Hum. Reprod. [JOURNAL]
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200 papers
Culture media age does not affect IVF outcomes.
Morbeck DE, Hesketh N, Bui D
Hum Reprod · 2026 Feb · PMID 41370230 · Publisher ↗
STUDY QUESTION: Does the storage duration of a single-step embryo culture medium within its labelled 1-year shelf-life affect embryo development, pregnancy outcomes, or birthweight in IVF? SUMMARY ANSWER: The age of a si...
STUDY QUESTION: Does the storage duration of a single-step embryo culture medium within its labelled 1-year shelf-life affect embryo development, pregnancy outcomes, or birthweight in IVF? SUMMARY ANSWER: The age of a single-step embryo culture medium with a 1-year shelf-life is not associated with embryo development, cumulative live birth, or neonatal outcomes such as birthweight or preterm birth. WHAT IS KNOWN ALREADY: Media composition, pH, and osmolality are recognized as important measures of media quality. In contrast, the shelf-life of culture media is poorly studied, resulting in different expiries among suppliers, with most between 120 days and 26 weeks. These differences have far-reaching implications, with the potential to affect success rates while increasing cost and waste. Most importantly, it is critical to know if 'old' media results in similar or worse IVF outcomes than 'fresh' media. STUDY DESIGN, SIZE, DURATION: A retrospective multicentre study was conducted using 9680 IVF/ICSI cycles from 6330 patients across eight clinics in Australia between October 2020 and December 2023. PARTICIPANTS/MATERIALS, SETTING, METHODS: Inclusion criteria were autologous cycles with ≥1 fertilized oocyte and known media production date. Cycles using thawed oocytes/embryos or non-standard transfer days were excluded. All embryos were cultured in time-lapse incubators using single-step media. Cycle outcomes, including embryo development, cumulative pregnancy, live birth, preterm birth, and birthweight for singleton, were analysed using unadjusted and adjusted regression models, as well as generalized estimating equation models to account for repeated measures within same patients. MAIN RESULTS AND THE ROLE OF CHANCE: Media age at use ranged from 38 to 365 days (mean ± SD: 190 ± 61 days). No statistically significant associations were observed between media age and embryo development outcomes, including percentage of Day 5/6 blastocysts (P = 0.389) and Day 5/6 usable blastocysts (P = 0.255). Similarly, media age was not associated with cumulative cycle outcomes including clinical pregnancy (P = 0.669), ongoing pregnancy (P = 0.986), or live birth (P = 0.257) in adjusted models. Subgroup analyses, including preimplantation genetic testing cycles and fresh transfers, yielded consistent results. Among 1070 singleton live births, media age was not associated with preterm birth (P = 0.818) or birthweight (P = 0.161). LIMITATIONS, REASONS FOR CAUTION: This was a retrospective study based on a single medium type; results may not generalize to other formulations. Post-opening media handling was not captured, which may introduce unmeasured variability. Prospective studies are needed to confirm these findings across diverse media types and settings. WIDER IMPLICATIONS OF THE FINDINGS: These results support more flexible use of culture media up to expiration and suggest longer shelf-life media can be used to reduce waste and logistical burdens. Broader application could support sustainability goals in IVF practice. STUDY FUNDING/COMPETING INTEREST(S): No funding was attached to this study. D.M. has received consulting fees from Dawn-bio, Fujifilm Irvine Scientific and Overture Life; and speaker's fees from Genea Biomedx and Organon. The other authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.
Semen analysis as a biomarker of male aging: biological mechanisms, clinical implications, and public health perspectives.
Ammar OF, Liperis G, Ali ZE … +9 more , Horta F, Anastasi A, Kalaitzopoulos DR, Ribeiro S, Salmeri N, Aitken RJ, Sangster P, Vazquez-Levin M, Fraire-Zamora JJ
Hum Reprod · 2026 Jan · PMID 41370226 · Publisher ↗
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Studies of post-partum placentas provide insights into the origin of structural chromosomal aberrations.
Thomsen SH, van Berkel A, van Veen S … +6 more , van Koetsveld N, Joosten M, Diderich KEM, van den Born M, Srebniak MI, Van Opstal D
Hum Reprod · 2026 Feb · PMID 41338242 · Full text
STUDY QUESTION: Can comprehensive cytogenetic follow-up of the placenta post-partum uncover possible explanations for discrepancies between non-invasive prenatal testing (NIPT) showing structural chromosomal aberrations...
STUDY QUESTION: Can comprehensive cytogenetic follow-up of the placenta post-partum uncover possible explanations for discrepancies between non-invasive prenatal testing (NIPT) showing structural chromosomal aberrations and foetal follow-up showing normal results or other chromosomal aberrations? SUMMARY ANSWER: In 18/31 (58%) cases of structural chromosomal aberrations detected with NIPT, where foetal and maternal follow-up was normal or the foetus had another chromosomal aberration, genome-wide examination of term placental chorionic villi confirmed the discrepancy and in 7/18 (39%) confirmed cases complex foeto-placental mosaicism was found. WHAT IS KNOWN ALREADY: Complex chromosomal rearrangements are often seen in single-cell studies of preimplantation embryos, but it is unknown if these persist into the mature placenta. Confined placental mosaicism explains most discordant NIPTs involving a trisomy, but little is known about structural chromosome aberrations. STUDY DESIGN, SIZE, DURATION: We performed a retrospective diagnostic test study of cytogenetic follow-up data from post-partum placentas. We included data from pregnancies where (i) NIPT showed a structural aberration, (ii) follow-up of foetus (amniotic fluid and/or cord blood) and mother (genomic DNA and/or cfDNA after birth) was normal or the foetus showed another chromosomal aberration, (iii) follow-up was performed in the Erasmus MC, (iv) more than one sample from the post-partum placenta was analysed, and (v) samples were of good quality (not in formaldehyde, sufficient material).In the period from January 2014 to March 2022, 115 231 NIPTs were performed in the Erasmus MC; 217 of these showed structural chromosomal aberrations and 123 were followed up in the Erasmus MC (inclusion criteria 3). After exclusion of the foetal (same aberration as with NIPT) and maternal structural chromosome aberrations, 48 placentas were requested to elucidate the discrepancies seen between NIPT (abnormal) and foetal karyotype (normal or differently abnormal; inclusion criteria 1-2). Of these, 31 met criteria 4 and 5 and were included in this study. PARTICIPANTS/MATERIALS, SETTING, METHODS: In a diagnostic setting, we performed a cytogenetic analysis of postpartum placentas in order to confirm confined placental mosaicism in 31 cases in which NIPT showed a structural chromosome aberration. Two to four chorionic villus biopsies were taken per placenta, and separated enzymatically into cytotrophoblast (CTB) and mesenchymal core (MC) and analysed using SNP arrays. In our analysis, cases were assessed for copy number variants ≥0.5 Mb and regions of homozygosity ≥3 Mb. MAIN RESULTS AND THE ROLE OF CHANCE: In 18/31 cases (58%), we could confirm the structural chromosome aberration detected with NIPT in one or more placental biopsies. In 13/31 cases (42%), the structural chromosomal aberration detected with NIPT was not confirmed, but in one case an apparently unrelated aberration was found in the CTB of two biopsies. In 11/18 confirmed cases, the same aberration as detected with NIPT, was confirmed in the placenta. All these cases concerned chromosomally normal foetuses with a chromosome aberration confined to the placenta. In one case, an extra, apparently unrelated, aberration was found in one placental biopsy. In 7/18 confirmed cases, the aberration detected with NIPT was confirmed in the placenta and showed to be involved in complex mosaicism involving different abnormal cell lines. In four of these seven cases, the foetus was affected with a pathogenic chromosome aberration that was different from the NIPT aberration. In three cases, a related but benign chromosome aberration was present in the foetus. LIMITATIONS, REASONS FOR CAUTION: As conventional karyotyping, FISH or whole genome sequencing were not performed, we can only hypothesize on the mechanisms behind the origin of the complex foeto-placental mosaicism we see in seven cases, although there is more strong evidence in the literature as well. WIDER IMPLICATIONS OF THE FINDINGS: Our results have several implications. First, a genome-wide rather than a targeted approach in foetal follow-up examinations after NIPT showing a structural chromosomal aberration is warranted, as other aberrations may be overlooked in the foetus. Second, counselling of pregnant couples after NIPT showing a structural chromosomal aberration should focus not only on the specific aberration detected by NIPT but also on the possibility that the foetus may harbour another, possibly related, structural aberration. Additionally, a structural chromosomal aberration of apparently uncertain significance may unmask truly pathogenic aberrations in the foetus itself, so all potential foetal cases of structural chromosome aberrations should be followed up. Third, we show how comprehensive examinations of the placenta, specifically the separation of CTB and MC, provides crucial insights into the embryonic origins and mechanisms behind structural chromosomal aberrations. Lastly, our results show that complex chromosomal rearrangements as often seen in single-cell studies of pre-implantation embryos, are not artefacts but a biological phenomenon that can actually persist into the mature placenta and foetus. STUDY FUNDING/COMPETING INTEREST(S): Simon H. Thomsen was funded by a private research donation and the Department of Clinical Medicine, Aarhus University. All authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.
