Effect of tumor necrosis factor-alpha on estrogen metabolism and endometrial cells: potential physiological and pathological relevance

J Clin Endocrinol Metab. 2009 Jan;94(1):285-93. doi: 10.1210/jc.2008-1389. Epub 2008 Oct 28.

Abstract

Context: Estrogen and its metabolites play a critical role in the pathophysiology of the endometrium. The bioavailability of estrogen and estrogen metabolites in endometrial tissues depends on the expression of enzymes involved in estrogen biosynthesis and metabolism. Substantial evidence indicates that estrogen-dependent endometrial disorders are also associated with proinflammatory milieu. However, the mechanism whereby inflammation contributes to these conditions is not known.

Objective: The objective of the study was to investigate the effect of TNF-alpha on estrogen metabolism and the expression of estrogen-metabolizing genes in human endometrial glandular epithelial cells (EM1).

Design: EM1 were treated with 17beta-estradiol (E2) with or without TNF-alpha. Capillary liquid chromatography-tandem mass spectrometry analysis was used for quantitative measurement of estrogens and estrogen metabolites. Western blot analysis, reporter gene assay, and real-time RT-PCR were used to assess the expression of estrogen-metabolizing genes.

Results: TNF-alpha treatment significantly increased the level of total estrogen and estrogen metabolites and significantly increased the rate of conversion of estrone (E1) into E2. TNF-alpha also enhanced the oxidative metabolism of estrogen into catecholestrogens with concomitant inhibition of their conversion into methoxyestrogens. Gene expression analysis revealed that TNF-alpha induced the expression of genes involved in E2 biosynthesis (steroidogenic factor-1 and aromatase) and activation (17beta- hydroxysteroid dehydrogenase type 1 and cytochrome P-450, 1B1) with simultaneous repression of genes involved in estrogen inactivation (17beta-hydroxysteroid dehydrogenase type 2; catechol O-methyltransferase; and nicotinamide adenine dinucleotide phosphate-quinone oxidoreductase 1).

Conclusion: TNF-alpha increases the local estrogen biosynthesis in human endometrial glandular cells and directs estrogen metabolism into more hormonally active and carcinogenic metabolites. These effects may impact many physiological and pathological processes that occur within the endometrium.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aromatase / genetics
  • Aryl Hydrocarbon Hydroxylases
  • Catechol O-Methyltransferase / genetics
  • Cell Line
  • Cytochrome P-450 CYP1A1 / genetics
  • Cytochrome P-450 CYP1B1
  • Cytochrome P-450 Enzyme System / genetics
  • Endometrium / cytology
  • Endometrium / metabolism*
  • Estradiol / pharmacology
  • Estradiol Dehydrogenases / genetics
  • Estrogens / metabolism*
  • Female
  • Gene Expression Regulation / drug effects
  • Humans
  • NAD(P)H Dehydrogenase (Quinone) / genetics
  • Steroidogenic Factor 1 / genetics
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • Estrogens
  • NR5A1 protein, human
  • Steroidogenic Factor 1
  • Tumor Necrosis Factor-alpha
  • Estradiol
  • Cytochrome P-450 Enzyme System
  • Estradiol Dehydrogenases
  • HSD17B1 protein, human
  • HSD17B2 protein, human
  • Aromatase
  • Aryl Hydrocarbon Hydroxylases
  • CYP1B1 protein, human
  • Cytochrome P-450 CYP1A1
  • Cytochrome P-450 CYP1B1
  • NAD(P)H Dehydrogenase (Quinone)
  • NQO1 protein, human
  • Catechol O-Methyltransferase