PROGESTERONE AND THE PATHOPHYSIOLOGY OF ENDOMETRIOSIS

子宫内膜异位症的定义是子宫内膜的生长 子宫外或“异位”部位的腺上皮和间质。 子宫内膜组织异位植入腹膜 腔通过逆行月经需要一个侵入性的事件， 建立子宫内膜异位症所必需的生物分子包括 基质金属蛋白酶（MMP）。MMPs在雌激素分泌过程中表达 相关的生长，并作为月经崩溃和随后 修复过程。MMPs在正常情况下不表达。 在体内以孕酮为主的分泌期， 体外孕酮。我们的实验室已经将MMP表达与人类的 子宫内膜组织建立实验性子宫内膜异位症。 在这个模型中，我们发现抑制分泌 或用天然抑制剂阻断它们的作用， 人体组织注射到 卵巢切除裸鼠的腹膜间隙。联盟 激素介导的MMP在异位病灶形成中的表达 在我们的实验模型中， 雌激素促进异位病变的建立， 实验模型似乎将雌激素的公认作用与 促进妇女子宫内膜异位症的发展， 黄体酮的保护作用。虽然局部组织 转化生长因子-β（TGF-β）的产生 与孕酮通过间质上皮通讯抑制MMPs 在正常子宫内膜中，TGF-β不能维持MMP抑制， 缺乏孕酮我们已经确定了当地的维甲酸（RA） 在子宫内膜合成，并发现RA可能是必要的， 与孕酮一致的MMP表达的形式抑制。在 相反，局部产生白细胞介素-1 α（IL-1 α）可能在 对抗孕酮刺激MMP表达。很显然， 关键细胞因子的正常产生的改变，记录在 子宫内膜异位症组织，可能会导致异常MMP表达。 为了通过实验解决这些问题，我们的具体目标是：1） 定义相对于异常MMP的孕酮介导的细胞因子 表达，2）以确定在子宫内膜异位症组织中的作用， MMP的异常表达在肿瘤的发生和发展中起着重要作用。 在实验模型中的增生性病变，3）检查 孕酮和RA在正常人MMP抑制中的相互作用 子宫内膜和子宫内膜异位症组织，和4）检查 孕酮和IL-1 α在MMP调节中交互作用 正常子宫内膜和子宫内膜异位症组织。

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.