Human Reproduction Open人类生殖开放
Human Reproduction Open(英文缩写 HUM REPROD OPEN),ISSN 2399-3529,eISSN 2399-3529,中文译名:人类生殖开放 是一本学术期刊。本页汇总该期刊的最新影响因子、分区信息以及最新收录于 PubMed 的文献,帮助您快速了解期刊全貌。
发文量统计区间：2025-11-01 至 2026-10-31，按本站收录文献的发表日期统计。
期刊介绍
Human Reproduction Open 最新收录文献
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1. Comparing the euploidy rate between the progestin-primed and gonadotrophin-releasing hormone antagonist protocols in preimplantation genetic testing for aneuploidy: a randomized controlled trial.
PMID:日期:2026-09-15In patients undergoing preimplantation genetic testing for aneuploidy (PGT-A), does the progestin-primed ovarian stimulation (PPOS) protocol result in a euploidy rate of blastocysts per patient comparable to that of the GnRH antagonist protocol? The euploidy rate of blastocysts per patient is comparable for patients using PPOS and GnRH antagonist protocols. Progestin is effective in blocking the pituitary LH surge during ovarian stimulation, and the PPOS protocol is simpler and cheaper. However, published studies comparing euploidy rates between the two protocols have yielded contradictory results. This was an open-label, randomized controlled trial of 400 women recruited between June 2020 and August 2024. Eligible women were randomly assigned in a ratio of 1:1 to the PPOS or GnRH antagonist group using an online randomization programme and sealed opaque envelopes. The primary outcome was the euploidy rate of blastocysts per patient. Women aged <43 years undergoing PGT-A cycles were randomly assigned to either the PPOS group (n = 200) or antagonist group (n = 200). PGT-A was indicated for advanced maternal age, recurrent pregnancy loss, repeated implantation failure, or history of foetal aneuploidy in previous pregnancies. PGT-A was performed using the next-generation sequencing technology. The PPOS and antagonist groups were similar in demographic characteristics and the numbers of oocytes obtained/fertilized, cleavage-stage embryos, and developed blastocysts. The PPOS group had a significantly lower total gonadotrophin doses and significantly higher serum oestradiol levels on the ovulation trigger day when compared to the GnRH antagonist group. No statistically significant difference was observed in the euploidy rate of blastocysts between the PPOS and antagonist groups (40.0 (0-66.7)% versus 44.4 (25.0-71.4)%, = 0.192). The number of euploid blastocysts per patient was comparable for the PPOS and antagonist groups (1 (1-2) versus 1 (1-2.5), = 0.47). There were 136 women in the PPOS group and 152 women in the antagonist group who had their first frozen embryo transfer after PGT-A. Both groups showed comparable clinical pregnancy, ongoing pregnancy, miscarriage, ectopic pregnancy, and live birth rates after the first frozen embryo transfer. The participants and researchers were not blinded to the treatment allocation. The sample size was powered only to detect a 10% euploidy rate difference; smaller differences cannot be excluded. Not all women completed their first transfer cycle, and outcomes from a single cycle do not represent cumulative live birth rates. Results are based solely on euploid embryo transfers, limiting generalizability to mosaic embryos. Generalization to other IVF populations or to the use of other progestins is also limited. The findings of the study support the use of PPOS for patients undergoing a freeze-all IVF cycle, whether for PGT-A or oocyte preservation. This study was supported by Shanghai Oriental Talent Award (QNWS2024045), the National Natural Science Foundation of China (82171644), and Shanghai Shen Kang Hospital Development Center Municipal Hospital New Frontier Technology Joint Project (SHDC12017105). The authors report no conflicts of interest. NCT04414748. 4 June 2020. 10 June 2020.
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2. A context-specific evaluation of polygenic embryo screening in best-prognosis preimplantation genetic testing cycles.
