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WORLD UNIVERSITY DIRECTORY
Medical Education Human Reproduction - current issue
<span class="paragraphSection"><div class="boxTitle">Abstract</div>Mitochondria are the powerhouses of cell and play crucial roles in proper oocyte competence, fertilization, and early embryo development. Maternally inherited mitochondrial DNA (mtDNA) mutations can have serious implications for individuals, leading to life-threatening disorders and contribute to ovarian ageing and female infertility due to poor oocyte quality. Mitochondrial replacement techniques (MRTs) have emerged as a promising approach not only to replace defective maternal mitochondria in patients carrying mtDNA mutations, but also to enhance oocyte quality and optimize IVF outcomes for individuals experiencing infertility. There are two main categories of MRT based on the source of mitochondria. In the heterologous approach, mitochondria from a healthy donor are transferred to the recipient’s oocyte. This approach includes several methodologies such as germinal vesicle, pronuclear, maternal spindle, and polar body transfer. However, ethical concerns have been raised regarding the potential inheritance of third-party genetic material and the development of heteroplasmy. An alternative approach to avoid these issues is the autologous method. One promising autologous technique was the autologous germline mitochondrial energy transfer (AUGMENT), which involved isolating oogonial precursor cells from the patient, extracting their mitochondria, and then injecting them during ICSI. However, the efficacy of AUGMENT has been debated following the results of a randomized clinical trial (RCT) that demonstrated no significant benefit over conventional IVF. Recent developments have focused on novel approaches based on autologous, non-invasively derived stem cells to address infertility. While these techniques show promising results, further RCTs are necessary to establish their effectiveness and safety for clinical use. Only after robust evidence becomes available could MRT potentially become a viable treatment option for overcoming infertility and enabling patients to have genetically related embryos. This review aims to provide an overview of the current state of MRTs in addressing low oocyte quality due to mitochondrial dysfunction.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">STUDY QUESTION</div>Can a video clip detailing the patient journey decrease women’s anxiety on the day of their first oocyte retrieval?<div class="boxTitle">SUMMARY ANSWER</div>The video clip does not affect women’s anxiety on the day of their first oocyte retrieval.<div class="boxTitle">WHAT IS KNOWN ALREADY</div>IVF triggers anxious reactions in women and men, with peaks of anxiety on the day of (especially the first) oocyte retrieval as shown by reliable questionnaires and biomarkers of distress. Several trials showed that videos with preparatory information reduce women’s and men’s anxiety for out-patient procedures.<div class="boxTitle">STUDY DESIGN, SIZE, DURATION</div>This monocentric open-label randomized controlled trial (RCT) randomized (computerized 1:1 allocation) 190 heterosexual couples about to start their first IVF cycle during a 24 months’ recruitment period (2018–2020). In addition to the standard of care offered to both the intervention group and the control group, the intervention group received a video clip, the day prior to their first oocyte retrieval, detailing the patient journey on the day of oocyte retrieval. After completion of the RCT, 35 additional couples were recruited as part of a qualitative process evaluation (QPE).<div class="boxTitle">PARTICIPANTS/MATERIALS, SETTING, METHODS</div>Upon arrival at a private secondary care fertility centre in Belgium for their first oocyte retrieval, women and men independently filled out the State module of the ‘State-Trait Anxiety Inventory’ (STAI) and the ‘Infertility-Specific Distress Scale’ (IDS) and evaluated the novel intervention, if applicable. In addition, clinical and discontinuation outcomes were extracted from couples’ electronic medical records 24 months later. The data of 155 couples (76–79/group) were subjected to an intention-to-treat analysis. The 35 couples taking part in the QPE filled out two questionnaires assessing knowledge and, if applicable, took part in an in-depth interview on their experience watching the video clip, immediately before their first oocyte retrieval.<div class="boxTitle">MAIN RESULTS AND THE ROLE OF CHANCE</div>The video clip did not affect women’s anxiety on the day of oocyte retrieval (mean STAI-State score intervention group = 42.7 ± 8.1 vs control group = 42.1 ± 8.5, <span style="font-style:italic;">P</span> = 0.68). Men who watched the video clip were, however, significantly less anxious than men who did not watch it (35.8 (±6.4) vs 38.2 (±7.6), <span style="font-style:italic;">P</span> = 0.034). Surprisingly, infertility-specific distress was higher among women and men who watched the video clip, as compared to women and men who did not watch the video clip (mean Infertility-specific Distress (IDS) scale score for women, 25.8 (±4.9) vs 24.3 (±4.6), <span style="font-style:italic;">P</span> = 0.051; men, 22.6 (±5.0) vs 20.8 (±4.7), <span style="font-style:italic;">P</span> = 0.023). The QPE clarified that watching the video clip did not increase knowledge about what would happen but that some women and men found the visualization of invasive procedural steps more confrontational than the earlier received, abstract, written, and verbal information. All but one woman and all men in the intervention group would recommend the video clip to friends and family going through IVF. The intervention and control groups did not differ regarding secondary clinical and discontinuation outcomes.<div class="boxTitle">LIMITATIONS, REASONS FOR CAUTION</div>Due to the nature of the intervention it was not possible to blind the participants. Furthermore, we did not have an attention control group, which could have separated plausible benefits of the intervention from attentional effects, although limiting performance bias in educational intervention studies is difficult as study personnel cannot be blinded. Of note, this RCT was partially conducted during the COVID-19 pandemic; thus, postponement of the oocyte retrieval and plausible side effects of the pandemic itself might have impacted our results, but group differences are corrected by the randomized controlled design of our trial.<div class="boxTitle">WIDER IMPLICATIONS OF THE FINDINGS</div>Providing additional procedural information is interesting for clinics as patients recommended the video clip and as it decreased men’s anxiety on the day of couples’ first oocyte retrieval. The effect of the intervention was observed in a Dutch-speaking population, and investigating beneficial effects of the video clip in non-native speakers and patients with a lower education or literacy level may be of interest, as they are more prone to health information overload and often benefit from visual rather than verbal or written information.<div class="boxTitle">STUDY FUNDING/COMPETING INTEREST(S)</div>This research was supported by the Research Council of the KU Leuven (C14/18/106; project of J.V., K.P., and E.A.F.D.) and it is an Investigator Sponsored Study for Merck N.V./S.A., an affiliate of Merck KGaA, Darmstadt, Germany. Merck N.V./S.A. had no ultimate authority nor any other role in the design, data collection, data management, data analysis, data processing, data interpretation, and on the decision to submit this study for publication. T.M.D. is vice president and Head of Global Medicine Affairs Fertility, Research and Development, Merck Healthcare KGaA, Darmstadt, Germany. He is also a visiting professor in Reproductive Medicine and Biology at KU Leuven, Belgium and an adjunct professor at the Department of Obstetrics and Gynecology at the University of Yale, New Haven, USA. Neither his corporate role nor his academic roles represent a conflict of interest with respect to the work done by him for this study. The other co-authors have no conflict of interest.<div class="boxTitle">TRIAL REGISTRATION NUMBER</div>This trial is registered at clinicaltrials.gov as NCT03717805.<div class="boxTitle">TRIAL REGISTRATION DATE</div>10 October 2018<div class="boxTitle">DATE OF FIRST PATIENT’S ENROLMENT</div>29 October 2018</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">STUDY QUESTION</div>Is semen quality associated with the lifespan of men?<div class="boxTitle">SUMMARY ANSWER</div>Men with a total motile sperm count of >120 million could expect to live 2.7 years longer than men with total motile sperm count of >0–5 million.<div class="boxTitle">WHAT IS KNOWN ALREADY</div>Male infertility and semen quality have been suggested to be markers of morbidity and thus mortality, but the role of underlying disease present at time of semen quality evaluation has not been thoroughly assessed. The aim of this study was to determine the association between semen quality and mortality, and to assess the impact of the health of the man prior to semen quality assessment.