Pub Date : 2025-03-25eCollection Date: 2025-01-01DOI: 10.1093/hropen/hoaf016
Maria Ekstrand Ragnar, Karin Hammarberg, Alexandra Carvalho, Ilse Delbaere, Anita Fincham, Joyce Harper, Münevver Serdarogullari, Mara Simopoulou, Christiana Antoniadou Stylianou, Randi Sylvest, Bola Grace
{"title":"Defending access to reproductive health information.","authors":"Maria Ekstrand Ragnar, Karin Hammarberg, Alexandra Carvalho, Ilse Delbaere, Anita Fincham, Joyce Harper, Münevver Serdarogullari, Mara Simopoulou, Christiana Antoniadou Stylianou, Randi Sylvest, Bola Grace","doi":"10.1093/hropen/hoaf016","DOIUrl":"https://doi.org/10.1093/hropen/hoaf016","url":null,"abstract":"","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2025 2","pages":"hoaf016"},"PeriodicalIF":8.3,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11981712/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144065090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-20eCollection Date: 2025-01-01DOI: 10.1093/hropen/hoaf011
Norbert Gleicher, Sonia Gayete-Lafuente, David H Barad, Pasquale Patrizio, David F Albertini
Embryo selection (ES) during IVF is expected to select the 'best' embryo(s) from among a cycle's embryo cohort and has been a core concept of IVF for over 40 years. However, among 36 492 articles on ES in a recent PubMed search, we were unable to locate even a single one questioning the concept that, beyond standard oocyte and embryo morphology, ES has remained an unproven hypothesis. In unselected patient populations, attempts at ES have universally, indeed, failed to improve cumulative pregnancy and live birth rates. The only benefit ES appears to offer is a marginal shortening in time to pregnancy, and even this benefit manifests only in best-prognosis patients with large oocyte and embryo numbers. Excluding in vitro maturation efforts, oocytes, once retrieved, and their resulting embryos have predetermined finite cumulative pregnancy and live birth chances that cannot be further improved. The hypothesis of ES has, however, remained a driving force for research and the introduction of a multitude of 'add-ons' to IVF. Enormous investments over decades in ES, therefore, should be better redirected from post- to pre-retrieval efforts.
{"title":"Why the hypothesis of embryo selection in IVF/ICSI must finally be reconsidered.","authors":"Norbert Gleicher, Sonia Gayete-Lafuente, David H Barad, Pasquale Patrizio, David F Albertini","doi":"10.1093/hropen/hoaf011","DOIUrl":"10.1093/hropen/hoaf011","url":null,"abstract":"<p><p>Embryo selection (ES) during IVF is expected to select the 'best' embryo(s) from among a cycle's embryo cohort and has been a core concept of IVF for over 40 years. However, among 36 492 articles on ES in a recent PubMed search, we were unable to locate even a single one questioning the concept that, beyond standard oocyte and embryo morphology, ES has remained an unproven hypothesis. In unselected patient populations, attempts at ES have universally, indeed, failed to improve cumulative pregnancy and live birth rates. The only benefit ES appears to offer is a marginal shortening in time to pregnancy, and even this benefit manifests only in best-prognosis patients with large oocyte and embryo numbers. Excluding <i>in vitro</i> maturation efforts, oocytes, once retrieved, and their resulting embryos have predetermined finite cumulative pregnancy and live birth chances that cannot be further improved. The hypothesis of ES has, however, remained a driving force for research and the introduction of a multitude of 'add-ons' to IVF. Enormous investments over decades in ES, therefore, should be better redirected from post- to pre-retrieval efforts.</p>","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2025 2","pages":"hoaf011"},"PeriodicalIF":8.3,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11928228/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143694442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-18eCollection Date: 2025-01-01DOI: 10.1093/hropen/hoaf015
Fang Liu, Zheng Wang, Ying Song, Tian Tian, Rong Li, Jie Qiao, Shuo Huang, Yuanyuan Wang
<p><strong>Study question: </strong>Do infectious diseases (hepatitis B virus [HBV], hepatitis C virus [HCV], and syphilis) impact embryo quality, pregnancy, and neonatal outcomes following a complete IVF cycle?</p><p><strong>Summary answer: </strong>Infections with HBV, HCV, or syphilis do not have detrimental impacts on live birth rates or neonatal outcomes in couples following a complete IVF cycle.</p><p><strong>What is known already: </strong>Maternal or paternal infections with HBV, HCV, or syphilis may decrease the clinical pregnancy rate, result in poorer embryo outcomes, and lower offspring birth weight. However, there is significant controversy regarding these effects across existing studies, highlighting the need for further research.</p><p><strong>Study design size duration: </strong>This is a retrospective matched cohort study. Data were obtained from the clinical database of couples who underwent IVF treatment at a single academically affiliated fertility clinic from January 2011 to December 2019, with follow-up extending to December 2020. Out of 180 666 complete cycles recorded, 2443 cycles fulfilled our inclusion criteria.</p><p><strong>Participants/materials setting methods: </strong>In cycles that fulfilled our inclusion criteria, there were 1997 cycles in the HBV study group, 154 cycles in the HCV study group, and 292 cycles in the syphilis study group. Each study cycle was paired with four controls based on participant age and the timing of IVF treatment, resulting in 7988 controls for the HBV group, 616 controls for the HCV group, and 1169 controls for the syphilis group. Infections could be either single-parent or biparental. The primary outcome was live birth per complete cycle (i.e. fresh cycle plus subsequent frozen-thawed cycles). Subgroup analyses were conducted dividing cycles into maternal infection and paternal infection.</p><p><strong>Main results and the role of chance: </strong>In the HBV group, pregnancy outcomes (clinical pregnancy, miscarriage, and live birth rates) and neonatal birth weight were similar to that of the controls. In the HCV group, no significant differences from the controls were observed except for a lower clinical pregnancy rate in the study group (36.4% vs 42.2%, adjusted β and 95% CI: 0.62 [0.39-0.96]). Similarly, no significant differences were found in pregnancy or neonatal outcomes between the syphilis group and the control group. As for subgroup analyses, the male-only HBV infection subgroup showed a higher miscarriage rate in the study group than in the control group (22.5% vs 17.7%, adjusted β and 95% CI: 1.56 [1.07-2.28]). For the HCV and syphilis subgroups, none of the outcomes showed significant differences between either the female-only infection or male-only infection subgroups and the controls.</p><p><strong>Limitations reasons for caution: </strong>Although potential confounders were considered and adjusted for, residual bias may still exist due to the study design. The inclusion
