Hum. Reprod. Update [JOURNAL]
Sun
200 papers
Clinical outcomes and euploidy rates of embryos derived from zygotes with nonpronuclear (0PN) and monopronuclear (1PN) in IVF or ICSI cycles: a systematic review and meta-analysis.
Chan HW, Wang CC, Chan DYL
Hum Reprod Update · 2026 Jun · PMID 42242296 · Publisher ↗
BACKGROUND: During routine fertilization checks, the presence of two pronuclei (2PN) with two polar bodies is generally regarded as normal fertilization. Nonpronuclear (0PN) zygotes often suggest failed fertilization, bu...
BACKGROUND: During routine fertilization checks, the presence of two pronuclei (2PN) with two polar bodies is generally regarded as normal fertilization. Nonpronuclear (0PN) zygotes often suggest failed fertilization, but some do cleave and develop into viable embryos due to delayed appearances of pronuclei that were originally missed. Monopronuclear (1PN) zygotes may result from a lack of maternal or paternal pronuclei, fusion of pronuclei, or asynchronous appearance of pronuclei. These embryos may sometimes be transferred when no others are available. OBJECTIVE AND RATIONALE: Current evidence on the euploidy rates (ER) and clinical outcomes of embryos derived from 0PN and 1PN zygotes is discordant across publications, resulting in conflicting conclusions regarding whether they are suitable for transfer. This review aims to present an updated synthesis of current knowledge regarding the potential adverse outcomes associated with 0PN and 1PN embryo transfers and to identify important gaps that should be addressed in future studies. SEARCH METHODS: CENTRAL, Embase, Fertility and Sterility, MEDLINE, and PubMed databases were searched on 10 November 2025 using the keywords '0PN embryo' and '1PN embryo'. All types of studies, except case reports and reviews, were included if they compared 0PN/1PN with 2PN zygotes in women of any age undergoing IVF/ICSI cycles, followed by single embryo transfer (SET) and/or preimplantation genetic testing for aneuploidy (PGT-A). Pronuclear status was assessed 16-18 h post insemination. Only data from SET cycles were included for embryo transfer outcomes. OUTCOMES: Eleven studies reporting on 37 240 SET cycles and 27 195 biopsied blastocysts were included. Compared to 2PN embryos, those derived from 0PN zygotes showed no significant differences in live birth rate (LBR) (OR = 0.94, 95% CI = 0.83-1.06, P = 0.33, I2 = 2%), clinical pregnancy rate (CPR) (OR = 0.96, 95% CI = 0.85-1.08, P = 0.48, I2 = 0%), miscarriage rate (MR) (OR = 1.04, 95% CI = 0.84-1.29, P = 0.70, I2 = 0%), malformation rate (OR = 1.05, 95% CI = 0.45-2.45, P = 0.91, I2 = 0%), and ER (OR = 0.86, 95% CI = 0.50-1.48, P = 0.59, I2=63%). However 0PN-derived embryos had a significantly lower blastulation rate (OR = 0.34, 95% CI = 0.17-0.68, P = 0.002; I2 = 99%). Compared to 2PN, 1PN embryos showed a significantly lower LBR (OR = 0.83, 95% CI = 0.70-0.98, P = 0.03, I2 = 12%), CPR (OR = 0.81, 95% CI = 0.68-0.96, P = 0.01, I2 = 22%), and blastulation rate (OR = 0.26, 95% CI = 0.14-0.48, P < 0.001; I2 = 96%), but a similar MR (OR = 1.34, 95% CI = 0.76-2.37, P = 0.31, I2 = 67%), malformation rate (OR = 0.46, 95% CI = 0.16-1.32, P = 0.15, I2 = 0%), and ER (OR = 1.05, 95% CI = 0.70-1.58, P = 0.80, I2 = 66%). WIDER IMPLICATIONS: In the meta-analysis, both 0PN- and 1PN-derived embryos showed no significant differences in rates of euploidy, miscarriage, and malformations compared to 2PN-derived embryos. However, clinical pregnancy and LBRs were significantly lower for 1PN, but not 0PN, embryos than for 2PN embryos. These findings suggest that 0PN-, and possibly even 1PN-, derived embryos, especially those that have undergone PGT-A, may represent a viable source for embryo transfer in certain clinical settings, particularly in cases where 2PN embryos are limited or unavailable. REGISTRATION NUMBER: CRD42024546685.
Sperm mitochondrial DNA copy number: a marker of male fertility and reproductive success.
Sawant S, Mann JM, Pilsner JR
Hum Reprod Update · 2026 May · PMID 42172631 · Publisher ↗
BACKGROUND: Sperm mitochondrial DNA copy number (mtDNAcn) has emerged as a promising biomarker of sperm health, providing molecular insight beyond what is captured by standard semen analysis. Elevated sperm mtDNAcn has b...
BACKGROUND: Sperm mitochondrial DNA copy number (mtDNAcn) has emerged as a promising biomarker of sperm health, providing molecular insight beyond what is captured by standard semen analysis. Elevated sperm mtDNAcn has been consistently associated with lower sperm motility, concentration, and morphology, as well as prolonged time-to-pregnancy in natural conception and reduced fertilization potential in ART. OBJECTIVE AND RATIONALE: This review summarizes current evidence on the biological underpinnings of sperm mtDNAcn, including its regulation during spermatogenesis, the role of nuclear-encoded mitochondrial proteins such as TFAM (mitochondrial transcription factor A), and its potential epigenetic modulation through sperm DNA methylation. We evaluate general population and clinic-based studies linking sperm mtDNAcn to semen quality, couple fecundity, and early embryo development, while highlighting methodological considerations such as quantification techniques and somatic cell contamination. SEARCH METHODS: A literature search was conducted to identify human studies evaluating sperm mtDNAcn in relation to male fertility, semen quality, reproductive outcomes, and embryology outcomes, as well as experimental models investigating the underlying biological mechanisms of mtDNA regulation during spermatogenesis via TFAM up to 1 April 2026. Searches were performed in PubMed, Web of Science, and Scopus using combinations of keywords and Medical Subject Headings (MeSH), including sperm mitochondrial DNA copy number, mtDNAcn, male infertility, pregnancy outcomes, ART outcomes, semen quality, sperm epigenetics, TFAM, mitochondrial transcription factor A, and sperm mtDNA regulation. Reference lists of relevant reviews and primary articles were manually screened to identify additional studies. Eligible studies included observational epidemiologic studies, clinical cohort studies, and experimental investigations that quantified sperm mtDNAcn and examined associations with semen parameters, fertility outcomes, or sperm epigenetics. No restrictions were placed on geographic location, while only articles published in English were considered. OUTCOMES: Across 21 epidemiologic, experimental, and clinical studies, elevated sperm mtDNAcn has been consistently associated with reduced sperm quality and inconsistently associated with diminished couple-level reproductive potential. Higher mtDNAcn is associated with lower sperm concentration, total sperm count, motility, and normal morphology, as well as higher sperm DNA fragmentation and chromatin abnormalities. It has also been linked to reduced likelihood of pregnancy and poorer embryo quality. Emerging evidence indicates associations between sperm mtDNAcn and altered nuclear DNA methylation patterns, supporting a role for mitochondrial-nuclear crosstalk. Collectively, these findings position sperm mtDNAcn as a biologically informative and clinically relevant indicator of male reproductive health that may complement, or potentially enhance, traditional semen analysis in both research and clinical settings. WIDER IMPLICATIONS: Sperm mtDNAcn holds promise as a biomarker for male fertility assessment, yet its full clinical potential has not been yet to be realized. Establishing standardized measurement protocols across sperm fractions and laboratory platforms will be essential for enabling cross-study comparability and facilitating clinical translation. Large prospective studies are needed to define clinically meaningful thresholds and better characterize the relationship between mtDNAcn alterations and spermatogenic impairment. Intervention strategies targeting mtDNA biogenesis and depletion, including antioxidant strategies and mitochondria-directed pharmacotherapy, warrant further investigation in the context of male fertility and fecundity. Collectively, sperm mtDNAcn may serve as an adjunctive marker in the assessment of male reproductive health and may inform future precision medicine approaches. REGISTRATION NUMBER: N/A.
Embryo-derived extracellular vesicles and their potential as biomarkers for embryo quality during IVF: a systematic review.