Microdeletion and microduplication syndromes, including recurrent rearrangements at 16p11.2 and 22q11.21, are enriched in unexplained male infertility.
Kikas T, Dutta A, Inno R … +6 more , Pomm K, Tjagur S, Poolamets O, Roomere H, Punab M, Laan M
Hum Reprod · 2026 Feb · PMID 41338233 · Publisher ↗
STUDY QUESTION: What is the impact of undiagnosed microdeletion and microduplication syndromes (MMS) for men with idiopathic low sperm count? SUMMARY ANSWER: Among idiopathic male infertility, ∼2% of cases harbour known...
STUDY QUESTION: What is the impact of undiagnosed microdeletion and microduplication syndromes (MMS) for men with idiopathic low sperm count? SUMMARY ANSWER: Among idiopathic male infertility, ∼2% of cases harbour known disease-causing microdeletions and duplications linked to clinically well-established syndromes, representing ∼2.5-fold higher prevalence than in the general population. WHAT IS KNOWN ALREADY: While infertility affects up to 10% of men, a substantial proportion of cases remain with no identifiable underlying cause. Recurrent submicroscopic losses or gains cause MMS, some of which also impact reproductive phenotypes, including cryptorchidism and reduced fertility. STUDY DESIGN, SIZE, DURATION: This retrospective study investigated the proportion of undiagnosed MMS among idiopathic male infertility cases. Patients with unexplained low total sperm counts (TSC; defined as ≤39 million sperm per ejaculate) were recruited to the ESTonian ANDrology (ESTAND) cohort at the Andrology Clinic of Tartu University Hospital (AC-TUH) in Estonia. A total of 504 men were included in the analysis, and the study capitalized on available whole-exome sequencing (WES) data to explore large (>500 kb) chromosomal deletions and duplications. PARTICIPANTS/MATERIALS, SETTING, METHODS: Copy number variant (CNV) calling was executed on the WES dataset, followed by a stringent, custom-developed filtering pipeline that retained only high-confidence CNVs larger than 500 kb. Candidate CNVs were validated by chromosomal microarray analysis (CMA) or whole-genome sequencing (WGS). Prevalence of identified MMS-linked deletions and duplications in the ESTAND cohort was compared to general population literature data. MAIN RESULTS AND THE ROLE OF CHANCE: A total of nine patients (1.8%) carried losses and gains linked to clinically well-characterized MMS-recurrent microdeletions at 16p11.2 (two cases), 2q13-14.1, and 15q13.2-13.3, and microduplications at 22q11.21 (three cases), 16p11.2, and 8p23.1. The total burden of MMS among infertile men was ∼2.5-fold higher compared to the general population (P = 0.01, χ2 test). Cryptorchidism was a novel shared feature among all individuals with 16p11.2 rearrangements, suggesting a potential role in disrupting testicular development. Three subjects with MMS-linked microduplications, but none with a microdeletion, had achieved biological fatherhood. An oligozoospermia case (TSC 1.92 × 106/ej.) with 16p11.2 duplication had a naturally conceived child in youthhood. For two men carrying 22q11.21 duplication (TSC 0 and 4.2 × 106/ej., respectively), implementation of ARTs-ICSI with or without preceding testicular sperm aspiration-resulted in successful conception and childbirth. Evidence for a plausible link to male gonadal development and function has been reported for MAZ and KCTD13 at 16p11.2, and LZTR1 at 22q11.21. As an additional finding, a novel ∼3.8 Mb microduplication at 3p25.1 was identified in an oligozoospermia patient and his azoospermic son, conceived naturally at the age of 28 years. This region encompasses a triplosensitive gene, NR2C2, linked to affected meiosis and oligozoospermia in mouse models. LIMITATIONS, REASONS FOR CAUTION: WES may not detect all structural variations, such as inversions or balanced translocations. As some MMS CNVs were only identified in singleton cases (8p23.1 duplication, 2q13-14.1 and 15q13.2-13.3 deletions), the link to male infertility could not be clarified. Further data are needed about the novel large 3p25.1 microduplication to understand its effect on spermatogenesis. WIDER IMPLICATIONS OF THE FINDINGS: The yield of identified MMS in idiopathic cases with low sperm counts (∼2%) was close to the carriership of Y-chromosome microdeletions, tested in routine infertility workup. Early identification of MMS can inform genetic counselling regarding congenital health risks to the patient and future offspring and options for decision-making in ART. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Estonian Research Council (Grant number PRG1021 to M.L.). The authors declare that they have no conflict of interest in relation to the data in this paper. TRIAL REGISTRATION NUMBER: N/A.
A North American preconception study of sleep health and semen quality.
Coleman CM, Wesselink AK, Yland JJ … +6 more , Sommer GJ, Eisenberg ML, Bertisch SM, Rothman KJ, Hatch EE, Wise LA
Hum Reprod · 2026 Feb · PMID 41330355 · Publisher ↗
STUDY QUESTION: To what extent are self-reported sleep health measures associated with semen quality? SUMMARY ANSWER: Poor sleep health-including short and long sleep durations, increased frequency of sleep trouble, and...
