F Parisi, C Fenizia, A Introini, A Zavatta, C Scaccabarozzi, M Biasin, V Savasi
<p><strong>Background: </strong>Estrogens regulate disparate female physiological processes, thus ensuring reproduction. Altered estrogen levels and signaling have been associated with increased risks of pregnancy failure and complications, including hypertensive disorders and low birthweight babies. However, the role of estrogens in the periconceptional period and early pregnancy is still understudied.</p><p><strong>Objective and rationale: </strong>This review aims to summarize the current evidence on the role of maternal estrogens during the periconceptional period and the first trimester of pregnancies conceived naturally and following ART. Detailed molecular mechanisms and related clinical impacts are extensively described.</p><p><strong>Search methods: </strong>Data for this narrative review were independently identified by seven researchers on Pubmed and Embase databases. The following keywords were selected: 'estrogens' OR 'estrogen level(s)' OR 'serum estradiol' OR 'estradiol/estrogen concentration', AND 'early pregnancy' OR 'first trimester of pregnancy' OR 'preconceptional period' OR 'ART' OR 'In Vitro Fertilization (IVF)' OR 'Embryo Transfer' OR 'Frozen Embryo Transfer' OR 'oocyte donation' OR 'egg donation' OR 'miscarriage' OR 'pregnancy outcome' OR 'endometrium'.</p><p><strong>Outcomes: </strong>During the periconceptional period (defined here as the critical time window starting 1 month before conception), estrogens play a crucial role in endometrial receptivity, through the activation of paracrine/autocrine signaling. A derailed estrogenic milieu within this period seems to be detrimental both in natural and ART-conceived pregnancies. Low estrogen levels are associated with non-conception cycles in natural pregnancies. On the other hand, excessive supraphysiologic estrogen concentrations at time of the LH peak correlate with lower live birth rates and higher risks of pregnancy complications. In early pregnancy, estrogen plays a massive role in placentation mainly by modulating angiogenic factor expression-and in the development of an immune-tolerant uterine micro-environment by remodeling the function of uterine natural killer and T-helper cells. Lower estrogen levels are thought to trigger abnormal placentation in naturally conceived pregnancies, whereas an estrogen excess seems to worsen pregnancy development and outcomes.</p><p><strong>Wider implications: </strong>Most current evidence available endorses a relation between periconceptional and first trimester estrogen levels and pregnancy outcomes, further depicting an optimal concentration range to optimize pregnancy success. However, how estrogens co-operate with other factors in order to maintain a fine balance between local tolerance towards the developing fetus and immune responses to pathogens remains elusive. Further studies are highly warranted, also aiming to identify the determinants of estrogen response and biomarkers for personalized estrogen administration regimens
{"title":"The pathophysiological role of estrogens in the initial stages of pregnancy: molecular mechanisms and clinical implications for pregnancy outcome from the periconceptional period to end of the first trimester.","authors":"F Parisi, C Fenizia, A Introini, A Zavatta, C Scaccabarozzi, M Biasin, V Savasi","doi":"10.1093/humupd/dmad016","DOIUrl":"10.1093/humupd/dmad016","url":null,"abstract":"<p><strong>Background: </strong>Estrogens regulate disparate female physiological processes, thus ensuring reproduction. Altered estrogen levels and signaling have been associated with increased risks of pregnancy failure and complications, including hypertensive disorders and low birthweight babies. However, the role of estrogens in the periconceptional period and early pregnancy is still understudied.</p><p><strong>Objective and rationale: </strong>This review aims to summarize the current evidence on the role of maternal estrogens during the periconceptional period and the first trimester of pregnancies conceived naturally and following ART. Detailed molecular mechanisms and related clinical impacts are extensively described.</p><p><strong>Search methods: </strong>Data for this narrative review were independently identified by seven researchers on Pubmed and Embase databases. The following keywords were selected: 'estrogens' OR 'estrogen level(s)' OR 'serum estradiol' OR 'estradiol/estrogen concentration', AND 'early pregnancy' OR 'first trimester of pregnancy' OR 'preconceptional period' OR 'ART' OR 'In Vitro Fertilization (IVF)' OR 'Embryo Transfer' OR 'Frozen Embryo Transfer' OR 'oocyte donation' OR 'egg donation' OR 'miscarriage' OR 'pregnancy outcome' OR 'endometrium'.</p><p><strong>Outcomes: </strong>During the periconceptional period (defined here as the critical time window starting 1 month before conception), estrogens play a crucial role in endometrial receptivity, through the activation of paracrine/autocrine signaling. A derailed estrogenic milieu within this period seems to be detrimental both in natural and ART-conceived pregnancies. Low estrogen levels are associated with non-conception cycles in natural pregnancies. On the other hand, excessive supraphysiologic estrogen concentrations at time of the LH peak correlate with lower live birth rates and higher risks of pregnancy complications. In early pregnancy, estrogen plays a massive role in placentation mainly by modulating angiogenic factor expression-and in the development of an immune-tolerant uterine micro-environment by remodeling the function of uterine natural killer and T-helper cells. Lower estrogen levels are thought to trigger abnormal placentation in naturally conceived pregnancies, whereas an estrogen excess seems to worsen pregnancy development and outcomes.</p><p><strong>Wider implications: </strong>Most current evidence available endorses a relation between periconceptional and first trimester estrogen levels and pregnancy outcomes, further depicting an optimal concentration range to optimize pregnancy success. However, how estrogens co-operate with other factors in order to maintain a fine balance between local tolerance towards the developing fetus and immune responses to pathogens remains elusive. Further studies are highly warranted, also aiming to identify the determinants of estrogen response and biomarkers for personalized estrogen administration regimens","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":" ","pages":"699-720"},"PeriodicalIF":14.8,"publicationDate":"2023-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10628507/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9677177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nienke E van Hoogenhuijze, Gemma Lahoz Casarramona, Sarah Lensen, Cindy Farquhar, Mohan S Kamath, Aleyamma T Kunjummen, Nick Raine-Fenning, Sine Berntsen, Anja Pinborg, Shari Mackens, Zeynep Ozturk Inal, Ernest H Y Ng, Jennifer S M Mak, Sachin A Narvekar, Wellington P Martins, Mia Steengaard Olesen, Helen L Torrance, Ben W Mol, Marinus J C Eijkemans, Rui Wang, Frank J M Broekmans