2. 在最佳预后植入前遗传学检测周期中对多基因胚胎筛查的情境特异性评估PMID:日期:2026-09-08In best-prognosis preimplantation genetic testing (PGT) cycles-defined by the availability of multiple transferable embryos-can polygenic embryo screening (PES) provide meaningful, context-dependent stratification that may influence embryo prioritization? In a sister-pair breast cancer validation cohort, the polygenic risk score (PRS) showed modest predictive performance, and when applied retrospectively to embryos, differences in modelled susceptibility were context-dependent, primarily influenced by the number of available embryos, parental polygenic risk profile, the limited discriminative power of the PRS, and the presence of disease-related monogenic variants. The use of PES as an embryo-ranking tool within PGT remains controversial. Its potential utility depends on embryo availability and clinical context, yet empirical evaluations in real-world PGT settings remain limited. This retrospective study combined (i) family-based validation using 184 affected-unaffected sisters, and (ii) embryo-level analysis of 310 PGT for monogenic disorders (PGT-M) cycles comprising 1722 embryos. Simulation modelling estimated differences in modelled embryo-level PRS percentile ranking under varying clinical and genetic scenarios. Family-based performance of a breast cancer PRS was evaluated using affected and unaffected sister pairs. Embryo genotype data from PGT-M cycles were used to model PES under varying conditions, including the number of transferable embryos, the presence of pathogenic monogenic variants, and parental PRS percentile strata. Within-family PRS discrimination was modest: sisters in the top 10% of the PRS distribution had 4.07-fold higher breast cancer odds than their siblings (95% CI: 1.55-6.33). In the PGT-M cohort, 55% of cycles produced ≥3 transferable embryos, with a median within-cycle spread of approximately 25 PRS percentiles. In -related cycles, PRS did not introduce distinct risk strata but revealed dispersion in modelled susceptibility among embryos sharing the same monogenic background. Embryo PRS distributions were concordant with parental profiles: 71% of embryos from couples with parental PRS ≥80th percentile were classified as high-PRS, compared with 7% when at least one parent was ≤20th percentile. Simulation analyses indicated that PRS-based embryo prioritization was associated with a 12-point lower mean embryo PRS percentile compared with morphology-based embryo prioritization in PGT-M cycles, attenuating to 10 points when PGT-A was incorporated. These differences reflect a statistical surrogate outcome only and do not demonstrate reduction in lifetime disease incidence or other clinical benefits. N/A. These findings derive from high-prognosis PGT-M cycles and may not generalize to other PGT settings. Current PRS models have modest performance and variable transferability across ancestries. The retrospective design, limited subgroup sizes, and modelling assumptions (e.g. aneuploidy and sex distribution) further constrain interpretation. The primary simulation outcome-PRS percentile shift-is a hypothesis-generating surrogate endpoint, not a clinical outcome; clinical benefit was not assessed or demonstrated. These findings should not be interpreted as supporting routine clinical implementation of PES; premature use may increase parental anxiety, inequitable access, and pressure to rank embryos using predictions that remain unvalidated at the embryo level. This study provides an empirical framework for evaluating the current limits of PES within PGT. The observed PRS percentile shifts appear concentrated in best-prognosis cycles with multiple transferable embryos and elevated parental PRS, whereas little change is observed when embryo numbers are limited or risk is dominated by high-penetrance monogenic variants. These findings are hypothesis-generating and may inform future prospective research and ethical discussion, while underscoring that clinical utility and implementation require further validation within appropriately governed settings. This study was funded by Major Scientific Program of CITIC Group (No. 2023ZXKYB34100), the Science Foundation of Hunan Province (Grant 2023JJ30422), and Health Research Project of Hunan Provincial Health Commission (grant number: W20243089). The authors declare no conflicts of interest.
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3. Multi-omics factor analysis v2 (MOFA+) reveals specific co-variation patterns in women with PMOS that are strongly influenced by obesity.
