The classical steroid receptors (nuclear receptors), including those for progesterone (nPRs), are thoroughly characterized. The knowledge about so-called non-genomic effects, which are mediated by extra-nuclear initiated signals, has increased immensely the last decades. In a previous clinical study of endometrial hyperplasia, we observed that the antiproliferative progestin effect persisted after 3 months treatment with levonorgestrel (LNG) intrauterine system (IUS) even with a complete downregulation of nPRs. This raised the question of what other mechanisms than signaling through nPRs could explain such an observation. In the present study, RT-qPCR was employed to characterize mRNA expression for nPRs, membrane progesterone receptors (mPRs) and progesterone receptor membrane components (PGRMCs) in women (n = 42) with endometrial hyperplasia that received intrauterine low dose LNG for 6 months. At the end of this period endometrial tissue showed that nPRs were virtually completely downregulated (≈ 10 % of baseline) whereas the levels of remaining mPRs, subtype-α, -β and -γ were 76 %, 59 % and 73 % of baseline, respectively. PGRMC1 was downregulated to 15 % of baseline, in contrast to PGRMC2, which was upregulated to about 30 % above baseline. We used human cancer cells from uterine cervix (C-4I cells) as control. Progesterone caused a concentration-dependent antiproliferative effect but in several and separate studies, we were unable to detect nPRs (immunocytochemistry) in the C-4I cells. The use of RT-qPCR showed that nPRs were undetectable in C-4I cells, in contrast to mPRs and PGRMCs with a distinct mRNA expression. The present study suggests that mPRs and/or PGRMCs preserve the antiproliferative effect of LNG in the human endometrium and are responsible for the concentration-dependent antiproliferative effect of progesterone in C-4I cells.

经典的类固醇受体（核受体），包括孕激素（nPRs）的受体，已得到充分表征。在过去的几十年中，关于由核外启动信号介导的所谓非基因组效应的知识已大大增加。在先前子宫内膜增生的临床研究中，我们观察到左炔诺孕酮（LNG）子宫内系统（IUS）治疗3个月后，即使nPR完全下调，抗孕激素作用仍然持续。这就提出了一个问题，除了通过nPR发出信号以外，还有什么其他机制可以解释这种观察。在本研究中，采用RT-qPCR表征nPR的mRNA表达，子宫内膜增生的妇女（n = 42）接受宫内低剂量LNG治疗6个月的子宫内膜孕酮受体（mPRs）和孕激素受体膜成分（PGRMCs）。在此期间结束时，子宫内膜组织显示nPRs几乎完全下调（约为基线的10％），而其余mPRs，亚型-α，-β和-γ的水平分别为基线的76％，59％和73％，分别。PGRMC1被下调至基线的15％，而PGRMC2被上调至基线的30％左右。我们使用来自子宫颈的人类癌细胞（C-4I细胞）作为对照。孕酮引起浓度依赖性的抗增殖作用，但在数个单独的研究中，我们无法检测C-4I细胞中的nPR（免疫细胞化学）。RT-qPCR的使用表明，与具有明显mRNA表达的mPR和PGRMC相比，在C-4I细胞中无法检测到nPR。本研究表明，mPRs和/或PGRMCs保留了LNG在人子宫内膜中的抗增殖作用，并负责孕激素在C-4I细胞中的浓度依赖性抗增殖作用。