<div class="boxTitle">STUDY DESIGN, SIZE, DURATION</div>The study was based on 78 284 men who had their semen quality assessed between 1965 and 2015 at the public semen analysis laboratory in the Copenhagen area, Denmark, due to reported couple infertility. Thus, the included men covered a wide range of semen quality. Semen quality assessment included semen volume, sperm concentration, and the proportion of motile and morphologically normal sperm, from which the total sperm count and the total motile sperm count were calculated. Utilizing the unique Danish national registers, follow-up of the men regarding all-cause mortality was performed with a median follow-up of 23 years (5–95th percentile: 8–45 years) during which 8600 deaths occurred, accounting for 11.0% of the total population.<div class="boxTitle">PARTICIPANTS/MATERIALS, SETTING, METHODS</div>Life expectancy was calculated according to semen quality. Furthermore, the relative differences in mortality were estimated using Cox regression analyses and presented as hazard ratios (HRs) with 95% CIs. A more recent subpopulation of 59 657 men delivered semen samples between 1987 and 2015, a period in which information on educational level and diseases prior to semen sampling was available and adjusted for in Cox regression analyses.<div class="boxTitle">MAIN RESULTS AND THE ROLE OF CHANCE</div>Men with a total motile count of >120 million could expect to live 80.3 years, compared to 77.6 years among men with total motile count of >0–5 million. In Cox regression analyses, all semen parameters were negatively associated with mortality in a dose–response manner both in the total population and the more recent subpopulation (<span style="font-style:italic;">P</span>-trend for all semen parameters <0.001), and adjustment for educational levels and prior diagnoses did not change the estimates in the latter. Looking at total motile sperm count as an example, men with a total motile sperm count >120 million served as the reference, and the adjusted HRs for all-cause mortality in the more recent subpopulation were: azoospermia: 1.39, >0–5 million: 1.61, >5–10 million: 1.38, >10–40 million: 1.27, >40–80 million: 1.16, >80–120 million: 1.19, <span style="font-style:italic;">P</span>-trend < 0.001.<div class="boxTitle">LIMITATIONS, REASONS FOR CAUTION</div>The study was well-powered and included a unique database of results from semen analyses combined with register follow-up. However, we did not have information on health behaviours, and assessment of the health of men prior to semen sampling was limited to diagnoses obtained from the National Patient Register, and only applied to a subpopulation of men. A further limitation is that the group of men with azoospermia represents a heterogeneous group regarding testicular function as they could not be stratified into those having obstructive azoospermia and those having non-obstructive azoospermia.<div class="boxTitle">WIDER IMPLICATIONS OF THE FINDINGS</div>We observed clear negative dose–response associations between all semen parameters and all-cause mortality. The associations were not explained by educational levels or diseases registered at the time of semen evaluation. Thus, some men with impaired semen quality may experience less healthy ageing than men with better semen quality and could benefit from being identified at the time of semen quality evaluation. However, finding relevant biomarkers to identify the subgroups of men at increased risk will be key to initiating relevant prevention strategies.<div class="boxTitle">STUDY FUNDING/COMPETING INTEREST(S)</div>Funding for this study was received from Johan and Hanne Weimann, F. Seedorff’s grant (F-24230-01), and the Research Fund of the Capital Region of Denmark (R-153-A6176). None of the funders had any role in the study design, collection, analysis or interpretation of data, writing of the article, or publication decisions. The authors declare they have no competing interests.<div class="boxTitle">TRIAL REGISTRATION NUMBER</div>N/A.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">STUDY QUESTION</div>Could real-time monitoring of volatile organic compounds (VOCs) in the embryology laboratory provide meaningful early warning for potential harm from the environment?<div class="boxTitle">SUMMARY ANSWER</div>Even in a laboratory environment with a total VOC concentration lower than the recommendation of the Cairo Consensus, the real-time monitored VOC concentrations are associated with changes in embryo morphological parameters.<div class="boxTitle">WHAT IS KNOWN ALREADY</div>VOCs have been considered a key environmental detriment in embryology laboratories. However, the current VOC thresholds established by the Cairo consensus were based on the practical experience of air pollution cases, and a scientifically derived threshold is lacking.<div class="boxTitle">STUDY DESIGN, SIZE, DURATION</div>The study included 7076 oocyte collection (OPU) cycles carried out between June 2020 and December 2022 in the Center for Reproductive Medicine of the affiliated Chenggong Hospital of Xiamen University, 6306 of which resulted in at least one embryo transfer (ET) attempt during the study. VOC monitoring data were recorded every 10 min. The average and peak concentrations of total VOCs and formaldehyde during culture were associated with embryo parameters and implantation following the first ET attempt of the cycle in generalized estimating equations and generalized additive models.<div class="boxTitle">MAIN RESULTS AND THE ROLE OF CHANCE</div>Real-time monitoring of VOCs showed a dynamic of VOC concentration in the laboratory. The concentration reached peaks during the working hours of the days and working days of the week and fell quickly at night and on weekends. The average concentrations of VOCs during the culture period were linearly associated with decreased early cleavage (OR 0.92, 95% CI: 0.85, 0.99), decreased Day 3 compaction (OR 0.51, 95% CI: 0.32, 0.83), increased asymmetry (OR 1.13, 95% CI: 1.01, 1.25), and increased grade C trophectoderm (TE) (OR 1.99, 95% CI: 1.32, 3.01). On the other hand, increased Day 3 arrest, delayed blastocyst formation, and decreased grade A TE showed a non-linear association with VOCs, suggesting a possible threshold of effect. In the first transfer attempt, negative associations were observed between maximal formaldehyde concentrations and pregnancy in both fresh transfer (RR 0.971, 95% CI: 0.94, 0.99) and freeze-all frozen-thawed ET (RR 0.959, 95% CI: 0.92, 0.99) cycles.<div class="boxTitle">LIMITATIONS, REASONS FOR CAUTION</div>The sensitivity and specificity of the monitor are not comparable to the standard protocols, such as chromatography-mass spectroscopy. Due to the lack of ability to identify the chemical nature of the components of VOCs, the toxicity and source of the VOCs were largely unknown. The representative sampling of the laboratory air may not necessarily reflect the exposure of embryos.<div class="boxTitle">WIDER IMPLICATIONS OF THE FINDINGS</div>While the environment of the embryology laboratory has been significantly improved, the data suggested that a low VOC level could still be a concern. Due to the dynamic of VOC concentration in the laboratory air, periodic monitoring may fail to capture the increased VOC levels and give an early alarm.<div class="boxTitle">STUDY FUNDING/COMPETING INTEREST(S)</div>This work was supported by the National Natural Science Foundation of China [grant number 22176159], the Xiamen Medical Advantage subspecialty construction project [grant number 2018296], and the Wu Jieping Medical Foundation [grant number 320.6750.2024-6-14]. All authors declare no competing interests.<div class="boxTitle">TRIAL REGISTRATION NUMBER</div>N/A.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div>Despite significant advances in fertility preservation, no proven pharmacological options exist to protect ovarian primordial follicle reserve from chemotherapy-induced damage. Developing targeted gonadoprotective treatments will require an improved understanding of the molecular mechanisms underlying chemotherapy-induced primordial follicle depletion. While there is robust evidence that gonadotoxic chemotherapy induces primordial follicle death by causing DNA double-strand breaks which trigger apoptotic death, follicle activation leading to ‘burn-out’ of the ovarian reserve has been suggested as an alternative mechanism. Here, we critically evaluated whether primordial follicle activation is a significant mechanism of chemotherapy-induced ovarian reserve depletion in humans. We assessed the causal relationship between chemotherapy exposure and primordial follicle activation by applying the Bradford Hill criteria.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">STUDY QUESTION</div>What are the patterns of health service use (HSU) before and after endometriosis diagnosis?<div class="boxTitle">SUMMARY ANSWER</div>Women with endometriosis had higher rates of visits to general practitioners (GPs), specialists, and diagnostic imaging before and after diagnosis compared to those without the condition; however, after diagnosis, their visits to GPs and specialists other than obstetricians/gynaecologists decreased compared to before, while visits to obstetricians/gynaecologists and use of diagnostic imaging increased.<div class="boxTitle">WHAT IS KNOWN ALREADY</div>Women with endometriosis have higher rates of healthcare use compared to those without the condition; however, no longitudinal study has examined patterns of HSU over a prolonged period before and after diagnosis.