PMID:日期:2026-09-08What are the mechanisms underlying the complex interactions between polyendocrine metabolic ovarian syndrome (PMOS) and obesity as studied by a multi-omics integration approach? Multi-Omics Factor Analysis v2 (MOFA+) suggested that PMOS was characterized by an androgen-driven metabolic reprogramming in which sexual dimorphism was reshaped in an obesity- and omics-specific manner, consisting of strong associations of proinflammatory proteins and adipokines with gut microbiota genera and metabolomics variables that were amplified by obesity. PMOS is a common metabolic-endocrine disorder in which androgen excess, weight excess, and obesity complex interactions define a particularly unfavorable cardiometabolic phenotype. Cross-sectional study with 2 control groups involving 46 Caucasian young adults, conducted at an academic hospital in Madrid, Spain. We recruited 15 women with PMOS, 16 healthy control women, and 15 control men of similar mean age and BMI. Participants were further grouped into non-obese (BMI < 30 kg/m²) or obese (BMI ≥ 30 kg/m²) subjects. We integrated serum metabolomics and circulating proteins with gut microbiota composition, using MOFA+. MOFA+ identified five latent factors explaining the main sources of variation across omics layers. Results showed sexual dimorphism in an omics- and obesity-specific manner: the metabolomics profile presented sexual dimorphism in non-obese individuals, whereas circulating proteins and gut microbiota differed between women with or without PMOS and men only in obese subjects. Correlation analyses revealed a global weakening of associations in men, particularly among metabolites, a reinforcement of protein-related associations with obesity, and a distinct PMOS-specific pattern characterized by strengthened correlations within and between gut microbiota and proteomic features. Women with PMOS exhibited the strongest metabolomics-proteomics correlations, further exacerbated by obesity. The relatively small sample size of our study might have missed relevant associations that could have reached statistical significance in larger samples. Also, we only included women with hyperandrogenic phenotypes of PMOS. Hence, our results may not apply to non-hyperandrogenic phenotypes of the syndrome. PMOS showed a metabolic profile similar to that of obesity even in the absence of excess weight, supporting the concept that adipose tissue dysfunction, proinflammatory proteins, and adipokines, rather than fat mass excess , were a central driver of the metabolic disturbances of the syndrome. Altogether, these findings highlight the complex interplay between androgen excess, adiposity, and host-microbiota interactions and provide a systems-level framework that may facilitate the identification of novel biomarkers and targeted therapeutic strategies in PMOS. Also, these findings highlight the importance of considering sex, sex hormones, and obesity-specific contexts in biomarker discovery and mechanistic studies. This research was funded by Instituto de Salud Carlos III grants PI11/0357, PI18/01122, PI21/00116 and PI25/00434 and co-funded by the European Union. F.G.-G. was supported by CIAICO/2023/149 and funded by the Consellería de Educación, Cultura y Universidades de la Generalitat Valenciana, and PID2021-124430OA-I00 funded by MICIU/AEI/10.13039/501100011033 and by ERDF/EU. CIBERDEM and IRYCIS are also initiatives of Instituto de Salud Carlos III. The funding organizations played no role in the study design; collection, analysis, and interpretation of data; the writing of the report; or the decision to submit the report for publication. The authors have no competing interests to disclose. N/A.
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4. Fetal exposure to paracetamol is associated with altered markers of ovarian development and reduced uterine volume in girls: the COPANA study.
4. 胎儿对乙酰氨基酚暴露与女孩卵巢发育标志物改变及子宫体积减小相关：COPANA研究PMID:日期:2026-09-08Is fetal exposure to paracetamol associated with markers of ovarian function in infancy? Mild to moderate doses of prenatal paracetamol exposure, assessed by detailed maternal reports and urinary measurements, are associated with ovarian morphology and activity as well as reduced size of estrogen-responsive tissues in infant girls. Maternal use of paracetamol is widespread. Across multiple independent animal studies, fetal exposure consistently impairs the formation of primordial ovarian follicles, causing subfertility and premature estropause in female offspring. The Copenhagen Analgesic study (COPANA) is a single-center, prospective, observational cohort study conducted at a university hospital (March 2020 to November 