Inhibition of Estrogen Signaling Reverses Established Inguinal Hernias

Background: An inguinal hernia occurs when an intestinal loop or fat pushes through a weak spot in the lower abdominal muscle (LAM), causing a painful bulge that has the potential to cause bowel obstruction. Despite a high prevalence in men (~25%), non-surgical approaches are not available to treat this disease. We recently found a critical role of estrogen and estrogen receptor alpha (ERα) in inguinal hernia formation. To examine this further, we use a humanized aromatase mouse model (Arom(hum)) where all of the male mice develop scrotal hernias as a pre-clinical model to test the first pharmacological intervention for inguinal hernias. These mice are utilized because their skeletal muscle tissue contains aromatase and produces estradiol (E2), which acts via ERα in the LAM stromal fibroblasts and leads to fibrosis and muscle atrophy. Hypothesis: E2-ERα modulation can inhibit and reverse the formation of inguinal hernias in Arom(hum) mice by reducing LAM fibrosis and atrophy. Results: We tested three types of treatments to inhibit E2-ERα signaling: letrozole, fulvestrant, and raloxifene. Letrozole, an aromatase inhibitor, was shown to inhibit hernia formation and reversed small (150-175 mm(2)) scrotal hernias (n = 10-15/group, p<0.0001). The LAM tissues also showed a reduction in fibrosis (n = 5-8/group, p = 0.0004) and a concurrent increase in myofiber cross-sectional area (n = 5-8, p=0.0356) compared to placebo-treated mice. Similarly, fulvestrant and raloxifene, E2-ERα antagonists, also inhibited hernia formation (n = 10-15/group). Most interestingly, both drugs reversed large and severe hernias (>200 mm(2), n = 10-15/group), accompanied by a decrease in muscle fibrosis and increase in myofiber cross-sectional area (ongoing study, n = 10-11, p<0.0001) compared to placebo mice. The drug-treated mice had lower expression of pro-fibrotic genes such as Mmp3, Emb, Spon2, Timp1, and Tgfb1 in the LAM tissues compared to placebo-treated LAM. Furthermore, we analyzed the differences in extracellular matrix producing genes and muscle regeneration markers between the placebo and drug-treated muscle tissues. Conclusion: We find that inhibition of the E2-ERα signaling pathway can reverse mild or severe inguinal hernias. Successful treatment is accompanied by decreased skeletal muscle fibrosis and reversal of myocyte atrophy. These interventions are promising non-surgical treatment options for patients suffering from severe and recurrent inguinal hernias.