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).

Rβ, and GPER). Insulin and estrogen signaling converge on Sirt1, mTOR, and PI3K in the joint regulation of autophagy and mitochondrial metabolism. Dysregulated insulin and estrogen signaling lead to metabolic diseases. This article reviews the up-to-date evidence that depicts the pathways of insulin signaling and estrogen-ER signaling in the regulation of metabolism. In addition, we discuss the cross-talk between estrogen signaling and insulin signaling via Sirt1, mTOR, and PI3K, as well as new therapeutic options such as agonists of GLP1 receptor, GIP receptor, and β3-AR. Mapping the molecular pathways of insulin signaling, estrogen signaling, and their interplays advances our understanding of metabolism and discovery of new therapeutic options for metabolic disorders. Keywords: autophagy, estrogen, Insulin, metabolic disease, metabolism, mitochondria Introduction Since the definition of hormone by the British physiologist Ernest Starling in 1905 [ 1 ], hormone research has advanced in many areas, including new hormone discovery, functional characterization, biotechnology-assisted synthesis, and clinical application [ 2 , 3 ]. A hormone was defined as a molecule produced by the glands with internal secretion and delivered by the blood circulatory system to target tissues, regulating physiological functions [ 1 ]. Nowadays, it has been recognized that cytokines produced by non-gland cells or tissues (e.g., adipose tissue, liver, and skeletal muscle) function as hormones [ 3–5 ]. Insulin is secreted from pancreatic β-cells, which is critical for metabolic health and functions of various tissues such as muscle, adipose tissue, and liver [ 6–9 ]. Studies have established canonical insulin signaling pathways (e.g., IRS-PI3K-PDK1-Akt) and non-canonical insulin signaling pathways (e.g., IRS-PI3K-PDPK1-aPKCλ) in the regulation of glucose metabolism [ 7 , 10 ]. Moreover, insulin signaling modulates mitochondrial metabolism including mitochondrial biogenesis, dynamics, and a