{"title":"The impact of HBV, HCV, or syphilis infections on embryo and pregnancy outcomes in couples undergoing IVF treatment: a matched cohort study.","authors":"Fang Liu, Zheng Wang, Ying Song, Tian Tian, Rong Li, Jie Qiao, Shuo Huang, Yuanyuan Wang","doi":"10.1093/hropen/hoaf015","DOIUrl":"10.1093/hropen/hoaf015","url":null,"abstract":"<p><strong>Study question: </strong>Do infectious diseases (hepatitis B virus [HBV], hepatitis C virus [HCV], and syphilis) impact embryo quality, pregnancy, and neonatal outcomes following a complete IVF cycle?</p><p><strong>Summary answer: </strong>Infections with HBV, HCV, or syphilis do not have detrimental impacts on live birth rates or neonatal outcomes in couples following a complete IVF cycle.</p><p><strong>What is known already: </strong>Maternal or paternal infections with HBV, HCV, or syphilis may decrease the clinical pregnancy rate, result in poorer embryo outcomes, and lower offspring birth weight. However, there is significant controversy regarding these effects across existing studies, highlighting the need for further research.</p><p><strong>Study design size duration: </strong>This is a retrospective matched cohort study. Data were obtained from the clinical database of couples who underwent IVF treatment at a single academically affiliated fertility clinic from January 2011 to December 2019, with follow-up extending to December 2020. Out of 180 666 complete cycles recorded, 2443 cycles fulfilled our inclusion criteria.</p><p><strong>Participants/materials setting methods: </strong>In cycles that fulfilled our inclusion criteria, there were 1997 cycles in the HBV study group, 154 cycles in the HCV study group, and 292 cycles in the syphilis study group. Each study cycle was paired with four controls based on participant age and the timing of IVF treatment, resulting in 7988 controls for the HBV group, 616 controls for the HCV group, and 1169 controls for the syphilis group. Infections could be either single-parent or biparental. The primary outcome was live birth per complete cycle (i.e. fresh cycle plus subsequent frozen-thawed cycles). Subgroup analyses were conducted dividing cycles into maternal infection and paternal infection.</p><p><strong>Main results and the role of chance: </strong>In the HBV group, pregnancy outcomes (clinical pregnancy, miscarriage, and live birth rates) and neonatal birth weight were similar to that of the controls. In the HCV group, no significant differences from the controls were observed except for a lower clinical pregnancy rate in the study group (36.4% vs 42.2%, adjusted β and 95% CI: 0.62 [0.39-0.96]). Similarly, no significant differences were found in pregnancy or neonatal outcomes between the syphilis group and the control group. As for subgroup analyses, the male-only HBV infection subgroup showed a higher miscarriage rate in the study group than in the control group (22.5% vs 17.7%, adjusted β and 95% CI: 1.56 [1.07-2.28]). For the HCV and syphilis subgroups, none of the outcomes showed significant differences between either the female-only infection or male-only infection subgroups and the controls.</p><p><strong>Limitations reasons for caution: </strong>Although potential confounders were considered and adjusted for, residual bias may still exist due to the study design. The inclusion","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2025 2","pages":"hoaf015"},"PeriodicalIF":8.3,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11961197/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-17eCollection Date: 2025-01-01DOI: 10.1093/hropen/hoaf014
Annesofie R Olsen, Louise L Asserhøj, Anja Pinborg, Tine D Clausen, Gorm Greisen, Rikke B Jensen, Katharina M Main, Niels G Vejlstrup, Per L Madsen, Ikram Mizrak
<p><strong>Study question: </strong>Is the ratio of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) comparable between children following ART and natural conception (NC)?</p><p><strong>Summary answer: </strong>Children conceived by frozen embryo transfer (FET) had slightly lower VAT/SAT ratios than children following NC; no difference in VAT/SAT ratio was observed in children born following fresh embryo transfer (Fresh-ET) as compared to those born from NC.</p><p><strong>What is known already: </strong>The VAT/SAT ratio is closely related to the metabolic profile, with a high ratio increasing the risk of cardiometabolic diseases. To our knowledge, no studies have reported the VAT/SAT ratio in children following ART.</p><p><strong>Study design size duration: </strong>This prospective exploratory observational cohort study included 150 singletons aged 7-10 years. All children were born in eastern Denmark. The study was conducted between November 2018 and August 2020.</p><p><strong>Participants/materials setting methods: </strong>This is a sub-study of the 'Health in Childhood following Assisted Reproductive Technology' (HiCART) study. The children were conceived after FET (n = 50), Fresh-ET (n = 50), and NC (n = 50), and children conceived by NC were matched to ART children by sex and birth year. The children underwent abdominal MRI for the quantification of abdominal adipose tissues along with measurements of blood pressure, fasting blood samples, anthropometric measurements, and dual-energy X-ray absorptiometry scans. The volumes of VAT and SAT were semi-automatically quantified, blinded for the mode of conception. The level of statistical significance was set to a <i>P</i>-level below 0.05. Multivariable linear regression analysis of the VAT/SAT ratio was performed to adjust for confounders in a five-step approach: Model 1: Adjusted for child age and sex; Model 2: Model 1 plus maternal age at delivery and maternal BMI at pregnancy; Model 3: Model 2 plus birth weight and child BMI; Model 4a: Model 3 plus maternal educational level; Model 4b: Model 3 plus pubertal status. The confounders were selected based on their association with metabolic risk factors according to previous studies.</p><p><strong>Main results and the role of chance: </strong>As previously reported in the HiCART studies, there were no differences between the groups in anthropometric measurements including BMI, lean body mass, blood pressure, or triglycerides. The crude VAT/SAT ratio differed significantly between the three groups (mean (SD); FET 0.26 (0.08), Fresh-ET 0.29 (0.07), NC 0.30 (0.08), ANOVA-<i>P</i> = 0.014). Pairwise comparison revealed that children conceived after FET had lower crude VAT/SAT ratio than children conceived after NC (<i>P</i> = 0.007) with a mean difference of -0.04, 95% CI (-0.07; -0.01), and a tendency for a lower VAT/SAT ratio as compared to the Fresh-ET group (<i>P</i> = 0.059) with a mean difference of -0.03, 95% CI (-0.06; 0.
