PROGESTERONE AND THE PATHOPHYSIOLOGY OF ENDOMETRIOSIS

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The disease endometriosis is defined as the growth of endometrial glandular epithelium and stroma at and extra-uterine or "ectopic" site. Ectopic implantation of endometrial tissue entering the peritoneal cavity via retrograde menstruation requires an invasive event and the biomolecules necessary for establishment of endometriosis include the matrix metalloproteinases (MMPs). The MMPs are expressed during estrogen associated growth and as component of menstrual breakdown and subsequent repair processes. The MMPs are not normally expressed during the progesterone-dominated secretory phase in vivo and are suppressed by progesterone in vitro. Our laboratory has linked MMP expression by human endometrial tissue to the establishment of experimental endometriosis. In this model, we find that suppressing that suppressing the secretion of MMPs or blocking their action with a natural inhibitor prevents formation of endometriotic-like lesions by human tissues injected into the peritoneal space of ovariectomized nude mice. The association of steroid-mediated MMP expression in the establishment of ectopic lesion in our experimental model appears to link the recognized role of estrogen to promoting the establishment of ectopic lesions in our experimental model appears to link the recognized role of estrogen to promoting the development of endometriosis in women and perhaps explains the protective effect ascribed to progesterone. Although local tissue production of transforming growth factor-beta (TGF-beta) acts in concert with progesterone via stromal epithelial communication to suppress MMPs in the normal endometrium, TGF-beta cannot sustain MMP suppression in the absence of progesterone. We have identified local retinoic acid (RA) synthesis in the endometrium and have found that RA may be necessary for formal suppression of MMP expression in concert with progesterone. In contrast, local production of interleukin-1alpha (IL-1alpha) may work in opposition to progesterone to stimulate MMP expression. Clearly, alterations in the normal production of key cytokines, documented in endometriosis tissues, may cause aberrant MMP expression. To address these issues experimentally, our specific aims are 1) to define the progesterone-mediated cytokines relative to aberrant MMP expression in endometriosis tissues, 2) to determine the role that aberrant MMP expression plays in the establishment and progression of endometriotic lesions in an experimental model, 3) to examine the interactive roles progesterone and RA in MMP suppression in normal endometrium and in endometriosis tissues, and 4) to examine the interactive role of progesterone and IL-1 alpha in MMP regulation in normal endometrium and endometriosis tissues.