Boom G, Jordan V, Chamley LW … +1 more , Cree L
Hum Reprod Update · 2026 May · PMID 42168775 · Publisher ↗
BACKGROUND: Over the past decade, extracellular vesicles (EVs) released from embryos have received increasing attention for their potential role in influencing embryo-maternal communication events during implantation. Se...
BACKGROUND: Over the past decade, extracellular vesicles (EVs) released from embryos have received increasing attention for their potential role in influencing embryo-maternal communication events during implantation. Several studies have explored the relationship between embryo-derived EVs and embryo developmental competence. To synthesize current insights, we conducted a systematic review of the literature, highlighting key findings and evaluating how embryo EV profiles relate to embryo developmental competence. OBJECTIVE AND RATIONALE: A systematic review was conducted in accordance with the PRISMA guidelines. The review intended to (i) synthesize the existing knowledge on embryo-derived EV concentration, size, and cargo and their association with embryo developmental competence in mammalian systems, (ii) propose recommendations for future research, and (iii) assess the potential impact of the current literature on embryo selection during IVF. SEARCH METHODS: A literature search was performed across five databases (MEDLINE, EMBASE, BIOSIS Previews, Web of Science, and Scopus), involving keywords 'Embryo' AND 'Extracellular vesicle'; many synonyms were included for each keyword along with map terms when available. The search was conducted on 14 January 2026. References were screened for additional relevant records. Abstract-only authors were contacted to determine whether full-text was available. The inclusion criteria were 'collection of culture media from embryos of any mammalian species and isolation and assessment of EVs from it'. Reasons for exclusion included: 'No collection of embryo culture media', 'No characterisation or assessment of EVs', 'Not embryo-derived EVs', and 'Review/Theory/Lacking primary data'. OUTCOMES: Our searches collected a total of 15 620 records; of these, 32 studies from 34 records were included in the systematic review. The included studies were divided into two groups: (i) studies of embryonic EV characteristics and (ii) studies that investigated the association of embryonic EV characteristics and embryo developmental competence, including embryo quality assessments based on morphology, ploidy, and pregnancy. Wide variations in embryo EV concentration and size were reported, largely due to differences in study designs. Overall, the quality of the existing literature ranged from low to moderate quality. Among the three human and eight bovine studies that examined the association of embryo EV concentration, size, and/or cargo with developmental competence, the certainty of the evidence for all outcomes was consistently very low. Studies often reported opposing directions of effects, whilst others showed no clear association. Inconsistencies in EV isolation techniques, timing of EV sampling, and methods for embryo quality assessments complicate efforts to assess whether embryonic EVs can be used as a reliable biomarker. WIDER IMPLICATIONS: Current evidence does not support the use of embryo EVs as biomarkers during IVF procedures. To enhance reproducibility and the production of high-quality studies, it is recommended that studies incorporate standardized approaches to EV isolation and characterization to align with best practices. In addition, the timing of EV sampling should be standardized, appropriate media controls used, and optimal measures of developmental competence, such as live birth, reported. Adherence to these recommendations will enable future studies to build constructively on the existing literature, with the possibility of informing clinical applications that improve patient outcomes. REGISTRATION NUMBER: https://doi.org/10.17605/OSF.IO/TPXVU.
Endometriosis and ovarian cancer: epidemiological evidence, molecular insights, and clinical decision-making.
Leone Roberti Maggiore U, Vignali M, Kvaskoff M … +5 more , Chiappa V, Somigliana E, Vercellini P, Raspagliesi F, Viganò P
Hum Reprod Update · 2026 May · PMID 42143676 · Publisher ↗
Endometriosis, particularly ovarian endometrioma, is associated with a 2-fold increased risk of ovarian cancer (OC), especially the clear cell and endometrioid subtypes. However, the absolute lifetime risk of OC in women...
Endometriosis, particularly ovarian endometrioma, is associated with a 2-fold increased risk of ovarian cancer (OC), especially the clear cell and endometrioid subtypes. However, the absolute lifetime risk of OC in women with endometriosis remains relatively low, estimated at 1.9%. This review provides a focused overview of the relationship between these two conditions, addressing epidemiologic data, molecular links, advances in diagnosis, and clinical management. Somatic mutations in ARID1A, PIK3CA, and KRAS are shared between endometriosis and certain OC subtypes, and the nature of the environment typical of ovarian endometriomas suggests a context-specific oncogenic journey. Although advances in imaging, like transvaginal ultrasound and MRI, have improved endometriosis diagnosis, these modalities remain unreliable for identifying malignant transformation. Biomarkers, including CA-125 and HE4, provide additional diagnostic information, although their low specificity limits their role in clinical practice. Hormonal therapies, particularly the long-term use of combined oral contraceptives (COCs), have proven to be highly effective in reducing OC risk in women with endometriosis. This protective effect persists for more than a decade after discontinuation and has been associated with a risk lower than that of the general population. In addition, COC use has been linked to further protective effects against endometrial and colorectal cancers, highlighting its potential value as a cancer prevention strategy, especially for high-risk groups. Surgical management, particularly the excision of ovarian endometriomas, may also confer protection against OC, although this must be balanced against the risks of recurrence and ovarian reserve loss, especially in younger women. Prophylactic salpingo-oophorectomy is recommended for women with known genetic predispositions, but is not routinely indicated for those with endometriosis alone. Emerging evidence highlights the need for personalized risk prediction models that incorporate genetic, clinical, and environmental factors to guide care. Long-term studies are required to assess the impact of conservative versus surgical management on OC risk and overall survival. This review emphasizes the importance of a multidisciplinary approach to the management of endometriosis in relation to OC risk. While the link between endometriosis and OC is well-established, treatment strategies must be tailored to balance cancer prevention, fertility preservation, and quality of life.
Maternal genetic variants associated with aneuploid conception: a narrative review.
Ha S, Liu W, Yuan P … +4 more , Yuan S, Cao C, Meng A, Chen H
Hum Reprod Update · 2026 May · PMID 42124334 · Publisher ↗
BACKGROUND: Human aneuploid conception, a leading cause of infertility, pregnancy loss, and congenital disorders (e.g. Down's syndrome), arises from errors in chromosome segregation during oocyte meiosis or embryonic mit...
BACKGROUND: Human aneuploid conception, a leading cause of infertility, pregnancy loss, and congenital disorders (e.g. Down's syndrome), arises from errors in chromosome segregation during oocyte meiosis or embryonic mitosis. While advanced maternal age is a well-established risk factor, significant inter-individual variation exists among younger women, suggesting a substantial role for maternal genetic determinants. OBJECTIVE AND RATIONALE: This review summarizes the identified maternal genetic variants associated with aneuploid conceptions and highlights directions for future research. SEARCH METHODS: We systematically searched PubMed, Embase, and the Cochrane Library (up to 12 January 2026), using key terms related to maternal genetics, genetic variants, aneuploidy, and pregnancy. Inclusion criteria were human studies, genetic confirmation of aneuploidy (in oocytes/embryos/products of conception/fetal cells), maternal variants (rare single-nucleotide variations, single-nucleotide polymorphisms, and small indels [≤50 bp]), and English-language publications. Exclusion criteria were non-human studies, structural/non-aneuploid numerical abnormalities, paternal factors, and conference abstracts. Extracted data items included study identifiers, population characteristics, variant details, detection methods, clinical phenotypes, type and origin of aneuploidy, pathogenicity or effect assessment, and gene inclusion in currently commercially available infertility next-generation sequencing (NGS) panels. Rare variants were classified per American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines, whereas common variants were evaluated based on effect estimates and functional validation. Study quality was appraised using a modified Newcastle-Ottawa Scale. Supplementary searches explored associations between the identified genes and a broader range of reproductive phenotypes. OUTCOMES: From 28 studies covering the broad clinical spectrum of aneuploid pregnancies (including embryo arrest, implantation failure, pregnancy loss, hydatidiform mole, and fetal aneuploidy), we identified maternal variants associated with aneuploid conceptions. These were functionally categorized into meiotic recombination, spindle dynamics, checkpoint enforcement, and the maternal-to-zygotic transition. Among them, variants in several genes are supported by higher-quality evidence, including likely pathogenic rare variants in KIF18A, ELL3, and CEP120, as well as common variants in PLK4 and CCDC66. Although some identified genes (HFM1, MCM9, MEI1, BUB1B, NLRP2, NLRP7, and TLE6) are included in commercial infertility NGS panels, their direct association with aneuploidy requires further validation. WIDER IMPLICATIONS: This review proposes that 'aneuploidy predisposition' constitutes a critical, mechanism-driven dimension for the genetic diagnosis of infertility, complementing phenotype-based frameworks. This approach would best serve women with unexplained infertility and a normal karyotype who have either a history of recurrent aneuploidy or heterogeneous reproductive phenotypes across different cycles. Adopting this perspective refines clinical genetic testing paradigms and underscores the need to prioritize artificial intelligence-enhanced clinico-genomic association studies and develop polygenic risk models integrated with clinical factors. PROSPERO REGISTRATION NUMBER: CRD42025636217.
