Background: Tryptophan and its kynurenine pathway (KP) metabolites play key roles in modulating the immune system and vasculature, and exhibit both pro- and antioxidant properties, making them crucial for a healthy pregnancy and fetal development. Disruptions in the KP may impact both prenatal and postnatal health, however, data on fetal KP metabolite concentrations and their alterations in pregnancy-related disorders remain scarce. This study aims to investigate the association between pregnancy complications and KP metabolite concentrations in umbilical cord blood.
Methods: Pregnancies complicated by preeclampsia (n = 40), fetal growth restriction (FGR, n = 33), pregestational diabetes mellitus (DM, n = 42), gestational diabetes mellitus (GDM, n = 61), and amniotic infection syndrome (AIS, n = 47) were included, along with 410 controls matched in a 1:2 ratio using Mahalanobis nearest-neighbor matching from a prospective birth cohort study. Tryptophan, kynurenine, anthranilic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid, kynurenic acid, xanthurenic acid, quinolinic acid, picolinic acid, and nicotinic acid were measured in umbilical cord blood using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Differences in metabolite concentrations were analyzed using unpaired t-tests and linear regression models to control for potential confounders.
Results: Tryptophan concentrations were decreased in cases of preeclampsia and DM. We identified elevated levels of 3-hydroxykynurenine in preeclampsia, kynurenine in GDM, and nicotinic acid in both FGR and DM. Quinolinic acid levels were also higher in preeclampsia and GDM, although this was not significant after adjusting for confounding variables. We observed no changes in KP metabolites in AIS.
Conclusion: This study identified distinct alterations in umbilical cord blood KP metabolite concentrations in pregnancies with preeclampsia, FGR, DM, and GDM, but not AIS. This suggests differential regulation and activation of the KP depending on the pregnancy disorder. Such changes may influence maternal and infant health and could play a role in fetal programming, with potential long-term effects on child development and health.
Background: Adults with polycystic ovary syndrome (PCOS) and obesity are at risk of depression, but less is known about the relationship between PCOS, obesity, and depression in adolescents. The objective of this study was to establish whether PCOS is associated with symptoms of depression in adolescents living with obesity.
Methods: This was an observational, case-control study of adolescents aged 12-19 years living with obesity (> 95th percentile) with (n = 45) and without (n = 26) PCOS diagnosed according to international criteria. Symptoms of depression were self-assessed using the Center for Epidemiological Studies Depression Scale for Children (CES-DC). Associations between demographic and biochemical variables, PCOS, and symptoms of depression were assessed with the chi-squared test or Student's t-test.
Results: The mean (SD) age and BMI Z-score of the study population were 14.8 (2.0) years and 2.19 (0.35), respectively. There were no significant differences in age, BMI Z-score, nor biochemical parameters between patients with and without PCOS. The mean (SD) CES-DC score was significantly higher in patients with PCOS than those without [31.2 (8.9) vs. 13.1 (6.0); p < 0.001]. A diagnosis of PCOS was associated with mild to moderate or major depressive symptoms (p < 0.001), with nearly all (95.6%) patients with PCOS screening positive for the possibility of depression.
Conclusion: Depressive symptoms are extremely common in adolescents with or without PCOS and matched BMI, suggesting that obesity is not the only mechanism leading to depression. The mechanisms leading to depression in adolescents with PCOS, including relationships between metabolic profiles, PCOS, and depression, require further exploration to personalize therapy in this group of particularly vulnerable individuals.
Circadian desynchrony, caused by a misalignment between the internal biological clock and environmental light cues, is increasingly prevalent in adolescents due to irregular light exposure and social pressures. However, its impact on reproductive maturation remains poorly understood. In this study, the effects of chronic circadian disruption, induced by the 223 light regimen (two days of constant light, two days of constant darkness, and three days of a 14:10 h light-dark cycle), were examined in juvenile and peripubertal male rats (postnatal days 21-49). Gene expression profiles associated with Leydig cell maturation, including steroidogenic, mitochondrial, and clock-related genes, as well as markers of germ cell differentiation, were analyzed alongside functional mitochondrial parameters in Leydig cells. Under control conditions, Leydig cell maturation was marked by increased expression of core clock genes, steroidogenic enzymes (Star, Cyp11a1, Hsd3b1/2), and mitochondrial biogenesis and dynamics markers (Tfam, Nrf1, Cytc, Opa1, Mfn2). These transcriptional changes coincided with rising mitochondrial content, membrane potential, ATP levels, serum androgens, and progression of spermatogenesis. Conversely, the 223-regimen disrupted behavioral rhythms, reduced circulating melatonin, blunted expression of maturation-associated genes, and shifted the acrophase of key steroidogenic and circadian transcripts in 49-day-old rats, indicating altered Leydig cell rhythmicity. These molecular disruptions were accompanied by decreased testosterone levels, altered expression of spermatid differentiation genes (Tnp1 and Prm2), and a reduction in the number of elongated spermatids at stage VII of spermatogenesis. In conclusion, circadian misalignment disrupts endocrine and transcriptional coordination during Leydig cell development, underscoring the vulnerability of pubertal reproductive maturation to environmental light disturbances.
