Abstract
Disclosure: T. You: None. H. Zhao: None. T. Potluri: None. P. Yin: None. J. Coon: None. R.L. Lieber: None. J.J. Stulberg: None. S.E. Bulun: None.
Introduction: Inguinal hernias are incredibly common, affecting up to 27% of men in their lifetime. Despite this high prevalence, non-surgical approaches are not available to treat this disease, as the molecular mechanisms underlying hernia formation are poorly understood. Using a transgenic mouse model expressing the human aromatase gene (Aromhum), we previously showed that high levels of estradiol (E2) production in lower abdominal muscle (LAM) would activate LAM fibroblasts via estrogen receptor alpha (ERα) signaling, leading to extensive LAM fibrosis and hernia formation. These ERα-positive fibroblasts in Aromhum LAM also expressed high levels of progesterone receptor (PGR) while wild-type (WT) LAM fibroblasts did not. PGR is a well-established E2/ERα-responsive gene in the female uterus and breast. However, the role of progesterone (P4)/PGR signaling in hernia formation in men is unknown. Methods: Two unique hernia mouse models (E2/P4-induced and Aromhum), primary LAM fibroblasts from Aromhum mice, and LAM and serum samples from human hernia patients were used for this study. Mice were treated with E2, P4, and/or RU486 (P4/PGR antagonist) for 12 weeks while tracking hernia development. Serum and LAM P4 levels were measured by LS-MS2. After treatment, LAM was harvested for histological analysis. Results: In cultured Aromhum LAM fibroblasts, PGR expression was induced by E2 and blocked by fulvestrant (ERα-antagonist). LAM fibroblasts exhibited increased proliferation and expression of fibrosis-related genes upon treatment with E2+R5020 (P4 analog), but not E2 or R5020 alone. These effects were blocked by concurrent RU486 administration. In WT male mice, E2 treatment induced the development of small hernias (125-175mm2) after 10-12 weeks, while P4 treatment did not. Intriguingly, all mice treated with E2+P4 concurrently developed significantly larger hernias (>225mm2) within just 2-4 weeks. The large hernias in E2+P4 treated mice were completely prevented with concurrent RU486 treatment. In Aromhum male mice, 12-week RU486 treatment starting at 4 weeks of age strikingly reduced hernia size or even prevented hernia development entirely. In both models, LAM fibrosis was significantly reduced with RU486 treatment. We confirmed the presence of P4 in the LAM of Aromhum mice and the serum of 212 male hernia patients. Consistent with our mouse findings, human fibroblasts from fibrotic LAM of hernia patients exhibited strikingly higher proliferation and PGR expression compared to fibroblasts from adjacent healthy muscle. Conclusion: Our results suggest that P4/PGR signaling induced by E2/ERα in highly P4-sensitive LAM tissues is critical for LAM fibrosis and hernia development. Our findings are one of the first to show the importance of PGR signaling in men and provide evidence that PGR antagonists may be useful as a therapeutic alternative to hernia repair surgery.
Presentation: 6/2/2024