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.
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
Figure 3
RU486 treatment prevents exogenous E2/P4-induced hernia development in WT mice.
