SUMMARY
Inguinal hernia is highly prevalent, occurring in more than 1 in 4 elderly men; inguinal hernia repair is among the
most frequently performed surgeries in the US. In male mice that express the human aromatase enzyme
(Aromhum), we previously found that increased conversion of testosterone to estradiol (E2) via aromatase and
increased E2 action via high expression of estrogen receptor-¿ (ESR1) in lower abdominal muscle (LAM)
fibroblasts drive LAM fibrosis and myocyte atrophy, leading to LAM wall weakness and hernia formation. These
histologic and molecular changes are analogous to those found in inguinal hernias in elderly men. Aromatase
inhibitors and anti-estrogens can reverse this process in male Aromhum mice but have serious side effects such
as sexual dysfunction and osteoporosis in humans. We discovered that progesterone (P4) receptor (PGR), the
key mediator of E2/ESR1 action, is exclusively expressed in LAM fibroblasts that express high levels of ESR1
in Aromhum mice. The long-term objective of the proposed study is to determine the role of P4/PGR action in LAM
fibrosis and myocyte atrophy associated with a subset of inguinal hernias. Preliminary data showed that: PGR-
expressing LAM fibroblasts were highly enriched in Aromhum but absent in WT control mice; PGR expression in
Aromhum LAM fibroblasts was induced by E2 and blocked by ESR1 antagonists or ESR1 deletion; Aromhum LAM
fibroblast proliferation was induced by P4+E2 treatment, but not by P4 or E2 alone; P4+E2 induced large hernias
within one week in all WT mice, whereas it took 6 weeks of E2 treatment to detect small hernias in fewer mice;
the P4/PGR antagonists mifepristone and ulipristal acetate prevented hernia development and maintained
normal LAM anatomy in Aromhum mice. We hypothesize that enhanced P4/PGR signaling caused by E2/ESR1
action in highly P4-sensitive LAM tissues drives LAM fibroblast proliferation, fibrosis, and myocyte atrophy,
leading to hernia formation. Our hypothesis is consistent with the remarkable and parallel increases in skeletal
muscle fibrosis and atrophy, inguinal hernia incidence, and PGR expression in fibroblasts of LAM tissues in most
aging men. We propose the following aims: 1. Determine the mechanisms whereby treatment with P4/PGR
antagonists prevents or reverses LAM fibrosis, muscle atrophy, and hernia formation in Aromhum mice. We will
examine P4/PGR-mediated genomic mechanisms responsible for LAM fibroblast proliferation and extracellular
matrix formation using integrative in vivo multiomic analyses and PGR-ChIP-seq on LAM fibroblasts of Aromhum
mice treated with P4 or a P4/PGR antagonist. 2. Determine whether the genetic disruption of PGR selectively in
skeletal muscle fibroblasts affects LAM tissue fibrosis and hernia formation in Aromhum mice. We will also assess
P4/E2 levels and expression of PGR and PGR-responsive and profibrotic genes in LAM biopsies from men with
or without hernia and determine the correlation between PGR, ESR1, and fibrosis. Our study will identify new
drug targets and likely lead to the discovery of preventive and therapeutic approaches for hernia in high-risk
populations since long-term treatment of men with P4/PGR antagonists such as mifepristone is well tolerated.