Hum. Reprod. [JOURNAL]
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200 papers
A de novo C-terminal truncation mutation in NUP205 as a key factor in premature ovarian insufficiency.
Cai S, Li H, Ma X … +8 more , Chen Q, Li S, Mei Q, Huang L, Zhang L, Li H, Zhao K, Xiang W
Hum Reprod · 2026 Apr · PMID 42049205 · Publisher ↗
STUDY QUESTION: Does nucleoporin 205 (NUP205) deficiency caused by a novel de novo truncation mutation underlie the pathogenesis of premature ovarian insufficiency (POI)? SUMMARY ANSWER: NUP205 plays a critical role in o...
STUDY QUESTION: Does nucleoporin 205 (NUP205) deficiency caused by a novel de novo truncation mutation underlie the pathogenesis of premature ovarian insufficiency (POI)? SUMMARY ANSWER: NUP205 plays a critical role in ovarian development, and mutations in NUP205 represent a key factor in the pathogenesis of POI. WHAT IS KNOWN ALREADY: POI is a highly heterogeneous disorder with a significant genetic basis. The nuclear pore complex (NPC) is a fundamental channel mediating nucleocytoplasmic transport, with NUP205 serving as a key scaffold component of the NPC. STUDY DESIGN, SIZE, DURATION: This study employed a multilevel genetic and functional investigation, starting with whole-exome sequencing (WES) of a POI pedigree. Clinical significance was further assessed through a large-scale cohort involving 1030 POI cases. Functional validation was performed using the in vitro human cell line COV434 and an in vivo zebrafish model. PARTICIPANTS/MATERIALS, SETTING, METHODS: A Chinese family with idiopathic POI was recruited. To evaluate the clinical prevalence of NUP205 variants, WES data from a previously published cohort of 1030 POI cases were rescreened. Candidate variants were prioritized based on American College of Medical Genetics and Genomics guidelines and the functional impact of the identified mutation was further evaluated through protein structural modeling. The expression of NUP205 in follicles was determined by reanalyzing public ovarian single-cell RNA sequencing datasets and confirmed via immunofluorescence on human ovarian tissues. Functional assays were performed through siRNA-mediated knockdown in COV434 cells, complementing phenotypic and ultrastructural analyses of a CRISPR/Cas9-generated nup205 (p.R1057*) truncation zebrafish model. MAIN RESULTS AND THE ROLE OF CHANCE: A novel heterozygous nonsense mutation in NUP205 c.3160C>T (p.R1054*) was identified in the index pedigree, which was absent in public genomic databases. Expanded screening of the cohort identified five additional families carrying NUP205 variants (three heterozygous and two compound heterozygous) affecting highly conserved residues. In vitro, NUP205 knockdown in COV434 cells impaired the protein stability of NUP93 and NUP62, ultimately leading to NPC structural defects. In vivo, a zebrafish model carrying the equivalent nup205 (p.R1057*) mutation exhibited impaired oogenesis, compromised fertility, and lower fertilization rates. Transmission electron microscopy revealed abnormal NPC morphology in the theca cells of the mutant follicles. These findings demonstrate that NUP205 is essential for ovarian development and suggest that its deficiency is a key factor in POI pathogenesis, indicating that the observed association is unlikely to be due to chance. LIMITATIONS, REASONS FOR CAUTION: Although we identified additional NUP205 variants in a large POI cohort, the detailed molecular mechanisms of these specific variants remain to be further investigated. WIDER IMPLICATIONS OF THE FINDINGS: These findings identify NUP205 as a novel genetic contributor to POI, expanding the spectrum of nucleoporin-related reproductive disorders. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Natural Science Foundation of China (U24A20659 and 82500964). The authors declare that they have no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.
Concerns regarding the WHO guideline on infertility: implications for contemporary reproductive medicine.
La Marca A, Longo M
Hum Reprod · 2026 Jun · PMID 42049204 · Publisher ↗
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Sperm DNA fragmentation: how to test, when to test, and what to do with abnormal results-a pragmatic mini-review for clinical practice.
Esteves SC, Humaidan P
Hum Reprod · 2026 Apr · PMID 42049202 · Publisher ↗
Sperm DNA fragmentation (SDF) represents strand breaks that may compromise embryo development, reproductive outcomes, and offspring health, particularly when the oocyte's repair capacity is limited. This mini-review prov...
Sperm DNA fragmentation (SDF) represents strand breaks that may compromise embryo development, reproductive outcomes, and offspring health, particularly when the oocyte's repair capacity is limited. This mini-review provides a clinically pragmatic framework addressing how to test, when to test, and whom to test for SDF, translating biological and laboratory insights into actionable andrology practice. The mechanistic basis of SDF is summarized, including the two-step hypothesis linking defective chromatin packaging to oxidative stress, and the combined influence of paternal and maternal aging on the creation and repair of DNA lesions. Contemporary methods for detecting both single- and double-strand breaks (DSBs), as well as DSB-specific platforms, are reviewed with emphasis on assay-specific cut-offs and clinical indications. Management strategies are outlined, prioritizing andrological optimization through lifestyle modification, antioxidant supplementation, treatment of genital tract infection, varicocele repair, and selected hormonal therapy, followed by retesting after one spermatogenic cycle. For persistently high SDF, selective use of testicular sperm for ICSI (Testi-ICSI) and laboratory adjuncts is discussed, supported by evidence of lower miscarriage and higher live-birth rates in defined high-SDF phenotypes. The limitations of the existing observational evidence base-particularly the paucity of phenotype-targeted randomized controlled trials-are highlighted. The review also underscores the value of embedding SDF testing within quality-managed programs and incorporating systematic audits of indications, treatment effects, and ART outcomes. Beyond ART, SDF assessment is positioned within preconception care, recognizing sperm chromatin integrity as a determinant of reproductive and intergenerational health. Future priorities include randomized trials comparing testicular and ejaculated sperm for ICSI in high-SDF cohorts, validation of DSB-specific assays, and longitudinal offspring follow-up to clarify intergenerational effects. This integrative approach promotes precision rather than proliferation of testing, aligning molecular insight with clinical prudence to improve reproductive and generational outcomes.
Once, twice, three times frozen: viability and post-transfer outcomes of fresh and vitrified-warmed mouse embryos.
Li T, Chow DJX, Li S … +3 more , Rose RD, Tan TCY, Dunning KR
Hum Reprod · 2026 Apr · PMID 42035726 · Publisher ↗
STUDY QUESTION: What is the impact of one, two, or three vitrification-warming cycles on embryo viability, implantation potential, and post-transfer development compared with fresh transfer? SUMMARY ANSWER: Repeated vitr...