<div class="boxTitle">STUDY DESIGN, SIZE, DURATION</div>The Australian Longitudinal Study on Women’s Health linked to a national administrative health record. A total of 30 473 women, born in 1973–1978 and 1989–1995, from two cohorts with data collected from 1996 to 2021, as online or postal questionnaires.<div class="boxTitle">PARTICIPANTS/MATERIALS, SETTING, METHODS</div>Women with endometriosis were identified using the self-report surveys and their administrative health records. A control group of women without endometriosis was randomly selected and age-matched with women with endometriosis. The final sample included 9545 women from the 1973–1978 cohort (1909 cases, 7636 controls) and 7510 from the 1989–1995 cohort (1502 cases, 6008 controls). Women’s HSU was assessed using the Medicare Benefits Schedule database. A random intercept zero-inflated negative binomial model was used to compare outcomes between cases and controls, addressing skewed data, over-dispersion, and excess zeros.<div class="boxTitle">MAIN RESULTS AND THE ROLE OF CHANCE</div>In both cohorts, women with endometriosis had a higher level of HSU, both before and after diagnosis, compared with those without the condition. For the 1973–1978 cohort, women with endometriosis had a higher rate of visits to GPs before and after diagnosis (adjusted incidence rate ratio: 1.19, 95% CI 1.14, 1.23 and 1.24, 95% CI 1.19, 1.30, respectively), specialists other than obstetricians/gynaecologists (1.50, 95% CI 1.40, 1.61, and 1.36, 95% CI 1.27, 1.46), and for diagnostic imaging (1.15, 95% CI 1.10, 1.21, and 1.20, 95% CI 1.15, 1.26). The average number of these visits remained consistent in the early years, peaked around 3 years before diagnosis, and then partly declined post-diagnosis, to later stabilize at a higher level than those without the condition. Following the diagnosis, women with endometriosis had a higher number of visits to obstetricians/gynaecologists (1.11, 95% CI 1.05, 1.17) than their matched controls, with a marked increase in the first 6 years post-diagnosis, but gradually returned to same levels as the control group. After diagnosis, women with endometriosis had a lower rate of visits to GPs (0.95, 95% CI 0.93, 0.98) and specialists other than obstetricians/gynaecologists (0.88, 95% CI 0.82, 0.93) compared to before their diagnosis, while they had a higher rate of visits to obstetricians/gynaecologists (1.09, 95% CI 1.01, 1.18) and diagnostic imaging (1.07, 95% CI 1.01, 1.14). Similar patterns of HSU were observed in the 1989–1995 cohort, regardless of whether surgically confirmed or clinically suspected cases of endometriosis were used, though the evidence for changes in specific HSU before and after diagnosis was weaker.<div class="boxTitle">LIMITATIONS, REASONS FOR CAUTION</div>Approximately half of the women with endometriosis were clinically suspected cases without laparoscopic confirmation, which may result in an overestimation of prevalence and introduce the risk of misdiagnosis, potentially influencing clinical management and research findings.<div class="boxTitle">WIDER IMPLICATIONS OF THE FINDINGS</div>The continued high level of HSU among women with endometriosis, even over a decade after diagnosis, suggests that they have substantially greater healthcare needs than other women. The distinct patterns of the use of healthcare in the years before and after endometriosis diagnosis can support efforts to improve diagnosis, management, and treatment outcomes for patients and to reduce healthcare costs.<div class="boxTitle">STUDY FUNDING/COMPETING INTEREST(S)</div>The Australian Longitudinal Study on Women’s Health is funded by the Australian Government Department of Health and Aged Care. G.D.M. and G.M. are Australian National Health and Medical Research Council Leadership Fellows (GNT2009577 and GNT1177194). D.G.G. was funded by MRFF EndoAIMM (RFEHP100126). Funding sources had no role in the study design, data analysis, interpretation, or manuscript writing. The authors have no conflict of interest to declare.<div class="boxTitle">TRIAL REGISTRATION NUMBER</div>N/A.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">STUDY QUESTION</div>How does the burden of somatic disorders compare between women with surgically verified endometriosis diagnosed in adolescence or early adulthood, and matched women without a history of endometriosis?<div class="boxTitle">SUMMARY ANSWER</div>Women with endometriosis diagnosed at a young age had a higher incidence of several somatic disorders and a higher number of hospital visits compared to women without endometriosis.<div class="boxTitle">WHAT IS KNOWN ALREADY</div>Endometriosis is associated with an increased risk of several somatic disorders, including autoimmune, inflammatory, and pain-related disorders with higher utility of health care resources. There may be differences in the experience of pain relating to the subtypes of endometriosis. Depression and anxiety are linked to endometriosis and increase overall somatic comorbidity.<div class="boxTitle">STUDY DESIGN, SIZE, DURATION</div>Longitudinal retrospective register-based cohort study utilizing episode data from specialized care; 2680 women under 25 years with a surgical of diagnosis endometriosis in 1998–2012, and 5338 reference women of the same age and municipality followed up from the index day to the end of 2019, emigration, death or the outcome of interest.<div class="boxTitle">PARTICIPANTS/MATERIALS, SETTING, METHODS</div>We analysed incidence rates, cumulative incidence rates, and crude hazard rate ratios (HR) with 95% CIs across 15 groups of somatic disorders. Subgroup analyses were conducted among women with endometriosis, by (i) type of endometriosis—ovarian only (n = 601) versus combined types (n = 2079), and (ii) pre-existing diagnosis of depression or anxiety (n = 270) versus those without such diagnoses (n = 2410).<div class="boxTitle">MAIN RESULTS AND THE ROLE OF CHANCE</div>Women reached a median age of 38 (IQR 34–42) years after a median follow-up of almost 16 (12, 19) years. Compared to the reference cohort, women with endometriosis had a higher incidence of several somatic disorders during the follow-up. By the age of 40 years, 38% of women with endometriosis and 9% of the reference cohort had diagnoses of infertility (HR 5.88 [95% CI 5.24–6.61]). The corresponding figures for genital tract infections were 24% and 6% (4.64 [4.03–5.36]), symptoms and signs of pain 62% and 28% (3.27 [3.04–3.51]), migraine 15% and 6.4% (2.49 [2.13–2.92]), and chronic pain conditions 33% and 19% (2.01 [1.83–2.22]), respectively. In women with endometriosis, a higher incidence was seen also for dyspareunia, uterine myomas, celiac disease, asthma, anaemia, high blood pressure, hypercholesterolemia or cardiovascular diseases; autoimmune diseases, and disorders of the thyroid gland. For women with ovarian endometriosis only, we observed a lower HR of high blood pressure, hypercholesterolemia or cardiovascular diseases, asthma, migraine, and pain-related disorders compared to those with other or combined types of endometriosis. Within the endometriosis cohort, women with pre-existing diagnoses of depression or anxiety had higher HRs of several somatic disorders compared to those without such diagnoses. The number of hospital visits after the index day was higher in women with endometriosis when compared to the reference cohort (40 vs 18).<div class="boxTitle">LIMITATIONS, REASONS FOR CAUTION</div>Confounding bias may arise from the reliance on registry-based hospital diagnoses, as women undergoing surgery are already engaged with health care, and, subsequently, more likely to receive new diagnoses. Furthermore, the homogenous population of Finland limits the generalizability of these findings.<div class="boxTitle">WIDER IMPLICATIONS OF THE FINDINGS</div>Surgical diagnosis of endometriosis at a young age is associated with a burden of somatic disorders, emphasizing importance of comprehensive approach to management of endometriosis and endometriosis-related conditions. Further studies are needed to clarify the varying reasons behind these associations. However, the results of this study suggest that pain and mental health may play a key role in the development of subsequent somatic disorders. Therefore, careful management of primary dysmenorrhea and mental health in young women is essential.<div class="boxTitle">STUDY FUNDING/COMPETING INTEREST(S)</div>Funding was received from the Hospital District of Helsinki and Uusimaa, and from Finska Läkaresällskapet. E.R. acknowledges financial support from The Finnish Society of Research for Obstetrics and Gynaecology and The Finnish Medical Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. O.H. serves occasionally on advisory boards for Bayer AG, Gedeon Richter, and Roche, has received travel support from Gedeon Richter, has received consulting fees from Orion Pharma and Nordic Pharma, and has helped to organize and lecture at educational events for Bayer AG and Gedeon Richter. The other authors report no conflict of interest concerning the present work.<div class="boxTitle">TRIAL REGISTRATION NUMBER</div>N/A.