Wise Phyllis M, Smith Matthew J, Dubal Dena B, Wilson Melinda E, Rau Shane W, Cashion Adrienne B, Böttner Martina, Rosewell Katherine L
Department of Physiology, University of Kentucky College of Medicine, Lexington 40536-0298, USA.
Recent Prog Horm Res. 2002;57:235-56. doi: 10.1210/rp.57.1.235.
The menopause marks the end of a woman's reproductive life. During the postmenopausal period, plasma estrogen concentrations decrease dramatically and remain low for the rest of her life, unless she chooses to take hormone replacement therapy. During the past 20 years, we have learned that changes in the central nervous system are associated with and may influence the timing of the menopause in women. Recently, it has become clear that estrogens act on more than just the hypothalamus, pituitary, ovary, and other reproductive organs. In fact, they play roles in a wide variety of nonreproductive functions. With the increasing life span of humans from approximately 50 to 80 years and the relatively fixed age of the menopause, a larger number of women will spend over one third of their lives in the postmenopausal state. It is not surprising that interest has increased in factors that govern the timing of the menopause and the repercussions of the lack of estrogen on multiple aspects of women's health. We have used animal models to better understand the complex interactions between the ovary and the brain that lead to the menopause and the repercussions of the hypoestrogenic state. Our results show that when rats reach middle age, the patterns and synchrony of multiple neurochemical events that are critical to the preovulatory gonadotropin-releasing hormone (GnRH) surge undergo subtle changes. The precision of rhythmic pattern of neurotransmitter dynamics depends on the presence of estradiol. Responsiveness to this hormone decreases in middle-aged rats. The lack of precision in the coordination in the output of neural signals leads to a delay and attenuation of the luteinizing hormone surge, which lead to irregular estrous cyclicity and, ultimately, to the cessation of reproductive cycles. We also have examined the impact of the lack of estrogen on the vulnerability of the brain to injury. Our work establishes that the absence of estradiol increases the extent of cell death after stroke-like injury and that treatment with low physiological levels of estradiol are profoundly neuroprotective. We have begun to explore the cellular and molecular mechanisms that underlie this novel nonreproductive action of estrogens. In summary, our studies show that age-related changes in the ability of estradiol to coordinate the neuroendocrine events that lead to regular preovulatory GnRH surges contribute to the onset of irregular estrous cycles and eventually to acyclicity. Furthermore, we have shown that the lack of estradiol increases the vulnerability of the brain to injury and neurodegeneration.
绝经标志着女性生殖生命的结束。在绝经后期，血浆雌激素浓度急剧下降，并在其余生中保持在低水平，除非她选择接受激素替代疗法。在过去20年里，我们了解到中枢神经系统的变化与女性绝经的时间相关，并且可能会影响绝经时间。最近，很明显雌激素的作用不仅仅局限于下丘脑、垂体、卵巢和其他生殖器官。事实上，它们在多种非生殖功能中发挥作用。随着人类寿命从大约50岁延长到80岁，而绝经年龄相对固定，越来越多的女性将在绝经后状态度过超过三分之一的人生。因此，人们对影响绝经时间的因素以及雌激素缺乏对女性健康多个方面的影响的兴趣增加也就不足为奇了。我们利用动物模型来更好地理解卵巢和大脑之间复杂的相互作用，这些相互作用导致了绝经以及雌激素缺乏状态的影响。我们的结果表明，当大鼠进入中年时，对排卵前促性腺激素释放激素（GnRH）激增至关重要的多种神经化学事件的模式和同步性会发生细微变化。神经递质动力学节律模式的精确性取决于雌二醇的存在。中年大鼠对这种激素的反应性会降低。神经信号输出协调缺乏精确性会导致黄体生成素激增延迟和减弱，从而导致发情周期不规律，最终导致生殖周期停止。我们还研究了雌激素缺乏对大脑易损伤性的影响。我们的研究证实，雌二醇的缺乏会增加类似中风损伤后的细胞死亡程度，而低生理水平的雌二醇治疗具有显著的神经保护作用。我们已经开始探索雌激素这种新型非生殖作用背后的细胞和分子机制。总之，我们的研究表明，与年龄相关的雌二醇协调导致规律排卵前GnRH激增的神经内分泌事件的能力变化，促成了不规律发情周期的开始，并最终导致无排卵。此外，我们已经表明，雌二醇的缺乏会增加大脑对损伤和神经退行性变的易感性。
