Estrogen production in endometriosis and use of aromatase inhibitors to treat endometriosis.
Estrogen is the most important known factor that stimulates the growth of endometriosis. Estrogen delivery to endometriotic implants was classically viewed to be only via the circulating blood in an endocrine fashion. We recently uncovered an autocrine positive feedback mechanism, which favored the continuous production of estrogen and prostaglandin (PG)E2 in the endometriotic stromal cells. The enzyme, aromatase, is aberrantly expressed in endometriotic stromal cells and catalyzes the conversion of C19 steroids to estrogens, which then stimulate cyclooxygenase-2 to increase the levels of PGE2. PGE2, in turn, is a potent inducer of aromatase activity in endometriotic stromal cells. Aromatase is not expressed in the eutopic endometrium. Aromatase expression in endometriosis and its inhibition in eutopic endometrium are controlled by the competitive binding of a stimulatory transcription factor, steroidogenic factor-1, and an inhibitory factor, chicken ovalbumin upstream promoter-transcription factor to a regulatory element in the aromatase P450 gene promoter. In addition, we find that endometriotic tissue is deficient in 17beta-hydroxysteroid dehydrogenase type 2, which is normally expressed in eutopic endometrial glandular cells and inactivates estradiol-17beta to estrone. This deficiency is another aberration that favors higher levels of estradiol-17beta in endometriotic tissues in comparison with the eutopic endometrium. The clinical relevance of local aromatase expression in endometriosis was exemplified by the successful treatment of an unusually aggressive form of recurrent endometriosis in a postmenopausal woman using an aromatase inhibitor.
Bulun
S E
SE
Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center at Dallas, USA.
Zeitoun
K
K
Takayama
K
K
Noble
L
L
Michael
D
D
Simpson
E
E
Johns
A
A
Putman
M
M
Sasano
H
H
D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors; D004715:Endometriosis / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D004967:Estrogens / Q000096:biosynthesis*; D005260:Female; D006801:Humans
D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D004967:Estrogens; D001141:Aromatase