Scott M Nelson, Susan R Davis, Sophia Kalantaridou, Mary Ann Lumsden, Nick Panay, Richard A Anderson
<p><strong>Background: </strong>The early onset of menopause is associated with increased risks of cardiovascular disease and osteoporosis. As a woman's circulating anti-Müllerian hormone (AMH) concentration reflects the number of follicles remaining in the ovary and declines towards the menopause, serum AMH may be of value in the early diagnosis and prediction of age at menopause.</p><p><strong>Objective and rationale: </strong>This systematic review was undertaken to determine whether there is evidence to support the use of AMH alone, or in conjunction with other markers, to diagnose menopause, to predict menopause, or to predict and/or diagnose premature ovarian insufficiency (POI).</p><p><strong>Search methods: </strong>A systematic literature search for publications reporting on AMH in relation to menopause or POI was conducted in PubMed®, Embase®, and the Cochrane Central Register of Controlled Trials up to 31 May 2022. Data were extracted and synthesized using the Synthesis Without Meta-analysis for diagnosis of menopause, prediction of menopause, prediction of menopause with a single/repeat measurement of AMH, validation of prediction models, short-term prediction in perimenopausal women, and diagnosis and prediction of POI. Risk-of-bias was evaluated using the Tool to Assess Risk of Bias in Cohort Studies protocol and studies at high risk of bias were excluded.</p><p><strong>Outcomes: </strong>A total of 3207 studies were identified, and 41, including 28 858 women, were deemed relevant and included. Of the three studies that assessed AMH for the diagnosis of menopause, one showed that undetectable AMH had equivalent diagnostic accuracy to elevated FSH (>22.3 mIU/ml). No study assessed whether AMH could be used to shorten the 12 months of amenorrhoea required for a formal diagnosis of menopause. Studies assessing AMH with the onset of menopause (27 publications [n = 23 835 women]) generally indicated that lower age-specific AMH concentrations are associated with an earlier age at menopause. However, AMH alone could not be used to predict age at menopause with precision (with estimates and CIs ranging from 2 to 12 years for women aged <40 years). The predictive value of AMH increased with age, as the interval of prediction (time to menopause) shortened. There was evidence that undetectable, or extremely low AMH, may aid early diagnosis of POI in young women with a family history of POI, and women presenting with primary or secondary amenorrhoea (11 studies [n = 4537]).</p><p><strong>Wider implications: </strong>The findings of this systematic review support the use of serum AMH to study the age of menopause in population studies. The increased sensitivity of current AMH assays provides improved accuracy for the prediction of imminent menopause, but diagnostic use for individual patients has not been rigorously examined. Prediction of age at menopause remains imprecise when it is not imminent, although the finding of very low AMH values in
背景:绝经的早发与心血管疾病和骨质疏松的风险增加有关。由于女性循环中的抗勒氏激素(AMH)浓度反映了卵巢中剩余卵泡的数量，并随着更年期的到来而下降，因此血清AMH可能在早期诊断和预测更年期年龄方面具有价值。目的和理由:本系统综述旨在确定是否有证据支持AMH单独使用，或与其他标志物联合使用，来诊断更年期，预测更年期，或预测和/或诊断卵巢早衰(POI)。检索方法:系统检索PubMed®、Embase®和Cochrane Central Register of Controlled Trials中关于AMH与更年期或POI相关的出版物，检索时间截止到2022年5月31日。采用综合无meta分析方法提取和综合绝经诊断、绝经预测、单次/重复测量AMH预测绝经、预测模型验证、围绝经期妇女短期预测、POI诊断和预测等数据。使用队列研究中评估偏倚风险的工具评估偏倚风险，排除高偏倚风险的研究。结果:总共确定了3207项研究，其中41项(包括28858名女性)被认为是相关的并被纳入。在评估AMH诊断更年期的三项研究中，一项研究表明，检测不到的AMH与FSH升高具有相同的诊断准确性(>22.3 mIU/ml)。没有研究评估AMH是否可以用来缩短正式诊断绝经所需的12个月闭经时间。评估AMH与绝经开始的研究(27篇出版物[n = 23835名妇女])普遍表明，年龄特异性AMH浓度较低与绝经年龄较早有关。然而，AMH不能单独用于准确预测绝经年龄(对于年龄较大的女性，估计和ci范围为2至12岁)。更广泛的意义:本系统综述的发现支持在人口研究中使用血清AMH来研究绝经年龄。目前AMH检测的敏感性增加，为预测即将到来的更年期提供了更高的准确性，但对个别患者的诊断用途尚未经过严格检查。虽然在年轻女性中发现非常低的AMH值在提示发生POI的风险增加方面具有临床价值，并且可能有助于及时诊断，但在不是迫在眉睫的情况下，绝经年龄的预测仍然是不精确的。
{"title":"Anti-Müllerian hormone for the diagnosis and prediction of menopause: a systematic review.","authors":"Scott M Nelson, Susan R Davis, Sophia Kalantaridou, Mary Ann Lumsden, Nick Panay, Richard A Anderson","doi":"10.1093/humupd/dmac045","DOIUrl":"https://doi.org/10.1093/humupd/dmac045","url":null,"abstract":"<p><strong>Background: </strong>The early onset of menopause is associated with increased risks of cardiovascular disease and osteoporosis. As a woman's circulating anti-Müllerian hormone (AMH) concentration reflects the number of follicles remaining in the ovary and declines towards the menopause, serum AMH may be of value in the early diagnosis and prediction of age at menopause.</p><p><strong>Objective and rationale: </strong>This systematic review was undertaken to determine whether there is evidence to support the use of AMH alone, or in conjunction with other markers, to diagnose menopause, to predict menopause, or to predict and/or diagnose premature ovarian insufficiency (POI).</p><p><strong>Search methods: </strong>A systematic literature search for publications reporting on AMH in relation to menopause or POI was conducted in PubMed®, Embase®, and the Cochrane Central Register of Controlled Trials up to 31 May 2022. Data were extracted and synthesized using the Synthesis Without Meta-analysis for diagnosis of menopause, prediction of menopause, prediction of menopause with a single/repeat measurement of AMH, validation of prediction models, short-term prediction in perimenopausal women, and diagnosis and prediction of POI. Risk-of-bias was evaluated using the Tool to Assess Risk of Bias in Cohort Studies protocol and studies at high risk of bias were excluded.</p><p><strong>Outcomes: </strong>A total of 3207 studies were identified, and 41, including 28 858 women, were deemed relevant and included. Of the three studies that assessed AMH for the diagnosis of menopause, one showed that undetectable AMH had equivalent diagnostic accuracy to elevated FSH (>22.3 mIU/ml). No study assessed whether AMH could be used to shorten the 12 months of amenorrhoea required for a formal diagnosis of menopause. Studies assessing AMH with the onset of menopause (27 publications [n = 23 835 women]) generally indicated that lower age-specific AMH concentrations are associated with an earlier age at menopause. However, AMH alone could not be used to predict age at menopause with precision (with estimates and CIs ranging from 2 to 12 years for women aged <40 years). The predictive value of AMH increased with age, as the interval of prediction (time to menopause) shortened. There was evidence that undetectable, or extremely low AMH, may aid early diagnosis of POI in young women with a family history of POI, and women presenting with primary or secondary amenorrhoea (11 studies [n = 4537]).</p><p><strong>Wider implications: </strong>The findings of this systematic review support the use of serum AMH to study the age of menopause in population studies. The increased sensitivity of current AMH assays provides improved accuracy for the prediction of imminent menopause, but diagnostic use for individual patients has not been rigorously examined. Prediction of age at menopause remains imprecise when it is not imminent, although the finding of very low AMH values in ","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":"29 3","pages":"327-346"},"PeriodicalIF":13.3,"publicationDate":"2023-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/79/09/dmac045.PMC10152172.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9458730","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}
Ioanna Clark, Mark F H Brougham, Norah Spears, Rod T Mitchell