STUDY QUESTION: What is the impact of one, two, or three vitrification-warming cycles on embryo viability, implantation potential, and post-transfer development compared with fresh transfer? SUMMARY ANSWER: Repeated vitrification-warming cycles progressively impaired embryo cryosurvival, blastocyst quality, and foetal growth after two or more cycles. WHAT IS KNOWN ALREADY: Cryopreservation is central to embryo storage and preimplantation genetic testing, where embryos are biopsied and frozen while awaiting results. However, the impact of repeated vitrification-warming cycles remains unclear due to confounding factors including biopsy effects, prior implantation failure, the absence of a true non-cryopreserved control, and fresh transfer comparisons confounded by supraphysiological hormonal exposure. STUDY DESIGN, SIZE, DURATION: To overcome the constraints of clinical studies, this study used the mouse as a controlled preclinical model. This allowed precise experimental control over embryo stage at cryopreservation and vitrification protocol and enabled direct comparison with a non-vitrified (fresh) control group without the confounding effects of supraphysiologic hormone exposure or biopsy. While species differences are recognized, this model enables focused assessment of cryopreservation-specific effects. Outcomes included post-warming survival, cell lineage allocation, as well as post embryo transfer outcomes on Day 18.5 of development (pregnancy and implantation rates, foetal and placental weights). Post-warming survival was assessed after one, two, or three freeze-warm cycles (3035, 1465, and 447 blastocysts, respectively; 23 independent experimental replicates). Inner cell mass (ICM) and trophectoderm (TE) cell numbers were quantified following one, two, or three freeze-warm cycles and compared to a fresh (non-vitrified) control (35, 36, 33, and 28 blastocysts, respectively; four independent experimental replicates). Post-transfer outcomes were evaluated after one, two, or three freeze-warm cycles and compared to a fresh (non-vitrified) control (30, 33, 39, and 22 pseudo-pregnant recipients, respectively). Sample size calculations were performed to ensure the study was appropriately powered. PARTICIPANTS/MATERIALS, SETTING, METHODS: Murine embryos were generated following IVF and cultured to the blastocyst stage, and underwent zero (fresh), one, two, or three repeated vitrification-warming cycles. Post-warming survival was assessed morphologically, and immunohistochemistry for OCT-3/4 (ICM) and CDX2 (TE) was used to assess cell lineage allocation. Embryo transfers were used to further evaluate developmental competence with pregnancy rate, implantation outcomes (implantation rate, viable implantation rate, resorption rate), foetal and placental outcomes (foetal weight, placental weight, and the foetal-to-placental weight ratio) measured on Day 18.5 of development. MAIN RESULTS AND THE ROLE OF CHANCE: Embryo cryosurvival declined significantly with increasing numbers of freeze-warm cycles, with marked reductions after two or three cycles compared with one cycle (P < 0.05) and a substantially higher proportion of non-viable embryos after three cycles (P < 0.001). ICM cell number was significantly reduced after two or three cycles compared with fresh embryos (P < 0.0001), while TE cell number increased after two cycles (P < 0.05). The ICM:TE ratio was significantly reduced after one, two, or three cycles compared with fresh (P < 0.01). Following embryo transfer, pregnancy rates were lower in all freeze-warm groups than in fresh controls, although these differences were not statistically significant. Relative risk of pregnancy compared with fresh transfer was 0.74 (95% CI 0.34-1.64) after one cycle, 0.75 (95% CI 0.35-1.62) after two cycles, and 0.59 (95% CI 0.27-1.32) after three cycles. Implantation and viable implantation rates showed similar nonsignificant reductions, while resorption rates were numerically higher after two or three freeze-warm cycles. Compared with the fresh group, foetal weights were significantly reduced after two and three cycles (P = 0.037 and P = 0.012), placental weight showed a nonsignificant trend towards increase, and the foetal:placental weight ratio was significantly decreased after two and three cycles (P = 0.009 and P = 0.002). While cryosurvival, ICM cell number, and foetal outcomes showed clear statistical effects, the nonsignificant pregnancy, implantation, and resorption measures indicate that chance may partly explain the post-transfer variability. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: The study used a murine model, and although procedures reflected clinical practice, species differences mean further mechanistic and translational studies are needed to evaluate relevance to human reproduction. Additionally, the study focused exclusively on blastocyst-stage embryos, limiting the applicability of the findings to other developmental stages. The effects of cryoprotectant exposure alone were not investigated. WIDER IMPLICATIONS OF THE FINDINGS: These findings provide quantitative evidence of the cumulative effects of repeated embryo vitrification-warming and may inform optimization of cryopreservation protocols, limit unnecessary re-freezing, and support refinement of clinical guidelines to improve embryo viability and foetal outcomes in IVF. STUDY FUNDING/COMPETING INTEREST(S): K.R.D. is supported by an Australian Research Council Future Fellowship (Adelaide University, FT240100291). The authors declare that there is no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.
Fertility preservation trends, perspectives, and reflections in gender diverse adults across the life course.
Dsouza KN, Orellana MA, Vasilev DV … +14 more , Lee Y, Whitney M, Aase D, Reckhow J, Nguyen E, Enders FT, Pacheco-Spann L, Winter SJ, Chang AY, Davidge-Pitts CJ, Gonzalez CA, Eleazer J, Ainsworth A, Khan Z
Hum Reprod · 2026 Apr · PMID 42035457 · Publisher ↗
STUDY QUESTION: What is the fertility preservation (FP) utilization rate among transgender and gender diverse (TGD) patients at the Transgender and Intersex Specialty Care Clinic (TISCC) within the Mayo Clinic? SUMMARY A...
STUDY QUESTION: What is the fertility preservation (FP) utilization rate among transgender and gender diverse (TGD) patients at the Transgender and Intersex Specialty Care Clinic (TISCC) within the Mayo Clinic? SUMMARY ANSWER: The rate of utilization of FP services by TGD patients at Mayo Clinic's TISCC was determined to be 6.62%. WHAT IS KNOWN ALREADY: TGD patients encounter several barriers when pursuing FP, which may contribute to a lower utilization rate of these services. These barriers include financial constraints and lack of insurance coverage, as well as societal and healthcare provider attitudes; TGD individuals face discrimination or lack of understanding, making it uncomfortable or difficult to discuss FP options. Additionally, there continues to be a lack of inclusive policies and support within healthcare systems that can further impede access to FP services for TGD individuals. STUDY DESIGN, SIZE, DURATION: The study was executed in two phases. In the first phase, a retrospective cohort study was completed with TGD patients who provided electronic health record (EHR) research authorization from Mayo Clinic's TISCC in Rochester, MN between 1 January 2015 and 30 July 2021. Search terms related to FP were used to determine the FP utilization rate among this patient population. In the second phase of the study, two sets of patients, (i) patients who were included in the cohort study in Phase 1, and (ii) members of JASMYN, a community organization specializing in care and wellness coordination for Lesbian, Gay, Bisexual, and Transgender (LGBT) teens and young adults in North Florida. Individuals were invited to participate in a qualitative interview exploring their cumulative healthcare experiences accessing gender-affirming care. Interviews were conducted from January 2023 to June 2023. Interviews examined participants' perceptions of FP options, motivations for pursuing FP, and barriers to accessing both gender and fertility care. When applicable, participants also discussed their experiences pursuing FP and reflected on their satisfaction with their fertility and family planning decisions. PARTICIPANTS/MATERIALS, SETTING, METHODS: In phase 1, a total of N = 1189 patients sought care from Mayo Clinic's TISCC in Rochester, MN. Out of these patients, N = 589 patients provided research authorization and were included in the retrospective cohort study. The study team assessed whether FP terms were mentioned in each patient's EHR, and whether patients scheduled and attended appointments with either the Department of Reproductive Endocrinology or the Department of Urology. FP search terms included sperm cryopreservation, sperm extraction, sperm aspiration, testicular tissue cryopreservation, oocyte cryopreservation, embryo cryopreservation, and ovarian tissue cryopreservation. In phase 2, N = 36 participants were interviewed, with N = 25 participants recruited from Mayo Clinic's TISCC in Rochester, MN, and N = 11 participants recruited from JASMYN in Jacksonville, FL. Participants recruited from the Mayo Clinic participated in a video-call-based interview and those enrolled from JASMYN were interviewed in person. MAIN RESULTS AND THE ROLE OF CHANCE: The study team observed a 6.62% utilization rate of FP services among N = 589 patients (median age: 28 years; age range: 8-78 years) included in the retrospective cohort study. N = 39 patients completed FP, with N = 14 receiving these services at other institutions before seeking care with the TISCC at Mayo Clinic. N = 25 patients pursued FP services within the Mayo Clinic. Patients with testes were more likely to complete FP via sperm cryopreservation when compared to the utilization of egg cryopreservation among patients with ovaries. Participants who completed an interview in Phase 2 (median age 27 years; age range: 22-80 years) reflected on their decision on whether to preserve their fertility and what factors influenced these decisions, and how their satisfaction with this decision has changed over their lifespan. The major themes reported here include the desire for biological children, planning gender care around fertility desires, conversations about FP options, physical and psychosocial barriers to pursuing FP, reflections on personal FP decisions, and reflections on having to make decisions about FP at a young age. LIMITATIONS, REASONS FOR CAUTION: All participants who completed an interview have done so voluntarily; as such, there is a possibility of selection and recall bias. WIDER IMPLICATIONS OF THE FINDINGS: Findings suggest that there is a need for more structured conversations around FP when TGD patients seek medical and surgical gender-affirming care. Accessibility, including financial barriers and limited insurance coverage, continues to limit the utilization of FP services among TGD patients. Increased affordability through insurance coverage may additionally improve FP utilization. STUDY FUNDING/COMPETING INTEREST(S): This project was funded by the Mayo Clinic Department of Obstetrics and Gynecology and the Mayo Clinic Center for Clinical and Translational Science (CCaTS), grant number UL1TR002377. This project was also supported by Clinical and Translational Science Award (CTSA) Grant Number TL1TR002380 from the National Center for Advancing Translational Sciences (NCATS). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Felicity Enders reports grants from the National Institutes of Health and the Agency for Healthcare Research and Quality paid to her institution; speakers' fees for lectures or presentations from Mount Sinai, University of Washington, University of Minnesota, University of Rochester, Cincinnati University, the National Institutes of Health, Duke University, Wake Forest University, the Patient Centered Outcomes Research Institute, Johns Hopkins University; travel support from the Association for Clinical and Translational Science and Cold Spring Harbor Laboratory; and an unpaid leadership role on the Board of Directors of the Association for Clinical and Translational Science. All other authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.