Background: Conservative treatment remains a viable option for selected patients with ectopic pregnancy (EP), but failure may lead to rupture and serious complications. Currently, serum β-hCG is the main predictor for treatment outcomes, yet its accuracy is limited. This study aimed to develop and validate a predictive model that integrates radiomic features derived from super-resolution (SR) ultrasound images with clinical biomarkers to improve risk stratification.
Methods: A total of 228 patients with EP receiving conservative treatment were retrospectively included, with 169 classified as treatment success and 59 as failure. SR images were generated using a deep learning-based generative adversarial network (GAN). Radiomic features were extracted from both normal-resolution (NR) and SR ultrasound images. Features with intraclass correlation coefficient (ICC) ≥ 0.75 were retained after intra- and inter-observer evaluation. Feature selection involved statistical testing and Least Absolute Shrinkage and Selection Operator (LASSO) regression. Random forest algorithms were used to construct NR and SR models. A clinical model based on serum β-hCG was also developed. The Clin-SR model was constructed by fusing SR radiomics with β-hCG values. Model performance was evaluated using area under the curve (AUC), calibration, and decision curve analysis (DCA). An independent temporal validation cohort (n = 40; 20 failures, 20 successes) was used to validation of the nomogram derived from the Clin-SR model.
Results: The SR model significantly outperformed the NR model in the test cohort (AUC: 0.791 ± 0.015 vs. 0.629 ± 0.083). In a representative iteration, the Clin-SR fusion model achieved an AUC of 0.870 ± 0.015, with good calibration and net clinical benefit, suggesting reliable performance in predicting conservative treatment failure. In the independent validation cohort, the nomogram demonstrated good generalizability with an AUC of 0.808 and consistent calibration across risk thresholds. Key contributing radiomic features included Gray Level Variance and Voxel Volume, reflecting lesion heterogeneity and size.
Conclusions: The Clin-SR model, which integrates deep learning-enhanced SR ultrasound radiomics with serum β-hCG, offers a robust and non-invasive tool for predicting conservative treatment failure in ectopic pregnancy. This multimodal approach enhances early risk stratification and supports personalized clinical decision-making, potentially reducing overtreatment and emergency interventions.
Background: Polycystic ovary syndrome (PCOS) patients typically undergo either an ovulation induction regimen or a programmed regimen for endometrial preparation before frozen embryo transfer (FET). However, the superiority of one approach over the other remains controversial. While previous studies suggest that the letrozole regimen may improve pregnancy outcomes, prospective studies are insufficient. Therefore, we designed a multi-center randomized controlled trial to compare the pregnancy outcomes between these two regimens in PCOS patients undergoing FET.
Methods: This multicentre, randomised controlled, open-label trial included 155 PCOS patients from six hospitals in China between September 2022 and February 2024. Patients were randomised into either the letrozole ovulation regimen group (n = 81) or the programmed regimen group (n = 74) during FET cycles. Subgroup analysis was used among patients with single blastocyst transfer. The primary outcome was clinical pregnancy rate, with secondary outcomes including abortion rate, live birth rate, and other pregnancy and neonatal outcomes.
Results: Analysis of 155 FET women showed no significant difference in clinical pregnancy rates between the letrozole group (62.96%) and the programmed group (60.81%, P > 0.05). Similarly, no differences were observed in abortion rate, live birth rate, hypertensive disorders of pregnancy, gestational diabetes mellitus, preterm birth, or neonatal birth weight. However, more patients in the letrozole group received single-drug luteal support (53.16% vs. 16.67%, P < 0.05). A subgroup analysis of 108 women involving patients who underwent single blastocyst transfer revealed no significant differences in clinical pregnancy rates (66.67% vs. 73.33%, P > 0.05) or live birth rates (58.73% vs. 55.56%, P > 0.05) between the two groups. A higher proportion of women in the letrozole ovulation regimen group received single-drug luteal support compared to those in the programmed regimen group (58.73% vs. 22.22%, P < 0.05). No statistically significant differences were observed between the groups in terms of fertilization method, abortion rate, or obstetric and neonatal outcomes.
Conclusions: The letrozole ovulation regimen demonstrated comparable clinical pregnancy rates to the programmed regimen in PCOS patients undergoing FET, while requiring only simple luteal support. These findings suggest that the letrozole regimen may be a favourable alternative for endometrial preparation in this population.
Trial registration: Chinese Clinical Trial Registry ChiCTR2200062244 ( https://www.chictr.org.cn ). Registered on 31 July 2022.