<p><strong>Background: </strong>Increasing childhood cancer survival rates in recent decades have led to an increased focus on fertility as a long-term complication of cancer treatment. Male childhood cancer survivors often face compromised testicular function as a late effect of chemotherapy exposure, with no well-established options to prevent such damage and subsequent infertility. Despite vincristine being considered to be associated with low-gonadotoxic potential, in prepubertal rodents, it was recently shown to result in morphological alterations of the testis and in severely impaired fertility.</p><p><strong>Objective and rationale: </strong>This systematic review aimed to evaluate the effects of vincristine-containing regimens on human prepubertal testis with reference to testicular function and fertility in adulthood.</p><p><strong>Search methods: </strong>The systematic search of the literature was conducted according to PRISMA guidelines, and the study was registered with PROSPERO. PubMed and Scopus were searched for articles published in English between 01 January 1900 and 05 March 2021, with the search including 'chemotherapy', 'vincristine', 'prepubertal', 'testis', 'spermatogenesis' and related terms. Abstracts and full-text articles were screened and selected for, providing they met the inclusion criteria (≤12 years at treatment, exposure to vincristine-containing regimens and long-term fertility outcomes). Additional studies were identified via bibliography screening. Bias evaluation across included studies was conducted using the ROBINS-I tool, subdivided into assessment for confounding, participant selection, intervention classification, missing data, outcome measurements and selection of reported results.</p><p><strong>Outcomes: </strong>Our initial search identified 288 articles of which 24 (8%; n = 7134 males) met all inclusion criteria. Control groups were included for 9/24 (38%) studies and 4/24 (17%) studies provided sub-analysis of the relative gonadotoxicity of vincristine-based agents. Primary outcome measures were: fertility and parenthood; semen analysis (World Health Organization criteria); and hormonal function and testicular volume. For the studies that performed vincristine sub-analysis, none reported negative associations with vincristine for the potential of siring a pregnancy, including the largest (n = 6224; hazard ratio = 0.56) controlled study. For semen analysis, no significant difference versus healthy controls was illustrated for mitotic inhibitors (including vincristine) following sub-analysis in one study (n = 143). For hormone analysis, a single study did not find significant impacts on spermatogenesis attributed to vincristine based on levels of FSH and semen analysis, which meant that its administration was unlikely to be responsible for the diminished testicular reserve; however, most of the studies were based on low numbers of patients receiving vincristine-containing chemotherapy. Analysis of bia
{"title":"The impact of vincristine on testicular development and function in childhood cancer.","authors":"Ioanna Clark, Mark F H Brougham, Norah Spears, Rod T Mitchell","doi":"10.1093/humupd/dmac039","DOIUrl":"10.1093/humupd/dmac039","url":null,"abstract":"<p><strong>Background: </strong>Increasing childhood cancer survival rates in recent decades have led to an increased focus on fertility as a long-term complication of cancer treatment. Male childhood cancer survivors often face compromised testicular function as a late effect of chemotherapy exposure, with no well-established options to prevent such damage and subsequent infertility. Despite vincristine being considered to be associated with low-gonadotoxic potential, in prepubertal rodents, it was recently shown to result in morphological alterations of the testis and in severely impaired fertility.</p><p><strong>Objective and rationale: </strong>This systematic review aimed to evaluate the effects of vincristine-containing regimens on human prepubertal testis with reference to testicular function and fertility in adulthood.</p><p><strong>Search methods: </strong>The systematic search of the literature was conducted according to PRISMA guidelines, and the study was registered with PROSPERO. PubMed and Scopus were searched for articles published in English between 01 January 1900 and 05 March 2021, with the search including 'chemotherapy', 'vincristine', 'prepubertal', 'testis', 'spermatogenesis' and related terms. Abstracts and full-text articles were screened and selected for, providing they met the inclusion criteria (≤12 years at treatment, exposure to vincristine-containing regimens and long-term fertility outcomes). Additional studies were identified via bibliography screening. Bias evaluation across included studies was conducted using the ROBINS-I tool, subdivided into assessment for confounding, participant selection, intervention classification, missing data, outcome measurements and selection of reported results.</p><p><strong>Outcomes: </strong>Our initial search identified 288 articles of which 24 (8%; n = 7134 males) met all inclusion criteria. Control groups were included for 9/24 (38%) studies and 4/24 (17%) studies provided sub-analysis of the relative gonadotoxicity of vincristine-based agents. Primary outcome measures were: fertility and parenthood; semen analysis (World Health Organization criteria); and hormonal function and testicular volume. For the studies that performed vincristine sub-analysis, none reported negative associations with vincristine for the potential of siring a pregnancy, including the largest (n = 6224; hazard ratio = 0.56) controlled study. For semen analysis, no significant difference versus healthy controls was illustrated for mitotic inhibitors (including vincristine) following sub-analysis in one study (n = 143). For hormone analysis, a single study did not find significant impacts on spermatogenesis attributed to vincristine based on levels of FSH and semen analysis, which meant that its administration was unlikely to be responsible for the diminished testicular reserve; however, most of the studies were based on low numbers of patients receiving vincristine-containing chemotherapy. Analysis of bia","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":"29 2","pages":"233-245"},"PeriodicalIF":14.8,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9976970/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9800899","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}
Majke H D van Bommel, Joanna IntHout, Guus Veldmate, C Marleen Kets, Joanne A de Hullu, Anne M van Altena, Marline G Harmsen
<p><strong>Background: </strong>Increasing numbers of BReast CAncer (BRCA) 1 or 2 pathogenic variant (PV) carriers, who have an inherited predisposition to breast and ovarian cancer, are being identified. Among these women, data regarding the effects of contraception on cancer risks are unclear and various guidelines provide various recommendations.</p><p><strong>Objective and rationale: </strong>We aim to optimize counselling regarding contraception for BRCA1/2-PV carriers. Therefore, we performed a systematic review and meta-analysis. We investigated the risk ratio for developing breast cancer or ovarian cancer in BRCA1/2-PV carriers who have used any form of contraception versus non-users. Second, we analysed breast and ovarian cancer risk among BRCA1/2-PV carriers as influenced by the duration of contraceptive use and by the time since last use. In addition, we provide an overview of all relevant international guidelines regarding contraceptive use for BRCA1/2-PV carriers.</p><p><strong>Search methods: </strong>A systematic search in the Medline database and Cochrane library identified studies describing breast and/or ovarian cancer risk in BRCA1/2-PV carriers as modified by contraception until June 2021. The search included medical subject headings, keywords and synonyms related to BRCA and contraceptives (any kind). PRISMA guidance was followed. Risk Of Bias In Non-randomized Studies of Interventions and Grading of Recommendations, Assessment, Development and Evaluations assessments were performed. Random-effects meta-analyses were used to estimate pooled effects for breast and ovarian cancer risk separately. Subgroup analyses were conducted for BRCA1 versus BRCA2 and for the various contraceptive methods.</p><p><strong>Outcomes: </strong>Results of the breast cancer risk with oral contraceptive pill (OCP) analysis depended on the outcome measure. Meta-analyses of seven studies with 7525 women revealed a hazard ratio (HR) of 1.55 (95% CI: 1.36-1.76) and of four studies including 9106 women resulted in an odds ratio (OR) of 1.06 (95% CI: 0.90-1.25), heterogeneity (I2) 0% and 52%, respectively. Breast cancer risk was still increased in ever-users compared with never-users >10 years after last OCP use. In contrast, ovarian cancer risk was decreased among OCP users: HR 0.62 (95% CI: 0.52-0.74) based on two studies including 10 981 women (I2: 0%), and OR 0.49 (95% CI: 0.38-0.63) based on eight studies including 10 390 women (I2: 64%). The protective effect vanished after cessation of use. Tubal ligation also protects against ovarian cancer: one study including 3319 women (I2: 0%): HR: 0.44 (95% CI: 0.26-0.74) and three studies with 7691 women (I2: 44%): OR: 0.74 (95% CI: 0.53-1.03). Data regarding other contraceptives were unavailable. No differences were observed between BRCA1 and BRCA2-PV carriers. The quality of evidence was either low or very low.</p><p><strong>Wider implications: </strong>The OCP potentially increases breast cancer risk, wh