{"title":"Visceral and subcutaneous adipose tissue in children born after ART with frozen and fresh embryo transfers.","authors":"Annesofie R Olsen, Louise L Asserhøj, Anja Pinborg, Tine D Clausen, Gorm Greisen, Rikke B Jensen, Katharina M Main, Niels G Vejlstrup, Per L Madsen, Ikram Mizrak","doi":"10.1093/hropen/hoaf014","DOIUrl":"10.1093/hropen/hoaf014","url":null,"abstract":"<p><strong>Study question: </strong>Is the ratio of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) comparable between children following ART and natural conception (NC)?</p><p><strong>Summary answer: </strong>Children conceived by frozen embryo transfer (FET) had slightly lower VAT/SAT ratios than children following NC; no difference in VAT/SAT ratio was observed in children born following fresh embryo transfer (Fresh-ET) as compared to those born from NC.</p><p><strong>What is known already: </strong>The VAT/SAT ratio is closely related to the metabolic profile, with a high ratio increasing the risk of cardiometabolic diseases. To our knowledge, no studies have reported the VAT/SAT ratio in children following ART.</p><p><strong>Study design size duration: </strong>This prospective exploratory observational cohort study included 150 singletons aged 7-10 years. All children were born in eastern Denmark. The study was conducted between November 2018 and August 2020.</p><p><strong>Participants/materials setting methods: </strong>This is a sub-study of the 'Health in Childhood following Assisted Reproductive Technology' (HiCART) study. The children were conceived after FET (n = 50), Fresh-ET (n = 50), and NC (n = 50), and children conceived by NC were matched to ART children by sex and birth year. The children underwent abdominal MRI for the quantification of abdominal adipose tissues along with measurements of blood pressure, fasting blood samples, anthropometric measurements, and dual-energy X-ray absorptiometry scans. The volumes of VAT and SAT were semi-automatically quantified, blinded for the mode of conception. The level of statistical significance was set to a <i>P</i>-level below 0.05. Multivariable linear regression analysis of the VAT/SAT ratio was performed to adjust for confounders in a five-step approach: Model 1: Adjusted for child age and sex; Model 2: Model 1 plus maternal age at delivery and maternal BMI at pregnancy; Model 3: Model 2 plus birth weight and child BMI; Model 4a: Model 3 plus maternal educational level; Model 4b: Model 3 plus pubertal status. The confounders were selected based on their association with metabolic risk factors according to previous studies.</p><p><strong>Main results and the role of chance: </strong>As previously reported in the HiCART studies, there were no differences between the groups in anthropometric measurements including BMI, lean body mass, blood pressure, or triglycerides. The crude VAT/SAT ratio differed significantly between the three groups (mean (SD); FET 0.26 (0.08), Fresh-ET 0.29 (0.07), NC 0.30 (0.08), ANOVA-<i>P</i> = 0.014). Pairwise comparison revealed that children conceived after FET had lower crude VAT/SAT ratio than children conceived after NC (<i>P</i> = 0.007) with a mean difference of -0.04, 95% CI (-0.07; -0.01), and a tendency for a lower VAT/SAT ratio as compared to the Fresh-ET group (<i>P</i> = 0.059) with a mean difference of -0.03, 95% CI (-0.06; 0.","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2025 2","pages":"hoaf014"},"PeriodicalIF":8.3,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11975283/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-12eCollection Date: 2025-01-01DOI: 10.1093/hropen/hoaf013
Jian Xu, Zhiheng Chen, Meiyi Li, Ling Sun
Study question: Compared with embryonic cytogenetic constitution of biopsied samples in human pre-implantation embryos, are there any differences in whole embryos?
Summary answer: Whole embryos exhibit a significantly higher euploidy rate and reduction in mosaic aneuploidy rate compared to biopsied samples.
What is known already: Much of the existing evidence of cytogenetic constitution of human pre-implantation embryos is based on biopsied cells obtained from blastomeres or trophectoderm biopsies. The mosaic rate of biopsies taken from blastocyst trophectoderm ranges widely, from 2% to 25%.
Study design size duration: We investigated the embryonic cytogenetic constitution of 221 whole human embryos/blastocysts from 2019 to 2022, including 41 high-quality blastocysts, 57 low-quality blastocysts, and 123 arrested embryos/blastocysts.
Participants/materials setting methods: The cytogenetic constitution of whole embryos/blastocysts was assessed using next-generation sequencing. Mosaicism was diagnosed using a cut-off threshold of 30-70%, with embryos displaying 30-70% aneuploid cells classified as mosaic.
Main results and the role of chance: Among high-quality blastocysts, the euploidy rate was 82.9%, with a remarkably low mosaic aneuploidy of only 2.5%. The euploidy rates of viable low-quality blastocysts and arrested embryos/blastocysts were 38.6% and 13.0%, respectively. The mosaic aneuploidy rate decreased progressively with embryonic development, from 93.2% at the cleavage stage to 40% at the blastocyst stage. Chaotic aneuploidy was the primary factor (66.1%, 39/59) contributing to embryonic arrest at the cleavage stage. Additionally, 26.1% of embryos/blastocysts exhibited segmental aneuploidy, with segmental duplications (30.6%, 22/72) and deletions (54.2%, 39/72) being the most common types of segmental aneuploidy.
Limitations reasons for caution: The sample size in this study is relatively small, especially in the subgroup analysis. Furthermore, whole-embryo analysis is not a foolproof diagnostic method, since it may underestimate the presence of mosaicism.
Wider implications of the findings: The cytogenetic constitution of whole embryos provides a more accurate reflection of their physiological state compared to biopsied samples. The low mosaic aneuploidy rate in high-quality blastocysts supports the practice of transferring mosaic embryos in patients without euploid embryos. If blastocysts reach stage III by Day 6 post-fertilization, nearly half are euploid, suggesting that extending embryo culture to Day 7 may be beneficial in cases where high-quality embryos are lacking.
Study funding/competing interests: This study was supported by the Natural Science Foundation of Guangdong Province (No. 2023A1515010250) and Pilot Program-China Reprodu
{"title":"Biopsy vs comprehensive embryo/blastocyst analysis: a closer look at embryonic chromosome evaluation.","authors":"Jian Xu, Zhiheng Chen, Meiyi Li, Ling Sun","doi":"10.1093/hropen/hoaf013","DOIUrl":"10.1093/hropen/hoaf013","url":null,"abstract":"<p><strong>Study question: </strong>Compared with embryonic cytogenetic constitution of biopsied samples in human pre-implantation embryos, are there any differences in whole embryos?</p><p><strong>Summary answer: </strong>Whole embryos exhibit a significantly higher euploidy rate and reduction in mosaic aneuploidy rate compared to biopsied samples.</p><p><strong>What is known already: </strong>Much of the existing evidence of cytogenetic constitution of human pre-implantation embryos is based on biopsied cells obtained from blastomeres or trophectoderm biopsies. The mosaic rate of biopsies taken from blastocyst trophectoderm ranges widely, from 2% to 25%.</p><p><strong>Study design size duration: </strong>We investigated the embryonic cytogenetic constitution of 221 whole human embryos/blastocysts from 2019 to 2022, including 41 high-quality blastocysts, 57 low-quality blastocysts, and 123 arrested embryos/blastocysts.</p><p><strong>Participants/materials setting methods: </strong>The cytogenetic constitution of whole embryos/blastocysts was assessed using next-generation sequencing. Mosaicism was diagnosed using a cut-off threshold of 30-70%, with embryos displaying 30-70% aneuploid cells classified as mosaic.</p><p><strong>Main results and the role of chance: </strong>Among high-quality blastocysts, the euploidy rate was 82.9%, with a remarkably low mosaic aneuploidy of only 2.5%. The euploidy rates of viable low-quality blastocysts and arrested embryos/blastocysts were 38.6% and 13.0%, respectively. The mosaic aneuploidy rate decreased progressively with embryonic development, from 93.2% at the cleavage stage to 40% at the blastocyst stage. Chaotic aneuploidy was the primary factor (66.1%, 39/59) contributing to embryonic arrest at the cleavage stage. Additionally, 26.1% of embryos/blastocysts exhibited segmental aneuploidy, with segmental duplications (30.6%, 22/72) and deletions (54.2%, 39/72) being the most common types of segmental aneuploidy.</p><p><strong>Limitations reasons for caution: </strong>The sample size in this study is relatively small, especially in the subgroup analysis. Furthermore, whole-embryo analysis is not a foolproof diagnostic method, since it may underestimate the presence of mosaicism.</p><p><strong>Wider implications of the findings: </strong>The cytogenetic constitution of whole embryos provides a more accurate reflection of their physiological state compared to biopsied samples. The low mosaic aneuploidy rate in high-quality blastocysts supports the practice of transferring mosaic embryos in patients without euploid embryos. If blastocysts reach stage III by Day 6 post-fertilization, nearly half are euploid, suggesting that extending embryo culture to Day 7 may be beneficial in cases where high-quality embryos are lacking.</p><p><strong>Study funding/competing interests: </strong>This study was supported by the Natural Science Foundation of Guangdong Province (No. 2023A1515010250) and Pilot Program-China Reprodu","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2025 2","pages":"hoaf013"},"PeriodicalIF":8.3,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11928226/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143694393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-03eCollection Date: 2025-01-01DOI: 10.1093/hropen/hoaf009
Umberto Leone Roberti Maggiore, Francesco Fanfani, Giovanni Scambia, Ilaria Capasso, Emanuele Perrone, Giuseppe Parisi, Gian Franco Zannoni, Francesca Falcone, Alessandra Di Giovanni, Mario Malzoni, Anna Myriam Perrone, Francesco Mezzapesa, Pierandrea De Iaco, Simone Garzon, Pier Carlo Zorzato, Stefano Uccella, Fabio Barra, Stefano Bogliolo, Simone Ferrero, Veronica Iannuzzi, Dorella Franchi, Tommaso Bianchi, Tommaso Grassi, Robert Fruscio, Giulia Vittori Antisari, Giovanni Roviglione, Marcello Ceccaroni, Fulvio Borella, Stefano Cosma, Alberto Revelli, Jvan Casarin, Anna Giudici, Fabio Ghezzi, Matteo Marchetti, Giulia Spagnol, Roberto Tozzi, Francesca Filippi, Michela Molgora, Giovanna Scarfone, Biagio Paolini, Stefano Fucina, Valentina Chiappa, Antonino Ditto, Giorgio Bogani, Francesco Raspagliesi
Study question: Can patients with uterine smooth muscle tumours of uncertain malignant potential (STUMP) be effectively and safely managed with fertility-sparing treatment?
