Kontula K, Paavonen T, Luukkainen T, Andersson L C
Biochem Pharmacol. 1983 May 1;32(9):1511-8. doi: 10.1016/0006-2952(83)90474-4.
A number of physiological and synthetic progestins were tested for their ability to compete with [3H]dexamethasone for the binding to the glucocorticoid receptor of human mononuclear leukocytes and their ability to elicit glucocorticoid-like effects on the same cells. As compared to the reference compound dexamethasone (relative receptor binding affinity defined as 100%), two potent synthetic progestins with a pregnane-type structure, megestrol acetate and medroxyprogesterone acetate, were found to display a considerable binding affinity towards the receptor (46 and 42%, respectively). The relative binding affinity of the naturally occurring ligand, cortisol, to the receptor was clearly lower (25%). The effective binding of medroxyprogesterone acetate to the glucocorticoid receptor was confirmed by direct binding studies utilizing a tritiated derivative of this steroid. No evidence for the existence of a specific progesterone receptor in human mononuclear leukocytes was obtained as judged by the results of competition experiments where a progesterone receptor-specific ligand [3H]Org 2058 was used. Medroxyprogesterone acetate and megestrol acetate also induced glucocorticoid-like effects on the lymphocyte functions. These included inhibition of the proliferative responses to the T-cell mitogens concanavalin A and phytohaemagglutinin and an enhanced accumulation of immunoglobulin secreting cells in pokeweed mitogen-stimulated cultures. The progestin effect appears to be mediated through a radiosensitive (suppressor) subpopulation of T lymphocytes. In contrast, the synthetic progestins related structurally to 19-nortestosterone, norethisterone and d-norgestrel, were virtually devoid of binding affinity towards the glucocorticoid receptor nor did they measurably influence the in vitro lymphocyte functions. These studies demonstrate that certain progestins in common clinical use probably possess inherent glucocorticoid activity and suggest that side effects attributable to this character (e.g. suppression of the pituitary-adrenal axis) might be expected when these compounds are used in pharmacological doses.
测试了多种生理性和合成孕激素与[3H]地塞米松竞争结合人单核白细胞糖皮质激素受体的能力，以及它们对同一细胞产生糖皮质激素样效应的能力。与参考化合物地塞米松（相对受体结合亲和力定义为100%）相比，发现两种具有孕烷型结构的强效合成孕激素，醋酸甲地孕酮和醋酸甲羟孕酮，对该受体具有相当大的结合亲和力（分别为46%和42%）。天然存在的配体皮质醇与该受体的相对结合亲和力明显较低（25%）。利用这种类固醇的氚化衍生物进行的直接结合研究证实了醋酸甲羟孕酮与糖皮质激素受体的有效结合。通过使用孕激素受体特异性配体[3H]Org 2058的竞争实验结果判断，未获得人单核白细胞中存在特异性孕激素受体的证据。醋酸甲羟孕酮和醋酸甲地孕酮也对淋巴细胞功能产生糖皮质激素样效应。这些效应包括抑制对T细胞有丝分裂原刀豆球蛋白A和植物血凝素的增殖反应，以及在商陆有丝分裂原刺激的培养物中增强免疫球蛋白分泌细胞的积累。孕激素效应似乎是通过T淋巴细胞的一个放射敏感（抑制）亚群介导的。相比之下，在结构上与19-去甲睾酮相关的合成孕激素炔诺酮和左炔诺孕酮，对糖皮质激素受体几乎没有结合亲和力，也未对体外淋巴细胞功能产生可测量的影响。这些研究表明，某些临床常用的孕激素可能具有内在的糖皮质激素活性，并提示当这些化合物以药理剂量使用时，可能会出现归因于这一特性的副作用（如抑制垂体-肾上腺轴）。