{"title":"Contraceptives and cancer risks in BRCA1/2 pathogenic variant carriers: a systematic review and meta-analysis.","authors":"Majke H D van Bommel, Joanna IntHout, Guus Veldmate, C Marleen Kets, Joanne A de Hullu, Anne M van Altena, Marline G Harmsen","doi":"10.1093/humupd/dmac038","DOIUrl":"10.1093/humupd/dmac038","url":null,"abstract":"<p><strong>Background: </strong>Increasing numbers of BReast CAncer (BRCA) 1 or 2 pathogenic variant (PV) carriers, who have an inherited predisposition to breast and ovarian cancer, are being identified. Among these women, data regarding the effects of contraception on cancer risks are unclear and various guidelines provide various recommendations.</p><p><strong>Objective and rationale: </strong>We aim to optimize counselling regarding contraception for BRCA1/2-PV carriers. Therefore, we performed a systematic review and meta-analysis. We investigated the risk ratio for developing breast cancer or ovarian cancer in BRCA1/2-PV carriers who have used any form of contraception versus non-users. Second, we analysed breast and ovarian cancer risk among BRCA1/2-PV carriers as influenced by the duration of contraceptive use and by the time since last use. In addition, we provide an overview of all relevant international guidelines regarding contraceptive use for BRCA1/2-PV carriers.</p><p><strong>Search methods: </strong>A systematic search in the Medline database and Cochrane library identified studies describing breast and/or ovarian cancer risk in BRCA1/2-PV carriers as modified by contraception until June 2021. The search included medical subject headings, keywords and synonyms related to BRCA and contraceptives (any kind). PRISMA guidance was followed. Risk Of Bias In Non-randomized Studies of Interventions and Grading of Recommendations, Assessment, Development and Evaluations assessments were performed. Random-effects meta-analyses were used to estimate pooled effects for breast and ovarian cancer risk separately. Subgroup analyses were conducted for BRCA1 versus BRCA2 and for the various contraceptive methods.</p><p><strong>Outcomes: </strong>Results of the breast cancer risk with oral contraceptive pill (OCP) analysis depended on the outcome measure. Meta-analyses of seven studies with 7525 women revealed a hazard ratio (HR) of 1.55 (95% CI: 1.36-1.76) and of four studies including 9106 women resulted in an odds ratio (OR) of 1.06 (95% CI: 0.90-1.25), heterogeneity (I2) 0% and 52%, respectively. Breast cancer risk was still increased in ever-users compared with never-users >10 years after last OCP use. In contrast, ovarian cancer risk was decreased among OCP users: HR 0.62 (95% CI: 0.52-0.74) based on two studies including 10 981 women (I2: 0%), and OR 0.49 (95% CI: 0.38-0.63) based on eight studies including 10 390 women (I2: 64%). The protective effect vanished after cessation of use. Tubal ligation also protects against ovarian cancer: one study including 3319 women (I2: 0%): HR: 0.44 (95% CI: 0.26-0.74) and three studies with 7691 women (I2: 44%): OR: 0.74 (95% CI: 0.53-1.03). Data regarding other contraceptives were unavailable. No differences were observed between BRCA1 and BRCA2-PV carriers. The quality of evidence was either low or very low.</p><p><strong>Wider implications: </strong>The OCP potentially increases breast cancer risk, wh","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":"29 2","pages":"197-217"},"PeriodicalIF":14.8,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/93/5e/dmac038.PMC9976973.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9450381","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}
Baris Ata, Nathalie Vermeulen, Edgar Mocanu, Luca Gianaroli, Kersti Lundin, Satu Rautakallio-Hokkanen, Juha S Tapanainen, Anna Veiga
<p><strong>Background: </strong>In 2020, SARS-CoV-2 and the COVID-19 pandemic had a huge impact on the access to and provision of ART treatments. Gradually, knowledge of the virus and its transmission has become available, allowing ART activities to resume. Still, questions on the impact of the virus on human gametes and fertility remain.</p><p><strong>Objective and rationale: </strong>This article summarizes published data, aiming to clarify the impact of SARS-CoV-2 and the COVID-19 disease on human fertility and assisted reproduction, as well as the impact of vaccination, and from this, provide answers to questions that are relevant for people contemplating pregnancy and for health care professionals.</p><p><strong>Search methods: </strong>PUBMED/MEDLINE and the WHO COVID-19 database were searched from inception to 5 October 2022 with search terms focusing on 'SARS-CoV-2' and gametes, embryos, reproductive function, fertility and ART. Non-English studies and papers published prior to 2020 were excluded, as well as reviews and non-peer reviewed publications. Full papers were assessed for relevance and quality, where feasible.</p><p><strong>Outcomes: </strong>From the 148 papers included, the following observations were made. The SARS-CoV-2-binding proteins, angiotensin-converting enzyme 2 (ACE2) and type II transmembrane serine protease (TMPRSS2), are expressed in the testis, but co-expression remains to be proven. There is some evidence of SARS-CoV-2 RNA in the ejaculate of COVID-19 patients with severe disease, but not in those with mild/moderate disease. SARS-CoV-2 infection can impair spermatogenesis, but this seems to resolve after one spermatogenic cycle. Testosterone levels seem to be lower during and after COVID-19, but long-term data are lacking; disease severity may be associated with testosterone levels. COVID-19 cannot be considered a sexually transmitted disease. There is no co-expression of ACE2 and TMPRSS2 in the myometrium, uterus, ovaries or fallopian tubes. Oocytes seem to have the receptors and protease machinery to be susceptible to SARS-CoV-2 infection; however, viral RNA in oocytes has not been detected so far. Women contemplating pregnancy following COVID-19 may benefit from screening for thyroid dysfunction. There is a possible (transient) impact of COVID-19 on menstrual patterns. Embryos, and particularly late blastocysts, seem to have the machinery to be susceptible to SARS-CoV-2 infection. Most studies have not reported a significant impact of COVID-19 on ovarian reserve, ovarian function or follicular fluid parameters. Previous asymptomatic or mild SARS-CoV-2 infection in females does not seem to negatively affect laboratory and clinical outcomes of ART. There are no data on the minimum required interval, if any, between COVID-19 recovery and ART. There is no evidence of a negative effect of SARS-CoV-2 vaccination on semen parameters or spermatogenesis, ovarian function, ovarian reserve or folliculogenesis. A transien
{"title":"SARS-CoV-2, fertility and assisted reproduction.","authors":"Baris Ata, Nathalie Vermeulen, Edgar Mocanu, Luca Gianaroli, Kersti Lundin, Satu Rautakallio-Hokkanen, Juha S Tapanainen, Anna Veiga","doi":"10.1093/humupd/dmac037","DOIUrl":"10.1093/humupd/dmac037","url":null,"abstract":"<p><strong>Background: </strong>In 2020, SARS-CoV-2 and the COVID-19 pandemic had a huge impact on the access to and provision of ART treatments. Gradually, knowledge of the virus and its transmission has become available, allowing ART activities to resume. Still, questions on the impact of the virus on human gametes and fertility remain.</p><p><strong>Objective and rationale: </strong>This article summarizes published data, aiming to clarify the impact of SARS-CoV-2 and the COVID-19 disease on human fertility and assisted reproduction, as well as the impact of vaccination, and from this, provide answers to questions that are relevant for people contemplating pregnancy and for health care professionals.</p><p><strong>Search methods: </strong>PUBMED/MEDLINE and the WHO COVID-19 database were searched from inception to 5 October 2022 with search terms focusing on 'SARS-CoV-2' and gametes, embryos, reproductive function, fertility and ART. Non-English studies and papers published prior to 2020 were excluded, as well as reviews and non-peer reviewed publications. Full papers were assessed for relevance and quality, where feasible.</p><p><strong>Outcomes: </strong>From the 148 papers included, the following observations were made. The SARS-CoV-2-binding proteins, angiotensin-converting enzyme 2 (ACE2) and type II transmembrane serine protease (TMPRSS2), are expressed in the testis, but co-expression remains to be proven. There is some evidence of SARS-CoV-2 RNA in the ejaculate of COVID-19 patients with severe disease, but not in those with mild/moderate disease. SARS-CoV-2 infection can impair spermatogenesis, but this seems to resolve after one spermatogenic cycle. Testosterone levels seem to be lower during and after COVID-19, but long-term data are lacking; disease severity may be associated with testosterone levels. COVID-19 cannot be considered a sexually transmitted disease. There is no co-expression of ACE2 and TMPRSS2 in the myometrium, uterus, ovaries or fallopian tubes. Oocytes seem to have the receptors and protease machinery to be susceptible to SARS-CoV-2 infection; however, viral RNA in oocytes has not been detected so far. Women contemplating pregnancy following COVID-19 may benefit from screening for thyroid dysfunction. There is a possible (transient) impact of COVID-19 on menstrual patterns. Embryos, and particularly late blastocysts, seem to have the machinery to be susceptible to SARS-CoV-2 infection. Most studies have not reported a significant impact of COVID-19 on ovarian reserve, ovarian function or follicular fluid parameters. Previous asymptomatic or mild SARS-CoV-2 infection in females does not seem to negatively affect laboratory and clinical outcomes of ART. There are no data on the minimum required interval, if any, between COVID-19 recovery and ART. There is no evidence of a negative effect of SARS-CoV-2 vaccination on semen parameters or spermatogenesis, ovarian function, ovarian reserve or folliculogenesis. A transien","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":"29 2","pages":"177-196"},"PeriodicalIF":14.8,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/c3/0d/dmac037.PMC9976972.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9800879","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}