<p><strong>Background: </strong>In IVF/ICSI treatment, the process of embryo implantation is the success rate-limiting step. Endometrial scratching has been suggested to improve this process, but it is unclear if this procedure increases the chance of implantation and live birth (LB) and, if so, for whom, and how the scratch should be performed.</p><p><strong>Objective and rationale: </strong>This individual participant data meta-analysis (IPD-MA) aims to answer the question of whether endometrial scratching in women undergoing IVF/ICSI influences the chance of a LB, and whether this effect is different in specific subgroups of women. After its incidental discovery in 2000, endometrial scratching has been suggested to improve embryo implantation. Numerous randomized controlled trials (RCTs) have been conducted, showing contradicting results. Conventional meta-analyses were limited by high within- and between-study heterogeneity, small study samples, and a high risk of bias for many of the trials. Also, the data integrity of several trials have been questioned. Thus, despite numerous RCTs and a multitude of conventional meta-analyses, no conclusion on the clinical effectiveness of endometrial scratching could be drawn. An IPD-MA approach is able to overcome many of these problems because it allows for increased uniformity of outcome definitions, can filter out studies with data integrity concerns, enables a more precise estimation of the true treatment effect thanks to adjustment for participant characteristics and not having to make the assumptions necessary in conventional meta-analyses, and because it allows for subgroup analysis.</p><p><strong>Search methods: </strong>A systematic literature search identified RCTs on endometrial scratching in women undergoing IVF/ICSI. Authors of eligible studies were invited to share original data for this IPD-MA. Studies were assessed for risk of bias (RoB) and integrity checks were performed. The primary outcome was LB, with a one-stage intention to treat (ITT) as the primary analysis. Secondary analyses included as treated (AT), and the subset of women that underwent an embryo transfer (AT+ET). Treatment-covariate interaction for specific participant characteristics was analyzed in AT+ET.</p><p><strong>Outcomes: </strong>Out of 37 published and 15 unpublished RCTs (7690 participants), 15 RCTs (14 published, one unpublished) shared data. After data integrity checks, we included 13 RCTs (12 published, one unpublished) representing 4112 participants. RoB was evaluated as 'low' for 10/13 RCTs. The one-stage ITT analysis for scratch versus no scratch/sham showed an improvement of LB rates (odds ratio (OR) 1.29 [95% CI 1.02-1.64]). AT, AT+ET, and low-RoB-sensitivity analyses yielded similar results (OR 1.22 [95% CI 0.96-1.54]; OR 1.25 [95% CI 0.99-1.57]; OR 1.26 [95% CI 1.03-1.55], respectively). Treatment-covariate interaction analysis showed no evidence of interaction with age, number of previous failed embryo
{"title":"Endometrial scratching in women undergoing IVF/ICSI: an individual participant data meta-analysis.","authors":"Nienke E van Hoogenhuijze, Gemma Lahoz Casarramona, Sarah Lensen, Cindy Farquhar, Mohan S Kamath, Aleyamma T Kunjummen, Nick Raine-Fenning, Sine Berntsen, Anja Pinborg, Shari Mackens, Zeynep Ozturk Inal, Ernest H Y Ng, Jennifer S M Mak, Sachin A Narvekar, Wellington P Martins, Mia Steengaard Olesen, Helen L Torrance, Ben W Mol, Marinus J C Eijkemans, Rui Wang, Frank J M Broekmans","doi":"10.1093/humupd/dmad014","DOIUrl":"10.1093/humupd/dmad014","url":null,"abstract":"<p><strong>Background: </strong>In IVF/ICSI treatment, the process of embryo implantation is the success rate-limiting step. Endometrial scratching has been suggested to improve this process, but it is unclear if this procedure increases the chance of implantation and live birth (LB) and, if so, for whom, and how the scratch should be performed.</p><p><strong>Objective and rationale: </strong>This individual participant data meta-analysis (IPD-MA) aims to answer the question of whether endometrial scratching in women undergoing IVF/ICSI influences the chance of a LB, and whether this effect is different in specific subgroups of women. After its incidental discovery in 2000, endometrial scratching has been suggested to improve embryo implantation. Numerous randomized controlled trials (RCTs) have been conducted, showing contradicting results. Conventional meta-analyses were limited by high within- and between-study heterogeneity, small study samples, and a high risk of bias for many of the trials. Also, the data integrity of several trials have been questioned. Thus, despite numerous RCTs and a multitude of conventional meta-analyses, no conclusion on the clinical effectiveness of endometrial scratching could be drawn. An IPD-MA approach is able to overcome many of these problems because it allows for increased uniformity of outcome definitions, can filter out studies with data integrity concerns, enables a more precise estimation of the true treatment effect thanks to adjustment for participant characteristics and not having to make the assumptions necessary in conventional meta-analyses, and because it allows for subgroup analysis.</p><p><strong>Search methods: </strong>A systematic literature search identified RCTs on endometrial scratching in women undergoing IVF/ICSI. Authors of eligible studies were invited to share original data for this IPD-MA. Studies were assessed for risk of bias (RoB) and integrity checks were performed. The primary outcome was LB, with a one-stage intention to treat (ITT) as the primary analysis. Secondary analyses included as treated (AT), and the subset of women that underwent an embryo transfer (AT+ET). Treatment-covariate interaction for specific participant characteristics was analyzed in AT+ET.</p><p><strong>Outcomes: </strong>Out of 37 published and 15 unpublished RCTs (7690 participants), 15 RCTs (14 published, one unpublished) shared data. After data integrity checks, we included 13 RCTs (12 published, one unpublished) representing 4112 participants. RoB was evaluated as 'low' for 10/13 RCTs. The one-stage ITT analysis for scratch versus no scratch/sham showed an improvement of LB rates (odds ratio (OR) 1.29 [95% CI 1.02-1.64]). AT, AT+ET, and low-RoB-sensitivity analyses yielded similar results (OR 1.22 [95% CI 0.96-1.54]; OR 1.25 [95% CI 0.99-1.57]; OR 1.26 [95% CI 1.03-1.55], respectively). Treatment-covariate interaction analysis showed no evidence of interaction with age, number of previous failed embryo","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":" ","pages":"721-740"},"PeriodicalIF":14.8,"publicationDate":"2023-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10628489/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9667357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Simon Alesi, Nahal Habibi, Thais Rasia Silva, Nicole Cheung, Sophia Torkel, Chau Thien Tay, Alejandra Quinteros, Hugo Winter, Helena Teede, Aya Mousa, Jessica A Grieger, Lisa J Moran
Background: Preconception diet is a proposed modifiable risk factor for infertility. However, there is no official guidance for women in the preconception period as to which dietary approaches may improve fertility.
Objective and rationale: A comprehensive synthesis of the relevant evidence is key to determine the potentially effective dietary patterns and components as well as evidence gaps, and to provide information for nutritional recommendations for couples planning a pregnancy.
Search methods: In this systematic scoping review, four electronic databases (Medline and EMBASE via Ovid processing, CAB Direct, and CINAHL via EBSCO) were searched for observational studies (prospective and retrospective cohort, cross-sectional, and case-control studies) from inception to 27 September 2021. Eligible studies included women of reproductive age during the preconception period, and evaluated exposures related to preconception diet and outcomes related to fertility. Results were synthesized using a descriptive approach.
Outcomes: A total of 36 studies were eligible for inclusion (31 prospective, 3 cross-sectional, and 2 case-control studies) and were published between 2007 and 2022. Of the assessed dietary exposures, increased adherence to the Mediterranean diet displayed the strongest and most consistent association with improved clinical pregnancy rates. Reducing trans fatty acids (TFAs), saturated fatty acids, and discretionary food intake (fast food and sugar-sweetened beverages) were associated with improvements in live birth, clinical pregnancy rates, and related ART outcomes. The dietary components of seafood, dairy, and soy demonstrated inconsistent findings across the few included studies.
Wider implications: Due to heterogeneity and the limited available literature on most exposures, there is insufficient evidence to support any specific dietary approach for improving fertility. However, following some of the dietary approaches outlined in this review (anti-inflammatory diets, reducing TFA, and discretionary food intake) are consistent with broad healthy eating guidelines, have little to no associated risk, and offer a plausible set of possible benefits. This warrants further exploration in randomized controlled trials.
