Endocrine therapy plays a central role in the treatment of hormone receptor-positive (HR+) breast cancer, but acquired resistance remains a major clinical challenge. Increasing evidence suggests that ESR1 alterations are key molecular events that maintain estrogen receptor (ER) signaling and drive endocrine treatment failure. In this review, we summarize the biological basis of ESR1/ERα signaling and place it within the broader context of the nuclear ER family, including the partially opposing role of ESR2/ERβ and its potential influence on the prognostic and predictive value of conventional ER/progesterone receptor (PR) status. We then discuss the main categories of ESR1 alterations in breast cancer, including ligand-binding domain (LBD) mutations, structural rearrangements/fusions, copy-number changes, and splice isoforms. Hotspot mutations such as Y537S and D538G cause ligand-independent receptor activation and are commonly detected after aromatase inhibitor exposure, supporting their central role in acquired endocrine resistance. ESR1 fusions, amplification, and isoform diversity further broaden the complexity of ER signaling through transcriptional reprogramming, bypass pathway activation, and nongenomic signaling. We also review the clinical application of circulating tumor DNA (ctDNA) in dynamic molecular monitoring and summarize current therapeutic advances, including oral selective ER degraders (SERDs), proteolysis-targeting chimera (PROTAC) ER degraders, and mechanism-based combination strategies targeting cyclin-dependent kinases 4/6 (CDK4/6), phosphoinositide 3-kinase (PI3K)-protein kinase B-mammalian target of rapamycin (mTOR), fibroblast growth factor receptor (FGFR), human epidermal growth factor receptor 2, and related pathways. Finally, we propose a stratified treatment framework that integrates alteration type, mutation subtype, ctDNA dynamics, treatment line, and coalterations to guide individualized therapy. Standardized molecular testing, real-time ctDNA surveillance, and next-generation ER-targeted therapies, together with a clearer understanding of the wider ER family, may provide new opportunities for precision treatment of endocrine-resistant breast cancer.

Hormones mediate inter-organ signaling, which is crucial in orchestrating diverse behaviors and physiological processes, including sleep and activity, feeding, growth, metabolism, and reproduction. The pars intercerebralis and pars lateralis in insects represent major hubs that contain neurosecretory cells (NSCs) that produce various peptide hormones. To obtain insight into how hormonal signaling is regulated, we have characterized the synaptic connectome of NSCs in the adult Drosophila brain. Identification of neurons providing inputs to multiple NSC classes implicates diuretic hormone 44-expressing NSCs as a major coordinator of physiology and behavior. Surprisingly, despite most NSCs having dendrites in the subesophageal zone (primary taste processing center), inputs from peripheral gustatory neurons to NSCs are largely indirect. We also deciphered pathways via which diverse olfactory inputs are relayed to NSCs. Using an influence metric, based on a linear dynamical systems approach, we identify enteric neurons as the strongest influencers of NSC activity compared to other sensory modalities. Further, our analyses revealed substantial inputs from brain descending neurons to NSCs, suggesting that descending neurons regulate both endocrine and motor output to synchronize physiological changes with appropriate behaviors. In contrast to NSC inputs, synaptic output from NSCs is sparse and mostly mediated by corazonin NSCs. We show that both corazonin-expressing NSCs and their downstream synaptic partner DNg27 influence egg-laying. We additionally explore putative paracrine interconnectivity between NSC classes and peptide hormone pathways from NSCs to peripheral tissues by analyzing single-cell transcriptomic datasets. Our comprehensive characterization of the Drosophila neurosecretory network connectome provides a platform to understand complex hormonal networks and how they orchestrate animal behaviors and physiology.

Chronic Kidney Disease (CKD) is a condition of abnormal kidney structure or function, pathologically characterized by chronic inflammation, tubular atrophy, vascular rarefaction, glomerulosclerosis, and interstitial fibrosis. CKD potentially represents a risk factor for several disease conditions, such as cardiovascular disease, mineral bone disorder, and electrolyte imbalance. Hormone dysregulation within the pituitary axis is yet another condition that CKD influences. Notably, CKD dysregulates several anterior pituitary hormones, either by directly influencing hypothalamic-pituitary secretion or by altering downstream hormones, which then dysregulate pituitary secretion via negative feedback. In the context of CKD-influenced hormone dysregulation, several contributors, including high uremic toxins, inflammatory cytokines, mineral imbalance, and dysregulated molecular mediators related to fibroblast growth factor 23-Klotho signaling, circulating microRNAs, the kidney-gut-brain axis, and glial and endothelial modulation, play integral roles. In conclusion, this review highlights the potential participation of CKD in pituitary dysregulation and provides insights into its potential contributors.