STUDY QUESTION: To what extent are self-reported sleep health measures associated with semen quality? SUMMARY ANSWER: Poor sleep health-including short and long sleep durations, increased frequency of sleep trouble, and poor sleep quality-was associated with reduced sperm concentration, total sperm count, and total motile sperm count, and, in the case of short sleep duration and increased frequency of sleep trouble, reduced semen volume. WHAT IS KNOWN ALREADY: Semen quality has declined over the past several decades. Sleep health may affect semen quality through multiple pathways, including endocrine dysfunction, and population-based prospective studies of the association are scarce. STUDY DESIGN, SIZE, DURATION: We analyzed cross-sectional data from 690 male participants (1247 semen samples) aged ≥21 years at enrollment (2015-2023) in Pregnancy Study Online, a North American preconception cohort study. PARTICIPANTS/MATERIALS, SETTING, METHODS: At baseline, participants provided self-reported data on sleep duration in the past month and frequency of sleep trouble in the previous 2 weeks. A subset of participants completed the Pittsburgh Sleep Quality Index. We used generalized estimating equations (GEE) models to estimate mean percentage differences (%D) and 95% CIs for the associations of sleep health with semen parameters (semen volume, sperm concentration, percent motility), ascertained using a validated at-home semen testing kit. We also used GEE models to estimate prevalence ratios for poor semen quality (low vs normal) based on World Health Organization (WHO) standards. MAIN RESULTS AND THE ROLE OF CHANCE: Comparing sleep durations of <6 vs 7-8.9 h/day, %Ds (95% CIs) were -11.3% (-23.6%, 1.1%), -16.4% (-45.0%, 26.9%), -27.1% (-53.1%, 13.2%), and -20.0% (-50.3%, 28.8%) for semen volume, sperm concentration, total sperm count, and total motile sperm count, respectively. We observed similar associations for ≥9 vs 7-8.9 h/day and sperm concentration (-14.4% [-44.9%, 33.0%]), total sperm count (-13.9% [-44.1%, 32.7%]), and total motile sperm count (-6.8% [-42.1%, 49.9%]). Comparing sleep trouble >50% of the time vs never, %Ds (95% CIs) were -3.3% (-12.0%, 5.4%), -11.9% (-29.9%, 10.8%), -16.2% (-34.3%, 7.0%), and -16.9% (-37.3%, 9.9%) for semen volume, sperm concentration, total sperm count, and total motile sperm count, respectively. Comparing global Pittsburgh Sleep Quality Index scores of >5 (poor sleep quality) vs ≤5 (good sleep quality), %Ds (95% CIs) were -18.1% (-33.5%, 0.9%), -19.2% (-34.6%, -0.1%), and -16.3% (-33.5%, 5.4%) for sperm concentration, total sperm count, and total motile sperm count, respectively. Analyses based on WHO semen quality standards showed consistent results. LIMITATIONS, REASONS FOR CAUTION: Non-differential misclassification of sleep health was possible due to our reliance on self-reported data collected at a single point in time. Non-differential misclassification of semen quality was also possible, as participants used an at-home semen testing kit to measure semen parameters. We cannot rule out bias due to residual or unmeasured confounding. Given that the study population was restricted to pregnancy planners who enrolled via the Internet, our findings may not be generalizable to other populations. WIDER IMPLICATIONS OF THE FINDINGS: Our findings are generally consistent with previous research, supporting a relationship between poor sleep health and worse semen quality. We analyzed data from a population-based sample of pregnancy planners, which overcomes limitations from most prior studies that relied on convenience samples of infertile couples or sperm donors. These findings may inform sleep interventions to improve reproductive health outcomes. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the following grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, USA: R01HD086742, R01HD105863, R21HD094322. J.J.Y. is an employee of Optum and owns stock in UnitedHealth Group. G.J.S. is an employee of and holds stock in Labcorp, which manufactures the male fertility testing kits used in this study. He is also a co-inventor on multiple patents related to the male fertility testing kits reported in this manuscript: US #10 376 877, US #11 471 881, and US #11 714 034. M.L.E. is an advisor for Doveras, Hannah, Next, Illumicell, Legacy, and HisTurn, which includes a small equity grant of options. S.M.B. has received consulting fees from Idorsia Pharmaceuticals and Apnimed in the past 12 months, participated in a Data Safety Monitoring Board or Advisory Board for PCORI and AHRQ, and served in a leadership role for the Sleep Research Society and American Academy of Sleep Medicine. All other authors have no disclosures to report. TRIAL REGISTRATION NUMBER: N/A.
WHO infertility guidelines 2025: a call for evidence-based practice.
Kirkegaard K, Barratt C
Hum Reprod · 2026 Jan · PMID 41312732 · Publisher ↗
Abstract loading — click title to view on PubMed.
Recommendations from the WHO guideline for the prevention, diagnosis, and treatment of infertility†.
World Health Organisation Guideline Development Group for Infertility, Mburu G, Santesso N … +19 more , Brignardello-Petersen R, Kennedy R, Farquhar C, Boivin J, Pennings G, Giudice LC, Rebar RW, Gianaroli L, Vuong LN, Esteves SC, De Jonge CJ, Pacey A, Ombelet W, Kucuk T, Collura BL, Kordic K, Amato P, Matsaseng T, Kiarie J
Hum Reprod · 2026 Jan · PMID 41312724 · Full text
STUDY QUESTION: What is the recommended prevention, diagnosis, and treatment of infertility among individuals and couples? SUMMARY ANSWER: The World Health Organization (WHO) made 40 recommendations and six good practice...
