Role of Progesterone Action in Inguinal Hernia Formation via Skeletal Muscle Fibrosis and Atrophy

Authors

• Tianming You
• Mehrdad Zandigohar
• Tanvi Potluri
• Natalie Piehl
• John S Coon V
• Elizabeth Baker
• Maya Kafali
• Yang Dai
• Jonah J Stulberg
• David J Escobar
• Richard L Lieber
• Hong Zhao
• Serdar E Bulun

Language

English

Publication Date

7-22-2025

Journal

JCI Insight

DOI

10.1172/jci.insight.193208

PMID

40504614

PMCID

PMC12288974

PubMedCentral® Posted Date

6-12-2025

PubMedCentral® Full Text Version

Post-print

Abstract

More than 1 in 4 men will undergo surgery for inguinal hernia, which is commonly associated with fibrotic degeneration of the lower abdominal muscle (LAM) in the groin region. Utilizing a male mouse model expressing the human aromatase gene (Aromhum), previous studies showed that locally produced estradiol acting via estrogen receptor α in LAM fibroblasts leads to fibrosis, myofiber atrophy, and hernia development. Here, we found that upregulation of progesterone receptor (PGR) in a LAM fibroblast population mediates this estrogenic effect. A PGR-selective progesterone antagonist in Aromhum mice decreased LAM fibrosis and atrophy, preventing hernia formation and stopping progression of existing hernias. Addition of progesterone to estradiol treatment was essential for early-onset development of LAM fibrosis and large hernias in wild-type mice, which was averted by a progesterone antagonist. Single-nuclei multiomics sequencing of herniated LAM revealed a unique population of Pgr-expressing fibroblasts that promotes fibrosis and myofiber atrophy through TGF-β2 signaling. Multiomics findings were validated in vivo in herniated LAM tissues of both mice and adult men. Our findings suggest an important and rare pathologic role of progesterone signaling in males and provide evidence for progesterone antagonists as a nonsurgical alternative for inguinal hernia management.

Keywords

Animals, Mice, Male, Fibrosis, Hernia, Inguinal, Humans, Progesterone, Muscle, Skeletal, Fibroblasts, Disease Models, Animal, Receptors, Progesterone, Aromatase, Muscular Atrophy, Adult, Estradiol, Mice, Transgenic, Mice, Inbred C57BL

Published Open-Access

yes

Recommended Citation

You, Tianming; Zandigohar, Mehrdad; Potluri, Tanvi; et al., "Role of Progesterone Action in Inguinal Hernia Formation via Skeletal Muscle Fibrosis and Atrophy" (2025). Faculty, Staff and Student Publications. 4527.
https://digitalcommons.library.tmc.edu/uthmed_docs/4527