{"title":"Assessing the influence of preconception diet on female fertility: a systematic scoping review of observational studies.","authors":"Simon Alesi, Nahal Habibi, Thais Rasia Silva, Nicole Cheung, Sophia Torkel, Chau Thien Tay, Alejandra Quinteros, Hugo Winter, Helena Teede, Aya Mousa, Jessica A Grieger, Lisa J Moran","doi":"10.1093/humupd/dmad018","DOIUrl":"10.1093/humupd/dmad018","url":null,"abstract":"<p><strong>Background: </strong>Preconception diet is a proposed modifiable risk factor for infertility. However, there is no official guidance for women in the preconception period as to which dietary approaches may improve fertility.</p><p><strong>Objective and rationale: </strong>A comprehensive synthesis of the relevant evidence is key to determine the potentially effective dietary patterns and components as well as evidence gaps, and to provide information for nutritional recommendations for couples planning a pregnancy.</p><p><strong>Search methods: </strong>In this systematic scoping review, four electronic databases (Medline and EMBASE via Ovid processing, CAB Direct, and CINAHL via EBSCO) were searched for observational studies (prospective and retrospective cohort, cross-sectional, and case-control studies) from inception to 27 September 2021. Eligible studies included women of reproductive age during the preconception period, and evaluated exposures related to preconception diet and outcomes related to fertility. Results were synthesized using a descriptive approach.</p><p><strong>Outcomes: </strong>A total of 36 studies were eligible for inclusion (31 prospective, 3 cross-sectional, and 2 case-control studies) and were published between 2007 and 2022. Of the assessed dietary exposures, increased adherence to the Mediterranean diet displayed the strongest and most consistent association with improved clinical pregnancy rates. Reducing trans fatty acids (TFAs), saturated fatty acids, and discretionary food intake (fast food and sugar-sweetened beverages) were associated with improvements in live birth, clinical pregnancy rates, and related ART outcomes. The dietary components of seafood, dairy, and soy demonstrated inconsistent findings across the few included studies.</p><p><strong>Wider implications: </strong>Due to heterogeneity and the limited available literature on most exposures, there is insufficient evidence to support any specific dietary approach for improving fertility. However, following some of the dietary approaches outlined in this review (anti-inflammatory diets, reducing TFA, and discretionary food intake) are consistent with broad healthy eating guidelines, have little to no associated risk, and offer a plausible set of possible benefits. This warrants further exploration in randomized controlled trials.</p>","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":" ","pages":"811-828"},"PeriodicalIF":14.8,"publicationDate":"2023-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10663051/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9834686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p><strong>Background: </strong>Mammalian reproduction requires the fusion of two specialized cells: an oocyte and a sperm. In addition to producing gametes, the reproductive system also provides the environment for the appropriate development of the embryo. Deciphering the reproductive system requires understanding the functions of each cell type and cell-cell interactions. Recent single-cell omics technologies have provided insights into the gene regulatory network in discrete cellular populations of both the male and female reproductive systems. However, these approaches cannot examine how the cellular states of the gametes or embryos are regulated through their interactions with neighboring somatic cells in the native tissue environment owing to tissue disassociations. Emerging spatial omics technologies address this challenge by preserving the spatial context of the cells to be profiled. These technologies hold the potential to revolutionize our understanding of mammalian reproduction.</p><p><strong>Objective and rationale: </strong>We aim to review the state-of-the-art spatial transcriptomics (ST) technologies with a focus on highlighting the novel biological insights that they have helped to reveal about the mammalian reproductive systems in the context of gametogenesis, embryogenesis, and reproductive pathologies. We also aim to discuss the current challenges of applying ST technologies in reproductive research and provide a sneak peek at what the field of spatial omics can offer for the reproduction community in the years to come.</p><p><strong>Search methods: </strong>The PubMed database was used in the search for peer-reviewed research articles and reviews using combinations of the following terms: 'spatial omics', 'fertility', 'reproduction', 'gametogenesis', 'embryogenesis', 'reproductive cancer', 'spatial transcriptomics', 'spermatogenesis', 'ovary', 'uterus', 'cervix', 'testis', and other keywords related to the subject area. All relevant publications until April 2023 were critically evaluated and discussed.</p><p><strong>Outcomes: </strong>First, an overview of the ST technologies that have been applied to studying the reproductive systems was provided. The basic design principles and the advantages and limitations of these technologies were discussed and tabulated to serve as a guide for researchers to choose the best-suited technologies for their own research. Second, novel biological insights into mammalian reproduction, especially human reproduction revealed by ST analyses, were comprehensively reviewed. Three major themes were discussed. The first theme focuses on genes with non-random spatial expression patterns with specialized functions in multiple reproductive systems; The second theme centers around functionally interacting cell types which are often found to be spatially clustered in the reproductive tissues; and the thrid theme discusses pathological states in reproductive systems which are often associated with unique
{"title":"Dissecting mammalian reproduction with spatial transcriptomics.","authors":"Xin Zhang, Qiqi Cao, Shreya Rajachandran, Edward J Grow, Melanie Evans, Haiqi Chen","doi":"10.1093/humupd/dmad017","DOIUrl":"10.1093/humupd/dmad017","url":null,"abstract":"<p><strong>Background: </strong>Mammalian reproduction requires the fusion of two specialized cells: an oocyte and a sperm. In addition to producing gametes, the reproductive system also provides the environment for the appropriate development of the embryo. Deciphering the reproductive system requires understanding the functions of each cell type and cell-cell interactions. Recent single-cell omics technologies have provided insights into the gene regulatory network in discrete cellular populations of both the male and female reproductive systems. However, these approaches cannot examine how the cellular states of the gametes or embryos are regulated through their interactions with neighboring somatic cells in the native tissue environment owing to tissue disassociations. Emerging spatial omics technologies address this challenge by preserving the spatial context of the cells to be profiled. These technologies hold the potential to revolutionize our understanding of mammalian reproduction.</p><p><strong>Objective and rationale: </strong>We aim to review the state-of-the-art spatial transcriptomics (ST) technologies with a focus on highlighting the novel biological insights that they have helped to reveal about the mammalian reproductive systems in the context of gametogenesis, embryogenesis, and reproductive pathologies. We also aim to discuss the current challenges of applying ST technologies in reproductive research and provide a sneak peek at what the field of spatial omics can offer for the reproduction community in the years to come.</p><p><strong>Search methods: </strong>The PubMed database was used in the search for peer-reviewed research articles and reviews using combinations of the following terms: 'spatial omics', 'fertility', 'reproduction', 'gametogenesis', 'embryogenesis', 'reproductive cancer', 'spatial transcriptomics', 'spermatogenesis', 'ovary', 'uterus', 'cervix', 'testis', and other keywords related to the subject area. All relevant publications until April 2023 were critically evaluated and discussed.</p><p><strong>Outcomes: </strong>First, an overview of the ST technologies that have been applied to studying the reproductive systems was provided. The basic design principles and the advantages and limitations of these technologies were discussed and tabulated to serve as a guide for researchers to choose the best-suited technologies for their own research. Second, novel biological insights into mammalian reproduction, especially human reproduction revealed by ST analyses, were comprehensively reviewed. Three major themes were discussed. The first theme focuses on genes with non-random spatial expression patterns with specialized functions in multiple reproductive systems; The second theme centers around functionally interacting cell types which are often found to be spatially clustered in the reproductive tissues; and the thrid theme discusses pathological states in reproductive systems which are often associated with unique","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":" ","pages":"794-810"},"PeriodicalIF":14.8,"publicationDate":"2023-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10628492/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9677176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mercedes Millán-de-Meer, Manuel Luque-Ramírez, Lía Nattero-Chávez, Héctor F Escobar-Morreale
<p><strong>Background: </strong>Current knowledge about the consequences of PCOS during the late reproductive years and after menopause is limited.</p><p><strong>Objective and rationale: </strong>We performed a systematic review and meta-analysis of data on the pathophysiology, clinical manifestations, diagnosis, prognosis, and treatment of women ≥45 years of age-peri- or postmenopausal-with PCOS.</p><p><strong>Search methods: </strong>Studies published up to 15 April 2023, identified by Entrez-PubMed, EMBASE, and Scopus online facilities, were considered. We included cross-sectional or prospective studies that reported data from peri- or postmenopausal patients with PCOS and control women with a mean age ≥45 years. Three independent researchers performed data extraction. Meta-analyses of quantitative data used random-effects models because of the heterogeneity derived from differences in study design and criteria used to define PCOS, among other confounding factors. Sensitivity analyses restricted the meta-analyses to population-based studies, to studies including only patients diagnosed using the most widely accepted definitions of PCOS, only menopausal women or only women not submitted to ovarian surgery, and studies in which patients and controls presented with similar indexes of weight excess. Quality of evidence was assessed using the GRADE system.</p><p><strong>Outcomes: </strong>The initial search identified 1400 articles, and another six were included from the reference lists of included articles; 476 duplicates were deleted. We excluded 868 articles for different reasons, leaving 37 valid studies for the qualitative synthesis, of which 28 studies-published in 41 articles-were considered for the quantitative synthesis and meta-analyses. Another nine studies were included only in the qualitative analyses. Compared with controls, peri- and postmenopausal patients with PCOS presented increased circulating total testosterone (standardized mean difference, SMD 0.78 (0.35, 1.22)), free androgen index (SMD 1.29 (0.89, 1.68)), and androstenedione (SMD 0.58 (0.23, 0.94)), whereas their sex hormone-binding globulin was reduced (SMD -0.60 (-0.76, -0.44)). Women with PCOS showed increased BMI (SMD 0.57 (0.32, 0.75)), waist circumference (SMD 0.64 (0.42, 0.86)), and waist-to-hip ratio (SMD 0.38 (0.14, 0.61)) together with increased homeostasis model assessment of insulin resistance (SMD 0.56 (0.27, 0.84)), fasting insulin (SMD 0.61 (0.38, 0.83)), fasting glucose (SMD 0.48 (0.29, 0.68)), and odds ratios (OR, 95% CI) for diabetes (OR 3.01 (1.91, 4.73)) compared to controls. Women with PCOS versus controls showed decreased HDL concentrations (SMD -0.32 (-0.46, -0.19)) and increased triglycerides (SMD 0.31 (0.16, 0.46)), even though total cholesterol and LDL concentrations, as well as the OR for dyslipidaemia, were similar to those of controls. The OR for having hypertension was increased in women with PCOS compared with controls (OR 1.79 (1.36, 2.36)).