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">STUDY QUESTION</div>Can a large-scale genome-wide association study (GWAS) meta-analysis identify genomic risk loci and likely involved genes for female genital tract (FGT) polyps, provide insights into the biological mechanism underlying their development, and inform of potential overlap with other traits, including endometrial cancer?<div class="boxTitle">SUMMARY ANSWER</div>GWAS meta-analysis of FGT polyps highlights potentially shared mechanisms between polyp development and cancerous processes.<div class="boxTitle">WHAT IS KNOWN ALREADY</div>Small-scale candidate gene studies have focused on biological processes such as oestrogen stimulation and inflammation to clarify the biology behind FGT polyps. However, the exact mechanism for the development of polyps is still elusive. At the same time, a genome-wide approach, which has become the gold standard in complex disease genetics, has never been used to uncover the genetics of the FGT polyps.<div class="boxTitle">STUDY DESIGN, SIZE, DURATION</div>We performed a GWAS meta-analysis including a total of 36 984 women with FGT polyps (International Classification of Diseases (ICD-10) diagnosis code N84) and 420 993 female controls (without N84 code) of European ancestry from the FinnGen study (11 092 cases and 94 394 controls), Estonian Biobank (EstBB, 14 008 cases and 112 799 controls), and the Pan-UKBB study (11 884 cases and 213 800 controls).<div class="boxTitle">PARTICIPANTS/MATERIALS, SETTING, METHODS</div>GWAS meta-analysis and functional annotation of GWAS signals were performed to identify genetic risk loci and prioritize genes in associated loci. To explore associations with other traits, we performed a look-up of associated variants across multiple traits and health conditions, genetic correlation analysis, and phenome-wide association study (PheWAS) with ICD-10 diagnosis codes.<div class="boxTitle">MAIN RESULTS AND THE ROLE OF CHANCE</div>Our GWAS meta-analysis revealed 16 significant (<span style="font-style:italic;">P</span> < 5 × 10<sup>−8</sup>) genomic risk loci. Based on exonic variants in GWAS signals, we prioritized <span style="font-style:italic;">EEFSEC</span>, <span style="font-style:italic;">ODF3</span>, <span style="font-style:italic;">PRIM1</span>, <span style="font-style:italic;">PLCE1</span>, <span style="font-style:italic;">LRRC34/MYNN</span>, <span style="font-style:italic;">EXO1</span>, and <span style="font-style:italic;">CHEK2</span> which are involved in DNA repair, cell proliferation, and cell growth. Several of the identified genomic loci have previously been linked to endometrial cancer and/or uterine fibroids, highlighting the potentially shared mechanisms underlying tissue overgrowth and cancerous processes. Genetic correlation analysis revealed a positive correlation with body mass index and reproductive traits, that can be classified as symptoms or risk factors of endometrial polyps (EPs), whereas a negative correlation was observed between FGT polyps and both menopause (genetic correlation estimate (rg) = −0.29, SE = 0.08, <span style="font-style:italic;">P</span> = 8.8×10<sup>−4</sup>) and sex hormone-binding globulin (SHBG) (rg = −0.22, SE = 0.04, <span style="font-style:italic;">P</span> = 2.4×10<sup>−8</sup>). On the phenotypic level, the strongest associations were observed with endometriosis, uterine fibroids, and excessive, frequent, and irregular menstruation.<div class="boxTitle">LARGE SCALE DATA</div>The complete GWAS summary statistics will be made available after publication through the GWAS Catalog (<a href="https://www.ebi.ac.uk/gwas/">https://www.ebi.ac.uk/gwas/</a>).<div class="boxTitle">LIMITATIONS, REASONS FOR CAUTION</div>In this study, we focused broadly on FGT polyps and did not differentiate between the polyp subtypes. Considering the prevalence of FGT polyp subtypes, we assumed that most women included in the study had EPs. Further research on the expression profile of FGT polyps could complement the GWAS study to substantiate the functional importance of the identified variants.<div class="boxTitle">WIDER IMPLICATIONS OF THE FINDINGS</div>The study findings have the potential to significantly enhance our understanding of the genetic mechanisms involved, paving the way for future functional follow-up, which in turn could improve the diagnosis, risk assessment, and targeted treatment options, since surgery is the only line of treatment available for diagnosed polyps.<div class="boxTitle">STUDY FUNDING/COMPETING INTEREST(S)</div>This study was funded by European Union through the European Regional Development Fund Project No. 2014-2020.4.01.15-0012 GENTRANSMED. Computations were performed in the High-Performance Computing Center of the University of Tartu. The study was also supported by the Estonian Research Council (grant no. PRG1076 and MOBJD1056) and Horizon 2020 innovation grant (ERIN, grant no. EU952516). All the authors declared no conflict of interest.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">STUDY QUESTION</div>What is the best-performing model currently predicting live birth outcomes for IVF or ICSI?<div class="boxTitle">SUMMARY ANSWER</div>Among the identified prognostic models, McLernon’s post-treatment model outperforms other models in both the meta-analysis and external validation of a Chinese cohort.<div class="boxTitle">WHAT IS KNOWN ALREADY</div>With numerous similar models available across different time periods and using various predictors in IVF prognostic models, there is a need to summarize and evaluate them, due to a lack of validated evidence distinguishing high-quality from low-quality prediction tools. However, there is a notable dearth of research in the form of meta-analysis or external validation assessing the performance of models in predicting live births in this field.<div class="boxTitle">STUDY DESIGN, SIZE, DURATION</div>The researchers conducted a comprehensive literature review in PubMed, EMBASE, and Web of Science, using keywords related to prognostic models and IVF/ICSI live birth outcomes. The search included studies published up to 3 April 2024, and was limited to English language studies.<div class="boxTitle">PARTICIPANTS/MATERIALS, SETTING, METHODS</div>The review included studies that developed or validated prognostic models for IVF live birth outcomes while providing clear reports on model characteristics. Researchers extracted and analysed the data in accordance with the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and other model-related guidelines. For model effects in meta-analysis, the choice would be based on the heterogeneity assessed using the <span style="font-style:italic;">I</span><sup>2</sup> statistic and the Cochrane <span style="font-style:italic;">Q</span> test. Model performance was evaluated by assessing their area under the receiver operating characteristic curves (AUCs) and calibration plots in the studies.<div class="boxTitle">MAIN RESULTS AND THE ROLE OF CHANCE</div>This review provides a comprehensive summary of data derived from 72 studies with an overall ROB of high or unclear. These studies contained a total of 132 predictors and 86 prognostic models, and then meta-analyses were performed for each of the five selected models. The total random effects of Templeton’s, Nelson’s, McLernon’s pre-treatment and post-treatment model demonstrated AUCs of 0.65 (95% CI: 0.61–0.69), 0.63 (95% CI: 0.63–0.64), 0.67 (95% CI: 0.62–0.71), and 0.73 (95% CI: 0.71–0.75), respectively. The total fixed effects of the intelligent data analysis score (iDAScore) model estimated an AUC of 0.66 (95% CI: 0.63–0.68). The external validation of the initial four models in our cohort produced AUCs ranging from 0.53 to 0.58, and the calibration was confirmed through calibration plots.<div class="boxTitle">LIMITATIONS, REASONS FOR CAUTION</div>While the focus on English-language studies and live birth outcomes may constrain the generalizability of the findings to diverse populations, this approach equips clinicians, who view live births as the ultimate objective, with more precise and actionable reference guidelines.<div class="boxTitle">WIDER IMPLICATIONS OF THE FINDINGS</div>This study represents the first meta-analysis in the field of IVF prediction models, definitively confirming the superior performance of McLernon’s post-treatment model. The conclusion is reinforced by independent validation from another perspective. Nevertheless, further investigation is warranted to develop new models and to externally validate existing high-performing models for prognostic accuracy in IVF outcomes.<div class="boxTitle">STUDY FUNDING/COMPETING INTEREST(S)</div>This study was supported by the National Natural Science Foundation of China (Grant No. 82174517). The authors report no conflict of interest.<div class="boxTitle">REGISTRATION NUMBER</div>2022 CRD42022312018.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">STUDY QUESTION</div>How frequently do infertility trials report live birth and pregnancy, and how consistently were their definitions reported?<div class="boxTitle">SUMMARY ANSWER</div>One-third of 1425 infertility trials published in the last decade reported live birth, with one in eight reporting clinical pregnancy, ongoing pregnancy, and live birth concurrently; absent, ambiguous, or heterogeneous definitions were common.