Human Reproduction (Oxford, England)[JOURNAL]
Sun
200 papers
Foundation models in IVF: from speculation to implementation with FEMI.
Shoham Z
Hum Reprod · 2026 Jan · PMID 41220066 · Publisher ↗
Abstract loading — click title to view on PubMed.
The contribution of single-cell omics technologies to improve knowledge on human early embryo development.
Girard O, Moinard E, David L … +1 more , Fréour T
Hum Reprod · 2026 Jan · PMID 41220060 · Publisher ↗
Understanding human early embryo development from fertilization to gastrulation is essential to improve medically assisted reproduction. Faced with technical and ethical limitations, research into peri-implantation stage...
Understanding human early embryo development from fertilization to gastrulation is essential to improve medically assisted reproduction. Faced with technical and ethical limitations, research into peri-implantation stages has been transformed by the recent onset of single-cell omics technologies. These approaches encompassing transcriptomics, epigenomics, and proteomics now enable unprecedented resolution of cellular heterogeneity, lineage specification, and spatial organization during early development. Here, we review the major discoveries permitted by single-cell omics methods, presented chronologically to reflect the progression of embryonic development. We address, among others, the delineation of blastomere contributions, mechanisms of embryonic genome activation, and the sequential specification of the trophectoderm, epiblast, and hypoblast lineages. We also explore how single-cell omics clarifies the effects of aneuploidy, uncovers mural-polar trophectoderm maturation, revises X chromosome regulation, and enables identification of rare post-implantation populations like primordial germ cells and amnion.
Increased OCT4 expression in Day 5 blastocysts may explain the increased clinical outcomes of D5 versus D6 blastocyst transfers.
Lee JH, Chang WF, Tzeng SY … +7 more , Lee YX, Tan SJ, Wang RS, Ho JY, Lin SY, Hwu YM, Tzeng CR
Hum Reprod · 2026 Jan · PMID 41218150 · Publisher ↗
STUDY QUESTION: Are the clinical pregnancy rates and cell lineage-related markers of equal-grade Day 5 (D5) and Day 6 (D6) embryos the same? SUMMARY ANSWER: High-grade D5 (HG D5) blastocysts have a higher live birth rate...
STUDY QUESTION: Are the clinical pregnancy rates and cell lineage-related markers of equal-grade Day 5 (D5) and Day 6 (D6) embryos the same? SUMMARY ANSWER: High-grade D5 (HG D5) blastocysts have a higher live birth rate than high-grade D6 (HG D6) blastocysts, which could be associated with differences in intrinsic OCT4 expression. WHAT IS KNOWN ALREADY: In IVF cycles, D5 blastocysts are generally considered to be of higher quality and are preferred for embryo transfer over D6 blastocysts. However, the differences between delayed D6 embryos and D5 embryos remain poorly understood. This study aimed to perform an immunofluorescence (IF)-based analysis to evaluate cell content-related differences between same-grade D5 and D6 blastocysts and to assess how these differences may be associated with the clinical pregnancy outcomes following frozen-thawed embryo transfer cycles. STUDY DESIGN, SIZE, DURATION: This retrospective study included 774 frozen-thawed single blastocyst transfer (SBT) cycles at the Taipei Fertility Center from March 2020 to February 2023. All D5 (D5-SBT) and D6 (D6-SBT) frozen-thawed cycles (n = 774) were classified as high grade (≥BB, n = 694) or low grade (<BB, n = 80). PARTICIPANTS/MATERIALS, SETTING, METHODS: For the cell content analyses, IF staining with the pluripotent marker OCT4 was used to determine the cell numbers in the inner cell mass (ICM), and the trophectoderm (TE) marker GATA3 was used to evaluate the TE region. Same-grade frozen-thawed D5 blastocysts (n = 20), D6 blastocysts (n = 20), and D5 blastocysts cultured to D6 (ExD6, n = 17) were used to assess differences in the cell number in the TE and ICM by evaluating OCT4 and GATA3 expression. The total number of cells was visualized using DAPI staining. OCT4 and GATA3 transcripts were analysed with quantitative reverse transcription polymerase chain reaction (qRT-PCR). MAIN RESULTS AND THE ROLE OF CHANCE: For the clinical results, in the single euploid embryo transfer cycle, the overall biochemical pregnancy rate (HCG+, 71.8% vs 52.3%, P < 0.0001), clinical pregnancy rate (SAC+, +66.7% vs 47.7%, P = 0.0001) and live birth rate (59.5% vs 37.9%, P < 0.0001) were significantly higher in the D5-SBT group than in the D6-SBT group. Among HG embryos, the D5-SBT group consistently demonstrated better clinical outcomes. A generalized linear mixed model revealed that the odds ratios were significantly elevated only for D5 embryos but not for other confounders, highlighting the importance of developmental timing. On the other hand, the staining results showed no significant differences in the numbers of TE, ICM, or total cells between the same-grade D5 and D6 blastocysts. However, a notable decrease in OCT4-positive cells was observed in D6 embryos, suggesting a reduction in embryo quality (D5 vs D6: 64 ± 4% vs 49 ± 5% per embryo). ExD6 blastocysts had a significantly increased number of TE cells compared to D6 blastocysts, reflecting greater expansion of the TE population. Gene expression analysis results aligned with these findings, showing a significant decrease in the OCT4/GATA3 ratio in TE cells from D6 embryos compared to D5 embryos. LIMITATIONS, REASONS FOR CAUTION: This study exclusively analysed euploid embryos in clinical assessments, omitting cases of mosaic embryo transfer. Due to the limited sample size for embryo staining, assessment of additional pluripotent markers was not feasible. WIDER IMPLICATION OF THE FINDINGS: Our research demonstrated a significant decrease in the live birth rate with D6 blastocysts compared to D5 blastocysts. The similar proportion of TE cells between D5 and D6 blastocysts suggests that reduced numbers of OCT4-positive cells in D6 blastocysts, rather than TE proliferation, may influence the embryo developmental potential. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was used for this study. W.F.C. is a co-investigator at Taipei Fertility Center and an employee of Taipei Medical Technology Co., Ltd All other authors declare no conflict of interest related to the content of this study. TRIAL REGISTRATION NUMBER: N/A.
Impact of gender-affirming hormone therapy on spermatogenesis: analysis of testicular histological specimens.
Wilk Goldsher Y, Al-Hadi H, Mullen B … +7 more , Potter E, MacLeod E, Lajkosz K, Karavani G, Krakowsky Y, Grober ED, Millman AL
Hum Reprod · 2026 Jan · PMID 41206903 · Publisher ↗
STUDY QUESTION: How does gender-affirming hormone therapy (GAHT) regimen impact testicular spermatogenesis in transgender and gender diverse (TGD) individuals? SUMMARY ANSWER: Cyproterone acetate (CPA) and progesterone s...
STUDY QUESTION: How does gender-affirming hormone therapy (GAHT) regimen impact testicular spermatogenesis in transgender and gender diverse (TGD) individuals? SUMMARY ANSWER: Cyproterone acetate (CPA) and progesterone significantly impair spermatogenesis, whereas spironolactone does not, compared to no use of anti-androgen. WHAT IS KNOWN ALREADY: GAHT is known to suppress spermatogenesis in TGD individuals assigned male at birth, but the extent of impairment varies across hormone regimens. Prior studies suggest that anti-androgens and progestogens may exert distinct effects on testicular function, but direct comparisons between regimens are limited. STUDY DESIGN, SIZE, DURATION: This was a retrospective single-center cohort study including 287 TGD patients who underwent gender-affirming orchiectomy between November 2017 and January 2024. A total of 573 testis specimens were histologically reviewed. PARTICIPANTS/MATERIALS, SETTING, METHODS: All included patients had received GAHT prior to surgery, with exposure categorized based on the type and duration of hormone therapy. The primary exposure variables were estrogen use (N = 287, 100%), anti-androgen type (CPA: N = 127, 44.3%; spironolactone: N = 110, 38.3%), and progesterone use (N = 73, 25.4%). Testicular histology was evaluated to determine spermatogenesis stage, and multivariable regression was performed to identify independent predictors of impaired sperm maturation. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 287 patients were included in the study period, and 573 testis specimens were reviewed. Mean age at surgery was 33.9 years (SD = 11.7, range = 18.4-80.6), and duration of GAHT was 3.8 years (SD = 3.0, range = 1-28). Older age was associated with impairment in spermatogenesis, with a mean age of 41.4 (SD = 12.8, range = 23.0-66.5) for end-stage testis failure and a mean age of 33.4 (SD = 11.2, range = 20.2-80.6) for complete maturation (P = 0.002). Hormone therapy duration did not show a significant difference between groups (P = 0.22). GAHT included estrogen (n = 287, 100%), progesterone (n = 73, 25.4%), and an anti-androgen (n = 259, 90.2%). CPA (n = 127, 44.3%) and spironolactone (N = 110, 38.3%) were the most common anti-androgens used. Spermatogenesis was most significantly impaired with the use of CPA, with only 8.7% of patients having active spermatogenesis versus 53.3% of patients taking spironolactone (P < 0.001). Progesterone use had an independent negative effect on spermatogenesis (P = 0.005). LIMITATIONS, REASONS FOR CAUTION: The retrospective design and absence of a control group of untreated individuals limit direct causal inferences. Variability in GAHT duration, adherence, and regimen composition may introduce confounding effects due to self-reporting. Additionally, histological assessment alone does not confirm functional fertility potential, and future studies should explore this aspect. WIDER IMPLICATIONS OF THE FINDINGS: These findings provide clinically relevant insights for fertility counseling in TGD individuals, emphasizing that CPA and progesterone significantly impair spermatogenesis, whereas spironolactone may allow for greater preservation of sperm maturation. This has implications for fertility preservation discussions prior to GAHT initiation and may inform individualized hormone regimen selection based on reproductive goals. STUDY FUNDING/COMPETING INTEREST(S): This research received no specific grant or funding. The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: n/a.