Large-scale analysis of FMR1 CGG repeat length and risk of premature ovarian insufficiency in over 92 000 women.
Morbey EJ, Day FR, Wright DJ … +5 more , Murzynowski JRA, McGlacken-Byrne SM, Murray A, Ong KK, Perry JRB
Hum Reprod · 2026 Jun · PMID 42001465 · Full text
STUDY QUESTION: Does FMR1 repeat length confer clinically meaningful predictive value for premature ovarian insufficiency (POI)? SUMMARY ANSWER: FMR1 repeat length increases POI risk from ∼36 repeats onward but has limit...
STUDY QUESTION: Does FMR1 repeat length confer clinically meaningful predictive value for premature ovarian insufficiency (POI)? SUMMARY ANSWER: FMR1 repeat length increases POI risk from ∼36 repeats onward but has limited diagnostic utility compared with a polygenic score for menopause timing. WHAT IS KNOWN ALREADY: FMR1 premutation carriers (≥55 repeats) are reported to have high risk of Fragile-X Associated Primary Ovarian Insufficiency (FXPOI), but prior studies were small and highly ascertained. STUDY DESIGN, SIZE, DURATION: Cross-sectional analysis of ∼92 000 women from the UK Biobank with genetic and health data. PARTICIPANTS/MATERIALS, SETTING, METHODS: Female UK Biobank participants were genotyped for FMR1 repeat length. Associations with self-reported POI, age at menopause, and other reproductive phenotypes were analysed in women. FMR1 protein levels were measured, and genome-wide analyses were conducted to identify potential genetic modifiers. MAIN RESULTS AND THE ROLE OF CHANCE: Of 518 female premutation carriers with available age at natural menopause, only 6.9% reported POI. Elevated POI risk was observed starting at 36 repeats, increasing continuously with repeat length, but no threshold showed strong predictive power (maximum AUC 0.60 vs AUC 0.64 for polygenic score). No association was found between repeat length and FMR1 protein levels, consistent with an RNA gain-of-function toxicity mechanism. RAD52 was identified as a potential genetic modifier. LARGE SCALE DATA: UK Biobank resource (https://www.ukbiobank.ac.uk). LIMITATIONS, REASONS FOR CAUTION: POI was self-reported rather than clinically confirmed. Analyses could not assess AGG interruptions, mosaicism, or X-inactivation. Genetic modifiers require replication. Findings are limited to a single population dataset. WIDER IMPLICATIONS OF THE FINDINGS: These results challenge the utility of the FXPOI disease category, suggest limited diagnostic value of clinical FMR1 premutation testing for POI, and highlight alternative mechanisms and potential modifiers such as RAD52. STUDY FUNDING/COMPETING INTEREST(S): This work was conducted using the UK Biobank resource (application 9905). This work was funded by the Medical Research Council (unit programs: MC_UU_12015/2, MC_UU_00006/2) and Wellcome (Discovery award 302536/Z/23/Z). The sponsors had no role in the study design, collection, analysis, or interpretation of the data, the writing of the manuscript or the decision to submit it for publication. J.R.B.P. and A.M. have engaged in paid consultancy for Ovartix Ltd. TRIAL REGISTRATION NUMBER: N/A.
Histological and immunohistochemical characteristics of superficial peritoneal endometriotic lesions of clinical responders and non-responders to dienogest treatment.
Berlanda N, Bandini V, Croci GA … +4 more , Dridi D, Nobili MV, Cipriani S, Vercellini P
Hum Reprod · 2026 Jun · PMID 41999626 · Publisher ↗
STUDY QUESTION: Are there histological and immunohistochemical patterns of superficial peritoneal endometriotic lesions of symptomatic patients that characterize non-response to dienogest treatment and may suggest proges...
STUDY QUESTION: Are there histological and immunohistochemical patterns of superficial peritoneal endometriotic lesions of symptomatic patients that characterize non-response to dienogest treatment and may suggest progesterone resistance? SUMMARY ANSWER: No significant histological or immunohistochemical differences were observed in superficial peritoneal endometriotic lesions between clinical responders and non-responders to dienogest treatment. WHAT IS KNOWN ALREADY: Progestogens are effective in reducing pelvic pain symptoms in approximately two-thirds of patients with endometriosis. Treatment failure can be reasonably explained by progesterone resistance, but the available evidence is not definitive. STUDY DESIGN, SIZE, DURATION: A prospective, single-centre, single-arm, observational study was conducted between January 2023 and January 2024 in 55 women treated with dienogest, 2 mg/day, before laparoscopic surgery for endometriosis. PARTICIPANTS/MATERIALS, SETTING, METHODS: All the participants had histologically confirmed endometriosis. Patients were classified as clinical responders (n = 36) or non-responders (n = 19) based on the self-reported 7-point Patient Global Impression of Change scale. In addition, pain severity was dichotomized as either 'absent/mild' (0-3 points) or 'moderate/severe' (4-10 points) across individual pain domains, using a 0-10-point numerical rating scale. The histological morphology and the immunohistochemical expression of progesterone receptors, oestrogen receptors, and CD15 were evaluated in the excised superficial peritoneal lesions. Tissue analyses were all performed by the same blinded pathologist. MAIN RESULTS AND THE ROLE OF CHANCE: A histological morphological response to chronic progestogen treatment, defined by the presence of stromal atrophy and absence of active glands, was observed in 29/36 (80.5%) clinical responders and 16/19 (84.2%) non-responders. Furthermore, no statistically significant between-group differences were observed in progesterone receptor (PR), oestrogen receptor (ER), and CD15 expression. At univariate logistic regression analysis, no significant associations were identified between clinical response to dienogest therapy and several individual variables (i.e. body mass index, age at diagnosis, duration of therapy, histological morphological response, phenotypic subtypes of peritoneal endometriotic lesions, and presence of adenomyosis or deep endometriosis). Exploratory analyses based on pain severity categorization yielded results broadly consistent with the main findings. However, patients with moderate/severe deep dyspareunia showed a significantly lower proportion of high-intensity glandular ER expression in comparison to those with absent/mild deep dyspareunia. In addition, a significantly lower glandular PR expression was detected in patients with moderate/severe dyschezia symptoms compared with those with absent/mild dyschezia. LIMITATIONS, REASONS FOR CAUTION: Only superficial peritoneal endometriotic lesions were evaluated, and no information was collected on ovarian endometriotic cysts or deep infiltrating endometriosis. In addition, due to the limited sample size, a type II error cannot be excluded. Moreover, receptor isoforms, including progesterone receptor isoforms A and B (PR-A, PR-B) and oestrogen receptor isoforms alpha and beta (ERα, ERβ) were not assessed. However, the clinical relevance of the variance of molecular expression of progesterone and oestrogen receptors in the pathogenesis of pelvic pain symptoms remains difficult to interpret. WIDER IMPLICATIONS OF THE FINDINGS: Considering that the vast majority of lesions excised from non-responders showed clear evidence of the effect of dienogest, this study does not support the notion that intrinsic progesterone resistance may represent the sole or prominent mechanism underlying clinical non-response to dienogest treatment in women with endometriosis. However, analyses based on pain intensity dichotomization suggest that the severity of deep dyspareunia and dyschezia may be influenced by ER and PR glandular expression in superficial peritoneal endometriotic lesions. Though larger studies are warranted to further clarify these aspects, mechanisms beyond tissue-level progesterone resistance, including central sensitization, should be explored as potential contributors to symptomatic non-response to dienogest. STUDY FUNDING/COMPETING INTEREST(S): This study was partially funded by the Italian Ministry of Health, Current research IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan. N.B. and P.V. have received royalties from Wolters Kluwer for chapters on endometriosis management in the clinical decision support resource UpToDate, and both maintain a private gynaecological practice. P.V. is a member of the Editorial Board of Human Reproduction Open, the Journal of Obstetrics and Gynaecology Canada, and the International Editorial Board of Acta Obstetricia et Gynecologica Scandinavica. All other authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.