{"title":"PCOS during the menopausal transition and after menopause: a systematic review and meta-analysis.","authors":"Mercedes Millán-de-Meer, Manuel Luque-Ramírez, Lía Nattero-Chávez, Héctor F Escobar-Morreale","doi":"10.1093/humupd/dmad015","DOIUrl":"10.1093/humupd/dmad015","url":null,"abstract":"<p><strong>Background: </strong>Current knowledge about the consequences of PCOS during the late reproductive years and after menopause is limited.</p><p><strong>Objective and rationale: </strong>We performed a systematic review and meta-analysis of data on the pathophysiology, clinical manifestations, diagnosis, prognosis, and treatment of women ≥45 years of age-peri- or postmenopausal-with PCOS.</p><p><strong>Search methods: </strong>Studies published up to 15 April 2023, identified by Entrez-PubMed, EMBASE, and Scopus online facilities, were considered. We included cross-sectional or prospective studies that reported data from peri- or postmenopausal patients with PCOS and control women with a mean age ≥45 years. Three independent researchers performed data extraction. Meta-analyses of quantitative data used random-effects models because of the heterogeneity derived from differences in study design and criteria used to define PCOS, among other confounding factors. Sensitivity analyses restricted the meta-analyses to population-based studies, to studies including only patients diagnosed using the most widely accepted definitions of PCOS, only menopausal women or only women not submitted to ovarian surgery, and studies in which patients and controls presented with similar indexes of weight excess. Quality of evidence was assessed using the GRADE system.</p><p><strong>Outcomes: </strong>The initial search identified 1400 articles, and another six were included from the reference lists of included articles; 476 duplicates were deleted. We excluded 868 articles for different reasons, leaving 37 valid studies for the qualitative synthesis, of which 28 studies-published in 41 articles-were considered for the quantitative synthesis and meta-analyses. Another nine studies were included only in the qualitative analyses. Compared with controls, peri- and postmenopausal patients with PCOS presented increased circulating total testosterone (standardized mean difference, SMD 0.78 (0.35, 1.22)), free androgen index (SMD 1.29 (0.89, 1.68)), and androstenedione (SMD 0.58 (0.23, 0.94)), whereas their sex hormone-binding globulin was reduced (SMD -0.60 (-0.76, -0.44)). Women with PCOS showed increased BMI (SMD 0.57 (0.32, 0.75)), waist circumference (SMD 0.64 (0.42, 0.86)), and waist-to-hip ratio (SMD 0.38 (0.14, 0.61)) together with increased homeostasis model assessment of insulin resistance (SMD 0.56 (0.27, 0.84)), fasting insulin (SMD 0.61 (0.38, 0.83)), fasting glucose (SMD 0.48 (0.29, 0.68)), and odds ratios (OR, 95% CI) for diabetes (OR 3.01 (1.91, 4.73)) compared to controls. Women with PCOS versus controls showed decreased HDL concentrations (SMD -0.32 (-0.46, -0.19)) and increased triglycerides (SMD 0.31 (0.16, 0.46)), even though total cholesterol and LDL concentrations, as well as the OR for dyslipidaemia, were similar to those of controls. The OR for having hypertension was increased in women with PCOS compared with controls (OR 1.79 (1.36, 2.36)). ","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":" ","pages":"741-772"},"PeriodicalIF":14.8,"publicationDate":"2023-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9682916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
T R Zaat, E B Kostova, P Korsen, M G Showell, F Mol, M van Wely
<p><strong>Background: </strong>The number of frozen embryo transfers (FET) has increased dramatically over the past decade. Based on current evidence, there is no difference in pregnancy rates when natural cycle FET (NC-FET) is compared to artificial cycle FET (AC-FET) in subfertile women. However, NC-FET seems to be associated with lower risk of adverse obstetric and neonatal outcomes compared with AC-FET cycles. Currently, there is no consensus about whether NC-FET needs to be combined with luteal phase support (LPS) or not. The question of how to prepare the endometrium for FET has now gained even more importance and taken the dimension of safety into account as it should not simply be reduced to the basic question of effectiveness.</p><p><strong>Objective and rationale: </strong>The objective of this project was to determine whether NC-FET, with or without LPS, decreases the risk of adverse obstetric and neonatal outcomes compared with AC-FET.</p><p><strong>Search methods: </strong>A systematic review and meta-analysis was carried out. A literature search was performed using the following databases: CINAHL, EMBASE, and MEDLINE from inception to 10 October 2022. Observational studies, including cohort studies, and registries comparing obstetric and neonatal outcomes between singleton pregnancies after NC-FET and those after AC-FET were sought. Risk of bias was assessed using the ROBINS-I tool. The quality of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation approach. We calculated pooled odds ratios (ORs), pooled risk differences (RDs), pooled adjusted ORs, and prevalence estimates with 95% CI using a random effect model, while heterogeneity was assessed by the I2.</p><p><strong>Outcomes: </strong>The conducted search identified 2436 studies, 890 duplicates were removed and 1546 studies were screened. Thirty studies (NC-FET n = 56 445; AC-FET n = 57 231) were included, 19 of which used LPS in NC-FET. Birthweight was lower following NC-FET versus AC-FET (mean difference 26.35 g; 95% CI 11.61-41.08, I2 = 63%). Furthermore NC-FET compared to AC-FET resulted in a lower risk of large for gestational age (OR 0.88, 95% 0.83-0.94, I2 = 54%), macrosomia (OR 0.81; 95% CI 0.71-0.93, I2 = 68%), low birthweight (OR 0.81, 95% CI 0.77-0.85, I2 = 41%), early pregnancy loss (OR 0.73; 95% CI 0.61-0.86, I2 = 70%), preterm birth (OR 0.80; 95% CI 0.75-0.85, I2 = 20%), very preterm birth (OR 0.66, 95% CI 0.53-0.84, I2 = 0%), hypertensive disorders of pregnancy (OR 0.60, 95% CI 0.50-0.65, I2 = 61%), pre-eclampsia (OR 0.50; 95% CI 0.42-0.60, I2 = 44%), placenta previa (OR 0.84, 95% CI 0.73-0.97, I2 = 0%), and postpartum hemorrhage (OR 0.43; 95% CI 0.38-0.48, I2 = 53%). Stratified analyses on LPS use in NC-FET suggested that, compared to AC-FET, NC-FET with LPS decreased preterm birth risk, while NC-FET without LPS did not (OR 0.75, 95% CI 0.70-0.81). LPS use did not modify the other outcomes. Heterogeneity varied from