Iron overload disorders in adults: a comprehensive review of gonadal function, reproductive, and sexual health.
Carlomagno F, Tenuta M, Sansone A … +6 more , Rastrelli G, Sciarra F, Cangiano B, Isidori AM, Gianfrilli D, Krausz C
Hum Reprod Update · 2026 May · PMID 42101252 · Publisher ↗
BACKGROUND: Iron overload (IO) disorders, including thalassaemias, hereditary haemochromatosis, and transfusion-dependent anaemias, represent a growing clinical challenge with widespread systemic implications. Reproducti...
BACKGROUND: Iron overload (IO) disorders, including thalassaemias, hereditary haemochromatosis, and transfusion-dependent anaemias, represent a growing clinical challenge with widespread systemic implications. Reproductive dysfunction remains severely underappreciated despite its high prevalence. Hormonal changes due to iron toxicity are frequently reported, yet are seldom the focus of reproductive medicine, causing fragmented knowledge, inconsistent clinical approaches, and a lack of consensus guidelines. OBJECTIVE AND RATIONALE: This review synthesizes evidence on the impact of IO on male and female reproductive function, including gonadal dysfunction, impaired fertility, sexual dysfunction, and endocrine-metabolic complications. By addressing gaps in study design, diagnostic criteria, and management, we aim to provide the first comprehensive, expert-driven synthesis on the topic, integrating clinical, translational, and mechanistic insights to establish a structured framework for future research and patient care. SEARCH METHODS: A systematic literature search was conducted across PubMed, Scopus, and Web of Science, including studies up to May 2025. Search terms included 'iron overload', 'thalassemia', 'hemochromatosis', 'hypogonadism', 'fertility', 'spermatogenesis', 'ovarian insufficiency', and 'pregnancy'. Quantitative synthesis involved pooling data on prevalence rates of hypogonadism, semen abnormalities, primary and secondary amenorrhoea, age at menarche, and pregnancy outcomes. OUTCOMES: Gonadal dysfunction primarily arises from iron deposition within the hypothalamic-pituitary-gonadal axis, coupled with oxidative damage to Leydig and Sertoli cells in males, disrupting testosterone synthesis and spermatogenesis, and to ovarian follicles and granulosa cells in females, causing reduced ovarian reserve and altered hormonal signalling. Iron-induced hypogonadism is the most frequent endocrine complication, significantly impacting reproductive health and quality of life. Our analysis of 1201 men and 2134 women indicated hypogonadism, reflecting impaired testicular endocrine function, in 47.0% of men; among those specifically assessed for spermatogenesis, over half presented azoospermia (17.6%) or other sperm abnormalities (37.5%). In women, primary amenorrhoea was reported in 45.7%, secondary amenorrhoea in 20.0%, and the weighted mean age at menarche was delayed (14.4 ± 2.1 years). Sexual dysfunction, notably erectile dysfunction, commonly accompanies hypogonadism, further impairing quality of life. Female sexual health has not been investigated at all. Pregnancy is increasingly achievable, but remains clinically challenging. Across 3536 reviewed pregnancies, ART was required in ∼20%, miscarriage occurred in 11.2%, and caesarean section was used in ∼80%. Mean gestational age at delivery was 37.1 ± 3.1 weeks, and mean birth weight was 2.64 ± 0.68 kg. Besides gonadal damage (direct or pituitary-related), systemic iron-related endocrine and metabolic disturbances, including hypothyroidism, growth hormone deficiency, diabetes mellitus, and cardiovascular disease, further aggravate reproductive impairments. Although effective iron chelation therapy reduces the systemic iron burden and is effective in preventing endocrine complications when initiated early, evidence supporting the reversal of established reproductive dysfunction remains limited, highlighting the need to optimize iron control from a young age to preserve reproductive health. WIDER IMPLICATIONS: This review underscores the critical need for standardized gonadal screening to facilitate personalized reproductive care and early intervention in subjects with IO disorders. We propose an integrated clinical framework, combining early endocrine monitoring, fertility preservation protocols, and reproductive counselling. Future multidisciplinary research should prioritize prospective studies with clearly defined reproductive endpoints and explore optimized chelation strategies to safeguard reproductive potential. Addressing these gaps will fundamentally reshape clinical management, bridging haematology, endocrinology, and reproductive medicine.
Intrauterine human chorionic gonadotropin administration before embryo transfer (IHABT): an individual participant data meta-analysis of randomized controlled trials.
Zou H, Abdallah KS, Wirleitner B … +14 more , Hong KH, Thanaboonyawat I, Laokirkkiat P, Hafezi M, Kokeguchi S, Makhlouf A, Libesman S, Nguyen D, Williams JG, Showell M, Gadalla M, Mol BWJ, Li W, Wang R
Hum Reprod Update · 2026 Jul · PMID 41990228 · Full text
BACKGROUND: Intrauterine administration of hCG has been considered as a promising IVF add-on before embryo transfer to improve fertility outcomes. A Cochrane review and four more recent systematic reviews all showed impr...
BACKGROUND: Intrauterine administration of hCG has been considered as a promising IVF add-on before embryo transfer to improve fertility outcomes. A Cochrane review and four more recent systematic reviews all showed improved clinical pregnancy rates and/or live birth rates following intrauterine administration of hCG, however, a high unexplained heterogeneity was also present. OBJECTIVE AND RATIONALE: To investigate the effectiveness and safety of intrauterine administration of hCG before embryo transfer in participants undergoing IVF. Individual participant data meta-analysis (IPD-MA) is recognized as the gold standard for evidence synthesis due to its ability to harmonize the data and to investigate treatment-covariate interactions. In addition, with recent experiences of guideline development and systematic review production raising increasing concerns about the trustworthiness of randomized controlled trials (RCTs) in women's health research, an IPD-MA provides a unique opportunity to summarize the best available and most trustworthy evidence on this topic. SEARCH METHODS: We searched MEDLINE, Embase, Cochrane Gynaecology and Fertility Group Specialised Register, Cochrane Central Register of Controlled Trials, PsycINFO, and clinical trial registries without language restrictions up to January 2026. Inclusion criteria included RCTs comparing intrauterine administration of hCG before embryo transfer versus placebo or no intervention in participants undergoing IVF. The IPD Integrity tool and the TRACT checklist were used to evaluate the trustworthiness of studies with and without IPD, respectively. Both one-stage and two-stage random-effect IPD meta-analyses were performed with one-stage being the primary analysis. OUTCOMES: We detected 28 RCTs, of which 7 RCTs with IPD involving 2244 participants were included. All seven RCTs with IPD met trustworthiness criteria and six RCTs had overall low risk of bias. All RCTs without IPD did not meet trustworthiness criteria. IPD-MA showed intrauterine administration of hCG before embryo transfer did not improve live birth rates (7 RCTs, 2244 participants, odds ratio [OR] 0.99, 95% CI 0.83-1.19) or clinical pregnancy rates (7 RCTs, 2244 participants, OR 1.04, 95% CI 0.83-1.31). Studies without IPD showed different results from those with IPD for live birth (1.99, 0.72-5.50, P for interaction <0.001) and clinical pregnancy (1.87 (1.48-2.35), 17 RCTs without IPD, 3152 participants, P for interaction 0.005). WIDER IMPLICATIONS: Our IPD-MA has shown that intrauterine administration of hCG before embryo transfer is unlikely to improve the chance of clinical pregnancy and live birth. In the comparison between studies with IPD and without IPD, we found that none of the RCTs without IPD met trustworthiness criteria but showed a significant improvement in clinical pregnancy. We therefore suggest that intrauterine administration of hCG should not be offered as an IVF add-on in practice. REGISTRATION NUMBER: PROSPERO (CRD42020177397).