Summary answer: This multicentre retrospective study demonstrates that fertility-sparing management for patients diagnosed with STUMP is both feasible and safe.
What is known already: Few studies, involving a limited number of patients, have investigated fertility-sparing management for STUMP in women with future pregnancy aspirations.
Study design size duration: This multicentre retrospective study was conducted in collaboration with 13 Italian institutions specializing in gynaecologic oncology. The primary objective was to evaluate the reproductive outcomes of the included patients, while the secondary objective was to analyse their clinical outcomes.
Participants/materials setting methods: A total of 106 patients with a histological diagnosis of STUMP who underwent fertility-sparing treatment for uterine tumours were included. Patient data were collected from 13 referral centres across Italy, and reproductive and clinical outcomes were documented during follow-up. The median (range) length of follow-up was 48 (7-191) months.
Main results and the role of chance: Of the 106 patients, 47 (44.3%) patients actively tried to conceive after fertility-sparing surgery, and 27 of them (57.4%) achieved a pregnancy. Among the patients trying to conceive, 12 (25.5%) women had more than one pregnancy after surgery for STUMP. At follow-up, 23 (21.7%) out of the 106 women had a recurrence of uterine disease. Furthermore, a higher rate of recurrence was observed among patients who became pregnant (17 out of 27 women (63.0%)) compared with those who did not (6 out of 79 women (7.6%); P < 0.001). Only two cases (1.9%) of malignant relapse were recorded, and one patient with a leiomyosarcoma recurrence died.
Limitations reasons for caution: The primary limitation of this study is the inherent biases associated with its retrospective design.
Wider implications of the findings: This multicentre retrospective study represents the largest case series to date examining the reproductive and clinical outcomes of patients undergoing conservative treatment for STUMP. The findings suggest that patients can be counselled on the feasibility and safety of fertility-sparing management, which should be considered by clinicians as both safe and effective.
Study funding/competing interests: No funding was received, and there are no competing interests.
{"title":"Uterine smooth muscle tumours with uncertain malignant potential: reproductive and clinical outcomes in patients undergoing fertility-sparing management.","authors":"Umberto Leone Roberti Maggiore, Francesco Fanfani, Giovanni Scambia, Ilaria Capasso, Emanuele Perrone, Giuseppe Parisi, Gian Franco Zannoni, Francesca Falcone, Alessandra Di Giovanni, Mario Malzoni, Anna Myriam Perrone, Francesco Mezzapesa, Pierandrea De Iaco, Simone Garzon, Pier Carlo Zorzato, Stefano Uccella, Fabio Barra, Stefano Bogliolo, Simone Ferrero, Veronica Iannuzzi, Dorella Franchi, Tommaso Bianchi, Tommaso Grassi, Robert Fruscio, Giulia Vittori Antisari, Giovanni Roviglione, Marcello Ceccaroni, Fulvio Borella, Stefano Cosma, Alberto Revelli, Jvan Casarin, Anna Giudici, Fabio Ghezzi, Matteo Marchetti, Giulia Spagnol, Roberto Tozzi, Francesca Filippi, Michela Molgora, Giovanna Scarfone, Biagio Paolini, Stefano Fucina, Valentina Chiappa, Antonino Ditto, Giorgio Bogani, Francesco Raspagliesi","doi":"10.1093/hropen/hoaf009","DOIUrl":"10.1093/hropen/hoaf009","url":null,"abstract":"<p><strong>Study question: </strong>Can patients with uterine smooth muscle tumours of uncertain malignant potential (STUMP) be effectively and safely managed with fertility-sparing treatment?</p><p><strong>Summary answer: </strong>This multicentre retrospective study demonstrates that fertility-sparing management for patients diagnosed with STUMP is both feasible and safe.</p><p><strong>What is known already: </strong>Few studies, involving a limited number of patients, have investigated fertility-sparing management for STUMP in women with future pregnancy aspirations.</p><p><strong>Study design size duration: </strong>This multicentre retrospective study was conducted in collaboration with 13 Italian institutions specializing in gynaecologic oncology. The primary objective was to evaluate the reproductive outcomes of the included patients, while the secondary objective was to analyse their clinical outcomes.</p><p><strong>Participants/materials setting methods: </strong>A total of 106 patients with a histological diagnosis of STUMP who underwent fertility-sparing treatment for uterine tumours were included. Patient data were collected from 13 referral centres across Italy, and reproductive and clinical outcomes were documented during follow-up. The median (range) length of follow-up was 48 (7-191) months.</p><p><strong>Main results and the role of chance: </strong>Of the 106 patients, 47 (44.3%) patients actively tried to conceive after fertility-sparing surgery, and 27 of them (57.4%) achieved a pregnancy. Among the patients trying to conceive, 12 (25.5%) women had more than one pregnancy after surgery for STUMP. At follow-up, 23 (21.7%) out of the 106 women had a recurrence of uterine disease. Furthermore, a higher rate of recurrence was observed among patients who became pregnant (17 out of 27 women (63.0%)) compared with those who did not (6 out of 79 women (7.6%); <i>P</i> < 0.001). Only two cases (1.9%) of malignant relapse were recorded, and one patient with a leiomyosarcoma recurrence died.</p><p><strong>Limitations reasons for caution: </strong>The primary limitation of this study is the inherent biases associated with its retrospective design.</p><p><strong>Wider implications of the findings: </strong>This multicentre retrospective study represents the largest case series to date examining the reproductive and clinical outcomes of patients undergoing conservative treatment for STUMP. The findings suggest that patients can be counselled on the feasibility and safety of fertility-sparing management, which should be considered by clinicians as both safe and effective.</p><p><strong>Study funding/competing interests: </strong>No funding was received, and there are no competing interests.</p><p><strong>Trial registration number: </strong>N/A.</p>","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2025 2","pages":"hoaf009"},"PeriodicalIF":8.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11906398/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143652452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-28eCollection Date: 2025-01-01DOI: 10.1093/hropen/hoaf012
Antonio La Marca, Michela Semprini, Elisa Mastellari, Valeria Donno, Martina Capuzzo, Carlo Alboni, Simone Giulini
Background: Endometriosis is a chronic disease that can compromise fertility in up to 30-50% of affected patients, and it is estimated that patients affected by endometriosis represent about 10% of patients undergoing ART treatments. The hypothesized underlying mechanisms explaining infertility are various, but great attention has been given to the relationship between ovarian endometriomas and reduced ovarian reserve.