背景:在过去的十年中,冷冻胚胎移植(FET)的数量急剧增加。根据目前的证据,在低生育能力妇女中,自然周期FET (NC-FET)与人工周期FET (AC-FET)相比,妊娠率没有差异。然而,与AC-FET周期相比,NC-FET似乎与较低的不良产科和新生儿结局风险相关。目前,对于NC-FET是否需要与黄体期支持(LPS)联合使用,尚未达成共识。如何为FET准备子宫内膜的问题现在变得更加重要,并考虑到安全方面,因为它不应简单地简化为有效性的基本问题。目的和理由:该项目的目的是确定与AC-FET相比,NC-FET在加或不加LPS的情况下是否降低了产科和新生儿不良结局的风险。检索方法:进行系统综述和荟萃分析。使用以下数据库进行文献检索:CINAHL、EMBASE和MEDLINE,检索时间为成立至2022年10月10日。观察性研究,包括队列研究,以及比较NC-FET和AC-FET后单胎妊娠的产科和新生儿结局的登记。使用ROBINS-I工具评估偏倚风险。采用建议分级评估、发展和评价方法评价证据质量。我们使用随机效应模型计算合并优势比(or)、合并风险差异(RDs)、合并调整后的or和95% CI的患病率估计值,同时通过I2评估异质性。结果:进行的检索确定了2436项研究,删除了890项重复,筛选了1546项研究。30项研究(NC-FET n = 56 445;共纳入AC-FET (n = 57 231),其中19例采用LPS处理NC-FET。与AC-FET相比,NC-FET的出生体重更低(平均差26.35 g;95% ci 11.61-41.08, i2 = 63%)。此外,与AC-FET相比,NC-FET导致大胎龄(OR 0.88, 95% 0.83-0.94, I2 = 54%)、巨大儿(OR 0.81;95% CI 0.71-0.93, I2 = 68%),低出生体重(OR 0.81, 95% CI 0.77-0.85, I2 = 41%),早孕丢失(OR 0.73;95% CI 0.61-0.86, I2 = 70%),早产(OR 0.80;95% CI 0.75-0.85, I2 = 20%),重度早产(OR 0.66, 95% CI 0.53-0.84, I2 = 0%),妊娠期高血压疾病(OR 0.60, 95% CI 0.50-0.65, I2 = 61%),先兆子痫(OR 0.50;95% CI 0.42-0.60, I2 = 44%)、前置胎盘(OR 0.84, 95% CI 0.73-0.97, I2 = 0%)和产后出血(OR 0.43;95% ci 0.38-0.48, i2 = 53%)。对LPS在NC-FET中使用的分层分析表明,与AC-FET相比,LPS的NC-FET降低了早产风险,而不使用LPS的NC-FET则没有(OR 0.75, 95% CI 0.70-0.81)。LPS的使用没有改变其他结果。异质性从低到高,证据质量从极低到中等。更广泛的影响:本研究证实,与AC-FET相比,NC-FET降低了不良产科和新生儿结局的风险。我们估计,对于每一种不良后果,使用NC-FET可预防每1000名妇女4至22例。因此,NC-FET应该是排卵周期接受FET的女性的首选治疗方法。基于非常低质量的证据,与AC-FET相比,在NC-FET中使用LPS可降低早产风险。然而,由于存在许多不确定性,主要是关于脂多糖使用的有效性的争论,因此需要对脂多糖的有效性和安全性进行进一步的研究,目前还不能对脂多糖的使用提出建议。
{"title":"Obstetric and neonatal outcomes after natural versus artificial cycle frozen embryo transfer and the role of luteal phase support: a systematic review and meta-analysis.","authors":"T R Zaat, E B Kostova, P Korsen, M G Showell, F Mol, M van Wely","doi":"10.1093/humupd/dmad011","DOIUrl":"https://doi.org/10.1093/humupd/dmad011","url":null,"abstract":"<p><strong>Background: </strong>The number of frozen embryo transfers (FET) has increased dramatically over the past decade. Based on current evidence, there is no difference in pregnancy rates when natural cycle FET (NC-FET) is compared to artificial cycle FET (AC-FET) in subfertile women. However, NC-FET seems to be associated with lower risk of adverse obstetric and neonatal outcomes compared with AC-FET cycles. Currently, there is no consensus about whether NC-FET needs to be combined with luteal phase support (LPS) or not. The question of how to prepare the endometrium for FET has now gained even more importance and taken the dimension of safety into account as it should not simply be reduced to the basic question of effectiveness.</p><p><strong>Objective and rationale: </strong>The objective of this project was to determine whether NC-FET, with or without LPS, decreases the risk of adverse obstetric and neonatal outcomes compared with AC-FET.</p><p><strong>Search methods: </strong>A systematic review and meta-analysis was carried out. A literature search was performed using the following databases: CINAHL, EMBASE, and MEDLINE from inception to 10 October 2022. Observational studies, including cohort studies, and registries comparing obstetric and neonatal outcomes between singleton pregnancies after NC-FET and those after AC-FET were sought. Risk of bias was assessed using the ROBINS-I tool. The quality of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation approach. We calculated pooled odds ratios (ORs), pooled risk differences (RDs), pooled adjusted ORs, and prevalence estimates with 95% CI using a random effect model, while heterogeneity was assessed by the I2.</p><p><strong>Outcomes: </strong>The conducted search identified 2436 studies, 890 duplicates were removed and 1546 studies were screened. Thirty studies (NC-FET n = 56 445; AC-FET n = 57 231) were included, 19 of which used LPS in NC-FET. Birthweight was lower following NC-FET versus AC-FET (mean difference 26.35 g; 95% CI 11.61-41.08, I2 = 63%). Furthermore NC-FET compared to AC-FET resulted in a lower risk of large for gestational age (OR 0.88, 95% 0.83-0.94, I2 = 54%), macrosomia (OR 0.81; 95% CI 0.71-0.93, I2 = 68%), low birthweight (OR 0.81, 95% CI 0.77-0.85, I2 = 41%), early pregnancy loss (OR 0.73; 95% CI 0.61-0.86, I2 = 70%), preterm birth (OR 0.80; 95% CI 0.75-0.85, I2 = 20%), very preterm birth (OR 0.66, 95% CI 0.53-0.84, I2 = 0%), hypertensive disorders of pregnancy (OR 0.60, 95% CI 0.50-0.65, I2 = 61%), pre-eclampsia (OR 0.50; 95% CI 0.42-0.60, I2 = 44%), placenta previa (OR 0.84, 95% CI 0.73-0.97, I2 = 0%), and postpartum hemorrhage (OR 0.43; 95% CI 0.38-0.48, I2 = 53%). Stratified analyses on LPS use in NC-FET suggested that, compared to AC-FET, NC-FET with LPS decreased preterm birth risk, while NC-FET without LPS did not (OR 0.75, 95% CI 0.70-0.81). LPS use did not modify the other outcomes. Heterogeneity varied from","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":"29 5","pages":"634-654"},"PeriodicalIF":13.3,"publicationDate":"2023-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/0a/93/dmad011.PMC10477943.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10216449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Isabelle M McGrath, Grant W Montgomery, Sally Mortlock
<p><strong>Background: </strong>Endometriosis remains a poorly understood disease, despite its high prevalence and debilitating symptoms. The overlap in symptoms and the increased risk of multiple other traits in women with endometriosis is becoming increasingly apparent through epidemiological data. Genetic studies offer a method of investigating these comorbid relationships through the assessment of causal relationships with Mendelian randomization (MR), as well as identification of shared genetic variants and genes involved across traits. This has the capacity to identify risk factors for endometriosis as well as provide insight into the aetiology of disease.</p><p><strong>Objective and rationale: </strong>We aim to review the current literature assessing the relationship between endometriosis and other traits using genomic data, primarily through the methods of MR and genetic correlation. We critically examine the limitations of these studies in accordance with the assumptions of the utilized methods.</p><p><strong>Search methods: </strong>The PubMed database was used to search for peer-reviewed original research articles using the terms 'Mendelian randomization endometriosis' and '"genetic correlation" endometriosis'. Additionally, a Google Scholar search using the terms '"endometriosis" "mendelian randomization" "genetic correlation"' was performed. All relevant publications (n = 21) published up until 7 October 2022 were included in this review. Upon compilation of all traits with published MR and/or genetic correlation with endometriosis, additional epidemiological and genetic information on their comorbidity with endometriosis was sourced by searching for the trait in conjunction with 'endometriosis' on Google Scholar.</p><p><strong>Outcomes: </strong>The association between endometriosis and multiple pain, gynaecological, cancer, inflammatory, gastrointestinal, psychological, and anthropometric traits has been assessed using MR analysis and genetic correlation analysis. Genetic correlation analyses provide evidence that genetic factors contributing to endometriosis are shared with multiple traits: migraine, uterine fibroids, subtypes of ovarian cancer, melanoma, asthma, gastro-oesophageal reflux disease, gastritis/duodenitis, and depression, suggesting the involvement of multiple biological mechanisms in endometriosis. The assessment of causality with MR has revealed several potential causes (e.g. depression) and outcomes (e.g. ovarian cancer and uterine fibroids) of a genetic predisposition to endometriosis; however, interpretation of these results requires consideration of potential violations of the MR assumptions.</p><p><strong>Wider implications: </strong>Genomic studies have demonstrated that there is a molecular basis for the co-occurrence of endometriosis with other traits. Dissection of this overlap has identified shared genes and pathways, which provide insight into the biology of endometriosis. Thoughtful MR studies are neces
