Treatment of Severe Postmenopausal Endometriosis With an Aromatase Inhibitor 4  Kazuto Takayama, Khaled Zeitoun, Robert T Gunby, Hironobu Sasano, Bruce R Carr, Serdar E Bulun  Fertility and Sterility  Volume 69, Issue 4, Pages 709-713 (April 1998) DOI: 10.1016/S0015-0282(98)00022-3

Fig. 1 Aromatase P450 mRNA levels determined by quantitative RT-PCR. A coding region of human aromatase P450 mRNA flanking three coding exons was amplified by RT-PCR in 2 μg of total RNA from five samples. Three picograms of homologous rat cRNA was coamplified in each reaction to control and correct for amplification efficiency. After hybridization of amplification products with human- and rat-specific radiolabeled probes and quantification of radioactivity in each band, aromatase P450 level was expressed as a ratio of the human amplification products to the rat value. Each reaction was run in duplicate, and the arbitrary mRNA level reflects the average of replicates. Lane 1: Vaginal endometriotic implant before treatment. Lane 2: Rebiopsy after 6 months of aromatase inhibitor treatment. Lane 3: Pelvic endometriotic implant from a woman of reproductive age (positive control). Lane 4: Endometriosis-derived stromal cells treated with prostaglandin E2 (positive control). Lane 5: Eutopic endometrium from a disease-free woman (negative control). Fertility and Sterility 1998 69, 709-713DOI: (10.1016/S0015-0282(98)00022-3)

Fig. 2 The molecular basis for the treatment of endometriosis using an aromatase inhibitor. (A), The origin of estradiol-17β in this postmenopausal woman. Her ovaries were removed surgically earlier. Therefore, the body sites of estrogen biosynthesis for this patient with endometriosis are peripheral tissues (adipose and skin) and the endometriotic implant itself. The most important precursor, androstenedione of adrenal origin, becomes converted to estrone that is in turn reduced to estradiol-17β in the peripheral tissues and endometriotic implants. We showed significant levels of 17β-hydroxysteroid dehydrogenase type 1 expression in endometriosis, which catalyzes the conversion of estrone to estradiol-17β [15]. Estradiol-17β directly induces prostaglandin synthase-2, which gives rise to elevated concentrations of prostaglandin E2 in patients with endometriosis [13]. Increased levels of cytokines (e.g., IL-1β and TNF-α) in the endometriotic tissue also stimulate prostaglandin synthase-2 activity. Prostaglandin E2, in turn, is the most potent known stimulator of aromatase in endometriotic stromal cells [9]. Therefore, a positive feedback loop in favor of continuous estrogen formation is established in endometriosis. (B), After administration of a nonsteroidal competitive aromatase inhibitor such as anastrozole, aromatase activity is significantly reduced in the peripheral tissues and in endometriotic implants, giving rise to markedly diminished estradiol-17β availability to endometriosis from both sources. Moreover, the positive feedback loop involving prostaglandin E2 stimulation of local aromatase expression also is interrupted. The end result is significantly lower concentrations of estradiol-17β in endometriotic tissues. Fertility and Sterility 1998 69, 709-713DOI: (10.1016/S0015-0282(98)00022-3)