# Role of progesterone action in inguinal hernia formation via skeletal muscle fibrosis and atrophy

## TL;DR

This study shows that progesterone signaling in muscle cells contributes to hernia formation in men and suggests progesterone blockers could be a non-surgical treatment.

## Contribution

The novel finding is that progesterone receptor signaling in fibroblasts mediates estrogen-driven hernia formation in males.

## Key findings

- Blocking progesterone receptors reduces fibrosis and prevents hernia formation in mice.
- Progesterone enhances estrogen's effect on muscle fibrosis and hernia development in mice.
- Pgr-expressing fibroblasts promote fibrosis via TGF-β2 signaling in herniated muscle.

## 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.

Utilizing mouse models and muscle samples from hernia patients, we show the potential for progesterone antagonists as a pharmacologic treatment for inguinal hernias.