2022). From 3425 eligible participants, 685 healthy singleton pregnant women of Caucasian origin, were enrolled in the first trimester of pregnancy, and 302 infant daughters were examined at follow-up. Exclusion criteria included maternal diabetes or thyroid disease, pre- or post-term delivery, or severe infant illness. Pregnant women reported paracetamol use biweekly and provided first-trimester urinary samples which were analyzed for paracetamol levels (LC-MS/MS) and adjusted for urinary osmolarity (n = 299). Girls were classified by timing of initial exposure: early fetal life (<17 weeks, n = 92), mid-late fetal life (≥17 weeks, n = 67), or unexposed controls (n = 143). Of the 92 girls initially exposed in early fetal life, a subgroup was exposed exclusively in early fetal life (n = 22).In an independent confirmatory cohort, 1210 girls were followed from infancy to adolescence. Their exposure was maternal self-reported (any) use of paracetamol during pregnancy and reported early in the third trimester (yes/no). Early fetal exposure was associated with reduced ovarian volume (-0.11 cm, 95% CI -0.19 to -0.03) and reduced uterine volume (-0.18 cm, -0.35 to -0.01), whereas mid-late fetal exposure was associated with fewer ovarian follicles (-1.05 follicles, -1.71 to -0.39) compared to unexposed girls. AMH levels were lower in girls exposed exclusively in early fetal life (-0.45 SDS, -0.87 to -0.03) compared to unexposed girls. Maternal urinary paracetamol concentrations were inversely associated with ovarian and uterine volume as well as breast tissue diameter. In the independent confirmatory cohort, fetal paracetamol exposure was associated with reduced uterine volume at puberty (-4.11 cm, -7.29 to -0.92) and smaller ovarian volume during adolescence (-2.76 cm, -4.82 to -0.70). The observational design of the study allows evaluation of exposure outcome associations, while the causality interpretation is supported by consistency with experimental models demonstrating comparable effects. Residual confounding by indication for paracetamol use cannot be completely excluded, although the results were robust after accounting for fever and other maternal factors. The analytic design of the current study limited our ability to evaluate whether frequency or patterns of paracetamol use influenced the observed associations. In this prospective cohort study of infant girls, prenatal exposure to paracetamol was associated with differences in several markers of ovarian development, including ovarian volume, follicle number, and circulating AMH, as well as uterine volume and breast tissue diameter. The associations with reduced ovarian and uterine size were also observed in a confirmatory cohort followed to adolescence. Whether these early-life differences have long-term clinical relevance, including effects on reproductive lifespan, remains uncertain and requires analyses in studies with extended follow-up. This research was supported by Rigshospitalets Research Council under grant (E-22717-21), Læge Sofus Carl Emil Friis og hustru Doris Friis'Legat (F-23936-01), Aase og Ejnar Danielsens Foundation (20-10-0367), Helsefonden (20-B-0388), Axel Muusfeldt Foundation (2020-0385), and The Danish Centre for Endocrine Disrupting Substances (CeHoS) (2022-23219). The funders had no role in considering the study design or in the collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication. The publication was completed as part of the MERLON project under grant agreement No. 101137411. The MERLON project is funded by the European Union. Views and opinions expressed are, however, those of the authors only and do not necessarily reflect those of the European Union or the European Health and Digital Executive Agency (HADEA). Neither the European Union nor HADEA can be held responsible for them. All authors declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years, and no other relationships or activities that could appear to have influenced the submitted work. One author (MA) is a government official. ClinicalTrials.gov ID: NCT0436922.
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6. Effect of cryopreservation duration on pregnancy outcomes in embryos: a systematic review and meta-analysis.