The risk for the development of hypertensive complications in oocyte donation pregnancy: a systematic review and individual participant data meta-analysis (DONOR IPD).
van Bentem K, van der Hoorn ML, Banker M … +17 more , de la Calle M, Elenis E, El Demellawy D, Fox NS, Jeve Y, Korb D, Letur H, Yinon Y, Farina A, Rizzello F, Rodriguez-Wallberg KA, Simchen M, Simeone S, Tarlatzi T, Giannubilo SR, Le Cessie S, Lashley E
Hum Reprod Update · 2026 Jul · PMID 41915703 · Full text
BACKGROUND: Oocyte donation (OD) is an established ART involving an oocyte donor and recipient with a rising number of treatments. Previous meta-analyses highlight increased risks of hypertensive complications compared t...
BACKGROUND: Oocyte donation (OD) is an established ART involving an oocyte donor and recipient with a rising number of treatments. Previous meta-analyses highlight increased risks of hypertensive complications compared to naturally conceived (NC) and IVF/ICSI pregnancies, including pregnancy-induced hypertension (PIH) and preeclampsia (PE), but limitations exist due to study quality and heterogeneity. OBJECTIVE AND RATIONALE: The DONOR (DONation of Oocytes in Reproduction) individual participant data (IPD) meta-analysis aims to generate clinically relevant and robust evidence regarding the development of hypertensive complications in OD pregnancies compared to autologous pregnancies. IPD meta-analyses offer an advantage over current meta-analyses, as bias is reduced by using IPD of original studies, allowing reliability checks, correction for confounders, and examining causes of heterogeneity by subgroup analyses. Furthermore, using IPD increases statistical power and generalizability of results. SEARCH METHODS: A literature search was conducted using PubMed, EMBASE, and Cochrane up to March 2024, with a last update performed in February 2025. We included observational studies that compared a cohort of women pregnant after OD beyond 20 weeks of gestation with an autologous pregnancy cohort (NC or IVF/ICSI), and reported on hypertensive pregnancy complications. Risk of bias was assessed using the ROBINS-I tool. Authors of eligible articles were invited to share IPD. The DONOR IPD meta-analyses were executed using both a one- and two-stage approach, adjusted for maternal age, parity, and multiple gestation. Furthermore, sensitivity, meta-regression and subgroup analysis were performed. OUTCOMES: IPD was requested for 48 cohorts, and provided from 16 cohorts with data of 2747 OD, 4699 IVF/ICSI, and 33 323 NC pregnancies. The one- and two-stage approach comparing OD to autologous pregnancies showed adjusted ORs of respectively 2.62 (95% CI 2.22-3.10) and 2.85 (95% CI 2.30-3.54; I2 44%; moderate certainty) for hypertensive complications in total, 2.15 (95% CI 1.73-2.68) and 1.49 (95% CI 0.80-2.80; I2 74%; low certainty) for PIH, and 2.28 (95% CI 1.88-2.78) and 2.39 (95% CI 1.94-2.94; I2 0%; high certainty) for PE. When the autologous group was split into NC and IVF/ICSI pregnancies, higher risks for hypertensive complications, including PIH and PE, persisted in the OD group. The results of the IPD meta-analyses for HELLP syndrome show a higher risk in OD pregnancy, though with a broad 95% CI. Sensitivity meta-analyses for risk of bias showed comparable results. Subgroup analyses indicated increased risks for hypertensive complications in OD pregnancy, regardless of maternal age, BMI, multiple pregnancy, parity, ethnicity, medical history, and number of transferred embryos. A potential lower risk for hypertensive complications was found when acetylsalicylic acid or heparin is used during OD pregnancy compared to both autologous and NC pregnancy. WIDER IMPLICATIONS: The DONOR IPD meta-analysis provided a unique opportunity to assess the risk for hypertensive complications in OD compared to autologous pregnancy. The results must increase alertness of health care professionals who are involved in OD health care towards the risk profile of these pregnancies, as the DONOR IPD meta-analysis results in the best evidence-based statement for international guidelines in obstetrics to date. Possibly, preventive treatment with low-dose acetylsalicylic acid is successful in lowering the risk for hypertensive complications, though more evidence is needed to confirm this effect, alongside the underlying pathological mechanism. REGISTRATION NUMBER: CRD42021267908.
Molecular interplay between sperm and oocyte: a narrative review.
Chang HY, Gierke T, Tang S … +1 more , Lu Y
Hum Reprod Update · 2026 Jul · PMID 41884958 · Full text
BACKGROUND: Fertilization ensures the transmission of genetic material across generations through a series of precisely coordinated physiological and molecular events. To fertilize an oocyte, a spermatozoon must pass thr...
BACKGROUND: Fertilization ensures the transmission of genetic material across generations through a series of precisely coordinated physiological and molecular events. To fertilize an oocyte, a spermatozoon must pass through the cumulus cell layer, penetrate the zona pellucida (ZP), and ultimately adhere to and fuse with the oolemma (the oocyte plasma membrane). Upon fusion, the oocyte initiates mechanisms to block additional sperm entry at both the ZP and oolemma. These processes are highly dynamic in space and time, posing substantial technical barriers to their mechanistic dissection. Nonetheless, recent in silico, in vitro, and in vivo studies have begun to elucidate how intricate networks of intracellular signaling cascades and extracellular protein-protein interactions orchestrate successful fertilization in vertebrates. However, the extent to which these findings accurately reflect the biology of human sperm-oocyte interactions remains obscure, owing to ethical constraints on human gamete experimentation and the limited availability of patients harboring pathogenic variants in fertilization-related genes. OBJECTIVE AND RATIONALE: This narrative review synthesizes current knowledge of the molecular determinants governing mammalian sperm-oocyte interactions, summarizes relevant genetic anomalies identified in infertile patients, and discusses emerging experimental approaches for the direct investigation of human fertilization. We also explore how recent mechanistic insights and technological innovations may inform the diagnosis and treatment of fertilization disorders and guide the development of novel contraceptive strategies. SEARCH METHODS: We searched PubMed, Google Scholar, and Scopus to identify research and review articles published in English. Studies limited to non-mammalian species and non-peer-reviewed preprints were excluded. Searches used terms related to fertilization, sperm-oocyte interactions, ZP, cumulus cells, polyspermy block, and human infertility, alone or in combination. Additional searches targeted key proteins and emerging technologies relevant to mammalian fertilization, clinical diagnostics, and contraceptive development. OUTCOMES: Our mechanistic understanding of mammalian gamete interactions has predominantly stemmed from in vitro and in vivo animal studies, which have revealed key molecular processes, such as sperm hyaluronidase-mediated cumulus matrix dispersal, translocation of sperm acrosomal membrane proteins to enable oolemma interaction, and ZP glycoprotein cleavage underlying the polyspermy block. While studies in model species remain indispensable, translating this knowledge to human biology requires meticulous validation. The integration of interdisciplinary approaches, such as humanized mouse models, artificial human oocytes, xenospecies fertilization assays, antibody inhibition studies, and high-throughput interactome screening, offers promising avenues to clarify interspecies discrepancies and generate insights more directly relevant to human gamete interactions. WIDER IMPLICATIONS: Advances in the mechanistic dissection of sperm-oocyte interactions are anticipated to support the development of diagnostic tools and therapeutic interventions for infertility caused by defective fertilization. In parallel, these discoveries may enable the rational design of safe, reversible contraceptives that selectively block gamete interactions without compromising other physiological processes. REGISTRATION NUMBER: N/A.
What do we mean by preconception health and preconception care in research and policy? A systematic review.
Chingara O, Sümegi A, Logan S … +2 more , Bhattacharya S, Woolner A
Hum Reprod Update · 2026 Jul · PMID 41784999 · Full text
BACKGROUND: Preconception health (PCH) is a globally accepted strategy to reduce preventable adverse pregnancy outcomes and ultimately improve the health of the unborn child. Optimal PCH can be achieved through preconcep...
