Chappell P E, Schneider J S, Kim P, Xu M, Lydon J P, O'Malley B W, Levine J E
Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois 60208, USA.
Endocrinology. 1999 Aug;140(8):3653-8. doi: 10.1210/endo.140.8.6895.
It is well known that estrogen (E2) stimulates expression of progesterone receptors (PRs), thereby inducing responsiveness of several tissues to the actions of progesterone (P). Recent studies have also suggested, however, that biological actions previously ascribed to E2 alone may also be mediated by activation of E2-induced PRs, even independently of signal changes in P concentrations. In the present experiments, the progesterone receptor knockout (PRKO) mice were used to assess the role of PR activation in the positive feedback actions of E2 on gonadotropin release. Ovariectomized (OVX) PRKO mice were tested for their capacity to mount primary gonadotropin surges in response to exogenous E2, and to exhibit a GnRH self-priming effect in response to sequential injections of the decapeptide. Wild-type (WT) and PRKO mice were OVX, treated with both 17beta-estradiol and estradiol benzoate (EB), and then killed at 1900 h on day 7 postOVX. Plasma LH RIA revealed that WT mice exhibited surges in response to the E2 treatment; the PRKO mice, however, showed no elevation in plasma LH above untreated controls. Instead, plasma LH levels in E2-treated, OVX PRKO mice decreased significantly in comparison to untreated OVX PRKO mice, suggesting that E2 can exert a negative feedback influence on LH release in PRKO mice, despite the absence of positive feedback effects. A slight but significant rise in plasma FSH was observed in E2-treated OVX WT mice in comparison to untreated controls: an effect not seen in E2-treated OVX PRKO mice, reinforcing the observation that estrogen's positive feedback effects are compromised in PRKO mice. In a second experiment, E2-treated OVX WT and PRKO mice were given either one or two pulses of GnRH 60 min apart, and killed 10 min later. The WT mice were found to exhibit a robust GnRH self-priming effect, as WT mice receiving two GnRH pulses displayed LH responses approximately 2-fold greater than those receiving only one pulse. By contrast, PRKO mice receiving two GnRH pulses exhibited no additional increase in plasma LH levels. We conclude that PR activation is obligatory for expression of the GnRH self-priming effect as well as for generation of E2-induced LH and FSH surges. The extent to which failure of LH surge secretion in PRKO mice is due to the absence of GnRH self-priming, lack of hypothalamic GnRH surges, and/or defects in other processes remains to be determined. These observations clearly demonstrate, however, that the presence of PR is an absolute requirement for the transmission of E2-induced signals leading to gonadotropin surges.
众所周知，雌激素（E2）可刺激孕激素受体（PRs）的表达，从而诱导多种组织对孕激素（P）的作用产生反应。然而，最近的研究也表明，以前认为仅由E2介导的生物学作用，也可能由E2诱导的PRs激活介导，甚至独立于P浓度的信号变化。在本实验中，使用孕激素受体基因敲除（PRKO）小鼠来评估PR激活在E2对促性腺激素释放的正反馈作用中的作用。对卵巢切除（OVX）的PRKO小鼠进行测试，以评估它们对外源性E2产生原发性促性腺激素激增的能力，以及对十肽的顺序注射表现出GnRH自我启动效应的能力。将野生型（WT）和PRKO小鼠进行卵巢切除，用17β-雌二醇和苯甲酸雌二醇（EB）处理，然后在卵巢切除后第7天的19:00处死。血浆LH放射免疫分析显示，WT小鼠对E2处理有激增反应；然而，PRKO小鼠的血浆LH水平没有高于未处理的对照组。相反，与未处理的OVX PRKO小鼠相比，E2处理的OVX PRKO小鼠的血浆LH水平显著降低，这表明尽管没有正反馈效应，但E2仍可对PRKO小鼠的LH释放产生负反馈影响。与未处理的对照组相比，E2处理的OVX WT小鼠的血浆FSH略有但显著升高：在E2处理的OVX PRKO小鼠中未观察到这种效应，这进一步证明了PRKO小鼠中雌激素的正反馈效应受到损害。在第二个实验中，对E2处理的OVX WT和PRKO小鼠每隔60分钟给予一次或两次GnRH脉冲，并在10分钟后处死。发现WT小鼠表现出强烈的GnRH自我启动效应，因为接受两次GnRH脉冲的WT小鼠的LH反应比仅接受一次脉冲的小鼠大约高2倍。相比之下，接受两次GnRH脉冲的PRKO小鼠的血浆LH水平没有进一步升高。我们得出结论，PR激活对于GnRH自我启动效应的表达以及E2诱导的LH和FSH激增的产生是必不可少的。PRKO小鼠中LH激增分泌失败在多大程度上是由于缺乏GnRH自我启动、下丘脑GnRH激增的缺乏和/或其他过程中的缺陷仍有待确定。然而，这些观察结果清楚地表明，PR的存在是E2诱导的导致促性腺激素激增的信号传递的绝对必要条件。
