Catecholestradiol Activation of Adrenergic Receptors Induces Endometrial Cell Survival via p38 MAPK Signaling

J Clin Endocrinol Metab. 2021 Jan 23;106(2):337-350. doi: 10.1210/clinem/dgaa866.

Abstract

Context: Enhanced levels of catecholestradiols, 2-hydroxyestradiol (2-OHE2) or 4-hydroxyestradiol (4-OHE2), are reported in endometriosis. During gestation, catecholestradiol activation of adrenergic receptors (AR) elevates estrogen receptor (ER)-independent proliferation of uterine arterial endothelial cells.

Objective: To investigate β-AR-mediated catecholestradiol effects on human endometrial stromal cell (HESC) and epithelial cell survival in endometriosis.

Design: β-AR immunostaining of eutopic and ectopic endometria (n = 9). Assays for cell viability, 5-bromo-2'-deoxyuridine proliferation, apoptosis, quantitative PCR, and estrogenicity (alkaline phosphatase activity), as well as siRNA β-AR silencing and immunoblot analyses of cultured HESCs or Ishikawa cells treated with control or 2-OHE2 or 4-OHE2 ±β-AR antagonist or ±p38 MAPK inhibitor.

Setting: University research institution.

Patients: Women with or without endometriosis.

Interventions: None.

Main outcome measures: β-AR expression in eutopic vs ectopic endometria and regulation of HESC survival by 2-OHE2 and 4-OHE2.

Results: Eutopic and ectopic endometrial stromal and epithelial cells displayed β2-AR immunoreactivity with increased staining in the functionalis vs basalis layer (P < 0.05). Both 2-OHE2 and 4-OHE2 enhanced HESC and Ishikawa cell survival (P < 0.05), an effect abrogated by β-AR antagonist propranolol, but not ER antagonist ICI182,780. 2-OHE2 or 4-OHE2 failed to induce cell survival and estrogenic activity in ADRB2-silenced HESCs and in Ishikawa cells, respectively. Although 2-OHE2 inhibited apoptosis and BAX mRNA expression, 4-OHE2 induced proliferation and decreased apoptosis (P < 0.05). Both catecholestradiols elevated phospho-p38 MAPK levels (P < 0.05), which was blocked by propranolol, and p38 MAPK inhibitor reversed catecholestradiol-enhanced HESC survival.

Conclusions: Catecholestradiols increase endometrial cell survival by an ER-independent β-AR-mediated p38 MAPK activation, suggesting that agents blocking β-AR (e.g., propranolol) or inhibiting 2-OHE2- or 4-OHE2-generating enzymes (i.e., CYP1A1/B1) could treat endometriosis.

Keywords: adrenergic receptor; catecholestradiol; endometrial cell survival; endometriosis; p38 MAPK.

MeSH terms

  • Adult
  • Case-Control Studies
  • Cell Proliferation
  • Cell Survival
  • Endometriosis / drug therapy*
  • Endometriosis / metabolism
  • Endometriosis / pathology
  • Endometrium / drug effects*
  • Endometrium / metabolism
  • Estrogens, Catechol / pharmacology*
  • Female
  • Follow-Up Studies
  • Humans
  • Middle Aged
  • Prognosis
  • Receptors, Adrenergic / metabolism*
  • Signal Transduction
  • Stromal Cells / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • Estrogens, Catechol
  • Receptors, Adrenergic
  • p38 Mitogen-Activated Protein Kinases