S): This research was funded by a Sir Charles Hercus Research Fellowship from the Health Research Council of New Zealand (grant number 18-027). The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.
Prenatal exposure to parental smoking and infertility in sons and daughters: a cohort study.
Stokholm MV, Ernst A, Håberg SE … +3 more , Kjersgaard CL, Thomsen AH, Ramlau-Hansen CH
Hum Reprod · 2026 Apr · PMID 41739999 · Full text
STUDY QUESTION: Is prenatal exposure to parental smoking associated with infertility in sons and daughters? SUMMARY ANSWER: The study does not provide robust evidence that prenatal smoking exposure increases the risk of...
STUDY QUESTION: Is prenatal exposure to parental smoking associated with infertility in sons and daughters? SUMMARY ANSWER: The study does not provide robust evidence that prenatal smoking exposure increases the risk of infertility, defined as clinically diagnosed infertility or ART use, in adult sons and daughters. WHAT IS KNOWN ALREADY: Reproductive function is established early in fetal life and may be adversely affected by prenatal exposure to parental smoking. STUDY DESIGN, SIZE, DURATION: In this cohort study, we used data from the Danish birth cohort, Health Habits for Two, established in 1984-1987. In total, 11 980 (87% of eligible) women participated and gave birth to 11 144 liveborn, singleton sons and daughters. PARTICIPANTS/MATERIALS, SETTING, METHODS: Adult sons and daughters born to mothers enrolled in the birth cohort constituted the study population and were aged 35-38 years at follow-up. Around gestational week 36, mothers provided information on parental smoking. The primary exposure of interest was maternal smoking. Paternal smoking and combined parental smoking were also assessed to explore individual and potential synergistic effects. Infertility among offspring was defined as either an ICD-10 infertility diagnoses or use of ART, identified within two nationwide registers and considering their partners' records. Associations were examined using Cox regression models estimating crude and adjusted hazard ratios (HRs) for categories of prenatal smoking, with non-smoking as the reference, accounting for competing risks of infertility. Dose-response associations were explored across categories of maternal and paternal smoking. The proportional hazards assumption was met only when stratifying analyses by age, using cutoffs of ≤26 and >26 years for sons, and ≤27 and >27 years for daughters. In a sensitivity analysis, follow-up was restricted to periods of registered partnership under the assumption that individuals in a relationship are more likely to be identified as infertile and vice versa. In a sub-analysis, analyses were stratified by offspring educational level to explore potential social gradients in being identified as infertile in medical records. MAIN RESULTS AND THE ROLE OF CHANCE: Maternal smoking of >9 cigarettes/day tended to be associated with higher risk of infertility among sons ≤26 years (HR 1.7 (95% CI: 0.8-3.5)) and daughters ≤27 years (HR 1.2 (95% CI: 0.7-1.9)), both indicating suggestive dose-response patterns with higher risk of infertility with increasing maternal smoking levels. No associations for sons >26 years or daughters >27 years were observed. Paternal smoking of >10 cigarettes/day tended to be associated with higher risk of infertility among sons >26 years (HR 1.3 (95% CI: 0.9-1.8)), indicating suggestive dose-response patterns. No higher risk of infertility following paternal smoking was observed among sons ≤26 years or daughters at any age. No synergistic effects of combined parental smoking were observed. When redefining the time at risk using the partnership model, we did not observe higher risks of infertility among maternally exposed sons and daughters. When stratifying the main analyses by the sons' and daughters' educational level, we observed tendencies of higher risks for infertility in some exposure groups among those with longer education. Overall, we found no robust evidence that prenatal exposure to parental smoking is associated with a higher risk of clinically recognized infertility in offspring. LIMITATIONS, REASONS FOR CAUTION: Parental smoking was self-reported by mothers late in pregnancy and might be subject to misclassification, most likely non-differential. Not all infertility cases may be captured in the registers as it requires pregnancy attempt and pursuing medical treatment. Most confidence intervals overlapped the null, indicating that the findings are also compatible with no association. Some analyses, particularly the stratified analyses, were limited by low statistical power. WIDER IMPLICATIONS OF THE FINDINGS: The observed diminishing effect estimates with increasing age for those exposed to maternal smoking may reflect growing influence from other dominant infertility risk factors. Results from analyses stratified by offspring educational level may be indicative of tendencies of greater awareness of fertility issues and higher health care-seeking among individuals from more advantaged socioeconomic backgrounds. A potential higher, although modest and uncertain, risk of infertility following prenatal smoking exposure cannot be excluded, supporting the current guidelines recommending smoking cessation prior to pregnancy. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the European Union (ERC, BIOSFER, 101071773); expressed views and opinions are however those of the authors' only and do not necessarily reflect those of the European Union or the European Research Council. Neither the European Union nor the granting authority can be held responsible for them. Additionally, this study received funding from Aarhus University and was supported by the Research Council of Norway, through its Centre of Excellence funding scheme (No. 262700). All authors have no conflicts or interests to declare. TRIAL REGISTRATION NUMBER: N/A.
The problem with the 'truth': rethinking ground truth for artificial intelligence in endometriosis diagnosis.
Deslandes A, Zhang Y, Leonardi M … +7 more , Chen HT, Carneiro G, Avery J, Condous G, Knox S, Hull ML, IMAGENDO Team
Hum Reprod · 2026 May · PMID 41739996 · Full text
Artificial intelligence (AI) is revolutionizing how we practice medicine. In areas where we have traditionally struggled, such as diagnosing endometriosis, AI has significant potential to improve the breadth and accuracy...
Artificial intelligence (AI) is revolutionizing how we practice medicine. In areas where we have traditionally struggled, such as diagnosing endometriosis, AI has significant potential to improve the breadth and accuracy of diagnostic services offering a great benefit to patient care. When developing AI models for diagnosis, the 'ground truth' refers to the reference standard used in the labelling of the data used to train the model. Conventionally, in clinical medicine, we correlate any new diagnostic tool to the established 'gold standard', which in the case of endometriosis is laparoscopic visualization of lesions and histological confirmation. This method however is increasingly recognized as imperfect. Acknowledgement of the limitations of surgery and recent improvements in the diagnostic capability of imaging technologies to detect endometriosis, has created a situation where endometriosis no longer has one clear 'gold standard' for diagnosis. In this commentary, we will explore the impact of this on AI-driven endometriosis diagnostic tools and propose novel ways this could be addressed in the context of creating ground truths for endometriosis diagnosis.
ESHRE guideline: ovarian stimulation for IVF/ICSI: an update in 2025†.
ESHRE Guideline Group on Ovarian Stimulation , Ata B, Bosch E … +15 more , Broer S, Griesinger G, Grynberg M, Kolibianakis E, Kunicki M, La Marca A, Lainas G, Le Clef N, Massin N, Polyzos NP, Sunkara SK, Timeva T, Töyli M, Urbancsek J, Broekmans F
Hum Reprod · 2026 Apr · PMID 41732035 · Full text
STUDY QUESTION: What is the recommended management of ovarian stimulation, based on the best available evidence in the literature? SUMMARY ANSWER: This updated ESHRE guideline on ovarian stimulation for IVF/ICSI provides...