Objective and rationale: Infertility in patients with endometriosis does not have univocal management, since surgical therapy can increase the chances of natural conception, but at the same time increases the risk of damage to the ovarian reserve. In some cases, IVF procedures should be considered instead of surgery, within a personalized strategy. It has therefore been proposed that patients with endometriosis are eligible for fertility preservation.
Search methods: This article is based on a critical review of literature on peer-reviewed article indexing databases including PubMed, Scopus and Medline, using as keywords: 'fertility preservation', 'oocyte vitrification', 'endometriosis', 'endometrioma', 'ovarian reserve' and 'in vitro fertilization'.
Outcomes: Data regarding the feasibility of oocyte cryopreservation in patients with endometriosis have increased over recent years, indicating that these patients seem to have the same number of oocytes retrieved and IVF outcomes similar to those who perform fertility preservation for other indications. However, probably due to a reduced ovarian reserve, several cycles of ovarian stimulation may be needed to gather a suitable number of retrieved oocytes per patient. Age, ovarian reserve, and previous ovarian surgery are the main factors affecting the success of fertility preservation. Bilateral endometriomas, a history of unilateral endometrioma surgery with a contralateral recurrence, and preoperative reduced ovarian reserve are the most common indications for fertility preservation. The choice between primary surgery and ART is often complex, requiring a therapeutic strategy tailored to the patient's clinical characteristics and needs, such as age, type and severity of endometriosis lesions, presence of symptoms, surgical history, and desire for pregnancy.
Limitations reasons for caution: The development of endometriosis-related infertility and the severity of ovarian damage due to endometriosis lesions per se or their surgical treatment are difficult to predict, and data are lacking concerning which subgroups of patients with endometriosis might benefit most from fertility preservation.
Wider implications: Women with endometriosis, and in particular women with bilateral ovarian endometriomas or recurrent surgery on the ovaries, should be advised about risk of ovarian reserve damage. Oocyte cryopreservation is an established technique t
{"title":"Fertility preservation in women with endometriosis.","authors":"Antonio La Marca, Michela Semprini, Elisa Mastellari, Valeria Donno, Martina Capuzzo, Carlo Alboni, Simone Giulini","doi":"10.1093/hropen/hoaf012","DOIUrl":"10.1093/hropen/hoaf012","url":null,"abstract":"<p><strong>Background: </strong>Endometriosis is a chronic disease that can compromise fertility in up to 30-50% of affected patients, and it is estimated that patients affected by endometriosis represent about 10% of patients undergoing ART treatments. The hypothesized underlying mechanisms explaining infertility are various, but great attention has been given to the relationship between ovarian endometriomas and reduced ovarian reserve.</p><p><strong>Objective and rationale: </strong>Infertility in patients with endometriosis does not have univocal management, since surgical therapy can increase the chances of natural conception, but at the same time increases the risk of damage to the ovarian reserve. In some cases, IVF procedures should be considered instead of surgery, within a personalized strategy. It has therefore been proposed that patients with endometriosis are eligible for fertility preservation.</p><p><strong>Search methods: </strong>This article is based on a critical review of literature on peer-reviewed article indexing databases including PubMed, Scopus and Medline, using as keywords: 'fertility preservation', 'oocyte vitrification', 'endometriosis', 'endometrioma', 'ovarian reserve' and '<i>in vitro</i> fertilization'.</p><p><strong>Outcomes: </strong>Data regarding the feasibility of oocyte cryopreservation in patients with endometriosis have increased over recent years, indicating that these patients seem to have the same number of oocytes retrieved and IVF outcomes similar to those who perform fertility preservation for other indications. However, probably due to a reduced ovarian reserve, several cycles of ovarian stimulation may be needed to gather a suitable number of retrieved oocytes per patient. Age, ovarian reserve, and previous ovarian surgery are the main factors affecting the success of fertility preservation. Bilateral endometriomas, a history of unilateral endometrioma surgery with a contralateral recurrence, and preoperative reduced ovarian reserve are the most common indications for fertility preservation. The choice between primary surgery and ART is often complex, requiring a therapeutic strategy tailored to the patient's clinical characteristics and needs, such as age, type and severity of endometriosis lesions, presence of symptoms, surgical history, and desire for pregnancy.</p><p><strong>Limitations reasons for caution: </strong>The development of endometriosis-related infertility and the severity of ovarian damage due to endometriosis lesions <i>per se</i> or their surgical treatment are difficult to predict, and data are lacking concerning which subgroups of patients with endometriosis might benefit most from fertility preservation.</p><p><strong>Wider implications: </strong>Women with endometriosis, and in particular women with bilateral ovarian endometriomas or recurrent surgery on the ovaries, should be advised about risk of ovarian reserve damage. Oocyte cryopreservation is an established technique t","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2025 2","pages":"hoaf012"},"PeriodicalIF":8.3,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11930344/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143694533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-26eCollection Date: 2025-01-01DOI: 10.1093/hropen/hoaf006
Wenxue Xiong, Xijia Tang, Lu Han, Li Ling
<p><strong>Study question: </strong>Is paternal age associated with neonatal outcomes?</p><p><strong>Summary answer: </strong>Paternal age is independently associated with preterm birth (PTB) and caesarean section.</p><p><strong>What is known already: </strong>Advanced maternal age has long been recognized as a major risk factor for adverse neonatal outcomes. However, the association between paternal age and neonatal outcomes are not well established, yet it is biologically plausible that an increasing number of genetic and epigenetic sperm abnormalities in older males may contribute to adverse neonatal outcomes.</p><p><strong>Study design size duration: </strong>This population-based cohort study was based on the National Free Preconception Checkups Project between 1 January 2014 and 31 December 2019 in Guangdong Province, China. Paternal age at the maternal last menstrual period was measured. The main outcomes included caesarean section, PTB, small for gestational age (SGA) and perinatal infant death (PID).</p><p><strong>Participants/materials setting methods: </strong>A total of 783 988 mother-neonate-father trios were included in this study. A modified Poisson regression model was employed to estimate relative risk (RR) and 95% CI and logistic regression models were used to analyse the relative importance of predictors. We used restricted cubic splines to flexibly model the non-linear dose-response association between paternal age and neonatal outcomes. We also assessed additive interactions between paternal and maternal age on neonatal outcomes.