STUDY QUESTION: What is the recommended prevention, diagnosis, and treatment of infertility among individuals and couples? SUMMARY ANSWER: The World Health Organization (WHO) made 40 recommendations and six good practice statements for the prevention, diagnosis, and treatment of infertility. WHAT IS KNOWN ALREADY: The field of sexual and reproductive health care, including family planning has progressed in the last several decades. Significant progress has also been made in the field of medically assisted reproduction. Globally, one in six people experience infertility in their lifetime. However, many countries do not include the prevention, diagnosis, and treatment of infertility in health policies, financing, and services, and many do not have national clinical guidelines for the prevention, diagnosis, and treatment of infertility. STUDY DESIGN, SIZE, DURATION: The guideline was developed according to the WHO handbook for guideline development. A Guideline Development Group (GDG) was assembled and included a multidisciplinary and regionally diverse set of clinicians, policymakers, researchers, implementers, and representatives of patient groups (n=30). The GDG prioritized key recommendation questions to address in the guideline. PARTICIPANTS/MATERIALS, SETTING, METHODS: New systematic reviews were conducted, or existing reviews updated, to inform the recommendations. The GRADE approach was used to assess the certainty of the evidence and to guide the formulation of recommendations. The GDG interpreted evidence and made judgments about the balance between benefits and harms (including patients' values) as well as costs, feasibility, acceptability, and equity. The recommendations were drafted, reviewed by an External Review Group (ERG) comprising 30 members, and approved by the WHO. MAIN RESULTS AND THE ROLE OF CHANCE: The guideline makes good practice statements related to the general management of infertility (n = 6) including (i) selection of tests, (ii) listening to individuals and couples with infertility, (iii) choosing treatment decisions, (iv) clinical follow-up, and (v) documenting outcomes of treatment. In relation to prevention, it provides recommendations related to the provision of information about fertility and infertility (n = 1) and reduction of infertility risk from sexually transmitted infections (STIs; n = 1), lifestyle factors (n = 1), and tobacco use (n = 1). In terms of diagnosis, recommendations for diagnosing infertility caused by ovulatory dysfunction (n = 3), tubal disease (n = 1), or uterine cavity abnormalities (n = 5) among females are provided. For males, the guideline provides recommendations regarding when a semen test should be repeated (n = 2). Also included is a recommendation for diagnosing unexplained infertility (n = 1). Regarding treatment, the guideline provides recommendations related to the treatment of polycystic ovary syndrome (n = 6), tubal disease (n = 5), uterine septae (n = 1), varicocele (n = 4), and unexplained infertility (n = 6). Based on available evidence, the GDG did not make a recommendation for or against the use of antioxidant supplements in males. Most recommendations were conditional because relevant evidence was either absent, or of low or very low certainty. Critical research gaps were identified. LIMITATIONS, REASONS FOR CAUTION: The recommendations do not cover all aspects of infertility and fertility care, but subsequent editions of the guideline will expand the scope of recommendations. WIDER IMPLICATIONS OF THE FINDINGS: By centring equity, science, and the imperative to provide fertility care as part of universal health coverage, the guideline aims to support countries in delivering high-quality, equitable, and effective healthcare for all. Although the guideline is primarily intended for use by health care professionals, it is an important source for policymakers to inform national guidelines and to inform the work of professional patient support, including advocacy organizations, funding and philanthropic agencies, civil society, professional societies, and other nongovernmental organizations that provide social, financial, and technical support to reproductive health programmes. STUDY FUNDING/COMPETING INTEREST(S): This work received funding from the UNDP-UNFPA-UNICEF-WHO-World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), a cosponsored programme executed by the World Health Organization (WHO). Full details of declared interests of all named authors are shown in Supplementary Table S1, those for members of the GDG who are not named authors are shown in Supplementary Table S2 and those for members of the ERG are shown in Supplementary Table S3. TRIAL REGISTRATION NUMBER: N/A. DISCLAIMER: This manuscript reports a summary of recommendations from a WHO guideline. All reasonable precautions have been taken by WHO to verify the information contained in the guideline publication. However, the published material is being distributed without warranty of any kind, either expressed or implied.
Safeguarding WHO guideline recommendations through strengthened scientific integrity to advance global health.
Mburu G, Santesso N, Brignardello-Petersen R … +3 more , Farquhar C, Kennedy R, Kiarie J
Hum Reprod · 2026 Jan · PMID 41312721 · Full text
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Patient-derived epithelial cell organoids mimic the phenotypic complexity of endometriosis subtypes.
Gunther K, Liu D, Cortesi M … +4 more , Powell E, Nesbitt-Hawes E, Abbott JA, Ford CE
Hum Reprod · 2026 Feb · PMID 41298340 · Full text
STUDY QUESTION: Can patient-derived organoid models be reliably established from diverse surgical phenotypes of endometriosis, and how do clinical factors such as hormonal treatment affect their growth success and morpho...
STUDY QUESTION: Can patient-derived organoid models be reliably established from diverse surgical phenotypes of endometriosis, and how do clinical factors such as hormonal treatment affect their growth success and morphology? SUMMARY ANSWER: Endometriosis organoids can be established across all major surgical phenotypes with variable efficiency, and hormonal treatment at the time of biospecimen collection significantly reduces organoid establishment success. WHAT IS KNOWN ALREADY: Organoid cultures have been developed from eutopic endometrium and select endometriosis tissue biospecimens previously, but their feasibility as pre-clinical models of endometriosis across diverse tissue types and clinical presentations remains unclear. STUDY DESIGN, SIZE, DURATION: Twenty-eight endometriosis tissue biospecimens were obtained from 23 patients undergoing surgery, with organoid cultures assessed through successive stages of establishment, passage, and cryopreservation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Endometriosis biospecimens, including deep infiltrating endometriosis (DIE), ovarian endometrioma (OMA), and superficial peritoneal (SUP) biospecimens, were processed into organoid cultures using a validated low-Wnt culture system. Organoid viability, morphology, hormone receptor expression, and cellular composition were evaluated by microscopy, immunohistochemistry, and quantitative morphometric analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, 22/28 (78.6%) biospecimens established 3-dimensional structures, with 15/28 (53.6%) remaining viable after cryopreservation. Establishment success differed by phenotype (OMA 71.4%, DIE 63.6%, SUP 30%). Progesterone receptor expression was retained in SUP and DIE-derived organoids (7/7, 100%), while OMA-derived organoids showed substantial reductions (4/5 cases). Biospecimens from patients receiving hormonal treatment were smaller (P = 0.038) and had reduced organoid establishment success (3/13, 23.1% vs 12/15, 80.0%, P = 0.003). Organoids exhibited distinct morphological patterns correlating with disease phenotype. LIMITATIONS, REASONS FOR CAUTION: Uniform culture conditions may limit growth of certain subtypes, and the in vitro organoid models may not fully represent in vivo tissue complexity. Sample sizes were modest, and pooling tissues from the same patient could mask intra-patient heterogeneity. WIDER IMPLICATIONS OF THE FINDINGS: These organoid models offer a promising platform for studying subtype-specific endometriosis biology, including hormone resistance mechanisms, and could inform personalized therapeutic development. The impact of hormonal treatment on organoid viability underscores the need to consider clinical context in pre-clinical models of endometriosis. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Endometriosis Clinical and Scientific Trials (NECST) Network, funded by the Australian Government Department of Health and Aged Care (Grant 4-I66SNMA), and by a research grant from Endometriosis Australia to C.E.F., D.L., and J.A.A. K.G. is supported by an Australian Government Research Training Program Scholarship and a NECST Network Top-Up Scholarship, which did not influence the conduct or outcomes of this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. J.A.A. has received consulting fees from Hologic, Gedeon Richter, and BD, personal payments from Hologic, Bayer, Organon, and Gedeon Richter, travel support from Gedeon Richter, and participated on data safety monitoring advisory boards for Hologic and Gideon Richter. He was the former chair of the Australian Endometriosis Guideline Committee and is the Co-Editor-in-Chief of the Journal of Minimally Invasive Gynaecology. All other authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.
Preimplantation genetic testing for neurofibromatosis type 1: molecular genetic aspects and impact on reproductive counseling.
Vernimmen V, De Rycke M, Moutou C … +17 more , Dreesen J, Blok MJ, van Minkelen R, Lauer-Zillhardt J, Verdyck P, Keymolen K, van Uum C, Homminga I, Brandts L, Stumpel CTRM, Coonen E, Heijligers M, van Zelst-Stams W, Zamani Esteki M, van den Wijngaard A, de Die-Smulders CEM, Paulussen ADC
Hum Reprod · 2026 Feb · PMID 41289058 · Full text
STUDY QUESTION: How do the genetic complexities of neurofibromatosis type 1 (NF1) impact reproductive counseling, preimplantation genetic testing (PGT) design, and PGT treatment? SUMMARY ANSWER: We established associatio...