STUDY QUESTION: What is the recommended management of ovarian stimulation, based on the best available evidence in the literature? SUMMARY ANSWER: This updated ESHRE guideline on ovarian stimulation for IVF/ICSI provides 121 recommendations, answering 21 key questions on ovarian stimulation for IVF/ICSI. WHAT IS KNOWN ALREADY?: Before the ESHRE guideline on ovarian stimulation for IVF/ICSI was published in 2019, ovarian stimulation for IVF/ICSI had only been discussed briefly in the National Institute for Health and Care Excellence guideline on fertility problems and in a statement by the Royal Australian and New Zealand College of Obstetricians and Gynaecologists. STUDY DESIGN, SIZE, DURATION: The guideline was developed according to the structured methodology for ESHRE guidelines. The 18 key questions from the 2019 version of the guideline were revised by the Guideline Development Group (GDG). This resulted in the addition of one new key question, the splitting of the key question on fertility preservation in three separate key questions (fertility preservation for women facing gonadotoxic treatment, elective oocyte cryopreservation, and oocyte donation) and several new interventions being added to the existing key questions. Papers published between 31 October 2018 and 2 February 2025 and written in English were included. The critical outcomes for this guideline were efficacy in terms of cumulative live birth rate per started cycle or live birth rate per started cycle, as well as safety in terms of the rate of occurrence of moderate and/or severe ovarian hyperstimulation syndrome (OHSS). PARTICIPANTS/MATERIALS, SETTING, METHODS: Based on the available evidence, recommendations were formulated and discussed until consensus was reached within the GDG. Following stakeholder review of the initial draft, the final version was approved by the GDG and ultimately by the ESHRE Executive Committee. MAIN RESULTS AND THE ROLE OF CHANCE: The guideline provides a total of 121 recommendations: 42 recommendations remained unchanged in 2019, 4 recommendations were reworded for better understanding, 29 recommendations were updated in view of new evidence, and 46 new recommendations for 2025 have been formulated. The guideline provides 4 recommendations on pre-stimulation evaluation, 7 recommendations on pre-treatment therapies, 50 recommendations on pituitary suppression and ovarian stimulation, 17 recommendations on monitoring, 18 recommendations on triggering of final oocyte maturation and luteal support, and 8 recommendations on the prevention of OHSS. In addition, the guideline provides 17 recommendations on fertility preservation, both oncologic and elective, and oocyte donation. These include 90 evidence-based recommendations, of which only 42 were formulated as strong recommendations and 48 as conditional, as well as 29 good practice points and 2 research-only recommendations. Of the evidence-based recommendations, none were supported by high-quality evidence, 6 by moderate-quality evidence, 36 by low-quality evidence, and 148 by very low-quality evidence. To support future research on ovarian stimulation for IVF/ICSI, a list of research recommendations was provided. LIMITATIONS, REASONS FOR CAUTION: Several newer interventions are not well studied yet. For most of these interventions, a recommendation against the intervention or a research-only recommendation was formulated based on insufficient evidence. Future studies may require these recommendations to be revised. WIDER IMPLICATIONS OF THE FINDINGS: The guideline provides clinicians with clear advice on best practice in ovarian stimulation, based on the best evidence available. In addition, a list of research recommendations is provided to promote further studies in ovarian stimulation. STUDY FUNDING/COMPETING INTEREST(S): The guideline was developed by ESHRE, who funded the guideline meetings, literature searches, and dissemination of the guideline. The guideline group members did not receive any financial incentives; all work was provided voluntarily. BA reports speaker's fees from Gedeon-Richter, Ferring, IBSA, Intas, Merck, Organon, consulting fees from Merck, Organon, Oxolife, stock options from Global Fertility Solutions LLC (employee co-investment), and was chair of the Turkish Society of Reproductive Medicine. EB reports research grants from Roche Diagnostics and IBSA, consulting fees from MSD, Abbot, Gedeon-Richter, Roche, speaker's fees from IBSA, MSD, Ferring Pharmaceuticals, Abbot, Gedeon-Richter, Merck, Roche, participation in the advisory board of Ferring Pharmaceuticals, IBSA and Merck, and ownership interest from IVI-RMS Valencia. GG was part of the ESHRE working group on Recurrent Implantation Failure and the ESHRE working group on clinical KPISs, reports travel support from Merck, Organon, Ferring, Theramex, Gedeon-Richter, Abbott, consulting fees from Organon, Ferring, Merck, Gedeon-Richter, Theramex, Abbott, ReproNovo, Igyxos, OxoLife, Philipps, ReprodWissen, PregLem, Guerbet, Roche, IBSA, and Besins, speaker's fees from Organon, Ferring, Merck, Gedeon-Richter, Theramex, Abbott, ReproNovo, Igyxos, OxoLife, Philipps, ReprodWissen, PregLem, Guerbet, Roche, IBSA, and Besins, and research grants from Besin, Merck, Abbott, Ferring, Theramex. MG reports speaker's fees from Merck Serono, Ferring, and Gedeon Richter. EK reports travel/hotel expenses from Ferring, Merck SERONO, Vianex, speaker's fees from Ferring, Merck SERONO, Vianex, and is chair of the Greek Society of Fertility and Sterility. MK reports travel support and speaker's fees from Ferring. ALM reports research grants from Merck, Ferring, IBSA, Roche, Organon, Theramex, Beckman Coulter, and Gedeon-Richter, consulting fees from Merck, Ferring, IBSA, Roche, Organon, Theramex, Beckman Coulter, and Gedeon-Richter, speaker's fees from Merck, Ferring, IBSA, Roche, Organon, Theramex, Beckman Coulter, Gedeon-Richter, and participation on an advisory board of Merck, Organon, Ferring, Theramex, Gedeon Richter, and IBSA. GL reports consulting fees from Ferring and Merck, speaker's fees from Ferring, Merck, Gedeon-Richter, Organon, and Vianex, expert testimony fees from Cook, travel support from ESHRE, Ferring, Merck, Gedeon-Richter, Organon, and Vianex, is on the advisory board of Merck and Ferring, and participated in an ESHRE committee and on the Greek Fertility and Sterility Committee. NM reports research grants from IBSA, Organon, consulting fees from Organon, Merck, GE, Ferring, Abbott, and Cooper, and speaker's fees from Ferring, GE, Organon, IBSA, Merck, Theramex. NPP reports research grants from Besins Healthcare, Ferring Pharmaceutical, Merck Serono, Organon, Roche Diagnostics, and Theramex, consulting fees from Besins Healthcare, Alife, Ferring, IBSA, Merck Serono, Organon, Abbott, FertilAI, and speaker's fees from Besins Healthcare, Roche Diagnostics, Ferring Pharmaceuticals, Gedeon-Richter, IBSA, Merck Serono, Organon, and Theramex. SKS reports a research grant from Ferring, travel support from Merck and INTAS, consulting fees from Merck, and speaker's fees from Merck, MSD, INTAS, and Ferring. TT reports travel support from Merck, speaker's fees from Merck, Organon, MSD and is editor-in-chief of a Bulgarian journal, Reproductive Health. MT reports travel support from IBSA, Ferring, and Merck, consulting fees from Abbott and is a member of the board of the Finnish Endocrine Society. JU is a member of the Steering Committee of Richter Reproduction Network and received travel support from IBSA. FB reports a research grant from Besins, is on the advisory board of Merck and Abbott, reports speaker's fees from Ferring, Merck, Besins, Intas Fermaceuticals, PREIS School; he is the owner of FRANKSCHOOL RforL. The other authors have nothing to disclose. TRIAL REGISTRATION NUMBER: N/A. DISCLAIMER: This guideline represents the views of ESHRE, which were achieved after careful consideration of the scientific evidence available at the time of preparation. In the absence of scientific evidence on certain aspects, a consensus between the relevant ESHRE stakeholders has been obtained.Adherence to these clinical practice guidelines does not guarantee a successful or specific outcome, nor does it establish a standard of care. Clinical practice guidelines do not replace the need for application of clinical judgment to each individual presentation, nor variations based on locality and facility type.ESHRE makes no warranty, express or implied, regarding the clinical practice guidelines and specifically excludes any warranties of merchantability and fitness for a particular use or purpose. (The full disclaimer is available at www.eshre.eu/guidelines.).
Genome-wide analysis highlights epigenetic link to age at menarche.
Ye Z, Xu R, Malone GL … +6 more , Dugué PA, Nguyen TL, Giles GG, Southey MC, Milne RL, Li S
Hum Reprod · 2026 Apr · PMID 41729831 · Publisher ↗
STUDY QUESTION: Do genome-wide DNA methylation patterns influence age at menarche? SUMMARY ANSWER: An epigenome-wide association study identified 63 differentially methylated regions (DMRs), with replication and Mendelia...