BACKGROUND: Preconception health (PCH) is a globally accepted strategy to reduce preventable adverse pregnancy outcomes and ultimately improve the health of the unborn child. Optimal PCH can be achieved through preconception care (PCC), which encompasses the behavioural, biomedical, and social interventions women and couples undertake and/or receive before conception. However, there is a lack of clarity on various aspects of PCH and PCC, such as what constitutes preconception risk factors, what the optimal interventions are, when the preconception period is, and who the overall target population is. Additionally, marginalised groups such as sexual and racial or ethnic minority individuals are routinely excluded from PCH research and PCC interventions. PCH and PCC are topical issues given changing societal norms worldwide, such as delayed childbirth, exponential rises in fertility treatments, and the growing trend of unplanned pregnancies. We hypothesised that the ambiguity surrounding the definition of PCH and PCC may limit their understanding and application to improve pregnancy and childhood outcomes. OBJECTIVE AND RATIONALE: This is a systematic review of existing definitions of PCH and PCC to understand the commonalities and disparities in definitions and critical components of PCH and PCC, to aid in the development of a comprehensive and globally standardised definition. SEARCH METHODS: MEDLINE, PubMed, EMBASE, Cochrane Library, CINAHL, Google Scholar, PsychINFO, and Google were searched to identify published studies, guidelines, and public health websites containing definitions of PCH and PCC published between January 1993 and October 2024. No restrictions were placed on language. We searched academic databases, organisational reports, and policy documents to capture the full range of definitions across clinical, health, and policy contexts. OUTCOMES: The narrative synthesis of 176 publications showed heterogeneity in the definitions of PCH and PCC. The themes developed from the thematic analysis showed that PCC is preventative care which identifies and utilises interventions to manage individuals' preconception risk factors and aims to improve pregnancy outcomes by optimising the short- and long-term health of potential parents and their children. The analysis also showed that PCH is relevant across the entire reproductive lifespan. PCC was described as a continuum of care that occurs before conception and encompasses the health of all potential parents, not just women. WIDER IMPLICATIONS: This systematic review found there is a lack of universality in the definitions of PCH and PCC. Current definitions often narrowly focus on women planning pregnancy, which may exclude important demographics such as unintended pregnancies and fathers, and aligned health needs such as contraception in the preconception period. We propose that there is a need for a definition that captures various demographics and emphasises a life-course approach to reproductive health, acknowledging that the preconception period is much wider than only the period in which couples are actively trying to conceive. Congruence between policymakers, researchers, and public health professionals on the definition of PCH and PCC may address research operationalisation and clinical implementation to better assess global uptake and impact. REGISTRATION NUMBER: CRD42023480536.
Seminal plasma cytokines in fertile versus infertile men: a systematic review and meta-analysis.
Lyons HE, Arriaran Scott CN, Robertson SA … +1 more , Sharkey DJ
Hum Reprod Update · 2026 Jul · PMID 41725605 · Full text
BACKGROUND: Male fertility investigation is currently limited to semen analysis. However, the origins of abnormal sperm parameters are not well-understood, and normal sperm do not assure fertility in men. Improved pathop...
BACKGROUND: Male fertility investigation is currently limited to semen analysis. However, the origins of abnormal sperm parameters are not well-understood, and normal sperm do not assure fertility in men. Improved pathophysiological and prognostic insight might be achieved utilising additional measures of male reproductive tract function. Cytokine and chemokine levels in seminal plasma (SP) may be relevant, but evidence on their clinical significance is unclear. The utility of measuring SP cytokines remains uncertain, and no consensus exists on which cytokines are most informative. OBJECTIVE AND RATIONALE: To perform a systematic review and meta-analysis on the association between fertility status and concentration of seminal plasma cytokines in men. The sixth edition of the WHO laboratory manual for the examination and processing of human semen raises the prospect of evaluating cytokines in SP as part of an extended examination. We performed a systematic search and meta-analysis to assess whether the current literature is sufficient to identify cytokines present in human SP that exhibit a relationship with fertility status in men. SEARCH METHODS: We searched PubMed, Web of Science, Scopus, and Embase from inception until April 2025, using keywords pertaining to seminal fluid and cytokines, restricted to humans and the English language. Original data with values reported as concentration of cytokines in SP of men clearly defined as infertile, compared to a discernible population of fertile/normozoospermic healthy control men, were included. A total of 5737 studies were identified, with 2737 duplicates removed. Title and abstract screening were performed for 3000 studies, then 291 studies underwent full-text screening, and 68 studies progressed to quality assessment using the NHLBI-NIH quality assessment tool and 52 studies underwent data extraction. OUTCOMES: We identified 52 research articles published from 1993 to 2025 that quantified at least one cytokine in the seminal plasma of 8153 men, after 19 studies of poor quality and/or containing serious flaws were excluded. Data on 30 cytokines in the SP of healthy control and infertile men were extracted and included in narrative synthesis. Compared to fertile controls, infertile men had elevated concentrations of IL6 (SMD 0.39, 95% CI; 0.14-0.64, I2 = 80.7%), TNFA (SMD 0.13, 95% CI; 0.00-0.25, I2 = 4.3%), and CXCL8 (SMD 0.24, 95% CI; 0.06-0.43, I2 = 0.0%) in seminal plasma. IL6 reported a high degree of heterogeneity between studies, whilst CXCL8 and TNFA reported low heterogeneity. No significant moderator effects due to study quality or composition of the control cohort were identified. WIDER IMPLICATIONS: With one in six couples experiencing infertility worldwide and a male factor identified as a primary or contributing cause in up to 50% of cases, there is a strong imperative to develop a better understanding of the pathophysiology of male infertility. This analysis identifies an association between infertility and elevated SP IL6, CXCL8, and TNFA, but whether these pro-inflammatory cytokines reflect events affecting fertility or are simply markers of transient inflammation and/or cofactors of fertility status remains to be determined. Greater precision in quantifying seminal plasma cytokines will be attained, and additional informative cytokines may be identified, by utilising standardised technical approaches in future studies. REGISTRATION NUMBER: CRD42023398438.
Making narrative review abstracts count.
van Wely M
Hum Reprod Update · 2026 May · PMID 41721715 · Publisher ↗
Abstract loading — click title to view on PubMed.
The placental tryptophan pathway across gestation: implications for pregnancy outcomes.
Karahoda R, Walker D, Abad C … +3 more , Anandam KY, Murthi P, Staud F
Hum Reprod Update · 2026 May · PMID 41712283 · Full text
BACKGROUND: Tryptophan metabolism within the placenta generates bioactive metabolites, including serotonin (5-hydroxytryptamine; 5-HT), melatonin, and kynurenine derivatives, that regulate immune tolerance, vascular func...
BACKGROUND: Tryptophan metabolism within the placenta generates bioactive metabolites, including serotonin (5-hydroxytryptamine; 5-HT), melatonin, and kynurenine derivatives, that regulate immune tolerance, vascular function, oxidative balance, and fetal neurodevelopment. Increasing evidence indicates that placental handling of tryptophan is dynamically regulated across gestation and is highly sensitive to maternal environmental and metabolic cues. OBJECTIVE AND RATIONALE: The aim of this review is to examine placental tryptophan metabolism across gestation, with a focus on the 5-HT, melatonin, and kynurenine pathways. We address how these pathways are regulated during normal pregnancy and how maternal factors, including inflammation, hypoxia, oxidative stress, and cardiometabolic dysfunction, influence placental tryptophan handling in pregnancy complications such as early pregnancy loss, preeclampsia, fetal growth restriction, and preterm birth. SEARCH METHODS: PubMed was searched using predefined terms related to placental tryptophan metabolism, 5-HT, melatonin, kynurenine, fetal programming, neurodevelopment, and pregnancy complications. Only full-text, peer-reviewed articles published in English were included. Abstracts and conference proceedings were excluded due to their limited data reliability. OUTCOMES: Placental tryptophan metabolism shows clear gestational stage-dependent regulation, and early pregnancy emerges as a formative period when pathway activity and metabolite balance are first established. From early pregnancy, maternal-decidual kynurenine pathway activity and placental 5-HT synthesis intersect with immune tolerance, vascular adaptation, and neurodevelopmental signaling. Across gestation, maternal inflammation, hypoxia, oxidative stress, and cardiometabolic disturbance can redirect the tryptophan flux and shift the balance between 5-HT/melatonin and downstream kynurenine metabolites. Evidence across pregnancy complications links early pathway disruption to pregnancy loss and supports the view that early metabolic perturbations contribute to vulnerability for later placental dysfunction, including preeclampsia, fetal growth restriction, and preterm birth. WIDER IMPLICATIONS: Placental tryptophan metabolism changes across gestation, making early pregnancy a critical window when pathway balance and fetal exposure to neuroactive metabolites are first set. Maternal inflammation, metabolic status, nutrition, and drug exposures may alter this balance, with the placenta acting as the key interface that transmits maternal signals to the fetus and shapes neurodevelopmental trajectories. To define the clinical relevance of altered tryptophan catabolism, longitudinal human studies are needed to link placental phenotypes with pregnancy outcomes and postnatal neurodevelopment. These should be complemented by mechanistic models that resolve regulation in early gestation. REGISTRATION NUMBER: n/a.