Association of neighborhood deprivation and live birth after 8155 first, single euploid frozen embryo transfers: the lived patient experience matters.
Willson S, Bollig K
Hum Reprod · 2026 Jan · PMID 41206902 · Publisher ↗
STUDY QUESTION: Is there an association between neighborhood deprivation and frozen embryo transfer outcomes? SUMMARY ANSWER: After adjusting for important reproductive characteristics most closely associated with embryo...
STUDY QUESTION: Is there an association between neighborhood deprivation and frozen embryo transfer outcomes? SUMMARY ANSWER: After adjusting for important reproductive characteristics most closely associated with embryo transfer outcomes, residual significant differences in live birth were present with a progressive decline in the probability of live birth as measures of socioeconomic disadvantage increased. WHAT IS KNOWN ALREADY: Residence in a socioeconomically disadvantaged neighborhood is associated with adverse reproductive health outcomes, including decreased fecundability, preeclampsia, gestational diabetes, preterm birth, and low birthweight. STUDY DESIGN, SIZE, DURATION: Retrospective cohort study including 8155 patients undergoing first, single, euploid, frozen embryo transfer between 2017 and 2022 at a single university-affiliated fertility center. The primary outcome was live birth. Secondary outcomes included any pregnancy loss, mode of delivery, birthweight, and gestational age at delivery. After accounting for all inclusion criteria, only 2.5% of the total cases were excluded due to missing information on BMI, insurance status, or type of transfer protocol. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 8155 patients met inclusion criteria. The primary exposure of this study was the state decile Area of Deprivation Index (ADI) score, or the composite score that measures overall socioeconomic disadvantage at the Census block level. ADI scores were then divided into four groups: low or least disadvantaged (score 1-2, n = 3138, 38.5%), low-middle (score 3-5, n = 3145, 38.5%), middle-high (score 6-8, n = 1573, 19.3%), and high or most disadvantaged (score 9-10, n = 299, 3.7%). MAIN RESULTS AND THE ROLE OF CHANCE: Individuals living in areas with higher neighborhood deprivation (more disadvantaged) had a higher BMI and were more likely to be uninsured than those in areas of lower deprivation (less disadvantaged). Overall, 60.9% (n = 4963) of patients had a live birth with significantly lower rates in those living in neighborhoods with higher levels of socioeconomic disadvantage compared to those in neighborhoods with lower levels of socioeconomic disadvantage (P = 0.002). Compared to couples living in areas with the lowest deprivation index scores census blocks, the probability of live birth was significantly decreased for couples living in areas with low-middle, middle-high, and high scores in multivariable regression analyses after adjustment for maternal age, BMI, duration of time from initial consult to decision for IVF, primary infertility diagnosis, office location, insurance status, FET protocol, endometrial thickness, max estradiol level, and embryo grade (aOR 0.90 (95% CI 0.81-0.99), P = 0.047; aOR 0.87 (95% CI 0.77-0.99), P = 0.047; aOR 0.70 (95% CI 0.54-0.90), P = 0.006; respectively). Additionally, there was a significant dose-response relationship between neighborhood deprivation and probability of live birth (P = 0.003). Compared to couples living in areas of low neighborhood deprivation, the probability of any pregnancy loss was significantly higher for couples living in the highest ADI census blocks in adjusted models (aOR 1.64 (95% CI 1.21-2.24), P = 0.002). There was no difference in mode of delivery, birthweight, or gestational age at delivery. LIMITATIONS, REASONS FOR CAUTION: Limitations of this study include its retrospective design, external validity, and variable patient experiences. Additionally, socioeconomic status remains a multifaceted and broad concept that includes factors often difficult to measure. WIDER IMPLICATIONS OF THE FINDINGS: This study highlights the significant differences in the probability of live birth among populations residing in neighborhoods of worsening area-based socioeconomic disadvantage after adjusting for important reproductive characteristics most closely associated with IVF outcomes. Our data emphasize that reproductive health providers should not only focus on optimizing clinical and laboratory processes to improve patient outcomes but also extend focus and efforts to understand the broader systemic, economic, and geographic factors that influence overall reproductive health. STUDY FUNDING/COMPETING INTEREST(S): Funding was not utilized for the purposes of this project. The authors declare that they have no conflicts of interest. TRIAL REGISTRATION NUMBER: Not applicable.
Secrets and lies and donor conceptions: what donor-conceived individuals feel about their disclosure/discovery experience.
Applegarth LD, Kaufman NL, Thomas C … +3 more , Beroukhim G, Tsai S, Joseph-Sohan M
Hum Reprod · 2025 Dec · PMID 41206682 · Publisher ↗
STUDY QUESTION: What are the satisfaction levels, as defined by emotional comfort or contentment, of adult individuals conceived via donor-assisted reproduction concerning the method, timing, and circumstances surroundin...
STUDY QUESTION: What are the satisfaction levels, as defined by emotional comfort or contentment, of adult individuals conceived via donor-assisted reproduction concerning the method, timing, and circumstances surrounding the disclosure/discovery of their conception? SUMMARY ANSWER: Inadvertent discovery and older age at the time of disclosure of donor-conceived status are associated with lower rates of satisfaction among donor-conceived individuals. WHAT IS KNOWN ALREADY: The proliferation of commercial DNA testing has resulted in many donor-conceived people learning inadvertently of their donor origins. As a result, donor-conceived people, healthcare professionals, and parents seek information and research about best disclosure practices and outcomes. STUDY DESIGN, SIZE, DURATION: A survey-based cross-sectional cohort study from 2022 to 2023 was conducted involving 530 participants, of whom 422 completed the survey. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 546 people ages 18 years and over opened the survey, with 530 people qualifying to complete the survey as donor-conceived persons (DCPs). Four hundred and twenty-two DCPs (79.6%) completed the survey. Descriptive statistics were applied, and data distributions were analyzed for a selection of appropriate statistical tests; parametric tests such as Student's t-test or ANOVA, and non-parametric tests such as Mann U Whitney or Kruskal-Wallis Rank Sum test were utilized as applicable, for comparing continuous data between groups. Multivariable logistic regression analyses were used to examine satisfaction levels, adjusting for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: After accounting for age at discovery, sex, the origin of disclosure, and education, individuals with early intentional disclosure were more than three times as likely to experience disclosure satisfaction as those with late unintentional disclosure/inadvertent discovery (P-value = 0.005). LIMITATIONS, REASONS FOR CAUTION: Lack of ethnic diversity among survey respondents, and limited control over reposting of the survey to other sites, potentially contributing to sampling bias. WIDER IMPLICATIONS OF THE FINDINGS: Preliminary but substantial evidence that early, intentional disclosure to DCPs results in greater satisfaction and acceptance. This data will ultimately assist all stakeholders, including reproductive health professionals and parents in family-building counseling and decision-making. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: N/A.
Mitochondrial metabolism influences meiotic maturation in human oocytes of young and advanced maternal age women.
Pietroforte S, Martins M, Barragan M … +6 more , Ibañez E, Vassena R, Popovic M, Sanchez T, Sakkas D, Zambelli F
Hum Reprod · 2025 Dec · PMID 41206610 · Publisher ↗
STUDY QUESTION: Is there a relationship between the mitochondrial activity and the meiotic progression of oocytes from germinal vesicle (GV) to metaphase II (MII) stages in young and advanced maternal age (AMA) women? SU...