STUDY QUESTION: Do genome-wide DNA methylation patterns influence age at menarche? SUMMARY ANSWER: An epigenome-wide association study identified 63 differentially methylated regions (DMRs), with replication and Mendelian randomization supporting suggestive causal effects of TRIM61 methylation on age at menarche. WHAT IS KNOWN ALREADY: Age at menarche is a key reproductive milestone, associated with cancer and metabolic outcomes. Genome-wide studies have suggested genetic influences, but the epigenetic mechanisms regulating pubertal timing remain largely unexplored. STUDY DESIGN, SIZE, DURATION: Cross-sectional epigenome-wide association study of blood DNA methylation in 3429 adult women (mean age 56 years) across discovery and replication cohorts. Discovery included 479 participants from the Australian Mammographic Density Twins and Sisters Study and 2614 from the Melbourne Collaborative Cohort Study. Replication was performed in 336 women from the European Prospective Investigation into Cancer and Nutrition-Italy. PARTICIPANTS/MATERIALS, SETTING, METHODS: Peripheral blood samples from adult women were profiled using the Illumina HumanMethylation450 BeadChip. Differentially methylated sites were identified using linear mixed-effect models, followed by identifying DMRs through DMRcate and combp methods and region-based effect analysis. Mendelian randomization assessed the causal effects of individual cytosine-phosphate-guanine (CpGs) within the identified DMR on age at menarche and nearby gene expression. Functional annotation integrated chromatin accessibility, transcription factor binding sites, and regulatory element mapping from public epigenomic databases. MAIN RESULTS AND THE ROLE OF CHANCE: Sixty-three DMRs were identified in the discovery cohort. The TRIM61 region was replicated (P < 0.05) with consistent positive effects across CpGs and the region. Mendelian randomization indicated that TRIM61 methylation causally influenced age at menarche and regulated the expression of nearby genes at a suggestive level. Functional annotation revealed overlap with active regulatory elements, supporting a mechanistic role in modulating chromatin accessibility and transcriptional regulation. LARGE SCALE DATA: European Prospective Investigation into Cancer and Nutrition-Italy data can be accessed through the Gene Expression Omnibus (GSE51032). The methylation quantitative trait locus (mQTL) data can be downloaded from https://data.bris.ac.uk/data/dataset/r9bxayo5mmk510dczq6golkmb. The expression quantitative trait locus (eQTL) data can be downloaded from the eQTLGen Consortium (https://www.eqtlgen.org/cis-eqtls.html). The genome-wide association studies summary statistics of age at menarche can be available from the IEU OPENGWAS (https://gwas.mrcieu.ac.uk/); dataset ID: ieu-a-1095. LIMITATIONS, REASONS FOR CAUTION: DNA methylation was derived from adult blood samples, which may not fully reflect pubertal tissues; causality was inferred using Mendelian randomization rather than experimental validation. WIDER IMPLICATIONS OF THE FINDINGS: This study provides molecular evidence that epigenetic regulation at TRIM61 contributes to pubertal timing, offering novel insights into mechanisms linking reproductive development and long-term health outcomes. Findings may inform future studies on epigenetic biomarkers and potential therapeutic targets for reproductive and metabolic disorders. STUDY FUNDING/COMPETING INTEREST(S): Funded by National Health and Medical Research Council: GNT2024867, GNT2017373, GNT2017325, 1011618, 1026892, 1027505, 1050198, 1043616, 1074383, 1050561, 1079102, 209057, and 396414; National Breast Cancer Foundation: 509307; VicHealth Postdoctoral Research Fellowships 2022; Cancer Council Victoria: AF7035; Cancer Australia: APP1187896; Victorian Cancer Agency: MCRF22025 and ECRF19020. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: n/a.
Clinical and molecular features of ovarian stimulation in peripubertal girls with mosaic Turner's syndrome.
Oktem O, Kalajahi HG, Esmaeilian Y … +6 more , Benlioglu C, Hela F, Yusufoglu S, Kalkan U, Turan V, Ata B
Hum Reprod · 2026 Apr · PMID 41719147 · Publisher ↗
STUDY QUESTION: Do peripubertal girls with mosaic Turner's syndrome (TS) respond to ovarian stimulation (OS) for oocyte freezing as adult women with normal ovarian reserve? SUMMARY ANSWER: Clinical and molecular reproduc...
STUDY QUESTION: Do peripubertal girls with mosaic Turner's syndrome (TS) respond to ovarian stimulation (OS) for oocyte freezing as adult women with normal ovarian reserve? SUMMARY ANSWER: Clinical and molecular reproductive/endocrine features of OS in these patients are similar to those of adult females. WHAT IS KNOWN ALREADY: OS for oocyte freezing is quite a new concept in peripubertal and young adolescent girls with TS because ovarian tissue cryopreservation (OTC) does not have proven efficacy, likely due to already diminished ovarian reserve and accelerated follicle atresia. No data are available in the literature regarding the molecular IVF characteristics of these cycles in this group of patients. We aimed to address this issue in the current study by analyzing gonadotropin receptor expression, response to gonadotropins, and steroidogenic function at the molecular level in four peripubertal patients aged 9, 12, 13, and 15 in comparison to control adult females with normal ovarian reserve undergoing OS for male factor infertility. STUDY DESIGN, SIZE, DURATION: This is a clinical and research study that simultaneously analyzes the clinical and molecular characteristics of OS in peripubertal young girls with TS between 2021 and 2023 at a university hospital and translational research center. PARTICIPANTS/MATERIALS, SETTING, METHODS: All participants underwent OS using a progestin-primed protocol with recombinant forms of FSH and LH, and final maturation was induced with recombinant hCG. Control patients who had normal ovarian reserve and underwent OS for male factor infertility were randomly recruited during the study period to simultaneously compare and analyze the clinical and molecular OS characteristics of the peripubertal TS cases. Luteinized mural granulosa cells obtained during oocyte retrieval procedures were used for the experiments. Cell culture, quantitative real-time PCR, immunoblotting, confocal time-lapse live-cell imaging, and hormone assays were used. MAIN RESULTS AND THE ROLE OF CHANCE: All TS cases responded to gonadotropin stimulation. Nine mature oocytes were retrieved and vitrified in the 9-year-old prepubertal mosaic TS case after four cycles of OS with r-FSH (300 IU) and r-LH (150 IU)/day after a mean stimulation period of 9.72 ± 2.1 days. Eight mature oocytes were retrieved in the case aged 13 after three rounds of OS. The other cases, aged 12 and 15, underwent only one cycle of OS, and two mature oocytes from each were retrieved. The expression of FSH/LH receptors and steroidogenic enzymes, basal and gonadotropin-induced up-regulation in the expression of the steroidogenic enzymes, and estradiol and progesterone productions of the GCs of the TS patients were similar to those of adult control patients. Confocal immunofluorescence microscopy and live imaging revealed no differences in cholesterol uptake/trafficking or in staining patterns of the steroidogenic enzymes and their co-localization with mitochondria and cholesterol-laden lipid droplets. LIMITATIONS, REASONS FOR CAUTION: Findings were obtained from a limited number of mosaic TS patients. It is unclear if these findings are reproducible in non-mosaic peripubertal cases. Furthermore, no data are available yet regarding the post-thaw survival, fertilization, embryo development competency, euploidy status, and obstetrical outcomes of the vitrified oocytes of these patients. WIDER IMPLICATIONS OF THE FINDINGS: This study provides reassuring clinical and molecular evidence that OS for oocyte freezing can be an option in young girls with mosaic TS who are not ideal candidates for OTC due to diminished ovarian reserve. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the School of Medicine, the Graduate School of Health Sciences, and the Research Center for Translational Medicine (KUTTAM) at Koç University. The authors declare no competing interests. TRIAL REGISTRATION NUMBER: Not applicable.
Microsimulation reveals that medically assisted reproduction is unlikely to compensate for cohort fertility decline due to increasing maternal ages.
Granholm R, Cantineau AEP, Hoek A … +1 more , Stulp G
Hum Reprod · 2026 Apr · PMID 41704049 · Full text
STUDY QUESTION: Can medically assisted reproduction (MAR) compensate for completed cohort fertility (CCF) decline within coresidential unions due to increasing maternal ages among Dutch women born during 1974-1984? SUMMA...