Variations in ovulation time and menstrual cycle characteristics: analysis of a prospective long-term cohort study.
Malliou-Becher MN, Herrmann PM, Freis A … +8 more , Freundl-Schütt T, Wallwiener LM, Baur S, Fehring RJ, Gnoth C, Mallios A, Strowitzki T, Frank-Herrmann P
Hum Reprod · 2026 Jun · PMID 41968388 · Publisher ↗
STUDY QUESTION: What are the variations in ovulation time and menstrual cycle characteristics among and within various individuals over the course of 12 menstrual cycles? SUMMARY ANSWER: There are considerable variations...
STUDY QUESTION: What are the variations in ovulation time and menstrual cycle characteristics among and within various individuals over the course of 12 menstrual cycles? SUMMARY ANSWER: There are considerable variations in both cycle length and ovulation time, with pronounced intra-individual variability over a 12-cycle observation period. WHAT IS KNOWN ALREADY: Although it is commonly believed that healthy women have regular cycles with a predictable mid-cycle ovulation, more recent research shows a significant variation in cycle length and ovulation time. Previous studies have focused only on cycle length, often excluding cycles outside the 25-35-day range, thus limiting the understanding of natural variation; they have also lacked precise ovulation diagnostics or included small sample sizes, making it difficult to capture the full scope of cycle and ovulation variability. Similarly, a recent big data study, while valuable, was limited by a self-selected group and the absence of accurate ovulation diagnostics, reducing its generalizability. STUDY DESIGN, SIZE, DURATION: This study was designed as a prospective long-term observational study, which involved collecting data from 1923 women with a total of 43 999 menstrual cycles from January 1985 to July 2019. After fulfilling the inclusion criteria, the main group consisted of 1051 women, all of whom contributed data for 12 cycles (12 612 cycles), including 420 conception cycles. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants in the study were between 18 and 44 years of age at study entry and did not take any reproductive hormones. Women who were postpartum, breastfeeding, amenorrheic, or within a 3-month period after stopping hormonal contraception were excluded. Participants agreed to keep cycle records according to the symptothermal method, 'Sensiplan'. Ovulation time was determined using an evidence-based algorithm based on evaluating cervical mucus patterns and basal body temperature shifts, with ovulation time defined as the day before the temperature rise. Data analysis was descriptive, using absolute and relative frequencies, standard deviation, percentiles, and ranges. Age dependency was assessed using unpaired sample t-tests and one-way ANOVA. Linear regression was used to assess long-term trends. MAIN RESULTS AND THE ROLE OF CHANCE: In 62.4% of women, cycle lengths varied by 1 week or more within 12 cycles. Accordingly, the time of ovulation varied by 1 week or more within 12 cycles in 54.8% of women, with 96.5% experiencing fluctuations of 4 days or more over the 12 months. The median spontaneous cycle length was 28 days, with a mean of 29.66 days (SD = 7.55). Only 52.7% of women consistently had cycle lengths between 23 and 35 days across all 12 cycles. Ovulation occurred most frequently between Days 12 and 16, with almost half of conceptions (45.7%) occurring after Day 16. A one-way analysis of variance revealed a significant reduction in mean cycle length with increasing age (P < 0.001), showing the shortest median cycle length of 27 days being in women aged 40-44 years. Age also impacted ovulation time, with women aged 35-39 years showing more stable ovulation patterns compared to younger women. Over the 34-year study period, average cycle length increased slightly but significantly (β = 0.0161, P = 0.0306), corresponding to approximately half a day. Intra-individual variability also showed a slight, but non-significant, upward trend (β = 0.0262, P = 0.2173). LIMITATIONS, REASONS FOR CAUTION: Comorbidities such as hyperprolactinemia, obesity, and PCOS were not systematically excluded. However, by including only women with at least 12 cycles, the study largely avoided severe hormonal disorders. WIDER IMPLICATIONS OF THE FINDINGS: This study highlights the considerable individual variation of ovulation time and cycle length over 12 menstrual cycles. These findings contribute to a better understanding of fertility awareness, and highlight the implications for family planning and reproductive health management. STUDY FUNDING/COMPETING INTEREST(S): The authors declare no conflicts of interest. No funding was provided. TRIAL REGISTRATION NUMBER: N/A.
Live birth rates after natural cycle versus artificial cycle in women receiving donated oocytes and the impact of female age.
Rafael F, David BN, Mascarós JM … +7 more , Neves A, Labarta E, Garrido N, Nunes S, Garcia-Velasco JA, Reis-Soares S, Santos-Ribeiro S
Hum Reprod · 2026 Jun · PMID 41968377 · Publisher ↗
STUDY QUESTION: Can natural cycles (NC) be effectively utilized in advanced maternal age (AMA) undergoing oocyte donation, without compromising live birth rates (LBRs) and miscarriage outcomes, when compared to artificia...
STUDY QUESTION: Can natural cycles (NC) be effectively utilized in advanced maternal age (AMA) undergoing oocyte donation, without compromising live birth rates (LBRs) and miscarriage outcomes, when compared to artificial cycles (ACs)? SUMMARY ANSWER: In donor oocyte embryo transfer cycles, NC demonstrated superior outcomes in reproductive efficacy and obstetrical safety compared to AC, independent of the recipient's age. WHAT IS KNOWN ALREADY: Previous studies have posited that NC may result in better outcomes when compared to AC embryo transfer, including a lower risk of miscarriage and hypertensive disorders of pregnancy. Recent studies support that NC-frozen embryo transfer (FET) decreases obstetrical and neonatal complications compared to AC-FET, even if LBR differences remain controversial in some general populations. There is limited research on the use of NCs in women of AMA. STUDY DESIGN, SIZE, DURATION: This retrospective, multicentre, cohort study included all single blastocyst embryo transfers following oocyte donation performed between January 2010 and December 2023, subdivided according to the type of endometrial preparation performed (NC or AC). The oocyte donation model was chosen to minimize the potential confounding effect related to poor oocyte competence in older women and the influence of ovarian stimulation performed during autologous IVF on endometrial receptivity prior to a fresh embryo transfer. PARTICIPANTS/MATERIALS, SETTING, METHODS: The main objective of the study was to compare LBR. Secondary outcomes included hCG-positive pregnancy rate, clinical pregnancy rate, miscarriage rate, obstetric, and perinatal outcomes. Confounder-adjustment was performed using a multivariable generalized estimating equations model regression analysis, adjusting for multiple confounders. A sub-analysis compared results when the AC protocol was optimized with progesterone (P4) monitoring and rescue therapy. Additionally, an interaction variable was added to the final multivariable model to assess whether female recipient age may modify the effect of each type of endometrial preparation on LBRs. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 67 048 embryo transfers were analysed, including NC (n = 6922) and AC (n = 60 126). The NC group demonstrated consistent superiority over AC after adjustment for confounders across all transfers. NC was associated with a higher LBR (aOR 1.38, 95% CI 1.29-1.47; P < 0.01) and significantly lower miscarriage rate per hCG-positive pregnancy (aOR 0.68, 95% CI 0.61-0.76; P < 0.01). This superiority persisted even in optimized AC cycles with P4 monitoring and rescue therapy (LBR aOR 1.42, 95% CI 1.31-1.54; P < 0.01). Furthermore, NC was associated with significantly lower obstetrical risks in singleton pregnancies, including hypertensive disorders of pregnancy (aOR 0.72, 95% CI 0.56-0.94; P = 0.01), Caesarean delivery (aOR 0.86, 95% CI 0.77-0.96; P < 0.01), and large for gestational age (aOR 0.77, 95% CI 0.67-0.89; P < 0.01). The interaction between endometrial preparation method and female recipient age was not statistically significant (aOR 1.02, 95% CI 0.99-1.03). LIMITATIONS, REASONS FOR CAUTION: The retrospective nature of the study and the inherent risk of bias related to unmeasured confounding factors may have impacted the results. Another limitation is the low percentage of NC included in the study (10.32% of all cycles), which could be related to the low uptake to this treatment modality in real-life practice. WIDER IMPLICATIONS OF THE FINDINGS: NC may offer superior reproductive outcomes and is associated with lower obstetrical risks, with differences unlikely to be modified by female age. Therefore, it seems reasonable to suggest NC for older women, as they could benefit from the decreased risk of miscarriage and hypertension during pregnancy. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was obtained for this study. A.R.N. has received research grants (to institution) from Theramex; Consulting and Speakers' fees and travel support from Organon and Merck KgaA; S.S.-R. has received consulting fees from Organon, IBSA, and Besins; Speakers' fees and travel support from Organon, Ferring Pharmaceuticals, Theramex, IBSA, Gedeon Richter, Abbott, and Besins. He has also received travel support from Organon, Ferring, Theramex, IBSA, Gedeon-Richter, Abbott, and Besins. He holds stocks/shares with IVIRMA Lisboa. He is a member of the ESHRE Executive Committee and was the Senior Deputy of Safety and Quality for ESHRE. TRIAL REGISTRATION NUMBER: N/A.
