Daily Endocrinology Research Analysis
Analyzed 62 papers and selected 3 impactful papers.
Summary
Analyzed 62 papers and selected 3 impactful articles.
Selected Articles
1. Modeling human embryo implantation in vitro.
The authors created a 3D in vitro model of receptive human endometrium comprising luminal, glandular, and stromal compartments that supports implantation of human embryos and blastoids to day 14. Single-cell RNA sequencing identified conceptus–endometrium signaling at the interface, and disrupting extravillous trophoblast–stromal signaling impaired trophoblast outgrowth, revealing essential crosstalk for early placental development.
Impact: This platform overcomes a major barrier in studying human implantation, enabling mechanistic dissection and functional perturbation of embryo–endometrium interactions up to day 14. It sets the stage for investigating early pregnancy loss, implantation failure, and placental disorders.
Clinical Implications: While preclinical, this model can inform diagnostics (endometrial receptivity biomarkers), embryo selection strategies, and drug safety studies by identifying pathways critical for implantation and early trophoblast invasion.
Key Findings
- Developed a 3D endometrial model recapitulating luminal, glandular, and stromal compartments that supports implantation of human embryos and blastoids.
- Achieved post-implantation hallmarks including advanced trophoblast structures and early placental development features up to day 14.
- Single-cell RNA-seq of the embryo–endometrium interface identified predicted ligand–receptor interactions; disrupting extravillous trophoblast–stromal signaling impaired trophoblast outgrowth.
Methodological Strengths
- Physiologically relevant multicompartment 3D co-culture enabling implantation and early placental differentiation.
- Integration of single-cell transcriptomics with functional perturbations to validate key signaling pathways.
Limitations
- In vitro model may not capture all systemic maternal factors; generalizability to in vivo conditions remains to be established.
- Developmental progression assessed only to day 14, limiting study of later placentation and fetal development.
Future Directions: External validation across diverse donor sources, integration with immune and vascular components, and application to model implantation failure, preeclampsia, and drug safety.
2. Reprogramming offspring liver health: maternal indole supplementation as a preventive strategy against MASLD.
Maternal indole or indole-3-acetic acid supplementation during gestation/lactation protected adult offspring from Western diet–induced weight gain, steatosis, stellate cell activation, and fibrosis. Perinatal AHR activation trans-repressed ceramidases (Asah2, Acer3), increasing hepatic very long-chain ceramides; protective phenotypes transferred by fecal microbiota. Indole and VLC ceramides exerted anti-fibrotic effects in LX-2 cells, abolished by AHR inhibition.
Impact: Identifies an AHR–ceramide axis linking maternal microbial metabolites to durable reprogramming of offspring liver, offering a mechanistically grounded prevention strategy for pediatric MASLD.
Clinical Implications: Translational potential for maternal dietary or microbiome-based interventions to prevent pediatric MASLD; AHR pathway and VLC ceramides emerge as candidate targets, though human studies are needed.
Key Findings
- Maternal indole or I3A supplementation conferred long-term protection in offspring against WD-induced weight gain, steatosis, stellate activation, and fibrosis.
- Perinatal AHR activation in gut and liver trans-repressed Asah2 and Acer3, increasing hepatic very long-chain ceramides.
- Fecal microbiota transfer from indole-exposed offspring protected recipients from WD-induced fibrogenesis and increased hepatic VLC ceramides.
- Indole and VLC ceramides reduced TGF-β–induced fibrotic signaling in LX-2 stellate cells; effects were abolished by AHR inhibition.
Methodological Strengths
- Multi-system validation including in vivo maternal-offspring model, fecal microbiota transfer, and human hepatic stellate cell assays.
- Mechanistic linkage via AHR signaling and ceramide metabolism with target gene (Asah2, Acer3) regulation.
Limitations
- Findings are preclinical; dosing, safety, and efficacy of indole supplementation in humans are unknown.
- Sex-specific effects and long-term transgenerational outcomes were not fully delineated.
Future Directions: Test maternal AHR ligand interventions in larger animal models, define optimal dosing and safety, and initiate observational studies correlating maternal tryptophan metabolite levels with pediatric MASLD risk.
3. Glucagon-like peptide-1 receptor agonists and risk for cardiovascular events in older adults treated with levothyroxine: a target trial emulation.
In a Medicare-based target trial emulation of older adults (>65 years) with T2D on stable levothyroxine, initiation of GLP-1RA versus SGLT2 inhibitors was associated with higher AF/Aflutter risk (HR 1.46; 95% CI 1.28–1.67) over a median 1.05-year follow-up, while stroke risk was not statistically different (HR 1.17; 95% CI 0.98–1.39). Results were consistent across sensitivity analyses.
Impact: Highlights a clinically actionable safety signal at the intersection of diabetes and thyroid therapy, informing medication selection and monitoring strategies in a common older population.
Clinical Implications: When initiating GLP-1RA in older adults on levothyroxine, consider closer TSH/FT4 monitoring, levothyroxine dose adjustment, and AF surveillance; SGLT2 inhibitors may be preferred in patients at high AF risk.
Key Findings
- After 1:1 propensity score matching (n=2,384 per group), GLP-1RA initiation was associated with higher AF/Aflutter risk versus SGLT2 inhibitors (HR 1.46; 95% CI 1.28–1.67).
- No statistically significant difference in stroke risk between groups (HR 1.17; 95% CI 0.98–1.39).
- Findings were robust across sensitivity analyses, including inpatient-only outcomes, intention-to-treat, prevalent new user design, and DPP-4 inhibitors as comparator.
Methodological Strengths
- Target trial emulation with active comparator and 1:1 propensity score matching in a nationally representative Medicare sample.
- Multiple sensitivity analyses to test robustness of findings.
Limitations
- Residual confounding and misclassification inherent to claims data; lack of direct thyroid function tests and levothyroxine dose adjustments in the dataset.
- Relatively short median follow-up (~1 year), limiting assessment of long-term outcomes.
Future Directions: Prospective studies measuring TSH/FT4 dynamics and arrhythmia monitoring after GLP-1RA initiation in levothyroxine users; mechanistic studies on gastric emptying, absorption, and weight-loss mediated effects.