Britt Derks, Greysha Rivera-Cruz, Synneva Hagen-Lillevik, E Naomi Vos, Didem Demirbas, Kent Lai, Eileen P Treacy, Harvey L Levy, Louise E Wilkins-Haug, M Estela Rubio-Gozalbo, Gerard T Berry
<p><strong>Background: </strong>Hypergonadotropic hypogonadism is a burdensome complication of classic galactosemia (CG), an inborn error of galactose metabolism that invariably affects female patients. Since its recognition in 1979, data have become available regarding the clinical spectrum, and the impact on fertility. Many women have been counseled for infertility and the majority never try to conceive, yet spontaneous pregnancies can occur. Onset and mechanism of damage have not been elucidated, yet new insights at the molecular level are becoming available that might greatly benefit our understanding. Fertility preservation options have expanded, and treatments to mitigate this complication either by directly rescuing the metabolic defect or by influencing the cascade of events are being explored.</p><p><strong>Objective and rationale: </strong>The aims are to review: the clinical picture and the need to revisit the counseling paradigm; insights into the onset and mechanism of damage at the molecular level; and current treatments to mitigate ovarian damage.</p><p><strong>Search methods: </strong>In addition to the work on this topic by the authors, the PubMed database has been used to search for peer-reviewed articles and reviews using the following terms: 'classic galactosemia', 'gonadal damage', 'primary ovarian insufficiency', 'fertility', 'animal models' and 'fertility preservation' in combination with other keywords related to the subject area. All relevant publications until August 2022 have been critically evaluated and reviewed.</p><p><strong>Outcomes: </strong>A diagnosis of premature ovarian insufficiency (POI) results in a significant psychological burden with a high incidence of depression and anxiety that urges adequate counseling at an early stage, appropriate treatment and timely discussion of fertility preservation options. The cause of POI in CG is unknown, but evidence exists of dysregulation in pathways crucial for folliculogenesis such as phosphatidylinositol 3-kinase/protein kinase B, inositol pathway, mitogen-activated protein kinase, insulin-like growth factor-1 and transforming growth factor-beta signaling. Recent findings from the GalT gene-trapped (GalTKO) mouse model suggest that early molecular changes in 1-month-old ovaries elicit an accelerated growth activation and burnout of primordial follicles, resembling the progressive ovarian failure seen in patients. Although data on safety and efficacy outcomes are still limited, ovarian tissue cryopreservation can be a fertility preservation option. Treatments to overcome the genetic defect, for example nucleic acid therapy such as mRNA or gene therapy, or that influence the cascade of events are being explored at the (pre-)clinical level.</p><p><strong>Wider implications: </strong>Elucidation of the molecular pathways underlying POI of any origin can greatly advance our insight into the pathogenesis and open new treatment avenues. Alterations in these molecular pathwa
{"title":"The hypergonadotropic hypogonadism conundrum of classic galactosemia.","authors":"Britt Derks, Greysha Rivera-Cruz, Synneva Hagen-Lillevik, E Naomi Vos, Didem Demirbas, Kent Lai, Eileen P Treacy, Harvey L Levy, Louise E Wilkins-Haug, M Estela Rubio-Gozalbo, Gerard T Berry","doi":"10.1093/humupd/dmac041","DOIUrl":"https://doi.org/10.1093/humupd/dmac041","url":null,"abstract":"<p><strong>Background: </strong>Hypergonadotropic hypogonadism is a burdensome complication of classic galactosemia (CG), an inborn error of galactose metabolism that invariably affects female patients. Since its recognition in 1979, data have become available regarding the clinical spectrum, and the impact on fertility. Many women have been counseled for infertility and the majority never try to conceive, yet spontaneous pregnancies can occur. Onset and mechanism of damage have not been elucidated, yet new insights at the molecular level are becoming available that might greatly benefit our understanding. Fertility preservation options have expanded, and treatments to mitigate this complication either by directly rescuing the metabolic defect or by influencing the cascade of events are being explored.</p><p><strong>Objective and rationale: </strong>The aims are to review: the clinical picture and the need to revisit the counseling paradigm; insights into the onset and mechanism of damage at the molecular level; and current treatments to mitigate ovarian damage.</p><p><strong>Search methods: </strong>In addition to the work on this topic by the authors, the PubMed database has been used to search for peer-reviewed articles and reviews using the following terms: 'classic galactosemia', 'gonadal damage', 'primary ovarian insufficiency', 'fertility', 'animal models' and 'fertility preservation' in combination with other keywords related to the subject area. All relevant publications until August 2022 have been critically evaluated and reviewed.</p><p><strong>Outcomes: </strong>A diagnosis of premature ovarian insufficiency (POI) results in a significant psychological burden with a high incidence of depression and anxiety that urges adequate counseling at an early stage, appropriate treatment and timely discussion of fertility preservation options. The cause of POI in CG is unknown, but evidence exists of dysregulation in pathways crucial for folliculogenesis such as phosphatidylinositol 3-kinase/protein kinase B, inositol pathway, mitogen-activated protein kinase, insulin-like growth factor-1 and transforming growth factor-beta signaling. Recent findings from the GalT gene-trapped (GalTKO) mouse model suggest that early molecular changes in 1-month-old ovaries elicit an accelerated growth activation and burnout of primordial follicles, resembling the progressive ovarian failure seen in patients. Although data on safety and efficacy outcomes are still limited, ovarian tissue cryopreservation can be a fertility preservation option. Treatments to overcome the genetic defect, for example nucleic acid therapy such as mRNA or gene therapy, or that influence the cascade of events are being explored at the (pre-)clinical level.</p><p><strong>Wider implications: </strong>Elucidation of the molecular pathways underlying POI of any origin can greatly advance our insight into the pathogenesis and open new treatment avenues. Alterations in these molecular pathwa","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":"29 2","pages":"246-258"},"PeriodicalIF":13.3,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e7/93/dmac041.PMC9976963.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9450399","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}
Hagai Levine, Niels Jørgensen, Anderson Martino-Andrade, Jaime Mendiola, Dan Weksler-Derri, Maya Jolles, Rachel Pinotti, Shanna H Swan
