Merchenthaler Istvan, Lane Malcolm, Sabnis Gauri, Brodie Angela, Nguyen Vien, Prokai Laszlo, Prokai-Tatrai Katalin
Department of Epidemiology &Public Health and Anatomy &Neurobiology, University of Maryland, Baltimore, MD 21154, USA.
Department of Pharmacology, University of Maryland, Baltimore, MD 21154, USA.
Sci Rep. 2016 Aug 1;6:30721. doi: 10.1038/srep30721.
Estrogen deprivation has a profound effect on the female brain. One of the most obvious examples of this condition is hot flushes. Although estrogens relieve these typical climacteric symptoms, many women do not want to take them owing to unwanted side-effects impacting, for example, the uterus, breast and blood. Therefore, there is a need for developing safer estrogen therapies. We show here that treatment with 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), a novel brain-targeting bioprecursor prodrug of the main human estrogen, 17β-estradiol, alleviates hot flushes in rat models of thermoregulatory dysfunction of the brain. Oral administration of DHED elicits a significant reduction of tail skin temperature (TST) rise representing hot flushes in the morphine-dependent ovariectomized rat model and results in the restoration of estrogen deprivation-induced loss of diurnal rhythm in TST. These beneficial effects occur without detrimental peripheral hormonal exposure; thus, the treatment avoids potentially harmful stimulation of estrogen-sensitive peripheral organs, including the uterus and the anterior pituitary, or the proliferation of MCF-7a breast cancer cell xenografts. Our promising preclinical assessments warrant further considerations of DHED for the development of a brain-selective 17β-estradiol therapy to relieve hot flushes without undesirable peripheral side-effects.
雌激素缺乏对女性大脑有深远影响。这种情况最明显的例子之一就是潮热。尽管雌激素能缓解这些典型的更年期症状，但许多女性因不良副作用（如对子宫、乳房和血液的影响）而不愿服用。因此，需要开发更安全的雌激素疗法。我们在此表明，用10β,17β - 二羟基雌 - 1,4 - 二烯 - 3 - 酮（DHED）进行治疗，它是主要人体雌激素17β - 雌二醇的一种新型脑靶向生物前体药物，可缓解大脑体温调节功能障碍大鼠模型中的潮热。口服DHED能显著降低吗啡依赖的去卵巢大鼠模型中代表潮热的尾部皮肤温度（TST）升高，并恢复雌激素缺乏导致的TST昼夜节律丧失。这些有益效果在没有有害外周激素暴露的情况下出现；因此，该治疗避免了对雌激素敏感的外周器官（包括子宫和垂体前叶）的潜在有害刺激，或MCF - 7a乳腺癌细胞异种移植物的增殖。我们有前景的临床前评估值得进一步考虑将DHED用于开发一种脑选择性17β - 雌二醇疗法，以缓解潮热且无不良外周副作用。