STUDY QUESTION: Can medically assisted reproduction (MAR) compensate for completed cohort fertility (CCF) decline within coresidential unions due to increasing maternal ages among Dutch women born during 1974-1984? SUMMARY ANSWER: MAR is unlikely to compensate for cohort fertility decline within coresidential unions due to continued increase in maternal ages in our sample cohort of Dutch women born during 1974-1984, even under ideal conditions. WHAT IS KNOWN ALREADY: The pregnancy- and live birth rates for both expectant management and MAR decline at older reproductive ages. Some infertile couples can conceive naturally without undergoing treatment by trying to conceive for a longer period of time, which complicates estimating the contribution of MAR to cohort fertility. STUDY DESIGN, SIZE, DURATION: We developed a microsimulation model, which includes MAR, that simulates the reproductive life courses of women. We simulate a sample of 1 000 000 women representing the 1974-1984 Dutch birth cohort. Sample sizes for the input parameters varied from hundreds to thousands to hundreds of thousands depending on the parameter and source (surveys, clinical studies, panel data, population registers). PARTICIPANTS/MATERIALS, SETTING, METHOD: Our Monte Carlo microsimulation model uses probability distributions and parameters based on representative data sources to determine a woman's transitions through union and reproductive events across her reproductive life course. We assess the contribution of various components of the MAR process to CCF within coresidential unions and estimate the net contributions of MAR to CCF with counterfactual simulations. MAIN RESULTS AND THE ROLE OF CHANCE: Increases in the maximum female age at MAR treatment, the time to starting IUI treatment, and the number of IUI cycles did not noticeably increase CCF. Out of the hypothetical policy levers that were adjusted, increasing the share of eligible women who took up MAR from 0% to 100% increased CCF linearly by 0.06 children. Increasing the waiting time to ART treatment after infertility diagnosis from 1 to 12 months reduced CCF by 0.01. Increasing the number of reimbursed IVF/ICSI cycles from 0 to 6 increased CCF by 0.05. The increase tapered off after cycle number 2, and levelled off after cycle number 4. Minimum ages at which MAR treatment was started that were between 20 and 30 resulted in near-identical patterns of change in CCF from the adjustment in the potential policy levers, whereas both the CCF levels and rate of increase or decline were reduced at age 35 years, and further at age 40 years. The main influences on the lower CCF levels and slower rate or increase or decline were the reduction in MAR pregnancy rates at advanced reproductive ages, the increasing probability of intrauterine mortality with age, and time spent trying to conceive naturally before starting MAR treatment. The net contribution of MAR (0.043 children per woman, 2.5% to non-MAR CCF) was 33% smaller than the observed MAR birth share of CCF (0.064 children per woman, 3.7% of simulated CCF including MAR). The relative contribution of MAR was strongest at ages 35-39 (6.0%) and at age 40 years and above (8.6%), and weakest at ages 20-24 (0%) and 25-29 years (1.0%). In absolute number of children born, most of the contribution of MAR occurred at ages 30-34 (0.016 children) and ages 35-39 years (0.015). The Monte Carlo variation in the simulation model was measured to be around ±0.001 based on 10 simulations of 1 000 000 women. Parameter uncertainty was accounted for where possible by allowing parameters to vary within nonparametrically bootstrapped values generated from the sample data. LIMITATIONS, REASONS FOR CAUTION: Our model cannot fully capture the complexity of the fertility and MAR processes with regards to factors like infertility diagnosis, partner characteristics, and health status. Due to missing information, an extensive number of parameters, and limited sample sizes when estimating some of the parameters; the model output deviates slightly from the reference data. We cannot establish causality due to endogeneity in the modelling. We are not entirely confident in the zero contribution of IUI, because clinical data suggest that IUI pregnancy rates are higher than expectant management pregnancy rates, but the quality of that clinical data is low and sparse. The scope of the study is limited to births within coresidential unions, because information on unions and births outside of coresidential union was insufficient for modelling purposes. WIDER IMPLICATIONS OF THE FINDINGS: While MAR remains an important tool to address infertility, our results suggest that it is unlikely to compensate for population fertility decline attributable to postponement of childbearing to older reproductive ages. Failing to account for the counterfactual case that some couples who undergo MAR may conceive naturally given longer expectant management may lead to overestimation of the contribution MAR can make to population fertility. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by a VIDI grant (VI.Vidi.201.119) from the Netherlands Organization for Scientific Research to G.S. A.H. reports consulting fees by Ferring Pharmaceutical company The Netherlands, paid to institution UMCG, not related to the presented work. TRIAL REGISTRATION NUMBER: N/A.
Free apical surface hetero-cellular CDH1 homophilic binding is a major mediator of blastocyst-endometrium interaction in humans.
Ruan H, Chen ACH, Xue Y … +16 more , Lee KC, Fong SW, Qiu Q, Tan Y, Feng Y, Lee CL, Hua R, Huang J, Wang T, Xu Y, Lee KF, Xi N, Li RHW, Ng EHY, Yeung WSB, Lee YL
Hum Reprod · 2026 Apr · PMID 41704048 · Full text
STUDY QUESTION: Is E-cadherin (CDH1) expressed on the free apical surface of endometrial epithelial cells (EECs) involved in embryo attachment? SUMMARY ANSWER: Embryonic signals induced apical expression of endometrial C...
STUDY QUESTION: Is E-cadherin (CDH1) expressed on the free apical surface of endometrial epithelial cells (EECs) involved in embryo attachment? SUMMARY ANSWER: Embryonic signals induced apical expression of endometrial CDH1, which facilitated attachment via hetero-cellular CDH1 homophilic binding. WHAT IS KNOWN ALREADY: Understanding human blastocyst-endometrium interaction helps fertility treatment by facilitating the evaluation of endometrial receptivity and blastocyst quality. CDH1 is an adhesion molecule commonly known for the maintenance of epithelial integrity through adherens junction formation on the lateral membranes of adjacent epithelial cells. The apical region of some epithelia also expressed CDH1 of unknown function. STUDY DESIGN, SIZE, DURATION: Laboratory experimental study. PARTICIPANTS/MATERIALS, SETTING, METHODS: The potential apical cell plasma membrane proteins participating in adhesion between blastocysts and EEC were identified by comparing the surface proteomes of polar trophectoderm-like trophoblastic spheroids (BAP-EB) and receptive EEC. The apical surface expression of CDH1 in human blastocysts and primary EEC was confirmed by live-cell immunofluorescent staining. Antibody blocking and gene knockdown approaches were used to study the functional roles of hetero-cellular homophilic binding of CDH1. The adhesiveness of EEC and polar trophectoderm-like cells was confirmed by atomic force microscopy upon gene knockdown. The embryonic signals induced endometrial apical surface relocations of CDH1 and its stabilizer delta-1 catenin (CTNND1) were studied by treatments with conditioned media of BAP-EB and human blastocysts, as well as with HCG. The correlations of endometrial CDH1 and CTNND1 with pregnancy outcomes were confirmed by western blotting analysis of their protein expressions in EEC and immunofluorescent staining of endometrium collected from women who gave live birth, those who failed to become pregnant after IVF, and those with repeated implantation failure. MAIN RESULTS AND THE ROLE OF CHANCE: We identified 27 pairs of potential interactive cell plasma membrane transmembrane proteins between BAP-EB and EEC, and CDH1 homophilic binding was one of them. CDH1 was localized to the apical surface of receptive EEC and the polar trophectoderm of human blastocysts. The CDH1 expression in EEC was higher during the window of implantation than those at the pre-receptive phase. With the use of atomic force microscopy, we revealed that the adhesiveness of the apical surface of polar trophectoderm-like cells and EEC decreased when CDH1 was silenced. The attachment rates of BAP-EB onto EEC were decreased when the surface CDH1 of BAP-EB and/or the EEC was blocked by an anti-CDH1 antibody, indicating that homophilic binding of trophectodermal CDH1 with endometrial CDH1 mediated the attachment of BAP-EB onto EEC. Besides cell surface adhesiveness, knockdown of CDH1 or CTNND1 in EEC also reduced expression of adhesion-related molecules and BAP-EB attachment. The conditioned media of BAP-EB and human blastocysts and HCG enhanced apical expression of CDH1 in EEC, suggesting embryonic signals, in particular, modulated the expression of CDH1 and stimulated the adhesion of EEC. The protein expression of CDH1 was significantly higher in EEC isolated from patients who gave live birth as compared to those with repeated implantation failure. Importantly, the expression of CDH1 in the apical region of the luminal epithelium of the endometrium from fertile women was also significantly higher than that from women with repeated implantation failure. LARGE SCALE DATA: none. LIMITATIONS, REASONS FOR CAUTION: This study only includes in vitro experiments. Due to the limited availability of human blastocysts and difficulty in long-term expandable culture of primary EEC, embryo surrogates BAP-EB and endometrial adenocarcinoma cell lines were used for most of the experimental work. The sample size of the primary EEC for protein analysis in this study was small, and the 2D culture of primary EEC in vitro might have impaired its native epithelial polarity. WIDER IMPLICATIONS OF THE FINDINGS: Endometrial factors can lead to infertility, but the exact molecules involved in endometrial receptivity remain unclear. Human endometrial receptivity is best assessed by determining whether a human blastocyst can attach and implant onto the endometrium of interest. With the use of a human embryo surrogate named BAP-EB, we demonstrated the important roles of CDH1 and CTNND1 in human embryo attachment. In particular, we showed that homophilic binding between trophectodermal CDH1 and epithelial CDH1 was one of the major mediators of the first contact in embryo-maternal interaction. Embryo-derived factors induced apical redistribution of CTNND1 and CDH1 in the EEC. Most importantly, the expression of CDH1 on the apical region of EEC represented endometrial receptivity. The results strengthen our understanding of embryo-maternal interaction in humans, and CDH1 could potentially be used for predicting IVF outcomes, which helps clinicians to better counsel the couples who fail with ART. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by Grant for Fertility Innovation 2016 from Merck; Health and Medical Research Fund (grant numbers: HMRF 04151546; 10212996; 11222296) from the Food and Health Bureau, Government of the Hong Kong Special Administrative Region; InnoHK initiative of the Innovation and Technology Commission of the Hong Kong Special Administrative Region Government (Health@InnoHK); Shenzhen Science and Technology Program (Grant No. KQTD20190929172749226); General Research Fund (grant number: 17212922); Collaborative Research Fund C7100-22GF from the Research Grants Council of Hong Kong; and Shenzhen Sanming Project of Medicine (SZSM202211014). The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.
