Hum. Reprod. Update [JOURNAL]
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200 papers
Microfluidics for in vitro fertilization: from science to clinical validation.
Pensabene V, Agate F, Santos Miranda A … +1 more , Picton HM
Hum Reprod Update · 2026 Mar · PMID 41349964 · Full text
BACKGROUND: This narrative review analyses the development of microfluidic technologies specifically applied to the IVF treatment, and their translation into clinical solution. OBJECTIVE AND RATIONALE: Starting with an a...
BACKGROUND: This narrative review analyses the development of microfluidic technologies specifically applied to the IVF treatment, and their translation into clinical solution. OBJECTIVE AND RATIONALE: Starting with an analysis of the latest scientific publications, the patent scenario and the current clinical trials were analysed aiming to identify the most developed applications, the challenges, and barriers for regulatory approval and clinical validation in different countries. SEARCH METHODS: Searches were completed in English, by using a combination of these keywords (exceptions are included in the text in the different sections): Microfluidic, IVF, Assisted, clinical, fertility, human fertility, women fertility, reproduction, pregnancy, Assisted Reproductive Technology. These were used for previously published reviews and scientific journal papers using PubMed (National Center for Biotechnology Information at the U.S. National Library of Medicine), and Google Scholar, limited to the last decade (2013-2025); for completed or ongoing clinical trials using Clinicaltrials.gov; for existing patents and intellectual properties commercialization using lens.org, and crosschecked on espacenet.com from 2000 to 2025. OUTCOMES: It is approximately 20 years since the design of the first microfluidic systems for IVF. In the last 5 years, there have been over 130 publications proposing new microfluidic solutions, with pre-clinical validation data in animal models and humans. Our analysis highlighted three main areas of development that are discussed in terms of trends and advancements in oocyte and sperm processing and handling; proposed solutions to support in vitro embryo development; and microfluidic-based approaches and techniques for cryopreservation and female fertility preservation. In the last 20 years, progression of the microfluidic technology and improvement of manufacturing processes have led to an exponential rise of patents (1405) where microfluidics is applied to different steps of the assisted conception cycle. However, of these innovative techniques, only a limited number have progressed to clinical validation (19 trials commenced since 2009) and these have focused primarily on microfluidic sperm sorting and selection with multiple trials investigating its effectiveness in enhancing sperm quality and fertilization rates, and microfluidic embryo culture systems, where additional research is still needed to establish benefits over traditional culture environments. The key barriers to adoption include the need for long-term clinical outcome data, standardization of results across various patient populations, and regulatory challenges. We summarize the pathways needed to ensure compliance with quality standards and regulations in different countries. This analysis evaluates the different clinical trial requirements and challenges for participant recruitment, as well as study design complexity, and the definition of achievable endpoints and establishment of appropriate control groups or comparators. WIDER IMPLICATIONS: Finally, this review highlights complementary technologies recently combined with microfluidics (e.g. automatic and artificial intelligence-powered imaging, in situ non-invasive metabolic sensing) which can guarantee a more precise and safe handling of biological samples, favour automation of sample processing (e.g. gametes), and provide new information and higher level of control of the laboratory techniques used by clinics to treat patients in the next 5-10 years. REGISTRATION NUMBER: N/A.
The value of narrative reviews: beyond data synthesis.
Van Wely M
Hum Reprod Update · 2026 Jan · PMID 41283815 · Publisher ↗
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Female fertility preservation: 25 years of progress, expanding indications and future prospects.
Sonmezer M, Sacinti KG, Oktay KH
Hum Reprod Update · 2026 Mar · PMID 41206517 · Full text
BACKGROUND: There has been an unprecedented progress in the field of fertility preservation (FP) beginning in the late 1990s. Specifically, technological innovations, refinements in the protocols, and a deeper understand...
BACKGROUND: There has been an unprecedented progress in the field of fertility preservation (FP) beginning in the late 1990s. Specifically, technological innovations, refinements in the protocols, and a deeper understanding of reproductive physiology have collectively contributed the increased success and utilization of FP methods. OBJECTIVE AND RATIONALE: The objectives of this review are: (i) to identify the most recent and significant advances in FP, and (ii) based on evidence, to provide a comprehensive and up-to-date source of contemporary FP management approaches to guide clinicians in critical decision-making. In addition to cancer treatments, the indications for FP have expanded to include various systemic conditions such as haematological, metabolic, genetic, and immunological disorders, as well as gonadal surgery and a wish to delay childbearing. Due to the introduction of random start ovarian stimulation protocols and use of anti-oestrogen agents along with ovarian stimulation drugs, coupled with increased success with oocyte cryopreservation, improvements in ovarian tissue cryopreservation and refinements of transplantation techniques, women can now benefit from various FP options through an individualized approach. SEARCH METHODS: We searched for peer-reviewed articles in PubMed, Embase, and Cochrane Library databases containing the key words: FP, ovarian ageing, chemotherapy, radiotherapy, embryo cryopreservation, oocyte cryopreservation, ovarian tissue cryopreservation, and in vitro follicle growth, in the English-language literature from inception to May 2025. OUTCOMES: Cryopreservation of embryos have long been performed successfully in the field of ART. With the advent and widespread of use vitrification, the experimental tag was removed and oocyte cryopreservation was defined as a standard technique of FP. The applicability, success, and safety of random start ovarian stimulation protocols have been demonstrated in many studies including meta-analyses. Improvements in ovarian tissue cryopreservation outcomes have been reported with robotic surgery, use of neovascularizing extracellular matrix, and adjuvant pharmacotherapy. The use of GnRH analogues along with chemotherapy has been trialled as a way of avoiding the need for FP. Although the rate of premature ovarian insufficiency was reported to be lower in some patient populations treated this way, no improvements in live birth rates have been demonstrated. Among the emerging and future options are the use of ovarian tissue freezing and pharmacological approaches to delay menopause and reproductive ageing, non-suppressive gonadoprotective pharmacotherapy, in vitro gametogenesis and in vitro purging of cancer cells from ovarian tissue for cryopreservation. Animal studies have reported success with in vitro follicle growth, and progress is being made with human ovarian tissue. WIDER IMPLICATIONS: The evolution of FP techniques has profound implications for clinical practice, not only for individuals facing fertility-compromising treatments or conditions, but also for the potential deferral of reproductive ageing. The advent of in vitro primordial follicle growth and gametogenesis may further revolutionize the landscape of reproductive medicine and FP. REGISTRATION NUMBER: N/A.
The effect of obesity interventions on male fertility: a systematic review and meta-analysis.
Peel A, Lyons H, Tully CA … +4 more , Vincent AD, Jesudason D, Wittert G, McPherson NO
Hum Reprod Update · 2026 Mar · PMID 41065428 · Full text
BACKGROUND: Obesity is a prevalent modifiable cause of male factor infertility. Preconception guidelines recommend men maintain a healthy weight; however, they provide limited guidance regarding methods or volume of weig...