The effect of preimplantation genetic testing for aneuploidy (PGT-A) on obstetric and neonatal outcomes: a systematic review and meta-analysis.
Hyttel CB, Løssl K, Wang NF … +1 more , Pinborg A
Hum Reprod · 2026 Jun · PMID 41966094 · Publisher ↗
STUDY QUESTION: Are pregnancies after preimplantation genetic testing for aneuploidy (PGT-A) with trophectoderm (TE) biopsy and preferable elective freeze-all procedure associated with an increased risk of adverse obstet...
STUDY QUESTION: Are pregnancies after preimplantation genetic testing for aneuploidy (PGT-A) with trophectoderm (TE) biopsy and preferable elective freeze-all procedure associated with an increased risk of adverse obstetric and neonatal outcomes compared to pregnancies after IVF/ICSI without PGT-A? SUMMARY ANSWER: In this systematic review and meta-analysis specifically focusing on comparing a homogenous infertile population treated with IVF/ICSI, PGT-A was not associated with any adverse obstetric or neonatal outcomes. WHAT IS KNOWN ALREADY: An increased risk of hypertensive disorders of pregnancy (HDP) following IVF/ICSI with PGT in general as compared to IVF/ICSI without PGT has been reported. However, people undergoing PGT for monogenic diseases or structural rearrangements are often fertile in contrast to infertile people undergoing general IVF/ICSI treatment. STUDY DESIGN, SIZE DURATION: A systematic literature search was performed in PubMed, Embase, and Cochrane Library on 15 November 2024 and the search was updated on 11 June 2025. Inclusion criteria were: (i) randomized clinical trials or cohort studies comparing IVF/ICSI with or without PGT-A, (ii) embryo cultivation until the blastocyst stage, (iii) TE biopsy, and (iv) vitrification as cryopreservation method. Exclusion criteria were: (i) case series and case reports, (ii) polar body- or cleavage-stage biopsy, (iii) slow freeze, (iv) use of donor oocytes, or (v) natural conception controls. The main outcomes were HDP, preterm delivery, abnormal placentation, low birth weight, very low birth weight, and small for gestational age. PARTICIPANTS/MATERIALS, SETTING, METHODS: Meta-analyses were performed for outcomes reported in ≥3 of the included studies. Frozen embryo transfer (FET)-cycles only subgroup-analyses were performed if the data were available in ≥3 of the included studies. Newcastle-Ottawa quality assessment score and Risk-of-Bias 2 were used to assess potential bias in the individual studies, and the GRADE approach was used to assess the certainty of evidence. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 2260 records were screened, and 12 studies comprising 56 113 live births were included, of which 17 254 resulted from PGT-A and 38 859 resulted from IVF/ICSI without PGT-A. No outcomes differed significantly between the PGT-A and non-PGT-A group in the main analyses or the subgroup-analyses on FET-cycles. LIMITATIONS, REASONS FOR CAUTION: The included studies were mainly retrospective, and the number of cases was low for some outcomes. WIDER IMPLICATIONS OF THE FINDINGS: Current evidence does not suggest adverse obstetric or neonatal effects of PGT-A, though further research is needed, particularly for rare outcomes. STUDY FUNDING/COMPETING INTERTEST(S): This study was not funded. A.P. has received independent research grants and lecture fees from Abbott, IBSA, Gedeon Richter, Ferring, and Merck A/S. A.P. is part of research advisory boards for Gedeon Richter and Ferring Pharmaceuticals A/S. K.L. has received an independent research grant from Gedeon Richter and lecture fees from Ferring Pharmaceuticals. K.L. participated in a research advisory board for Ferring Pharmaceuticals A/S. N.F.W. has received a speaker's fee from Ferring Pharmaceuticals and travel support paid to institution from Gedeon Richter. The other authors had no conflict of interest to declare in relation to this work. REGISTRATION NUMBER: PROSPERO No: CRD42024599519.
Correction to: Intracytoplasmic sperm injection: a paradigm shift in reproductive medicine.
Hum Reprod · 2026 Jun · PMID 41955468 · Publisher ↗
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Endometrial organoids to model benign disorders affecting the endometrium.
Dolmans MM, Beaussart C
Hum Reprod · 2026 Jun · PMID 41915931 · Publisher ↗
The endometrium is a highly dynamic and complex tissue lining the uterus, playing a central role in reproductive health. Despite its importance, the pathogenesis of many benign endometrial disorders remains poorly unders...
The endometrium is a highly dynamic and complex tissue lining the uterus, playing a central role in reproductive health. Despite its importance, the pathogenesis of many benign endometrial disorders remains poorly understood, largely due to limitations in current experimental models. Traditional in vivo models like murine and primate models fail to replicate key human-specific features like menstruation or spontaneous disease development. Similarly, conventional 2-dimensional in vitro cultures using cell lines or primary cells lack the structural and functional complexity of native endometrium, often losing physiological relevance over time. To address these challenges, endometrial epithelial organoids (EEOs), 3-dimensional self-organizing epithelial structures derived from endometrial biopsies, have emerged as a promising in vitro model. EEOs mimic many aspects of in vivo endometrial glands, including apical-basal polarity, hormone responsiveness, long-term preservation of epithelial identity, and retention of patient-specific genetic and molecular signatures. Their ability to reproduce cellular interactions and tissue architecture makes them an invaluable tool for studying endometrial physiology and disease. This review explores the application of EEOs in modeling various benign conditions affecting the endometrium, including endometriosis, adenomyosis, uterine fibroids, implantation failure, endometrial aging, endometritis, and endometrial hypoplasia, as well as systemic diseases and exposure to environmental or pharmacological agents. While EEOs do not yet fully replicate functional human endometrium, they represent a significant step forward in bridging the gap between basic research and clinical understanding of endometrial disorders.
Disentangling ovarian reserve and embryo quality in vaginal progesterone effectiveness studies.
Peralta S, Ata B, Lawrenz B … +2 more , Salame A, Fatemi HM
Hum Reprod · 2026 Jun · PMID 41911380 · Publisher ↗
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Reply: Disentangling ovarian reserve and embryo quality in vaginal progesterone effectiveness studies.
Dhillon-Smith R, Coomarasamy A
Hum Reprod · 2026 Jun · PMID 41911376 · Publisher ↗
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Decoding serotonin in endometriosis: unveiling its role in disease pathogenesis via the gut-reproductive microbiota axis.