</p><p><strong>Main results and the role of chance: </strong>Neonates born to fathers aged 35-44 years had higher risks of caesarean section (RR: 1.07; 95% CI: 1.06-1.09) and PTB (RR: 1.15; 95% CI: 1.10-1.19) compared with neonates of fathers aged 25-34 years, after adjustment for confounders. The increased risks of PTB associated with paternal age appeared to be 'dose' dependent, with a J-shaped association curve (<i>P</i> for non-linearity<0.001). The relative importance of paternal age in predicting PTB and caesarean section was similar to, or even higher than, that of maternal age. The combined effects of advanced maternal and paternal age appeared to be less than additive joint effects (relative excess risk due to interaction<0). The association of paternal age with SGA or PID was not statistically significant (<i>P </i>><i> </i>0.05).</p><p><strong>Limitations reasons for caution: </strong>As with all observational studies, residual confounding could not be ruled out. Only couples who planned to conceive were included.</p><p><strong>Wider implications of the findings: </strong>In this population-based cohort study, paternal age was independently associated with caesarean section and PTB. These findings may be clinically useful in preconception counselling on parental age-related pregnancy risks. Our findings emphasize the need to further investigate the public health implications of increasing p
{"title":"Paternal age and neonatal outcomes: a population-based cohort study.","authors":"Wenxue Xiong, Xijia Tang, Lu Han, Li Ling","doi":"10.1093/hropen/hoaf006","DOIUrl":"10.1093/hropen/hoaf006","url":null,"abstract":"<p><strong>Study question: </strong>Is paternal age associated with neonatal outcomes?</p><p><strong>Summary answer: </strong>Paternal age is independently associated with preterm birth (PTB) and caesarean section.</p><p><strong>What is known already: </strong>Advanced maternal age has long been recognized as a major risk factor for adverse neonatal outcomes. However, the association between paternal age and neonatal outcomes are not well established, yet it is biologically plausible that an increasing number of genetic and epigenetic sperm abnormalities in older males may contribute to adverse neonatal outcomes.</p><p><strong>Study design size duration: </strong>This population-based cohort study was based on the National Free Preconception Checkups Project between 1 January 2014 and 31 December 2019 in Guangdong Province, China. Paternal age at the maternal last menstrual period was measured. The main outcomes included caesarean section, PTB, small for gestational age (SGA) and perinatal infant death (PID).</p><p><strong>Participants/materials setting methods: </strong>A total of 783 988 mother-neonate-father trios were included in this study. A modified Poisson regression model was employed to estimate relative risk (RR) and 95% CI and logistic regression models were used to analyse the relative importance of predictors. We used restricted cubic splines to flexibly model the non-linear dose-response association between paternal age and neonatal outcomes. We also assessed additive interactions between paternal and maternal age on neonatal outcomes.</p><p><strong>Main results and the role of chance: </strong>Neonates born to fathers aged 35-44 years had higher risks of caesarean section (RR: 1.07; 95% CI: 1.06-1.09) and PTB (RR: 1.15; 95% CI: 1.10-1.19) compared with neonates of fathers aged 25-34 years, after adjustment for confounders. The increased risks of PTB associated with paternal age appeared to be 'dose' dependent, with a J-shaped association curve (<i>P</i> for non-linearity<0.001). The relative importance of paternal age in predicting PTB and caesarean section was similar to, or even higher than, that of maternal age. The combined effects of advanced maternal and paternal age appeared to be less than additive joint effects (relative excess risk due to interaction<0). The association of paternal age with SGA or PID was not statistically significant (<i>P </i>><i> </i>0.05).</p><p><strong>Limitations reasons for caution: </strong>As with all observational studies, residual confounding could not be ruled out. Only couples who planned to conceive were included.</p><p><strong>Wider implications of the findings: </strong>In this population-based cohort study, paternal age was independently associated with caesarean section and PTB. These findings may be clinically useful in preconception counselling on parental age-related pregnancy risks. Our findings emphasize the need to further investigate the public health implications of increasing p","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2025 1","pages":"hoaf006"},"PeriodicalIF":8.3,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11878789/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143560188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-24eCollection Date: 2025-01-01DOI: 10.1093/hropen/hoaf010
Apostol Apostolov, Danilo Mladenović, Kadi Tilk, Andres Lõhmus, Vesselin Baev, Galina Yahubyan, Alberto Sola-Leyva, Mathilde Bergamelli, André Görgens, Cheng Zhao, Samir E L Andaloussi, Aive Kalinina, Ganesh Acharya, Fredrik Lanner, Merli Saare, Maire Peters, Paola Piomboni, Alice Luddi, Andres Salumets, Elina Aleksejeva
Study question: Does the molecular composition of uterine fluid extracellular vesicles (UF-EVs) reflect endometrial tissue changes across the menstrual cycle?
Summary answer: Concordance between endometrial tissue and UF-EVs exists on miRNA and mRNA levels along the menstrual cycle phases and UF-EV surface proteomic signatures suggest EVs originate from several major endometrial cell populations.
What is known already: The clinical value of endometrial receptivity testing is restricted by invasiveness and the use of only one omics level of input. There is promising evidence that UF-EVs can reflect changes in mid-secretory endometrium, highlighting the potential to establish endometrial receptivity testing right before embryo transfer. However, the dynamic changes of UF-EVs molecular cargo have not been directly compared to endometrial tissue on multiple omics levels.
Study design size duration: This cross-sectional study included fertile women from four menstrual cycle phases: proliferative and early-, mid-, and late-secretory phases. In total, 26 paired samples of UF and endometrial tissue were collected. mRNA and miRNA were sequenced, and differential analysis was performed on consecutive phases. UF-EVs were profiled for various protein surface markers associated with different cell types. EVs from epithelial endometrial organoid-conditioned culture media were used as a reference of pure epithelial endometrial EVs.
Participants/materials setting methods: Paired UF and endometrial tissue samples were collected from 26 fertile, reproductive-age women. EV isolation from UF was validated using electron microscopy and western blotting, and particle numbers were measured by nanoparticle tracking analysis. The transcriptome and miRNome of UF-EVs and endometrial tissue were sequenced, and differential expression analysis was conducted on consecutive phases of the menstrual cycle. Bead-based EV flow cytometry targeting 37 surface protein markers was used to characterize EVs from UF and endometrial organoids.
