SAT-747 A Prospective Non-surgical Treatment for Inguinal Hernias

BACKGROUND: Inguinal hernias are a widespread public health issue and typically diagnosed in one-fourth of all men. Despite hernia repair being the most commonly performed surgery in the US, the mechanisms causing this disease are currently unknown. We previously developed a mouse model that expresses the human aromatase gene (Arom(hum)) wherein all male mice develop inguinal hernias. We further showed that high production of estradiol by aromatase in the lower abdominal muscle (LAM) via binding to estrogen receptor caused increased fibroblast proliferation and muscle atrophy which leads to inguinal hernia formation (1). Hypothesis: Disruption of estrogen signaling via ablation of estrogen production using an aromatase inhibitor or inhibition of estrogen receptor by an estradiol antagonist can prevent or reverse the formation of inguinal hernias. Results: We previously demonstrated that aromatase inhibitor, letrozole, completely prevented the formation of inguinal hernias in Arom(hum) mice (1). Here we show that ER-dependent estradiol antagonist fulvestrant can also prevent LAM tissue fibrosis, muscle atrophy and hernia formation in Arom(hum) mice (n=4, p=0.0007). WT littermates did not show hernia formation with or without fulvestrant treatment (n=4). Furthermore, we demonstrate that aromatase inhibitor letrozole can reverse mild to moderate size of hernia (150-160 mm(2)), while placebo-treated mice had progressively enlarged hernias (n=7, p=0.04). We subsequently show a reduction in muscle fibrosis and a restoration of myocyte size in Arom(hum) mice with letrozole treatment. Conclusion: Estrogen produced as a result of aromatase expression in estrogen-sensitive LAM tissue stimulates the proliferation of estrogen receptor-expressing fibroblasts, fibrosis, muscle atrophy, and hernia formation. Ablation of estrogen production or its signaling not only completely prevents this phenotype but also reverses mild to moderate-sized hernias. Our findings pave the pathway for developing the first potential preventive and therapeutic pharmacological approach for combating recurrent inguinal hernias in elderly men through modulation of estrogen signaling in abdominal muscle tissue. Reference: (1) Zhao H, et al.,PNAS. 2018 Oct 30;115(44):E10427-36.