Wang X, Jia Y, Wang C … +6 more , Li D, Guo X, Jiang S, Zhou Z, Gao C, Wang F
Hum Reprod · 2026 Jun · PMID 41903570 · Publisher ↗
STUDY QUESTION: How can the potential mechanisms and targets of endometriosis be explored through multi-omics and multi-location approaches? SUMMARY ANSWER: This exploration of the gut-reproductive axis in patients with...
STUDY QUESTION: How can the potential mechanisms and targets of endometriosis be explored through multi-omics and multi-location approaches? SUMMARY ANSWER: This exploration of the gut-reproductive axis in patients with endometriosis found that serotonin is elevated in endometriosis and promotes disease progression through enhanced cell proliferation and inflammation. WHAT IS KNOWN ALREADY: Endometriosis is a common inflammatory disease. Recent studies indicate that peripheral serotonin, which is regulated by the gut microbiota, can promote the progression of irritable bowel syndrome and various cancers. STUDY DESIGN, SIZE, DURATION: This cross-sectional study enrolled 22 endometriosis patients and 22 control patients with uterine fibroids (surgical cases, October 2022-June 2023). Samples of vaginal secretions, endometrial tissue, peritoneal lavage fluid, feces, and ectopic lesions were collected from both groups. For validation, serum samples were added from 20 additional endometriosis patients and 20 healthy reproductive-age volunteers. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study employed 16S rRNA gene sequencing to analyze the microbiota in the vagina, endometrial tissue, peritoneal fluid, and feces of patients with endometriosis and control groups, complemented by untargeted metabolomic analysis of peritoneal fluid. The results identified serotonin as a key metabolite and revealed specific bacterial species, shared between the reproductive and gastrointestinal tracts of endometriosis patients, which were significantly correlated with serotonin levels. Mendelian randomization analysis was conducted to explore the relationship between serotonin, these bacterial species, and endometriosis. Serum serotonin levels in endometriosis patients, BALB/C mouse models, and their respective controls were measured using ELISA. Immunohistochemistry and fluorescence staining were used to detect the expression of serotonin and its receptors in both ectopic and normal endometrium. The effects of serotonin on the biological behavior of various endometriosis cell models, including proliferation, migration, invasion, and apoptosis, were investigated using CCK8 assay, wound healing test, Transwell assay, apoptosis detection, ELISA, transcriptomics, and qPCR. The impact of serotonin on BALB/C mouse models was evaluated using H&E staining, flow cytometry, and ELISA. MAIN RESULTS AND THE ROLE OF CHANCE: We identified a significant enrichment of Akkermansia muciniphila (a bacterium shared by the gut and reproductive tract) in endometriosis patients, which positively correlated with peritoneal serotonin levels; Mendelian randomization analysis linked both to elevated endometriosis risk. Serotonin levels were elevated in patients' serum (using mouse models) and in ectopic endometrium, in comparison to those of controls. In vitro, serotonin boosted endometriosis cell proliferation, migration, invasion, and inflammation, with upregulated IL-17/NF-κB pathways. In mice, serotonin treatment increased lesion growth, cell proliferation, and inflammation. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: (a) The relatively limited sample size, together with potential imbalance in endometriosis ASRM stage distribution and cesarean section rates, may restrict the generalizability of our findings. In addition, due to the requirement for peritoneal lavage fluid collection, the control group could not consist of entirely healthy women, which may have resulted in a more conservative estimation of group differences. Serum sex hormone levels were not assessed; however, strict inclusion criteria and uniform surgical timing were applied to minimize hormonal confounding. Future studies incorporating cycle-phase-standardized hormone measurements may provide additional insights. (b) Dietary information was not collected in this study, despite the known influence of diet on gut microbiota composition and serotonin metabolism. (c) The direct causal relationship between Akkermansia muciniphila and elevated serotonin levels remains to be established and warrants further validation using germ-free mouse models or fecal microbiota transplantation approaches. (d) The precise mechanisms by which the gut-reproductive tract microbiota axis regulates local and systemic serotonin synthesis remain unclear and require further investigation. WIDER IMPLICATIONS OF THE FINDINGS: Our study is the first to utilize a multi-omics approach combined with a joint analysis of the female gut-reproductive tract axis across multiple loci, revealing and validating a significant increase in serotonin levels in patients with endometriosis. This change may be regulated by the gut-reproductive microbiota axis. These findings provide new insights into the pathogenesis of endometriosis and identify potential targets for prevention and treatment. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Jilin Provincial Key Laboratory of Precision Infectious Diseases (Grant No. 20200601011JC), Key Laboratory of Health and Family Planning Commission of Jilin Province (Grant No. 3D5200117426). The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. TRIAL REGISTRATION NUMBER: ChiCTR2300077490.
Double-stranded sperm DNA fragmentation measured with neutral comet assay as a predictor of IVF outcomes: evidence from three European clinics in a multi-centred prospective study.
Humaidan P, Povlsen BB, Drakeley AJ … +15 more , Jensen MB, Gabrielsen AV, McDowell SH, Moore L, Ledgerwood CJ, Rae L, Sloan A, Lawlor M, Poots L, Bailie E, Lunt RL, Newton E, Gregoire RC, Moore TCB, Esteves SC
Hum Reprod · 2026 May · PMID 41903517 · Full text
STUDY QUESTION: Can measurement of double-stranded sperm DNA fragmentation (dsSDF) via a neutral comet assay predict the probability of live birth following IVF? SUMMARY ANSWER: In a multicentre IVF cohort, dsSDF measure...
STUDY QUESTION: Can measurement of double-stranded sperm DNA fragmentation (dsSDF) via a neutral comet assay predict the probability of live birth following IVF? SUMMARY ANSWER: In a multicentre IVF cohort, dsSDF measured by a neutral comet assay was a strong, independent predictor of live birth. WHAT IS KNOWN ALREADY: While much of the focus has traditionally been on female factors, emerging research highlights sperm DNA fragmentation as a significant contributor to reproductive outcomes. Over the past decade, studies have shown that different types of sperm DNA damage can affect reproduction differently, with single-stranded breaks being closely linked to reduced spontaneous conception rates, while double-stranded breaks are linked to higher miscarriage rates. STUDY DESIGN, SIZE, DURATION: Prospective cohort study including a total of 302 males from three European IVF clinics, over a 3-year study period (March 2021-October 2024), with 126 healthy sperm donors with confirmed live birth serving as controls. PARTICIPANTS/MATERIALS, SETTING, METHODS: dsSDF was quantified with a neutral comet assay, expressed as Average Comet Score (ACS) and Incidence of Damage (IOD). The primary outcome was live birth per initiated cycle. Associations were evaluated using multivariable logistic regression, adjusting for female and male age (and centre in sensitivity analyses). MAIN RESULTS AND THE ROLE OF CHANCE: Across the cohort, 30% of couples achieved a live birth. Higher dsSDF was associated with reduced odds of live birth, and this association remained statistically significant after adjustment for female age, male age, and recruitment site. Both ACS and IOD were independently predictive of live birth in adjusted models. For ACS, each 1-point increase was associated with 16% lower odds of live birth (OR = 0.84, 95% CI 0.72-0.97; P = 0.026). For IOD, each 1-point increase corresponded to 5% lower odds of live birth (OR = 0.95, 95% CI 0.90-0.99; P = 0.025). As expected, female age remained a strong inverse predictor of live birth across models (OR = 0.86, 95% CI 0.78-0.94; P < 0.001). Using a pragmatic threshold of IOD ≥ 6%, couples were identified with approximately half the odds of achieving a live birth compared to those with IOD < 6% at similar female ages (OR = 0.51, 95% CI 0.28-0.94; P = 0.029). The adverse association between dsSDF and live birth was stronger at higher female ages. LIMITATIONS, REASONS FOR CAUTION: This study examined couples undergoing their first or only IVF cycle and did not include couples with repeat IVF failures. Limitations include potential centre-level confounding, which may benefit from mixed-effects modelling. We did not collect or adjust for several cycle-level covariates that influence live birth (e.g. IVF vs ICSI, number of oocytes retrieved, embryo transfer strategy, use of preimplantation genetic testing for aneuploidy, stimulation protocol), so residual confounding is possible. WIDER IMPLICATIONS OF THE FINDINGS: These results support dsSDF as a clinically relevant biomarker that complements conventional semen parameters. STUDY FUNDING/COMPETING INTEREST(S): The study was part-funded using an unrestricted medical educational grant provided by Merck Serono Limited (0111897641) to the Liverpool Women's Hospital. T.C.B.M., S.H.M., and E.B. were funded in part by UKRI SIP FMI and Peace Plus HF-TIC grants with Ulster University. L.R., A.S., M.L., C.J.L., L.P., and T.C.B.M. are employed at Examen Lab LTD. A.J.D. is a recipient of Merck Serono Limited (0111897641) grant to the Liverpool Women's Hospital. P.H. has received unrestricted research grants from Merck and Gedeon Richter Nordics and honoraria for lectures from Merck, Gedeon Richter, and IBSA. The remaining authors have nothing to disclose. TRIAL REGISTRATION NUMBER: N/A.
