Merchenthaler Istvan, Stennett Christina A, Haughey Bethany, Puche Adam, Urbanski Henryk F
Department of Epidemiology and Public Health, University of Maryland Baltimore.
Department of Anatomy and Neurobiology, University of Maryland Baltimore.
EC Gynaecol. 2020 Jan;9(1). Epub 2019 Dec 11.
Menopause affects the quality of life of millions of women. With modern lifespan the postmenopausal attenuation of circulating estrogen levels can negatively impact a women's life for 30-40 years. The major hypoestrogenic consequence is hot flushes but decline in cognitive function, sleep disorders, depression/anxiety, cardiovascular disease, and osteoporosis are also characteristic for the menopause. Current treatments of hot flushes include estrogen therapy alone or in combination with progestins, soy products, and serotonin and norepinephrine reuptake inhibitors. However, with the exception of estrogens, none of these have satisfactory efficacy. But estrogens come with the unwanted side effects in the periphery, including stimulation of the uterus and breast leading to elevated cancer risk. Therefore, a tremendous effort has been devoted to developing safer therapies and the research has utilized classic rodent models of hot flush with considerable limitations. As hot flushes are primate-specific symptoms, the development of a non-invasive primate hot flush model would have a tremendous impact on drug development. Therefore, our aim was to develop such a non-human primate (NHP) model a hot flush that both recapitulates flushes women experience and is minimally invasive. We investigated if recent developments in thermal imaging have made it possible to accurately monitor skin temperature via camera imaging. In this study, the skin temperature of an ovariectomized rhesus monkey was measured continuously with an infrared camera in a freely moving animal over long time period. Following mapping skin temperatures of several areas of the neck and face we found that the nose of the monkeys showed that largest changes in skin temperature. In the ovariectomized monkey the temperature of the skin on the nose shows up to 9 °C elevations representing hot flushes. In the untreated monkey, hot flushes occurred more frequently in late afternoon/early evening hours than in the morning and last for several minutes. We observed 58 flushes in the 64 evenings of observation. The average number of hot flushes was 0.51 per evening. Oral administration of biotin (niacin) for seven days exaggerated the number of hot flushes to 2.43 per evening. Oral treatment with estradiol benzoate prevented hot flushes and only 2 flushes were detected in the 12 evenings after treatment, averaging 0.17 per evening. The development of this NHP model of hot flush provides great hope for utilizing it for future drug development and mechanistic studied.
更年期会影响数百万女性的生活质量。随着现代寿命的延长，绝经后循环雌激素水平的衰减会对女性的生活产生负面影响达30至40年之久。雌激素水平降低的主要后果是潮热，但认知功能下降、睡眠障碍、抑郁/焦虑、心血管疾病和骨质疏松也是更年期的特征。目前治疗潮热的方法包括单独使用雌激素疗法或与孕激素联合使用、食用豆制品以及使用血清素和去甲肾上腺素再摄取抑制剂。然而，除了雌激素之外，这些方法都没有令人满意的疗效。但是雌激素会带来外周的不良副作用，包括刺激子宫和乳房，导致癌症风险升高。因此，人们付出了巨大努力来开发更安全的疗法，并且该研究利用了具有相当局限性的经典啮齿动物潮热模型。由于潮热是灵长类动物特有的症状，因此开发一种非侵入性灵长类动物潮热模型将对药物开发产生巨大影响。因此，我们的目标是开发这样一种非人类灵长类动物（NHP）潮热模型，它既能重现女性经历的潮热，又具有最小的侵入性。我们研究了热成像技术的最新发展是否使得通过相机成像准确监测皮肤温度成为可能。在这项研究中，用红外相机在一只自由活动的动物身上长时间连续测量一只去卵巢恒河猴的皮肤温度。在绘制了颈部和面部几个区域的皮肤温度图之后，我们发现猴子的鼻子显示出皮肤温度的最大变化。在去卵巢的猴子中，鼻子上的皮肤温度升高高达9摄氏度，代表潮热。在未经治疗的猴子中，潮热在傍晚/傍晚早期比早晨更频繁地发生，并且持续几分钟。在64个观察夜晚中我们观察到58次潮热。平均每晚潮热次数为0.51次。口服生物素（烟酸）七天将潮热次数夸大到每晚2.43次。口服苯甲酸雌二醇可预防潮热，在治疗后的12个夜晚仅检测到2次潮热，平均每晚0.17次。这种NHP潮热模型的开发为将其用于未来的药物开发和机制研究带来了巨大希望。
