Estradiol

In the global CAPItello-291 randomized phase 3 study (NCT04305496) in patients with hormone receptor-positive/HER2-negative advanced breast cancer and progression during/after aromatase inhibitor treatment, capivasertib-fulvestrant significantly improved progression-free survival (PFS) in the overall population and patients with PIK3CA/AKT1/PTEN-altered tumors versus placebo-fulvestrant. We assessed efficacy and safety of capivasertib-fulvestrant in a prespecified exploratory analysis of a Chinese cohort (n = 24) and extended study with the same protocol (n = 110). Clinically meaningful PFS benefit for capivasertib-fulvestrant was observed in the overall population (median PFS: 6.9 [capivasertib-fulvestrant] versus 2.8 [placebo-fulvestrant] months; hazard ratio 0.51, 95% CI 0.34-0.76), patients with PIK3CA/AKT1/PTEN-altered tumors (n = 46; 5.7 versus 1.9 months; hazard ratio 0.41, 95% CI 0.19-0.85) and PIK3CA/AKT1/PTEN-non-altered tumors (patients with confirmed next-generation sequencing results [n = 68]; 9.2 versus 2.7 months; hazard ratio 0.38; 95% CI 0.21-0.68). The most frequent adverse events (AEs) with capivasertib-fulvestrant were diarrhea (60.6% versus 11.3% with placebo-fulvestrant) and hyperglycemia (57.7% versus 17.7%). AEs leading to capivasertib-fulvestrant discontinuation were reported in 11.3% of patients versus 3.2% for placebo-fulvestrant. The benefit-risk profile of capivasertib-fulvestrant in the Chinese cohort was favorable; further exploration in patients with PIK3CA/AKT1/PTEN-non-altered tumors is warranted.

BACKGROUNDMen with chronic kidney disease (CKD) experience faster kidney function decline than women. Studies in individuals undergoing sex hormone therapy suggest a role for sex hormones, as estimated glomerular filtration rate (eGFR) increases with feminizing therapy and decreases with masculinizing therapy. However, effects on measured GFR (mGFR), glomerular and tubular function, and involved molecular mechanisms remain unexplored.METHODSThis prospective, observational study included individuals initiating feminizing (estradiol and antiandrogens; n = 23) or masculinizing (testosterone; n = 21) therapy. Baseline and 3-month assessments included mGFR (iohexol clearance), kidney perfusion (para-aminohippuric acid clearance), tubular injury biomarkers, and plasma proteomics.RESULTSDuring feminizing therapy, mGFR and kidney perfusion increased (+3.6% and +9.1%, respectively; P < 0.05) without increased glomerular pressure. Tubular injury biomarkers, including urine neutrophil gelatinase-associated lipocalin, epidermal growth factor (EGF), monocyte chemoattractant protein-1, and chitinase 3-like protein 1 (YKL-40), decreased significantly (-53%, -42%, -45%, and -58%, respectively). During masculinizing therapy, mGFR and kidney perfusion remained unchanged, but urine YKL-40 and plasma tumor necrosis factor receptor 1 (TNFR-1) increased (+134% and +8%, respectively; P < 0.05). Proteomic analysis revealed differential expression of 49 proteins during feminizing and 356 proteins during masculinizing therapy. Many kidney-protective proteins were positively associated with estradiol and negatively associated with testosterone, including proteins involved in endothelial function (SFRP4, SOD3), inflammation reduction (TSG-6), and maintaining kidney tissue structure (agrin).CONCLUSIONSex hormones influence kidney physiology, with estradiol showing protective effects on glomerular and tubular function, while testosterone predominantly exerts opposing effects. These findings emphasize the role of sex hormones in sexual dimorphism observed in kidney function and physiology and suggest new approaches for sex-specific precision medicine.TRIAL REGISTRATIONDutch Trial Register (ID: NL9517); ClinicalTrials.gov (ID: NCT04482920).