BACKGROUND: Obesity is a prevalent modifiable cause of male factor infertility. Preconception guidelines recommend men maintain a healthy weight; however, they provide limited guidance regarding methods or volume of weight loss for men with obesity. First-line interventions for weight loss involve lifestyle optimization (healthy diet and exercise), followed by pharmacotherapy or bariatric surgery in severe cases. Each modality has differing weight loss potential and complications for which the reproductive implications are currently unclear. OBJECTIVE AND RATIONALE: To synthesize the available evidence regarding the reproductive effects of obesity interventions in men with obesity. Where possible, to evaluate whether the observed effects depend on the magnitude of weight loss. SEARCH METHODS: Searches for articles published in English was performed using PubMed, Web of Science, Embase, Cochrane Central Register of Controlled Trials and Scopus from inception until December 2024, using prespecified keywords pertaining to four categories: male, overweight/obesity, weight loss (bariatric surgery, nutrition, diet, lifestyle, exercise, pharmacotherapy) and fertility (conception, assisted reproduction, sperm, semen). Studies of reproductive-aged men (18-50 years) who underwent an obesity intervention with established weight loss benefits and undertook repeated assessment of reproduction capacity (semen analysis, conception rates, assisted reproduction outcomes) before and after the intervention were included. Meta-analysis was performed when two or more studies of the same modality assessed an outcome measure in a manner suitable for meta-analysis. A meta-regression considering weight loss achieved was performed when five or more suitable studies were available. Narrative review of studies not suitable for meta-analysis occurred. OUTCOMES: 32 studies were included in the analysis, with one study assessing both lifestyle interventions and pharmacotherapy. Assessment of conception rates and assisted reproduction was limited across all modalities. In almost all cases, the effect of obesity interventions on semen quality was examined as a surrogate for reproductive capacity and the certainty of evidence was low. Bariatric surgery was assessed in 18 studies, including 12 quasi-experimental studies, one randomized controlled trial, one case series and four case reports. Fixed- and random-effects meta-analysis of randomized controlled trials identified no differences in sperm parameters between control and intervention arms across any intervention, although small sample size limits interpretability. Random-effects meta-analyses of pre-post outcomes identified no clinically significant semen parameters or DNA damage changes following bariatric surgery. Pharmacotherapy (metformin and liraglutide) was assessed in five studies, including four quasi-experimental studies and one case report. There were insufficient data to draw clear conclusions regarding the impact of these agents on fertility outcomes. Lifestyle interventions were assessed in 10 studies, including five quasi-experimental studies and five randomized controlled trials. Fixed-effect meta-analysis identified improvements in sperm normal morphology (Mean difference = 0.59%, 95% Confidence interval = [0.23, 0.94]), and progressive motility (10.56% [8.97, 12.15]) following a lifestyle intervention. WIDER IMPLICATIONS: Data regarding weight loss interventions and male fertility is limited primarily to observational studies examining semen quality. Improvements in semen quality following lifestyle interventions suggest a potential benefit of optimizing nutrition and physical activity, whereas a limited change with bariatric surgery indicates obesity-associated sperm dysfunction does not resolve in a dose-dependent manner with weight loss and/or negative effects of rapid weight loss exist. Substantial knowledge gaps were identified, including limited randomized trials, inadequate examination of conception outcomes and limited assessment of GLP-1 agonist effects. REGISTRATION NUMBER: CRD 42022349665.
The diagnosis and management of extrauterine and uterine ectopic pregnancy.
Farren J, Al Wattar BH, Jurkovic D
Hum Reprod Update · 2026 Jan · PMID 41061761 · Full text
In the last two decades, we have consolidated our knowledge of the epidemiology and risk factors for ectopic pregnancies. Minimally invasive surgical skills are now widespread, and laparoscopic surgery is recognized as t...
In the last two decades, we have consolidated our knowledge of the epidemiology and risk factors for ectopic pregnancies. Minimally invasive surgical skills are now widespread, and laparoscopic surgery is recognized as the best and safest operative treatment for extrauterine ectopic pregnancies. Based on the evidence from randomized trials published a decade ago, laparoscopic salpingectomy is accepted as the optimal surgical treatment for tubal ectopic pregnancy. However, with recent advances in surgical techniques and improvement in surgical skills, the appropriateness of tubal removal versus conservation is under increasing scrutiny. Improvements in the organization and provision of care for women presenting with early pregnancy complications, in conjunction with better quality and wider use of ultrasound imaging, have resulted in an increased ability to detect small failing ectopic pregnancies, which were impossible to diagnose in the past. Many of these pregnancies are destined to resolve spontaneously without the need for any intervention. The necessity to avoid overtreatment and the potential for iatrogenic harm in such cases has facilitated the introduction of expectant management into mainstream clinical practice. This represents one of the key developments in the care for women with ectopic pregnancies. By contrast, the efficacy of medical management with methotrexate has been questioned. Another important development in recent years has been a rapid rise in the prevalence of ectopic pregnancies that are located outside the uterine cavity but within the confines of the uterus, the largest burden of which is from Caesarean scar ectopic pregnancies. This has promoted the development of new terminology and classification of ectopic pregnancies, with the aim of raising awareness of these increasingly prevalent types and minimizing the risk of misdiagnosis. In comparison to ectopic pregnancies outside the uterus, uterine ectopic pregnancies are more difficult to diagnose and manage, and are also associated with increased maternal morbidity, mortality, and adverse reproductive outcomes. Another challenge, which is peculiar to uterine ectopic pregnancies, is their potential to progress to reach foetal viability, albeit with a high risk of extreme prematurity. This requires women and clinicians to make difficult decisions about whether these pregnancies should be terminated to protect maternal health, despite some possibility of a good foetal outcome. Herein, we provide a comprehensive review of published literature to summarize new evidence and explore emerging themes with respect to ectopic pregnancy. Our aim is to provide an overview of modern classification and diagnosis, to summarize available treatment options and recommendations, and to emphasize longer-term outcomes, including the potential psychological impact of ectopic pregnancy. We examine current knowledge gaps and outline priorities for further research.
The epidemiology, clinical burden, and prevention of intrauterine adhesions (IUAs) related to surgically induced endometrial trauma: a systematic literature review and selective meta-analyses.
Munro MG, Salazar CA, Bhagavath B … +9 more , Emanuel MH, Huddleston HG, Sobti D, Jaiswal AK, Gamburg R, Kumar J, Martin C, Hooker AB, Women’s Health Research Collaborative’s Endometrial Trauma Group
Hum Reprod Update · 2025 Nov · PMID 40914965 · Full text
BACKGROUND: Reproductive-age women with intrauterine adhesions (IUAs) following uterine surgery may be asymptomatic or may experience light or absent menstruation, infertility, preterm delivery, and/or peripartum hemorrh...
BACKGROUND: Reproductive-age women with intrauterine adhesions (IUAs) following uterine surgery may be asymptomatic or may experience light or absent menstruation, infertility, preterm delivery, and/or peripartum hemorrhage. Understanding procedure- and technique-specific risks and the available evidence on the impact of surgical adjuvants is essential to the design of future research. OBJECTIVE AND RATIONALE: While many systematic reviews have been published, most deal with singular aspects of the problem. Consequently, a broadly scoped systematic review and selective meta-analyses identifying evidence strengths and gaps are necessary to inform future research and treatment strategies. SEARCH METHODS: A systematic literature review was performed seeking evidence on IUA incidence following selected uterine procedures and the effectiveness of hysteroscopic adhesiolysis on menstrual, endometrial, fertility, and pregnancy-related outcomes. An evaluation of the impact of surgical adjuvants designed to facilitate adhesion-free endometrial repair was included. Searches were conducted in the PubMed, Embase, and Cochrane databases following PRISMA guidelines and included English-language publications from inception to 8 November 2024. Inclusion criteria restricted articles to those reporting IUA epidemiology or related clinical outcomes. Risk of bias assessment used the US NIH tools for interventional and observational studies. Meta-analyses were conducted and reported only for outcomes where there were sufficient data. Per analysis, we report on proportions (with 95% CI), heterogeneity (I2), and the risk of bias for each study included. OUTCOMES: The review identified 249 appropriate publications. The risks of new-onset IUAs following the removal of products of conception after early pregnancy loss, hysteroscopic myomectomy, and hysteroscopic metroplasty for septum correction were 17% (95% CI: 11-25%; 13 studies, I2 = 87%, poor to good evidence quality), 16% (95% CI: 6-28%; 8 studies, I2 = 93%, fair to good evidence quality), and 28% (95% CI: 13-46%; 8 studies, I2 = 91%, fair to good evidence quality), respectively. For primary IUA prevention with adjuvant intrauterine gel barriers, the relative risks were 0.45 (95% CI: 0.30-0.68; three studies, I2 = 0%, poor to good evidence quality), 0.38 (95% CI: 0.20-0.73; three studies, I2 = 0%, fair evidence quality), and 0.29 (95% CI: 0.12-0.69; three studies, I2 = 0%, fair to good evidence quality), respectively, following the above potentially adhesiogenic procedures. Following adhesiolysis without adjuvants, the IUA recurrence rate was 35% (95% CI: 24-46%; 13 studies, I2 = 95%, poor to good evidence quality), similar to the rate of 43% for both those treated adjuvantly with an intrauterine balloon (95% CI: 35-51%; 14 studies, I2 = 85%, poor to good evidence quality), or an IUD (95% CI: 27-59%; four studies, I2 = 85%, fair to good evidence quality). The recurrence rate for secondary prevention with gel barriers was 28% (95% CI: 4-62%; three studies, I2 = 94%, good evidence quality). Notably, there was an excess rate of associated adverse obstetrical outcomes, including preterm delivery, placenta accreta spectrum, placenta previa, peripartum hemorrhage, and hysterectomy, with evidence demonstrating the beneficial impact of adjuvant therapies on these outcomes. WIDER IMPLICATIONS: This systematic review comprehensively analyzes IUA formation following uterine surgical procedures and adjuvant therapy effectiveness. Even following adhesiolysis, it is apparent that the basilar endometrial trauma thought to facilitate the formation of IUAs may persist and contribute to adverse reproductive outcomes. Many critical gaps remain in our knowledge of the pathogenesis, prevention, and management of endometrial trauma and IUAs. PREGISTRATION NUMBER: PROSPERO (ID: CRD42023366218).
