Department of Obstetrics and Gynecology, Division of Reproductive Science in Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Department of Pathology, Division of Neuropathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Proc Natl Acad Sci U S A. 2018 Oct 30;115(44):E10427-E10436. doi: 10.1073/pnas.1807765115. Epub 2018 Oct 16.
Inguinal hernia develops primarily in elderly men, and more than one in four men will undergo inguinal hernia repair during their lifetime. However, the underlying mechanisms behind hernia formation remain unknown. It is known that testosterone and estradiol can regulate skeletal muscle mass. We herein demonstrate that the conversion of testosterone to estradiol by the aromatase enzyme in lower abdominal muscle (LAM) tissue causes intense fibrosis, leading to muscle atrophy and inguinal hernia; an aromatase inhibitor entirely prevents this phenotype. LAM tissue is uniquely sensitive to estradiol because it expresses very high levels of estrogen receptor-α. Estradiol acts via estrogen receptor-α in LAM fibroblasts to activate pathways for proliferation and fibrosis that replaces atrophied myocytes, resulting in hernia formation. This is accompanied by decreased serum testosterone and decreased expression of the androgen receptor target genes in LAM tissue. These findings provide a mechanism for LAM tissue fibrosis and atrophy and suggest potential roles of future nonsurgical and preventive approaches in a subset of elderly men with a predisposition for hernia development.
腹股沟疝主要发生在老年男性中，超过四分之一的男性在其一生中将需要接受腹股沟疝修补术。然而，疝形成的潜在机制仍然未知。已知睾丸酮和雌二醇可以调节骨骼肌质量。我们在此证明，芳香化酶在腹部下肌肉（LAM）组织中将睾丸酮转化为雌二醇会导致强烈的纤维化，从而导致肌肉萎缩和腹股沟疝；芳香酶抑制剂完全阻止了这种表型。LAM 组织对雌二醇非常敏感，因为它表达非常高水平的雌激素受体-α。雌二醇通过 LAM 成纤维细胞中的雌激素受体-α 发挥作用，激活增殖和纤维化途径，取代萎缩的肌细胞，导致疝形成。这伴随着血清睾丸酮水平降低和 LAM 组织中雄激素受体靶基因表达降低。这些发现为 LAM 组织纤维化和萎缩提供了一种机制，并提示未来对有疝发展倾向的老年男性亚组采取非手术和预防性方法的潜在作用。