Spatial transcriptomics in the human adult ovary: insights into key signalling pathways during follicular atresia.
Vlieghe H, Wei F, Cheng H … +5 more , Stolk THR, Huirne JA, van Mello NM, Amorim CA, Chuva de Sousa Lopes SM
Hum Reprod · 2026 Jun · PMID 41886635 · Full text
STUDY QUESTION: Are key signalling pathways WNT, TGFβ/BMP, NOTCH, and HH involved in follicular atresia in the human adult ovary? SUMMARY ANSWER: In this study, we used spatial transcriptomics to investigate the progress...
STUDY QUESTION: Are key signalling pathways WNT, TGFβ/BMP, NOTCH, and HH involved in follicular atresia in the human adult ovary? SUMMARY ANSWER: In this study, we used spatial transcriptomics to investigate the progression of follicular atresia, focusing on genes of interest associated with steroidogenesis and key signalling pathways WNT, TGFβ/BMP, NOTCH, and HH. WHAT IS KNOWN ALREADY: While extensive research has focused on the mechanisms driving follicular growth, much less is known about the process of follicular atresia, despite its relevance for ovarian aging and reproductive longevity. Follicular atresia is characterized by complex molecular and cellular changes, that lead to the degeneration of granulosa and theca cells. STUDY DESIGN, SIZE, DURATION: Spatial transcriptomics was conducted on 16 regions of human ovarian tissue from different donors (N = 6) containing 21 small antral follicles (diameter 0.5-4 mm) healthy and at different stages of atresia. PARTICIPANTS/MATERIALS, SETTING, METHODS: We selected 80 genes to facilitate cell type identification in the ovary and to investigate the key signalling pathways WNT, TGFβ/BMP, NOTCH, and HH. Haematoxylin and eosin staining was used to manually select different follicle types for spatial transcriptomics. The Molecular Cartography platform (Resolve BioSciences) multiplexing single-molecule fluorescence in situ hybridization on cryo-sections was used for spatial transcriptomics. The cell segmentation masks were obtained from Resolve BioSciences and transcripts for each gene were assigned to individual cells based on the segmentation mask. Downstream visualization and quantification were performed using AnnData and Python. MAIN RESULTS AND THE ROLE OF CHANCE: By comparing the molecular signature of cell types present in healthy small antral follicles to those observed during the progression of atresia, we revealed a profound cellular and molecular shift. Key signalling pathways exhibited a general downregulation in granulosa cells, whereas expression in internal theca cells increased transiently at the onset of atresia, in line with ongoing cellular degeneration and follicular remodelling. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: This study was conducted on ovarian tissue from transmasculine donors. We cannot exclude that testosterone therapy impacts follicular dynamics. WIDER IMPLICATIONS OF THE FINDINGS: Our study provides novel insights into the spatial and molecular mechanisms of follicular atresia, contributing to a deeper understanding of the ovarian biology in humans. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Fonds National de la Recherche Scientifique de Belgique (T.0004.20 to H.V. and C.A.A.), the Novo Nordisk Foundation (NNF21CC0073729, reNEW to F.W., H.C., and S.M.C.S.L.), the Dutch Organization for Health Research and Development (ZonMW PSIDER-2021-10250022120001 to S.M.C.S.L.), and the China Scholarship Council (CSC 202008450034 to F.W., CSC 202008320362 to H.C.). The authors have no conflicts of interest to declare.
Heat exposure during susceptible windows of spermatogenesis and sperm epigenetic age.
Nobles C, Canty TP, Mendola P … +12 more , Russo LM, Rabeya K, Schliep KC, Shaaban M, Singh A, Ring AM, Hemmert R, Perkins NJ, Oluwayiose OA, Peterson CM, Nowak K, Pilsner JR
Hum Reprod · 2026 Jun · PMID 41875434 · Full text
STUDY QUESTION: Does preconception exposure to outdoor heat stress during spermatogenesis alter sperm epigenetic age among men from an infertility treatment population? SUMMARY ANSWER: Exposure to outdoor heat stress dur...
STUDY QUESTION: Does preconception exposure to outdoor heat stress during spermatogenesis alter sperm epigenetic age among men from an infertility treatment population? SUMMARY ANSWER: Exposure to outdoor heat stress during the developmental stages of mitosis and meiosis during spermatogenesis was associated with accelerated sperm epigenetic age. WHAT IS KNOWN ALREADY: Spermatogenesis is uniquely susceptible to redox stress. Age-related disruption of the blood-testes barrier is associated with changes in sperm DNA methylation linked to reduced fecundity and pregnancy complications. Preconception heat stress may cause similar disruptions in the sperm epigenome, providing a pathway through which high temperatures may impair men's reproductive health. STUDY DESIGN, SIZE, DURATION: We evaluated exposure to high ambient temperatures and sperm epigenetic age among 1,220 men residing along the Wasatch Front in Utah in an ancillary prospective cohort study set within the Folic Acid and Zinc Supplementation Trial (FAZST; 2013-2018). PARTICIPANTS/MATERIALS, SETTING, METHODS: Sperm epigenetic age (SEA), the acceleration or deceleration of age-related changes in sperm DNA methylation, was calculated in semen samples collected 6 months after enrollment. Utilizing local hourly temperature data, average temperature and hours per day exceeding the 98th, 95th, 90th, and 75th percentile thresholds for dry bulb temperature (ambient air) and wet bulb temperature (relative temperature with 100% humidity) were calculated across spermatogenesis and susceptible windows of mitosis, meiosis I + II, spermiogenesis, and spermiation. Temperature was modeled using three approaches: (i) Generalized linear models (GLMs) for average temperature by warm vs. cold season, (ii) GLMs incorporating natural cubic splines for average temperature, and (iii) GLMs for temperature thresholds. MAIN RESULTS AND THE ROLE OF CHANCE: Across spermatogenesis, each additional 10% increase in proportion of time exposed to wet bulb temperatures ≥90th (16.1°C), ≥95th (17.2°C), and ≥98th (17.8°C) percentiles was associated with 0.063 (95% CI -0.001, 0.128), 0.121 (95% CI 0.022, 0.220), and 0.173 (95% CI 0.030, 0.316) years accelerated sperm epigenetic age, respectively. For spermatogenic-specific developmental windows, associations were strongest during meiosis I + II (e.g. 0.146 [95% CI 0.028, 0.264] years for ≥98th percentile) and, in spline models, both warmer and colder wet bulb temperatures during meiosis I + II were associated with accelerated sperm epigenetic age (P = 0.028). Associations for dry bulb temperatures were similar, although less precise, and no clear associations were observed when modeling average temperature by season. LIMITATIONS, REASONS FOR CAUTION: Due to reliance on outdoor temperatures rather than personal exposure, misclassification of exposure to temperature is likely. Findings should be generalized with caution to groups with different levels of exposure to and susceptibility to outdoor heat. While we observed modest effect sizes up to 0.173 years for accelerated SEA per 10% increased time exposed to heat conditions, these changes at the population-level may be impactful for downstream impacts on fertility and pregnancy health, and future work replicating and extending findings is an important next step. WIDER IMPLICATIONS OF THE FINDINGS: Associations between high wet bulb temperatures, which capture impaired efficiency of sweating for cooling body temperature, and accelerated epigenetic aging add evidence that heat-related disruption of sperm DNA methylation may adversely impact men's reproductive health. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by K01ES034005 from the National Institute of Environmental Health Sciences. The parent trial was supported by funding from the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (HHSN275201200007C and HHSN275201300026I).The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: NCT01857310.