STUDY QUESTION: Is there a relationship between the mitochondrial activity and the meiotic progression of oocytes from germinal vesicle (GV) to metaphase II (MII) stages in young and advanced maternal age (AMA) women? SUMMARY ANSWER: Poor mitochondrial metabolism impairs the meiotic progression of human GV oocytes, contributing to a lower oocyte maturation capacity of AMA oocytes. WHAT IS KNOWN ALREADY: AMA oocytes are characterized by diminished quality, mostly due to the higher rates of chromosomal segregation errors occurring during meiosis I. Another hallmark of AMA oocytes is impaired mitochondrial metabolism. Studies in mice have suggested a link between metabolic dysfunction and meiotic failure, but this relationship has not been fully elucidated in humans. Metabolic dynamics can be visualized by indirect measurements through mitochondrial staining and quantified more directly using fluorescence lifetime imaging microscopy (FLIM). This live-imaging approach can generate metabolic timelapse profiles of oocytes throughout meiosis. In the present study, we explored mitochondrial distribution and functionality in human oocytes at the GV and MII stages, obtained from young and AMA women, to establish the role of mitochondrial metabolism in meiosis progression. STUDY DESIGN, SIZE, DURATION: A total of 340 GV oocytes from young (≤34 years) and AMA (>37 years) women were included in the study. Denuded GVs were matured in vitro in G2-plus medium for 30 h. Maturation was determined by the presence of the extruded first polar body (PB1). The collected oocytes were processed for mitochondrial protein imaging (n = 80), or for live imaging (n = 171). Moreover, 89 oocytes were used for loss-of-function analysis by treating young GVs with 1 μM trifluoromethoxy-carbonylcyanide-phenylhydrazone (FCCP) for 30 min before in vitro maturation. PARTICIPANTS/MATERIALS, SETTING, METHODS: The proteins dihydrolipoamide-S-acetyltransferase (D-LAT) and translocase-of-outer mitochondrial-membrane (TOMM20) were analyzed in young and AMA oocytes by immunofluorescence to assess mitochondrial activity and localization, respectively. Fluorescence mean intensities (arbitrary-unit, AU) were quantified with ImageJ and compared by t-test; maturation rates were compared by chi-squared test. FLIM comprehensive metabolism (NAD(P)H; FAD+) was taken at GV stage. Different FLIM parameters (fluorescence intensity, fraction bound, short/long lifetime) and the Redox ratio (NAD(P)H intensity/FAD+ intensity) were evaluated. MAIN RESULTS AND THE ROLE OF CHANCE: The findings revealed that active mitochondria are specifically localized in the subcortical area, while mitochondria in general are distributed across the whole oocyte. This pattern was substantially maintained in AMA oocytes, which were in turn characterized by a lower mitochondrial activity (D-LAT intensity of 78 614 ± 58 534 AU in young, 12 517 ± 10 187 AU in AMA, P = 0.003), while a lower number of mitochondria was observed In AMA patients but the difference did not reach statistical significance (TOMM20 intensity of 61 674 ± 24 322 AU in young, 32 186 ± 33 414 AU in AMA, P = 0.195). Using non-invasive FLIM, we assessed the metabolic dynamics of maturing oocytes (Redox ratio in young 2e + 00 ± 0.15, in AMA 1e + 00 ± 0.16, P = 2.969e-05), confirming a similar pattern observed by immunofluorescence. Specifically, FLIM microscopy revealed that GV oocytes from young women slightly increased their metabolism, by 4% on average, after the GV breakdown, and the increase was very consistent across different oocytes. On the contrary, in AMA maturing oocytes, little to no increase in metabolism was observed; they were characterized instead by higher variability, and more AMA oocytes failed to successfully reach the MII stage [AMA oocytes (62.3%; 38/61) compared with young oocytes (86.3%; 63/73; P = 0.002). These differential trends observed in AMA oocytes compared to the young oocytes suggest that impaired metabolic activity significantly compromises maturation capacity, revealing a functional link between adequate metabolic levels and successful meiosis progression. LIMITATIONS, REASONS FOR CAUTION: Maturation rates were assessed by the presence of an extruded PB1 and variations in spindle assembly timings may have been overlooked. The quantification of mitochondrial activity in loss-of-function studies was assessed only by immunofluorescence staining. Additionally, the oocytes included in the present study were collected from women who underwent ovarian stimulation and may not faithfully recapitulate physiological maturation. WIDER IMPLICATIONS OF THE FINDINGS: Our findings demonstrate the presence of a functional link between oocyte mitochondrial metabolism and meiosis progression, which may contribute to the decline of oocyte quality with aging. Overall, we provided evidence to understand the biological mechanisms in mitochondrial metabolism that might contribute to driving the decay in oocyte quality in AMA women. STUDY FUNDING/COMPETING INTEREST(S): This project received intramural funding from the Eugin Group and funding from the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 860960. T.S. is a former owner and former stock owner of Optiva Fertility Inc (company closed) and filed two patents for Optiva Fertility Inc (both abandoned). D.S.: Presenter EMD Senoro and Dep. Editor of Human Reproduction. All of the other authors (S.P., M.M., M.B., E.I., M.P., R.V., and F.Z.) have no conflicts of interest to declare. All of the authors contributed substantially to the manuscript and approve its submission. TRIAL REGISTRATION NUMBER: N/A.
A novel CFTR-AQP7 protein complex regulates glycerol transport and motility of human sperm.
Ribeiro JC, Bernardino RL, Jorge P … +9 more , Geraldo M, Vieira E, Santos R, Barros A, Touré A, Castro TG, Cavaco-Paulo A, Alves MG, Oliveira PF
Hum Reprod · 2025 Dec · PMID 41206608 · Publisher ↗
STUDY QUESTION: Does the interaction between CFTR and AQP7 in human spermatozoa play a role in the molecular mechanisms underlying sperm motility? SUMMARY ANSWER: CFTR inhibition reduces sperm motility and AQP7-mediated...
STUDY QUESTION: Does the interaction between CFTR and AQP7 in human spermatozoa play a role in the molecular mechanisms underlying sperm motility? SUMMARY ANSWER: CFTR inhibition reduces sperm motility and AQP7-mediated glycerol permeability in human spermatozoa, and CFTR and AQP7 co-localize in the equatorial segment of the sperm head, with in silico modeling suggesting a potential interaction between these proteins. WHAT IS KNOWN ALREADY: CFTR modulates the permeability of aquaglyceroporins in multiple tissues, and their interaction is mediated by the scaffolding protein NHERF1. AQP7-mediated glycerol permeability correlates with sperm motility. STUDY DESIGN, SIZE, DURATION: Semen samples were collected from normozoospermic men (normal motility; n = 33) and men with asthenozoospermia (reduced motility; n = 15) at a fertility clinic between September 2020 and January 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: Isolated sperm from men with normozoospermia were used to study the effect of CFTR on sperm motility (N = 10) and glycerol permeability (N = 23). Sperm from 14 asthenozoospermic samples and 13 normozoospermic samples were used to compare the effect of CFTR on AQP7-mediated glycerol permeability, after screening for the absence of common CFTR gene variants. Sperm membrane permeability to glycerol was measured using stopped-flow light scattering, and the effect of CFTR conductance was modulated using a specific inhibitor (CFTRinh172). The interaction between CFTR and AQP7 was investigated using co-immunofluorescence, proximity ligation assay, and in silico approaches like ColabFold and GROMACS. Gaussian distribution of the data was measured by the Shapiro-Wilk normality test. Data showing non-normal distribution was treated with the Kruskal-Wallis test, whereas normal distribution data were treated with an ordinary one-way ANOVA. Comparisons between normozoospermic and asthenozoospermic groups were performed using an unpaired two-tailed Mann-Whitney U test. A P-value less than 0.05 was considered significantly different. MAIN RESULTS AND THE ROLE OF CHANCE: CFTR inhibition negatively affected sperm motility (0.53 ± 0.11-fold variation to control, P < 0.05) and AQP7-mediated glycerol permeability (0.459-fold [0.314; 0.537] variation to control, P < 0.01). Despite this, the effect of CFTR dysfunction on AQP7-mediated glycerol permeability of sperm from normo- versus asthenozoospermic samples did not reach statistical significance (P = 0.068) due to low statistical power, but a tendency was apparent. A larger sample size is needed to confirm this trend. CFTR and AQP7 (the main glycerol diffuser in human sperm) co-localize and are in proximity in the midpiece and in the equatorial section of the sperm head in human sperm. In silico analysis supports the interaction of CFTR with AQP7 intermediated by NHERF1, indicating a mechanism of physical modulation of AQP7 permeability by CFTR. LIMITATIONS, REASONS FOR CAUTION: Only cystic fibrosis-associated CFTR variants were screened during this study; the presence of assumed benign variants that could slightly decrease CFTR function may have impacted the results. Glycerol permeability was measured indirectly by assuming its proportionality with the change in sperm volume through time after the osmotic shock. A larger sample size would be needed to confirm the trends that did not reach statistical significance. Furthermore, pharmacological assays were conducted in a non-nutrient buffer to specify direct effects of the channel; this condition differs from physiological media and represents a specific limitation of this study. WIDER IMPLICATIONS OF THE FINDINGS: Our findings suggest that a novel mechanism based on the functional and physical interaction between CFTR and AQP7 may underlie some cases of asthenozoospermia and idiopathic male infertility; the results also increase our knowledge of the molecular mechanisms governing sperm motility. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by Fundação para a Ciência e a Tecnologia (FCT) to UMIB (UIDB/00215/2020, and UIDP/00215/2020), ITR-Laboratory for Integrative and Translational Research in Population Health (LA/P/0064/2020), and the post-graduate student João C. Ribeiro (UI/BD/150749/2020). The work was co-funded by FEDER through the COMPETE/QREN, FSE/POPH, and POCI-COMPETE 2020 (POCI-01-0145-FEDER-007491) funds. P.F.O. is funded by national funds through FCT, I.P., under the Scientific Employment Stimulus-Institutional Call-reference CEEC-INST/00026/2018. This work also received support and help from FCT/MCTES to LAQV-REQUIMTE (LA/P/0008/202-DOI 10.54499/LA/P/0008/2020, UIDP/50006/2020-DOI 10.54499/UIDP/50006/2020, and UIDB/50006/2020-DOI 10.54499/UIDB/50006/2020) and to iBiMed (UIDB/04501/2020-DOI 10.54499/UIDB/04501/2020 and UIDP/04501/2020-DOI 10.54499/UIDP/04501/2020), through national funds. There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.
Investigating metabolic activity during oocyte and early embryo development through label-free metabolic imaging: a systematic approach for timelapse applications.
Horta F, Vuyyuru A, Newman H … +9 more , Ballerin G, Mercer S, Rolfe E, Haft-Tananian M, Pangestu M, Temple-Smith P, Vollenhoven B, Gilchrist RB, Catt S
Hum Reprod · 2025 Dec · PMID 41206605 · Full text
STUDY QUESTION: Is it possible to assess label-free live cell metabolic imaging during early oocyte and embryo development? SUMMARY ANSWER: Label-free metabolic imaging can be systematically used during early development...
