Laboratory of Cellular Physiology, Department of Physiology, Federal University of Rio Grande do Sul, Rua Sarmento Leite 500, ICBS, 2nd Floor, Suite 350, Porto Alegre, RS 90050-170, Brazil.
Federal Institute of Education, Science and Technology 'Farroupilha', Rua Uruguai 1675, Santa Rosa, RS 98900-000, Brazil.
Hum Reprod Update. 2017 Sep 1;23(5):600-628. doi: 10.1093/humupd/dmx020.
Although some unequivocal underlying mechanisms of menopausal hot flushes have been demonstrated in animal models, the paucity of similar approaches in humans impedes further mechanistic outcomes. Human studies might show some as yet unexpected physiological mechanisms of metabolic adaptation that permeate the phase of decreased oestrogen levels in both symptomatic and asymptomatic women. This is particularly relevant because both the severity and time span of hot flushes are associated with increased risk of chronic inflammatory disease. On the other hand, oestrogen induces the expression of heat shock proteins of the 70 kDa family (HSP70), which are anti-inflammatory and cytoprotective protein chaperones, whose expression is modulated by different types of physiologically stressful situations, including heat stress and exercise. Therefore, lower HSP70 expression secondary to oestrogen deficiency increases cardiovascular risk and predisposes the patient to senescence-associated secretory phenotype (SASP) that culminates in chronic inflammatory diseases, such as obesities, type 2 diabetes, neuromuscular and neurodegenerative diseases.
This review focuses on HSP70 and its accompanying heat shock response (HSR), which is an anti-inflammatory and antisenescent pathway whose intracellular triggering is also oestrogen-dependent via nitric oxide (NO) production. The main goal of the manuscript was to show that the vasomotor symptoms that accompany hot flushes may be a disguised clue for important neuroendocrine alterations linking oestrogen deficiency to the anti-inflammatory HSR.
Results from our own group and recent evidence on hypothalamic control of central temperature guided a search on PubMed and Google Scholar websites.
Oestrogen elicits rapid production of the vasodilatory gas NO, a powerful activator of HSP70 expression. Whence, part of the protective effects of oestrogen over cardiovascular and neuroendocrine systems is tied to its capacity of inducing the NO-elicited HSR. The hypothalamic areas involved in thermoregulation (infundibular nucleus in humans and arcuate nucleus in other mammals) and whose neurons are known to have their function altered after long-term oestrogen ablation, particularly kisspeptin-neurokinin B-dynorphin neurons, (KNDy) are the same that drive neuroprotective expression of HSP70 and, in many cases, this response is via NO even in the absence of oestrogen. From thence, it is not illogical that hot flushes might be related to an evolutionary adaptation to re-equip the NO-HSP70 axis during the downfall of circulating oestrogen.
Understanding of HSR could shed light on yet uncovered mechanisms of menopause-associated diseases as well as on possible manipulation of HSR in menopausal women through physiological, pharmacological, nutraceutical and prebiotic interventions. Moreover, decreased HSR indices (that can be clinically determined with ease) in perimenopause could be of prognostic value in predicting the moment and appropriateness of starting a HRT.
尽管一些明确的绝经热潮相关的潜在机制已经在动物模型中得到了证明，但人类缺乏类似的方法阻碍了进一步的机制研究。人类研究可能会揭示一些代谢适应的生理机制，这些机制贯穿于有症状和无症状女性雌激素水平下降的阶段。这一点尤其重要，因为热潮红的严重程度和持续时间与慢性炎症性疾病的风险增加有关。另一方面，雌激素诱导 70kDa 家族热休克蛋白（HSP70）的表达，这些蛋白是抗炎和细胞保护蛋白伴侣，其表达受不同类型的生理应激情况的调节，包括热应激和运动。因此，雌激素缺乏导致的 HSP70 表达降低会增加心血管风险，并使患者易患衰老相关分泌表型（SASP），从而导致慢性炎症性疾病，如肥胖、2 型糖尿病、神经肌肉和神经退行性疾病。
本文综述了 HSP70 及其伴随的热休克反应（HSR），这是一种抗炎和抗衰老途径，其细胞内触发也依赖于雌激素通过一氧化氮（NO）的产生。本文的主要目的是表明伴随热潮红出现的血管舒缩症状可能是一个伪装的线索，表明雌激素缺乏与抗炎 HSR 之间存在重要的神经内分泌改变。
我们小组的研究结果和最近关于下丘脑对中枢温度控制的证据指导我们在 PubMed 和 Google Scholar 网站上进行了搜索。
雌激素迅速产生血管扩张性气体一氧化氮（NO），这是一种强有力的 HSP70 表达激活剂。雌激素对心血管和神经内分泌系统的部分保护作用与其诱导 NO 诱导的 HSR 能力有关。参与体温调节的下丘脑区域（人类的漏斗核和其他哺乳动物的弓状核），其神经元在长期雌激素消融后功能发生改变，特别是 kisspeptin-neurokinin B-dynorphin 神经元（KNDy），同样驱动 HSP70 的神经保护表达，在许多情况下，即使没有雌激素，这种反应也是通过一氧化氮进行的。因此，热潮红可能与雌激素水平下降时重新装备 NO-HSP70 轴的进化适应有关，这并非没有道理。
对 HSR 的理解可以揭示与绝经相关疾病相关的未被发现的机制，以及通过生理、药理、营养和益生菌干预在绝经妇女中对 HSR 进行可能的操纵。此外，围绝经期 HSR 指数（通过临床检测很容易确定）的降低可能对预测开始 HRT 的时机和适当性具有预后价值。
