Endocrine defects in mice carrying a null mutation for the progesterone receptor gene
Endocrine defects in mice carrying a null mutation for the progesterone receptor gene
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DOI：
10.1210/en.138.10.4147
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发表时间：
1997-10-01
期刊：
影响因子：
4.8
通讯作者：
Levine, JE
中科院分区：
文献类型：
--
作者：
Chappell, PE;Lydon, JP;Levine, JE
携带孕酮受体基因无效突变的小鼠表现出几种生殖异常，包括无排卵、减弱的脊柱前凸行为、子宫增生和乳腺发育缺乏。然而，这些异常的激素相关性是未知的，并且是这些研究的重点。从雌性野生型（WT）和孕酮受体敲除（PRKO）小鼠中获得血清样品，并通过RIA分析LH、FSH、PRL、雌激素（E-2）和孕酮。下丘脑组织也被处理用于通过RIA测量LHRH。发现PRKO小鼠的血清LH水平比WT小鼠的基础（动情后期）值升高约2倍。相比之下，PRKO和WT小鼠的基础FSH水平没有差异。血清中E-2和孕酮的基础水平在两组中也相似，下丘脑LHRH浓度也相似。PRKO小鼠的基础PRL水平略高于WT小鼠。两组小鼠的卵巢切除术均伴随LH和FSH的显著增加。在卵巢切除术后5天，两组中LH水平均升高，超过PRKO基础水平2倍，超过WT基础水平4倍;然而，到卵巢切除术后10天，PRKO小鼠中LH水平继续升高，其程度大于WT动物。PRKO小鼠在第5天时对卵巢切除术的FSH反应更大，但在第10天时与WT没有差异。在7只暴露于雄性气味的PRKO小鼠中，3天后，在推定的发情前期当天，没有一只表现出排卵前激增;这与WT雌性小鼠形成鲜明对比，WT雌性小鼠100%表现出强烈的LH激增。这些结果证实了孕激素受体在调节下丘脑和/或垂体促性腺激素分泌过程中的重要作用。PRKO小鼠基础LH水平升高的发现证实了循环孕酮通常传递促性腺激素的总卵巢负反馈控制的显著部分。PRKO小鼠对卵巢切除术的促性腺激素反应略有增强，这表明肾上腺孕酮可能有助于负反馈控制的实施。PRKO小鼠对雄性气味明显无反应表明，这些小鼠的无排卵可能不仅仅是由于卵巢本身的生殖异常，相反，PRKO小鼠还具有神经内分泌缺陷，使其无法安装正常的排卵前促性腺激素激增。PRKO小鼠脑和垂体中PR的缺失如何产生这种激素非周期性，以及WT小鼠脑和垂体中PR的存在如何在促性腺激素激增的产生中是强制性的，仍有待确定。
Mice carrying a null mutation of the progesterone receptor gene exhibit several reproductive abnormalities, including anovulation, attenuated lordotic behavior, uterine hyperplasia, and lack of mammary gland development. The hormonal correlates of these abnormalities are unknown, however, and were the focus of these studies. Serum samples from female wild-type (WT) and progesterone receptor knockout (PRKO) mice were obtained and analyzed by RIA for LH, FSH, PRL, estrogen (E-2), and progesterone. Hypothalamic tissues were also processed for measurement of LHRH by RIA. Serum LH levels in PRKO mice were found to be elevated by approximately 2-fold over basal (metestrus) values in WT mice. By contrast, basal FSH levels were not different in PRKO and WT mice. Basal levels of E-2 and progesterone in serum were likewise similar in the two groups, as were hypothalamic LHRH concentrations. Basal PRL levels were slightly higher in PRKO vs. WT mice. Ovariectomy of both groups of mice was accompanied by significant increases in both LH and FSH. At 5 days following ovariectomy, LH levels were elevated in both groups by 2-fold over PRKO basal and 4-fold over WT basal levels; however, by 10 days postovariectomy LH levels had continued to rise to a greater extent in PRKO mice than in WT animals. The FSH response to ovariectomy was greater for the PRKO mice at 5 days, but was no different from WT at 10 days. Of seven PRKO mice that were exposed to male odor, none exhibited preovulatory surges 3 days later, on the day of presumptive proestrus; this was in marked contrast with WT females, in which 100% exhibited robust LH surges. These results confirm the essential role of progesterone receptors in the regulation of hypothalamic and/or pituitary processes that govern gonadotropin secretion. The finding that basal LH levels are elevated in PRKO mice confirms that circulating progesterone normally conveys a significant portion of the total ovarian negative feedback control of the gonadotropin. That gonadotropin responses to ovariectomy are slightly enhanced in PRKO mice suggests that adrenal progesterone may contribute to the imposition of negative feedback control. The apparent inability of PRKO mice to respond to male odor suggests that anovulation in these mice may not be solely due to reproductive abnormalities within the ovary itself, rather, PRKO mice additionally harbor neuroendocrine defects that render them incapable of mounting normal preovulatory gonadotropin surges. It remains to be determined how the absence of PR in brain and pituitary of PRKO mice may produce this hormonal acyclicity and, conversely, how the presence of PR in brain and pituitary of WT mice may be obligatory in the generation of gonadotropin surges.