STUDY QUESTION: Is it possible to assess label-free live cell metabolic imaging during early oocyte and embryo development? SUMMARY ANSWER: Label-free metabolic imaging can be systematically used during early development, showing no differences between controls and illuminated oocytes and embryos in terms of early development, blastocyst formation, and embryo outgrowth. WHAT IS KNOWN ALREADY: Non-invasive methods that are reliable to assess oocyte and embryo quality are a significant aim for ARTs. Changes in metabolic activity could lead to cell death or altered early development and low implantation potential. This could potentially be predicted by incorporating non-invasive measurements of metabolism. Metabolic imaging has been investigated through complex methodologies; however, scientific evidence for its utility during early oocyte and embryo development requires further investigation to assess potential translation in clinical settings. Measurements of metabolic activity could be a useful tool, as the autofluorescence of molecules such as nicotinamide adenine dinucleotide phosphate hydrogen (NAD(P)H) and flavin adenine dinucleotide (FAD) are a straightforward representation of mitochondrial function. STUDY DESIGN, SIZE, DURATION: Female mice (n = 15) and super-ovulated female mice (n = 30) were used to produce oocytes and embryos, respectively. Oocytes and in-vivo produced embryos were divided into the control group, sham control group, and illuminated group. Illuminated samples were assessed for both NAD(P)H and FAD levels in oocytes and NAD(P)H levels during early embryo development every 3 h using arbitrary units of autofluorescence (AU). Produced blastocysts were assessed for total cell and inner-cell-mass (ICM) number (by immunostaining for Oct4) and embryo outgrowth assays. Furthermore, safety live birth studies were also conducted. PARTICIPANTS/MATERIALS, SETTING, METHODS: F1 (C57BL6/CBA) mouse strain was used. NAD(P)H and FAD autofluorescence levels were measured during oocyte and embryo development using confocal microscopy (Olympus FV1200). A confocal Z-stacking function was used to record 15 focal planes, using a 20×/0.95 NA air objective of the entire oocytes and embryos and opening the confocal pinhole system completely. Images were then collected and analysed using FIJI software (version: 2.0.0-rc-69/1.52n; ImageJ). Developmental rates, blastocyst cell numbers, outgrowth rates (for 4 days post blastocyst formation), and live birth rates were assessed. MAIN RESULTS AND THE ROLE OF CHANCE: Oocyte IVM and embryo culture experiments showed no significant differences in developmental rates between study groups (P > 0.05). Similarly, the total number of cells from blastocysts (control: 82.9 ± 5.6; sham: 76.5 ± 3.3; Illuminated: 77.1 ± 4.2; ± SEM) and ICM cells (control: 10.8 ± 1.3; sham: 9.4 ± 0.7; Illuminated: 11.9 ± 0.8; ± SEM) did not differ between groups (P > 0.05). Outgrowth assays of the study groups presented similar outgrowth areas during Days 5-8 (post) blastocyst development (P > 0.05). Illumination of oocytes demonstrated a significant increase in metabolic activity during IVM, measured by the optical redox ratio (ORR: FAD/NAD(P)H + FAD; P < 0.001). Illumination of embryos demonstrated significantly different NAD(P)H activity levels during embryo development, particularly between the two-cell stage (987.1 ± 36.2 AU), morula stage (1226.0 ± 31.5 AU) and blastocyst stage (649 ± 42.9 AU; ± SEM; P < 0.05). Additionally, embryos that did not form blastocysts also presented significantly decreased NAD(P)H activity levels at the two-cell stage (normal development: 987.1 ± 36.2; no blastocyst: 726.9 ± 121.7 AU; P < 0.05) to the morula stage (normal development: 1226.0 ± 31.5; no blastocyst: 886.0 ± 150.4 AU; P < 0.05) when compared with normally developing embryos. Our study indicated that metabolic imaging during early oocyte and embryo development presents no negative effects on developmental rates, blastocyst quality, and embryo outgrowths. Subsequently, live birth rates and offspring health showed no differences between controls and illuminated embryos at the blastocyst stage. Current results provide significant useful information about metabolic activity during live cell imaging as a potential method for timelapse metabolic imaging. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: The study was conducted using a mouse model and focused on early oocyte and embryo development, embryo outgrowths, live birth, and early offspring health. Thus, further studies of long-term offspring health are required to fully assess safety and to further validate potential wider applications. Validation in ageing models is also required to assess potential applications for embryo selection. WIDER IMPLICATIONS OF THE FINDINGS: Measurements of metabolic activity could be applied to determine oocyte and embryo metabolic activity using a variety of microscopy technology with low energy doses as described in this study. Further applications could link the use of metabolic imaging with timelapse technology and artificial intelligence applications to monitor culture conditions. STUDY FUNDING/COMPETING INTEREST(S): This study was funded in part by a research/educational grant from Ferring Pharmaceuticals, awarded from the Fertility Society of Australia and New Zealand (FSANZ). Funding was also provided in part by the Education Program in Reproduction and Development (EPRD), Department of Obstetrics and Gynaecology, Monash University. F.H. and M.H.-T. have applied for a patent in the topic of metabolic imaging. R.B.G. declares speakers' fees from Gedeon Richter and Ferring. The other authors have nothing to declare.
The emerging role of the oocyte cortical domain in maturation, fertilization, and development.
Coticchio G, Casciani V, Rienzi L … +5 more , Cimadomo D, Cosseddu C, Taggi M, Ledda S, Bebbere D
Hum Reprod · 2025 Dec · PMID 41206604 · Publisher ↗
The cell cortex, a cytoskeletal network with regulatory signalling pathways, is localized beneath the cell membrane: it is especially prominent in mammalian oocytes. As in other cells, the cortex ensures appropriate shap...
The cell cortex, a cytoskeletal network with regulatory signalling pathways, is localized beneath the cell membrane: it is especially prominent in mammalian oocytes. As in other cells, the cortex ensures appropriate shape and robustness of oocytes. It is also involved in other key and more specific functions. The cortex is part of the interface between the germinal and somatic cell compartments; as such, it participates in the delicate bi-directional interaction by which oocytes regulate cumulus cell function and in return, oocytes receive nutrients and regulative factors from cumulus cells. During oocyte maturation, fertilization, and early development, the cortex undergoes major structural and functional modifications. Such changes are needed to support crucial processes, including meiotic spindle localization, polar body extrusion, chromosome segregation, and pronuclear formation. Cortex dysregulation may be also implicated in blastomere fragmentation during early embryo development. Mechanical properties of the cortex are associated with oocyte quality and developmental competence; with appropriate technology, such properties could be harnessed to develop new approaches to non-invasive oocyte assessment in human IVF.
Proteomic profiling reveals the molecular signatures of chemotherapy-induced human ovarian damage.
Grosbois J, Bisteau X, Imbault V … +5 more , Conrard L, Condorelli M, Findikli N, Lybaert P, Demeestere I
Hum Reprod · 2025 Dec · PMID 41206366 · Full text
STUDY QUESTION: How does first-line chemotherapy alter follicular survival and the ovarian microenvironment? SUMMARY ANSWER: First-line chemotherapy exposure prior to ovarian tissue cryopreservation (OTC) induces follicu...
STUDY QUESTION: How does first-line chemotherapy alter follicular survival and the ovarian microenvironment? SUMMARY ANSWER: First-line chemotherapy exposure prior to ovarian tissue cryopreservation (OTC) induces follicular DNA damage and apoptosis, and causes microenvironmental alterations including immune dysfunction, increased hypoxia and apoptosis, impaired cell cycle and DNA repair capacity, and disruption of the extracellular matrix (ECM). WHAT IS KNOWN ALREADY: Although the mechanisms underlying chemotherapy-induced damage to germ cells are being increasingly deciphered, its impact on the ovarian microenvironment remains largely unexplored. The ovarian stroma is equally exposed to chemotherapy, and since its cells and components are in active communication with follicles, any microenvironmental changes induced by chemotherapy might affect follicles as well. STUDY DESIGN, SIZE, DURATION: Cryopreserved ovarian cortex samples from 10 cancer patients (aged 24-30 years) who donated tissue for research purposes were analyzed. Of the 10 patients, 5 had received first-regimen chemotherapy and 5 age-matched controls had not undergone chemotherapy prior to OTC. Chemotherapy-induced ovarian injury was evaluated by comparing stromal and follicular alterations between chemotherapy-exposed and control patients. PARTICIPANTS/MATERIALS, SETTING, METHODS: Cryopreserved ovarian cortex were processed directly after thawing. Proteins and biological processes dysregulated in response to chemotherapy were identified by mass spectrometry, and the data obtained were validated by western blotting and immunohistochemistry. Stromal and follicular alterations were further examined by (immuno)histochemistry, focusing on apoptosis (TUNEL), DNA damage (γH2Ax), oxidative stress (8-OHdG), proliferation (Ki67), fibrosis (picrosirius red), and analysis of follicle number, developmental stage and morphology. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 5209 proteins were detected in both chemotherapy-exposed and control ovaries, of which 237 proteins (4.5%) showed differential expression. Biological pathways related to immune response, hypoxia and apoptosis were upregulated after chemotherapy exposure, while those involved in cell cycle and DNA repair were downregulated. Markers of the ECM network were also dysregulated. Western blotting and immunostaining confirmed the significant upregulation of complement C3 (innate immunity; P = 0.032), SELENBP1 (hypoxia; P = 0.030) and KRT18 (apoptosis; P = 0.015) as well as a non-significant increase in SERPIN A3 level (ECM; P = 0.077) following chemotherapy-exposure, while NCBP2 (DNA repair) was reduced, though not significantly (P = 0.067). Targeted analyses demonstrated that despite increased stromal cell density following chemotherapy treatment (1.84 ± 0.15 × 106 cells/mm3 vs. 1.62 ± 0.13 × 106 cells/mm3; P = 0.036), no fibrosis was observed. Stromal apoptosis and oxidative stress levels were comparable in both groups (P = 0.464 and P = 0.247, respectively). In contrast, first-regimen chemotherapy persistently affected germ cells, increasing follicular apoptosis (P = 0.013), DNA damage (P = 0.033) and possibly morphological defects (P = 0.061), without depleting the ovarian reserve. LIMITATIONS, REASONS FOR CAUTION: Patients previously exposed to chemotherapy had received different low-gonadotoxic chemotherapy regimens at different times before OTC, making it challenging to isolate the effects of individual agents or to differentiate between short- and long-term dysregulated biological processes. Additionally, analyses were performed on a small cohort and results should be interpreted cautiously. WIDER IMPLICATIONS OF THE FINDINGS: These findings provide evidence that chemotherapy significantly alters both the ovarian germ cells and stroma, emphasizing the need to further investigate the underlying molecular mechanisms and their impact on ovarian function and fertility preservation. They also suggest target proteins which may drive these chemotherapy-associated ovarian damage for future investigations. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by a grant from the Fond National de la Recherche Scientifique de Belgique-FNRS (grant 1.B.218.24F awarded to J.G.). The support is provided by the Funds Suzanne Duchesne, Serge Rousseau and Docteur Jean Gérard, managed by the King Baudouin Foundation, and by the Jaumotte-Demoulin Foundation. The CMMI is supported by the European Regional Development Fund and the Walloon Region. J.G. and I.D. are supported by FNRS as a postdoctoral researcher and a senior research associate, respectively. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.