Objective: While varicocele is a major cause of male infertility, the role of vitamin D in sperm DNA integrity remains unclear. This study aimed to investigate the association between serum vitamin D levels and sperm DNA fragmentation index (DFI) in varicocele patients.
Methods: This retrospective cohort study conducted at Fujian Maternity and Child Health Hospital included 355 varicocele patients aged 18-45 years (June 2021-June 2024). The primary exposure was serum 25-hydroxyvitamin D level, and the primary outcome was DFI. Multiple linear regression models were used to analyze the association between vitamin D and DFI, adjusting for age, BMI, smoking, alcohol consumption, and other confounders.
Results: A significant inverse association was found between vitamin D levels and DFI (β = -0.24, 95% CI: -0.28 to -0.19, P < 0.0001). Piecewise linear regression identified a threshold at 25.9 nmol/L, below which the inverse association was more pronounced (β = -1.0, 95% CI: -1.2 to -0.8, P < 0.001).
Conclusion: Serum vitamin D levels have been demonstrated to be significantly associated with the rate of sperm DNA fragmentation index in patients with varicocele, particularly at levels below 25.9 nmol/l.
Background: Abnormal sperm quality, particularly high sperm DNA fragmentation levels, is associated with infertility and a higher risk of pregnancy loss. While short abstinence periods may improve semen quality, the specific role of ejaculation frequency (EF) remains unclear. EF refers to the number of times an individual ejaculates within a given period, which is distinct from the abstinence period, defined as the time interval between ejaculations. This study investigates the association between EF and semen quality, including sperm DNA fragmentation.
Methods: This cross-sectional study included 1,349 men who underwent semen analysis at a reproductive center between November 2023 and July 2024. The subjects were categorized into three groups based on their self-reported EF over the past four weeks: EF1: <1/week, EF2: ≥1 and <2/week, and EF3: ≥2/week.
Results: As EF increased, significant decreases were observed in sperm DNA fragmentation index (DFI) (P < 0.001), semen volume (P = 0.012), sperm concentration (P < 0.001), and total sperm count (P < 0.001). Sperm vitality showed a positive association with EF (P < 0.001), while no association was found between sperm progressive motility and EF. Lower risks of elevated sperm DFI and necrozoospermia were observed in EF2 and EF3 compared to EF1. However, there was no increased risk of oligozoospermia or asthenozoospermia with increased EF.
Conclusions: Higher ejaculation frequency is associated with improved sperm vitality and lower DFI without negatively impacting motility. EF should be considered alongside abstinence in male fertility assessments.
Trial registration: The study was registered on ClinicalTrials.gov (identifier NCT06127875).
Date of registration: November 11th, 2023. Date of enrollment of the first subject: November 11th, 2023.
Background: In the field of in vitro fertilization (IVF), the search for reliable success predictors is ongoing, with novel biomarkers gaining increasing attention. Epigenetic clocks, mathematical models based on DNA methylation (DNAm) patterns, have revolutionized aging research by providing insights into biological aging. However, the magnitude of the benefit of the use of a simplified and non-specific epigenetic clock is still insufficient to claim for its clinical use. We investigated the potential role of epigenetic clocks in predicting IVF success.
Methods: This prospective observational study involved 379 women of reproductive age who underwent IVF treatment. On the day of recruitment, blood samples were collected, and genomic DNA was isolated from white blood cells. Epigenetic age was calculated using an algorithm based on the methylation patterns of 5 specific CpG sites and derived by pyrosequencing technique ("Zbieć-Piekarska2" model). Epigenetic age acceleration (EPA) was estimated from the residuals of a linear model, with epigenetic age regressed on chronological age. We compared the resulting epigenetic age and EPA between women who achieved a live birth and those who did not, alongside traditional ovarian reserve parameters (antral follicular count AFC; anti-müllerian hormone AMH).
Results: Among 379 women, 204 (54%) achieved LB. They were younger, had better ovarian reserve markers, retrieved more oocytes and had lower epigenetic age (36 ± 5 vs. 39 ± 5 years, p < 0.001) with moderate predictive power (area under the curve AUC = 0.652). After adjusting for antral follicular count (AFC), epigenetic age remained significantly associated with live birth (adjusted odds ratio OR = 0.91 per year; p < 0.001), suggesting IVF success is more likely in epigenetically younger women, beyond their ovarian reserve. This association was lost in subgroup analysis by infertility cause. In women aged 31-35, epigenetic age and EPA were the best predictors (AUC = 0.637). Combining epigenetic age with ovarian reserve markers slightly improved predictive accuracy (AUC = 0.692 with AFC, 0.693 with AMH) over chronological age alone (AUC = 0.672).
Conclusions: Epigenetic clocks may enhance IVF success prediction, particularly in women between 31 and 35. Our findings support the need for further research in this area and emphasize the importance of developing epigenetic models specifically tailored to fertility outcomes.
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