PMID:日期:2026-08-13Is prolonged cryopreservation associated with adverse clinical pregnancy and live birth after frozen-thawed embryo transfer? Prolonged embryo cryopreservation is associated with lower clinical pregnancy and live birth rates, particularly within the first 3-12 months of storage, but rates plateau after 2 years. Evidence on the impact of cryopreservation duration on reproductive outcomes remains scarce and conflicting, with some studies reporting no adverse effects and others suggesting increased risks of pregnancy loss, preterm birth, and epigenetic alterations after prolonged storage. Systematic review and meta-analysis of studies comparing pregnancy outcomes by cryopreservation duration. PubMed, Embase, and the Cochrane Library were searched from inception to 31 December 2025, for English-language articles. The search strategy combined terms for embryos (e.g. 'Embryo', 'Blastocyst'), cryopreservation techniques (e.g. 'vitrification', 'cryopreservation', 'freezing'), and pregnancy outcomes (e.g. 'pregnancy', 'live birth') using Boolean operators. A total of 5208 records were identified from PubMed, 9272 from Embase, and 331 from the Cochrane Library. Two independent reviewers screened studies, extracted data, and assessed quality using the Newcastle-Ottawa Scale. Inclusion required reporting of clinical pregnancy rate (CPR) or live birth rate (LBR) stratified by cryopreservation duration. Studies on donated embryos, preimplantation genetic testing, or gamete cryopreservation were excluded. Pooled odds ratios (ORs) with 95% CIs were calculated using fixed- or random-effects models based on heterogeneity (²). Subgroup analyses were performed for neonatal outcomes (singleton vs. multiple births). Publication bias was assessed via funnel plots. A total of 14 811 records were screened (5208 from PubMed, 9272 from Embase, 331 from Cochrane). After removal of duplicates, 11 077 records were screened by title and abstract, and 785 full-text articles were assessed for eligibility. Twenty-three studies (254 017 transfer cycles/patients) were included. Embryos cryopreserved >5 years had lower survival rates (OR = 0.84, 95% CI: 0.72-0.98, = 0.03; = 0%, = 0.99). Compared with ≤3 months storage, longer storage was associated with reduced CPR (>3 months: OR = 0.87, 95% CI: 0.78-0.96, = 0.005; >6 months: OR = 0.70, 95% CI: 0.66-0.74, < 0.00001; >12 months: OR = 0.71, 95% CI: 0.61-0.82, < 0.00001; >2 years: OR = 0.77, 95% CI: 0.65-0.91, = 0.003), reduced LBR (>3 months: OR = 0.90 95% CI: 0.84-0.95, = 0.0008; >6 months: OR = 0.74, 95% CI: 0.69-0.80, < 0.00001; >12 months: OR = 0.72, 95% CI: 0.63-0.84, < 0.0001; >2 years: OR = 0.80, 95% CI: 0.72-0.89, < 0.0001) and reduced biochemical pregnancy rate (>3 months: OR = 0.82, 95% CI: 0.73-0.92, = 0.0007; >6 months: OR = 0.70, 95% CI: 0.63-0.77, < 0.00001; >12 months: OR = 0.72, 95% CI: 0.65-0.80, < 0.00001; >2 years: OR = 0.74, 95% CI: 0.61-0.90, = 0.002). Miscarriage rate (OR = 1.16, 95% CI: 1.09-1.25, < 0.0001) and preterm birth rate (OR = 1.10, 95% CI: 1.00-1.20, = 0.04) were higher after >12 months storage. High birth weight and malformation rates were not significantly increased, but low birth weight was less frequent after >6 (OR = 0.83, 95% CI: 0.70-0.99, = 0.04) or >12 months (OR = 0.75, 95% CI: 0.57-0.98, = 0.03), and the proportion of male infants was lower after >3 months (OR = 0.92, 95% CI: 0.86-0.98, = 0.02) and >2 years (OR = 0.79, 95% CI: 0.64-0.97, = 0.02), compared with those cryopreserved for ≤3 months. No significant publication bias was detected. Limitations include substantial heterogeneity across studies (design, cryopreservation method, embryonic stage, confounder adjustment), inability to evaluate frozen-thawed embryo transfer (FET) cycle type, maternal age, and embryo quality due to inconsistent reporting, retrospective observational design precluding causal inference, residual confounding, potential survivor bias, and combined singleton/multiple-birth data for neonatal outcomes. Despite a large sample size (254 017 cycles), these factors warrant cautious interpretation. This comprehensive meta‑analysis reveals a non‑linear relationship between cryopreservation duration and outcomes, reconciling previous conflicting reports by demonstrating early declines (first 3-12 months) followed by a plateau beyond 2 years. The stability of outcomes in ultra‑long storage is reassuring for patients requiring delayed transfer. These findings support clinical counselling that encourages early transfer when feasible, but provides reassurance that ultra‑long storage does not lead to progressive deterioration in pregnancy or neonatal outcomes. This work was funded by the First-class discipline innovation-driven talent program of Guangxi Medical University (to J.L.) and the College Students' Innovation Training Project of Guangxi Medical University (X202410598348). The authors declare no conflicts of interest. CRD42024555362.
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7. Geographic patterns of ovarian tissue cryopreservation utilisation across age groups in a nationwide multicentre cohort.