<div class="boxTitle">WHAT IS KNOWN ALREADY</div>Absent or inconsistent outcome definitions in randomized controlled trials (RCTs) limit their interpretation and complicate subsequent evidence synthesis. While reporting live birth in infertility trials has been a long-running recommendation, the extent to which this is adhered to, and the temporal trend of adherence, is unclear. Furthermore, it is unknown if outcome reporting in infertility trials is clear and consistent.<div class="boxTitle">STUDY DESIGN, SIZE, DURATION</div>We studied all RCTs in infertility published between 2012 and 2023. We aimed to assess (i) whether biochemical pregnancy, clinical pregnancy, ongoing pregnancy, and live birth were reported; the temporal trends in reporting these pregnancy outcomes, and compare the characteristics of trials reporting each type of outcome; (ii) whether and how these pregnancy outcomes were defined.<div class="boxTitle">PARTICIPANTS/MATERIALS, SETTING, METHODS</div>We systematically searched Embase, Medline, and CENTRAL for RCTs in infertility from January 2012 to August 2023. RCTs involving infertile women that reported either biochemical pregnancy, clinical pregnancy, ongoing pregnancy, or live birth were eligible. Secondary analyses, interim analyses, or conference abstracts were not eligible. Two authors independently screened articles. We extracted pregnancy definitions and trial characteristics primarily using text mining in R, a programming environment for data analysis, and supplemented by manual checking. The accuracy of extracted data was validated in a random sample of 50 articles, with sensitivity and specificity all at or above 90%.<div class="boxTitle">MAIN RESULTS AND THE ROLE OF CHANCE</div>We included 1425 infertility RCTs. Among these, 419 (29.4%) reported biochemical pregnancy. While 1359 (95.4%) RCTs reported clinical pregnancy, 404 (28.4%) reported ongoing pregnancy, and 484 (34.0%) reported live birth, only 174 (12.2%) reported all three outcomes. The proportion of trials reporting live birth increased from 23.1% in 2012 to 33.7% in 2023. Trials reporting up to biochemical pregnancy or clinical pregnancy were more likely to be unregistered, smaller, single-centered, and published in non-first quarter journals. Definitions for biochemical, clinical, ongoing pregnancy, and live birth were provided in 68.5% (287/419), 64.5% (876/1359), 70.5% (285/404), and 41.1% (199/484) of articles reporting on these outcomes. Among 876 clinical pregnancy definitions, 63.4% (n = 555) specified the pregnancy confirmation timing. Of the 220 definitions that reported gestational weeks (ranging from 4 to 16 weeks), the most common cut-off was 6 weeks, used in 48.2% (n = 106) of cases. For ongoing pregnancy definitions, 96.1% (n = 274) of the 285 definitions included gestational age in weeks (ranging from 6 to 32 weeks), with 12 weeks being the most common cut-off used in 49.1% (n = 140) of definitions. Among 199 live birth definitions, 62.3% (n = 124) used a gestational age threshold (ranging from 20 to 37 weeks), with 24 weeks being the most common cut-off, used in 28.6% (n = 57) of trials.<div class="boxTitle">LIMITATIONS, REASONS FOR CAUTION</div>Due to the vast data we needed to extract, we used text-mining supplemented by manual data extraction. While we optimized the text-mining algorithm attempting to identify all types of outcome definitions and manually curated all extracted definitions, definitions were missed in less than 10% of randomly checked studies, which is a limitation of this study. We only described definition patterns in published RCTs, and our results cannot be extrapolated to unpublished RCTs.<div class="boxTitle">WIDER IMPLICATIONS OF THE FINDINGS</div>Despite long-standing recommendations to report live birth in infertility trials, in the last decade only a third of RCTs did so. This highlights a disconnection between the advocated outcome and what researchers are reporting. We observed an encouraging trend that there has been a consistent rise in the proportion of trials reporting live birth. Furthermore, the significant lack and variability of pregnancy definitions underscore the imperative to increase the dissemination and uptake of standardized pregnancy outcomes.<div class="boxTitle">STUDY FUNDING/COMPETING INTEREST(S)</div>No funding was received for the study. Q.F. reports receiving a PhD scholarship from Merck. B.W.M. is supported by an NHMRC Investigator grant (GNT1176437). B.W.M. reports consultancy, travel support, and research funding from Merck and consultancy for Organon and Norgine. B.W.M. holds stock from ObsEva. W.T.L. is supported by an NHMRC Investigator grant (GTN2016729). W.L.L. reports receiving a PhD scholarship from the China Scholarship Council. T.D.H and S.L. are employees of Merck Healthcare KGaA, Darmstadt, Germany. R.W. is supported by an NHMRC Investigator grant (GTN2009767). The other author has no conflict of interest to declare.<div class="boxTitle">REGISTRATION NUMBER</div>CRD42024498624.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">STUDY QUESTION</div>Does the maternal pregnancy history affect the course of their offspring’s pubertal development?<div class="boxTitle">SUMMARY ANSWER</div>Maternal pregnancy history, particularly adverse outcomes, significantly influences the timing of menarche and the tempo of breast development in girls.<div class="boxTitle">WHAT IS KNOWN ALREADY</div>Preliminary evidence indicates that parity may affect the onset of puberty, mainly as reflected by changes in the timing of pubic and axillary hair development.<div class="boxTitle">STUDY DESIGN, SIZE, DURATION</div>This 8-year cohort, conducted semi-annually, was recruited from four primary schools. The average follow-up duration was 6.09 years (range: 2–8 years).<div class="boxTitle">PARTICIPANTS/MATERIALS, SETTING, METHODS</div>The study cohort comprised 1390 children, including 710 girls and 680 boys, with age ranges of 6.58–19.26 years and 5.81–19.28 years, respectively, over an 8-year follow-up period. The primary exposure was whether the mother has a history of pregnancy prior to the birth of the child, including childbearing, miscarriage, and other adverse pregnancy outcomes. Pubertal milestones as assessed by a professional, including breast and genital development, were modeled using logistic regression, and the age of menarche was documented for girls. Associations between maternal pregnancy history and pubertal progression in both genders were analyzed using generalized linear regression models.<div class="boxTitle">MAIN RESULTS AND THE ROLE OF CHANCE</div>Girls from non-first pregnancies experienced a delayed age at menarche by 0.22 years (95% CI: 0.05, 0.38) and a more rapid tempo of breast development (0.06; 95% CI: 0.01, 0.11) compared to those from first pregnancies, particularly among girls with a history of maternal adverse pregnancy outcomes. The effect of maternal pregnancy history on pubertal development was less pronounced in boys than in girls.<div class="boxTitle">LIMITATIONS, REASONS FOR CAUTION</div>The sample was relatively small, and the cohort also lacks sufficient data due to missing data points and some study participants still maturing. While model fitting aids in describing incomplete pubertal development, the logistic growth mixed-effects model’s assumptions about growth curves may not fully reflect reality.<div class="boxTitle">WIDER IMPLICATIONS OF THE FINDINGS</div>Maternal pregnancy history, particularly adverse outcomes, can markedly influence pubertal progression in girls. Previous studies have shown that the timing and tempo of pubertal development impact adolescent psychological and behavioral health, and have implications for reproductive health and diseases in adulthood. Optimal pregnancy planning by mothers is essential for enhancing the well-being of both mother and offspring.<div class="boxTitle">STUDY FUNDING/COMPETING INTEREST(S)</div>This work was supported by Chongqing Natural Science Foundation project (CSTB2023NSCQ-MSX0133), National Natural Science Foundation of China (81973067), National Youth Science Fund Project (81502825), and Program for Youth Innovation in Future Medicine, Chongqing Medical University (W0054). This study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Chongqing Medical University (Reference Number: 2023003). Informed consent was obtained from all participants and their guardians involved in the study. The authors declared that they have no conflicts of interest to disclose.<div class="boxTitle">TRIAL REGISTRATION NUMBER</div>N/A.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">STUDY QUESTION</div>What is the effect of attenuating the physiological hypergonadotropic activity encountered at minipuberty on female reproductive function in a mouse model?<div class="boxTitle">SUMMARY ANSWER</div>Decreasing the surge of gonadotropins at minipuberty extended reproductive lifespan, coinciding with alterations in neuroendocrine and ovarian aging.<div class="boxTitle">WHAT IS KNOWN ALREADY</div>Minipuberty is characterized by the tremendous activation of the gonadotrope axis, as evidenced by elevated levels of gonadotropins regulating folliculogenesis and the synthesis of ovarian hormones, but its role in fertility remains unclear.