Early pregnancy concentrations of pregnancy-associated plasma protein-A (PAPP-A) and insulin-like growth factor-1 (IGF-1) following frozen embryo transfer: secondary analyses from a randomized controlled trial.
Mørch NF, Nøhr B, Kirk M … +2 more , Rode L, Svendsen PF
Hum Reprod · 2026 Jun · PMID 41875321 · Publisher ↗
STUDY QUESTION: Are maternal concentrations of pregnancy-associated plasma protein-A (PAPP-A) and insulin-like growth factor-1 (IGF-1) influenced by the frozen embryo transfer (FET) protocol in early pregnancy? SUMMARY A...
STUDY QUESTION: Are maternal concentrations of pregnancy-associated plasma protein-A (PAPP-A) and insulin-like growth factor-1 (IGF-1) influenced by the frozen embryo transfer (FET) protocol in early pregnancy? SUMMARY ANSWER: Maternal concentrations of PAPP-A and IGF-1 were significantly lower in programmed cycle (PC) FET compared to modified natural cycle (mNC) FET among ovulatory women and compared to gonadotrophin-stimulated cycle (gSC) FET in anovulatory women. WHAT IS KNOWN ALREADY: PC-FET has been associated with increased risks of preeclampsia and other placenta-related complications, pointing to altered placental development. PAPP-A and IGF-1 are biochemical markers of early placental function, and reduced levels have been linked to preeclampsia and other adverse outcomes. These markers may therefore provide insight into the pathways underlying the distinct risk profile of PC-FET. STUDY DESIGN, SIZE, DURATION: This is a secondary analysis from a randomized controlled trial investigating estradiol and progesterone concentrations in FET treatments. The trial was conducted at Copenhagen University Hospital-Herlev, Denmark, from April 2021 to December 2024. Biochemical analyses for PAPP-A and IGF-1 were performed on stored biobank samples from the trial. The main analyses included women with ongoing pregnancies (n = 116), while additional analyses of IGF-1 were conducted in all ovulatory women with available biobank samples (n = 193). PARTICIPANTS/MATERIALS, SETTING, METHODS: Eligible participants were women aged 18-40 years with BMI ≤35 kg/m2 undergoing frozen-thawed autologous blastocyst transfer. Ovulatory women were randomized to mNC or PC, and anovulatory women to gSC or PC. Samples were collected at the following 7 timepoints throughout treatment: on the 2nd or 3rd day of menstrual bleeding, on the day of trigger/endometrial thickness ≥7 mm, on the day of embryo transfer and by gestational ages (GA) 4 + 2, 6 + 0, 8 + 0, and 9 + 6. Data on placental weight were collected at delivery. MAIN RESULTS AND THE ROLE OF CHANCE: The present analyses included women with ongoing pregnancies from the parent trial: 43 in the ovulatory mNC group, 42 in the ovulatory PC group, 16 in the anovulatory gSC group, and 15 in the anovulatory PC group. PC had substantially lower IGF-1 concentrations from treatment initiation through GA 8 + 0 compared to both mNC and gSC. Ovulatory women treated with PC showed significantly lower PAPP-A concentrations during endometrial preparation (7.4 vs 8.7 mU/l; adjusted P = 0.02), at embryo transfer (6.7 vs 8.8 mU/l; adjusted P < 0.001), and GA 4 + 2 (7.2 vs 8.5 mU/l; adjusted P = 0.03) than women treated with mNC. Among anovulatory women, PAPP-A concentrations were also reduced during endometrial preparation (5.8 vs 9.1 mU/l; adjusted P = 0.008) in PC compared to gSC. LIMITATIONS, REASONS FOR CAUTION: As this was a secondary analysis, no formal power calculation was made, and statistical power may therefore be limited. WIDER IMPLICATIONS OF THE FINDINGS: We provide evidence that PC-FET was followed by lower IGF-1 concentrations in early pregnancy and by time-dependent reductions in PAPP-A compared to mNC-FET and gSC-FET. These findings suggest alterations in early placental biology that may contribute to the adverse obstetric risk profile associated with PC-FET. Future studies should clarify whether these changes are related to the use of oral estradiol and whether alternative administration routes could modify this risk. STUDY FUNDING/COMPETING INTEREST(S): The trial was funded by Gedeon Richter Nordics AB, including analysis of biobank samples (grant numbers DK-2019-04, DK-2022-03, DK-2023-08, DK-2023-06, DK-2024-08). The trial also received one grant from the Gangsted-Rasmussen Foundation (grant number A39784) and a grant was obtained from the local research board at Copenhagen University Hospital-Herlev. The study was designed and planned independently, with no involvement from the funders in data analysis or interpretation of the results. N.F.M. has received funding for congress attendance from Gedeon Richter Nordics AB and Merck A/S, unrelated to the present work. B.N. has received grants to the institution from Merck A/S, Gedeon Richter Nordics AB, and Ferring Pharmaceuticals A/S, along with personal fees from Ferring Pharmaceuticals A/S, travel support from Gedeon Richter Nordics AB, and has participated in a data safety monitoring or advisory board for Ferring Pharmaceuticals A/S, outside of this research. M.K. has received funding from Rigshospitalets Research Board outside of this research. L.R. has received a research grant from the Novo Nordisk Foundation outside of this research. P.F.S. has received grants from Merck A/S, Gedeon Richter Nordics AB, and Ferring Pharmaceuticals A/S, travel support from Ferring Pharmaceuticals A/S, and personal fees from Novo Nordisk for webinars, outside of this study. TRIAL REGISTRATION NUMBER: 2020-001218-39 in EudraCT.
Human stem cell-based embryo models: innovation, ethics, and policy.
Arias AM, Rivron N, Tajbakhsh S … +41 more , Johnston J, Alev C, Bally-Cuif L, Böke E, Cavazza T, Cave E, Cyranoski D, David L, Esteban MA, Fu J, Geijsen N, de Graeff N, Hanna JH, Hopwood N, Inamdar MS, Lanner F, Leeners B, Liu Z, Jean Leon M, Minchiotti G, Moris N, Munsie M, Niakan KK, Pourquie O, Pasque V, Pera M, Peng Y, Petropoulos S, Ramanathan S, Rossant J, Rugg-Gunn P, Saitou M, Sermon K, Silva J, Theunissen T, Turco M, Wallingford J, Wang H, Warmflash A, Wu J, Yu L
Hum Reprod · 2026 Jun · PMID 41875051 · Full text
The aim of this White Paper is to establish a foundational framework for research, technological development, and regulation in the emerging field of stem cell-based embryo models (SCBEMs). These models, generated from P...
The aim of this White Paper is to establish a foundational framework for research, technological development, and regulation in the emerging field of stem cell-based embryo models (SCBEMs). These models, generated from Pluripotent Stem Cells, are designed to recapitulate essential events in early stages of human development. They have the potential to illuminate the early stages of embryo development and implantation and hold promise as an avenue to address global health challenges, including infertility and pregnancy loss, congenital, neonatal and adult conditions, and the need for organ transplants. While SCBEMs are not a substitute for human embryos, their tractability for large-scale analysis and their abilities to model the earliest stages of embryonic development suggest that they will have a significant impact on reproductive biology and regenerative medicine. But SCBEMs do not just raise novel scientific questions; they pose ethical and legal questions that need to be addressed. The paper stems from a meeting of a core group of researchers that met at the Institut Pasteur in Paris in November 2024 and represents the views of an extended group that has worked to elaborate the documents as a consensus for the field. Here, we provide a framework to guide research in this new field. We do this by summarizing the state of the science, assessing current SCBEM research in relation to its primary future applications and addressing the need for continued ethical and regulatory oversight associated with this new field.
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