Revisiting natural cycle frozen embryo transfer: a systematic review and meta-analysis.
Erden M, Mumusoglu S, Uyanik E … +4 more , Yarali Ozbek I, Esteves SC, Humaidan P, Yarali H
Hum Reprod Update · 2026 Jul · PMID 41689846 · Publisher ↗
BACKGROUND: The optimal endometrial preparation protocol for frozen embryo transfer (FET) remains a subject of ongoing investigation. HRT is the most commonly used approach, but natural cycle (NC) FET has regained attent...
BACKGROUND: The optimal endometrial preparation protocol for frozen embryo transfer (FET) remains a subject of ongoing investigation. HRT is the most commonly used approach, but natural cycle (NC) FET has regained attention due to potential improvements in maternal and perinatal outcomes. Despite growing observational evidence supporting NC FET, its adoption is limited by logistical challenges in cycle monitoring and scheduling. Recently, the natural proliferative phase (NPP) FET protocol has been introduced, combining the physiological benefits of a functional corpus luteum with greater scheduling flexibility. OBJECTIVE AND RATIONALE: Previous systematic reviews have largely focused on luteal phase support (LPS) or have provided narrative summaries susceptible to selection bias. This systematic review aimed to evaluate the impact of different execution strategies on reproductive outcomes across true-NC and modified-NC and to compare NPP FET with other protocols. SEARCH METHODS: A comprehensive search of MEDLINE, Embase, Global Health, and Cochrane Library was conducted from database inception to 10 November 2024. The search included keywords such as 'frozen embryo transfer', 'natural cycle', 'pregnancy', 'live birth', and 'delivery' with no language or filter restrictions. Reference lists of included studies were screened to identify additional relevant studies. OUTCOMES: A total of 70 studies were included: 8 randomized controlled trials (1 with low risk of bias and 7 with some concerns), 16 non-randomized interventional studies (with risk of bias being moderate for 4, serious for 6, and critical for another 6), and 46 observational studies (80.4% of which were good quality) assessing prognostic factors. In true-NC FET, prolonged follicular phases did not adversely affect outcomes. Ovulatory cycles were associated with significantly higher live birth rates (LBRs) than cycles with luteinized unruptured follicle (risk ratio (RR): 1.16, 95% CI: 1.04-1.29, I2 = 0%, three studies, 2907 cycles, very low-certainty evidence). Despite variability in ovulation timing methods, performing FET on serum LH surge +6 to +7 days yielded comparable reproductive outcomes. In modified-NC FET, two observational studies reported similar LBRs when triggering ovulation at follicle diameters between 13 and 22 mm, provided the endometrial thickness was >7 mm and serum progesterone was below 1.5 ng/ml. LPS with vaginal progesterone improved LBRs in true-NC compared to no LPS (RR: 1.43, 95% CI: 1.16-1.78, I2 = 0%, 923 cycles, two studies, moderate-certainty evidence), but showed no benefit in modified-NC FET (RR: 1.04, 95% CI: 0.82-1.32, I2 = 0%, 667 cycles, two studies, moderate-certainty evidence). In NPP FET, a meta-analysis showed higher LBRs compared to HRT FET (RR: 1.25, 95% CI: 1.13-1.38, I2 = 5.36%, 3397 cycles, three studies, very low-certainty evidence). WIDER IMPLICATIONS: NC FET protocols are associated with operational constraints. Modified-NC and NPP strategies may balance physiological benefits with scheduling convenience, though high-quality evidence remains limited. Routine LPS improves LBRs in true-NC FET but not in modified-NC. The apparent equivalence of outcomes when hCG is administered across a follicle size range of 13-22 mm suggests a potential 7-day window of scheduling flexibility for modified-NC FET; however, this finding warrants further validation. NPP FET may offer enhanced scheduling convenience without compromising reproductive outcomes, but warrants additional investigation through high-quality trials. REGISTRATION NUMBER: PROSPERO: CRD42023385304.
Advantages, limitations, and innovative considerations for established and emerging models of human placental syncytiotrophoblast.
Fisher JJ, Williams A, Soheilmoghaddam F … +1 more , Kafer GR
Hum Reprod Update · 2026 May · PMID 41589863 · Full text
BACKGROUND: Understanding the mechanisms that promote or hinder healthy placental development and functionality is fundamental to advancing the field of fetal and reproductive medicine. Syncytiotrophoblast (STB) are high...
BACKGROUND: Understanding the mechanisms that promote or hinder healthy placental development and functionality is fundamental to advancing the field of fetal and reproductive medicine. Syncytiotrophoblast (STB) are highly specialized trophoblast which develop and gain functional maturity during the first trimester of pregnancy. STB are critical to many placental functions and are often implicated in the etiology of placental pathologies. Recent advancements in cell biology have facilitated the development of innovative in vitro STB model systems. However, as the variety of available in vitro STB models grows, a critical assessment of the strengths, limitations, and appropriate applications of both established and emerging model systems is important for the field. OBJECTIVE AND RATIONALE: With this review, we set out to compile and synthesize current knowledge on in vitro modeling of STB. Using this information, we sought to develop a balanced and thoughtful discussion regarding the use and suitability of various in vitro STB models. Our approach is grounded in a framework that considers placental development and physiology, with a specific focus on the capability of different models to recapitulate and thus enable the study of human STB differentiation, development, function, and dysfunction. SEARCH METHOD: This review assessed published literature sourced through the PubMed database. Search terms included 'human placenta models,' 'syncytiotrophoblast models,' 'syncytiotrophoblast development,' 'trophoblast stem cells,' 'trophoblast organoids,' and 'trophoblast cell models.' The literature search was limited to English-language publications available up to August 2025. OUTCOMES: We provide a narrative which explores the features, potential applications, and limitations of various STB models, including explant systems, immortalized trophoblast cell lines, stem cell-derived trophoblast, and a range of established and emerging 3D culture systems. Our evaluation focuses on the potential of each model to address specific research questions and highlights the challenges associated with modeling different stages of STB development and different unique aspects of STB functionality. Moreover, while remarkable progress in developing STB models has been made, no single system fully recapitulates the complex in vivo features of STB formation and function. Rather than being exhaustive, this review seeks to provide an evidence-based perspective on STB modeling in vitro which can encourage the careful consideration of the strengths and limitations of STB models. WIDER IMPLICATIONS: This review provides an overview of the in vitro STB models currently available and a commentary of the knowledge that these systems have contributed to our understanding of STB biology. While the field has made significant progress, ongoing refinement of existing models is essential for advancing our understanding of STB and their role in both the health and dysfunction of the human placenta. By summarizing the unique adaptations and physiological changes of STB throughout gestation and aligning these with the capabilities of current models, we have developed a framework to guide future research and innovation in STB modeling. This framework is underscored by the importance of selecting models which align with specific research questions and simultaneously acknowledging the inherent limitations in extrapolating data from any in vitro systems to the biological context of the developing human placenta. By generating this discussion, we hope to contribute to the ongoing refinement of placental research methodologies and to inspire continued innovation in STB model systems. REGISTRATION NUMBER: N/A.
Prevalence of polycystic ovary syndrome: a global and regional systematic review and meta-analysis.
Neven ACH, Forslund M, Ranasinha S … +6 more , Sethi P, Dhungana RR, Mousa A, Tay CT, Teede H, Boyle JA
Hum Reprod Update · 2026 May · PMID 41528735 · Publisher ↗
BACKGROUND: Polycystic ovary syndrome (PCOS) affects women globally, but its prevalence across World Health Organization (WHO) regions has not previously been reported. OBJECTIVE AND RATIONALE: We aimed to synthesize evi...
