Androstenedione up-regulation of endometrial aromatase expression via local conversion to estrogen: Potential relevance to the pathogenesis of endometriosis

Orhan Bukulmez, Daniel B. Hardy, Bruce R. Carr, Richard J. Auchus, Tannaz Toloubeydokhti, R. Ann Word, Carole R. Mendelson

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Abstract

Context: Up-regulation of aromatase expression in endometrial cells disseminated into the peritoneal cavity may enhance their survival via local estrogen synthesis, which may lead to endometriosis. The factors that mediate induction of aromatase in the endometrium are not well defined, but increased expression of steroidogenic factor (SF)-1 may play a role. Objective: The objective of the study was to determine whether androstenedione (A4), the predominant sex steroid in peritoneal fluid, regulates endometrial aromatase expression. Design: This was a cell/tissue culture study. Setting: The study was conducted at an academic center. Methods: Quantitative real-time PCR, HPLC, and chromatin immunoprecipitation were used in this study. Results: Treatment of cultured human endometrial explants and stromal cells with A4 (10 nM) significantly up-regulated expression of aromatase mRNA transcripts containing exon IIa at their 5′-ends. In endometrial stromal cells and the human endometrial surface epithelial (HES) cell line, induction of aromatase mRNA by A4 was associated with increased expression of SF-1. In HES cells, tritiated A4 was metabolized to estradiol, testosterone (T), dihydrotestosterone, and androstanediol. Both estradiol and T, but not nonaromatizable androgens, up-regulated aromatase and SF-1 mRNA in HES cells. Chromatin immunoprecipitation revealed that A4 enhanced recruitment of SF-1 to its response element (-136 bp) upstream of CYP19 exon IIa. This, together with the findings that both estrogen receptor antagonist, ICI 182,780, and aromatase inhibitor, fadrozole, suppressed A4 and T induction of aromatase and SF-1 mRNA, indicates that the inductive effects of A4 and T are mediated by their conversion to estrogens. Conclusions: Exposure of endometrial cells to A4 may enhance CYP19 gene expression through its aromatization to estrogens.

Original languageEnglish (US)
Pages (from-to)3471-3477
Number of pages7
JournalJournal of Clinical Endocrinology and Metabolism
Volume93
Issue number9
DOIs
StatePublished - Sep 2008

Fingerprint

Aromatase
Androstenedione
Endometriosis
Steroidogenic Factor 1
Estrogens
Up-Regulation
Messenger RNA
Chromatin Immunoprecipitation
Epithelial Cells
Stromal Cells
Chromatin
Estradiol
Exons
Fadrozole
Aromatization
Tissue culture
Aromatase Inhibitors
Dihydrotestosterone
Ascitic Fluid
Peritoneal Cavity

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

Cite this

@article{6e14957ff8a043ffac514b22d03076bc,
title = "Androstenedione up-regulation of endometrial aromatase expression via local conversion to estrogen: Potential relevance to the pathogenesis of endometriosis",
abstract = "Context: Up-regulation of aromatase expression in endometrial cells disseminated into the peritoneal cavity may enhance their survival via local estrogen synthesis, which may lead to endometriosis. The factors that mediate induction of aromatase in the endometrium are not well defined, but increased expression of steroidogenic factor (SF)-1 may play a role. Objective: The objective of the study was to determine whether androstenedione (A4), the predominant sex steroid in peritoneal fluid, regulates endometrial aromatase expression. Design: This was a cell/tissue culture study. Setting: The study was conducted at an academic center. Methods: Quantitative real-time PCR, HPLC, and chromatin immunoprecipitation were used in this study. Results: Treatment of cultured human endometrial explants and stromal cells with A4 (10 nM) significantly up-regulated expression of aromatase mRNA transcripts containing exon IIa at their 5′-ends. In endometrial stromal cells and the human endometrial surface epithelial (HES) cell line, induction of aromatase mRNA by A4 was associated with increased expression of SF-1. In HES cells, tritiated A4 was metabolized to estradiol, testosterone (T), dihydrotestosterone, and androstanediol. Both estradiol and T, but not nonaromatizable androgens, up-regulated aromatase and SF-1 mRNA in HES cells. Chromatin immunoprecipitation revealed that A4 enhanced recruitment of SF-1 to its response element (-136 bp) upstream of CYP19 exon IIa. This, together with the findings that both estrogen receptor antagonist, ICI 182,780, and aromatase inhibitor, fadrozole, suppressed A4 and T induction of aromatase and SF-1 mRNA, indicates that the inductive effects of A4 and T are mediated by their conversion to estrogens. Conclusions: Exposure of endometrial cells to A4 may enhance CYP19 gene expression through its aromatization to estrogens.",
author = "Orhan Bukulmez and Hardy, {Daniel B.} and Carr, {Bruce R.} and Auchus, {Richard J.} and Tannaz Toloubeydokhti and Word, {R. Ann} and Mendelson, {Carole R.}",
year = "2008",
month = "9",
doi = "10.1210/jc.2008-0248",
language = "English (US)",
volume = "93",
pages = "3471--3477",
journal = "Journal of Clinical Endocrinology and Metabolism",
issn = "0021-972X",
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number = "9",