Prolonged vaginal progesterone supplementation does not improve outcomes for Day 6 frozen blastocyst transfers in oocyte donation cycles.
Blázquez A, Miguel-Escalada I, Portas-Gómez L … +4 more , Guillén-Quílez JJ, Mataró D, Popovic M, Rodríguez-Aranda A
Hum Reprod · 2026 Jan · PMID 41206359 · Publisher ↗
STUDY QUESTION: Does extending vaginal progesterone administration from 5-6 days improve pregnancy outcomes in Day 6 (D6) frozen embryo transfers (FETs) in oocyte donation cycles? SUMMARY ANSWER: Prolonging the time of v...
STUDY QUESTION: Does extending vaginal progesterone administration from 5-6 days improve pregnancy outcomes in Day 6 (D6) frozen embryo transfers (FETs) in oocyte donation cycles? SUMMARY ANSWER: Prolonging the time of vaginal progesterone supplementation does not improve pregnancy outcomes after D6 FETs in oocyte recipients. WHAT IS KNOWN ALREADY: Progesterone is critical for endometrial preparation prior to embryo transfer, but the optimal duration of administration remains unclear. D6 blastocysts are associated with poorer clinical outcomes compared to Day 5 (D5) blastocysts, potentially due to either intrinsic limitations in implantation capacity or a shifted window of implantation (WOI). Extending progesterone administration has been hypothesized to optimize the WOI for D6 blastocysts. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study included 485 FETs performed in 420 oocyte donation recipients, conducted from January 2020 to December 2023 in a single IVF center. Participants were divided into two groups based on the duration of progesterone supplementation: 5 days (P + 5, n = 282) and 6 days (P + 6, n = 203). PARTICIPANTS/MATERIALS, SETTING, METHODS: The study involved oocyte recipients undergoing single D6 blastocyst transfer following endometrial preparation with vaginal progesterone (800 mg/day). Outcomes were analyzed using univariate and multivariate tests, including logistic regression adjusted for estrogen type and endometrial thickness. MAIN RESULTS AND THE ROLE OF CHANCE: Mean recipient age (±SD) was 43.5 (±4.24) years, mean BMI was 25.1, and mean endometrial thickness was 9.6 mm on the day of transfer. Good-quality blastocysts accounted for 35% of all transfers. Clinical outcomes, including biochemical (26.24% vs 26.60%, P = 1.00), clinical (21.99% vs 20.69%, P = 0.83), and ongoing pregnancy (14.54% vs 13.30%, P = 0.79), as well as live birth (14.18% vs 10.66%, P = 0.27) and miscarriage rates (7.45% vs 7.39%, P = 1.00), were all similar between 5 and 6 days of progesterone supplementation, respectively. Adjusted analyses confirmed these findings. LIMITATIONS, REASONS FOR CAUTION: The retrospective design warrants careful interpretation. Results are specific to vaginal progesterone in oocyte donation cycles and may not apply to other populations or progesterone delivery methods. Additionally, the D6 embryos analyzed were those that did not reach blastocyst by Day 5 (delayed, poor-prognosis, and typically transferred last), which likely biases outcomes toward lower live birth rates. WIDER IMPLICATIONS OF THE FINDINGS: Compromised outcomes following D6 FETs compared to those of D5 blastocysts, likely reflect the intrinsic limitations of slow-developing embryos rather than a misaligned WOI. As prolonged progesterone exposure did not improve outcomes, the WOI may be broader than previously assumed, particularly in oocyte donation programs, where superior embryo quality may mitigate synchronization drawbacks. STUDY FUNDING/COMPETING INTEREST(S): This study was internally funded by the Eugin Clinic, with no external sponsorship. The authors declare no competing interests. TRIAL REGISTRATION NUMBER: NA.
Identification of novel differentiation trajectories and gene network associations with ectopic pregnancy in fallopian tube epithelium.
Wright LI, Wangsaputra I, Garner T … +4 more , Sharps MC, Sturmey R, Ruane PT, Stevens A
Hum Reprod · 2025 Dec · PMID 41183511 · Full text
STUDY QUESTION: Can network modelling of single-cell transcriptomic data identify cellular developmental trajectories of fallopian tube (FT) epithelium and reveal functional and pathological divergence from the endometri...
STUDY QUESTION: Can network modelling of single-cell transcriptomic data identify cellular developmental trajectories of fallopian tube (FT) epithelium and reveal functional and pathological divergence from the endometrium? SUMMARY ANSWER: A bidirectional differentiation trajectory originating from a novel OVGP1+ progenitor population of FT epithelial cells was uncovered, and causal network modelling of whole-transcriptome activity in the FT and endometrium revealed functional divergence between their secretory epithelial cells, with implications for ectopic pregnancy candidate genes. WHAT IS KNOWN ALREADY: The FT forms the in vivo peri-conceptual environment, which has a significant impact on programming offspring health. The FT epithelium establishes this environment; however, the epithelial cell types are poorly characterized in health and disease. STUDY DESIGN, SIZE, DURATION: Publicly available, benign FT single-cell RNA sequencing (scRNA-seq) samples from 13 women across three previous studies were combined. Endometrial scRNA-seq samples from 13 women from one study were used to demonstrate transcriptomic differences between the epithelia of the two tissues. Network models of transcriptomic action were constructed with hypergraphs. PARTICIPANTS/MATERIALS, SETTING, METHODS: A meta-analysis of FT scRNA-seq samples was performed to identify epithelial populations. Differential gene expression assessed differences between FT and endometrial epithelial scRNA-seq data. Functional differences between secretory cells in the tissues were characterized using hypergraph models. To identify associations with ectopic pregnancy, expression quantitative trait loci (eQTLs) from a recent GWAS were mapped onto the network models. MAIN RESULTS AND THE ROLE OF CHANCE: Epithelial cells (n = 14 360) were clustered into eight secretory and ciliated epithelial populations in the meta-analysis of three scRNA-seq datasets. A novel OVGP1+ epithelial progenitor cell was also identified, and its bidirectional differentiation to mature secretory or mature ciliated populations was mapped by RNA velocity analysis. This progenitor exhibited a high velocity magnitude (12.47) and low confidence (0.69): a combination strongly indicative of multipotent progenitor status. Comparing FT epithelial cells with endometrial epithelial cells revealed 5.3-fold fewer shared genes between FT and endometrial glandular secretory cells than between FT and endometrial ciliated cells, suggesting functional divergence of secretory cells along the reproductive tract. Hypergraphs were used to identify highly coordinated regions of the transcriptome robustly associated with functional gene networks. In the FT secretory cells, these networks were enriched for lipid-related (false discovery rate (FDR) < 0.002) and immune-related (FDR < 0.00007) pathways. We mapped eQTLs from a GWAS meta-analysis of 7070 women with ectopic pregnancy over a range of significance (P = 1.68 × 10-21-5.8 × 10-4) to the hypergraphs of FT and endometrium. Of the 22 genes present in the hypergraphs, 13 of these clustered as highly coordinated genes. This demonstrated the functional importance of MUC1 in the FT and endometrium (GWAS Study P = 5.32 × 10-9) and identified additional genes (SLC7A2, CLDN1, GLS, PEX6, PLXNA4, NR2F1, CLGN, PGGHG, and ANKRD36) implicated in ectopic pregnancy and eutopic pregnancy. LIMITATIONS, REASONS FOR CAUTION: The sample size of reproductive age women was limited in previous studies, and though causal network modelling was used and previous mechanistic data supports candidate gene involvement, no in vitro or in vivo validation of candidate was performed. WIDER IMPLICATIONS OF THE FINDINGS: These findings consolidate the existing single-cell transcriptomic datasets of the FT to provide a comprehensive understanding of epithelial populations and define functionally distinct secretory cells that contribute to the peri-conceptual environment of the FT. This study further implicates the role of MUC1 and secretory cells in ectopic pregnancy and suggests future targets for investigating embryo implantation in the FT and endometrium. STUDY FUNDING/COMPETING INTEREST(S): No funding was received for this study. The authors do not disclose any competing interests. TRIAL REGISTRATION NUMBER: N/A.
Administration of ethiodized poppy seed oil-based contrast agent into the uterus enhances fertilization rate in mice inseminated with low sperm numbers.
Del Llano E, Rasschaert M, Arnoult C … +3 more , Robert P, Ray PF, Loeuillet C
Hum Reprod · 2026 Jan · PMID 41183506 · Full text
STUDY QUESTION: Does the administration of an oil-based iodinated contrast medium (OSCM) in the mouse uterus have a positive effect on fertility similarly to what is observed in women following hysterosalpingography (HSG...