7. 全国多中心队列中不同年龄组卵巢组织冷冻保存利用的地理分布模式PMID:日期:2026-08-13Does geographic proximity to a centralised cryobank reflect age-dependent differences in ovarian tissue cryopreservation (OTC) utilisation? Paediatric patients resided significantly closer to the cryobank than adolescents and adult women, suggesting age-dependent geographic differences in the utilisation of fertility preservation services. OTC is an established fertility preservation option, and previous studies have primarily focused on return rates of cryopreserved ovarian tissue and subsequent pregnancy and live birth outcomes. However, less is known about utilisation patterns of fertility preservation, particularly for OTC in paediatric oncology, where utilisation may be influenced by factors such as clinician-initiated counselling and local referral pathways. This retrospective nationwide multicentre cohort study included 2,426 patients referred from 124 centres who underwent OTC at a central cryobank between 2000 and 2021. Patients were stratified into children (<15 years, n = 149), adolescents (15-19 years, n = 296), and adults (≥20 years, n = 1,981). Residential addresses were geocoded, and distances to the cryobank were calculated. Regional distribution was categorised by population size. Statistical analyses included Chi-square and non-parametric tests with Bonferroni correction. Median distance to the cryobank increased with age (children: 136 km; adolescents: 183 km; adults: 222 km), with children living significantly closer than adolescents ( = 0.03) and adults ( = 0.001). Overall, 44.8% of patients resided in large cities, with significant age-group differences ( < 0.001). Paediatric cases were concentrated in urban areas, whereas adults were more geographically dispersed. Among adults, distance varied by indication ( = 0.021), but not in younger groups. This pattern persisted despite the nationwide referral network. The retrospective design precludes causal inference. Distances were calculated as straight-line measures instead of real travel time, and socioeconomic factors were not available. Furthermore, only patients who successfully underwent OTC were available for analysis. Consequently, the study cannot assess true access to fertility preservation, referral rates, counselling rates, or the number of eligible patients who did not proceed to treatment. Although patients were referred from centres across Germany, cryopreservation was centralized in Bonn. Regional referral relationships and the structure of the referral network may therefore have influenced the observed geographic distribution, particularly in paediatric patients, and may limit generalisability to the entire German population. The findings demonstrate age-dependent geographic utilisation patterns among patients who underwent OTC. These patterns may reflect differences in referral pathways, counselling practices, and utilisation of fertility preservation services. However, because only patients who successfully underwent OTC were included, the study cannot directly assess referral rates, unmet need, or access barriers. Expanding structured referral pathways and reimbursement policies may improve equitable utilisation of fertility preservation services. Intramural funding from the University Hospital Bonn. This publication was supported by the Open Access Publication Fund of the University of Bonn. No external grant funding was received from any funding agency in the public, commercial, or not-for-profit sectors. The authors declare that they have no competing interests. N/A.
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8. Hyperestrogenic imprinting and developmental origins of endometriosis and adenomyosis.
8. 高雌激素印记与子宫内膜异位症及子宫腺肌症的发展起源PMID:日期:2026-08-10The pathogenesis of endometriosis and adenomyosis remains incompletely understood, and a notable gap persists between the reported heritability and the disease variation explained by identified susceptibility loci. In this manuscript, we showcase key epidemiological and clinical observations-including associations with early menarche, shorter anogenital distance, specific childhood growth trajectories, hypospadias in males, and developmental exposure to endocrine-disrupting chemicals-that collectively point to the influence of early-life developmental programming. Recent evidence revealing a hyperestrogenic/hypoandrogenic hormonal imbalance in the umbilical cord blood of pregnant women with endometriosis provides a critical link between these seemingly disparate findings. We propose a novel hypothesis of hyperestrogenic imprinting: Female offspring of women with endometriosis and/or adenomyosis are exposed to a distinct hormonal environment, which induces lasting epigenetic changes in the developing reproductive tract, thereby imprinting a lifelong susceptibility to these two diseases. This mechanism offers a cohesive explanation for the familial aggregation of endometriosis and possibly adenomyosis, addresses the issue of 'missing heritability', and integrates various risk factors rooted in early development. A limitation of this opinion piece is that its hypothesis is primarily informed by animal studies and conceptual synthesis, and would benefit from further validation through original human data. As a falsifiable hypothesis, it presents a clear pathway for future validation and, if proven, opens avenues for novel preventive strategies.
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9. Long-term systemic outcomes of postmenopausal hormone replacement therapy by age at menopause: a real-world cohort study.