<p><strong>Background: </strong>Numerous studies have reported declines in semen quality and other markers of male reproductive health. Our previous meta-analysis reported a significant decrease in sperm concentration (SC) and total sperm count (TSC) among men from North America-Europe-Australia (NEA) based on studies published during 1981-2013. At that time, there were too few studies with data from South/Central America-Asia-Africa (SAA) to reliably estimate trends among men from these continents.</p><p><strong>Objective and rationale: </strong>The aim of this study was to examine trends in sperm count among men from all continents. The broader implications of a global decline in sperm count, the knowledge gaps left unfilled by our prior analysis and the controversies surrounding this issue warranted an up-to-date meta-analysis.</p><p><strong>Search methods: </strong>We searched PubMed/MEDLINE and EMBASE to identify studies of human SC and TSC published during 2014-2019. After review of 2936 abstracts and 868 full articles, 44 estimates of SC and TSC from 38 studies met the protocol criteria. Data were extracted on semen parameters (SC, TSC, semen volume), collection year and covariates. Combining these new data with data from our previous meta-analysis, the current meta-analysis includes results from 223 studies, yielding 288 estimates based on semen samples collected 1973-2018. Slopes of SC and TSC were estimated as functions of sample collection year using simple linear regression as well as weighted meta-regression. The latter models were adjusted for predetermined covariates and examined for modification by fertility status (unselected by fertility versus fertile), and by two groups of continents: NEA and SAA. These analyses were repeated for data collected post-2000. Multiple sensitivity analyses were conducted to examine assumptions, including linearity.</p><p><strong>Outcomes: </strong>Overall, SC declined appreciably between 1973 and 2018 (slope in the simple linear model: -0.87 million/ml/year, 95% CI: -0.89 to -0.86; P < 0.001). In an adjusted meta-regression model, which included two interaction terms [time × fertility group (P = 0.012) and time × continents (P = 0.058)], declines were seen among unselected men from NEA (-1.27; -1.78 to -0.77; P < 0.001) and unselected men from SAA (-0.65; -1.29 to -0.01; P = 0.045) and fertile men from NEA (-0.50; -1.00 to -0.01; P = 0.046). Among unselected men from all continents, the mean SC declined by 51.6% between 1973 and 2018 (-1.17: -1.66 to -0.68; P < 0.001). The slope for SC among unselected men was steeper in a model restricted to post-2000 data (-1.73: -3.23 to -0.24; P = 0.024) and the percent decline per year doubled, increasing from 1.16% post-1972 to 2.64% post-2000. Results were similar for TSC, with a 62.3% overall decline among unselected men (-4.70 million/year; -6.56 to -2.83; P < 0.001) in the adjusted meta-regression model. All results changed only minimally in multiple sens
{"title":"Temporal trends in sperm count: a systematic review and meta-regression analysis of samples collected globally in the 20th and 21st centuries.","authors":"Hagai Levine, Niels Jørgensen, Anderson Martino-Andrade, Jaime Mendiola, Dan Weksler-Derri, Maya Jolles, Rachel Pinotti, Shanna H Swan","doi":"10.1093/humupd/dmac035","DOIUrl":"https://doi.org/10.1093/humupd/dmac035","url":null,"abstract":"<p><strong>Background: </strong>Numerous studies have reported declines in semen quality and other markers of male reproductive health. Our previous meta-analysis reported a significant decrease in sperm concentration (SC) and total sperm count (TSC) among men from North America-Europe-Australia (NEA) based on studies published during 1981-2013. At that time, there were too few studies with data from South/Central America-Asia-Africa (SAA) to reliably estimate trends among men from these continents.</p><p><strong>Objective and rationale: </strong>The aim of this study was to examine trends in sperm count among men from all continents. The broader implications of a global decline in sperm count, the knowledge gaps left unfilled by our prior analysis and the controversies surrounding this issue warranted an up-to-date meta-analysis.</p><p><strong>Search methods: </strong>We searched PubMed/MEDLINE and EMBASE to identify studies of human SC and TSC published during 2014-2019. After review of 2936 abstracts and 868 full articles, 44 estimates of SC and TSC from 38 studies met the protocol criteria. Data were extracted on semen parameters (SC, TSC, semen volume), collection year and covariates. Combining these new data with data from our previous meta-analysis, the current meta-analysis includes results from 223 studies, yielding 288 estimates based on semen samples collected 1973-2018. Slopes of SC and TSC were estimated as functions of sample collection year using simple linear regression as well as weighted meta-regression. The latter models were adjusted for predetermined covariates and examined for modification by fertility status (unselected by fertility versus fertile), and by two groups of continents: NEA and SAA. These analyses were repeated for data collected post-2000. Multiple sensitivity analyses were conducted to examine assumptions, including linearity.</p><p><strong>Outcomes: </strong>Overall, SC declined appreciably between 1973 and 2018 (slope in the simple linear model: -0.87 million/ml/year, 95% CI: -0.89 to -0.86; P < 0.001). In an adjusted meta-regression model, which included two interaction terms [time × fertility group (P = 0.012) and time × continents (P = 0.058)], declines were seen among unselected men from NEA (-1.27; -1.78 to -0.77; P < 0.001) and unselected men from SAA (-0.65; -1.29 to -0.01; P = 0.045) and fertile men from NEA (-0.50; -1.00 to -0.01; P = 0.046). Among unselected men from all continents, the mean SC declined by 51.6% between 1973 and 2018 (-1.17: -1.66 to -0.68; P < 0.001). The slope for SC among unselected men was steeper in a model restricted to post-2000 data (-1.73: -3.23 to -0.24; P = 0.024) and the percent decline per year doubled, increasing from 1.16% post-1972 to 2.64% post-2000. Results were similar for TSC, with a 62.3% overall decline among unselected men (-4.70 million/year; -6.56 to -2.83; P < 0.001) in the adjusted meta-regression model. All results changed only minimally in multiple sens","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":"29 2","pages":"157-176"},"PeriodicalIF":13.3,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9333893","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}
Annelore Van Der Kelen, Özlem Okutman, Elodie Javey, Münevver Serdarogullari, Charlotte Janssens, Manjusha S Ghosh, Bart J H Dequeker, Florence Perold, Claire Kastner, Emmanuelle Kieffer, Ingrid Segers, Alexander Gheldof, Frederik J Hes, Karen Sermon, Willem Verpoest, Stéphane Viville
Background: As in other domains of medicine, high-throughput sequencing methods have led to the identification of an ever-increasing number of gene variants in the fields of both male and female infertility. The increasing number of recently identified genes allows an accurate diagnosis for previously idiopathic cases of female infertility and more appropriate patient care. However, robust evidence of the gene-disease relationships (GDR) allowing the proper translation to clinical application is still missing in many cases.
Objective and rationale: An evidence-based curation of currently identified genes involved in female infertility and differences in sex development (DSD) would significantly improve both diagnostic performance and genetic research. We therefore performed a systematic review to summarize current knowledge and assess the available GDR.
Search methods: PRISMA guidelines were applied to curate all available information from PubMed and Web of Science on genetics of human female infertility and DSD leading to infertility, from 1 January 1988 to 1 November 2021. The reviewed pathologies include non-syndromic as well as syndromic female infertility, and endocrine and reproductive system disorders. The evidence that an identified phenotype is caused by pathogenic variants in a specific gene was assessed according to a standardized scoring system. A final score (no evidence, limited, moderate, strong, or definitive) was assigned to every GDR.
Outcomes: A total of 45 271 publications were identified and screened for inclusion of which 1078 were selected for gene and variant extraction. We have identified 395 genes and validated 466 GDRs covering all reported monogenic causes of female infertility and DSD. Furthermore, we present a genetic diagnostic flowchart including 105 genes with at least moderate evidence for female infertility and suggest recommendations for future research. The study did not take into account associated genetic risk factor(s) or oligogenic/polygenic causes of female infertility.
Wider implications: We have comprehensively reviewed the existing research on the genetics of female infertility and DSD, which will enable the development of diagnostic panels using validated genes. Whole genome analysis is shifting from predominantly research to clinical application, increasing its diagnostic potential. These new diagnostic possibilities will not only decrease the number of idiopathic cases but will also render genetic counselling more effective for infertile patients and their families.