Gestational diabetes mellitus (GDM), the most common pregnancy-related metabolic disorder, is characterized by exacerbated oxidative stress (OS). The inhibition of phosphoglycerate kinase 1 (PGK1), the first ATP-generating enzyme in the glycolytic pathway, activates Keap1-Nrf2 antioxidant pathways and reduces OS. However, the detailed roles of PGK1 in GDM remain unexplored. Disruption of pro-oxidant/antioxidant homeostasis was observed in the placentas of GDM patients. PGK1 was significantly upregulated in both human GDM placentas and streptozotocin (STZ)-induced model mice. Pharmacological inhibition of PGK1 in vivo ameliorated placental dysfunction, attenuated excessive ROS production, and improved pregnancy outcomes. Lentivirus-mediated PGK1 knockdown in HTR8/SVneo trophoblasts increased Nrf2-dependent antioxidant protein expression while reducing ROS generation. Mechanistically, PGK1 inhibition elevated estradiol levels, facilitating Keap1 dimerization, and this dimerization destabilized the Keap1-Nrf2 complex, enabling Nrf2 accumulation and antioxidant activation. Exogenous estradiol supplementation recapitulated the effect of inhibiting PGK1 by enhancing Keap1 dimer formation, effectively mitigating placental OS and adverse pregnancy phenotypes in GDM models. This study elucidates the critical role of PGK1 in restoring redox homeostasis through the estradiol-Keap1-Nrf2 axis in the pathogenesis of GDM. PGK1/estradiol crosstalk represents a druggable target, and pharmacological PGK1 inhibition has translational potential for mitigating oxidative stress-related pregnancy complications.

BackgroundGenetic polymorphisms in sphingolipid metabolism, particularly involving the orosomucoid-like 3 (ORMDL3) gene, have been associated with asthma risk. Notably, asthma prevalence and severity exhibit pronounced sex differences, emerging in childhood and persisting into adulthood. However, the molecular mechanisms underlying this sexual dimorphism remain incompletely elucidated.ObjectiveWe investigated whether ORMDL3 contributes to sex differences in airway function and asthma-like features.MethodsORMDL3 expression was measured in lung tissues from healthy male and female human donors and in human bronchial epithelial cells (BEAS-2B) after exposure to 17β-estradiol (E2), Dermatophagoides pteronyssinus 1 (Der p 1), or both. A murine preparation of asthma was used to evaluate sex-dependent differences in ORMDL3 expression, airway responsiveness, and remodeling. Pharmacologic modulation of estrogen signaling and the ORMDL3-sphingosine-1-phosphate (S1P) axis were used. Methods included quantitative real-time PCR, immunostaining, liquid chromatography-tandem mass spectrometry, and airway function measurements.ResultsFemale lungs exhibited higher ORMDL3 expression than male lungs, and this correlated with elevated forced expiratory volume to forced vital capacity ratios in the same patients. In BEAS-2B cells, E2 significantly upregulated ORMDL3 and altered sphingolipid metabolism by inducing expression of ceramidase, sphingosine kinases 1/2, and S1P receptors. Der p 1 also increased ORMDL3 and triggered epithelial activation via inflammasome signaling, while E2 enhanced IFN-β signaling and MUC5AC expression. Combination Der p 1/E2 synergistically activated sphingolipid, interferon, and inflammasome pathways. These in vitro findings prompted in vivo investigation using a murine asthma preparation, where female mice displayed elevated ORMDL3, sphingosine, and S1P levels, with increased airway hyperresponsiveness and remodeling. Treatment with tamoxifen or E2 normalized airway hyperresponsiveness and S1P signaling across sexes. Allergen sensitization intensified female-biased ORMDL3 expression and airway inflammation. Inhibition of the ORMDL3-S1P axis attenuated asthma-like features only in female animals.ConclusionThis study identifies ORMDL3 as an estrogen-responsive regulator of airway responsiveness that may contribute to sex-related differences in asthma features through modulation of sphingolipid metabolism.