Glyceryl tribenzoate (GTB) or tribenzoin is a flavoring agent with characteristic anti-microbial property. We have already delineated GTB's immunomodulatory role via the enrichment of regulatory T cells in mouse models of multiple sclerosis and anti-neuroinflammatory role via the reduction of glial activation in a monkey model of Parkinson's disease and a mouse model of Huntington's disease. However, its role has never been explored in Alzheimer's disease (AD), the most common neurodegenerative disorder in human. This study underlines the importance of GTB in promoting the growth and function of hippocampal neurons via upregulation of plasticity-associated genes, enrichment of dendritic spines and stimulation of inotropic calcium influx. Accordingly, oral GTB improved hippocampal plasticity and protected memory and learning in 5xFAD mice. Similarly, GTB treatment also reduced cerebral plaque load and increased the life span of aged 5xFAD mice. Interestingly, we observed that peroxisome proliferator-activated receptor alpha (PPARα), a nuclear hormone receptor, served as a receptor of GTB. Consequently, GTB was shown to improve hippocampal plasticity and increase cognitive functions in 5xFAD, but not 5xFAD/Ppara-null, mice, indicating an important role of PPARα in GTB-mediated neuroprotection. These results suggest that oral GTB may have therapeutic importance for improving hippocampal functions in AD patients.

Oncocytic (Hurthle cell) carcinoma is an uncommon thyroid malignancy that tends to spread through the bloodstream and often concentrates radioactive iodine poorly. Spread to the brain is rare, and a solitary cerebellar deposit is rarer still. We describe a 44-year-old man who presented with neck swelling and was found to have a widely invasive oncocytic carcinoma with extensive vascular invasion and a minor classic papillary component (5%). He underwent total thyroidectomy with central neck dissection followed by radioactive iodine ablation with 150 mCi of iodine-131. The post-therapy scan showed uptake confined to the thyroid bed. Over the next 18 months, his serum thyroglobulin climbed steadily from 1.5 µg/L to 11.6 µg/L even though the thyroid-stimulating hormone (TSH)-stimulated diagnostic whole-body iodine scan remained negative. Fluorodeoxyglucose positron emission tomography/computed tomography then showed multiple hypermetabolic bilateral pulmonary nodules suspicious for metastases. Roughly 22 months after thyroidectomy, he developed progressive dizziness and headache. Magnetic resonance imaging (MRI) revealed a 3.3 × 3.2 × 3.1 cm mixed cystic and solid left cerebellar mass with surrounding vasogenic edema and mass effect on the brainstem. The mass was resected through a left suboccipital craniotomy. Histology showed a malignant epithelioid neoplasm with nested and trabecular growth, abundant granular eosinophilic cytoplasm, prominent nucleoli, scattered bizarre giant nuclei, and 8 mitoses per 2 mm[2] without necrosis. The tumor cells expressed cytokeratin AE1/AE3, CK7, TTF-1, and PAX-8 and were negative for CK20, CDX-2, synaptophysin, chromogranin, and S100, confirming thyroid origin. The metastasis fulfilled criteria for high-grade differentiated thyroid carcinoma with oncocytic features. His symptoms resolved after surgery, and stereotactic radiosurgery for the resection cavity was recommended. A rising thyroglobulin with negative iodine imaging represents a biochemical incomplete response and should prompt a search for structural disease recurrence. Because the brain lesion in our patient came to light only when symptoms appeared, brain MRI may be worth considering in patients with radiodiodine-refractory distant metastases.

Female infertility remains a major women's reproductive health challenge, with impaired endometrial receptivity contributing to recurrent implantation failure, early pregnancy loss, and pregnancy complications. Mechanistic studies of human early pregnancy are limited by the lack of physiologically relevant models, and existing in vitro endometrial models rely on exogenous hormone treatment and do not recapitulate the dynamic ovarian control of endometrial growth and differentiation. Here, as a proof of concept, we developed a 3D in vitro ovarian follicle-endometrial organoid co-culture model. Immature murine follicles were cultured in vitro to obtain preovulatory follicles, followed by human chorionic gonadotropin (hCG) stimulation to induce ovulation and luteinization. Luteinized follicles were co-cultured with human endometrial stroma organoids for 6 days. The results showed that luteinized follicles generated a dynamic endocrine environment characterized by progressively increasing progesterone levels and declining estradiol levels. Follicle co-culture induced morphological differentiation and expression of decidualization markers in human endo-organoids. Transcriptomic analysis revealed strong genome-wide concordance between follicle co-culture and conventional decidualization induction using estradiol/progesterone/cAMP (EPC), with significant enrichment of decidualization-associated genes and pathways under both conditions. Nevertheless, the two conditions also exhibited distinct transcriptional states, with EPC preferentially enriched for more mature decidualization-associated programs, whereas luteinized follicle co-culture retained features of the early stage of decidualization. Functional perturbation testing revealed that the progesterone receptor (PR) antagonist RU486 attenuated co-culture-induced endometrial decidualization. Together, these results establish a new in vitro new approach methodology (NAM) that recapitulates ovarian control of endometrial decidualization. This platform provides a human-relevant NAM model to investigate the physiology and pathophysiology of endometrial decidualization, and to evaluate how drugs and environmental chemicals perturb uterine receptivity and early pregnancy.