STUDY QUESTION: How do the genetic complexities of neurofibromatosis type 1 (NF1) impact reproductive counseling, preimplantation genetic testing (PGT) design, and PGT treatment? SUMMARY ANSWER: We established association between both incidence and tissue mosaicism with multiple exon deletions and specific single-nucleotide variants (SNVs) in neurofibromin 1 (NF1), a clinical actionable finding that we structured as a flowchart outlining challenges in and an approach for reproductive counseling, PGT design, and PGT treatment for NF1. WHAT IS KNOWN ALREADY: NF1 has a prevalence of 1 in 2500-3000 and is one of the most frequently requested autosomal dominant indications for PGT. NF1 is a large gene with a high mutation rate, resulting in a 50% de novo occurrence, many different reported variants scattered across the gene and relatively frequent mosaicism. STUDY DESIGN, SIZE, DURATION: We conducted a retrospective, observational cohort study on PGT molecular design for NF1 in three large PGT centers (n = 281 couples), starting from the first assay for NF1 developed in 2004 until 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: A PGT assay was developed for 281 couples with 218 different variants in NF1. Newly described variants (n = 76) were scored using the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) classification system and submitted prior to publication in the Leiden Open Variation Database (LOVD). The employed techniques were PCR-based PGT using short tandem repeat markers (n = 230), SNP-array-based PGT (n = 39), and next-generation sequencing (NGS)-based PGT (n = 12). Minisequencing (SNAPshot) or double amplification refractory mutation system (D-ARMS) was used to incorporate SNVs. Small deletions and insertions were incorporated using fragment length analysis. All PGT assays were designed and validated according to local protocols and ESHRE guidelines. MAIN RESULTS AND THE ROLE OF CHANCE: Mosaicism was present in 8% of the sporadic cases (n = 13/168), of which about half were unknown prior to PGT (n = 6/13). Mosaicism was significantly higher in patients with multiple exon deletions (n = 4/6) as compared to patients with SNVs (n = 9/162) (P < 0.001, Fisher's exact test). Additionally, two recurrent SNVs were significantly associated with mosaicism (P <0.0167, Fisher's exact test). Importantly, three unrelated families with different NF1 variants in close relatives were identified. LIMITATIONS, REASONS FOR CAUTION: Due to its retrospective design, not all details on the genetic test results and clinical phenotype could be retrieved for some cases (n = 6). The extent to which our findings are applicable to centers worldwide depends on their local procedures and legislation. WIDER IMPLICATIONS OF THE FINDINGS: Our findings substantially impact reproductive counseling for couples with NF1, enabling informed reproductive decision-making. For couples affected with NF1 proceeding with PGT, our findings alert colleagues worldwide on NF1-specific pitfalls in PGT molecular design and treatment. STUDY FUNDING/COMPETING INTEREST(S): There was no funding involved in the research for this publication. M.Z.E. is an inventor on two patent applications: ZL910050-PCT/EP2011/060211-WO/2011/157846 'Methods for haplotyping single cells' and ZL913096-PCT/EP2014/068315-WO/2015/028576 'Haplotyping and copy-number typing using polymorphic variant allelic frequencies'. The other authors have no competing interests to disclose. TRIAL REGISTRATION NUMBER: N/A.
Male infertility and risk of cardiometabolic conditions: a population-based cohort study.
Marozzi J, Hanly M, Venetis C … +3 more , O'Bryan MK, McLachlan R, Chambers GM
Hum Reprod · 2026 Jan · PMID 41285026 · Full text
STUDY QUESTION: Is male infertility independently associated with an increased risk of incident hypertension, ischemic and non-ischemic heart disease, diabetes, and/or cerebrovascular disease? SUMMARY ANSWER: Fathers dia...
STUDY QUESTION: Is male infertility independently associated with an increased risk of incident hypertension, ischemic and non-ischemic heart disease, diabetes, and/or cerebrovascular disease? SUMMARY ANSWER: Fathers diagnosed with male infertility have a modestly increased risk of heart disease, diabetes, and hypertension compared with fertile fathers, after controlling for measured confounders; however, some important confounders remain inadequately measured. WHAT IS KNOWN ALREADY: Cohort studies suggest that infertile men have an increased risk of incident cardiometabolic diseases, including diabetes, hypertension, heart disease, and cerebrovascular disease, although findings are mixed. The reasons for this association are unclear, but cardiometabolic conditions and male infertility share a wide range of shared etiological factors including age, chronic conditions such as obesity and obstructive sleep apnea, cancers and their treatments, environmental exposures such as pollution and pesticides, lifestyle factors such as smoking and cardiorespiratory fitness, autoimmune conditions such as lupus and Hashimoto's thyroiditis, as well as congenital conditions such as cystic fibrosis and muscular dystrophy. STUDY DESIGN, SIZE, DURATION: Our population-based cohort study included 445 909 men whose partner conceived a child between January 2009 and September 2016 in New South Wales (NSW), Australia. We excluded men with a diagnosis of infertility prior to 2009, men who were under the age of 14 at the time of the child's conception, and men diagnosed with cardiometabolic conditions in the 6.5 years prior to their index date. The index date was the later of the date of the child's conception or the date of the vasectomy for fertile men or the date of diagnosis of infertility for infertile men, i.e. the time when the exposure status was determined. From the index date, we followed participants for 5 years up until the latest available date of September 2021. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: The study was conducted in NSW, Australia. We determined infertility status by a diagnosis of male infertility in the Australian and New Zealand Assisted Reproduction Database, hospital records, or a record of fertility-related procedures. We assessed the following outcomes: incident hypertension, ischemic and non-ischemic heart disease, all heart disease, diabetes, and cerebrovascular disease. We calculated age-standardized prevalence rates at baseline. We mapped potential confounding pathways using directed acyclic graphs and controlled for measured confounders using inverse probability of treatment weighting and g-computation. We estimated adjusted marginal risk ratios (aRR) and adjusted marginal risk differences (aRD) using robust Poisson regression. MAIN RESULTS AND THE ROLE OF CHANCE: The number of events and 5-year crude incidence rate for the outcomes were: hypertension (events: 17 433, fertile: 41.09 per 1000 population, infertile: 70.03 per 1000 population), all heart disease (events: 15 549, fertile: 36.44 per 1000 population, infertile: 59.88 per 1000 population), ischemic heart disease (events: 12 628 fertile: 29.24 per 1000 population, infertile: 47.1 per 1000 population), non-ischemic heart disease (events: 5183, fertile: 11.69 per 1000 population, infertile: 20.24 per 1000 population), cerebrovascular disease (events: 512, fertile: 1.14 per 1000 population, infertile: 1.78 per 1000 population) and diabetes (events: 7064, fertile: 16.05 per 1000 population, infertile: 27.59 per 1000 population). Compared with fertile men, men diagnosed with infertility demonstrated increased risk of incident disease for: hypertension aRR = 1.20 (95% CI 1.11-1.31, P < 0.001), aRD = 1.1% (95% CI: 0.6%-1.6%, P < 0.001); all heart disease aRR = 1.20 (95% CI 1.09-1.31, P < 0.001), aRD =0.9% (95% CI: 0.4%-1.4%, P < 0.001); non-ischemic heart disease aRR = 1.26 (95% CI 1.08-1.48, P = 0.004), aRD = 0.4% (95% CI: 0.1%-0.7%, P = 0.009); ischemic heart disease aRR = 1.13 (95% CI 1.02-1.25, P = 0.020), aRD = 0.4% (95% CI: 0.1%-0.7%, P = 0.028); and diabetes aRR = 1.28 (95% CI 1.12-1.46, P < 0.001), aRD 0.6% (0.2%-0.9%, P = 0.001). There was no significant difference in the incidence of cerebrovascular disease, aRR = 1.0 (95% CI 0.56-1.80, P = 0.996), aRD = 0.0% (95% CI: -0.1% to 0.1%, P = 0.996). These results remained consistent in sensitivity analyses, including an expanded exposure definition of infertility, a 10-year follow-up period, changing the outcomes of people who died in follow-up, and using an alternative index date. LIMITATIONS, REASONS FOR CAUTION: The cohort includes men who fathered a child, so men who did not seek to, or were unable to, have a child, and men with poor access to the reproductive healthcare may not be included. This may generate selection effects, biasing the estimates toward the null. We were unable to adequately control for several confounders, including important lifestyle factors like smoking, diet, cardiorespiratory fitness, and alcohol intake, due to data limitations, which may bias estimates away from the null. It appears plausible that a combination of unmeasured and inadequately measured confounders may attenuate the observed estimates. WIDER IMPLICATIONS OF THE FINDINGS: These findings suggest that male infertility may serve as an early indicator for a slightly heightened cardiometabolic risk, specifically relating to hypertension, diabetes, and various forms of heart disease. Our study is the largest on this topic, with extensive control for confounders. Our findings align with published research, indicating that men diagnosed with infertility have a slightly higher risk of incident diabetes, hypertension, and heart disease. From a public health perspective, fertility treatment may be an opportunity for earlier detection and intervention to help prevent the onset of cardiometabolic conditions in men diagnosed with infertility, particularly given that men generally have low rates of contact with the health system. STUDY FUNDING/COMPETING INTEREST(S): The PhD candidacy of J.M. is supported by Medical Research Future Fund (MRFF) Emerging Priorities and Consumer Driven Research initiative: EPCD000007, 2020. M.K.O'B. and G.M.C. declare receiving payment to their institution by the same MRFF grant. G.M.C. reports receiving funding from an Australian MRFF grant paid to UNSW to support this work, and J.M. reports receiving PhD funding from the same MRFF grant. C.V. declares an unpaid role on Human Reproduction's Editorial Board, and paid employment at the University of New South Wales (UNSW) until January 2023. The National Perinatal Epidemiology and Statistics Unit (NPESU), which belongs to UNSW, is custodian of the Australian and New Zealand Assisted Reproduction Database (ANZARD). Data from ANZARD were used in this study. G.M.C. also declares paid employment from UNSW. The remaining authors have nothing to declare. TRIAL REGISTRATION NUMBER: N/A.
A comparison of progesterone via vaginal oil capsules versus pessaries for luteal phase support in assisted reproduction treatment: a multicentre cohort study of 42 291 cycles.
Dhillon-Smith RK, Khairy M, Bamford T … +4 more , Sephton V, Richardson A, Balen AH, Coomarasamy A
Hum Reprod · 2026 Jan · PMID 41270285 · Full text
STUDY QUESTION: What is the effect of progesterone administered via vaginal oil capsules versus pessaries, on clinical outcomes, when used for luteal phase support (LPS) in ART? SUMMARY ANSWER: Our study findings indicat...
STUDY QUESTION: What is the effect of progesterone administered via vaginal oil capsules versus pessaries, on clinical outcomes, when used for luteal phase support (LPS) in ART? SUMMARY ANSWER: Our study findings indicate a higher live birth rate with vaginal oil capsules compared with pessaries, in both fresh and frozen cycles; in the frozen cycles, a lower miscarriage rate was observed with vaginal oil capsules compared with pessaries. WHAT IS KNOWN ALREADY: Sufficient LPS, with exogenous progesterone, is essential during ART to improve implantation and pregnancy rates. Micronized vaginal progesterone (MVP) is the most commonly used form of luteal support worldwide. There are no head-to-head comparisons of vaginal oil capsules versus pessaries, with a focus on clinical efficacy, for LPS. STUDY DESIGN, SIZE, DURATION: Retrospective cohort study of patients who completed ART cycles with either only vaginal oil capsules 600-800 mg/day or only pessaries 800 mg/day for LPS. Primary outcomes were live birth and miscarriage. Data for fresh IVF/ICSI cycles and frozen embryo transfer cycles with hormone replacement therapy (HRT-FET) were analysed separately. Multivariable regression analyses were performed with adjustment for female age, BMI, ethnicity, ovarian reserve, duration and cause of subfertility, stimulation protocol, number of previous cycles, number of oocytes, number of embryos transferred, previous live births, and previous miscarriages. PARTICIPANTS/MATERIALS, SETTING, METHODS: Our study population consisted of women undergoing treatment across 14 Care Fertility clinics in the UK, from January 2017 to December 2022. We included women with stimulated IVF/ICSI cycles with fresh embryo transfer and autologous HRT-FET cycles. A total of 42 291 cycles were analysed; vaginal oil capsules were exclusively used in 25 738 cycles and pessaries exclusively in 16 553 cycles. MAIN RESULTS AND THE ROLE OF CHANCE: In the IVF/ICSI group, the live birth rate was higher in those taking vaginal oil capsules compared with pessaries: 34.3% vs 27.8%; adjusted risk ratio (aRR) 1.11 (95% CI 1.04-1.19; P < 0.001). In the HRT-FET group, the live birth rate was also higher in those taking vaginal oil capsules compared to pessaries: 36.7% vs 32.9% (aRR 1.09; 95% CI 1.04-1.14; P < 0.001). The miscarriage rate was lower in those taking vaginal oil capsules compared to pessaries for both IVF/ICSI (13.4% vs 14.5%, P < 0.05) and HRT-FET cycles (17.2% vs 19.7%, P < 0.001) in the crude analysis. The adjusted analysis for miscarriage found a statistically significant difference only for HRT-FET cycles (aRR 0.87; 95% CI 0.82-0.93). LIMITATIONS, REASONS FOR CAUTION: This is a retrospective cohort study. Whilst we have extensively adjusted for confounding, there can still be residual confounding. WIDER IMPLICATIONS OF THE FINDINGS: An appropriately powered randomized controlled trial directly comparing the two drugs, focusing on clinical efficacy, is required to determine if one is superior to the other. STUDY FUNDING/COMPETING INTEREST(S): This study has been delivered through the National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre (BRC). R.K.D.S. is in receipt of honoraria for lectures and presentations from Ferring Pharmaceuticals and Besins Healthcare UK. R.K.D.S. has received travel support from IBSA Pharma and Theramex UK and payment for participation on an advisory board for educational meetings for Ferring Pharmaceuticals and IBSA Pharma. A.C. has contributed to the scientific advisory boards of Ferring Pharmaceuticals, Theramax UK, Besins Healthcare UK, and Organon Pharma UK. M.K. has received travel support from Besins Healthcare UK and Merck. A.H.B. is on an advisory board and has received speaker fees from NovoNordisk Pharmaceuticals and is a shareholder at Care Fertility UK and Care Fertility Leeds. T.B. is in receipt of honoraria for lectures and presentations from Merck and Gedeon Richter. T.B. has received travel support from IBSA Pharma, Vitrolife, and Theramex and payment for participation on an advisory basis for IBSA Pharma and Conceivable Life Sciences. A.R. has received honoraria for lectures and presentations from Gedeon Richter. A.R. has received travel support from Gedeon Richter and payment for participation on an advisory board for educational meetings for Ferring Pharmaceuticals. V.S. has received travel support from IBSA Pharma and payment for educational meetings and participation in an advisory role for Theramex. TRIAL REGISTRATION NUMBER: n/a.