Transcript profiling and gene regulation of the human pre-implantation embryo: parental effects and impact of ARTs.
Ferreux L, Ducreux B, Firmin J … +7 more , Chargui A, Pocate-Cheriet K, Maignien C, Santulli P, Borensztein M, Fauque P, Patrat C
Hum Reprod Update · 2026 Jan · PMID 40891422 · Publisher ↗
BACKGROUND: Infertility is a growing global challenge, with ARTs significantly improving birth rates for infertile couples. However, ART conceptions are associated with a higher risk of negative obstetrical and perinatal...
BACKGROUND: Infertility is a growing global challenge, with ARTs significantly improving birth rates for infertile couples. However, ART conceptions are associated with a higher risk of negative obstetrical and perinatal outcomes, with potential long-term effects on offspring health. Many pre-implantation embryos exhibit abnormal morphokinetics, implantation failure, or arrested development. ART procedures and parental factors are suspected to perturb the embryonic transcriptome, potentially affecting molecular and epigenetic events during gametogenesis and early development. The timing and mechanisms of these perturbations remain unclear. Genome-wide transcriptomic misregulation in ART-conceived human pre-implantation embryos may provide important insights into observed differences between ART and naturally conceived offspring. OBJECTIVE AND RATIONALE: This narrative review aims to explore how the transcriptome of the human pre-implantation embryo is influenced by parental characteristics, ART conditions, and embryonic factors, with the characterization of the temporal sequence of acquisition of lineage-specific markers at the blastocyst stage serving as a prerequisite. The primary objective is to compile changes in gene expression resulting from parental and intrinsic characteristics or from ART-specific interventions. A secondary aim is to identify common dysregulated molecular pathways across all factors studied. SEARCH METHODS: A comprehensive PubMed search (up to December 2024) was conducted to identify studies assessing transcriptomic profiles in human blastocysts. Studies were included based on parental infertility characteristics (e.g. age, polycystic ovary syndrome (PCOS), endometriosis, diminished ovarian reserve (DOR), sperm alterations, unexplained infertility (UI), and obesity), ART interventions (e.g. hormonal stimulation, IVM, IVF, culture conditions, and vitrification), and intrinsic embryo factors (e.g. morphology, ploidy, sex, and developmental arrest). Differentially expressed genes between different embryo groups were compared across studies, and Gene Ontology analysis identified common or specific pathways. Single-cell RNA sequencing data were used to map lineage-specific transcriptomic patterns in human blastocysts, categorizing expression changes by cell lineages (epiblast, primitive endoderm, and trophectoderm). Where human data on blastocysts were limited, animal studies or other cleaved stages were discussed. OUTCOMES: Maternal age was the most significant contributor to misregulated gene expression in human blastocysts, affecting metabolic and developmental processes. Variations in culture medium impacted cell cycle regulation, carbohydrate metabolism, and RNA biosynthesis. Blastocyst morphology mostly influenced metabolic process changes. Blastocyst aneuploidy induced significant changes in developmental pathways and pluripotency gene expression in the epiblast. Evidence on the effects of PCOS, endometriosis, DOR, sperm alterations, UI, and ART technologies remains limited. Dysregulated pathways commonly involve metabolic, cellular, reproductive, and developmental processes. Dysregulation of genomic imprinting and chromatin-modifier genes was also observed across at least two conditions. WIDER IMPLICATIONS: This review highlights the complexity of interpreting gene expression in human pre-implantation embryos due to diverse influences, including parental age, ART conditions, developmental stage, and embryo sex. ART procedures may have cumulative effects on the blastocyst transcriptome. Modifiable factors, such as culture conditions, offer opportunities for improving IVF outcomes. Epigenetic modifications may also be sensitive to these diverse influences and involved in observed transcriptomic changes, opening further research investigation to clarify long-term health effects. REGISTRATION NUMBER: n/a.
The intricate dance of RNA-binding proteins: unveiling the mechanisms behind male infertility.
Gao Y, Zhou Y, Hong Z … +7 more , Ma B, Wang X, Nie L, Ma L, Zhang Y, Zhang M, Wang M
Hum Reprod Update · 2026 Jan · PMID 40847540 · Full text
BACKGROUND: RNA-binding proteins (RBPs) are indispensable for transcriptional and post-transcriptional processes during spermatogenesis, orchestrating germ cell proliferation, differentiation, and maturation. Despite the...