背景:与其他医学领域一样，高通量测序方法已经导致在男性和女性不育领域识别出越来越多的基因变异。最近发现的基因数量的增加使得以前特发性女性不孕症病例的准确诊断和更适当的患者护理成为可能。然而，在许多情况下，仍然缺乏基因-疾病关系(GDR)允许适当转化为临床应用的有力证据。目的和理由:对目前已确定的与女性不育和性发育差异(DSD)有关的基因进行循证管理，将显著提高诊断性能和基因研究。因此，我们进行了一项系统综述，以总结当前的知识并评估可用的GDR。检索方法:从1988年1月1日至2021年11月1日，应用PRISMA指南整理PubMed和Web of Science中关于人类女性不孕症和DSD导致不孕症的遗传学的所有可用信息。综述的病理包括非综合征性和综合征性女性不孕症，以及内分泌和生殖系统疾病。根据标准化评分系统评估已确定的表型是由特定基因的致病变异引起的证据。每个GDR都有一个最终评分(无证据、有限、中等、强烈或明确)。结果:共鉴定和筛选了45271份出版物，其中1078份被选择用于基因和变异提取。我们已经确定了395个基因，并验证了466个gdr，涵盖了所有报道的女性不育和DSD的单基因原因。此外，我们提出了一个遗传诊断流程图，其中包括105个基因，至少有中等证据表明女性不孕症，并提出了未来研究的建议。该研究没有考虑相关的遗传风险因素或女性不育的少基因/多基因原因。更广泛的意义:我们全面回顾了现有的关于女性不孕症和DSD的遗传学研究，这将使使用经过验证的基因开发诊断面板成为可能。全基因组分析正从主要的研究转向临床应用，增加了其诊断潜力。这些新的诊断可能性不仅将减少特发性病例的数量，而且还将使遗传咨询对不孕症患者及其家属更有效。
{"title":"A systematic review and evidence assessment of monogenic gene-disease relationships in human female infertility and differences in sex development.","authors":"Annelore Van Der Kelen, Özlem Okutman, Elodie Javey, Münevver Serdarogullari, Charlotte Janssens, Manjusha S Ghosh, Bart J H Dequeker, Florence Perold, Claire Kastner, Emmanuelle Kieffer, Ingrid Segers, Alexander Gheldof, Frederik J Hes, Karen Sermon, Willem Verpoest, Stéphane Viville","doi":"10.1093/humupd/dmac044","DOIUrl":"https://doi.org/10.1093/humupd/dmac044","url":null,"abstract":"<p><strong>Background: </strong>As in other domains of medicine, high-throughput sequencing methods have led to the identification of an ever-increasing number of gene variants in the fields of both male and female infertility. The increasing number of recently identified genes allows an accurate diagnosis for previously idiopathic cases of female infertility and more appropriate patient care. However, robust evidence of the gene-disease relationships (GDR) allowing the proper translation to clinical application is still missing in many cases.</p><p><strong>Objective and rationale: </strong>An evidence-based curation of currently identified genes involved in female infertility and differences in sex development (DSD) would significantly improve both diagnostic performance and genetic research. We therefore performed a systematic review to summarize current knowledge and assess the available GDR.</p><p><strong>Search methods: </strong>PRISMA guidelines were applied to curate all available information from PubMed and Web of Science on genetics of human female infertility and DSD leading to infertility, from 1 January 1988 to 1 November 2021. The reviewed pathologies include non-syndromic as well as syndromic female infertility, and endocrine and reproductive system disorders. The evidence that an identified phenotype is caused by pathogenic variants in a specific gene was assessed according to a standardized scoring system. A final score (no evidence, limited, moderate, strong, or definitive) was assigned to every GDR.</p><p><strong>Outcomes: </strong>A total of 45 271 publications were identified and screened for inclusion of which 1078 were selected for gene and variant extraction. We have identified 395 genes and validated 466 GDRs covering all reported monogenic causes of female infertility and DSD. Furthermore, we present a genetic diagnostic flowchart including 105 genes with at least moderate evidence for female infertility and suggest recommendations for future research. The study did not take into account associated genetic risk factor(s) or oligogenic/polygenic causes of female infertility.</p><p><strong>Wider implications: </strong>We have comprehensively reviewed the existing research on the genetics of female infertility and DSD, which will enable the development of diagnostic panels using validated genes. Whole genome analysis is shifting from predominantly research to clinical application, increasing its diagnostic potential. These new diagnostic possibilities will not only decrease the number of idiopathic cases but will also render genetic counselling more effective for infertile patients and their families.</p>","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":"29 2","pages":"218-232"},"PeriodicalIF":13.3,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9117575","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}
Giulia Fiorentino, Danilo Cimadomo, Federica Innocenti, Daria Soscia, Alberto Vaiarelli, Filippo Maria Ubaldi, Gianluca Gennarelli, Silvia Garagna, Laura Rienzi, Maurizio Zuccotti
<p><strong>Background: </strong>Folliculogenesis occurs in the highly dynamic environment of the ovary. Follicle cyclic recruitment, neo-angiogenesis, spatial displacement, follicle atresia and ovulation stand out as major events resulting from the interplay between mechanical forces and molecular signals. Morphological and functional changes to the growing follicle and to the surrounding tissue are required to produce oocytes capable of supporting preimplantation development to the blastocyst stage.</p><p><strong>Objective and rationale: </strong>This review will summarize the ovarian morphological and functional context that contributes to follicle recruitment, growth and ovulation, as well as to the acquisition of oocyte developmental competence. We will describe the changes occurring during folliculogenesis to the ovarian extracellular matrix (ECM) and to the vasculature, their influence on the mechanical properties of the ovarian tissue, and, in turn, their influence on the regulation of signal transduction. Also, we will outline how their dysregulation might be associated with pathologies such as polycystic ovary syndrome (PCOS), endometriosis or premature ovarian insufficiency (POI). Finally, for each of these three pathologies, we will highlight therapeutic strategies attempting to correct the altered biomechanical context in order to restore fertility.</p><p><strong>Search methods: </strong>For each area discussed, a systematic bibliographical search was performed, without temporal limits, using PubMed Central, Web of Science and Scopus search engines employing the keywords extracellular matrix, mechanobiology, biomechanics, vasculature, angiogenesis or signalling pathway in combination with: ovary, oogenesis, oocyte, folliculogenesis, ovarian follicle, theca, granulosa, cumulus, follicular fluid, corpus luteum, meiosis, oocyte developmental competence, preimplantation, polycystic ovary syndrome, premature ovarian insufficiency or endometriosis.</p><p><strong>Outcomes: </strong>Through search engines queries, we yielded a total of 37 368 papers that were further selected based on our focus on mammals and, specifically, on rodents, bovine, equine, ovine, primates and human, and also were trimmed around each specific topic of the review. After the elimination of duplicates, this selection process resulted in 628 papers, of which 287 were cited in the manuscript. Among these, 89.2% were published in the past 22 years, while the remaining 8.0%, 2.4% or 0.3% were published during the 1990s, 1980s or before, respectively. During folliculogenesis, changes occur to the ovarian ECM composition and organization that, together with vasculature modelling around the growing follicle, are aimed to sustain its recruitment and growth, and the maturation of the enclosed oocyte. These events define the scenario in which mechanical forces are key to the regulation of cascades of molecular signals. Alterations to this context determine impaired folliculogen
背景:卵泡发生发生在卵巢的高动态环境中。卵泡周期募集、新生血管生成、空间位移、卵泡闭锁和排卵是机械力和分子信号相互作用的主要结果。卵泡和周围组织的形态和功能改变是产生能够支持着床前发育到囊胚期的卵母细胞的必要条件。目的与原理:本文综述了卵泡募集、生长和排卵以及卵母细胞发育能力获得的卵巢形态学和功能背景。我们将描述在卵泡形成过程中发生的卵巢细胞外基质(ECM)和脉管系统的变化，它们对卵巢组织机械特性的影响，以及它们对信号转导调节的影响。此外，我们还将概述它们的失调如何与多囊卵巢综合征(PCOS)、子宫内膜异位症或卵巢早衰(POI)等病理相关。最后，对于这三种病理中的每一种，我们将强调试图纠正改变的生物力学环境以恢复生育能力的治疗策略。检索方法:对于所讨论的每个领域，使用PubMed Central、Web of Science和Scopus搜索引擎进行系统的书目检索，不受时间限制，检索关键词为细胞外基质、机械生物学、生物力学、脉管系统、血管生成或信号通路，并结合:卵巢、卵发生、卵母细胞、卵泡发生、卵巢卵泡、卵泡膜、颗粒、积云、卵泡液、黄体、减数分裂、卵母细胞发育能力、着床前、多囊卵巢综合征、卵巢早衰或子宫内膜异位症。结果:通过搜索引擎查询，我们共获得37368篇论文，这些论文是根据我们对哺乳动物的关注，特别是啮齿动物、牛、马、羊、灵长类动物和人类的关注，并围绕综述的每个特定主题进行了修剪。在剔除重复项后，这一选择过程产生了628篇论文，其中287篇在原稿中被引用。其中，89.2%发表于过去22年，其余8.0%、2.4%和0.3%分别发表于90年代、80年代和之前。在卵泡形成过程中，卵巢ECM的组成和组织发生变化，这些变化与生长卵泡周围的血管模型一起，旨在维持其招募和生长，以及封闭卵母细胞的成熟。这些事件定义了机械力是调节分子信号级联的关键的场景。这种情况的改变决定了卵泡发生受损和卵母细胞发育潜力下降，这在病理条件下是导致不育的原因，如多囊卵巢综合征、子宫内膜异位症或POI。更广泛的影响:对这些机制和支配它们的规则的了解为解释卵泡的募集和生长是如何被调节的奠定了坚实的基础，并激发了在临床实践中开发改善卵泡募集和卵母细胞能力的策略的见解，特别是对于多囊卵巢综合征、子宫内膜异位症和POI等病理。