STUDY QUESTION: Does the administration of an oil-based iodinated contrast medium (OSCM) in the mouse uterus have a positive effect on fertility similarly to what is observed in women following hysterosalpingography (HSG)? SUMMARY ANSWER: Following IUI of a small number of sperm (mimicking oligozoospermia), fertilization and birth rates were improved in female mice who had previously received an intrauterine administration of an OSCM confirming a pro-fertility effect. WHAT IS KNOWN ALREADY: HSG is a common diagnostic procedure used in infertile or subfertile women, primarily to assess the patency of fallopian tubes. It consists in injecting an iodinated contrast medium into the uterus to enable the imaging of the female reproductive tract by radiography. In the absence of obstruction, the contrast medium fills the uterus and transits through the fallopian tubes before overflowing in the peritoneal cavity. Several studies reported that in the few months following HSG, women injected with an OSCM (ethyl esters of iodinated fatty acids of poppy seed oil) had an enhanced pregnancy rate (either spontaneous or following IUI) compared to those administered with a water-based contrast medium. This suggests that OSCM administration in the female reproductive tract could improve fertility. However, the physiological mechanisms underlying this potential effect remain unknown. STUDY DESIGN, SIZE, DURATION: OSCM or PBS (phosphate buffered saline, control) were administered into the uteri of B6D2 female mice (5-9 weeks old, total n = 73). Two weeks later, intrauterine insemination was performed with mouse epididymis sperm from B6D2 male mice (8-16 weeks old). Females were euthanized and fertilized oocytes collected and incubated for 4 days up to the blastocyst stage (n = 52). Alternatively, females were left until delivery (n = 21). PARTICIPANTS/MATERIALS, SETTING, METHODS: Female nulliparous mice were administered either with PBS or OSCM directly into the uterus. After 2 weeks, females were inseminated with a controlled number of sperm. The resulting fertilized/unfertilized oocytes were collected and counted the following day to calculate the fertilization rates and then further incubated in vitro to follow the development to the blastocyst stage. In addition, females were mated with vasectomized males to allow implantation, subsequent pregnancy and birth. MAIN RESULTS AND THE ROLE OF CHANCE: First, females were inseminated with a high number of sperm (5 × 10e5 spermatozoa). Comparable fertilization rates (67.0 ± 5.4% and 60.0 ± 8.0%, P > 0.05) were observed from oocytes originating from OSCM and PBS-administered mice, respectively. This showed that when inseminating with a high number of sperm, uterine OSCM administration had no deleterious effect but did not improve fertilization. We postulated that the potential beneficial effect of OSCM administration might be masked by the optimal reproductive system of young mice. It was therefore decided to test the effect of OSCM in suboptimal reproductive conditions such as those observed when sperm concentration is low (oligozoospermia). As could be expected, fertilization rate decreased proportionally to the reduction of inseminated sperm suggesting that it is a relevant model for oligozoospermia and to mimic subfertility. When using a suboptimal number of spermatozoa (15 × 10e3), the fertilization rate was significantly increased in OSCM administered mice compared to controls (29.9 ± 4.8% and 12.6 ± 3.0%, P < 0.05, respectively). Moreover, OSCM administered females also gave birth to a higher number of pups than controls (3.7 ± 1.7 and 0.9 ± 0.9, P < 0.05). LARGE SCALE DATA: No large scale data were produced in this study. LIMITATIONS, REASONS FOR CAUTION: The reason for studying the effects of oil soluble iodinated contrast media on mouse fertility is based on the results from several clinical studies in humans. Those reports included women of different age and suffering from different types of infertility or subfertility. Moreover, the timing of their pregnancies after OSCM treatment also occurred at different times. Our mouse model and experiments do not include such heterogeneity as the inclusion of variables related to age, time of pregnancy and fertility deficiencies, which would demand a much larger number of mice, contrary to the 3R principles (Replacement, Reduction and Refinement of animal experimentation). For the same reason, our results are based upon mice treated with OSCM in contrast to mice treated with PBS, while human clinical reports may include alternatives to OSCM. Moreover, it is important to note that mouse and human reproductive systems differ at several levels such as morphology, hormonal influences, oestrus, menstrual cycles and pregnancy, raising the possibility that OSCM action may differ across species. In our mouse model, OSCM does not cross the uterotubal junction in the mice during administration, restricting it to the uterus, thus excluding any possible effects on the oviducts and peritoneal cavity, which are reached by OSCM in humans. Additionally, as the mouse reproductive cycle is much faster than that of women, it is likely that the amount of OSCM remaining in the mouse uterus after 2 weeks differs from what is left in women after several months. WIDER IMPLICATIONS OF THE FINDINGS: In our mouse model, OSCM administration in the uterus increased the number of embryos and pups obtained when inseminated with low sperm numbers. This suggests that the increased fertilization rate is most probably due to an effect on the uterus itself or on the sperm which go through it before reaching the fertilization site. In the mouse, the presence of OSCM in the oviduct and inside the peritoneal cavity is not necessary to observe a beneficial effect of the contrast agent. These initial results demonstrate that the mouse model could be used to further study the OSCM mechanisms in the uterus. Most importantly, our results confirm a beneficial effect of OSCM on fertility and suggest that it could help couples with fertility issues, improving fertilization and pregnancy rates following IUI with substandard sperm samples. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Guerbet Group, INSERM, CNRS, Université Grenoble Alpes and the French Agence Nationale pour la Recherche (ANR) grant "LIPIOFERT" (ANR-23-CE18-0039) to C.L. Guerbet Group is producer and distributor of Lipiodol®, provided by Guerbet free of charge for this study. The study was partly financed by Guerbet and M.R. and P.Ro. are Guerbet's employees. Data were produced and analysed independently by academic researchers from the GETI's laboratory E.L., C.A., P.Ra., and C.L. E.L. was temporarily employed by Guerbet from 1 December 2022 to 31 May 2023.
Patient characteristics associated with symptoms of anxiety, depression, and reduced body appreciation in women with polycystic ovary syndrome.
Jannink TI, Bordewijk EM, Lehmann V … +3 more , Hoek A, Goddijn M, van Wely M
Hum Reprod · 2025 Dec · PMID 41182285 · Full text
STUDY QUESTION: Which polycystic ovary syndrome (PCOS)-related and general patient characteristics are associated with higher levels of anxiety and depressive symptoms, as well as with reduced body appreciation in women...
STUDY QUESTION: Which polycystic ovary syndrome (PCOS)-related and general patient characteristics are associated with higher levels of anxiety and depressive symptoms, as well as with reduced body appreciation in women with PCOS? SUMMARY ANSWER: Anxiety was more common among participants with alopecia, obesity, younger age, and a history of anxiety or depression; depression was more common in participants with alopecia, unemployment, and a history of depression; and body appreciation scores were lower in participants with hirsutism, acne, alopecia, obesity, younger age, and a history of anxiety or depression. WHAT IS ALREADY KNOWN: Women diagnosed with PCOS face over 30% likelihood of clinically relevant anxiety symptoms, over a 15% likelihood of clinically relevant depressive symptoms, and also experience reduced body appreciation. Evidence suggests that in women with PCOS, various factors may contribute to increased levels of anxiety and depression and reduced body appreciation. However, findings across studies are inconsistent, and the nature of these associations, as well as the potential influence of patient characteristics that have been less studied, are still not well understood. STUDY DESIGN, SIZE, DURATION: A cross-sectional online survey study was carried out from May 2021 to July 2023. Recruitment occurred through fertility clinics in the Netherlands, employing posters, leaflets with QR codes, and online platforms run by patient organizations. PARTICIPANTS/MATERIALS, SETTING, METHODS: The participants were women with self-reported PCOS. They completed the Hospital Anxiety and Depression Scale (HADS) and the Body Appreciation Scale-2 (BAS-2). We assessed the association with mental health outcomes (symptoms of anxiety and depression, as well as body appreciation) with PCOS-related patient characteristics (hirsutism, acne, alopecia, obesity, and oligomenorrhea) and general characteristics (age, employment status, medical history, and medication use). Multivariable logistic and linear regression analyses were used, and adjusted odds ratios (aORs) or adjusted mean differences (aMDs) with 95% CI were calculated. MAIN RESULTS AND THE ROLE OF CHANCE: We included 982 women, with 37.0% showing clinically relevant symptoms of anxiety (score ≥11) and 17.4% showing clinically relevant depressive symptoms (score ≥11). Risk factors associated with anxiety symptoms were alopecia (aOR: 1.79, 95% CI 1.35-2.38), obesity (aOR: 1.40, 95% CI 1.03-1.90), younger age (aOR per year older: 0.93, 95% CI: 0.91-0.96), and medical history of anxiety or depression (aOR: 2.63, 95% CI 1.82-3.79 and aOR: 1.60, 95% CI 1.13-2.28). Risk factors associated with symptoms of depression were alopecia (aOR: 1.74, 95% CI 1.21-2.50), unemployment (aOR: 2.59, 95% CI 1.56-4.31), and a medical history of depression (aOR: 1.89, 95% CI 1.25-2.85). Risk factors associated with reduced body appreciation were hirsutism (aMD: -2.29, 95% CI -3.41 to -1.16), acne (aMD: -1.14, 95% CI -2.11 to -0.17), alopecia (aMD: -1.93, 95% CI -2.89 to -0.97), obesity (aMD: -6.31, 95% CI -7.36 to -5.27), oligomenorrhea (aMD: -1.81, 95% CI -2.78 to -0.83), and younger age (aMD per year older: 0.13, 95% CI 0.04-0.23). A medical history of anxiety or depression disorder was also associated with reduced body appreciation (aMD: -1.80, 95% CI -3.10 to -0.50; aMD: -2.81, 95% CI -4.05 to -1.57, respectively). LIMITATIONS, REASONS FOR CAUTION: Results are based on self-reported PCOS diagnoses and may have been affected by sampling bias. WIDER IMPLICATIONS OF THE FINDINGS: It is crucial for healthcare providers to understand which characteristics in women with PCOS may influence the development of anxiety, depression, or reduced body appreciation. Such awareness helps them to be more alert and better recognize the different types of mental health concerns, enabling referrals and more targeted mental health support. STUDY FUNDING/COMPETING INTEREST(S): This study was not funded by a specific grant. No conflicts of interest were reported in relation to the current research. TRIAL REGISTRATION NUMBER: Not applicable.
Identification of potential NAD-related biomarkers of recurrent miscarriage risk.
Cuny H, Shand AW, Goth J … +8 more , Sheng DZ, Tossey T, Martin EMMA, Sipka A, Aleshin O, Schneuer FJ, Nassar N, Dunwoodie SL
Hum Reprod · 2025 Dec · PMID 41170824 · Full text
STUDY QUESTION: Do women with a history of recurrent miscarriage have altered nicotinamide adenine dinucleotide (NAD)-related metabolites that can be detected in blood, plasma, or urine samples? SUMMARY ANSWER: Women wit...