BACKGROUND: RNA-binding proteins (RBPs) are indispensable for transcriptional and post-transcriptional processes during spermatogenesis, orchestrating germ cell proliferation, differentiation, and maturation. Despite their established importance, the contributions of RBPs in male infertility remain underexplored. Recently, a seminal Science publication reported an RBP atlas of 1744 murine testicular RBPs, 22 loss-of-function variants, and 137 deleterious missense variants identified in 1046 infertile patients, providing unprecedented opportunities to investigate their molecular and clinical relevance. Variants in RBP-related genes associated with azoospermia, oligozoospermia, teratozoospermia, and asthenozoospermia highlight their potential as diagnostic biomarkers and therapeutic targets. However, comprehensive analyses that integrate genetic, functional, and clinical insights are still lacking. OBJECTIVE AND RATIONALE: This review aims to systematically analyze the roles of RBPs in male infertility. Leveraging state-of-the-art datasets and experimental insights, it examines pathogenic variants and variants of uncertain significance (VUS), and elucidates the gene-disease relationships (GDRs). Furthermore, it explores known RBP functions across spermatogenesis stages and identifies candidate RBP genes. By integrating these findings, this work provides a comprehensive framework to advance the genetic understanding of RBPs, and their potential as clinical biomarkers and therapeutic targets in male infertility. SEARCH METHODS: We searched the PubMed database for articles until 13 July 2025, using the keywords 'RNA-binding protein', 'male infertility', 'spermatogenesis', 'sperm', 'genetic variant', 'functional analyses', and 'knockout mouse model'. Pathogenic variants and VUS in 1744 RBP-coding genes, retrieved from the ClinVar and PubMed databases, were systematically analyzed to classify GDRs by the International Male Infertility Genomics Consortium database. Functional data from RBP knockout mouse models were assessed to elucidate stage-specific roles in spermatogenesis. Candidate RBP genes lacking knockout mouse models were identified by mining the RBP atlas, alongside data from the Genotype-Tissue Expression, Human Protein Atlas, and Uniprot databases. The clinical potential of RBPs as diagnostic biomarkers and therapeutic targets was also discussed. OUTCOMES: Our search generated ∼2000 records, and 331 relevant articles were ultimately included in the final text. Firstly, this review identified 177 pathogenic variants in 62 RBP genes and 91 VUS in 35 RBP genes, 15 of which have been confidently linked to human male infertility. Secondly, functional analyses of 124 RBP knockout mouse models revealed their stage-specific regulatory roles in spermatocytogenesis, spermatidogenesis, and spermiogenesis, offering insights into key processes such as piwi-interacting RNA biogenesis, chromatin remodeling, and RNA stability. Thirdly, 38 RBP genes lacking knockout mouse models were screened as candidate RBP genes in male infertility, underscoring their potential for future functional investigations. Finally, this review discusses the clinical potential of RBPs as biomarkers and therapeutic targets, including RNA-based drugs, small molecules, and gene editing technologies as innovative strategies to address RBP-related male infertility. WIDER IMPLICATIONS: This review highlights the role of RBPs in male infertility and offers a framework for integrating genetic, functional, and clinical data. By identifying candidate RBPs and their therapeutic potential, it lays the groundwork for future diagnostic advancements and personalized treatments in reproductive medicine. REGISTRATION NUMBER: N/A.
Preconception lifestyle interventions for women-a systematic review and meta-analysis of intervention characteristics and behaviour change techniques.
Torkel S, Mantzioris E, Villani A … +13 more , Kellow NJ, Bhatnagar D, Osei-Safo EK, McGowan M, Abdul Jafar NK, Bogatzke N, Alesi S, Astarcioglu T, Mol BW, Norman RJ, Cowan S, Wang R, Moran L
Hum Reprod Update · 2026 Jan · PMID 40847529 · Full text
BACKGROUND: The time before conception is an important opportunity to improve maternal lifestyle, and hence improve fertility and health. However, the components of effective preconception lifestyle interventions are unc...
BACKGROUND: The time before conception is an important opportunity to improve maternal lifestyle, and hence improve fertility and health. However, the components of effective preconception lifestyle interventions are unclear. OBJECTIVE AND RATIONALE: This review aimed to assess the association of intervention characteristics and behaviour change techniques with the effect of lifestyle interventions on fertility, obstetric, foetal, anthropometric, and metabolic outcomes in women planning a pregnancy. Understanding the optimal components of preconception lifestyle interventions is essential to improve success of future interventions. SEARCH METHODS: We searched Ovid MEDLINE, PsycINFO, Embase, Emcare, Scopus, Cochrane Central Register of Controlled Trials, and CINAHL (6 December 2024). We included randomized controlled trials on women planning a pregnancy which assessed the effect of lifestyle intervention compared to standard minimal care or no intervention on fertility, obstetric, foetal, anthropometric, and metabolic outcomes. We performed random-effects meta-analysis with subgroup analysis based on participant characteristics, intervention characteristics (using the Template for Intervention Description and Replication (TIDieR) framework), and behaviour change techniques (using the Behaviour Change Taxonomy v1). We assessed trustworthiness (using the Trustworthiness in Randomised Controlled Trials (TRACT) checklist), risk of bias (using the Cochrane Risk of Bias 2.0 tool), and certainty of the evidence (using the GRADE approach). OUTCOMES: Following eligibility screening and trustworthiness assessments, we included 24 studies (n = 7795 women), of which the majority were conducted in high-income countries (79%) and studied women with infertility (67%). Risk of bias was low for seven studies, some concerns for 15 studies and high for two studies. Overall, there was no difference in clinical pregnancy (odds ratio [95% CI]: 1.06 [0.84, 1.35], I2 = 24.22%) or live birth (odds ratio [95% CI]: 1.17 [0.82, 1.67], I2 = 48.73%) with lifestyle intervention. Odds of clinical pregnancy were higher for interventions delivered over ≥10 sessions (2.17 [1.21, 3.86] vs 0.88 [0.72, 1.07], P = 0.004 for subgroup differences) and with the behaviour change technique Adding objects to the environment (e.g. provision of intervention-compliant food and/or exercise equipment) (3.51 [1.70, 7.23] vs 0.90 [0.75, 1.08], P < 0.001 for subgroup differences). Lifestyle interventions reduced weight (mean difference [95% CI]: -3.87 kg [-5.76, -1.97], I2 = 95.03%) and fasting blood glucose (mean difference [95% CI]: -0.15 mM [-0.25, -0.04], I2 = 0%). Greater weight loss was observed for interventions with a weight loss aim (-4.19 kg [-6.30, -1.92] vs -0.81 kg [-1.48, -0.14], P = 0.003 for subgroup differences). Greater weight loss was observed for interventions delivered solely via face-to-face (-6.02 kg [-8.96, -3.07]) compared to those delivered via a combination of face-to-face and technology (-2.21 kg [-3.62, -0.81], P = 0.02 for subgroup differences). WIDER IMPLICATIONS: Effectiveness of preconception lifestyle interventions aiming to enhance fertility may be improved by a structured, intensive approach. Preconception lifestyle interventions reduce weight, particularly face-to-face interventions with a weight loss aim. However, these findings based on subgroup analyses should be interpreted with caution and warrant further investigation due to the exploratory nature of the analysis, limited number of studies included, and potential aggregation bias of study-level subgroup effects. Selection of intervention characteristics for future preconception lifestyle interventions should consider patient preferences and practical considerations. REGISTRATION: This review was prospectively registered in the Prospective Register of Systematic Reviews (PROSPERO) (CRD42022333066).
A meta-analysis and systematic review of advanced maternal age patients in IVF.
Ganer Herman H, Feferkorn I, Dahan MH … +3 more , Reinblatt S, Demirtas E, Buckett W
Hum Reprod Update · 2025 Nov · PMID 40803331 · Publisher ↗
BACKGROUND: There has been an increase in the average age of patients seeking fertility treatments over the past decades, with a significantly higher rate of advanced maternal age (AMA) patients undergoing IVF. It is unc...
BACKGROUND: There has been an increase in the average age of patients seeking fertility treatments over the past decades, with a significantly higher rate of advanced maternal age (AMA) patients undergoing IVF. It is unclear if different treatment strategies in IVF improve outcomes in AMA patients. OBJECTIVE AND RATIONALE: The aim of this systematic review was to assess the efficacy of different interventions employed in IVF in patients of AMA. SEARCH METHODS: A comprehensive search in Embase, Medline, and the Cochrane Library was performed. The search strategy included keywords related to IVF and AMA. We included all original peer-reviewed articles published in English, from January 1985 to September 2024, primarily designed to assess the efficacy of different interventions in IVF on clinical outcomes in AMA patients. Meta-analyses were performed for interventions for which sufficient randomized controlled trials existed. OUTCOMES: A total of 151 studies were included in the review. AMA was not consistently defined in all studies reviewed, although common to all studies was an age above 35 years. For the majority of evidence, there appeared to be no clear advantage to any stimulation protocol in AMA patients. There also appeared to be no advantage to any specific FSH medication, while a meta-analysis performed for the addition of LH to follicular stimulating hormone in stimulation demonstrated similar clinical pregnancy and live birth rates. No good evidence was found to support the routine implementation of ICSI in AMA patients, while a meta-analysis performed for assisted hatching (AH) pointed to decreased live birth rates with its implementation. Low-quality evidence demonstrated an increase in live birth rates with multiple embryos transferred with an increase in multiple pregnancies delivered. Finally, a meta-analysis performed for preimplantation genetic testing for aneuploidy (PGT-A) pointed to similar live birth rates as for no testing. WIDER IMPLICATIONS: This review failed to find an advantage to the routine implementation of treatment strategies such as specific stimulation protocols and gonadotropins, ICSI, and PGT-A, and a potential harmful effect for AH. Future high-quality randomized controlled trials are needed to affirm the majority of this review's conclusions. REGISTRATION NUMBER: PROSPERO ID: CRD42022335889.