{"title":"Biomechanical forces and signals operating in the ovary during folliculogenesis and their dysregulation: implications for fertility.","authors":"Giulia Fiorentino, Danilo Cimadomo, Federica Innocenti, Daria Soscia, Alberto Vaiarelli, Filippo Maria Ubaldi, Gianluca Gennarelli, Silvia Garagna, Laura Rienzi, Maurizio Zuccotti","doi":"10.1093/humupd/dmac031","DOIUrl":"https://doi.org/10.1093/humupd/dmac031","url":null,"abstract":"<p><strong>Background: </strong>Folliculogenesis occurs in the highly dynamic environment of the ovary. Follicle cyclic recruitment, neo-angiogenesis, spatial displacement, follicle atresia and ovulation stand out as major events resulting from the interplay between mechanical forces and molecular signals. Morphological and functional changes to the growing follicle and to the surrounding tissue are required to produce oocytes capable of supporting preimplantation development to the blastocyst stage.</p><p><strong>Objective and rationale: </strong>This review will summarize the ovarian morphological and functional context that contributes to follicle recruitment, growth and ovulation, as well as to the acquisition of oocyte developmental competence. We will describe the changes occurring during folliculogenesis to the ovarian extracellular matrix (ECM) and to the vasculature, their influence on the mechanical properties of the ovarian tissue, and, in turn, their influence on the regulation of signal transduction. Also, we will outline how their dysregulation might be associated with pathologies such as polycystic ovary syndrome (PCOS), endometriosis or premature ovarian insufficiency (POI). Finally, for each of these three pathologies, we will highlight therapeutic strategies attempting to correct the altered biomechanical context in order to restore fertility.</p><p><strong>Search methods: </strong>For each area discussed, a systematic bibliographical search was performed, without temporal limits, using PubMed Central, Web of Science and Scopus search engines employing the keywords extracellular matrix, mechanobiology, biomechanics, vasculature, angiogenesis or signalling pathway in combination with: ovary, oogenesis, oocyte, folliculogenesis, ovarian follicle, theca, granulosa, cumulus, follicular fluid, corpus luteum, meiosis, oocyte developmental competence, preimplantation, polycystic ovary syndrome, premature ovarian insufficiency or endometriosis.</p><p><strong>Outcomes: </strong>Through search engines queries, we yielded a total of 37 368 papers that were further selected based on our focus on mammals and, specifically, on rodents, bovine, equine, ovine, primates and human, and also were trimmed around each specific topic of the review. After the elimination of duplicates, this selection process resulted in 628 papers, of which 287 were cited in the manuscript. Among these, 89.2% were published in the past 22 years, while the remaining 8.0%, 2.4% or 0.3% were published during the 1990s, 1980s or before, respectively. During folliculogenesis, changes occur to the ovarian ECM composition and organization that, together with vasculature modelling around the growing follicle, are aimed to sustain its recruitment and growth, and the maturation of the enclosed oocyte. These events define the scenario in which mechanical forces are key to the regulation of cascades of molecular signals. Alterations to this context determine impaired folliculogen","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":"29 1","pages":"1-23"},"PeriodicalIF":13.3,"publicationDate":"2023-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9263400","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}
Vasily Ashapkin, Alexander Suvorov, J Richard Pilsner, Stephen A Krawetz, Oleg Sergeyev
<p><strong>Background: </strong>Modern reproductive behavior in most developed countries is characterized by delayed parenthood. Older gametes are generally less fertile, accumulating and compounding the effects of varied environmental exposures that are modified by lifestyle factors. Clinicians are primarily concerned with advanced maternal age, while the influence of paternal age on fertility, early development and offspring health remains underappreciated. There is a growing trend to use assisted reproductive technologies for couples of advanced reproductive age. Thus, the number of children born from older gametes is increasing.</p><p><strong>Objective and rationale: </strong>We review studies reporting age-associated epigenetic changes in mammals and humans in sperm, including DNA methylation, histone modifications and non-coding RNAs. The interplay between environment, fertility, ART and age-related epigenetic signatures is explored. We focus on the association of sperm epigenetics on epigenetic and phenotype events in embryos and offspring.</p><p><strong>Search methods: </strong>Peer-reviewed original and review articles over the last two decades were selected using PubMed and the Web of Science for this narrative review. Searches were performed by adopting the two groups of main terms. The first group included 'advanced paternal age', 'paternal age', 'postponed fatherhood', 'late fatherhood', 'old fatherhood' and the second group included 'sperm epigenetics', 'sperm', 'semen', 'epigenetic', 'inheritance', 'DNA methylation', 'chromatin', 'non-coding RNA', 'assisted reproduction', 'epigenetic clock'.</p><p><strong>Outcomes: </strong>Age is a powerful factor in humans and rodent models associated with increased de novo mutations and a modified sperm epigenome. Age affects all known epigenetic mechanisms, including DNA methylation, histone modifications and profiles of small non-coding (snc)RNA. While DNA methylation is the most investigated, there is a controversy about the direction of age-dependent changes in differentially hypo- or hypermethylated regions with advanced age. Successful development of the human sperm epigenetic clock based on cross-sectional data and four different methods for DNA methylation analysis indicates that at least some CpG exhibit a linear relationship between methylation levels and age. Rodent studies show a significant overlap between genes regulated through age-dependent differentially methylated regions and genes targeted by age-dependent sncRNA. Both age-dependent epigenetic mechanisms target gene networks enriched for embryo developmental, neurodevelopmental, growth and metabolic pathways. Thus, age-dependent changes in the sperm epigenome cannot be described as a stochastic accumulation of random epimutations and may be linked with autism spectrum disorders. Chemical and lifestyle exposures and ART techniques may affect the epigenetic aging of sperm. Although most epigenetic modifications are erased in the
背景:大多数发达国家的现代生殖行为以延迟生育为特征。年龄较大的配子通常生育能力较差，受生活方式因素影响的各种环境暴露的影响不断累积和复合。临床医生主要关注高龄产妇，而父亲年龄对生育能力、早期发育和后代健康的影响仍未得到充分重视。高龄夫妇使用辅助生殖技术的趋势越来越明显。因此，年龄较大的配子所生的孩子的数量正在增加。目的和基本原理:我们回顾了哺乳动物和人类精子中与年龄相关的表观遗传变化的研究，包括DNA甲基化、组蛋白修饰和非编码rna。环境，生育，ART和年龄相关的表观遗传特征之间的相互作用进行了探讨。我们专注于精子表观遗传学对胚胎和后代表观遗传和表型事件的关联。搜索方法:通过PubMed和Web of Science，选取了过去二十年来同行评议的原创文章和评论文章作为本文的叙述性综述。通过采用两组主要术语进行搜索。第一组包括“高龄父亲”、“高龄父亲”、“晚育父亲”、“高龄父亲”、“高龄父亲”;第二组包括“精子表观遗传学”、“精子”、“精液”、“表观遗传学”、“遗传”、“DNA甲基化”、“染色质”、“非编码RNA”、“辅助生殖”、“表观遗传时钟”。结果:在人类和啮齿动物模型中，年龄是与新生突变增加和精子表观基因组修饰相关的一个重要因素。年龄影响所有已知的表观遗传机制，包括DNA甲基化，组蛋白修饰和小非编码(snc)RNA的谱。虽然DNA甲基化是研究最多的，但随着年龄的增长，不同的低甲基化或高甲基化区域的年龄依赖性变化方向存在争议。基于横断面数据和四种不同DNA甲基化分析方法的人类精子表观遗传时钟的成功开发表明，至少一些CpG在甲基化水平与年龄之间表现出线性关系。啮齿动物研究表明，通过年龄依赖性差异甲基化区域调控的基因与年龄依赖性sncRNA靶向的基因之间存在显著的重叠。这两种年龄依赖的表观遗传机制都针对胚胎发育、神经发育、生长和代谢途径丰富的基因网络。因此，精子表观基因组的年龄依赖性变化不能被描述为随机变异的随机累积，而可能与自闭症谱系障碍有关。化学物质和生活方式暴露以及ART技术可能会影响精子的表观遗传老化。尽管大多数表观遗传修饰在哺乳动物早期胚胎中被消除，但越来越多的证据表明，由于父亲的精子随着时间的推移积累了表观遗传变化，后代表观基因组和表型的改变与父亲的高龄有关。据推测，随着年龄的增长，精子表观基因组的变化是深刻的、生理的、动态的，但在几天或几个月里是稳定的，而且可能是不可逆的。更广泛的影响:这篇综述引起了人们对延迟生育和精子表观基因组年龄相关变化的关注，这些变化可能会损害父亲的生殖健康，并将改变的表观遗传信息传递给后代。建议使用考虑混杂因素的健康男性进行前瞻性研究。我们建议需要更广泛的讨论，集中在自然和人工受孕中对父亲年龄的调节。专业团体应该了解情况，并在人群中提高认识，在为老年男性提供咨询时也应该提高认识。
{"title":"Age-associated epigenetic changes in mammalian sperm: implications for offspring health and development.","authors":"Vasily Ashapkin, Alexander Suvorov, J Richard Pilsner, Stephen A Krawetz, Oleg Sergeyev","doi":"10.1093/humupd/dmac033","DOIUrl":"https://doi.org/10.1093/humupd/dmac033","url":null,"abstract":"<p><strong>Background: </strong>Modern reproductive behavior in most developed countries is characterized by delayed parenthood. Older gametes are generally less fertile, accumulating and compounding the effects of varied environmental exposures that are modified by lifestyle factors. Clinicians are primarily concerned with advanced maternal age, while the influence of paternal age on fertility, early development and offspring health remains underappreciated. There is a growing trend to use assisted reproductive technologies for couples of advanced reproductive age. Thus, the number of children born from older gametes is increasing.</p><p><strong>Objective and rationale: </strong>We review studies reporting age-associated epigenetic changes in mammals and humans in sperm, including DNA methylation, histone modifications and non-coding RNAs. The interplay between environment, fertility, ART and age-related epigenetic signatures is explored. We focus on the association of sperm epigenetics on epigenetic and phenotype events in embryos and offspring.