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TY - JOUR

T1 - Androstenedione up-regulation of endometrial aromatase expression via local conversion to estrogen

T2 - Potential relevance to the pathogenesis of endometriosis

AU - Bukulmez, Orhan

AU - Hardy, Daniel B.

AU - Carr, Bruce R.

AU - Auchus, Richard J.

AU - Toloubeydokhti, Tannaz

AU - Word, R. Ann

AU - Mendelson, Carole R.

PY - 2008/9

Y1 - 2008/9

N2 - Context: Up-regulation of aromatase expression in endometrial cells disseminated into the peritoneal cavity may enhance their survival via local estrogen synthesis, which may lead to endometriosis. The factors that mediate induction of aromatase in the endometrium are not well defined, but increased expression of steroidogenic factor (SF)-1 may play a role. Objective: The objective of the study was to determine whether androstenedione (A4), the predominant sex steroid in peritoneal fluid, regulates endometrial aromatase expression. Design: This was a cell/tissue culture study. Setting: The study was conducted at an academic center. Methods: Quantitative real-time PCR, HPLC, and chromatin immunoprecipitation were used in this study. Results: Treatment of cultured human endometrial explants and stromal cells with A4 (10 nM) significantly up-regulated expression of aromatase mRNA transcripts containing exon IIa at their 5′-ends. In endometrial stromal cells and the human endometrial surface epithelial (HES) cell line, induction of aromatase mRNA by A4 was associated with increased expression of SF-1. In HES cells, tritiated A4 was metabolized to estradiol, testosterone (T), dihydrotestosterone, and androstanediol. Both estradiol and T, but not nonaromatizable androgens, up-regulated aromatase and SF-1 mRNA in HES cells. Chromatin immunoprecipitation revealed that A4 enhanced recruitment of SF-1 to its response element (-136 bp) upstream of CYP19 exon IIa. This, together with the findings that both estrogen receptor antagonist, ICI 182,780, and aromatase inhibitor, fadrozole, suppressed A4 and T induction of aromatase and SF-1 mRNA, indicates that the inductive effects of A4 and T are mediated by their conversion to estrogens. Conclusions: Exposure of endometrial cells to A4 may enhance CYP19 gene expression through its aromatization to estrogens.

AB - Context: Up-regulation of aromatase expression in endometrial cells disseminated into the peritoneal cavity may enhance their survival via local estrogen synthesis, which may lead to endometriosis. The factors that mediate induction of aromatase in the endometrium are not well defined, but increased expression of steroidogenic factor (SF)-1 may play a role. Objective: The objective of the study was to determine whether androstenedione (A4), the predominant sex steroid in peritoneal fluid, regulates endometrial aromatase expression. Design: This was a cell/tissue culture study. Setting: The study was conducted at an academic center. Methods: Quantitative real-time PCR, HPLC, and chromatin immunoprecipitation were used in this study. Results: Treatment of cultured human endometrial explants and stromal cells with A4 (10 nM) significantly up-regulated expression of aromatase mRNA transcripts containing exon IIa at their 5′-ends. In endometrial stromal cells and the human endometrial surface epithelial (HES) cell line, induction of aromatase mRNA by A4 was associated with increased expression of SF-1. In HES cells, tritiated A4 was metabolized to estradiol, testosterone (T), dihydrotestosterone, and androstanediol. Both estradiol and T, but not nonaromatizable androgens, up-regulated aromatase and SF-1 mRNA in HES cells. Chromatin immunoprecipitation revealed that A4 enhanced recruitment of SF-1 to its response element (-136 bp) upstream of CYP19 exon IIa. This, together with the findings that both estrogen receptor antagonist, ICI 182,780, and aromatase inhibitor, fadrozole, suppressed A4 and T induction of aromatase and SF-1 mRNA, indicates that the inductive effects of A4 and T are mediated by their conversion to estrogens. Conclusions: Exposure of endometrial cells to A4 may enhance CYP19 gene expression through its aromatization to estrogens.

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U2 - 10.1210/jc.2008-0248

DO - 10.1210/jc.2008-0248

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