Second report of registry of the International Society of Uterus Transplantation (ISUTx): international activities 2000-2024.
Brännström M, Racowsky C, Wiik J … +17 more , Tullius SG, Deans R, Porrett PM, Andraus W, Koon TH, Carmona F, Akouri R, Scollo P, Solanki S, Vivek P, Smith JR, Puntambekar SP, Kim SE, Özkan Ö, Ayoubi JM, Fronek J, Brucker SY
Hum Reprod · 2026 Apr · PMID 41701557 · Full text
STUDY QUESTION: What have been the activities, characteristics, and outcomes of uterus transplantation (UTx) performed worldwide from 2000 through 2024? SUMMARY ANSWER: In 91 UTx cases, 67 involved live donors and 80 of...
STUDY QUESTION: What have been the activities, characteristics, and outcomes of uterus transplantation (UTx) performed worldwide from 2000 through 2024? SUMMARY ANSWER: In 91 UTx cases, 67 involved live donors and 80 of the recipients had Mayer-Rokitansky-Küster-Hauser syndrome, with 12-month graft survival of 74%, enabling pregnancy attempts that yielded 44 healthy singleton deliveries with a live birth rate per embryo transfer of 30.3%. WHAT IS KNOWN ALREADY: UTx is the only treatment for women with absolute uterine factor infertility who wish to carry a pregnancy. According to a comprehensive report including data up to 2020 on 45 UTx cases, 19 live births occurred (35.8% per embryo transfer) at a mean of 35.3 weeks gestation. STUDY DESIGN, SIZE, DURATION: Data were extracted from the web-based registry of the International Society of Uterus Transplantation (ISUTx). This registry captures information on donor and recipient characteristics, transplantation procedures, postoperative complications, immunosuppression, complications including rejections, and reproductive outcome. Analyses were undertaken of the 91 transplants performed between 6 April 2000 and 31 December 2024, that were recorded in the registry. PARTICIPANTS/MATERIALS, SETTING, METHODS: Twenty-four medical centers in five continents registered their uterus transplants by entering data from the day of transplantation until 3 months after graft removal. The following variables were assessed: the demographic and laboratory characteristics of donors and recipients, the source of graft (live versus deceased donor), surgical specifics including technique, duration, ischemic times, and post-op complications, immunosuppression, rejection data, pregnancy with live birth(s), and hysterectomy. MAIN RESULTS AND THE ROLE OF CHANCE: In 91 uterus transplantations (67 from live donors, 24 from deceased donors), the overall surgical success rate, defined as graft viability by 12 months, was 75%. Most recipients (88%) had Mayer-Rokitansky-Küster-Hauser syndrome, with mothers being the most frequent (64%) live donors. Live donor hysterectomies were performed by laparotomy (54%), robotics (28%), or laparoscopy (18%). Total ischemic time was shorter in live- versus deceased-donor UTx procedures. Rejection episodes that were treated with escalations of immunosuppression were more frequent during months 1-5 (44%) than during months 6-10 (28%) post-UTx. Graft survival during the first 12 months was superior when grafts from premenopausal donors were used as compared to from postmenopausal donors. Forty-four singleton live births (mean gestational length of 34.5 weeks), including eight second births, were reported, with a live birth rate per embryo transfer of 30%. Preeclampsia was the most common pregnancy complication, occurring in 23% of live-birth pregnancies. Major postnatal complications occurred in 11 infants, 9 with respiratory distress syndrome; no major malformations were observed. LIMITATIONS, REASONS FOR CAUTION: Data in the registry are self-reported and not subjected to validation. Although the ISUTx registry represents the most comprehensive quality registry of UTx activity in the world, cases from at least four centers are excluded as they were not entered into the registry. Birth outcomes from some registry cases are as yet unknown as these ongoing cases have not yet reached the endpoint of hysterectomy. WIDER IMPLICATIONS OF THE FINDINGS: This study presents the most comprehensive analysis to date of UTx, the only fertility treatment for absolute uterine factor infertility. The registry serves as the prime source for quality assessment and process improvement in UTx. STUDY FUNDING/COMPETING INTEREST(S): The establishment and operation of the registry were funded by the Swedish Research Council (2024-03487 to M.B.) and Jane and Dan Olsson Foundation (2024-11 to M.B.). There was no competing interest. TRIAL REGISTRATION NUMBER: Not applicable.
Single-step warming for blastocysts: a clinically validated alternative to conventional multi-step protocols.
De Gheselle S, De Vuyst L, Lierman S … +4 more , De Croo I, Vanden Meerschaut F, Stoop D, Tilleman K
Hum Reprod · 2026 Apr · PMID 41701553 · Publisher ↗
STUDY QUESTION: Can a single-step warming protocol for vitrified blastocysts provide comparable or superior outcomes to a conventional multi-step warming approach in a clinical IVF setting? SUMMARY ANSWER: Single-step wa...
STUDY QUESTION: Can a single-step warming protocol for vitrified blastocysts provide comparable or superior outcomes to a conventional multi-step warming approach in a clinical IVF setting? SUMMARY ANSWER: Single-step warming resulted in higher blastocyst survival, intactness, and transfer rates compared to the conventional multi-step protocol, with comparable ongoing pregnancy rates and a consistent trend toward lower miscarriage rates across all subgroups. WHAT IS KNOWN ALREADY: While vitrification has become the gold standard for embryo cryopreservation, the warming process remains critical to embryo survival and implantation potential. Traditional warming relies on multi-step dilution protocols to minimize osmotic stress. Preliminary studies have suggested that single-step rehydration protocols may be equally effective, but data on clinical validation remain scarce. STUDY DESIGN, SIZE, DURATION: A three-phase validation study was conducted at a single university-based IVF centre including (i) risk analysis, (ii) preclinical validation (n = 246 blastocysts), and (iii) a clinical comparison of outcomes over one year (March 2024-March 2025) between single-step warming (n = 1925 cycles) and the conventional multi-step protocol (n = 1744 cycles, March 2023-March 2024). PARTICIPANTS/MATERIALS, SETTING, METHODS: In the preclinical phase, vitrified surplus and PGT blastocysts were rewarmed using the single-step protocol and compared to historical controls. Survival (≥50% intact cells), intactness (100% intact), and transfer suitability were assessed. Single-step warmed blastocysts were monitored for 24 h post-warming in a time-lapse incubator, and viability was further evaluated using live/dead fluorescent staining to quantify cell damage. In the clinical phase, outcomes (survival, transfer rate, pregnancy, ongoing pregnancy, miscarriage) were retrospectively compared across protocols, stratified by PGT status and day of vitrification. MAIN RESULTS AND THE ROLE OF CHANCE: In the preclinical phase, blastocyst survival was ≥50% in 99.1% of cases after single-step warming versus 96.8% after multi-step warming (P = 0.0924). Fully intact blastocysts were significantly more frequent in the single-step group (85.4% vs. 76.3%, P = 0.0058), and transfer suitability at 2 h post-warming was also higher (96.7% vs. 91.2%, P = 0.0076). Time-lapse monitoring confirmed a high re-expansion rate (93.9%) with a mean re-expansion time of 3.3 ± 2.7 h. Fluorescent viability staining showed that 90.5% of blastocysts exhibited no or minimal cell damage. In the clinical cohort, significantly higher survival rates were seen in the single-step group across multiple subgroups, including non-PGT Day 5 (98.5% vs. 96.1%, P = 0.0003) and PGT Day 5 (100% vs. 98.2%, P = 0.0407) blastocysts. Fully intact rates were significantly higher in all subgroups and transfer rates were significantly higher in the single-step group for non-PGT Day 6 (97.2% vs. 92.8%, P = 0.0060) and PGT Day 5 cycles (100% vs. 97.8%, P = 0.0209). While some early pregnancy outcomes (e.g. clinical pregnancy in non-PGT Day 5) favoured the multi-step protocol (40.5% vs. 35.7%, P = 0.0286), ongoing pregnancy rates were not significantly different in any subgroup. Miscarriage rates showed a consistent trend in favour of single-step warming but did not reach statistical significance. LIMITATIONS, REASONS FOR CAUTION: This was a single-centre study, and the control group was retrospective. WIDER IMPLICATIONS OF THE FINDINGS: The single-step warming protocol is a clinically validated, safe, and efficient alternative to conventional multi-step warming. Its implementation may improve workflow and streamline blastocyst handling without compromising clinical outcomes. STUDY FUNDING/COMPETING INTEREST(S): No external funding was received. The authors declare no conflicts of interest apart from KT, who has received travel support related to the manuscript from Fuijifilm Irvine Scientific, in the form of payment to her institution. TRIAL REGISTRATION NUMBER: N/A.
