HORMONAL CONTROL OF FEMALE REPRODUCTIVE TRACT

我们的目标是增加对基质上皮细胞的了解， 卵巢激素的相互作用 生殖道 我们的研究集中在两个方面的调节 基质源性生长因子、肝细胞生长因子（HGF）和 角质形成细胞生长因子（KGF），以及对特定 称为基质金属蛋白酶（MMP）的酶。 首先我们得 开发了用于检测猴HGF的核酸酶保护试验 转录，并确定子宫内膜表达长（完整） 长度）和较短（截短）形式的HGF。 其次，我们测试了 外源性KGF对幼鱼生殖道的影响， 成年恒河猴，发现KGF抑制子宫内膜 上皮细胞凋亡，并阻止螺旋动脉萎缩后， 停药。 第三，我们用免疫细胞化学方法分析了 三种关键MMP的分布，包括基质溶解素（Mat）， 明胶酶-A（Gel-A）、基质溶解素-1（Str-1）和MMP抑制剂 TIMP-1在猕猴子宫内膜中的表达。 分析显示，所有 三种MMPs和TIMP-1在P 无论E2是否存在。 凝胶-A和Str-1是 在上功能区直接上调， 分裂，而matrilysin表达在腺体下面的 破碎带 因此，Gel-A和Str-1可能更直接地与 参与基质断裂，而matrilysin可能起作用 腺体重塑 第四，我们定义了P的临界期 停药后不同时间点替换P诱导出血 人工周期结束时停药。 替换P 停药36小时之前（而不是之后）阻止了月经的坦率。 一 需要大约36小时的“关键期”停磷 对于关键因子如细胞因子和MMPs， 不可避免地导致月经崩溃的阈值。 P不能 一旦超过阈值就抑制这些因素。

Our goal is to increase understanding of the stromal-epithelial interactions that mediate actions of ovarian steroids in the reproductive tract. Our studies have focused on regulation of two stromally-derived growth factors, hepatocyte growth factor (HGF) and keratinocyte growth factor (KGF), and on regulation of specific enzymes called matrix metalloproteinases (MMPs). First, we have developed a nuclease protection assay for detection of monkey HGF transcript, and determined that the endometrium expresses a long (full length) and a shorter (truncated) form of HGF. Second, we tested the effects of exogenous KGF on the reproductive tract of juvenile and adult rhesus monkeys and found that KGF inhibited endometrial epithelial apoptosis, and blocked atrophy of the spiral arteries after P withdrawal. Third, we have immunocytochemically analyzed the distribution of three key MMPs including, matrilysin (Mat), gelatinase-A (Gel-A), stromelysin-1 (Str-1) and the MMP inhibitor TIMP-1 in the macaque endometrium. This analysis revealed that all three MMPs and TIMP-1 were strongly detectable 2 days after P withdrawal whether E2 was present or not. Gel-A and Str-1 were upregulated in the upper functionalis directly within the zone of fragmentation, while matrilysin was expressed in the glands below the fragmenting zone. Therefore, Gel-A and Str-1 may be more directly involved in stromal fragmentation, while matrilysin probably functions in glandular remodeling. Fourth, we defined the critical period for P withdrawal-induced bleeding by replacing P at various timepoints after P withdrawal at the end of the artificial cycle. Replacement of P before but not after 36 h of P withdrawal blocked frank menses. A critical period' of approximately 36 hours of P withdrawal is needed for key factors such as cytokines and MMPs to rise above a functional threshold that inevitably results in menstrual breakdown. P cannot suppress these factors once that threshold is passed.