{"title":"Insights from Mendelian randomization and genetic correlation analyses into the relationship between endometriosis and its comorbidities.","authors":"Isabelle M McGrath, Grant W Montgomery, Sally Mortlock","doi":"10.1093/humupd/dmad009","DOIUrl":"10.1093/humupd/dmad009","url":null,"abstract":"<p><strong>Background: </strong>Endometriosis remains a poorly understood disease, despite its high prevalence and debilitating symptoms. The overlap in symptoms and the increased risk of multiple other traits in women with endometriosis is becoming increasingly apparent through epidemiological data. Genetic studies offer a method of investigating these comorbid relationships through the assessment of causal relationships with Mendelian randomization (MR), as well as identification of shared genetic variants and genes involved across traits. This has the capacity to identify risk factors for endometriosis as well as provide insight into the aetiology of disease.</p><p><strong>Objective and rationale: </strong>We aim to review the current literature assessing the relationship between endometriosis and other traits using genomic data, primarily through the methods of MR and genetic correlation. We critically examine the limitations of these studies in accordance with the assumptions of the utilized methods.</p><p><strong>Search methods: </strong>The PubMed database was used to search for peer-reviewed original research articles using the terms 'Mendelian randomization endometriosis' and '\"genetic correlation\" endometriosis'. Additionally, a Google Scholar search using the terms '\"endometriosis\" \"mendelian randomization\" \"genetic correlation\"' was performed. All relevant publications (n = 21) published up until 7 October 2022 were included in this review. Upon compilation of all traits with published MR and/or genetic correlation with endometriosis, additional epidemiological and genetic information on their comorbidity with endometriosis was sourced by searching for the trait in conjunction with 'endometriosis' on Google Scholar.</p><p><strong>Outcomes: </strong>The association between endometriosis and multiple pain, gynaecological, cancer, inflammatory, gastrointestinal, psychological, and anthropometric traits has been assessed using MR analysis and genetic correlation analysis. Genetic correlation analyses provide evidence that genetic factors contributing to endometriosis are shared with multiple traits: migraine, uterine fibroids, subtypes of ovarian cancer, melanoma, asthma, gastro-oesophageal reflux disease, gastritis/duodenitis, and depression, suggesting the involvement of multiple biological mechanisms in endometriosis. The assessment of causality with MR has revealed several potential causes (e.g. depression) and outcomes (e.g. ovarian cancer and uterine fibroids) of a genetic predisposition to endometriosis; however, interpretation of these results requires consideration of potential violations of the MR assumptions.</p><p><strong>Wider implications: </strong>Genomic studies have demonstrated that there is a molecular basis for the co-occurrence of endometriosis with other traits. Dissection of this overlap has identified shared genes and pathways, which provide insight into the biology of endometriosis. Thoughtful MR studies are neces","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":"29 5","pages":"655-674"},"PeriodicalIF":13.3,"publicationDate":"2023-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10477944/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10583589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mats Brännström, Catherine Racowsky, Marie Carbonnel, Joseph Wu, Antonio Gargiulo, Eli Y Adashi, Jean Marc Ayoubi
Women suffering from absolute uterine factor infertility (AUFI) had no hope of childbearing until clinical feasibility of uterus transplantation (UTx) was documented in 2014 with the birth of a healthy baby. This landmark accomplishment followed extensive foundational work with a wide range of animal species including higher primates. In the present review, we provide a summary of the animal research and describe the results of cases and clinical trials on UTx. Surgical advances for graft removal from live donors and transplantation to recipients are improving, with a recent trend away from laparotomy to robotic approaches, although challenges persist regarding optimum immunosuppressive therapies and tests for graft rejection. Because UTx does not involve transplantation of the Fallopian tubes, IVF is required as part of the UTx process. We provide a unique focus on the intersection between these two processes, with consideration of when oocyte retrieval should be performed, whether, and for whom, preimplantation genetic testing for aneuploidy should be used, whether oocytes or embryos should be frozen and when the first embryo transfer should be performed post-UTx. We also address the utility of an international society UTx (ISUTx) registry for assessing overall UTx success rates, complications, and live births. The long-term health outcomes of all parties involved-the uterus donor (if live donor), the recipient, her partner and any children born from the transplanted graft-are also reviewed. Unlike traditional solid organ transplantation procedures, UTx is not lifesaving, but is life-giving, although as with traditional types of transplantation, costs, and ethical considerations are inevitable. We discuss the likelihood that costs will decrease as efficiency and efficacy improve, and that ethical complexities for and against acceptability of the procedure sharpen the distinctions between genetic, gestational, and social parenthood. As more programs wish to offer the procedure, we suggest a scheme for setting up a UTx program as well as future directions of this rapidly evolving field. In our 2010 review, we described the future of clinical UTx based on development of the procedure in animal models. This Grand Theme Review offers a closing loop to this previous review of more than a decade ago. The clinical feasibility of UTx has now been proved. Advancements include widening the criteria for acceptance of donors and recipients, improving surgery, shortening time to pregnancy, and improving post-UTx management. Together, these improvements catalyze the transition of UTx from experimental into mainstream clinical practice. The procedure will then represent a realistic and accessible alternative to gestational surrogacy for the treatment of AUFI and should become part of the armamentarium of reproductive specialists worldwide.