The landscape of chromosomal aberrations in couples seeking assisted reproductive treatment.
Yuan S, Cheng D, Zhang Q … +33 more , Zheng Q, Zhang H, Zhang J, Mo L, Di Y, Liu X, Xiao D, Xiong Q, Wang Y, Yi D, Guo Y, She X, Yang Q, Nie S, Tan Q, Xie C, Wang Q, Song X, Zhang D, Hu X, Meng L, Peng Y, Du J, Hu L, Zhong C, Hu H, Li X, Zhang K, Feng L, Gong F, Lu G, Lin G, Tan YQ
Hum Reprod · 2026 Apr · PMID 41689847 · Publisher ↗
STUDY QUESTION: What are the prevalence, type, and stratified risks (reproductive failure subtype, sex, age, semen quality, and prior adverse pregnancy events) of chromosomal aberrations in couples seeking ART treatment...
STUDY QUESTION: What are the prevalence, type, and stratified risks (reproductive failure subtype, sex, age, semen quality, and prior adverse pregnancy events) of chromosomal aberrations in couples seeking ART treatment in a large-scale cohort study? SUMMARY ANSWER: The prevalence of chromosomal aberrations in couples with reproductive failure was 3.42%, with a higher prevalence in younger individuals, men with poorer semen quality, and those experiencing multiple adverse pregnancy outcomes. WHAT IS KNOWN ALREADY: Reproductive failure is a global health issue, with chromosomal aberrations playing an important role. ART is widely used for the treatment of reproductive failure; however, large-scale, comprehensive studies characterizing the stratified risks of chromosomal aberrations in couples seeking ART remain scarce. STUDY DESIGN, SIZE, DURATION: This retrospective study analysed chromosomal data from 227 818 couples seeking ART at our hospital between January 1993 and March 2024. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study included 227 818 couples with reproductive failure, including 130 213 couples with primary infertility, 58 161 with secondary infertility, and 39 444 with adverse pregnancy outcomes. All participants underwent routine cytogenetic analysis using GTG-banding prior to ART. Statistical analysis was performed using R software (v4.4.0), with significance set at P < 0.05. MAIN RESULTS AND THE ROLE OF CHANCE: Chromosomal aberrations were detected in 7785 couples (3.42%), with the highest prevalence in those with adverse pregnancy outcomes (4.83%), followed by those with primary infertility (3.54%) or secondary infertility (2.18%) (all P < 0.001). Significant sex differences were observed in infertile couples (men: 1.91% vs women: 1.52%) and couples with adverse pregnancy outcomes (men: 2.04% vs women: 2.81%), (P < 0.001). The prevalence of chromosomal aberrations was inversely correlated with age (2.36% in <25 years to 1.29% in ≥35 years) and increased significantly with poorer semen quality (0.89% in normozoospermia to 12.54% in azoospermia) and more adverse pregnancy events (3.07% in 1 event to 9.38% in ≥3 events, P < 0.001). Common structural aberrations included reciprocal and Robertsonian translocations and inversions, with frequent breakpoints at 11q23, 22q11, and 7q22. The percentage of haploid length of each autosome and the corresponding percentage of breakpoints showed a strong Pearson's correlation (R = 0.933, P < 0.001, two-tailed test). Robertsonian translocations and t(11;22)(q23;q11) were recurrent. The most frequent aneuploidies identified were 47,XXY (Klinefelter) and 45, X (Turner) syndromes, in both mosaic and non-mosaic forms. LIMITATIONS, REASONS FOR CAUTION: The lack of detailed clinical characteristics limited patient stratification and hindered the in-depth analysis of karyotype-phenotype relationships. The absence of a large fertile control group restricted comparative analysis. Conventional GTG-banding resolution may miss some cryptic chromosomal abnormalities. Single-centre data may limit the generalizability of our findings to more diverse populations. WIDER IMPLICATIONS OF THE FINDINGS: Stratified risk data (such as the higher prevalence of chromosomal aberrations in younger populations, individuals with poor semen quality, or those with a history of multiple adverse pregnancies) provide crucial evidence for clinicians to assess reproductive risks associated with chromosomal aberrations and make karyotyping decisions prior to ART treatment. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Key Research and Development Program of China (2023YFC2705605). The authors declare that there are no competing interests. TRIAL REGISTRATION NUMBER: N/A.
DNAH14 deficiency disrupts sperm annulus positioning and compromises offspring postnatal development.
Wang X, Shen G, Li J … +12 more , Ruan T, Jiang X, Ge Y, Ma J, Zhao S, Jiang C, Zhuo L, Tian Y, Zhao G, Tang X, Yang Y, Shen Y
Hum Reprod · 2026 Apr · PMID 41686705 · Publisher ↗
STUDY QUESTION: Does DNAH14 deficiency impair sperm flagellar integrity and contribute to male infertility? SUMMARY ANSWER: Loss of DNAH14 leads to disrupted sperm annulus positioning, defective mitochondrial assembly, r...
STUDY QUESTION: Does DNAH14 deficiency impair sperm flagellar integrity and contribute to male infertility? SUMMARY ANSWER: Loss of DNAH14 leads to disrupted sperm annulus positioning, defective mitochondrial assembly, reduced sperm motility, and impaired male fertility in both humans and mice. WHAT IS KNOWN ALREADY: Pathogenic variants in several axonemal dynein heavy chain (DNAH) genes have been implicated in male infertility and primary ciliary dyskinesia. DNAH14 remains the only member whose roles are undefined. STUDY DESIGN, SIZE, DURATION: Genetic analysis was performed on two unrelated Han Chinese infertile men. Functional studies were carried out in a CRISPR-Cas9 Dnah14 knockout (KO) mouse model, with phenotyping of males and their offspring. PARTICIPANTS/MATERIALS, SETTING, METHODS: Whole-exome sequencing was applied to patient samples. Dnah14 KO mice were generated to assess reproductive phenotypes. Sperm morphology and motility were analyzed using Papanicolaou staining, scanning electron microscopy (SEM), transmission electron microscopy (TEM), immunofluorescence staining, and computer-assisted sperm analysis (CASA). Intracytoplasmic sperm injection (ICSI) was performed in both patients and KO mice, and offspring survival and growth were monitored. MAIN RESULTS AND THE ROLE OF CHANCE: Biallelic DNAH14 variants were identified in two men with asthenoteratozoospermia. Patient HX-042 carried compound heterozygous variants c.1055T>C and c.9788T>C, whereas Patient HX-137 harbored compound heterozygous variants c.10434G>T and c.12512A>G. In both cases, sperm exhibited markedly reduced motility, disrupted annulus positioning and mitochondrial disorganization. DNAH14 was specifically localized to the midpiece of both human and mouse sperm. Dnah14 KO mice exhibited subfertility, characterized by reduced sperm motility, sperm mitochondrial sheath anomaly, annulus mislocalization, and midpiece bending, whereas ciliogenesis in non-reproductive tissues remained unaffected. ICSI achieved normal fertilization and embryonic development in both patients and KO mice. Offspring of KO males exhibited reduced survival and growth retardation. LARGE SCALE DATA: Not available. LIMITATIONS, REASONS FOR CAUTION: We have, for the first time, established genotype and phenotype associations of DNAH14/Dnah14 in humans and mice; however, mechanistic studies remain limited. Further in vivo investigations using animal models are necessary to elucidate the molecular mechanisms by which DNAH14 regulates the structural integrity of sperm flagella. In addition, potential epigenetic mechanisms underlying the role of DNAH14 in postnatal growth also warrant further clarification. WIDER IMPLICATIONS OF THE FINDINGS: These findings identify DNAH14 as a novel contributor to sperm flagellar architecture and male fertility, expanding the genetic spectrum of DNAH-related disorders. In particular, we identified a critical role of DNAH14 in the precise positioning of the sperm annulus, and further found that DNAH14 may regulate offspring growth and development through sperm epigenetic mechanisms, thereby revealing its important biological functions and providing new perspectives for genetic counselling in infertility. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Natural Science Foundation of China (82471650), Sichuan Science and Technology Program (2024YFFK0267), and the National Key Research and Development Program of China (2023YFC2706402). The authors declare no conflict of interests. TRIAL REGISTRATION NUMBER: N/A.