Serum miRNA-based diagnostic models for endometriosis: from discovery to validation.
Ravaggi A, Bergamaschi C, Conforti J … +11 more , Ciravolo G, Zanotti L, Fabricio ASC, Gion M, Cappelletto E, Leon AE, Rossetti DO, Romagnolo C, Calza S, Bignotti E, Odicino F
Hum Reprod · 2026 Feb · PMID 41270284 · Full text
STUDY QUESTION: Can a serum miRNA signature serve as a potential diagnostic biomarker for endometriosis (END)? SUMMARY ANSWER: A miRNA-based diagnostic model demonstrated an accuracy of 65.8% in distinguishing END patien...
STUDY QUESTION: Can a serum miRNA signature serve as a potential diagnostic biomarker for endometriosis (END)? SUMMARY ANSWER: A miRNA-based diagnostic model demonstrated an accuracy of 65.8% in distinguishing END patients from control subjects (CTR), demonstrating good sensitivity but limited specificity. WHAT IS KNOWN ALREADY: Existing research has examined the potential utility of circulating miRNAs as biomarkers for END diagnosis, revealing their differential expression between women with END and CTR. Nevertheless, the findings remain conflicting, and at present, neither a single miRNA nor a panel of them has yet been established as a reliable diagnostic test in clinical practice for the management of END. STUDY DESIGN, SIZE, DURATION: We previously reported different miRNA expression patterns in serum samples from 67 END patients and 60 CTR by high-throughput RT-qPCR. In this multicenter study, a total of 364 patients with pathology-confirmed diagnosis of END or a benign non-END gynecological condition were retrospectively selected from a biobank or prospectively enrolled. The aims of the present study were to analyze, in the entire cohort of patients, a set of 23 potential diagnostic miRNAs via RT-qPCR and to create models capable of diagnosing END through cross-validated machine learning algorithms. PARTICIPANTS/MATERIALS, SETTING, METHODS: Total RNA was extracted from serum samples collected before surgical treatment and miRNAs were evaluated by RT-qPCR. Diagnostic models were developed using both the Random Forest and Logistic Regression algorithms. The performance assessment of the various models was derived from internal validation, using repeated cross-validation. MAIN RESULTS AND THE ROLE OF CHANCE: The most effective diagnostic model was constructed with 11 miRNAs: miR-140-3p, miR-181a-5p, miR-192-5p, miR-22-3p, miR-29a-3p, miR-30b-5p, miR-338-3p, miR-340-5p, miR-342-3p, miR-486-5p, and miR-652-3p. The diagnostic efficacy of the model was defined by an AUC of 70.4%, a sensitivity of 75.6%, a specificity of 53.5%, and an accuracy of 65.8%. The model that used six miRNAs (miR-192-5p, miR-30b-5p, miR-335-5p, miR-338-3p, miR-486-5p, miR-652-3p) was the best at identifying deep infiltrating endometriosis compared to the control group, with an AUC of 80.4% and an accuracy of 75.9%. A lower accuracy was achieved by the model differentiating ovarian endometrioma (OMA) from CTR (AUC = 65.8%; accuracy = 62.4%). LARGE SCALE DATA: miRNA expression profiles have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO Series accession numbers GSE279435. LIMITATIONS, REASONS FOR CAUTION: Despite the internal cross-validation, the models still need to be tested on larger cohorts of prospectively enrolled patients across several centers to enhance their accuracy and robustness. This testing will also facilitate monitoring the model in a real-world setting, potentially integrating the miRNA-based model with other diagnostic tools, such as ultrasound. WIDER IMPLICATIONS OF THE FINDINGS: If proven effective in larger cohorts, this model could serve as a tool for the diagnosis of END, thereby enhancing early identification and clinical care of this disease. Moreover, given its low false negative rate, the miRNA-based model may be useful as a screening tool to help identify patients who are likely to have END but warrant further evaluation to confirm END diagnosis. STUDY FUNDING/COMPETING INTEREST(S): This research was financed by the Italian Ministry of Health, grant number "LOMBARDIA ENDO-2021-12371946", project title: FREEDOM TRIAL. The authors disclose no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.
Correction to: Reply: Biosimilars versus the originator of follitropin alfa in ART: eyes wide shut?
Hum Reprod · 2026 Jan · PMID 41259780 · Publisher ↗
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New models of implantation: towards a whole better than the sum of parts.
Rawlings TM, Guttridge SA, Lucas ES
Hum Reprod · 2026 Feb · PMID 41247772 · Full text
Recent advances in the development of stem-cell-based embryo models and endometrial assembloids have fuelled understanding of their respective biology. However, a faithful combined approach is required to truly advance o...
Recent advances in the development of stem-cell-based embryo models and endometrial assembloids have fuelled understanding of their respective biology. However, a faithful combined approach is required to truly advance our understanding of implantation processes. This mini-review considers the most recent developments in producing reliable in vitro models of the human endometrium and human embryo, and the next steps required to combine their respective potential. While the fundamental biology of implantation is the primary driver of in vitro model development, the combined effort of embryo and endometrial models to generate new models of implantation provides the opportunity to manipulate either compartment to further understand the aetiologies of reproductive dysfunction. Through combining both systems, their efforts are symbiotic, each extending the relevance and utility of their counterpart to generate a whole greater than the sum of its parts.
Female infertility diagnosis and adult-onset psychiatric conditions: a matched cohort study.
Ben Messaoud K, Zaks N, Licciardi F … +3 more , Ramlau-Hansen CH, Kahn LG, Janecka M
Hum Reprod · 2026 Jan · PMID 41247428 · Publisher ↗
STUDY QUESTION: Is there an association between infertility diagnosis and long-term adult-onset psychiatric conditions in women? SUMMARY ANSWER: Infertility diagnosis in women is linked to higher risks of mood disorders,...
