Estrogen activity and novel tissue selectivity of Δ8,9-dehydroestrone sulfate in postmenopausal women
Estrogen activity and novel tissue selectivity of Δ8,9-dehydroestrone sulfate in postmenopausal women
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DOI：
10.1210/jc.84.6.2020
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发表时间：
1999-06-01
影响因子：
5.8
通讯作者：
Negro-Vilar, A
中科院分区：
文献类型：
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作者：
Baracat, E;Haidar, R;Negro-Vilar, A
最近的基础和临床进展巩固了组织选择性雌激素的概念，即在不同组织或细胞中表达不同程度的部分激动剂、完全激动剂或拮抗剂活性的分子。德尔塔(8,9)-硫酸脱氢雌酮（德尔塔(8,9)-DHES）是一种共轭雌激素，也是共轭马雌激素（CEE）的一个组成部分。它在人体内以至少1:1的比例代谢其17 β形式，17 β - δ (8,9)-DHES。为了评估其在不同临床和生化参数中的活性，我们在绝经后妇女中以Delta(8,9)-DHES和硫酸雌酮作为比较物进行了临床研究。10名女性口服Delta(8,9)-DHES，每日剂量为0.125 mg，持续12周。另外两组妇女接受单独硫酸雌酮（1.25 mg/天）或先前规定剂量的Delta(8,9)-DHES和硫酸雌酮的联合治疗。Delta(8,9)-DHES对潮热（次数、严重程度和总分）的抑制显著且一致，在血管舒缩症状的所有参数中均达到95%以上的抑制。这种活性水平与高剂量硫酸雌酮获得的活性水平相同，并且在治疗期间（12周）持续存在。骨吸收标记物的测量。即尿中n -末端肽的排泄，表明Delta(8,9)-DHES在8周时产生的抑制程度（40%）与高剂量硫酸雌酮观察到的相似。在接受Delta(8,9)-DHES的女性中，促性腺激素分泌（FSH和LH）明显受到抑制，与单独使用雌酮或两者联合使用的情况相似。其他参数，如总胆固醇、低密度脂蛋白胆固醇和高密度脂蛋白胆固醇没有明显改变，而血清球蛋白（性激素结合球蛋白和皮质类固醇结合球蛋白）在服用Delta(8,9)-DHES后仅显示出边际升高。结合临床前数据，我们发现Delta(8,9)-DHES是一种活性雌激素，具有独特的药理特征，在血管舒张、神经内分泌（促性腺激素和PRL）和骨保存参数方面具有显著的临床活性，而在测试剂量下，对通常受雌激素影响的其他外周参数几乎没有或没有效果。总的来说，这些信息支持Delta(8,9)-DHES是GEE不可缺少的组成部分的概念。具有独特的组织选择性，有助于CEE的整体临床活性，并将这种雌激素作为一类具有独特外周组织选择性的新型中枢活性分子的独特成员。
Recent basic and clinical advances have consolidated the concept of tissue-selective estrogens, i.e. molecules that express different degrees of partial agonist, full agonist or antagonist activity in different tissues or cells. Delta(8,9)-Dehydroestrone sulfate (Delta(8,9)-DHES) is a conjugated estrogen and a component of conjugated equine estrogens (CEE). It is metabolized in the human in at least a 1:1 ratio to its 17 beta form, 17 beta-Delta(8,9)-DHES. To evaluate its activity in different clinical and biochemical parameters, a clinical research study was conducted with Delta(8,9)-DHES and estrone sulfate as a comparator in postmenopausal women. Delta(8,9)-DHES was given orally at a daily dose of 0.125 mg for 12 weeks in a group of 10 women. Two additional groups of women received either estrone sulfate alone (1.25 mg/day) or the combination of Delta(8,9)-DHES and estrone sulfate at the previously specified doses. A significant and consistent suppression of hot flushes (number, severity, and total score) was observed with Delta(8,9)-DHES, reaching more than 95% suppression in all parameters of vasomotor symptoms. This level of activity was equal to that obtained with the much higher dose of estrone sulfate, and it was sustained for the duration of the treatment period (12 weeks). Measurements of a bone resorption marker. i.e. urinary excretion of N-telopeptide, demonstrated that Delta(8,9)-DHES at 8 weeks produced a degree of suppression (40%) similar to that observed with the higher dose of estrone sulfate. Gonadotropin secretion (FSH and LH) was significantly suppressed in women receiving Delta(8,9)-DHES, similar to that observed with estrone sulfate alone or with the combination of the two. Other parameters, such as total cholesterol, low density lipoprotein cholesterol and high density lipoprotein cholesterol were not modified significantly, whereas serum globulins (sex hormone-binding globulin and corticosteroid-binding globulin) showed only marginal increases after Delta(8,9)-DHES administration.Taken together with preclinical data, it is found that Delta(8,9)-DHES is an active estrogen with a distinct pharmacological profile that results in significant clinical activity in vasomotor, neuroendocrine (gonadotropin and PRL) and bone preservation parameters, whereas displaying little or no efficacy, at the dose tested, on other peripheral parameters normally affected by estrogens, Collectively, this information supports the concept that Delta(8,9)-DHES is an integral component of GEE, with distinct tissue selectivity contributing to the CEE's overall clinical activity, and places this estrogen as a distinct member of a novel class of centrally active molecules with unique peripheral tissue selectivity.