{"title":"Uterus transplantation: from research, through human trials and into the future.","authors":"Mats Brännström, Catherine Racowsky, Marie Carbonnel, Joseph Wu, Antonio Gargiulo, Eli Y Adashi, Jean Marc Ayoubi","doi":"10.1093/humupd/dmad012","DOIUrl":"https://doi.org/10.1093/humupd/dmad012","url":null,"abstract":"<p><p>Women suffering from absolute uterine factor infertility (AUFI) had no hope of childbearing until clinical feasibility of uterus transplantation (UTx) was documented in 2014 with the birth of a healthy baby. This landmark accomplishment followed extensive foundational work with a wide range of animal species including higher primates. In the present review, we provide a summary of the animal research and describe the results of cases and clinical trials on UTx. Surgical advances for graft removal from live donors and transplantation to recipients are improving, with a recent trend away from laparotomy to robotic approaches, although challenges persist regarding optimum immunosuppressive therapies and tests for graft rejection. Because UTx does not involve transplantation of the Fallopian tubes, IVF is required as part of the UTx process. We provide a unique focus on the intersection between these two processes, with consideration of when oocyte retrieval should be performed, whether, and for whom, preimplantation genetic testing for aneuploidy should be used, whether oocytes or embryos should be frozen and when the first embryo transfer should be performed post-UTx. We also address the utility of an international society UTx (ISUTx) registry for assessing overall UTx success rates, complications, and live births. The long-term health outcomes of all parties involved-the uterus donor (if live donor), the recipient, her partner and any children born from the transplanted graft-are also reviewed. Unlike traditional solid organ transplantation procedures, UTx is not lifesaving, but is life-giving, although as with traditional types of transplantation, costs, and ethical considerations are inevitable. We discuss the likelihood that costs will decrease as efficiency and efficacy improve, and that ethical complexities for and against acceptability of the procedure sharpen the distinctions between genetic, gestational, and social parenthood. As more programs wish to offer the procedure, we suggest a scheme for setting up a UTx program as well as future directions of this rapidly evolving field. In our 2010 review, we described the future of clinical UTx based on development of the procedure in animal models. This Grand Theme Review offers a closing loop to this previous review of more than a decade ago. The clinical feasibility of UTx has now been proved. Advancements include widening the criteria for acceptance of donors and recipients, improving surgery, shortening time to pregnancy, and improving post-UTx management. Together, these improvements catalyze the transition of UTx from experimental into mainstream clinical practice. The procedure will then represent a realistic and accessible alternative to gestational surrogacy for the treatment of AUFI and should become part of the armamentarium of reproductive specialists worldwide.</p>","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":"29 5","pages":"521-544"},"PeriodicalIF":13.3,"publicationDate":"2023-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10477946/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10584101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Noemia A P Mariani, Joana V Silva, Margarida Fardilha, Erick J R Silva
<p><strong>Background: </strong>The high rates of unintended pregnancy and the ever-growing world population impose health, economic, social, and environmental threats to countries. Expanding contraceptive options, including male methods, are urgently needed to tackle these global challenges. Male contraception is limited to condoms and vasectomy, which are unsuitable for many couples. Thus, novel male contraceptive methods may reduce unintended pregnancies, meet the contraceptive needs of couples, and foster gender equality in carrying the contraceptive burden. In this regard, the spermatozoon emerges as a source of druggable targets for on-demand, non-hormonal male contraception based on disrupting sperm motility or fertilization.</p><p><strong>Objective and rationale: </strong>A better understanding of the molecules governing sperm motility can lead to innovative approaches toward safe and effective male contraceptives. This review discusses cutting-edge knowledge on sperm-specific targets for male contraception, focusing on those with crucial roles in sperm motility. We also highlight challenges and opportunities in male contraceptive drug development targeting spermatozoa.</p><p><strong>Search methods: </strong>We conducted a literature search in the PubMed database using the following keywords: 'spermatozoa', 'sperm motility', 'male contraception', and 'drug targets' in combination with other related terms to the field. Publications until January 2023 written in English were considered.</p><p><strong>Outcomes: </strong>Efforts for developing non-hormonal strategies for male contraception resulted in the identification of candidates specifically expressed or enriched in spermatozoa, including enzymes (PP1γ2, GAPDHS, and sAC), ion channels (CatSper and KSper), transmembrane transporters (sNHE, SLC26A8, and ATP1A4), and surface proteins (EPPIN). These targets are usually located in the sperm flagellum. Their indispensable roles in sperm motility and male fertility were confirmed by genetic or immunological approaches using animal models and gene mutations associated with male infertility due to sperm defects in humans. Their druggability was demonstrated by the identification of drug-like small organic ligands displaying spermiostatic activity in preclinical trials.</p><p><strong>Wider implications: </strong>A wide range of sperm-associated proteins has arisen as key regulators of sperm motility, providing compelling druggable candidates for male contraception. Nevertheless, no pharmacological agent has reached clinical developmental stages. One reason is the slow progress in translating the preclinical and drug discovery findings into a drug-like candidate adequate for clinical development. Thus, intense collaboration among academia, private sectors, governments, and regulatory agencies will be crucial to combine expertise for the development of male contraceptives targeting sperm function by (i) improving target structural characterization a
{"title":"Advances in non-hormonal male contraception targeting sperm motility.","authors":"Noemia A P Mariani, Joana V Silva, Margarida Fardilha, Erick J R Silva","doi":"10.1093/humupd/dmad008","DOIUrl":"https://doi.org/10.1093/humupd/dmad008","url":null,"abstract":"<p><strong>Background: </strong>The high rates of unintended pregnancy and the ever-growing world population impose health, economic, social, and environmental threats to countries. Expanding contraceptive options, including male methods, are urgently needed to tackle these global challenges. Male contraception is limited to condoms and vasectomy, which are unsuitable for many couples. Thus, novel male contraceptive methods may reduce unintended pregnancies, meet the contraceptive needs of couples, and foster gender equality in carrying the contraceptive burden. In this regard, the spermatozoon emerges as a source of druggable targets for on-demand, non-hormonal male contraception based on disrupting sperm motility or fertilization.</p><p><strong>Objective and rationale: </strong>A better understanding of the molecules governing sperm motility can lead to innovative approaches toward safe and effective male contraceptives. This review discusses cutting-edge knowledge on sperm-specific targets for male contraception, focusing on those with crucial roles in sperm motility. We also highlight challenges and opportunities in male contraceptive drug development targeting spermatozoa.</p><p><strong>Search methods: </strong>We conducted a literature search in the PubMed database using the following keywords: 'spermatozoa', 'sperm motility', 'male contraception', and 'drug targets' in combination with other related terms to the field. Publications until January 2023 written in English were considered.