STUDY QUESTION: Is there an association between infertility diagnosis and long-term adult-onset psychiatric conditions in women? SUMMARY ANSWER: Infertility diagnosis in women is linked to higher risks of mood disorders, anxiety- and stress-related disorders, and behavioral syndromes with physical components, but not schizophrenia or other psychotic disorders, particularly notable from 9 years after the first infertility diagnosis. WHAT IS KNOWN ALREADY: Infertility, especially in women, is associated with major mental health challenges around the time of diagnosis. However, the long-term connection with a wide range of psychiatric disorders is largely unknown. STUDY DESIGN, SIZE, DURATION: This study employed a matched-pair design within the UK Biobank (UKB) cohort, including 3893 females with a diagnosis of infertility and 15 603 matched female controls, totaling 19 496 participants. PARTICIPANTS/MATERIALS, SETTING, METHODS: Female UKB participants with a diagnosis of infertility were matched to females without the diagnosis in a 1:4 ratio based on year of birth, index of deprivation of their residency area, and primary care data linkage status. The diagnosis of female infertility was identified by the first occurrence of a primary or secondary diagnosis in either primary care or hospital records. Additional analyses explored interactions between infertility diagnosis and both miscarriage and childbearing status on psychiatric conditions. MAIN RESULTS AND THE ROLE OF CHANCE: Diagnosis of infertility was associated with higher risks of mood disorders, anxiety- and stress-related disorders, and behavioral syndromes with physical components, but not with schizophrenia or other psychotic disorders. The most notable increases in the risk of psychiatric diagnoses were observed 9 years after the first infertility diagnosis. No significant interactions were found between infertility diagnosis and either miscarriage or childbearing status on psychiatric conditions. Sensitivity analysis confirmed the robustness of these associations across different data sources for infertility diagnosis and psychiatric condition ascertainment. LIMITATIONS, REASONS FOR CAUTION: The study's limitations include the racial homogeneity and the overall healthier status of the UKB cohort compared to the general UK population and the potential underestimation of associations due to misclassification of subfecund women. WIDER IMPLICATIONS OF THE FINDINGS: These results emphasize the need for integrated mental health support in infertility care and long-term monitoring of infertility patients for psychiatric risks. STUDY FUNDING/COMPETING INTEREST(S): None. No competing interests were declared. TRIAL REGISTRATION NUMBER: n/a.
Sustained soluble adenylyl cyclase (sAC)-generated cAMP is necessary and sufficient for hyperactivated motility in human sperm.
Ritagliati C, Devine F, Buck J … +1 more , Levin LR
Hum Reprod · 2026 Feb · PMID 41247380 · Full text
STUDY QUESTION: How does soluble adenylyl cyclase (sAC)-generated cyclic AMP (cAMP) control hyperactivated motility in human sperm? SUMMARY ANSWER: sAC-generated cAMP rapidly initiates and is required to maintain hyperac...
STUDY QUESTION: How does soluble adenylyl cyclase (sAC)-generated cyclic AMP (cAMP) control hyperactivated motility in human sperm? SUMMARY ANSWER: sAC-generated cAMP rapidly initiates and is required to maintain hyperactivated motility in human sperm. WHAT IS KNOWN ALREADY: Mouse and human sperm devoid of sAC activity (either genetically or pharmacologically) are immotile and do not undergo capacitation; thus, the HCO3--dependent stimulation of sAC and consequent increase in cAMP is responsible for activating basal motility and initiating capacitation in multiple mammalian species. Among the changes sperm undergo during capacitation is acquisition of hyperactivated motility, which is presumed to be essential for male fertility. STUDY DESIGN, SIZE, DURATION: In this study, the kinetics of cAMP generation and motility were assessed in sperm from healthy semen donors with no known fertility issues subjected to capacitating media components (HCO3- and albumin). Controls included cAMP agonists and adenylyl cyclase inhibitors. PARTICIPANTS/MATERIALS, SETTING, METHODS: The motility of sperm purified from donors' semen samples was analyzed by a Computer-Assisted Sperm Analysis (CASA) system, and the intracellular cAMP was quantified using a cAMP ELISA. MAIN RESULTS AND THE ROLE OF CHANCE: HCO3- stimulates sAC-dependent cAMP production and the transition to hyperactivated motility at the earliest times measured. Sperm hyperactivated motility seems to be a reversible process, as maintaining hyperactivated motility requires sustained sAC activation. LIMITATIONS, REASONS FOR CAUTION: The CASA system, used to measure hyperactivated motility, employs snapshot technology; sperm trajectories are observed for only short segments of time. This is an ex vivo study of sperm motility parameters in aqueous solutions. The conditions used were established for successful IVF, and the capacitation-induced hyperactivated motility studied here is proven essential for IVF and positively correlated with in vivo fertilization competence. However, in vivo, ejaculated sperm must navigate through the female reproductive tract, which is lined by viscous mucus, to reach the site of fertilization. Future studies should examine motility behaviors in solutions whose viscosity more accurately reflects the mucus-lined environment of the female reproductive tract. WIDER IMPLICATIONS OF THE FINDINGS: There are two novel findings presented here; that hyperactivation of human sperm occurs early during capacitation and that hyperactivated motility is reversible. These findings raise the possibility that the rapid, sAC-dependent hyperactivated motility allows human sperm to escape the harsh vaginal environment. Its roles modulating sperm motility define sAC as an optimal target for both male and female contraception. Additionally, sAC inhibitors with different off-rates are shown here to be useful tools enabling us to study the kinetics of sAC activation in a physiological context. STUDY FUNDING/COMPETING INTEREST(S): The research was funded by Male Contraceptive Initiative (to J.B. and L.R.L.) and National Institutes of Health via HD113015 and HD111549 (to J.B. and L.R.L.). C.R. was awarded a Male Contraceptive Initiative fellowship. L.R.L. and J.B. are co-inventors of a panel of in vivo, validated sAC inhibitors (patent PCT/US2022/02652) and are co-founders, co-owners, and members of the Board of Directors of Sacyl Pharmaceuticals Inc., which licensed the sAC inhibitors for development into on-demand male contraceptives. C.R. has been a paid consultant to Sacyl Pharmaceuticals Inc. TRIAL REGISTRATION NUMBER: N/A.
Correction to: Endometrial preparation protocols for frozen embryo transfer: Risk assessment and individualized management.
Hum Reprod · 2026 Jan · PMID 41238391 · Publisher ↗
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Are infertile men at a higher risk of morbidity and early mortality?
Caroppo E, Eisenberg ML
Hum Reprod · 2026 Feb · PMID 41237188 · Full text
Increasing evidence supports the role of male infertility as a harbinger of broader health issues, given that infertile men often exhibit higher rates of chronic conditions later in life. Infertile men have double the ri...
Increasing evidence supports the role of male infertility as a harbinger of broader health issues, given that infertile men often exhibit higher rates of chronic conditions later in life. Infertile men have double the risk of developing testicular and breast cancer and an increased risk of high-grade prostate cancer, are more likely to develop ischemic heart disease, hypertension, heart disease, and hyperlipidemia, and have higher cardiovascular mortality compared to fertile men. The risk of developing Type 2 diabetes seems to increase with the severity of the spermatogenic dysfunction, and metabolic abnormalities such as insulin resistance, increased visceral adiposity, and systemic inflammation are often reported in men with male factor infertility. The relative risk of developing autoimmune diseases such as rheumatoid arthritis, psoriasis, systemic lupus erythematosus, and thyroiditis is significantly higher in infertile compared to fertile men, although the absolute risk is low. Male infertility also confers a 26% increased risk of early mortality, and the risk is even increased for men with azoospermia. On the other hand, a linear relationship between all semen parameters and life expectancy was found in a recent study. To explain the relationship between male infertility and increased risk of morbidity and mortality, hormonal, lifestyle/behavior, and genetic factors have been previously called into question. In the present mini review, the immune system alteration and the epigenetic hypotheses are exposed in more detail. The proposed evidence suggest that health screening for related conditions should be offered as part of the routine male infertility workup, to facilitate earlier detection and preventative care, and to position reproductive evaluations as a pivotal moment for long-term health intervention.
Reply: Foundation models in IVF: from speculation to implementation with FEMI.
Hammer HL, Thambawita V, Riegler MA
Hum Reprod · 2026 Jan · PMID 41220067 · Publisher ↗
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