Abstract
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.
Highlights
Physiogical and pharmacological progesterone effects were known long before the search for molecular mechanisms was initiated
A group of 61 women were recruited to a prospective, multicenter pilot study to assess the efficacy of LNG-intrauterine system (IUS) 13.5 mg (JaydessTM, Bayer Pharmaceuticals, Berlin, Germany) for treatment of endometrial hyperplasia [16,17]
Maintained exposure of LNG to the endometrium caused a profound effect on the mRNA expression of classical progesterone receptors
Summary
Physiogical and pharmacological progesterone effects were known long before the search for molecular mechanisms was initiated. The identification of high affinity binding proteins (nPRs) in cytoplasm with [3H]-progesterone was a breakthrough [1]. In the classical genomic signaling pathway progesterone and other progestins bind to nPRs located in the cytoplasm, which leads to a conformational change with dissociation of heat shock proteins, dimerization, translocation to the nucleus and binding to hormone responsive elements in target genes [2]. Other mechanisms of progesterone action have been reported, such as non-genomic effects due to the rapid onset [3]. The knowledge about these extranuclear-initiated mechanisms gradually emerged [4,5,6,7]. The discovery and characterization of membrane progesterone receptors (mPRs) [8,9]were important contribution to the understanding of non-genomic effects
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