<div class="boxTitle">STUDY DESIGN, SIZE, DURATION</div>To determine the link between gonadotrope axis activity at minipuberty and reproductive parameters, we used a pharmacological approach to suppress gonadotropin levels in Swiss mice by injecting daily a GnRH receptor antagonist (GnRHR) (Ganirelix, 10 µg/mouse) or its vehicle between 10 and 16 postnatal days, to cover the entire duration of minipuberty. We analyzed the onset of puberty and estrous cyclicity as well as fertility in young (3–5 months) and middle-aged (11 months) mice from control (CTR) and antagonist-treated groups (<span style="font-style:italic;">n</span> = 17–20 mice/age and treatment group). Ovaries and brains were collected, fixed, and sectioned (for histology, follicle count, and immunohistochemistry) or frozen (for analysis of follicular markers, aging, and inflammation) from adult females, and blood was collected by cardiac puncture for hormonal assays (<span style="font-style:italic;">n</span> = 3–8 mice/age and treatment group).<div class="boxTitle">PARTICIPANTS/MATERIALS, SETTING, METHODS</div>To analyze the initiation of puberty, we monitored vaginal opening and performed vaginal smears in CTR and antagonist-treated mice. We studied estrous cyclicity on vaginal smears at the beginning of reproductive life. Mice were mated several times with males to assess fertility rates, delay of conception, and litter size. To evaluate ovarian function, we counted follicles at different stages and corpora lutea, and we determined the relative intra-ovarian abundance of key follicular markers by real-time RT-PCR, as well as the levels of circulating anti-Müllerian hormone (AMH) and progesterone by ELISA and GC-MS, respectively. We also analyzed features of ovarian aging and inflammation by histology and by measuring the relative intra-ovarian abundance of some markers using real-time RT-PCR. To determine the impact on neuroendocrine determinants related to the CTR of reproduction, we analyzed circulating gonadotropin levels using Luminex assays as well as kisspeptin and GnRH immunoreactivity in the hypothalamus by immunohistochemistry.<div class="boxTitle">MAIN RESULTS AND THE ROLE OF CHANCE</div>Our results show that the treatment had no impact on the initiation of puberty, estrous cyclicity, or fertility at the beginning of reproductive life. However, it increased reproductive lifespan, as shown by the higher percentage of antagonist-treated females than CTRs still fertile at 11 months of age (33% versus 6%; <span style="font-style:italic;">P </span>=<span style="font-style:italic;"> </span>0.0471). There were no significant differences in the number of kisspeptin and GnRH neurons, nor in the density of kisspeptin- and GnRH-immunoreactive neurons in the hypothalamic areas involved in reproduction between the two groups of mice studied at either 4 or 11 months. In addition, basal levels of FSH were comparable between the two groups at 4 and 11 months, but not those of LH at 11 months which were much lower in females treated with antagonist than in their age-matched CTRs (237 ± 59.6 pg/ml in antagonist-treated females versus 1027 ± 226.3 pg/ml in CTRs, <span style="font-style:italic;">P </span>=<span style="font-style:italic;"> </span>0.0069). Importantly, at this age, antagonist-treated mice had basal LH levels comparable to young mice (e.g. in 4-month-old CTRs: 294 ± 71.75 pg/ml, <span style="font-style:italic;">P</span> > 0.05). Despite their prolonged reproductive lifespan and delayed neuroendocrine aging, antagonist-treated mice exhibited earlier depletion of their follicles, as shown by lower numbers of primordial, primary, and preantral follicles associated with lower circulating AMH levels and relative intra-ovarian abundance of <span style="font-style:italic;">Amh</span> transcripts than CTR mice. However, they exhibited comparable completion of folliculogenesis, as suggested by the numbers of antral follicles and corpora lutea, relative intra-ovarian abundance of <span style="font-style:italic;">Cyp19a1</span>, <span style="font-style:italic;">Inhba</span>, and <span style="font-style:italic;">Inhbb</span> transcripts, and circulating progesterone levels that all remained similar to those of the CTR group. These observed alterations in ovarian function were not associated with increased ovarian aging or inflammation.<div class="boxTitle">LARGE-SCALE DATA</div>None.<div class="boxTitle">LIMITATIONS, REASONS FOR CAUTION</div>This study was carried out on mice, which is a validated research model. However, human research is needed for further validation.<div class="boxTitle">WIDER IMPLICATIONS OF THE FINDINGS</div>This study, which is the first to investigate the physiological role of minipuberty on reproductive parameters, supports the idea that suppressing the high postnatal levels of gonadotropins may have long-term effects on female fertility by extending the duration of reproductive life. Perturbations in gonadotropin levels during this period of life, such as those observed in infants born prematurely, may thus have profound consequences on late reproductive functions.<div class="boxTitle">STUDY FUNDING/COMPETING INTEREST(S)</div>This research was conducted with the financial support of ANR AAPG2020 (ReproFUN), CNRS, Inserm, Université Paris Cité, and Sorbonne Université. The authors declare that they have no conflicts of interest.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">STUDY QUESTION</div>What is the diagnostic performance of the ART-ET screening tool, an easy-to-use non-invasive screening tool for prediction of difficult embryo transfers?<div class="boxTitle">SUMMARY ANSWER</div>A simple scoring of transvaginal ultrasound examination of the cervical canal can predict difficult embryo transfers with high specificity, positive likelihood ratio, and accuracy; the inclusion of cervical position and history of cesarean without a vaginal delivery improved predictive performance.<div class="boxTitle">WHAT IS KNOWN ALREADY</div>Difficult embryo transfer procedures are associated with significantly lower clinical pregnancy and live birth rates, and some interventions may facilitate an anticipated difficult embryo transfer.<div class="boxTitle">STUDY DESIGN, SIZE, DURATION</div>A diagnostic test study prospectively conducted on 239 single euploid blastocyst transfer procedures between March and December 2023. The sample size was calculated to include about 20 difficult transfer procedures. Physicians conducting the transfers were blinded to screening results.<div class="boxTitle">PARTICIPANTS/MATERIALS, SETTING, METHODS</div>The study was conducted in two tertiary-level private assisted reproduction centers. The ART-ET Screening tool collected information on patients’ body mass index, obstetric history, cervical position, external cervical ostium appearance, and ultrasound examination of the cervical canal. A difficult embryo transfer was defined if one or more of the following occurred during the procedure; use of a malleable obturator to insert the guiding catheter until the internal ostium, use of a forceps to pull the cervix, if there were blood in the transfer catheter following the procedure, if the transfer catheter needed to be reloaded, and if the physician found the procedure difficult.<div class="boxTitle">MAIN RESULTS AND THE ROLE OF CHANCE</div>Ongoing pregnancy rates were 47.6% vs 59.6% after a difficult and easy embryo transfer. With a difficult embryo transfer prevalence of 8.8%, screening score including cervical position, visibility and the length of cervical canal, and <span style="font-style:italic;">obstetric history</span> had the best diagnostic performance with sensitivity of 33.3% (14.59–56.97%), specificity of 99.5% (97.47–99.99%), positive likelihood ratio of 72.67 (9.38–562.73), negative likelihood ratio of 0.67 (0.49–0.91), and an accuracy of 93.7% (89.86–96.45%) for predicting difficult embryo transfers. The simpler cervical ultrasound score also had a good diagnostic performance with a sensitivity of 28.6% (11.28–52.18%), specificity of 98.2% (95.37–99.50%), positive likelihood ratio of 15.57 (4.77–50.84), negative likelihood ratio of 0.73 (0.55–0.95), positive predictive value of 60.0% (31.46–83.03%), negative predictive value of 93.5% (91.59–94.93%), and an accuracy of 93.5% (91.59–94.93%).<div class="boxTitle">LIMITATIONS, REASONS FOR CAUTION</div>The diagnostic performance of the proposed ART-ET Screening tool would depend on the prevalence of difficult embryo transfers in a clinic. How much the scoring system can decrease difficult embryo transfers and improve live birth rates need to be determined in further studies.<div class="boxTitle">WIDER IMPLICATIONS OF THE FINDINGS</div>Anticipation of a difficult transfer can help to adjust patient expectations and to take appropriate measures in advance.<div class="boxTitle">STUDY FUNDING/COMPETING INTEREST(S)</div>No funding was received for the study. None of the authors have any competing interests associated with the present study.<div class="boxTitle">TRIAL REGISTRATION NUMBER</div>NCT05701072.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">STUDY QUESTION</div>How does testosterone gender-affirming hormone therapy (T-GAHT) impact breeding success in female mice?<div class="boxTitle">SUMMARY ANSWER</div>T-GAHT causes reversible subfertility in female mice and persistent changes to reproductive tract anatomy, gene expression, and hormone receptors.