Micevych Paul, Sinchak Kevin
Department of Neurobiology, David Geffen School of Medicine at ULCA, Los Angeles, CA 90095, USA.
Mol Cell Endocrinol. 2008 Aug 13;290(1-2):44-50. doi: 10.1016/j.mce.2008.04.016. Epub 2008 May 3.
Steroidogenesis is now recognized as a global phenomenon in the brain, but how it is regulated and its relationship to circulating steroids of peripheral origin have remained more elusive issues. Neurosteroids, steroids synthesized de novo in nervous tissue, have a large range of actions in the brain, but it is only recently that the role of neuroprogesterone in the regulation of arguably the quintessential steroid-dependent neural activity, regulation of the reproduction has been appreciated. Circuits involved in controlling the LH surge and sexual behaviors were thought to be influenced by estradiol and progesterone synthesized in the ovary and perhaps the adrenal. It is now apparent that estradiol of ovarian origin regulates the synthesis of neuroprogesterone, and it is the locally produced neuroprogesterone that is involved in the initiation of the LH surge and subsequent ovulation. In this model, estradiol induces the transcription of progesterone receptors while stimulating synthesis of neuroprogesterone. Although the complete signaling cascade has not been elucidated, many of the features have been characterized. The synthesis of neuroprogesterone occurs primarily in astrocytes and requires the interaction of membrane-associated estrogen receptor-alpha with metabotropic glutamate receptor-1a. This G protein-coupled receptor activates a phospholipase C that in turn increases inositol trisphosphate (IP3) levels mediating the release of intracellular stores of Ca2+ via an IP3 receptor gated Ca2+ channel. The large increase in free cytoplasmic Ca2+ ([Ca2+]i) stimulates the synthesis of progesterone, which can then diffuse out of the astrocyte and activate estradiol-induced progesterone receptors in local neurons to trigger the neural cascade to produce the LH surge. Thus, it is a cooperative action of astrocytes and neurons that is needed for estrogen positive feedback and stimulation of the LH surge.
甾体激素生成如今被认为是大脑中的一种普遍现象，但它是如何被调控的，以及它与外周来源的循环甾体激素之间的关系，仍然是更难以捉摸的问题。神经甾体，即在神经组织中从头合成的甾体激素，在大脑中具有广泛的作用，但直到最近，神经孕酮在调节可以说是典型的甾体激素依赖性神经活动——生殖调节中的作用才得到认识。参与控制促黄体生成素激增和性行为的神经回路，被认为受到卵巢或许还有肾上腺合成的雌二醇和孕酮的影响。现在很明显，卵巢来源的雌二醇调节神经孕酮的合成，而正是局部产生的神经孕酮参与了促黄体生成素激增的启动和随后的排卵。在这个模型中，雌二醇诱导孕酮受体的转录，同时刺激神经孕酮的合成。尽管完整的信号级联尚未阐明，但许多特征已经得到表征。神经孕酮的合成主要发生在星形胶质细胞中，并且需要膜相关的雌激素受体α与代谢型谷氨酸受体-1a相互作用。这种G蛋白偶联受体激活一种磷脂酶C，进而增加肌醇三磷酸（IP3）水平，通过IP3受体门控的Ca2+通道介导细胞内Ca2+储存的释放。游离细胞质Ca2+（[Ca2+]i）的大幅增加刺激孕酮的合成，然后孕酮可以扩散出星形胶质细胞，并激活局部神经元中雌二醇诱导的孕酮受体，以触发神经级联反应，产生促黄体生成素激增。因此，雌激素正反馈和促黄体生成素激增的刺激需要星形胶质细胞和神经元的协同作用。