STUDY QUESTION: Do women with a history of recurrent miscarriage have altered nicotinamide adenine dinucleotide (NAD)-related metabolites that can be detected in blood, plasma, or urine samples? SUMMARY ANSWER: Women with a history of recurrent miscarriage have higher blood, plasma, and urine concentrations of NAD Salvage Pathway excretion products, and urinary excretion of nicotinamide (NAM) is also elevated, compared to control women. WHAT IS KNOWN ALREADY: Recurrent miscarriage risk is associated with advancing age, high and low BMI, dietary factors, various medical conditions including inflammation, as well as environmental exposures, e.g. to chemicals and pollution. Perturbation of NAD synthesis due to genetic and/or environmental factors causes NAD deficiency, which is implicated in Congenital NAD Deficiency Disorder (CNDD) characterized by recurrent pregnancy loss and congenital anomalies. In CNDD mouse models, foetal anomalies and embryo loss are prevented if NAD levels are raised by supplementing the mother's diet with an NAD precursor, such as vitamin B3, during pregnancy. STUDY DESIGN, SIZE, DURATION: This prospective pilot cohort study included 88 non-pregnant women between 20 and 40 years of age, 37 with and 51 without a history of recurrent miscarriage. Recurrent miscarriage was defined as a history of two or more consecutive spontaneous miscarriages <20 weeks' gestation, with the last miscarriage between 6 weeks and 2 years prior to recruitment. The study was conducted at the Royal Hospital for Women, Sydney, Australia, between March 2022 and December 2023. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants completed a questionnaire about their socio-demographic characteristics, health, lifestyle, diet, medication, and vitamin use; and provided morning fasting blood and urine samples. Levels of NAD and 25 related metabolites were measured in whole blood, plasma, and urine using a validated ultra-high performance liquid chromatography-tandem mass spectrometry method. Differences in NAD metabolism between the groups were assessed by volcano plots and partial least-squares discriminant analysis. Characteristics of women between the two groups were compared using chi-squared statistics. Multivariable generalized additive models were used to assess the association between NAD metabolites and miscarriage. Predictive accuracy of metabolites alone and with age was examined using three machine learning models, including Logistic Regression, Random Forest, and Gradient Boosting Classifier and assessed using the area under the receiver operating characteristic curve (AUROC). MAIN RESULTS AND THE ROLE OF CHANCE: Elevated levels of the metabolites 1-methylnicotinamide (1MNA), N-methyl-2-pyridone-5-carboxamide (2PY), and N-methyl-4-pyridone-3-carboxamide (4PY), representing excretion metabolites of the NAD Salvage Pathway, were associated with a higher risk of recurrent miscarriage. These metabolites showed a strong positive correlation among the three tested biological matrices, confirming the suitability of all three matrices to quantify these markers. Whole blood anthranilic acid and urine NAM levels were also elevated in women with recurrent miscarriage. 1MNA in plasma was associated with recurrent miscarriage on univariate analysis, with the effect sustained after taking into account maternal age (adjusted odds ratio 1.02; 95% CI 1.01, 1.03) with every one-unit increase in 1MNA, the odds of miscarriage increasing by 2%. The predictive accuracy using machine learning approaches was highest when all three metabolites 1MNA, 2PY, and 4PY, and age were included in the model (AUROC 0.89; 95% CI 0.83, 0.95). LIMITATIONS, REASONS FOR CAUTION: This study was conducted in a single hospital, which assures high internal validity but may limit external validity. Sample size was small, and findings should be replicated in larger studies. The measured levels of NAD-related metabolites represent a snapshot at the time of sample collection but might not be reflective of when the women had been pregnant. WIDER IMPLICATIONS OF THE FINDINGS: Our novel finding of elevated excretion of NAM and its derived products in women experiencing recurrent miscarriage suggests differences in the NAD synthesis pathway are linked to adverse pregnancy outcomes. The significant differences in 2PY and 4PY levels in the circulation and urine between the study groups indicate that these metabolites are potential biomarkers associated with recurrent miscarriage. Several conditions which are associated with adverse pregnancy outcomes also affect NAD metabolism and cause elevated levels of these metabolites. Thus, these metabolites may not simply be biomarkers but also be an indicator of the underlying mechanisms in many cases of recurrent miscarriage. Further evaluation of NAD metabolism in women with recurrent miscarriage in other populations and of other associations including diet is required. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by funds to S.L.D. from: the National Health and Medical Research Council (NHMRC), Principal Research Fellowship (ID1135886), Leadership Level 3 Fellowship (ID2007896), and Project Grant (ID1162878); a New South Wales (NSW) Health Cardiovascular Research Capacity Program Senior Researcher Grant; philanthropic support from The Key Foundation, The Ross Trust, and Steven and Linda Harker. N.N. was supported by NHMRC Leadership Level 1 Fellowship (ID1197940) and Financial Markets Foundation for Children. We gratefully acknowledge the Victor Chang Cardiac Research Institute Innovation Centre, funded by the NSW Government, as well as funding from the Freedman Foundation for the Metabolomics Facility. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.
Correction to: O-020 Impact of an oral antioxidant supplement in men on semen quality and pregnancy rates, results of a multicentre, randomised, triple-blind, placebo-controlled trial (SUMMER trial).
Hum Reprod · 2025 Dec · PMID 41147359 · Publisher ↗
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Obstetric and perinatal outcomes from the follow-up of a multicentre randomized controlled trial investigating time-lapse embryo monitoring.
Kieslinger DC, Vergouw CG, von Estorff F … +26 more , Ramos L, Arends B, Curfs MHJM, Slappendel E, Kostelijk EH, Pieters MHEC, Consten D, Verhoeven MO, Besselink DE, Broekmans F, Cohlen BJ, Smeenk JMJ, Mastenbroek S, de Koning CH, van Kasteren YM, Moll E, van Disseldorp J, Brinkhuis EA, Kuijper EAM, van Baal WM, van Weering HGI, van der Linden PJQ, Gerards MH, Bossuyt PM, van Wely M, Lambalk CB
Hum Reprod · 2026 Jan · PMID 41139424 · Full text
STUDY QUESTION: Does uninterrupted culture in a time-lapse incubator with or without a commercially available machine learning embryo selection algorithm result in comparable obstetric and perinatal outcomes as interrupt...
STUDY QUESTION: Does uninterrupted culture in a time-lapse incubator with or without a commercially available machine learning embryo selection algorithm result in comparable obstetric and perinatal outcomes as interrupted culture and morphological embryo selection? SUMMARY ANSWER: The application of uninterrupted culture in a time-lapse incubator with and without the use of an embryo selection algorithm is comparable to interrupted embryo culture and morphological embryo selection in terms of obstetric and perinatal results. WHAT IS KNOWN ALREADY: There is very limited evidence regarding the safety of time-lapse monitoring (TLM) from prospective randomized controlled trials (RCT). Recent RCTs have demonstrated that the application of TLM does not increase (cumulative) live birth rates or shorten the time to pregnancy within 1 year. Although most studies only report pregnancy rates, the safety of this commonly used method is also relevant for decision-making. STUDY DESIGN, SIZE, DURATION: The obstetric and perinatal outcomes of patients scheduled for Day 3 single embryo transfer who participated in a multicentre RCT on TLM were studied (SelecTIMO trial). Three groups were compared: (i) TLE: embryo selection based on a commercially available Day 3 TLM algorithm, used adjunctively with morphology, and uninterrupted culture. (ii) TLR: routine morphological embryo selection and uninterrupted culture. (iii) CON: routine morphological embryo selection and interrupted culture. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, 1731 IVF/ICSI patients undergoing their first, second, or third oocyte retrieval cycle were randomized. Obstetric and perinatal data were registered for all pregnancies occurring after fresh and frozen embryo transfers associated with the initial oocyte retrieval cycle as well as natural conceptions within 1 year. Serious pregnancy complications and birth weight were considered main safety outcomes. Mean differences (MD) and age-adjusted relative risks (RRadj) and mean differences with 95% CI were calculated for TLE and TLR versus CON. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 827 women gave birth to a singleton during the follow-up period (TLE = 275, TLR = 278, CON = 274; P = 0.99). Of the 827 women who gave birth to a singleton, 497 deliveries originated from a fresh embryo transfer (60%), 294 from a frozen embryo transfer (36%), and 36 women conceived naturally (4%), with similar proportions in each study group. The proportion of women with serious pregnancy complications was comparable across the three groups (TLE vs CON: RRadj 0.95, 95% CI 0.65-1.40 and TLR vs CON: RRadj 1.03, 95% CI 0.70-1.50; P = 0.89). Mean (SD) gestational age at birth was 39.4 (1.9) weeks, 39.5 (1.5) weeks, and 39.3 (1.9) weeks, respectively. We found no evidence of differences in preterm and very preterm births between groups. Mean (SD) weight at birth was 3413 (588) g, 3412 (588) g, and 3377 (578) g, respectively (TLE vs CON: MD 34, 95% CI -62 to 129 and TLR vs CON: MD 32, 95% CI -635 to 120; P = 0.70). We did not observe substantial differences in babies with low and very low birth weight. Health problems immediately after delivery were reported for eight babies in the TLE group, 12 in the TLR group, and 11 in the CON group. Major congenital malformations occurred in four children in the TLE group, four in the TLR group, and seven in the CON group. Minor congenital malformations occurred in five children in the TLE group, three in the TLR group, and five in the CON group. LIMITATIONS, REASONS FOR CAUTION: This study reports safety outcomes for one type of time-lapse incubator, however, more systems are currently available. WIDER IMPLICATIONS OF THE FINDINGS: Our results suggest that uninterrupted time-lapse culture with and without embryo selection based on machine learning can be regarded as safe compared to interrupted embryo culture and routine morphological selection in terms of obstetric and perinatal risks. STUDY FUNDING/COMPETING INTEREST(S): The authors received a grant from the Netherlands Organisation for Health Research and Development (ZonMw) for the execution of the SelecTIMO study (Health Care Efficiency Research programme grant 843001602). Merck (Germany and The Netherlands) supplied the six time-lapse incubators, funded the laboratory adjustments, and provided technical support and training to laboratory personnel before and during the study. D.C.K. received the Fertility Society of Australia exchange award. The following declarations of interest were made outside of the submitted work: F.B. reports additional financial support for the LUMO trial from Besins Healthcare Monaco, fellowship grants for ongoing basic research from Merck, consulting fees and payment or honoraria from Merck, Besins, and Ferring, and is member of the DSMB of the POISE study UK. J.M.J.S. has received grants or contracts from Ferring BV and Merck (payments to ETZ in both cases); consulting fees for an advisory board from Ferring BV; speakers fee from Merck BV; and support for conference attendance from Ferring BV, Merck, and Goodlife. M.v.W. is Senior Editor of Cochrane and Editor-in-Chief of Human Reproduction Update. C.B.L. reports a speakers honorarium from Organon (The Netherlands) and was Editor In Chief for Human Reproduction at the time of submitting this manuscript. TRIAL REGISTRATION NUMBER: NTR5423: ICTRP Search Portal (who.int).
