Bigsby Robert M
Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis 46202-5121, USA.
Ann N Y Acad Sci. 2002 Mar;955:110-7; discussion 118, 396-406. doi: 10.1111/j.1749-6632.2002.tb02771.x.
Early work with neonatal mice showed that estrogen receptor-negative uterine epithelium responded to estrogen treatment. Since the underlying mesenchymal cells were estrogen receptor-positive, it was suggested that these cells mediated the hormonal response through elaboration of a paracrine factor. Cell culture work showed that mesenchymal cells produced soluble factors that stimulate uterine epithelium, but hormonal regulation was absent or minimal. The paracrine hypothesis of estrogen action has been proved by the use of tissue recombinant studies in which epithelium from estrogen receptor-alpha knockout mice was combined with wild-type mesenchyme; estrogen stimulated the ER alpha-negative epithelium if the underlying stromal cells were receptor-positive. Also, it is hypothesized that there is a reciprocal paracrine interaction during stimulation with progesterone and estrogen. Accordingly, under progesterone dominance, the epithelium elaborates factors that direct the underlying stroma to proliferate when estrogen is administered. Although this hypothesis needs further testing, it has been shown that the uterine epithelium is required for stromal responsiveness to hormones. The question arises: What are the factors that mediate the effects of the steroid hormones in the uterus? Several peptide growth factors are regulated by estrogen and/or progesterone. Use of knockout animals will allow a determination of the role that these factors play in the uterus. However, ablation of many of these growth factor genes has proved lethal to the newborn animals, making it impossible to study hormonal effects using standard techniques. Tissue xenograft and tissue recombination studies offer a means of defining the role of specific growth factors in uterine physiology.
早期对新生小鼠的研究表明，雌激素受体阴性的子宫上皮对雌激素治疗有反应。由于底层的间充质细胞是雌激素受体阳性的，因此有人提出这些细胞通过分泌旁分泌因子来介导激素反应。细胞培养研究表明，间充质细胞产生可刺激子宫上皮的可溶性因子，但激素调节不存在或很微弱。雌激素作用的旁分泌假说已通过组织重组研究得到证实，在该研究中，将雌激素受体α基因敲除小鼠的上皮与野生型间充质结合；如果底层基质细胞受体呈阳性，雌激素会刺激雌激素受体α阴性的上皮。此外，有人推测在孕酮和雌激素刺激过程中存在相互的旁分泌相互作用。因此，在孕酮占主导地位的情况下，当给予雌激素时，上皮会分泌因子来指导底层基质增殖。尽管这一假说需要进一步验证，但已经表明子宫上皮是基质对激素产生反应所必需的。问题来了：介导类固醇激素在子宫中作用的因素是什么？几种肽生长因子受雌激素和/或孕酮调节。使用基因敲除动物将有助于确定这些因子在子宫中所起的作用。然而，事实证明，许多这些生长因子基因的缺失对新生动物是致命的，这使得无法使用标准技术研究激素的作用。组织异种移植和组织重组研究提供了一种确定特定生长因子在子宫生理学中作用的方法。