A comparison of spermatogenesis between flies and men-conserved processes of male gamete production.
Houston BJ, Cauchi LM, Dunleavy JEM … +3 more , Burke R, Hime GR, O'Bryan MK
Hum Reprod Update · 2025 Nov · PMID 40802929 · Full text
BACKGROUND: Spermatogenesis is a dynamic process that involves the co-ordinated development of millions of cells, from stem cells to highly polarized sperm capable of motility and fertility. It is, therefore, not surpris...
BACKGROUND: Spermatogenesis is a dynamic process that involves the co-ordinated development of millions of cells, from stem cells to highly polarized sperm capable of motility and fertility. It is, therefore, not surprising that many thousand genes are required for male fertility. Mutant mouse models are routinely employed to test the function of these genes as well as to validate genetic variants that may be causing human male infertility. The use of mice and other animal models has led to significant knowledge gain regarding the genetic regulation of mammalian male fertility. However, due to the sheer number of genes and genetic variants to be tested these approaches are expensive and time-consuming. We and others have investigated the use of alternate model organisms to expedite validation approaches, including the utility of the fruit fly Drosophila melanogaster. OBJECTIVE AND RATIONALE: This review explores the conserved mechanisms of sperm production between mammals and flies, with a focus on the human setting where possible. SEARCH METHODS: Studies were identified via PubMed using searches including keywords related to the focus of this review, including human, mammalian, and fly or Drosophila spermatogenesis and male fertility. Follow-up searches including using search terms for specific structures and processes for comparison between species included, but were not limited to, male reproductive tract, spermatogenesis, spermatogonia and stem cell niche, meiosis, spermiogenesis and its sub-processes, and sperm/spermatozoa. No time frame or species restrictions were placed on searches. OUTCOMES: We identify key phases of spermatogenesis that are highly conserved between humans and flies, including the early germ cell divisions and the ratio of haploid germ cells generated for each spermatogonial stem cell, allowing their use as a model organism to explore such processes. Some processes are moderately well conserved between mammals and flies, including meiosis with the notable absence of 'crossing over' in flies. We also identify some processes that are poorly conserved, such as a divergence in sperm tail accessory structures, for which flies are not likely a suitable model organism to decipher human biology or for mammals broadly. Examples of where the fly has been or could be useful to study mammalian gene function in male fertility have also been described. WIDER IMPLICATIONS: Drosophila melanogaster is undoubtedly a useful model organism for studying a wide range of human diseases with genetic origins, including male infertility. Both humans and flies possess a pair of testes with the primary role of generating sperm. The formation of cysts in Drosophila testes allows germ cells to constantly proliferate and stay synchronized at the respective maturation phase, as is the case for humans. While both organisms use a method of sperm storage, mammalian sperm undergo post-testicular modifications and are stored in the epididymis. In Drosophila, sperm are stored in the seminal vesicle, and do not appear to undergo any overt post-testicular modifications in this epididymis-like structure. The seminal vesicle is a separate organ in mammals that is responsible for generation of the seminal fluid. It is important to note that male fertility and thus spermatogenesis are subject to significant evolutionary pressure, and there is a degree of variation in its processes between all species. As such, the absence of a phenotype in mutants would not determine that the gene is dispensable for fertility in humans. While flies are useful for genetic studies to confirm human disease causality, we propose they should be used primarily to pre-screen and select strong candidates for further interrogation in mammalian species for translational pathways in the context of human fertility. REGISTRATION NUMBER: N/A.
BMI in children aged 1-18 years conceived after ART with fresh and frozen embryo transfer: a systematic review and meta-analyses.
Asserhøj LL, Kielstrup LR, Grønholdt CL … +4 more , Kjaer ASL, Bülow N, Jensen RB, Pinborg A
Hum Reprod Update · 2025 Nov · PMID 40795372 · Publisher ↗
BACKGROUND: Children conceived by ART exhibit varying birthweights based on the specific ART method employed. Those born after frozen embryo transfer (FET) are more prone to being born with a high birthweight and more ch...
BACKGROUND: Children conceived by ART exhibit varying birthweights based on the specific ART method employed. Those born after frozen embryo transfer (FET) are more prone to being born with a high birthweight and more children are born large-for-gestational age, while those born after fresh embryo transfer (fresh-ET) tend to have lower birthweights and are more often categorized as small-for-gestational age. Extensive research has established a link between both low and high birthweight and an increased risk of childhood obesity. One of the prevailing hypotheses suggests that ART may induce epigenetic modifications during fertilization, implantation, and early embryonic stages, influencing not only size at birth but also BMI and overall health of the offspring later in life. OBJECTIVE AND RATIONALE: This systematic review was undertaken to determine if available evidence in the literature supports the hypothesis that BMI is affected in children born after ART compared with naturally conceived children. SEARCH METHODS: A literature search was performed until 20 March 2025, in PubMed (MEDLINE), EMBASE, and the Cochrane databases for original papers using medical subject headings, Emtree-terms, and free text words. The inclusion criteria were growth and anthropometrics (including BMI) in children born after ART aged 1-18 years. The review was done according to the PRISMA guidelines and data were extracted from the included studies whenever possible. The Robins-I tool was used to assess bias and GRADE was used to evaluate the certainty of the evidence in the included studies. OUTCOMES: A total of 22 026 studies were found after removal of duplicates. Of these, 80 articles were selected for a full-length read-through. Additionally, 52 studies from the reference lists were identified and included for full-length read-through. Of these 132 studies, 32 met the inclusion criteria and were included in the qualitative analysis. Three meta-analyses were conducted. The first (A) compared BMI as SD scores (SDS) in children born after ART (n = 8902) with children born after natural conception (NC) (n = 61 818), and resulted in no difference in BMI (mean-difference 0.02, 95% CI: (-0.03; 0.06), I2 = 9%, moderate certainty). The second (B) investigated the difference in BMI (kg/m2) in children born after ART (n = 4297) and children born after NC (n = 37 233), and showed a slight decline in BMI of -0.16 kg/m2 (95% CI: (-0.26; -0.07), I2=87%, moderate certainty) in ART-conceived children versus NC children. The third meta-analysis (C) examined BMI (SDS) in children born after FET (n = 5146) compared with those born after fresh-ET (n = 15 709), and resulted in no difference in BMI (SDS) (mean-difference 0.08, 95% CI: (-0.02; 0.18), I2=84%) between FET and fresh-ET. Of the 32 studies included, 24 were classified as having low-quality evidence, while 8 were rated as very low quality, when combining the tools of Robins-I and GRADE. WIDER IMPLICATIONS: This systematic review provides a comprehensive summary of the existing literature investigating the BMI of children born after ART compared with children conceived naturally. It adds novel and reliable information to the field by using age and sex-standardized values. The results of this systematic review and meta-analyses are reassuring. To further understand the health of the ART population, there is a need for longitudinal research on body composition among children and adults conceived through various ART methods including cryopreservation. REGISTRATION NUMBER: PROSPERO CRD42021257788.
Embryo metabolism as a novel non-invasive preimplantation test: nutrients turn over and metabolomic analysis of human spent embryo culture media (SECM).
