Aromatase, microRNA, and inflammation: a complex relationship

Endometriosis is an ancient, enigmatic disease that has perplexed physicians and researchers for centuries.1 Pelvic endometriosis is thought to arise primarily from retrograde menstruation of epigenetically defective endometrial tissue along with blood at the time of menses.2 Since pelvic endometriotic implants are primarily comprised of endometrial stromal cells, retrograde menstruation of intrauterine endometrial stromal cells seem to play a major role in the establishment of this peritoneal disease. A salient feature of endometriosis is its extraordinarily high sensitivity to estrogen, which increases the survival, inflammation and remodeling capacity of pelvic endometriotic implants.2 Interestingly, pelvic endometriotic tissue responds to the biologically active estrogen, estradiol, in an exquisitely sensitive fashion possibly primarily through estrogen receptor-β (ERβ) via activation of specific kinases and stimulation of inflammatory pathways in endometriotic stromal cells.3 Aromatase, which catalyzes the key enzymatic step, is indispensable for estradiol biosynthesis. Aromatase is present in ovarian follicles, peripheral adipose and skin tissue, and also in estrogen dependent disease tissue such as endometriotic stromal cells.2 In fact, the endometriotic stromal cell is capable of making estradiol de novo without the requirement for exogenous steroid precursors.4 A number of signaling mechanisms, including those dependent on prostaglandin E2, stimulate aromatase expression, thus estrogen production in endometriotic stromal cells.2,4 The clinical relevance of aromatase in endometriotic tissue and peripheral tissues was demonstrated by the therapeutic effects of aromatase inhibitors in post-menopausal endometriosis and also by the beneficial effects of an aromatase inhibitor when added to a GnRH agonist.2 The original article authored by Cho and co-workers in today’s issue of Fertility and Sterility, uncovers a novel mechanism whereby the microRNA let-7f inhibits aromatase, and the aromatase inhibitor letrozole stimulates the levels of let-7f and some of the other members of this microRNA family in endometriotic stromal cells.5 Moreover, let-7f exhibits an in vitro therapeutic effect on endometriotic stromal cells. These data collectively led us to speculate locally produced estrogen may suppress beneficial microRNA species and thus aggravate the pathologic features of endometriosis, whereas aromatase inhibitors via an intracrine effect stimulate the expression of members of the let-7f family to suppress and treat endometriosis (Figure 1). This article opens the way for developing new nanomedical approaches to the treatment of endometriosis. Let-7 microRNA species may be administered via various delivery systems to treat endometriosis. Importantly, let-7f may be used as a tissue specific aromatase inhibitor to treat endometriosis without having to deny beneficial estrogen action in other tissues such as bone and the brain, which is the basis for the side effects of the currently available non-tissue selective aromatase inhibitors such as letrozole. The authors should be congratulated for introducing these new potential therapeutic avenues.5 Acknowledgments Support: This work was supported by the R37-HD36691 grant awarded by the Eunice Kennedy Shriver National Institute of Child Health & Human Development. Footnotes Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. References - 1.Nezhat C, Nezhat F, Nezhat CH. Endometriosis: Ancient Disease, Ancient Treatment. Fertil Steril. 2012;98(6):S1–62. doi: 10.1016/j.fertnstert.2012.08.001. [DOI] [PubMed] [Google Scholar] - 2.Bulun SE. Endometriosis. 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