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The binding characteristics, content and intracellular distribution of cytosolic and nuclear progesterone receptors have been investigated, using [3H]progesterone as ligand, in the rat uterus bearing a unilateral intra-uterine device (IUD) during the oestrous cycle and from days 3 to 6 of pregnancy. The dissociation constants of nuclear and cytosolic progesterone–receptor complexes for IUD-containing and control uterine horns were similar. Cytosolic receptor concentrations in the IUD-containing uterus were always lower but changed in a manner similar to the control during the periods studied. Nuclear receptor concentrations in the control horn reflected changes in hormone levels during the oestrous cycle although concentrations measured were greater than previously reported. However, in IUD-containing uteri the pattern was completely reversed with minimal levels at pro-oestrus. Nuclear receptor concentrations were little different in both horns during early pregnancy. Total progesterone receptor synthesis determined between metoestrus and pro-oestrus in IUD-containing horns was significantly less than that of control horns. This correlated with the attenuated rise of nuclear oestrogen receptor levels previously observed between these times in IUD-containing uterine horns.
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The presence of an intra-uterine device in the rat results in a lower nuclear concentration of the oestrogen receptor in the treated horn at pro-oestrus when it is compared with the contralateral control horn. This effect was also seen after the administration of hyperphysiological doses of oestradiol and when the horn was exposed in vitro to high concentrations of oestradiol. The cyclic changes during the oestrous cycle in the activity of the oestrogen-induced enzyme peroxidase were similar in the treated and control horns. These observations have discounted the possibility that the relatively lower nuclear receptor content in the treated horn at pro-oestrus was due to a decreased exposure to oestrogen. A significantly lower nuclear content was also observed in the treated horn on days 4 and 5 of pregnancy. This was not associated with a deficiency in cytosol receptor content which increased concurrently with that of the control horn in the 6 days of pregnancy that were studied. The proportional content of the putative cytosol factor implicated in receptor translocation was similar in both horns, increasing on days 4 and 6 in concert with reported changes in 'induced protein' synthesis. There appeared to be reduced levels of nuclear receptor at a time when blastocyst implantation normally occurs.
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The amount of cortisol available to its receptors is increased by the pre-receptor enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) which converts cortisone to cortisol. We examined the molecular mechanisms of the feedback effect of cortisol on 11β-HSD1 mRNA expression in human amnion fibroblasts. Our data showed that cortisol-induced 11β-HSD1 mRNA expression dose dependently in amnion fibroblasts, which could be completely blocked both by the mRNA transcription inhibitor 5,6-dichlorobenzimidazole riboside and by the glucocorticoid receptor (GR) antagonist RU486, and partially blocked by global inhibition of CCAAT/enhancer-binding proteins (C/EBPs) with transfection of C/EBP-specific dominant-negative expression CMV500 plasmid (AC/EBP) into the cells. Likewise, the induction of the promoter activity by cortisol could also be completely blocked by RU486 and partially by AC/EBP transfection. Progressive 5′ deletion of the 11β-HSD1promoter located the region responsible for cortisol’s induction within −204 bp upstream to the transcription start site. Specific nucleotide mutations of the putative glucocorticoid responsive element or CCAAT in this promoter region attenuated the induction by cortisol. Moreover, chromatin immunoprecipitation assay and electrophoretic mobility shift assay showed that GR and C/EBPα but not C/EBPβ could bind this promoter region upon cortisol stimulation of amnion fibroblasts. In conclusion, we demonstrated that GR and C/EBPα were involved in cortisol-induced 11β-HSD1 mRNA expression via binding to 11β-HSD1 promoter in amnion fibroblasts, which may cast a feed-forward production of cortisol in the fetal membranes at the end of gestation.