Main results and the role of chance: Surface proteome analysis revealed that UF-EVs from the mid-secretory phase had significantly increased expression of natural killer cell marker CD56 (P < 0.005), pan-leukocyte marker CD45 (P < 0.005), pan-T-cell marker CD3 (P < 0.005), and coagulation-related protein CD142 (P < 0.005) compared to those from the proliferative phase, whereas markers associated with endometrial epithelial cells (CD29, CD133, and CD326) did not significantly change across the menstrual cycle. Transcriptomic analysis highlighted differential expression of histone and metallothionein genes that correlated between paired UF-EVs and endometrial tissues in each tested menstrual cycle phase. Principal component analysis of miRNomes of paired UF-EVs and endometrial tissue samples
研究问题：子宫液细胞外囊泡（uf - ev）的分子组成是否反映了整个月经周期子宫内膜组织的变化？总结回答：子宫内膜组织和UF-EV在月经周期阶段的miRNA和mRNA水平上存在一致性，UF-EV表面蛋白质组学特征表明ev起源于几种主要的子宫内膜细胞群。已知情况：子宫内膜容受性检测的临床价值受到侵入性和仅使用一个组学水平输入的限制。有令人鼓舞的证据表明，uf - ev可以反映中期分泌子宫内膜的变化，突出了在胚胎移植前建立子宫内膜容受性测试的潜力。然而，目前还没有在多组学水平上直接比较uf - ev分子载货量与子宫内膜组织的动态变化。研究设计规模持续时间：这项横断面研究包括四个月经周期阶段的有生育能力的妇女：增殖期和分泌早期、中期和晚期。共收集26份UF和子宫内膜组织配对样本。对mRNA和miRNA进行测序，并对连续期进行差异分析。对uv - ev进行了与不同细胞类型相关的各种蛋白质表面标记的分析。以上皮子宫内膜类器官条件培养基中的ev作为纯上皮子宫内膜ev的对照。参与者/材料设置方法：从26名育龄妇女中收集配对UF和子宫内膜组织样本。利用电子显微镜和免疫印迹法对UF中EV的分离进行了验证，并通过纳米颗粒跟踪分析测定了EV的颗粒数量。对uf - ev和子宫内膜组织的转录组和miRNome进行测序，并在月经周期的连续阶段进行差异表达分析。采用靶向37种表面蛋白标记物的珠状上皮细胞流式细胞术对UF和子宫内膜类器官的上皮细胞进行了表征。主要结果及其作用：表面蛋白质组学分析显示，分泌中期的uf - ev显著增加了自然杀伤细胞标志物CD56 （P P P P P）的表达。注意的局限性：月经周期阶段的临床日期是基于月经的第一天和LH峰值的时间，这并不排除未达到预期子宫内膜阶段的可能性。我们研究的更大局限性是缺乏在妇科实践中收集UF样本的标准化程序，这可能会挑战我们研究结果的复制。研究结果的更广泛意义：uf - ev反映月经周期子宫内膜阶段的证据支持在子宫内膜容受性检测中使用uf - ev。此外，考虑到更具侵入性的组织活检只反映活检部位而不是整个子宫内膜，进一步研究子宫内膜病变中的uf - ev可能有助于诊断。研究经费/竞争利益：本研究由欧洲区域发展基金企业爱沙尼亚应用研究计划（资助协议号：2014-2020.4.02.21-0398 (EVREM)）、爱沙尼亚研究委员会（资助号：PRG1076和PSG1082）、Horizon Europe NESTOR资助(资助号：101120075)欧盟委员会，瑞典研究理事会(批准号：2024-02530)，诺和诺德基金会(批准号：NNF24OC0092384)，以及保加利亚共和国国家恢复和复原计划，项目编号BG-RRP-2.004-0001-C01。A.S.L.获得了Becas Fundación Ramón arees para estudio Postdoctorales的资助。所有作者均声明无利益冲突。
{"title":"Multi-omics analysis of uterine fluid extracellular vesicles reveals a resemblance with endometrial tissue across the menstrual cycle: biological and translational insights.","authors":"Apostol Apostolov, Danilo Mladenović, Kadi Tilk, Andres Lõhmus, Vesselin Baev, Galina Yahubyan, Alberto Sola-Leyva, Mathilde Bergamelli, André Görgens, Cheng Zhao, Samir E L Andaloussi, Aive Kalinina, Ganesh Acharya, Fredrik Lanner, Merli Saare, Maire Peters, Paola Piomboni, Alice Luddi, Andres Salumets, Elina Aleksejeva","doi":"10.1093/hropen/hoaf010","DOIUrl":"10.1093/hropen/hoaf010","url":null,"abstract":"<p><strong>Study question: </strong>Does the molecular composition of uterine fluid extracellular vesicles (UF-EVs) reflect endometrial tissue changes across the menstrual cycle?</p><p><strong>Summary answer: </strong>Concordance between endometrial tissue and UF-EVs exists on miRNA and mRNA levels along the menstrual cycle phases and UF-EV surface proteomic signatures suggest EVs originate from several major endometrial cell populations.</p><p><strong>What is known already: </strong>The clinical value of endometrial receptivity testing is restricted by invasiveness and the use of only one omics level of input. There is promising evidence that UF-EVs can reflect changes in mid-secretory endometrium, highlighting the potential to establish endometrial receptivity testing right before embryo transfer. However, the dynamic changes of UF-EVs molecular cargo have not been directly compared to endometrial tissue on multiple omics levels.</p><p><strong>Study design size duration: </strong>This cross-sectional study included fertile women from four menstrual cycle phases: proliferative and early-, mid-, and late-secretory phases. In total, 26 paired samples of UF and endometrial tissue were collected. mRNA and miRNA were sequenced, and differential analysis was performed on consecutive phases. UF-EVs were profiled for various protein surface markers associated with different cell types. EVs from epithelial endometrial organoid-conditioned culture media were used as a reference of pure epithelial endometrial EVs.</p><p><strong>Participants/materials setting methods: </strong>Paired UF and endometrial tissue samples were collected from 26 fertile, reproductive-age women. EV isolation from UF was validated using electron microscopy and western blotting, and particle numbers were measured by nanoparticle tracking analysis. The transcriptome and miRNome of UF-EVs and endometrial tissue were sequenced, and differential expression analysis was conducted on consecutive phases of the menstrual cycle. Bead-based EV flow cytometry targeting 37 surface protein markers was used to characterize EVs from UF and endometrial organoids.</p><p><strong>Main results and the role of chance: </strong>Surface proteome analysis revealed that UF-EVs from the mid-secretory phase had significantly increased expression of natural killer cell marker CD56 (<i>P</i> < 0.005), pan-leukocyte marker CD45 (<i>P</i> < 0.005), pan-T-cell marker CD3 (<i>P</i> < 0.005), and coagulation-related protein CD142 (<i>P</i> < 0.005) compared to those from the proliferative phase, whereas markers associated with endometrial epithelial cells (CD29, CD133, and CD326) did not significantly change across the menstrual cycle. Transcriptomic analysis highlighted differential expression of histone and metallothionein genes that correlated between paired UF-EVs and endometrial tissues in each tested menstrual cycle phase. Principal component analysis of miRNomes of paired UF-EVs and endometrial tissue samples","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2025 2","pages":"hoaf010"},"PeriodicalIF":8.3,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11904304/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143627034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-21eCollection Date: 2025-01-01DOI: 10.1093/hropen/hoaf008
