Shift from androgen to estrogen action causes abdominal muscle fibrosis, atrophy, and inguinal hernia in a transgenic male mouse model.

Abstract

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.

• Authors: Hong Zhao, Ling Zhou, Lin Li, John Coon V, Robert T Chatterton, David C Brooks, Enze Jiang, Li Liu, Xia Xu, Zhiyong Dong, Francesco J DeMayo, Jonah J Stulberg, Warren G Tourtellotte, Serdar E Bulun
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 115 Issue 44 Pg. E10427-E10436 (10 30 2018) ISSN: 1091-6490 [Electronic] United States
• PMID: 30327348 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2018 the Author(s). Published by PNAS.

Chemical References

• Estrogen Receptor alpha
• Receptors, Androgen
• Testosterone
• Estradiol
• Aromatase

Topics

• Abdominal Muscles (pathology)
• Animals
• Aromatase (metabolism)
• Estradiol (metabolism)
• Estrogen Receptor alpha
• Fibrosis (pathology)
• Gene Expression Regulation, Enzymologic
• Hernia, Inguinal (pathology)
• Male
• Mice
• Mice, Transgenic
• Models, Animal
• Muscle, Skeletal (pathology)
• Muscular Atrophy (metabolism, pathology)
• Receptors, Androgen
• Testosterone (metabolism)