</p><p><strong>Search methods: </strong>Peer-reviewed original and review articles over the last two decades were selected using PubMed and the Web of Science for this narrative review. Searches were performed by adopting the two groups of main terms. The first group included 'advanced paternal age', 'paternal age', 'postponed fatherhood', 'late fatherhood', 'old fatherhood' and the second group included 'sperm epigenetics', 'sperm', 'semen', 'epigenetic', 'inheritance', 'DNA methylation', 'chromatin', 'non-coding RNA', 'assisted reproduction', 'epigenetic clock'.</p><p><strong>Outcomes: </strong>Age is a powerful factor in humans and rodent models associated with increased de novo mutations and a modified sperm epigenome. Age affects all known epigenetic mechanisms, including DNA methylation, histone modifications and profiles of small non-coding (snc)RNA. While DNA methylation is the most investigated, there is a controversy about the direction of age-dependent changes in differentially hypo- or hypermethylated regions with advanced age. Successful development of the human sperm epigenetic clock based on cross-sectional data and four different methods for DNA methylation analysis indicates that at least some CpG exhibit a linear relationship between methylation levels and age. Rodent studies show a significant overlap between genes regulated through age-dependent differentially methylated regions and genes targeted by age-dependent sncRNA. Both age-dependent epigenetic mechanisms target gene networks enriched for embryo developmental, neurodevelopmental, growth and metabolic pathways. Thus, age-dependent changes in the sperm epigenome cannot be described as a stochastic accumulation of random epimutations and may be linked with autism spectrum disorders. Chemical and lifestyle exposures and ART techniques may affect the epigenetic aging of sperm. Although most epigenetic modifications are erased in the","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":"29 1","pages":"24-44"},"PeriodicalIF":13.3,"publicationDate":"2023-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/16/fd/dmac033.PMC9825272.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9349557","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>Reproductive tract infection is an important factor leading to male and female infertility. Among female infertility factors, microbial and viral infections are the main factors affecting female reproductive health and causing tubal infertility, ectopic tubal pregnancy and premature delivery. Among male infertility factors, 13-15% of male infertility is related to infection. Defensins are cationic antibacterial and antiviral peptides, classified into α-defensins, β-defensins and θ-defensins. Humans only have α-defensins and β-defensins. Apart from their direct antimicrobial functions, defensins have an immunomodulatory function and are involved in many physiological processes. Studies have shown that defensins are widely distributed in the female reproductive tract (FRT) and male reproductive tract (MRT), playing a dual role of host defence and fertility protection. However, to our knowledge, the distribution, regulation and function of defensins in the reproductive tract and their relation to reproduction have not been reviewed.</p><p><strong>Objective and rationale: </strong>This review summarizes the expression, distribution and regulation of defensins in the reproductive tracts to reveal the updated research on the dual role of defensins in host defence and the protection of fertility.</p><p><strong>Search methods: </strong>A systematic search was conducted in PubMed using the related keywords through April 2022. Related data from original researches and reviews were integrated to comprehensively review the current findings and understanding of defensins in the human reproductive system. Meanwhile, female and male transcriptome data in the GEO database were screened to analyze defensins in the human reproductive tracts.</p><p><strong>Outcomes: </strong>Two transcriptome databases from the GEO database (GSE7307 and GSE150852) combined with existing researches reveal the expression levels and role of the defensins in the reproductive tracts. In the FRT, a high expression level of α-defensin is found, and the expression levels of defensins in the vulva and vagina are higher than those in other organs. The expression of defensins in the endometrium varies with menstrual cycle stages and with microbial invasion. Defensins also participate in the local immune response to regulate the risk of spontaneous preterm birth. In the MRT, a high expression level of β-defensins is also found. It is mainly highly expressed in the epididymal caput and corpus, indicating that defensins play an important role in sperm maturation. The expression of defensins in the MRT varies with androgen levels, age and the status of microbial invasion. They protect the male reproductive system from bacterial infections by neutralizing lipopolysaccharide and downregulating pro-inflammatory cytokines. In addition, animal and clinical studies have shown that defensins play an important role in sperm maturation, motility and fertilization.</p><p><st
{"title":"Defensins: defenders of human reproductive health.","authors":"Yu-Jia Zhai, Ying Feng, Xue Ma, Fang Ma","doi":"10.1093/humupd/dmac032","DOIUrl":"https://doi.org/10.1093/humupd/dmac032","url":null,"abstract":"<p><strong>Background: </strong>Reproductive tract infection is an important factor leading to male and female infertility. Among female infertility factors, microbial and viral infections are the main factors affecting female reproductive health and causing tubal infertility, ectopic tubal pregnancy and premature delivery. Among male infertility factors, 13-15% of male infertility is related to infection. Defensins are cationic antibacterial and antiviral peptides, classified into α-defensins, β-defensins and θ-defensins. Humans only have α-defensins and β-defensins. Apart from their direct antimicrobial functions, defensins have an immunomodulatory function and are involved in many physiological processes. Studies have shown that defensins are widely distributed in the female reproductive tract (FRT) and male reproductive tract (MRT), playing a dual role of host defence and fertility protection. However, to our knowledge, the distribution, regulation and function of defensins in the reproductive tract and their relation to reproduction have not been reviewed.</p><p><strong>Objective and rationale: </strong>This review summarizes the expression, distribution and regulation of defensins in the reproductive tracts to reveal the updated research on the dual role of defensins in host defence and the protection of fertility.</p><p><strong>Search methods: </strong>A systematic search was conducted in PubMed using the related keywords through April 2022. Related data from original researches and reviews were integrated to comprehensively review the current findings and understanding of defensins in the human reproductive system. Meanwhile, female and male transcriptome data in the GEO database were screened to analyze defensins in the human reproductive tracts.</p><p><strong>Outcomes: </strong>Two transcriptome databases from the GEO database (GSE7307 and GSE150852) combined with existing researches reveal the expression levels and role of the defensins in the reproductive tracts. In the FRT, a high expression level of α-defensin is found, and the expression levels of defensins in the vulva and vagina are higher than those in other organs. The expression of defensins in the endometrium varies with menstrual cycle stages and with microbial invasion. Defensins also participate in the local immune response to regulate the risk of spontaneous preterm birth. In the MRT, a high expression level of β-defensins is also found. It is mainly highly expressed in the epididymal caput and corpus, indicating that defensins play an important role in sperm maturation. The expression of defensins in the MRT varies with androgen levels, age and the status of microbial invasion. They protect the male reproductive system from bacterial infections by neutralizing lipopolysaccharide and downregulating pro-inflammatory cytokines. In addition, animal and clinical studies have shown that defensins play an important role in sperm maturation, motility and fertilization.</p><p><st","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":"29 1","pages":"126-154"},"PeriodicalIF":13.3,"publicationDate":"2023-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/87/a5/dmac032.PMC9825273.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9279728","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：