Investigating the anti-mineralocorticoid properties of synthetic progestins used in hormone therapy
Investigating the anti-mineralocorticoid properties of synthetic progestins used in hormone therapy
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DOI：
10.1016/j.bbrc.2013.02.086
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发表时间：
2013-04-12
影响因子：
3.1
通讯作者：
Hapgood, Janet P.
中科院分区：
文献类型：
--
作者：
Africander, Donita;Louw, Renate;Hapgood, Janet P.
需要更详细地了解合成孕激素醋酸甲羟孕酮（MPA）和醋酸炔诺酮（NET-A）通过盐皮质激素受体（MR）进行转录调控的亲和力和功效，以更好地了解其相对风险特征。MPA和NET-A都与MR结合，尽管亲和力比Prog低约100倍。MPA和NET-A没有表现出激动剂活性，但与MPA不同，NET-A对含有内源性盐皮质激素/糖皮质激素反应元件（MRE/GRE）的基因、α-糖酵解蛋白或乳清类粘蛋白-1（Orm-1）和纤溶酶原激活物抑制剂-1（派-1）具有与Frog相似的拮抗功效。这项研究是第一次表明，NET-A，但不是MPA，可以通过MR的反式阻遏和反式激活之间的解离。鉴于相对较低的亲和力和效力的MPA和NET-A的MR，我们的研究结果表明，这些，孕激素是不太可能发挥显着的作用，通过MR在激素治疗中使用的剂量。然而，考虑到与内源性激素相比它们的相对游离浓度，不应排除NET-A可能表现出显著的MR拮抗剂活性的可能性，以及一些可能的心血管保护益处。(C)2013 Elsevier Inc. All rights reserved.
A more detailed understanding of the affinities and efficacies for transcriptional regulation by the synthetic progestins medroxyprogesterone acetate (MPA) and norethisterone acetate (NET-A) via the mineralocorticoid receptor (MR) is required, to better understand their relative risk profiles. Both MPA and NET-A bind to the MR, although with about 100-fold lower affinities than that of Prog. MPA and NET-A exhibit no agonist activity, but NET-A, unlike MPA, has similar antagonistic efficacy to Frog on the endogenous mineralocorticoid/glucocorticoid response element (MRE/GRE)-containing genes, alpha-glycolytic protein or orosomucoid-1 (Orm-1) and plasminogen activator inhibitor-1 (PAI-1). This study is the first to show that NET-A, but not MPA, can dissociate between transrepression and transactivation via the MR. Given the relatively low affinity and potency of MPA and NET-A for the MR, our results suggest that these, progestins are unlikeley to exert significant effects via the MR at doses used in hormonal therapy. However, considering their relative free concentrations compared to endogenous hormones, the possibility that NET-A may exhibit significant MR antagonist activity, with some possible cardiovascular protective benefits, should not be excluded. (C) 2013 Elsevier Inc. All rights reserved.