<div class="boxTitle">WHAT IS KNOWN ALREADY</div>Adult female mice implanted with capsules containing 10 mg of testosterone mimic many aspects of reproductive phenotypes of T-GAHT patients, who may desire future gestation while pausing T-GAHT. In mice, oocytes retrieved from T-GAHT mice had decreased IVF rates, and T cessation prior to stimulation improved these outcomes. However, the effects of T-GAHT on breeding have not been examined.<div class="boxTitle">STUDY DESIGN, SIZE, DURATION</div>Adult female CD1 mice were subcutaneously implanted with capsules containing 10 mg of testosterone or blank controls. In separate studies, capsules were removed after 6 (‘short’) or 12 weeks (‘long’ n = 15/group), then mice were paired with proven-breeder CD1 males. Breeding pair success and pup development (15–20/group) were measured for first and second litters, then terminal measurements were taken from dams and their adult offspring (10/group).<div class="boxTitle">PARTICIPANTS/MATERIALS, SETTING, METHODS</div>The reproductive success of explanted T-GAHT and control mice was investigated by pairing them with proven-breeder CD1 males. Regular observations of dams and litters enabled analysis of fertility and the development of male and female pups for two litters. Terminal measures for dams and/or adult offspring focused on endpoints tied to reproductive tract function and gestation, including reproductive hormones, vaginal cytology, sperm analysis and ovarian and uterine anatomy, histology, and gene expression.<div class="boxTitle">MAIN RESULTS AND THE ROLE OF CHANCE</div>All but one T-GAHT dams gave birth, but the time between pairing and their first birth was longer than controls after long (22.3 ± 1.3 days vs 24.5 ± 3.1) and short (23.2 ± 1.4 days vs 25.5 ± 4) treatments. Dams given long T-GAHT treatment had fewer pups in their first litters (11.9 ± 2.7 pups vs 7.8 ± 3.1) but pup number was unaltered after short treatment (11.5 ± 2.4 pups vs 11.4 ± 3.7). Further, offspring from first litters displayed accelerated puberty. Fertility differences and offspring developmental effects were absent for second gestations and litters. Despite fertility rescue, several anatomical, genetic, and histological changes persisted in T-GAHT dams after two litters. Offspring reproductive system outcomes were not significantly altered once dam fertility was restored. This study powerfully demonstrates a subfertile phenotype in T-GAHT-treated animals that is rescued over time and identifies gonadotropin and steroid hormone signaling as potential mechanisms for further investigation.<div class="boxTitle">LARGE SCALE DATA</div>No large-scale data were generated in this study.<div class="boxTitle">LIMITATIONS, REASONS FOR CAUTION</div>Significant effects of T-GAHT on dam terminal measures may be unrelated to subfertility, and similar endpoints must be examined during the subfertile period to identify and fully understand their roles in T-GAHT-dependent reproductive changes.<div class="boxTitle">WIDER IMPLICATIONS OF FINDINGS</div>The assumption that T-GAHT causes irreversible damage to reproduction has harmfully informed public opinion, medical practice, and government policies. The finding in T-GAHT mice that fertility and offspring outcomes are not permanently impacted are of translational relevance and opens avenues to be tested first in non-human primate models and then humans.<div class="boxTitle">STUDY FUNDING/COMPETING INTEREST(S)</div>NIH R01 HD098233, NIH T32 DK071212. The authors declare no competing interests.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">STUDY QUESTION</div>Does maternal age impact hormonal secretions from granulosa cells, theca cells, and the oocyte in human small antral follicles?<div class="boxTitle">SUMMARY ANSWER</div>Major hormones secreted by granulosa and theca cells, as well as the oocyte-specific TGF-β members—GDF9, BMP15, and the GDF9/BMP15 heterodimer cumulin—maintain a consistent concentration within the follicular fluid of human small antral follicles, regardless of maternal age.<div class="boxTitle">WHAT IS KNOWN ALREADY</div>It is well established that female fertility declines with increasing age. However, it is not known whether this decline is exclusively due to a reduction in oocyte quality and quantity or also involves a decline in the hormone-secreting capabilities of granulosa cells, theca cells, and the oocyte itself.<div class="boxTitle">STUDY DESIGN, SIZE, DURATION</div>This is a retrospective study of follicular fluid obtained from human small antral follicles collected in connection with cryopreservation of ovarian tissue at the Laboratory of Reproductive Biology, University Hospital Copenhagen, Rigshospitalet, Denmark, between 2010 and 2020 as part of the hospital’s fertility preservation program.<div class="boxTitle">PARTICIPANTS/MATERIALS, SETTING, METHODS</div>Follicular fluid samples from human small antral follicles measuring 3–13 mm in diameter from macroscopically normal ovaries of 381 patients aged 5–43 years were included in the study, provided that at least one of the following parameters was measured: AMH, Inhibin A, Inhibin B, oestradiol (E2), progesterone (P4), androstenedione, testosterone, and/or the oocyte-specific TGF-β members GDF9, BMP15, or cumulin.<div class="boxTitle">MAIN RESULTS AND THE ROLE OF CHANCE</div>In a linear regression analysis adjusted for follicular volume, female age did not predict the follicular fluid concentrations of AMH, Inhibin B, Inhibin A, E2, androstenedione, testosterone, GDF9, BMP15, or cumulin. Although a significant association was observed between female age and follicular fluid P4 levels, the predictive value of age was poor, accounting for at most 5% of the variation in P4.<div class="boxTitle">LIMITATIONS, REASONS FOR CAUTION</div>Hormonal levels may vary with the degree of atresia in each follicle; however, the health status of the small antral follicles in this study was not characterized. Additionally, we cannot exclude possible age-related differences in human follicles larger than 10 mm, as very few of these were included. Furthermore, we did not include women above the age of 43, despite the potential for more pronounced age-related effects in these patients.<div class="boxTitle">WIDER IMPLICATIONS OF THE FINDINGS</div>Our results support the idea that the age-related decline in female fertility is primarily due to a reduction in oocyte quality and quantity, but further research is needed to confirm this.<div class="boxTitle">STUDY FUNDING/COMPETING INTEREST(S)</div>No specific funding was obtained, and the authors have no conflicts of interest to declare in relation to this work.<div class="boxTitle">TRIAL REGISTRATION NUMBER</div>N/A.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">STUDY QUESTION</div>Does the slow-freezing and thawing process have a negative impact on the transcriptome of oocytes isolated from early-stage human follicles compared to fresh controls?<div class="boxTitle">SUMMARY ANSWER</div>The transcriptional profiles of fresh and frozen/thawed oocytes did not cluster separately, indicating undetectable differences between the two groups when compared to within-donor heterogeneity.<div class="boxTitle">WHAT IS KNOWN ALREADY</div>Previous studies using histological analysis of follicle morphology, density, and stage distribution in slow-frozen/thawed human ovarian cortex compared to fresh controls showed no differences between the two groups. Clinical cases reported in the past 10 years have demonstrated that transplanted slow-frozen/thawed and fresh ovarian cortex restored normal serum FSH levels and regular menstrual cycles by 5 months. However, the slow-frozen and thawed tissue resulted in lower rates of pregnancies and live births, albeit not statistically significant.<div class="boxTitle">STUDY DESIGN, SIZE, DURATION</div>We utilized single-cell RNA-sequencing (scRNAseq) of 144 human oocytes isolated from cadaver ovaries obtained from three donors.<div class="boxTitle">PARTICIPANTS/MATERIALS, SETTING, METHODS</div>Human ovarian cortex from three healthy premenopausal donors 16, 18, and 27 years old was cut into squares measuring 10 × 10 × 1 mm<sup>3</sup> and either slow-frozen and thawed or processed fresh. First, using a novel method for isolating live oocytes from primordial and primary follicles, the ovarian cortex squares were fragmented with a McIlwain tissue chopper and enzymatically digested. Next, oocytes were mechanically denuded under a dissection microscope and placed individually into wells containing lysis buffer for scRNAseq. Lysed single oocytes were subjected to library prep using the seqWell PlexWell rapid single-cell RNA protocol. Pooled libraries were subjected to 150-bp paired-end sequencing on the NovaSeq6000 Illumina platform. In total, we sequenced 144 oocytes—24 oocytes isolated fresh and 24 oocytes isolated after slow-freezing and thawing from each of the three donors. Additionally, we performed histological analysis of fresh and frozen/thawed ovarian cortex tissue from all three donors using hematoxylin and eosin staining and analyzed morphology, follicle density, and follicle stage distribution differences between fresh and cryopreserved ovarian cortex.