9. 按绝经年龄分层的绝经后激素替代治疗的长期全身结局：一项真实世界队列研究PMID:日期:2026-08-06Does postmenopausal hormone replacement therapy (HRT), initiated within 1 year after menopause diagnosis, confer differential long-term health effects according to age at menopause? Long-term postmenopausal HRT was associated with age-dependent clinical outcomes, with broadly consistent cardiovascular and skeletal associations across age groups, but more variable metabolic and oncological associations according to age at menopause. The 'timing hypothesis' suggests that HRT initiated closer to menopause may have more favorable cardiometabolic associations than later initiation, but evidence across distinct age-at-menopause strata remains limited. This retrospective new-user cohort study utilized de-identified data from the TriNetX Research Network, which provided access to electronic medical records for ∼111 million patients globally. To establish a relatively healthy baseline cohort, we included women aged 30-90 years without prior major systemic diseases who had a documented diagnosis of menopause. To ensure adequate time for the development of hard clinical endpoints, we required that the index event (initial menopause diagnosis) occurred at least 10 years before data extraction (31 December 2025), thereby guaranteeing a minimum follow-up period of one decade. To reduce immortal time bias and survivor bias inherent in prevalent-user designs, we employed a new-user, time-to-event cohort design. Women with a pre-existing history of type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), osteoporosis, compression fracture, venous thromboembolism (VTE), breast cancer, or colorectal cancer on or before the index date were excluded. Women who initiated postmenopausal HRT containing estrogen and/or progestogen within 1 year after menopause diagnosis were propensity score-matched 1:1 with non-users using baseline demographic, clinical, and laboratory covariates. Primary matching yielded 83 670 matched pairs in women who experienced menopause at age ≤60 years and 12 175 matched pairs in women who experienced menopause at age >60 years. Time-to-event analyses using Cox proportional hazards regression were conducted across four clinically defined menopausal age strata: premature ovarian insufficiency (POI, <40 years), early menopause (40-45 years), normal menopause (46-60 years), and late menopause (>60 years). Hazard ratios (HRs) were calculated for incident T2DM, CVD, compression fracture, breast cancer, colorectal cancer, and VTE. Interaction -values were calculated using the normal menopause group (46-60 years) as the reference for interaction testing. Sensitivity analyses were conducted in both the overall ≤60-year and >60-year cohorts using an alternative 1:1 matching strategy based only on age, race, and baseline BMI, excluding laboratory parameters. In the overall matched cohort of women experiencing menopause at age ≤60 years, postmenopausal HRT was associated with lower hazards across all evaluated systemic endpoints. Compared with non-users, postmenopausal HRT was associated with lower hazards of T2DM (events: 3517 vs 4580; crude incidence: 4.20% vs 5.47%; HR: 0.595, 95% CI: 0.575-0.615) and CVD (events: 3960 vs 4413; crude incidence: 4.74% vs 5.29%; HR: 0.699, 95% CI: 0.688-0.709). Skeletal health was preserved, evidenced by a lower hazard of compression fractures (events: 426 vs 441; crude incidence: 0.51% vs 0.53%; HR: 0.780, 95% CI: 0.719-0.846). Furthermore, postmenopausal HRT was associated with lower hazards of breast cancer (events: 1281 vs 1504; crude incidence: 1.53% vs 1.80%; HR: 0.786, 95% CI: 0.743-0.831), colorectal cancer (events: 222 vs 276; crude incidence: 0.27% vs 0.33%; HR: 0.847, 95% CI: 0.738-0.971), and VTE (events: 1247 vs 1346; crude incidence: 1.49% vs 1.61%; HR: 0.859, 95% CI: 0.811-0.910). In the primary age-stratified model, the >60-year cohort showed a higher breast cancer hazard (HR: 1.151, 95% CI: 1.057-1.255); in the corresponding >60-year group sensitivity analysis, using alternative matching, the estimate remained directionally similar (HR: 1.218, 95% CI: 1.027-1.444). Across the remaining >60-year sensitivity outcomes, the direction of association was preserved, including continued lower hazards of T2DM, CVD, VTE, and compression fracture, while the colorectal cancer association remained neutral. Important limitations include residual confounding, incomplete socioeconomic and screening data, limited details on HRT formulation, route, dose and duration, unavailable breast cancer subtype information, unavailable exact maximum follow-up duration, and the inability to directly incorporate standardized patient-level geography into the matching or regression models. Region-restricted inference was additionally constrained because the Europe, Middle East, and Africa (EMEA) > 60-year HRT cohort contained only 48 exposed users, precluding stable matched analysis. While cardiovascular and skeletal associations appeared broadly consistent across menopausal ages, the associations with breast cancer in the older age group highlight the critical need for individualized prescribing. These real-world findings are most consistent with earlier initiation of postmenopausal HRT for symptomatic women and those with POI, while urging extreme caution with initiation in late-onset menopause. No specific external funding was received. The study was supported by departmental funds from the Department of Obstetrics and Gynecology, Taichung Veterans General Hospital. The authors declare no competing interests. N/A.
