Unveiling mechanisms underlying kidney function changes during sex hormone therapy
Sarah A. van Eeghen, … , Daniël H. van Raalte, Natalie J. Nokoff
Sarah A. van Eeghen, … , Daniël H. van Raalte, Natalie J. Nokoff
Published April 7, 2025
Citation Information: J Clin Invest. 2025;135(9):e190850. https://doi.org/10.1172/JCI190850.
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Clinical Research and Public Health Endocrinology Nephrology

Unveiling mechanisms underlying kidney function changes during sex hormone therapy

Abstract

BACKGROUND Men 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.METHODS This 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.RESULTS During 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).CONCLUSION Sex 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 REGISTRATION Dutch Trial Register (ID: NL9517); ClinicalTrials.gov (ID: NCT04482920).

Authors

Sarah A. van Eeghen, Laura Pyle, Phoom Narongkiatikhun, Ye Ji Choi, Wassim Obeid, Chirag R. Parikh, Taryn G. Vosters, Irene G.M. van Valkengoed, Merle M. Krebber, Daan J. Touw, Martin den Heijer, Petter Bjornstad, Daniël H. van Raalte, Natalie J. Nokoff

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Figure 2

mGFR and intrakidney hemodynamic function before and during 3 months of feminizing and masculinizing therapy with percentage changes.

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mGFR and intrakidney hemodynamic function before and during 3 months of ...
(A) mGRF (ml/min per 1.72 m2). (B) ERPF (ml/min per 1.72 m2). (C) FF (%). (D) RBF (ml/min per 1.72 m2). (E) RVR (mmHg/L/min). (F) PGLO (mmHg). (G) RA (dyne x s x cm–5). (H) RE (dyne x s x cm–5). (I) RA/RE. Data were collected from 23 individuals receiving feminizing hormone therapy and 21 individuals receiving masculinizing hormone therapy. Data are presented as median (IQR). y axis is in linear scale. *P < 0.05. Percentage changes for PGLO, RA, and RA/RE, during feminizing hormone therapy were adjusted for Δ total protein. For percentage change, variables were log transformed, and linear mixed models were applied to the log-transformed data, clustering measurements within participants. The resulting ratios, along with 95% confidence intervals, were back transformed and presented as percentage changes for comparison between baseline and 3-month measurements.