<div class="boxTitle">MAIN RESULTS AND THE ROLE OF CHANCE</div>The histological analysis revealed no differences in follicle stage distribution or follicle morphology between conditions, with the percentage of normal follicles in fresh and frozen/thawed tissue, respectively, as 86.7% and 91.0% for Donor 1, 91.7% and 92.5% for Donor 2, and 96.1% and 91.1% for Donor 3. The follicle density per mm<sup>3</sup> in fresh and frozen/thawed tissue, respectively, was 279.4 and 235.8 for Donor 1, 662.2 and 553.5 for Donor 2, and 55.8 and 71.4 for Donor 3. The difference in follicle density was not statistically significant between fresh and frozen/thawed conditions for Donors 2 and 3, and significant (<span style="font-style:italic;">P </span>=<span style="font-style:italic;"> </span>0.017) for Donor 1. The stromal cell densities in fresh and frozen/thawed tissue, respectively, were 0.014 in both conditions for Donor 1, 0.014 and 0.016 for Donor 2, and 0.013 and 0.014 for Donor 3. There was no statistically significant difference in stromal cell density between conditions in Donor 1 and Donor 3, though it was statistically significant (<span style="font-style:italic;">P</span> ≤ 0.001) for Donor 2. The transcriptional profiles of fresh and frozen/thawed oocytes did not cluster separately, suggesting insignificant differences between the two groups. However, at the group mean level, there was a small shift between the fresh and frozen/thawed oocytes and the shifts were parallel across the three donors. In this comparison, fresh oocytes were enriched for gene ontology terms related to chromosome segregation and mitosis, whereas frozen/thawed oocytes were enriched for terms related to wound response, cAMP signaling, and extracellular matrix organization.<div class="boxTitle">LARGE SCALE DATA</div>Datasets available on Zenodo.org. DOI: <a href="https://zenodo.org/records/13224872">https://zenodo.org/records/13224872</a><div class="boxTitle">LIMITATIONS, REASONS FOR CAUTION</div>In this study, we only sequenced the oocytes isolated from early-stage follicles due to technical challenges collecting and sequencing the somatic cells surrounding the oocytes. Investigating the transcriptomic changes after freezing and thawing in the somatic cells would need to be studied in the future. Additionally, we built RNAseq libraries immediately after thawing focusing on the immediate changes. Investigation of the effects that manifest at later timepoints, either in culture or upon implantation in an animal model, may reveal additional effects of the freeze/thaw process on the transcriptome.<div class="boxTitle">WIDER IMPLICATIONS OF THE FINDINGS</div>The only clinically approved method of fertility preservation for prepubertal cancer patients and adult patients who cannot delay cancer treatment is ovarian tissue cryopreservation. Investigation of cryopreservation-induced changes in follicles at all stages is critical to further our understanding of the safety and efficacy of using these tissues for fertility preservation in the clinic. Our study is the first to analyze transcriptomic changes between individual fresh and slow-frozen/thawed human oocytes collected from early-stage follicles. To accomplish this, we developed a novel method for dissociating both fresh and frozen/thawed human ovarian cortex to obtain live denuded oocytes from early-stage follicles. Our findings provide insights into the use of cryopreserved tissue and follicles for fertility preservation efforts.<div class="boxTitle">STUDY FUNDING/COMPETING INTEREST(S)</div>This work was funded by National Institutes of Health (NIH) R01HD099402, Career Training in Reproductive Biology (CTRB) Training Grant National Institutes of Health (NIH) T32 to Jordan Machlin, National Institutes of Health (NIH) F31-HD106626 and National Institutes of Health (NIH) T31H-D079342 to Andrea Jones, National Institutes of Health (NIH) T32-GM70449 to D. Ford Hannum, and The Chan Zuckerberg Initiative Grant CZF2019-002428. We have no conflicts of interest to declare.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">STUDY QUESTION</div>What is the risk of endometrial cancer after long-term follow-up in women treated with ART between 1983 and 2001 compared with women in the general population and subfertile women who did not undergo ART?<div class="boxTitle">SUMMARY ANSWER</div>The risk of endometrial cancer is not increased in women who underwent ART in the Netherlands between 1983 and 2001, neither compared with women from the general population nor compared with subfertile women not treated with ART.<div class="boxTitle">WHAT IS KNOWN ALREADY</div>Concerns have been raised that subfertility treatment may be associated with increased risk of endometrial cancer. However, published studies show inconsistent results regarding the effects of ovarian stimulation and specific subfertility diagnoses on endometrial cancer risk.<div class="boxTitle">STUDY DESIGN, SIZE, DURATION</div>A nationwide historic cohort study (the OMEGA-cohort) was conducted to examine the risk of cancer in women after ovarian stimulation for ART. The OMEGA-cohort comprises 30 625 women who received ovarian stimulation for ART (ART group) in 1983–2000 and 9988 subfertile women not treated with ART (non-ART group). After a median follow-up of 24 years, endometrial cancer incidence was ascertained through linkage with the Netherlands Cancer Registry. Endometrial cancer risk in the cohort was compared with that in the general population using person-years analyses, and between the ART group and non-ART group using multivariable Cox regression analyses.<div class="boxTitle">PARTICIPANTS/MATERIALS, SETTING, METHODS</div>Detailed ART-treatment data were obtained from the medical records and complete information on parity and age at first birth was obtained through linkage with the Personal Records Database. Information on hysterectomy and endometriosis was collected through linkage with the Dutch Nationwide Pathology Databank (Palga). Data about lifestyle factors, including BMI, were obtained through a self-administered questionnaire.<div class="boxTitle">MAIN RESULTS AND THE ROLE OF CHANCE</div>After a median follow-up duration of 24 years, 137 endometrial cancers were diagnosed. Endometrial cancer risk after ART was not significantly increased compared with that in the general population (standardized incidence ratio = 1.19; 95% CI = 0.97–1.44) nor compared with that in the non-ART group (multivariably adjusted hazard ratio = 1.11; 95% CI = 0.74–1.67). Risk of endometrial cancer did not increase with longer follow-up or with more ART cycles, and the risk within the cohort, did not vary by cause of subfertility (male, tubal, unexplained, and other). Irrespective of ART treatment, endometrial cancer risk was increased in obese women and women with endometriosis, but decreased among parous women and women who used oral contraceptives.<div class="boxTitle">LIMITATIONS, REASONS FOR CAUTION</div>Although the findings of the study are reassuring, the median age of the women at the end of follow-up (median age 56 years) was still rather young. Therefore, there is a need for at least 10–15 additional follow-up years to draw definitive conclusions. In addition, other large studies are needed to investigate the risk of endometrial cancer in women who underwent ART.<div class="boxTitle">WIDER IMPLICATIONS OF THE FINDINGS</div>The results of this study contribute to knowledge about long-term health after ART treatment, which is valuable to subfertile couples, considering or undergoing fertility treatments, and their healthcare providers.<div class="boxTitle">STUDY FUNDING/COMPETING INTEREST(S)</div>This study was supported by a grant from the Dutch Cancer Society (NKI 2006-3631) and a departmental grant from the Department of Obstetrics and Gynecology of Erasmus Medical Center, Rotterdam, the Netherlands (2011-019). Ma.S. is Associate Editor of Human Reproduction Open; A.W.vd.B.-D received support for attending meetings and/or travel from the Dutch Cancer Society; C.B.L. is Editor-in-Chief of Human Reproduction; A.E.P.C. is Associate Editor of Human Reproduction Update, received royalties from Uptodate Hyperthecosis, and participated at the Data Safety Monitoring Board of the DSMB POEM Study; F.B. has received research support from Merck, honoraria or consultation fees from Merck Healthcare KGaA, Bensis Healthcare, CooperSurgical, and participated in an advisory board for Merck and Ferring; J.L. has received research support from Ferring, Merck, and Roche Diagnostics, consulting fees and honoraria from Ferring, participated on a Data Safety Monitoring Board or Advisory Board of the LOCI trial, is President of the AE-PCOS society, and Member of the ASRM Integrity Committee; J.M.J.S. has received honoraria from Ferring and Merck, support for attending meetings and/or travel from Ferring, Merck, and Good Life, and participated in the advisory board of Merck; L.L.v.L. received support for attending meetings and/or travel from Olympus Medical Expert training; M.M.v.R. received support for attending meetings and/or travel from Ferring; M.G. declares departmental research and educational grants from Ferring (location VUmc), unrelated to the presented work. The other authors declare no competing interests.<div class="boxTitle">TRIAL REGISTRATION NUMBER</div>N/A.</span>
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