PubMed · 13124833
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H P KLOTZ, J AVRIL. 1953. [Adreno-cortical hyperfunction of hypothalamic origin].. https://pubmed.ncbi.nlm.nih.gov/13124833/
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Pregnant guinea pigs were treated with dexamethasone (1 mg kg(-1)) or vehicle on days 40-41, 50-51 and 60-61 of gestation, after which animals delivered normally. Adult male offspring were catheterized at 145 days of age and subjected to tests of hypothalamic-pituitary-adrenal (HPA) axis function in basal and activated states. Animals exposed to dexamethasone in utero (mat-dex) exhibited increased hippocampus-to-brain weight ratio, increased adrenal-to-body weight ratio and increased mean arterial pressure. There were no effects on gestation length, birth weight and postnatal growth. There were no overall differences in diurnal plasma adrenocorticotropic hormone (ACTH) and cortisol profiles, though there were subtle differences during the subjective afternoon between control and mat-dex offspring. A significant decrease in initial ACTH suppression was observed following dexamethasone injection in mat-dex offspring compared to control offspring. Molecular analysis revealed significantly increased MR mRNA expression in the limbic system and particularly in the dentate gyrus in mat-dex offspring. In the anterior pituitary, both pro-opiomelanocortin (POMC) and glucocorticoid receptor (GR) mRNA levels were significantly elevated in mat-dex offspring. In conclusion, (1) repeated prenatal treatment with synthetic glucocorticoid (sGC) permanently programmes organ growth, blood pressure and HPA regulation in mature male offspring and these changes involve modification of corticosteroid receptor expression in the brain and pituitary; (2) the effects of prenatal sGC exposure on HPA function appear to change as a function of age, indicating the importance of investigating HPA and cardiovascular outcome at multiple time points throughout life.
Previous studies have suggested that activation of normal human adrenal and adrenal tumor luteinizing hormone (LH)/chorionic gonadotropin (hCG) receptors results in an increased secretion of steroid hormones. Since it is not feasible to test this suggestion on normal human adrenal cells, we used human adrenal cortical carcinoma H295R cells, which are similar in some respects to normal adrenal cortical cells. These cells contained LH/hCG receptor transcripts and receptor protein that can bind (125)I-hCG in a hormone-specific manner. Culturing the cells with highly purified hCG resulted in a time- and dose-dependent significant increase in dehydroepiandrosterone sulfate (DHEAS) secretion as compared with the controls. The DHEAS response was hormone as well as steroid specific. Since hCG treatment did not increase DHEA secretion, we suspected that the hCG might increase DHEA sulfotransferase (ST). Consistent with this possibility, hCG treatment increased steady-state DHEA-ST mRNA levels. The hCG effects require its receptors, as inhibition of their synthesis by treatment with antisense phosphorothioate oligodeoxynucleotides (ODN) made from the LH/hCG receptor sequence resulted in loss of DHEA-ST and DHEAS responses. The findings that 1) hCG treatment increased cAMP levels and activated protein kinase A (PKA), 2) 8-bromo cAMP mimicked hCG, and 3) blocking PKA activation prevented hCG as well as 8-bromo cAMP from increasing both DHEA-ST mRNA and DHEAS levels suggested that cAMP/PKA signaling was involved in the hCG actions. In conclusion, H295R cells contain LH/hCG receptors, which are coupled to increasing DHEAS secretion through upregulating the ST enzyme mRNA level. This action is mediated by the cAMP/PKA signaling pathway. These findings support the concept that adrenal function in normal and pathological conditions could be influenced by LH and hCG.
Post-translational modifications such as phosphorylation and specific proteolysis affect the steroidogenic acute regulatory protein (StAR) activity. We have found that in pcDNA3.1-StAR-transfected COS-1 cells, StAR was phosphorylated on S55, S56 and S194 (Fleury et al., unpublished). In this study, we are comparing the two-dimensional gel electrophoresis (2D-PAGE) characteristics of the WT StAR with those of the S194A and S55A/S56A/S194A-StAR mutants under control and (Bu)(2)-cAMP stimulation, using an anti-StAR antibody and an anti-phospho-(Ser/Thr) PKA substrate antibody. The 2D-PAGE migration pattern of the WT StAR analyzed by immunoblotting with the anti-StAR antibody revealed many StAR species with different pI and different molecular weights. In the (Bu)(2)-cAMP-WT preparations, except for three, all these StAR species were also recognized by the anti-phospho-(Ser/Thr) PKA substrate antibody; in contrast, less phosphorylated species were found in the non-stimulated WT preparations. The two-dimensional (2D) patterns of StAR revealed by the anti-StAR and the anti-phospho-(Ser/Thr) PKA substrate antibodies were modified for the S194A mutant and further modified for the S55A/S56A/S194A mutant. Whereas many species could still be detected by the anti-StAR antibody in the triple mutant S55A/S55A/S194A, none of these could be revealed by the anti-phospho-(Ser/Thr) PKA substrate antibody. Finally we found that, in addition to phosphorylation, the formation of different StAR species was also due to the hydrolysis of the molecule at its N-terminal and to a lesser degree at its C-terminal.