A prospective study of periconceptional perceived stress and rate of miscarriage.
Wesselink AK, Geller RJ, Lovett SM … +5 more , Nillni YI, Savitz DA, Rothman KJ, Hatch EE, Wise LA
Hum Reprod · 2026 Apr · PMID 41677054 · Full text
STUDY QUESTION: To what extent is perceived stress during preconception and pregnancy associated with miscarriage incidence? SUMMARY ANSWER: Perceived stress during early pregnancy, but not preconception, was associated...
STUDY QUESTION: To what extent is perceived stress during preconception and pregnancy associated with miscarriage incidence? SUMMARY ANSWER: Perceived stress during early pregnancy, but not preconception, was associated with higher miscarriage incidence. WHAT IS KNOWN ALREADY: Some studies have found that higher stress levels are associated with miscarriage risk. However, many of these studies were retrospective, focused on occupational stress only, and/or suffered from under-ascertainment of miscarriage. STUDY DESIGN, SIZE, DURATION: Pregnancy Study Online (PRESTO) is an ongoing prospective preconception cohort study that recruited participants during 2013-2025. Eligible participants were females aged 21-45 years, who resided in the USA or Canada and were trying to conceive without fertility treatments. Eligible partners were males aged ≥21 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: We collected data on perceived stress using the 10-item version of the Perceived Stress Scale (PSS-10) during preconception (every 8 weeks) and early pregnancy for female participants and during preconception only for male participants. We identified pregnancies and miscarriages on bimonthly follow-up questionnaires during preconception and additional questionnaires during early and late pregnancy and postpartum. We fit Cox proportional hazards regression models to estimate hazard ratios (HR) and 95% CIs for the effect of preconception PSS-10 scores (n = 11 189 female and 2656 male participants) and early pregnancy PSS-10 scores (n = 8319 female participants) on miscarriage incidence, adjusting for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: About 20% of the pregnancies ended in miscarriage, with the loss occurring at a median of six gestational weeks. Preconception PSS-10 scores in the female or male partner were not appreciably associated with miscarriage incidence. Female PSS-10 scores during gestational weeks 5-8 were strongly associated with higher miscarriage incidence: adjusted HRs for PSS-10 scores of 10-14, 15-19, 20-24, and ≥25 vs <10 in gestational weeks 5-8 were 1.38 (95% CI: 1.07, 1.77), 1.17 (95% CI: 0.89, 1.52), 1.35 (95% CI: 1.00, 1.83), and 2.05 (95% CI: 1.40, 2.99), respectively. In week-specific analyses, an association existed during weeks 4-8 and peaked at week 7. LIMITATIONS, REASONS FOR CAUTION: Our results may be susceptible to reverse causation, unmeasured confounding by nausea and vomiting in pregnancy, and exposure misclassification. WIDER IMPLICATIONS OF THE FINDINGS: Interventions aimed at decreasing stress during early pregnancy may be effective at reducing miscarriage incidence, but confirmation of our results in randomized studies is warranted. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01-HD086742, R01-HD105863). Lauren Wise has received in-kind donations for primary data collection in PRESTO from ChartNeo.com. The other authors have no conflicts to report. TRIAL REGISTRATION NUMBER: N/A.
Immature oocyte proportion may or may not compromise ICSI outcomes, but methods do: a critical appraisal.
Aktoz F, Sahin Y
Hum Reprod · 2026 Apr · PMID 41653408 · Publisher ↗
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Reply: immature oocyte proportion may or may not compromise ICSI outcomes, but methods do: a critical appraisal.
Sripada V, Sakkas D, Vaughan D … +2 more , Morse B, Fouks Y
Hum Reprod · 2026 Apr · PMID 41653405 · Publisher ↗
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The impact of endometrial fluid on single euploid frozen embryo transfers, to cancel or not?
Patel K, Sakkas D, Morse B … +3 more , Duvall DW, Penzias A, Vaughan DA
Hum Reprod · 2026 Mar · PMID 41639890 · Publisher ↗
STUDY QUESTION: What is the impact of endometrial fluid (EF) on single, euploid frozen embryo transfer (FET) cycles on live birth rate (LBR) and is cycle cancellation for EF a worthwhile intervention? SUMMARY ANSWER: The...
STUDY QUESTION: What is the impact of endometrial fluid (EF) on single, euploid frozen embryo transfer (FET) cycles on live birth rate (LBR) and is cycle cancellation for EF a worthwhile intervention? SUMMARY ANSWER: The LBR of single euploid FETs was significantly lower by 20.2 percentage points when EF was persistent on the day of decision for progesterone start/trigger, but despite the lower LBR, cycle cancellation may not confer an improved chance at live birth. WHAT IS KNOWN ALREADY: The incidence of EF in cycles ranges from 3% to 8%, thus, only a few small studies have been performed to evaluate its impact. Existing literature generally concludes that the presence of EF leading up to an embryo transfer is detrimental to successful implantation, however, these studies examined untested embryos. STUDY DESIGN, SIZE, DURATION: A retrospective cohort study was performed at a single, academically affiliated infertility center in the USA from January 2014 to December 2022. Inclusion criteria comprised patients who underwent their first IVF cycle, had pre-implantation genetic testing for aneuploidy performed by trophectoderm biopsy, had at least one euploid embryo, and were undergoing their first FET. Cycles were subdivided into three groups: no EF present in the cycle (no EF group), EF present but resolved prior to the day of decision for progesterone start/trigger (EF resolved group), and lastly, EF persistent on the day of decision for progesterone start/trigger (EF persistent group). Clinical outcomes were compared between the groups. In a secondary analysis, all single, euploid FET cycles that were cancelled due to EF were identified. The first subsequent completed single, euploid FET during the same study period was identified and analyzed. PARTICIPANTS/MATERIALS, SETTING, METHODS: Four thousand three hundred eight FET cycles met inclusion criteria. Four thousand one hundred forty documented no EF, 108 documented EF that resolved, and 60 documented EF that persisted. The primary outcome was LBR per ET. A logistic regression analysis was performed adjusting for baseline characteristics (age, BMI, gravidity, parity, reason for infertility) and cycle characteristics (method of fertilization, protocol, endometrial thickness achieved during FET, embryo grade/day cryopreserved). In our secondary analysis, 90 single, euploid FET cycles were identified as cancelled specifically due to the presence of EF. Following these 90 cancelled cycles, there were 58 cycles that were identified as the first subsequent completed FET after cancellation. For the first subsequent completed single, euploid FET after index cycle cancellation, the presence of EF and overall LBR were recorded. MAIN RESULTS AND THE ROLE OF CHANCE: When EF was present, but resolved prior to decision for progesterone start/trigger, the LBR was 9.4 percentage points lower compared to the no EF group, however, this did not reach statistical significance (49.1% vs 58.5%, aOR 0.71 (95% CI 0.47, 1.05)). When EF was persistent on ultrasound on day of decision for progesterone start/trigger, the LBR was significantly lower by 20.2 percentage points when compared to the no EF group (38.3% vs 58.5%, aOR 0.50 (95% CI 0.28, 0.88)). Of 58 subsequent FET cycles identified after initial FET cancellation, 23 demonstrated EF recurrence (but were not cancelled). The overall LBR for all 58 subsequent cycles was 39.7% which was not significantly different from the EF persistent group (aOR 0.99 (95% CI 0.38, 2.64)). LIMITATIONS, REASONS FOR CAUTION: The retrospective, single center design may limit generalizability. Analysis of only euploid embryos introduces selection bias. Challenges of studying EF include the variable and unknown etiology of EF and non-uniform documentation of quantity/measurement of EF. Given the low incidence of EF, the sample sizes are small in the EF groups but are similar in size to previous studies. Power analysis was conducted and to achieve an 80% chance of finding a 10% difference in LBR, 385 patients would be needed in each group. In light of the actual LBR difference of 20.2 percentage points (58.5% vs 38.3%), our sample size of 60 patients in the EF group provided an 88% chance of finding a statistically significant difference. WIDER IMPLICATIONS OF THE FINDINGS: The LBR was 9.4 percentage points lower when EF resolved and 20.2 percentage points lower when EF was persistent. We identified a small cohort of subsequent cycles after initial cycle cancellation and the LBR achieved in these cycles was similar to the LBR in the index transfer cycle if the transfer was performed even in the setting of persistent EF at time of progesterone start/trigger; perhaps if EF is persistent, cycle cancellation may not confer an improved LBR. Overall, many cases of EF likely result from underlying endometrial pathology. Patients should be counseled accordingly. STUDY FUNDING/COMPETING INTEREST(S): No funding was used for this study. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.