BACKGROUND: Polycystic ovary syndrome (PCOS) affects women globally, but its prevalence across World Health Organization (WHO) regions has not previously been reported. OBJECTIVE AND RATIONALE: We aimed to synthesize evidence on the prevalence of PCOS by diagnostic criteria and by WHO geographic regions to inform the International Evidence-Based PCOS Guideline. SEARCH METHODS: A systematic search of OVID MEDLINE, All EBM, PsycInfo, EMBASE, and Cumulative Index to Nursing and Allied Health Literature was conducted from 1990 to November 2024. Studies assessing PCOS prevalence in an unselected population were included. Non-primary studies or those with unclear diagnostic criteria were excluded. The primary outcome was PCOS prevalence among adult women. The secondary outcome was PCOS prevalence among women of all ages. Random effects meta-analysis using the DerSimonian and Laird method was applied for estimating the overall effect size. Two reviewers independently assessed risk-of-bias (RoB) and evidence certainty. OUTCOMES: The search yielded 16 664 articles, of which 119 unique studies (in 137 articles) were eligible, and 92 (including 157 181 participants) were pooled in a meta-analysis. By diagnostic criteria, PCOS global prevalence among adult women only was 12.1% (95% CI: 9.8, 14.8; I2: 98.8%) using Rotterdam criteria, 7.9% (95% CI: 6.2, 9.9; I2: 96.2%) using the original National Institute of Health (NIH) criteria, 12.7% (95% CI: 8.2, 17.9; I2: 98.0%) using the Androgen Excess (AE)-PCOS criteria, and 7.8% (95% CI: 5.8, 10.0; I2: 99.4%) by self-report. By WHO regions, PCOS prevalence among adult women when using Rotterdam criteria was highest in the Eastern Mediterranean region (15.1%; 95% CI: 11.1, 19.7) and the South-East Asian region (14.3%; 95% CI: 5.8, 25.9), followed by the European region (11.7%; 95% CI: 5.1, 20.3), the region of the Americas (10.5%; 95% CI: 3.0, 21.7), and the Western Pacific region (9.1%; 95% CI: 6.2, 12.5), with no data from Africa. Subgroup analysis using Cochran's Q test indicated a statistically significant difference in prevalence by WHO region (P = 0.022). Subgroup analyses including adolescents yielded a lower prevalence globally, with a global prevalence of 11.4% (95% CI: 9.5, 13.5) by Rotterdam criteria, 7.1% (95% CI: 5.7, 8.7) by NIH criteria, 11.2% (95% CI: 7.4, 15.5) by AE-PCOS criteria, and 7.6% (95% CI: 5.8, 9.6) on self-report. Of the 119 studies, 30 had low, 49 had moderate, and 40 had high RoB. Certainty of evidence ranged from very low to low. WIDER IMPLICATIONS: This is the most comprehensive and contemporary review of PCOS prevalence and highlights past inconsistencies in diagnostic criteria and individual diagnostic features. Pooled PCOS prevalence was 12.1% by the Rotterdam criteria and was highest in the Eastern Mediterranean and the South-East Asian regions, with a potentially different health burden of PCOS across world regions. These findings directly inform International PCOS Guidelines, including updated guideline diagnostic criteria and refined individual features, emphasizing early, accurate diagnosis. REGISTRATION NUMBER: PROSPERO CRD42022372029.
Beyond integration: towards benchmarks for developmental potential in human stem cell-derived embryo models.
Luijkx DG, Ashtar L, de Graeff N … +6 more , Coonen E, Giselbrecht S, de Wert GMWR, Vrij EJ, Grant R, Pereira Daoud AM
Hum Reprod Update · 2026 May · PMID 41489619 · Full text
BACKGROUND: Stem cell-based embryo models (SCBEMs) are clusters of pluripotent stem cells that can mimic morphological and functional aspects of early human embryos to different degrees. When cultured from human cells, S...
BACKGROUND: Stem cell-based embryo models (SCBEMs) are clusters of pluripotent stem cells that can mimic morphological and functional aspects of early human embryos to different degrees. When cultured from human cells, SCBEMs offer technically scalable and amenable tools that can help refine, reduce, and, in the future, perhaps replace the use of animals and human embryos in fundamental and clinical research. These advantages propelled the development of SCBEMs, and several distinct types have been generated over the past decade, including gastruloids, axioloids, blastoids, and post-implantation-like embryoids. For purposes of governance, advisory reports distinguish between SCBEMs based on their presumed capacity to continuously undergo organized human development-referred to here as developmental potential. However, since functionally testing this potential by transferring human SCBEMs to a uterus would be unethical and is recommended to be prohibited, scientists lack clear or consistent ways to assess it. OBJECTIVE AND RATIONALE: This narrative review aims to tackle the question of how to assess developmental potential in SCBEMs by clarifying the different ways in which it can be and is being conceptualized. We achieve this by synthesizing insights from governance, science, and ethics. First, we examine how developmental potential is described in contemporary governance frameworks, and which aspects are emphasized. Next, we discuss biological markers for developmental potential and show how their scientific basis (in embryos, let alone SCBEMs) remains poorly understood. Then, we explore how the aspects considered relevant for assessments of developmental potential in governance and science may pre-emptively hinge on underlying conceptual interpretations and lead to differing normative implications. SEARCH METHODS: This narrative review combines insights from both the academic and grey literature on the (ethics of) embryo models. Original and review articles were selected from PubMed and Biorxiv with the main focus on articles published since 2015. Search terms included: embryo quality, in vitro fertilization, Gardner system, blastoid, gastruloid, embryo research, potentiality argument, developmental potential, transcriptomics, epigenetics, embryo metabolism, and related terms. Additional sources were identified through snowballing. This work focuses predominantly on human SCBEMs, but references to animal models are made. OUTCOMES: Comparison of the descriptions currently recommended for governance suggests at least three criteria that are used to assess developmental potential in SCBEMs: composition, organization, and interaction. Scientifically, developmental potential is multifaceted and only partly characterized, making it necessary to measure a broader range of aspects, using human embryos as benchmarks when possible. Since the range and significance of these aspects can be shaped by underlying accounts of developmental potential, contemporary advisory reports are examined to explore if and how they connote interpretations of developmental potential as possibility, probability, and predisposition. WIDER IMPLICATIONS: Categorization of the regulatory and scientific criteria currently used to assess developmental potential shows that they are underpinned by distinct interpretations of the concept, revealing tensions and questions for further inquiry. By synthesizing insights from governance, science, and ethics, this review thus aims to contribute to the responsible advancement of the SCBEM field and to support its coherent and transparent governance. REGISTRATION NUMBER: N/A.
The human ovarian reserve: the narrative and the science.
Kerr JB, Rodgers RJ
Hum Reprod Update · 2026 May · PMID 41453395 · Full text
BACKGROUND: The ovarian reserve is the quantity of non-growing primordial follicles (NGF) in paired ovaries. A low or high ovarian reserve at birth respectively may foreshadow early or late age at menopause. In textbooks...
BACKGROUND: The ovarian reserve is the quantity of non-growing primordial follicles (NGF) in paired ovaries. A low or high ovarian reserve at birth respectively may foreshadow early or late age at menopause. In textbooks, published papers, and internet modalities, a recurring theme is that for human females, on average, mid-gestation marks the peak supply of 7 million germ cells/NGF followed by large-scale depletion to about 1-2 million in paired ovaries at birth. OBJECTIVE AND RATIONALE: We test this narrative against the evidence for germ cell quantity and degeneration reported in peer-reviewed publications. Ovary sizes, volumes/shapes are particularly variable among same-age foetuses and at birth. Coupled with genomic mechanisms determining germ cell proliferation/differentiation/survival, substantial variations of germ cell numbers are recorded within and between individual studies. Across published papers, textbooks, and webpages, germ cell numbers in foetal-newborn ovaries range from thousands to 20 million. A massive 70-85% die-off among germ cells in foetal ovaries is reported during the second half of gestation. Although germ cell degeneration is a reality, we review also the evidence for the timing and extent of germ cell death in foetal/newborn human ovaries. SEARCH METHODS: We cite primary publications of human embryonic, foetal/newborn ovaries where data on germ cell numbers and death are reported, and similarly for studies of ovarian volume, shape, histology, and growth in foetal-early postnatal life. Searches to September 2025 used PubMed, Google Scholar, and DOIs/URLs from published papers, textbooks, and webpages, including keywords listed below. Textbook and webpage citations are a selection and not comprehensive, serving to illustrate the widespread narrative on human ovarian development. OUTCOMES: Germ cell number estimates (oogonia, oocytes, NGF) in human embryonic, foetal, and newborn ovaries (n = 139) in seven studies from 1953 until 2011 used three different quantitation methods: (i) volumetric/model-based with correction factors, (ii) volumetric/modified stereology, and (iii) fractionator/optical dissector. In a 1963 study, germ cells in paired foetal ovaries at 20 weeks (n = 2) reported 6.8 million in total with 20% atretic, and at birth (n = 2), 2 million in total with 50% atretic, leading to the narrative that the mid-gestation human female foetus has 7 million germ cells/NGF that are subsequently depleted to 1-2 million by birth. Independent investigations of germ cell quantitation/degeneration do not confirm these findings for total numbers nor the substantial fractions reported as degenerating. In adult women, ovarian volume is strongly correlated with the numbers of NGF but an equivalent correlation between germ cell supply and ovarian volume during foetal life up to birth has not been investigated. We conclude that the narrative whereby human foetal ovaries develop millions of germ cells followed by most degenerating up to birth has not been verified. Systematic analysis of total numbers and estimates of viable versus degenerating germ cells across gestation is needed. WIDER IMPLICATIONS: Does it matter how many germ cells or primordial follicles are in the ovaries at birth? Yes, not only with regard to scientific authenticity but also for clinical investigations of gynaecological and reproductive conditions. These include situations where follicle numbers and growth dynamics are of consideration, such as premature ovarian insufficiency, early menopause, chemotherapy for cancer treatments, polycystic ovary syndrome, assisted conception and/or IVF particularly for poor responders to gonadotrophins and predictions of age at the menopause. For fertility counselling and for women electing to delay pregnancy, it is suggested that clinicians and health professionals be aware that the age-related ovarian reserve in adults may not necessarily be in the expected range if the NGF reserve at birth was significantly lower than the narrative of 1-2 million at that time. REGISTRATION NUMBER: N/A.