Embryos not showing pronuclei by single static observation arise from atypical pronuclear dynamics or rare unfertilized oocytes with abortive cleavage behaviour.
Coticchio G, Taggi M, Asturi F … +7 more , Stati A, Bordignon M, Innocenti F, Saturno G, Vaiarelli A, Rienzi L, Cimadomo D
Hum Reprod · 2025 Dec · PMID 41139421 · Publisher ↗
STUDY QUESTION: Is the non-pronuclear (0PN) fertilization pattern, as assessed by single static observation during the 16- to 18-h post-insemination (hpi) interval, compatible with embryo developmental competence? SUMMAR...
STUDY QUESTION: Is the non-pronuclear (0PN) fertilization pattern, as assessed by single static observation during the 16- to 18-h post-insemination (hpi) interval, compatible with embryo developmental competence? SUMMARY ANSWER: A few zygotes show pronuclei (PN) solely outside the static fertilization assessment time interval and can develop to blastocyst stage, while rare cases of cleavage without pronuclear formation always result in early developmental arrest or degeneration. WHAT IS KNOWN ALREADY: Recently, the use of atypically pronucleated zygotes-showing no, one, or three PN (0PN, 1PN, and 3PN), or other less frequent patterns-has been increasingly proposed as a measure to maximize the number of embryos available for treatment and the cumulative clinical outcome per cycle. The use of such zygotes poses important clinical and ethical concerns; it also raises scientific questions, such as the hypothesis that the 0PN pattern can be compatible with pre- and post-implantation development in the absence of actual formation of PN. Allowing detailed observation of embryo morphokinetics, time-lapse technology (TLT) can be decisive in resolving such questions. STUDY DESIGN, SIZE, DURATION: Retrospective observational study (2013-2020) including 6035 oocytes inseminated by ICSI and cultured in a time-lapse imaging incubator system. Zygotes (N = 4479), classified by PN-type, were divided into sub-groups based on timings of PN appearance (tPNa: <16hpi, >16hpi) and PN fading (tPNf: <16hpi, 16-18hpi, 18-20hpi, >20hpi). Their development was monitored until blastocyst stage. The remaining 1556 injected oocytes were either degenerated (N = 801) or did not show PN (true-0PN; N = 755). Among the latter, 186 showed ≥1 cleavage(s) and then degenerated. Their videos were analysed to assess events preceding developmental arrest. PARTICIPANTS/MATERIALS, SETTING, METHODS: Ovarian stimulation with GnRH-antagonist and hCG/agonist trigger was performed, with all patients undergoing ICSI and blastocyst culture. The study endpoints were the blastulation rates across different PN-appearance and -fading thresholds, as well as a thorough description of the events during cell division(s) in 0PN embryos that experienced early arrest. Regression analyses were conducted, adjusting for confounders such as maternal age, male factor, and PN-type, with associations confirmed using generalized estimating equations. MAIN RESULTS AND ROLE OF CHANCE: Zygotes showing two PN (2PN, N = 4479) monitored by TLT were distributed in sub-groups based on tPNf (<16 hpi, N = 11; 16-18 hpi, N = 44; 18-20 hpi, N = 309; >20 hpi, N = 4115). In a few cases (N = 85), PN formation occurred after 16 hpi, up until 31 hpi. Single static observation during the 16- to 18-hpi conventional interval would have missed the zygotes undergoing very early PNf and at least part of those undergoing late PNa. Comparison between the above sub-groups showed that pronuclear fading occurring at 18-20 hpi was associated with the highest blastocyst formation rate (36.4%, 47.7%, 65.4%, and 53.3%, for the diverse tPNf, respectively; P < 0.001). Late tPNa (>16 hpi) was accompanied by reduced blastocyst formation rate (54.5% vs 29.4%; P < 0.001). tPNf occurring at 18-20 hpi was also associated with a higher blastocyst euploidy rate. Of 755 true-0PN oocytes, 186 (24.6%) underwent ≥1 cleavage(s). However, all of them arrested before compaction, often displaying irregular cleavage(s) (including direct, reverse, and chaotic), vacuolization, and/or extensive fragmentation. LIMITATIONS, REASONS FOR CAUTION: The study data are derived from a single, although large, dataset. Therefore, they require independent confirmation. In addition, assessment of fertilization morphokinetics can only be applied to ICSI insemination, leaving fertilization morphokinetics achieved by standard IVF unexplored. WIDER IMPLICATIONS OF THE FINDINGS: TLT confirms the limitations of single static observation, which fails to detect a significant proportion of zygotes, especially if executed relatively late. This has implications for fertilization assessment, prediction of blastulation, and utilization of atypically pronucleated zygotes. Moreover, TLT demystifies the belief that blastocyst development may occur in the absence of pronuclear formation. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: None.
Universal preimplantation genetic testing for monogenic disease (Karyomapping): diagnosis of >1000 unique disorders with no detected misdiagnoses.
Schadwell A, Whiting O, Xanthopoulou L … +7 more , Colls P, Bakosi E, Goodall NN, Ribustello L, Ellis P, Gordon T, Griffin DK
Hum Reprod · 2025 Dec · PMID 41139420 · Full text
STUDY QUESTION: Can a universal diagnostic test (Karyomapping) be applied for preimplantation genetic testing for multiple monogenic disorders (PGT-M) and what is the misdiagnosis rate? SUMMARY ANSWER: Among 9020 cases o...
STUDY QUESTION: Can a universal diagnostic test (Karyomapping) be applied for preimplantation genetic testing for multiple monogenic disorders (PGT-M) and what is the misdiagnosis rate? SUMMARY ANSWER: Among 9020 cases of PGT-M, >1000 different disorders were diagnosed by Karyomapping; independent validation of >70% of cases did not detect a misdiagnosis. WHAT IS KNOWN ALREADY: PGT-M, first performed in 1992, has been used for ∼40 000 clinical cases worldwide. A limiting factor in direct testing for disease mutations, however, is the need to design assays specific for each affected allele. Karyomapping, based on haplotype phasing using SNP microarrays, was developed in 2010 as a single, method tracing inheritance of any monogenic disorder. Karyomapping eliminates the impact of allele drop-out and DNA contamination on test accuracy and facilitates a short work-up time as the same assay platform is used for every case. STUDY DESIGN, SIZE, DURATION: Here, we used Karyomapping on a large PGT-M series from one diagnostic base from January 2014 to December 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: The 9020 individual Karyomapping cases were performed in three CooperSurgical genetic testing laboratories, in Livingston NJ, Michigan, or London (UK). All cases involved trophectoderm biopsy with embryo vitrification. DNA from cheek brush samples was obtained from both parents and an affected reference family member where possible. Genomic DNAs and that of whole genome amplified DNA from embryo biopsies were subjected to SNP microarray. Karyomapping was performed according to manufacturer's instructions by first importing into BlueFuse Multi software. Inheritance was determined as to where at-risk allele(s) were inherited, with 10 supporting 5' and 3' Key SNPs in a 2 Mbp flanking window. Wherever possible, direct mutation testing was performed using Sanger sequencing. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 1017 unique disorders were detected from mutations in 912 genes. Validation of 4120 mutations was possible in 73% of cases by direct sequencing, which confirmed that all diagnoses that could be assayed were accurate. LIMITATIONS, REASONS FOR CAUTION: Karyomapping can be limited by the availability of a reference, as well as parental genomic DNA, and some loci near the telomere may be more difficult to detect because of the limitations of the SNP array rather than the Karyomapping algorithm. Of the 27% of cases where we could not confirm the findings, we cannot comment on the misdiagnosis rate. WIDER IMPLICATIONS OF THE FINDINGS: Karyomapping is now the single most used approach for PGT-M. As new approaches increasingly involve DNA sequencing, PGT for all genetic disease becomes possible by encapsulating the principles of Karyomapping and incorporating chromosome copy number analysis. TRIAL REGISTRATION NUMBER: N/A. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by CooperSurgical. The PhD programs of A.S. and O.W. were supported by CooperSurgical (paid to institution). A.S. has received travel support and IT equipment from CooperSurgical. O.W. has received travel support and provision of a company laptop from CooperSurgical. L.X., P.C., E.B., and T.G. are employees of and hold stock/share ownership in CooperSurgical. N.-N.G. is an employee of, has received meeting registration fees from, and holds stock/share ownership in CooperSurgical. L.R. is an employee of CooperSurgical. D.K.G. has received consulting fees and travel support from CooperSurgical. P.E. has nothing to declare.
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