Public attitudes towards consent for the donation of surplus frozen eggs to research.
Langford J, Demaree-Cotton J, Johnston M
Hum Reprod · 2026 Mar · PMID 41633831 · Full text
STUDY QUESTION: In the context of donating surplus frozen eggs (SFE) to research, what level of information disclosure, and associated consent model, do the public believe most effectively allows donors to make an inform...
STUDY QUESTION: In the context of donating surplus frozen eggs (SFE) to research, what level of information disclosure, and associated consent model, do the public believe most effectively allows donors to make an informed decision, exercise autonomy, and be treated morally? SUMMARY ANSWER: The public supports the information disclosure requirements of both a specific and broad consent model in this context, with the latter considered to better enhance autonomy and facilitate the moral treatment of SFE donors. WHAT IS KNOWN ALREADY: Despite research indicating that many individuals' first preference is to donate their SFEs to research, donation rates remain low. One possible reason for this is the way consent processes for the donation of SFEs to research are currently regulated, specifically that their high information requirements limit opportunities to donate. There is a notable lack of research on how consent processes should operate, and more specifically, how much information a person should be provided before providing consent, in the context of donating SFEs to research. STUDY DESIGN, SIZE, DURATION: An online experimental survey of 225 participants was conducted. The survey assessed the impact of two variables-Information Disclosure and Preference Fulfilment-on participants' views towards whether a consent process allowed for informed, autonomous consent and the moral treatment of donors. PARTICIPANTS/MATERIALS, SETTING, METHODS: A nationally representative sample of the UK public was recruited using the online platform Prolific. The survey consisted of a vignette-based experimental design, one free-text question, and demographic data collection. Quantitative data were summarized using descriptive statistics and the relationship between variables was tested using ANOVAs and t-tests, where appropriate. Inductive content analysis through manual coding was performed on the free-text question. MAIN RESULTS AND THE ROLE OF CHANCE: Participants considered both specific and broad information disclosure as sufficient for informed consent (mean Consent Judgements M = 6.49/7 and M = 5.79/7, respectively). The ability to fulfil disposition preferences was critical to the public's assessment of whether a consent process enabled donors to act autonomously and be treated morally. Participants agreed that a potential donor was able to make an autonomous decision if their preference to donate their SFEs to research was fulfilled (mean Autonomy Judgement M = 5.46/7, mean Moral Judgement M = 5.63/7), but not when it was not (mean Autonomy Judgement M = 3.96/7, mean Moral Judgement: M = 4.76/7). LIMITATIONS, REASONS FOR CAUTION: Ecological validity of online surveys is limited, and data may be subject to response biases. Additionally, the sample size was relatively small. Finally, since the sample population was based in the UK, the generalizability of the survey findings to other countries may be limited. WIDER IMPLICATIONS OF THE FINDINGS: Our findings underscore the need to review and possibly update consent processes for the donation of SFEs to research. We encourage policy discussion in light of our findings, specifically the consideration of a shift towards a broad consent model. Doing so may allow more donors to fulfil their disposition preference, facilitate the movement of SFEs out of storage, and respond to the shortage of eggs currently available for research. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by The British Academy (grant number KF8\230096). The survey component of this study was funded by the Uehiro Oxford Institute. M.J. has received research funding from Monash IVF and Ferring Pharmaceuticals. She reports honorarium and travel support from Gideon Richter. TRIAL REGISTRATION NUMBER: N/A.
Contribution of endometrial microbiome to inflammation-mediated infertility in women undergoing ART.
Giangrazi F, Sugrue JA, Sularea VM … +6 more , Brugman AAI, Horan M, Wingfield M, Crosby DA, Glover LE, O'Farrelly C
Hum Reprod · 2026 Mar · PMID 41633818 · Full text
STUDY QUESTION: Is the endometrial microbiome altered in women who fail to get pregnant after ART and do microbial-derived metabolites influence endometrial cellular mechanisms important for embryo implantation? SUMMARY...
STUDY QUESTION: Is the endometrial microbiome altered in women who fail to get pregnant after ART and do microbial-derived metabolites influence endometrial cellular mechanisms important for embryo implantation? SUMMARY ANSWER: The endometrial microbiome in women who fail to get pregnant after ART is more diverse and has fewer lactobacilli species than the endometrial microbiomes of women who become pregnant; the short-chain fatty acid butyrate, a common metabolite found in the presence of increased microbial diversity, diminishes endometrial epithelial barrier function and increases the expression of inflammatory markers. WHAT IS KNOWN ALREADY: Shifts in the endometrial microbial community structure have been linked to fertility and pregnancy complications although the underlying mechanisms are poorly understood. Microbial metabolites at other mucosal surfaces, such as the gut, act as important modulators of immune and barrier function, particularly in epithelial cells. Effects of changes in local bacterial microbial populations on fertility, and how their metabolites might influence endometrial cell function have not been explored. STUDY DESIGN, SIZE, DURATION: In this prospective longitudinal study of ART outcomes, 29 nulliparous women with unexplained infertility were recruited between October 2016 and February 2018. Endometrial tissue samples were taken for microbiome analysis and endometrial transcriptomics prior to ART. For primary cell culture studies, endometrial biopsies were obtained from fertile women of reproductive age undergoing laparoscopic surgical investigation between February 2021 and September 2023. In vitro models of implantation were established using endometrial cell lines and primary endometrial stromal cells. PARTCIPANTS/MATERIALS, SETTING, METHODS: Microbiome 16S sequencing analysis was performed on bacterial DNA isolated from endometrial biopsies and correlated with receptivity markers. Endometrial RNA sequencing data from women undergoing ART were used to analyse differential gene expression of receptivity and decidualization markers in women who had a positive or negative ART cycle outcome. In vitro models, using both established endometrial cell lines and primary human endometrial epithelial cells and stromal cells, were developed to investigate the effects of microbial-derived metabolites. An in vitro model of peri-implantation was used to test the effect of butyrate on endometrial epithelial receptivity and stromal cell decidualization. MAIN RESULTS AND THE ROLE OF CHANCE: Endometrial microbiome 16S sequencing revealed a lower abundance of Lactobacillus spp. and significantly higher abundance of pathogenic species such as Prevotella spp. and Corynebacterium spp. in women who did not become pregnant after ART. Endometrial microbiota from women who had positive ART outcomes showed significantly lower diversity indices. Intriguingly, analysis of endometrial RNA sequencing data from women with unexplained infertility undergoing ART showed that negative ART outcomes were associated with higher levels of some receptivity and decidualization markers in their endometrial tissue. Butyrate, but not lactate or acetate, also increased some markers of epithelial receptivity and stromal decidualization. Butyrate exposure also activated defence mechanisms in cultured endometrial epithelial cells by inducing expression of antimicrobial peptide(s) and inflammation markers, as well as impairing the barrier integrity of endometrial epithelial cell monolayers. LARGE SCALE DATA: The RNA-seq data used for the study can be found in GEO database, GEO ID GSE144895. The data for the 16S sequencing can be accessed in SRA BioProject number PRJNA1338067. LIMITATIONS, REASONS FOR CAUTION: Limitations of our study include the cohort size and technical challenges that precluded absolute butyrate measurement in endometrial tissue biopsies. Biopsy collection from women undergoing gynaecological investigation varied in menstrual cycle staging and fertility diagnoses, which may contribute to the variability between responses obtained from in vitro stimulations. The transferred embryos were not genetically tested, but were all of good or top quality. WIDER IMPLICATIONS OF THE FINDINGS: Our findings indicate that the endometrial microbiome is altered in women who fail to become pregnant after ART, and that the microbial-derived metabolite butyrate can induce inflammation and impair endometrial epithelial barrier function and drive increased gene expression levels of markers for epithelial receptivity and stromal decidualization in in vitro models of peri-implantation. Endometrial microbial dysbiosis and higher expression of receptivity markers were found in women who failed to establish pregnancy post-ART. Negative ART outcomes in this cohort were found to correlate with the presence of a wider, more diverse microbial community that includes Prevotella spp., which is among the butyrate-producing bacteria. Further investigation of the microbial metabolome in healthy endometrium would help clarify the physiological role of butyrate and other bacterial metabolites in endometrial function. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the Grant for Fertility Innovation from Merck KGaA, grant award number 15692. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. TRIAL REGISTRATION NUMBER: N/A.
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