Alizadeh Moghadam Masouleh A, Eftekhari-Yazdi P, Ebrahimi Sadrabadi A … +5 more , Jafarzadeh Esfehani R, Tobler M, Schuchardt S, Gianaroli L, Schmutzler A
Hum Reprod Update · 2025 Sep · PMID 40690766 · Publisher ↗
BACKGROUND: Single embryo transfer is globally recommended during IVF treatments. Hence, there is a growing demand for better embryo selection. Additionally, to morphology and genetics, nutrient uptake/release and metabo...
BACKGROUND: Single embryo transfer is globally recommended during IVF treatments. Hence, there is a growing demand for better embryo selection. Additionally, to morphology and genetics, nutrient uptake/release and metabolome profiles in spent embryo culture media (SECM) are proposed as non-invasive biomarkers. Are they ready to be applied for clinical purposes? OBJECTIVE AND RATIONALE: We reviewed methods of metabolism analysis for embryos, focusing on human SECM. SEARCH METHODS: Until November 2024, the Cochrane Library, PubMed, and Google Scholar were surfed for peer-reviewed English-language studies in the human, with MeSH terms and keywords: ART, IVF, ICSI, aneuploidy, embryo transfer, embryo selection, culture media, metabolome, metabolomics, metabolic profile, artificial intelligence (AI), nutrients, carbohydrates, glucose, pyruvate, lactate, amino acids (AAs), fatty acids (FAs), and spent embryo culture medium (SECM). Also, the reference lists of all relevant articles were searched. OUTCOMES: Forty-nine original publications (1989-2024) were found in which SECM samples were collected from 20 countries, focusing on preimplantation embryo metabolism single biomarker(s) of energy sources (glucose and pyruvate), AAs and free FAs (17 studies), or metabolomic analysis (32 studies). Focal points were blastocyst development, aneuploidy, embryo sex prediction, implantation, and pregnancy outcome. Eleven major companies, which supply embryo culture media, dominate the market. Nutrient composition of their culture media presents major challenges because they are not normally disclosed. In single-biomarker(s) studies, eight studies focus on glucose and pyruvate, eight on AAs, both alone and in combination with glucose or pyruvate, and their ratios. Since the absolute quantities of some AAs or glucose levels were reported in some studies, they all have the potential to become future biomarkers for clinical application. In metabolomics studies, almost all studies reported qualitative results, such as decrease/increase or the metabolite ratios. For absolute concentrations, the basal concentrations of the culture media must be considered. In sum, all differences in the experimental design, the platforms, and the results were analyzed. WIDER IMPLICATIONS: Establishing a unified guideline for the reporting of metabolomics studies and a specific guideline outlining the minimum information required for SECM experiment publication will ensure that future studies provide all necessary and critical information. The metabolomics studies primarily focused on implantation and pregnancy, whereas we, as a first step, preferred multi-omics studies on absolute concentrations of metabolites of good vs poor quality and euploid vs aneuploid embryos. Following this step, these quantitative approaches might lead to more convincing successes. If small numbers of predictive biomarkers were identified, a simple, rapid, and cheap test could be developed for each medium, clinically performed in the fertility center. Furthermore, further research on basal media ingredients is needed, combined with targeted metabolomics. The future could be an integration of all-primarily non-invasive-information, omics, and other, by AI. REGISTRATION NUMBER: The review protocol is registered on the OSF platform: https://osf.io/mxtbg.
Awareness and attitudes toward fertility preservation among healthcare providers: a scoping review of quantitative evidence.
Tirsina A, de Freitas C, Silva S
Hum Reprod Update · 2025 Sep · PMID 40580925 · Publisher ↗
BACKGROUND: The number of people who could benefit from fertility preservation is increasing. However, access to fertility preservation services has been hampered by a lack of awareness and misconceptions among healthcar...
BACKGROUND: The number of people who could benefit from fertility preservation is increasing. However, access to fertility preservation services has been hampered by a lack of awareness and misconceptions among healthcare providers (HCPs). There is a need for multifaceted educational programs that consider the perceptions and needs of HCPs. Systematic knowledge of the factors influencing the awareness and attitudes of HCPs toward the use of fertility preservation can help to identify the topics to be included in curricula and the specialties where these programs are most needed. OBJECTIVE AND RATIONALE: This comprehensive scoping review aims to synthesize quantitative evidence on the factors influencing the awareness and attitudes of HCPs toward fertility preservation, identifying the segments of HCPs (i.e. occupation groups and specialties) that are considered and the fertility preservation indications and topics assessed. SEARCH METHODS: The protocol and the scoping review were conducted according to the PRISMA Extension for Scoping Reviews (PRISMA-ScR): Checklist and Explanation. Literature searches were conducted in three databases: PubMed®, Web of Science™, and PsycINFO®. Original empirical, peer-reviewed, and full-length quantitative or mixed-methods articles concerning the awareness and attitudes of HCPs toward fertility preservation were included. Studies involving undergraduate students, interns, residents, and fellows were not considered, nor was qualitative data. The variables of interest were extracted using an individualized data charting tool, and an MS Excel spreadsheet was used to chart the data. OUTCOMES: The studies reviewed, comprising 54 quantitative studies and 6 mixed-methods studies, were primarily sourced from the USA, Asian countries (China, Japan, Turkey, India, Iran), and European countries (Netherlands, France, UK). The study participants were predominantly composed of specialist medical practitioners and/or nursing professionals with expertise in the fields of oncology, obstetrics and gynecology, and pediatrics. Almost all studies assessed the awareness and attitudes of HCPs toward fertility preservation in the context of oncologic diseases and oocyte freezing. The primary topics addressed in the literature are information needs and provision and the organization of care and practice. Additional topics include legal aspects, access and coverage, as well as fertility preservation interventions. The results suggested that awareness and attitudes of HCPs toward fertility preservation tended to be influenced by factors related to their professional trajectories (level of involvement in fertility preservation issues with peers and patients, number of patients treated, and advanced training), rather than their sociodemographic characteristics or perceptions of patient's characteristics. WIDER IMPLICATIONS: Further empirical research is required, including studies involving HCPs working in primary healthcare institutions and those specializing in psychosocial care, as well as studies into fertility preservation for reproductive aging and gender-transitioning reasons. It is necessary to invest in the provision of education regarding fertility preservation to a diverse range of HCPs, extending beyond specialist medical practitioners involved in oncology. The implementation of educational programs encompassing the legal aspects, access, coverage, and fertility preservation interventions could enhance awareness and attitudes of HCPs toward fertility preservation. Changes in policy and advocacy are needed to support better integration of fertility preservation as a tool for patients in their reproductive health journey. REGISTRATION NUMBER: osf.io/h56ds.
Building a human pluripotent stem cell-based gonadal niche: improving in vitro systems with in vivo insights.
Lakshmipathi M, Dartée N, Puchkina A … +7 more , Vaz Santos M, de Bruin IJ, Hamer G, van Pelt AMM, Chuva de Sousa Lopes SM, Mulder CL, Baarends WM
Hum Reprod Update · 2025 Nov · PMID 40580487 · Full text
BACKGROUND: The gonadal somatic niche is crucial for sex determination and gamete formation throughout the human life cycle. However, key steps in gonadal somatic lineage differentiation occur during embryonic and foetal...