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10. Once-daily, late-night, modified-release hydrocortisone rapidly normalizes menstrual cyclicity in women with non-classic congenital adrenal hyperplasia.
PMID:日期:2026-08-05Does late-night, modified-release hydrocortisone (MR-HC) improve biochemical control and restore menstrual regularity in women with non-classic congenital adrenal hyperplasia (NCCAH)? Once-daily MR-HC substantially improved biochemical androgen control and rapidly restored menstrual cyclicity in women with NCCAH, including those with longstanding irregular cycles. While pregnancy rates in women with NCCAH are generally comparable to those of the general population, time to conception is often prolonged and assisted reproductive techniques are frequently required. Optimizing adrenal androgen suppression through the superior pharmacokinetic profile of MR-HC may shorten this interval and reduce the need for fertility interventions. So far, MR-HC has not been tested in NCCAH. Prospective observational cohort study conducted between September 2021 and November 2025 at a tertiary referral center and European Reference Network (Endo-ERN) hub for congenital adrenal hyperplasia. Thirty women with NCCAH were enrolled and followed for a median of 22.5 months (interquartile range [IQR] 8.25-36.75), with up to five study visits. Only women with at least 3 months of follow-up were included in the analysis. The cohort comprised 30 women with NCCAH. At initiation of MR-HC, 20 women transitioned from conventional glucocorticoid therapy, and 10 were treatment-naïve. Sixteen women had an active desire to conceive, while 15 presented with irregular menstrual cycles or secondary amenorrhea at baseline. Among 14 evaluable women, ovulatory function, defined as return of regular menstrual cycles or conception, was restored in 13 (92.6%) of women within 6 months of MR-HC initiation. One woman with concomitant hypothalamic hypogonadism remained amenorrhoeic and commenced hormone replacement therapy. Cycle normalization occurred at a median MR-HC dose of 10 mg (IQR 10-15 mg), with all but one woman receiving a single bedtime dose. Among 16 women seeking pregnancy, ten conceived within a median of 2.65 months (IQR 2.0-12.4) compared to 8 months (IRQ 1.0-24.0) in a historic cohort of NCCAH women before the approval of MR-HC (not significant). Among those seeking pregnancy, 10 women had been attempting to conceive unsuccessfully for a median of 28.5 months (IQR 12-46) before. Six women did not become pregnant during follow-up (13.5 months; IQR 6.25-23). The hydrocortisone equivalent dose (HCeq) at the time of conception was significantly lower under MR-HC (10.0 mg (IQR 10-12.5) vs. 16.9 mg (IQR 15-25), = 0.02) in the historic cohort. Transition to MR-HC led to marked reductions in early-morning salivary 17-hydroxyprogesterone and serum testosterone, independent of prior glucocorticoid (GC) exposure. Metabolic effects were minimal: body weight decreased slightly, glycated hemoglobin (HbA1c) rose transiently, predominantly in treatment-naïve women, before returning to baseline. Blood pressure, fasting glucose, and lipid profiles remained stable. While the rapid normalization of, in part, long-standing menstrual irregularities was striking, the absence of a control group does not allow causal inferences, and the single-center design within a specialized tertiary setting may limit generalizability. A single nightly dose of MR-HC appears sufficient to achieve hormonal control and subsequent menstrual-cycle restoration in most women with NCCAH and may improve time to conception. These findings support MR-HC as a promising therapeutic option in the management of NCCAH. This work was supported by the Deutsche Forschungsgemeinschaft (Heisenberg Professorship 325768017, project 314061271 TRR205 to NR and FBCRC-1665 -515637292 to NR and UK). LT was supported by the LMU Munich funding scheme (FöFoLe) and by the IFCAH (International Fund Congenital Adrenal Hyperplasia) grant 2023. HN was supported by the Clinician Scientist Program RISE, supported by the Eva Luise und Horst Köhler Stiftung & Else Kröner-Fresenius-Stiftung (2019_KollegSE.03 to HN). N.R. was Principal Investigator and consulted for Neurocrine Biosciences and Diurnal Ltd. L.T., M.K. A. und H.F.N. were Sub-Investigators for Neurocrine Biosciences and Diurnal Ltd. N/A.