The estrogen-injected female mouse: new insight into the etiology of PCOS
The estrogen-injected female mouse: new insight into the etiology of PCOS
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DOI：
10.1186/1477-7827-7-47
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发表时间：
2009-05-18
影响因子：
4.4
通讯作者：
Michael, Sandra D.
中科院分区：
文献类型：
--
作者：
Chapman, John C.;Min, Soo Hong;Michael, Sandra D.
背景：围产期注射雌激素的雌性小鼠和大鼠变得无排卵并形成卵泡囊肿。目前的共识是，这种对雌激素的不良反应涉及下丘脑，是由于雌激素诱导的GnRH传递系统的改变而发生的。这是否属实还有待确定。本研究探讨了另一种可能性，其中排卵障碍和囊肿的发展发生通过雌激素诱导的破坏免疫系统，实现通过中介的thymus glands.Methods，结果和结论：一个假定的作用胸腺在雌激素诱导的排卵障碍和卵泡囊肿的形成（PCOS的一个模型）进行了检查，在雌性小鼠中，通过去除腺体前雌激素注射。尽管所有5-7日龄时注射20 μ g雌激素的完整雌性小鼠的卵巢都有滤泡囊肿，但在注射雌激素前3日龄时切除胸腺的动物中未观察到囊肿。事实上，在通过胸腺细胞替代恢复免疫功能后，大多数切除胸腺、注射雌激素的小鼠的卵巢都有黄体。因此，当雌激素不能作用于胸腺时，排卵发生，卵泡囊肿不发展。这暗示胸腺在囊肿的发生中起作用，并低估了下丘脑的作用。随后的研究证实，这种疾病可以通过淋巴细胞输注转移。转移发生在100日龄的雌激素注射和15日龄的幼稚小鼠之间，只有当受体在3日龄时切除胸腺。因此，囊肿形成的先决条件是缺乏调节性T细胞。它们在供体小鼠中的缺失被认为是雌激素诱导的胸腺血管渗透性增加的结果，导致事实上规避了调节性T细胞发育的最后阶段。人类胸腺在胎儿阶段对类固醇作用具有类似的脆弱性。我们认为，在子宫内暴露于过量的类固醇如雌激素对胸腺产生调节性T细胞的能力有长期影响。在女性后代中，这可能导致PCOS。
Background: Female mice and rats injected with estrogen perinatally become anovulatory and develop follicular cysts. The current consensus is that this adverse response to estrogen involves the hypothalamus and occurs because of an estrogen-induced alteration in the GnRH delivery system. Whether or not this is true has yet to be firmly established. The present study examined an alternate possibility in which anovulation and cyst development occurs through an estrogen-induced disruption in the immune system, achieved through the intermediation of the thymus gland.Methods, Results and Conclusion: A putative role for the thymus in estrogen-induced anovulation and follicular cyst formation (a model of PCOS) was examined in female mice by removing the gland prior to estrogen injection. Whereas all intact, female mice injected with 20 ug estrogen at 5-7 days of age had ovaries with follicular cysts, no cysts were observed in animals in which thymectomy at 3 days of age preceded estrogen injection. In fact, after restoring immune function by thymocyte replacement, the majority of thymectomized, estrogen-injected mice had ovaries with corpora lutea. Thus, when estrogen is unable to act on the thymus, ovulation occurs and follicular cysts do not develop. This implicates the thymus in the cysts' genesis and discounts the role of the hypothalamus. Subsequent research established that the disease is transferable by lymphocyte infusion. Transfer took place between 100-day-old estrogen-injected and 15-day-old naive mice only when recipients were thymectomized at 3 days of age. Thus, a prerequisite for cyst formation is the absence of regulatory T cells. Their absence in donor mice was judged to be the result of an estrogen-induced increase in the thymus' vascular permeability, causing de facto circumvention of the final stages of regulatory T cell development. The human thymus has a similar vulnerability to steroid action during the fetal stage. We propose that in utero exposure to excessive levels of steroids such as estrogen has a long-term effect on the ability of the thymus to produce regulatory T cells. In female offspring this can lead to PCOS.