BACKGROUND: The gonadal somatic niche is crucial for sex determination and gamete formation throughout the human life cycle. However, key steps in gonadal somatic lineage differentiation occur during embryonic and foetal development, making them difficult to study in humans. In vitro differentiation models are therefore needed to investigate gonadal development, support in vitro gametogenesis, and study infertility. A comprehensive overview of gonadal somatic niche differentiation, both in vivo and in vitro, is thus crucial. OBJECTIVE AND RATIONALE: This review connects in vivo knowledge with in vitro differentiation systems for gonadal somatic niches, predominantly focusing on cell-cell signalling factors. It evaluates existing in vitro protocols for differentiating testicular and ovarian somatic niches, discusses them in the context of in vivo findings, and explores potential advancements in model systems. SEARCH METHODS: A narrative review was conducted after a comprehensive search of the PubMed database through to February 2025; the review focused on search topics including: in vivo gonadal differentiation in humans and mice; in vitro differentiation of human embryonic stem cells or human-induced pluripotent stem cells into gonadal somatic cells (bipotential, Sertoli or granulosa cells); and evidence for the cell-cell signalling factors used in these protocols. OUTCOMES: We investigated various strategies that aim to differentiate human pluripotent stem cells into gonadal somatic cell lineages. These include sequential growth factor differentiation recapitulating all known developmental progenitor stages, directed growth factor differentiation that omitted one or more developmental intermediates, and directed overexpression of key transcription factors. To induce differentiation, the growth factor-based protocols used various cell-cell signalling factors, with some derived from in vivo studies, while others lacked direct in vivo evidence. Despite significant advances in guiding pluripotent stem cells towards gonadal differentiation, challenges remain, such as the limited molecular and functional validation of the generated cell types. Consequently, complete human in vitro gametogenesis through co-culture techniques with pluripotent cell-derived germ cells has not yet been achieved, indicating that full functional maturation of the gonadal niche has not been attained with the current protocols. WIDER IMPLICATIONS: Integrating knowledge on in vivo gonadal development with enhanced differentiation protocols offers the potential to reliably generate the gonadal somatic niche in vitro. This allows for more accurate modelling of the gonad, facilitating deeper insights into the normal and pathological processes involved in gonadal development and germ cell maturation. For example, it could help to identify mechanisms linked to infertility or differences of sex development. Importantly, as many of these models are based on human pluripotent stem cells, they have the potential for personalization, enabling future patient-specific models for studying reproductive disorders and developing tailored fertility treatments. REGISTRATION NUMBER: n/a.
Bias busters: using the right risk-of-bias tools.
van Wely M, Hastings JM, Tarlatzis BC … +1 more , Wang R
Hum Reprod Update · 2025 Sep · PMID 40574325 · Publisher ↗
Abstract loading — click title to view on PubMed.
Protein O-GlcNAcylation in reproductive biology and the impact of metabolic disease.
Scrivener AL, Westwood M, Ruane PT … +1 more , Aplin JD
Hum Reprod Update · 2025 Sep · PMID 40574323 · Full text
BACKGROUND: Protein O-GlcNAcylation is a reversible post-translational modification which regulates the function of thousands of proteins to control generic and cell type-specific actions. O-GlcNAc addition and removal d...
BACKGROUND: Protein O-GlcNAcylation is a reversible post-translational modification which regulates the function of thousands of proteins to control generic and cell type-specific actions. O-GlcNAc addition and removal downstream of the hexosamine biosynthetic pathway (HBP) is mediated by only two enzymes: O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively. Crucially, O-GlcNAcylation provides a regulatory layer to protein function that is responsive to metabolic status and thus metabolic disease impinges on this system. Animal and ex vivo models show that O-GlcNAcylation is important for peri-conceptual and pregnancy processes. OBJECTIVE AND RATIONALE: Fundamental knowledge about O-GlcNAcylation of proteins involved in reproductive processes is lacking. Here, we give relevant, and mechanistically well understood, examples of how protein O-GlcNAcylation can affect cellular processes and examine available data on germ cells, embryonic development, endometrial receptivity, and placentation. OGT and OGA regulation are placed within the wider context of reproductive biology. We also highlight gaps in knowledge and suggest avenues for next-phase research. SEARCH METHODS: PubMed and Google Scholar (2013-2024) were interrogated, including only publications in English. Search terms included: GlcNAc AND Oocyte, GlcNAc AND Sperm, GlcNAc AND Embryo, GlcNAc AND Cell Differentiation, GlcNAc AND Endometrium, GlcNAc AND Endometrial Receptivity, GlcNAc AND Placenta, GlcNAc AND diabetes, and GlcNAc AND obesity. OUTCOMES: Some evidence for the global impact of O-GlcNAcylation in maturation of oocytes and sperm, pre-implantation development, implantation, and placentation has been gathered by pharmacological inhibition and/or targeted mutagenesis of OGT and OGA. Blocking or inactivating OGT gives an embryonic lethal phenotype in most species. Mouse embryos can tolerate inactivation of OGA, but the offspring are growth-restricted and die postnatally. In general, HBP utilization in pre-implantation differs between species. This is likely to be the case in post-implantation development too, but it is already clear from stem cell biology that O-GlcNAcylation is important in the differentiation of most embryonic cell lineages including neurones, osteoclasts, enterocytes, and adipocytes. The identification of the progesterone receptor as an OGT target suggests important and widespread involvement of O-GlcNAcylation in reproductive processes. In the adult endometrium, protein O-GlcNAcylation decreases during decidualization, however, there is some evidence to suggest that O-GlcNAcylation of specific proteins promotes receptivity to the implanting embryo. In placenta, key aspects of development (e.g. angiogenesis) and function (e.g. transport, hormone production) are influenced by O-GlcNAcylation. Hyperglycaemia-induced changes in protein O-GlcNAcylation have negative impacts throughout reproductive systems and while there is less information on the consequences of lipid-mediated alterations to this post-translational modification, available evidence points to skewed protein O-GlcNAcylation contributing to impaired reproductive function in individuals living with obesity. WIDER IMPLICATIONS: This review highlights protein O-GlcNAcylation as a regulator of reproductive processes and identifies large knowledge gaps which must be filled to improve fundamental understanding. Targeting O-GlcNAcylation regulatory networks, including acceptor site mutagenesis, in defined cell populations of reproductive tissues will advance knowledge. The interface of O-GlcNAcylation with metabolic disease needs disentangling to determine how interventions to alleviate disease impact reproductive outcomes. REGISTRATION NUMBER: N/A.
Reproductive outcomes after letrozole stimulated versus artificial frozen-thawed embryo transfer cycles in women with PCOS and/or oligo-anovulation: a systematic review and meta-analysis.
Bülow NS, Wissing ML, Macklon N … +2 more , Pinborg A, Løssl K
Hum Reprod Update · 2025 Sep · PMID 40420416 · Publisher ↗
BACKGROUND: The global increase in frozen-thawed embryo transfer (FET) cycles has led to a critical evaluation of endometrial preparation methods. While various approaches such as natural or modified natural cycle FET, s...
