PROGESTERONE AND THE PATHOPHYSIOLOGY OF ENDOMETRIOSIS

子宫内膜异位症的定义是子宫内膜的生长 腺上皮和间质位于子宫外或“异位”部位。 异位种植子宫内膜组织进入腹膜 经逆行月经的空洞需要侵入性事件， 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(MMPs)。基质金属蛋白酶在雌激素过程中表达。 月经不调和随后的相关生长和AS成分 维修流程。MMP通常不会在 体内孕酮主导的分泌期，并被抑制 黄体酮在体外。我们的实验室已经将基质金属蛋白酶的表达与人类 以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其作用可防止 体内注射人组织形成异位内膜样病变 去卵巢裸鼠的腹膜间隙。联谊会 激素介导的基质金属蛋白酶在异位病变中的表达 在我们的实验模型中似乎将公认的角色 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 促进女性子宫内膜异位症的发生和可能解释 这种保护作用归因于黄体酮。虽然局部组织 转化生长因子-β的产生协同作用 黄体酮通过间质上皮细胞通讯抑制MMPs 在正常子宫内膜，转化生长因子-β不能维持基质金属蛋白酶的抑制。 黄体酮的缺失。我们已经确定了局部维甲酸(RA) 在子宫内膜中的合成，并发现RA可能是 联合黄体酮正式抑制基质金属蛋白酶的表达。在……里面 相比之下，局部产生的白介素1α(IL-1α)可能在 反对孕酮刺激基质金属蛋白酶的表达。显然， 关键细胞因子正常产生的改变，记录在 子宫内膜异位症组织中，可引起基质金属蛋白酶的异常表达。 为了试验性地解决这些问题，我们的具体目标是 明确孕酮介导的细胞因子与异常基质金属蛋白酶的关系 在子宫内膜异位症组织中的表达，2)确定其作用 基质金属蛋白酶的异常表达在肿瘤的发生和发展中的作用 实验模型中的子宫内膜异位病变，3)检查 黄体酮和视黄酸在正常人体基质金属蛋白酶抑制中的相互作用 子宫内膜和子宫内膜异位症组织中，以及4)检查 孕酮和IL-1α在基质金属蛋白酶调节中的相互作用 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.