Epitranscriptomic modifications in embryonic development: insights into natural and ART-induced mechanisms and implications.
Volsa AM, Hoffmann ER, Ross PJ … +1 more , Canovas S
Hum Reprod Update · 2026 Mar · PMID 41445111 · Full text
BACKGROUND: Mammalian embryo development involves a complex process governed by multiple layers of cellular and molecular regulation mechanisms. ART is widely used around the world to assist fertility in humans, with ∼12...
BACKGROUND: Mammalian embryo development involves a complex process governed by multiple layers of cellular and molecular regulation mechanisms. ART is widely used around the world to assist fertility in humans, with ∼12 million babies being born by ART in the last 40 years. These technologies are also used extensively for reproductive purposes in other mammalian species that have many analogies with human reproductive biology. Epitranscriptomic marks, including RNA modifications such as N6-methyladenosine (m6A) and N1-methyladenosine (m1A), modulate gene expression during gametogenesis and embryo development, and their dynamics are regulated by genes encoding m6A writers (METTL3, METTL14, and WTAP), readers (YTHDF2, YTHDC1-2, and PRRC2A), and erasers (ALKBH5 and FTO). However, the impact of ART on these epigenetic modifications remains poorly understood. OBJECTIVE AND RATIONALE: This narrative review explores the role of epitranscriptomic modifications in both naturally and ART-conceived embryos. It examines how RNA modifications regulate gametogenesis and early embryonic development and how ART-induced cellular stress might perturb these regulatory layers, potentially affecting gametogenesis, embryo competence, and offspring health. Understanding the interaction between ART and epitranscriptomic regulation is crucial for optimizing ART procedures and safeguarding offspring health. SEARCH METHODS: The PubMed and Scopus literature databases were utilized to search for peer-reviewed articles and reviews using terms such as 'epitranscriptomic', 'RNA modification', 'gametogenesis', 'embryo development', 'mammalian development', 'in vitro fertilization', 'ART', and 'assisted reproductive technologies' in combination or individually. All relevant publications until the current year have been critically evaluated and discussed. OUTCOMES: Epitranscriptomic modifications, particularly m6A, have emerged as key regulators of RNA metabolism during gametogenesis and early embryo development. Evidence from both human and animal studies indicates that ART-related stressors, such as oxidative imbalance, hormonal stimulation, and cryopreservation, can disturb RNA methylation at the epitranscriptomic marks m1A and 5-methylcytosine by modulating the expression and activity of m6A writers, erasers, and readers, independently of global transcriptional changes. These alterations can affect embryo competence, placental function, lineage specification, and subsequent offspring development. Moreover, m6A-associated factors participate in stress adaptation and developmental signalling beyond their canonical methylation activity. Collectively, these findings underscore the remarkable sensitivity of the embryonic transcriptome to in vitro manipulation and highlight epitranscriptomic marks as both predictive biomarkers and mechanistic targets for improving the safety, efficacy, and long-term outcomes of assisted reproduction. WIDER IMPLICATIONS: Understanding how ARTs influence the epitranscriptome and its downstream effects is crucial for improving reproductive outcomes. In vitro manipulation, fertilization, and embryo culture can influence RNA regulation in gametes, causing reduced cell differentiation, and, in early embryos, contributing to recurrent implantation failure, decidualization failure, and pregnancy loss. This review aims to share with the scientific community insights into the critical role of epitranscriptomic modifications during gametogenesis and embryogenesis, as well as the potential consequences of in vitro procedures, to guide safer and more effective ART practices. REGISTRATION NUMBER: N/A.
The road to restore male fertility using in vitro-derived germ cells.
Macedo T, Alves-Lopes JP
Hum Reprod Update · 2026 Mar · PMID 41416641 · Full text
BACKGROUND: Human-induced pluripotent stem cells (hiPSCs) offer immense potential in reproductive medicine, particularly for males who lack germ cells and cannot achieve biological parenthood through conventional ARTs. E...
BACKGROUND: Human-induced pluripotent stem cells (hiPSCs) offer immense potential in reproductive medicine, particularly for males who lack germ cells and cannot achieve biological parenthood through conventional ARTs. Early efforts to derive human germ cells from stem cells were hindered by low efficiency, subpar characterization, and the lack of standardized differentiation approaches. However, recent advancements have led to the development of defined protocols that mimic early embryonic development and allow the specification of transcriptomically and epigenetically validated human primordial germ cell-like cells (hPGCLCs). Current research focuses on maturing hPGCLCs in vitro, particularly within 3D culture systems that resemble their physiological microenvironment, with the aim of producing transplantable hiPSC-derived spermatogonial stem cells (SSCs) or differentiating them to sperm. At the same time, researchers are also testing whether hiPSCs generated from infertile patients can resume germline differentiation. OBJECTIVE AND RATIONALE: This narrative review aimed to summarize the key efforts and remaining challenges in differentiating male germ cells from human pluripotent stem cells (hPSCs), with a particular focus on defined and validated protocols for hPGCLC specification. In parallel, we addressed key safety and ethical considerations that must be accounted for the development of clinical applications. A deeper understanding of the approaching therapeutic use of hiPSCs in reproductive medicine is essential for developing novel regenerative fertility strategies. SEARCH METHODS: PubMed, Scopus, and Web of Science were searched for studies attempting germ cell differentiation from hPSCs using relevant keywords ('stem cells', 'human pluripotent stem cells', 'human embryonic stem cells', 'human induced pluripotent stem cells', 'somatic cell reprogramming', 'infertility', 'germline', 'spermatogenesis', 'germ cells', and 'primordial germ cells'). No time period restriction was established. Studies with an exclusive focus on female germline differentiation were excluded. To maintain a human-focused perspective, only key animal studies are presented. OUTCOMES: The literature reveals a clear segregation among protocols for deriving germ cells from hPSCs, particularly between earlier studies lacking standardized differentiation conditions and characterization, and the most recent, defined protocols having transcriptomic and epigenetic validation against in vivo hPGCs. Moreover, during the last decade, the field has seen remarkable progress, with multiple efforts aimed at maturing hPGCLCs, closely recapitulating late male embryonic germline development. Additionally, hiPSCs derived from male patients at risk of infertility, particularly those without underlying genetic syndromes, generally retain the capacity for early germline commitment. While attempts at maturating patient germ cells beyond the hPGCLC state remain limited, the rapid pace of discovery and refinement in recent years suggests that further breakthroughs, including clinically applicable fertility restoration strategies, are likely to be achieved in the near future. WIDER IMPLICATIONS: The ability to generate hiPSCs from infertile patients and to specify them into hPGCLCs supports the feasibility of obtaining hiPSC-derived SSCs for future therapeutic use. These advances raise important ethical, regulatory, and societal questions that must be actively discussed among researchers, clinicians, policymakers, and the general public to ensure responsible and equitable access to these technologies. REGISTRATION NUMBER: N/A.
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