Anu Valkna, Anna-Grete Juchnewitsch, Lisanna Põlluaas, Kristiina Lillepea, Stanislav Tjagur, Avirup Dutta, Kristjan Pomm, Margus Punab, Maris Laan
<p><strong>Study question: </strong>What is the load and profile of hereditary cancer-linked germline variants in infertile compared to fertile men?</p><p><strong>Summary answer: </strong>This study showed almost 5-fold enrichment of disease-causing findings in hereditary cancer genes in infertile compared to fertile men (6.9% vs 1.5%, <i>P </i>=<i> </i>2.3 × 10<sup>-4</sup>).</p><p><strong>What is known already: </strong>Epidemiological studies have revealed that men with low sperm count have a 2-fold higher risk of developing cancer during their lifetime. Our recent study observed a 4-fold increased prevalence of cancer in men with monogenic infertility compared to the general male population (8% vs 2%). Shared molecular etiologies of male infertility and cancer have been proposed.</p><p><strong>Study design size duration: </strong>This retrospective study analyzed germline likely pathogenic and pathogenic (LP/P) variants in 157 hereditary cancer genes in 522 infertile and 323 fertile men recruited to the ESTonian ANDrology (ESTAND) cohort.</p><p><strong>Participants/materials setting methods: </strong>All study participants (n = 845) had been recruited and phenotyped at an Andrology Clinic. Identification of LP/P variants in the cancer gene panel was performed from an exome sequencing dataset generated for the study cohort. All variants passed an automated filtering process, final manual assessment of pathogenicity, and experimental confirmation using Sanger sequencing. Retrospective general health records were available for 36 out of 41 (88%) men with LP/P findings.</p><p><strong>Main results and the role of chance: </strong>Infertile men presented a nearly 5-fold higher load of LP/P findings (36 of 522 cases, 6.9%) compared to fertile subjects (5 of 323, 1.5%; odds ratio (OR) = 4.7, 95% CI 1.81-15.5; <i>P</i> = 2.3 × 10<sup>-4</sup>) spanning over 24 hereditary cancer genes. The prevalence of findings was not significantly different between azoospermic and oligozoospermic cases. There was also no enrichment of findings in men with a history of cryptorchidism. By the time of the study, six men carrying hereditary cancer variants had been diagnosed with a tumor. Family members affected with cancer had been documented for 10 of 14 cases with available pedigree health data.Nearly half of the infertile men with LP/P findings (17 out of 36) carried variants in genes belonging to the Fanconi anemia (FA) pathway involved in the maintenance of genomic integrity in mitosis and meiosis, repair of DNA double-stranded breaks, and interstrand crosslinks. Overall, FA-pathway genes <i>BRCA2</i> (monoallelic) and <i>FANCM</i> (biallelic) were the most frequently affected loci (five subjects per gene).LP/P findings in pleiotropic genes linked to human development and hereditary cancer (<i>TSC1</i>, <i>PHOX2B</i>, <i>WT1</i>, <i>SPRED1</i>, <i>NF1</i>, <i>LZTR1</i>, <i>HOXB13</i>) were identified in several patients with syndromic phenotypes. Four cryptorchid
研究问题：与有生育能力的男性相比，不育男性中遗传性癌症相关生殖系变异的负荷和特征是什么？摘要回答：这项研究显示，不育男性的遗传性癌症基因致病性发现几乎是有生育能力男性的5倍（6.9% vs 1.5%, P = 2.3 × 10-4）。已知情况：流行病学研究表明，精子数量低的男性一生中患癌症的风险要高出两倍。我们最近的研究发现，与普通男性人群相比，单基因不育男性的癌症患病率增加了4倍（8%对2%）。男性不育和癌症的共同分子病因已被提出。研究设计规模持续时间：本回顾性研究分析了爱沙尼亚男科（ESTAND）队列中522名不育和323名可育男性157种遗传癌症基因的可能致病性和致病性（LP/P）变异。参与者/材料设置方法：所有研究参与者（n = 845）均在男科诊所招募并进行表型分析。通过为研究队列生成的外显子组测序数据集，对癌症基因面板中的LP/P变异进行了鉴定。所有变异都通过了自动过滤过程，最终人工评估致病性，并使用Sanger测序进行实验确认。41名有LP/P症状的男性中有36名（88%）可获得回顾性一般健康记录。主要结果和偶然性的作用：不育男性（522例中有36例，6.9%）的LP/P检查结果负荷比有生育能力的男性(323例中有5例，1.5%；优势比(OR) = 4.7, 95% CI 1.81 ~ 15.5；P = 2.3 × 10-4)，跨越24个遗传癌基因。无精子和少精子病例的患病率无显著差异。在有隐睾病史的男性中也没有丰富的发现。到研究开始时，六名携带遗传性癌症变异的男性被诊断出患有肿瘤。14例中有10例的家庭成员患有癌症，有家谱健康数据。近一半患有LP/P的不育男性（36人中有17人）携带属于范可尼贫血（FA）途径的基因变异，该途径涉及有丝分裂和减数分裂中基因组完整性的维持，DNA双链断裂的修复以及链间交联。总的来说，fa通路基因BRCA2（单等位基因）和FANCM（双等位基因）是最常受影响的基因座（每个基因5个受试者）。与人类发育和遗传性癌症相关的多效基因（TSC1, PHOX2B, WT1, SPRED1, NF1, LZTR1, HOXB13）的LP/P发现在一些综合征表型患者中。4名隐睾不育男性携带MLH1、MSH2和MSH6变异，与Lynch综合征有关。未来的研究将揭示这一观察结果是偶然的还是可复制的。大多数具有LP/P变异的遗传性癌症基因在一种或多种睾丸细胞类型中表现出高表达，据报道，24种受影响基因中的15种小鼠模型表现出男性亚不育或不育。这些数据支持精子发生受损和癌症的共同遗传病因学。与有生育能力的男性相比，不育男性中癌症相关变异的比例显著增加，这也可以解释癌症作为男性不育合并症的高患病率。大规模数据：本研究中发现的所有与癌症相关的遗传变异都已提交给国家生物技术信息中心（NCBI） ClinVar数据库（https://www.ncbi.nlm.nih.gov/clinvar/）.Limitations)。注意事项：所有招募的参与者都是居住在爱沙尼亚的欧洲白人血统。因此，结果可能不适用于其他种族群体。由于研究参与者的年龄较小（中位年龄为34.4岁），因此无法评估一生中癌症的真实发病率。由于回顾性临床数据不能用于所有男性，因此不可能评估所有可能的基因型-表型联系。由于缺乏来自家庭成员的遗传数据，因此无法评估变异的遗传性质或其潜在的重新发生。研究结果的更广泛含义：全球约有7-10%的男性患有不育症。在这项研究中，每15名生精失败的男性中就有1人在遗传癌症基因中携带种系LP/P变异。随着外显子组测序逐渐进入男科的分子诊断领域，分析不育男性的遗传癌症相关变异将提供额外的临床益处。男性因素不育症通常在30多岁的男性中被诊断出来，通常在癌症或其症状出现之前。早期了解生殖系易感性的癌症可以及时筛查和多学科的管理选择，潜在地改善预后。 该研究数据为遗传性癌症和生精失败的共同单基因病因提供了支持。研究经费/竞争利益：本研究由爱沙尼亚研究委员会拨款PRG1021 （M.L.和M.P.）资助。作者声明无利益冲突。
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