BACKGROUND: The global increase in frozen-thawed embryo transfer (FET) cycles has led to a critical evaluation of endometrial preparation methods. While various approaches such as natural or modified natural cycle FET, stimulated FET by use of letrozole (LTZ) and/or gonadotrophins, and artificial cycle (AC) FET, are currently in clinical use, the optimal regimen remains unclear, particularly for women with oligo-anovulation or polycystic ovarian syndrome (PCOS). This systematic review and meta-analysis compares LTZ FET with AC FET regarding reproductive, obstetric, and neonatal outcomes in these populations. OBJECTIVE AND RATIONALE: The aim was to determine whether LTZ FET improves reproductive, obstetric, and neonatal outcomes compared to AC FET in women with ovulatory disorders and/or PCOS. SEARCH METHODS: A comprehensive search of MEDLINE, Cochrane, and ClinicalTrials.gov databases was conducted for studies until June 2024. Eligible studies included women with ovulatory disorders and/or PCOS, comparing LTZ FET to AC FET. Data extraction focused on the live birth rate (LBR), ongoing pregnancy rate, clinical pregnancy rate, pregnancy loss rate, hypertensive disorders of pregnancy (HDP), gestational diabetes mellitus (GDM), birth weight, small for gestational age (SGA), large for gestational age (LGA), and congenital malformations. OUTCOMES: The search identified 74 studies, and included 15 observational studies and two randomized controlled trials (RCTs) meeting the inclusion criteria; the studies encompassed a total of 8307 women treated with LTZ FET (±additional gonadotropin) and 16,940 women treated with AC FET. The meta-analysis comparing LTZ FET to AC FET demonstrated a modest yet statistically significant increase in the odds of LB (OR 1.37, 95% CI 1.21-1.56), corresponding to an 8% risk difference (95% CI 4%-11%). The one RCT that reported on LB yielded a similar LBR for LTZ FET and AC FET, thus did not support a better outcome after LTZ FET. Pregnancy losses, defined either as a loss following a positive serum hCG or following a clinical pregnancy, were compared between LTZ FET and AC FET. The meta-analysis indicated a reduction in the odds of PL with LTZ FET (OR 0.63, 95% CI 0.51-0.78). However, the two RCTs reporting this outcome exhibited high heterogeneity, introducing uncertainty of the result. LTZ FET was associated with lower risks of HDP (OR 0.70, 95% CI 0.58-0.84) and LGA (OR 0.75, 95% CI 0.67-0.85), but no significant differences were observed for GDM or SGA. For all outcomes, the certainty of evidence was low. WIDER IMPLICATIONS: LTZ FET may offer a modest improvement in reproductive outcomes and a lower risk of some obstetric complications compared to AC FET, particularly in women with oligo-anovulation. However, the quality of evidence remains low, and more well-designed RCTs are needed to confirm these findings. While awaiting further data, LTZ FET may be recommended as a viable alternative to AC FET for women with ovulatory disorders. REGISTRATION NUMBER: PROSPERO-CRD42023395117.
Spermatogonia: a unique stem cell orchestrating species-specific transition from pluripotency to sperm production.
Schlag F, Dion C, Sepulveda-Rincon LP … +2 more , Schlatt S, Sharma S
Hum Reprod Update · 2025 Sep · PMID 40407420 · Publisher ↗
BACKGROUND: Male germline stem cells are relevant for stem cell researchers but also for andrologists as they are crucial for testis function and initiation/maintenance of spermatogenesis. They are also considered a targ...
BACKGROUND: Male germline stem cells are relevant for stem cell researchers but also for andrologists as they are crucial for testis function and initiation/maintenance of spermatogenesis. They are also considered a target for fertility preservation in the male; e.g. germ cell transplantation or testicular grafting rely on spermatogonial stem cells (SSCs) and may soon become clinical tools to recover fertility. In the current review, we report new insights into genesis of spermatogonia, germline plasticity, and models of spermatogonial expansion. These insights and an array of novel cellular and molecular tools have provided great technological advances and new knowledge and therefore the field of SSCs needs an up-to-date review. OBJECTIVE: In this review, we focus on the male germline starting with pluripotent precursors and ending with sperm. The recent discoveries on mechanisms and cellular events involved in the derivation of SSCs are highlighted. We summarize all information on clonal expansion of SSCs in several species. We revisit old models and formulate novel models for the initial phases of spermatogenesis considering species-specific differences. Specifically, the human situation will be presented, informing the reader on many primate-specific features (i.e. the existence of self-renewing progenitors, limited premeiotic mitotic steps, and small clonal sizes). This review is important as the current view on spermatogonia in the human testis needs an update taking in novel and unexpected findings derived from studies using new technologies, such as microfluidics, single-cell analysis, and xenografting. These findings also require re-interpretations of previously published results and models for spermatogonial function. SEARCH METHODS: We used PubMed and other relevant databases to reveal all available information. Search terms were flexibly combined. Baseline search terms were: spermatogonia/testis/stem cell/mitotic expansion/clone/primate/human/spermatogenesis/meiotic entry/germ cell niche/sperm production/spermatogenic efficiency. OUTCOMES: Spermatogenesis in men relies on a stem cell system which is highly distinct from that of rodents. Derivation of spermatogonia from pluripotent precursors has been explored in approaches using embryonic stem cells and induced pluripotent stem cells leading to novel concepts which are highlighted. The testis is populated with five subpopulations of premeiotic germ cells with specific tasks and functions. We will specifically focus on these features in this review. Based on the internal or external stimuli received from the microenvironment through underlying signalling and regulatory networks, subpopulations may show diverse responses. The high plasticity and variable potency of spermatogonial populations may play an important and distinct role during normal or aberrant germline developments alike. SSC models are helpful tools to understand the rigorous checkpoints maintaining germline quality at pre-meiotic and meiotic stages. Evidence from calculated spermatogonial ratios for various species indicates that clonal expansion rates are slower in higher primates like macaques and humans. In contrast, clonal expansion takes place at a faster rate in small animals like rodents. The consequences of these species-specific differences in germline development are discussed. Further options for future clinical applications and new therapies are also discussed in this review. WIDER IMPLICATIONS: Our revised understanding of the SSCs and their somatic niches creates a novel view on the causes of male infertility and may open strategies not only for curative actions but also for fertility preservation and ex vivo strategies to generate spermatozoa.
Modeling the extension of ovarian function after therapeutic targeting of the primordial follicle reserve.
Johnson J, Emerson JW, Smith A … +4 more , Medina K, Telfer EE, Anderson RA, Lawley SD
Hum Reprod Update · 2025 Sep · PMID 40324778 · Full text
BACKGROUND: Women are increasingly choosing to delay childbirth, and those with low ovarian reserves indicative of primary ovarian insufficiency are at risk for sub- and infertility and also the early onset of menopause....
BACKGROUND: Women are increasingly choosing to delay childbirth, and those with low ovarian reserves indicative of primary ovarian insufficiency are at risk for sub- and infertility and also the early onset of menopause. Experimental strategies that promise to extend the duration of ovarian function in women are currently being developed. One strategy is to slow the rate of loss of existing primordial follicles (PFs), and a second is to increase, or 'boost', the number of autologous PFs in the human ovary. In both cases, the duration of ovarian function would be expected to be lengthened, and menopause would be delayed. This might be accompanied by an extended production of mature oocytes of sufficient quality to extend the fertile lifespan. OBJECTIVE AND RATIONALE: In this work, we consider how slowing physiological ovarian aging might improve the health and well-being of patients, and summarize the current state-of-the-art of approaches being developed. We then use mathematical modeling to determine how interventions are likely to influence the duration of ovarian function quantitatively. Finally, we consider efficacy benchmarks that should be achieved so that individuals will benefit, and propose criteria that could be used to monitor ongoing efficacy in different patients as these strategies are being validated. SEARCH METHODS: Current methods to estimate the size of the ovarian reserve and its relationship to the timing of the menopausal transition and menopause were compiled, and publications establishing methods designed to slow loss of the ovarian reserve or to deliver additional ovarian PFs to patients were identified. OUTCOMES: We review our current understanding of the consequences of reproductive aging in women, and compare different approaches that may extend ovarian function in women at risk for POI. We also provide modeling of primordial reserve decay in the presence of therapies that slow PF loss or boost PF numbers. An interactive online tool is provided that estimates how different interventions would impact the duration of ovarian function across the natural population. Modeling output shows that treatments that slow PF loss would need to be applied as early as possible and for many years to achieve significant delay of menopause. In contrast, treatments that add additional PFs should occur as late as possible relative to the onset of menopause. Combined approaches slowing ovarian reserve loss while also boosting numbers of (new) PFs would likely offer some additional benefits in delaying menopause. WIDER IMPLICATIONS: Extending ovarian function, and perhaps the fertile lifespan, is on the horizon for at least some patients. Modeling ovarian aging with and without such interventions complements and helps guide the clinical approaches that will achieve this goal. REGISTRATION NUMBER: Not applicable.
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