</p><p><strong>Outcomes: </strong>Efforts for developing non-hormonal strategies for male contraception resulted in the identification of candidates specifically expressed or enriched in spermatozoa, including enzymes (PP1γ2, GAPDHS, and sAC), ion channels (CatSper and KSper), transmembrane transporters (sNHE, SLC26A8, and ATP1A4), and surface proteins (EPPIN). These targets are usually located in the sperm flagellum. Their indispensable roles in sperm motility and male fertility were confirmed by genetic or immunological approaches using animal models and gene mutations associated with male infertility due to sperm defects in humans. Their druggability was demonstrated by the identification of drug-like small organic ligands displaying spermiostatic activity in preclinical trials.</p><p><strong>Wider implications: </strong>A wide range of sperm-associated proteins has arisen as key regulators of sperm motility, providing compelling druggable candidates for male contraception. Nevertheless, no pharmacological agent has reached clinical developmental stages. One reason is the slow progress in translating the preclinical and drug discovery findings into a drug-like candidate adequate for clinical development. Thus, intense collaboration among academia, private sectors, governments, and regulatory agencies will be crucial to combine expertise for the development of male contraceptives targeting sperm function by (i) improving target structural characterization a","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":"29 5","pages":"545-569"},"PeriodicalIF":13.3,"publicationDate":"2023-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10207968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Danilo Cimadomo, Laura Rienzi, Alessandro Conforti, Eric Forman, Stefano Canosa, Federica Innocenti, Maurizio Poli, Jenna Hynes, Laura Gemmell, Alberto Vaiarelli, Carlo Alviggi, Filippo Maria Ubaldi, Antonio Capalbo
<p><strong>Background: </strong>A normal chromosomal constitution defined through PGT-A assessing all chromosomes on trophectoderm (TE) biopsies represents the strongest predictor of embryo implantation. Yet, its positive predictive value is not higher than 50-60%. This gap of knowledge on the causes of euploid blastocysts' reproductive failure is known as 'the black box of implantation'.</p><p><strong>Objective and rationale: </strong>Several embryonic, maternal, paternal, clinical, and IVF laboratory features were scrutinized for their putative association with reproductive success or implantation failure of euploid blastocysts.</p><p><strong>Search methods: </strong>A systematic bibliographical search was conducted without temporal limits up to August 2021. The keywords were '(blastocyst OR day5 embryo OR day6 embryo OR day7 embryo) AND (euploid OR chromosomally normal OR preimplantation genetic testing) AND (implantation OR implantation failure OR miscarriage OR abortion OR live birth OR biochemical pregnancy OR recurrent implantation failure)'. Overall, 1608 items were identified and screened. We included all prospective or retrospective clinical studies and randomized-controlled-trials (RCTs) that assessed any feature associated with live-birth rates (LBR) and/or miscarriage rates (MR) among non-mosaic euploid blastocyst transfer after TE biopsy and PGT-A. In total, 41 reviews and 372 papers were selected, clustered according to a common focus, and thoroughly reviewed. The PRISMA guideline was followed, the PICO model was adopted, and ROBINS-I and ROB 2.0 scoring were used to assess putative bias. Bias across studies regarding the LBR was also assessed using visual inspection of funnel plots and the trim and fill method. Categorical data were combined with a pooled-OR. The random-effect model was used to conduct the meta-analysis. Between-study heterogeneity was addressed using I2. Whenever not suitable for the meta-analysis, the included studies were simply described for their results. The study protocol was registered at http://www.crd.york.ac.uk/PROSPERO/ (registration number CRD42021275329).</p><p><strong>Outcomes: </strong>We included 372 original papers (335 retrospective studies, 30 prospective studies and 7 RCTs) and 41 reviews. However, most of the studies were retrospective, or characterized by small sample sizes, thus prone to bias, which reduces the quality of the evidence to low or very low. Reduced inner cell mass (7 studies, OR: 0.37, 95% CI: 0.27-0.52, I2 = 53%), or TE quality (9 studies, OR: 0.53, 95% CI: 0.43-0.67, I2 = 70%), overall blastocyst quality worse than Gardner's BB-grade (8 studies, OR: 0.40, 95% CI: 0.24-0.67, I2 = 83%), developmental delay (18 studies, OR: 0.56, 95% CI: 0.49-0.63, I2 = 47%), and (by qualitative analysis) some morphodynamic abnormalities pinpointed through time-lapse microscopy (abnormal cleavage patterns, spontaneous blastocyst collapse, longer time of morula formation I, time of blastulation
{"title":"Opening the black box: why do euploid blastocysts fail to implant? A systematic review and meta-analysis.","authors":"Danilo Cimadomo, Laura Rienzi, Alessandro Conforti, Eric Forman, Stefano Canosa, Federica Innocenti, Maurizio Poli, Jenna Hynes, Laura Gemmell, Alberto Vaiarelli, Carlo Alviggi, Filippo Maria Ubaldi, Antonio Capalbo","doi":"10.1093/humupd/dmad010","DOIUrl":"https://doi.org/10.1093/humupd/dmad010","url":null,"abstract":"<p><strong>Background: </strong>A normal chromosomal constitution defined through PGT-A assessing all chromosomes on trophectoderm (TE) biopsies represents the strongest predictor of embryo implantation. Yet, its positive predictive value is not higher than 50-60%. This gap of knowledge on the causes of euploid blastocysts' reproductive failure is known as 'the black box of implantation'.</p><p><strong>Objective and rationale: </strong>Several embryonic, maternal, paternal, clinical, and IVF laboratory features were scrutinized for their putative association with reproductive success or implantation failure of euploid blastocysts.</p><p><strong>Search methods: </strong>A systematic bibliographical search was conducted without temporal limits up to August 2021. The keywords were '(blastocyst OR day5 embryo OR day6 embryo OR day7 embryo) AND (euploid OR chromosomally normal OR preimplantation genetic testing) AND (implantation OR implantation failure OR miscarriage OR abortion OR live birth OR biochemical pregnancy OR recurrent implantation failure)'. Overall, 1608 items were identified and screened. We included all prospective or retrospective clinical studies and randomized-controlled-trials (RCTs) that assessed any feature associated with live-birth rates (LBR) and/or miscarriage rates (MR) among non-mosaic euploid blastocyst transfer after TE biopsy and PGT-A. In total, 41 reviews and 372 papers were selected, clustered according to a common focus, and thoroughly reviewed. The PRISMA guideline was followed, the PICO model was adopted, and ROBINS-I and ROB 2.0 scoring were used to assess putative bias. Bias across studies regarding the LBR was also assessed using visual inspection of funnel plots and the trim and fill method. Categorical data were combined with a pooled-OR. The random-effect model was used to conduct the meta-analysis. Between-study heterogeneity was addressed using I2. Whenever not suitable for the meta-analysis, the included studies were simply described for their results. The study protocol was registered at http://www.crd.york.ac.uk/PROSPERO/ (registration number CRD42021275329).</p><p><strong>Outcomes: </strong>We included 372 original papers (335 retrospective studies, 30 prospective studies and 7 RCTs) and 41 reviews. However, most of the studies were retrospective, or characterized by small sample sizes, thus prone to bias, which reduces the quality of the evidence to low or very low. Reduced inner cell mass (7 studies, OR: 0.37, 95% CI: 0.27-0.52, I2 = 53%), or TE quality (9 studies, OR: 0.53, 95% CI: 0.43-0.67, I2 = 70%), overall blastocyst quality worse than Gardner's BB-grade (8 studies, OR: 0.40, 95% CI: 0.24-0.67, I2 = 83%), developmental delay (18 studies, OR: 0.56, 95% CI: 0.49-0.63, I2 = 47%), and (by qualitative analysis) some morphodynamic abnormalities pinpointed through time-lapse microscopy (abnormal cleavage patterns, spontaneous blastocyst collapse, longer time of morula formation I, time of blastulation ","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":"29 5","pages":"570-633"},"PeriodicalIF":13.3,"publicationDate":"2023-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10220108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}