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Prenatal glucocorticoid exposure has been associated with a reduction in birth weight and postnatal alterations in glucose homeostasis and hypothalamic-pituitary-adrenal (HPA) axis function. The mechanisms underlying these responses are unknown, although changes in fetal hepatic development may play an important role. The fetal liver produces key regulators of fuel metabolism and of the developing HPA axis that are altered by glucocorticoids. The local availability of glucocorticoids is regulated, in part, by corticosteroid-binding protein (CBG), glucocorticoid receptors (GR) and by the enzyme 11beta-hydroxysteroid dehydrogenase (11betaHSD), but the effects of maternal glucocorticoid administration on the expression of these genes in the fetal liver are unknown. 11betaHSD1 is the predominant form of this enzyme present in the liver and is responsible for the conversion of cortisone to cortisol. To determine if prenatal glucocorticoid exposure alters fetal hepatic regulation of CBG, 11betaHSD1 and GRs, we treated pregnant ewes with betamethasone (0.5 mg/kg) intramuscularly at 104, 111 and 118 days of gestation (term 150 days). Animals were killed at 125 or 146 days of gestation. Maternal betamethasone administration did not alter mean cord plasma glucose but significantly decreased cord plasma insulin levels (P<0.05) at 125 days of gestation. At 146 days of gestation, cord plasma glucose levels were significantly increased without alterations in insulin levels following maternal betamethasone treatment (P<0.05). Maternal betamethasone administration resulted in a significant increase in fetal hepatic 11betaHSD1 mRNA and protein levels at 125 days of gestation (P<0.05). CBG mRNA levels were significantly elevated over control at 125 days although levels of CBG protein were not significantly different. GR protein levels were not statistically different at either 125 or 146 days of gestation following glucocorticoid administration. These data suggest that prenatal betamethasone exposure in the ovine fetus results in alterations in cord glucose and insulin levels as well as alterations in hepatic 11betaHSD1 mRNA and protein expression. These changes in 11betaHSD1 increase the potential to generate local cortisol from circulating cortisone. We speculate that this could affect expression of glucocorticoid-dependent hepatic enzymes involved with the regulation of glucose production and HPA responsiveness.
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Osteoprotegerin (OPG) is a recently cloned member of the tumour necrosis factor receptor family. It has been suggested that this secreted glycoprotein acts as an inhibitor of osteoclastic differentiation. Expression of OPG has previously been demonstrated in a number of tissues. However, it is still unclear whether or not OPG is expressed by human osteoblasts. We have used the RNase protection assay to demonstrate the OPG transcript in primary cultured human osteoblast-like cells, human marrow stroma cells and osteosarcoma cell lines. Furthermore, we have studied the effect of glucocorticoids on OPG mRNA levels in these cells. We demonstrate that glucocorticoids decrease the OPG transcript in a dose- and time-dependent manner. The time-course study reveals that hydrocortisone (10(-6) M) decreases OPG mRNA levels within 2 h. This decrease is transient, reaching control levels again after 24 h. Our findings demonstrate that human osteoblasts express the mRNA corresponding to OPG, an inhibitor of osteoclast differentiation. The finding that OPG mRNA levels are decreased by glucocorticoids indicates that a reduced production of OPG from osteoblasts and/or marrow stroma cells could, in part, explain glucocorticoid-induced bone resorption.
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ABSTRACT
The cytosolic glucocorticoid receptor of ovine placental zona intima has been characterized and measured between day 51 of pregnancy and term, and levels compared with those in fetal lung. By ion-exchange and gel-filtration chromatography the molybdate-stabilized receptor was found to be an acidic molecule with Stokes radius approximately 8 nm; these physicochemical characteristics of the ovine placental receptor are comparable to those of receptors in glucocorticoid target tissues from non-ruminants. Concentrations of cytosolic receptor in placenta (mean, 139 fmol/mg protein) were lower than those in fetal lung (627 fmol/mg) at all stages of gestation investigated. To some extent this difference was accounted for by a twofold higher concentration of protein in placental cytosols compared with those from fetal lung. In both tissues, cytosolic receptor concentrations were maximal between days 91 and 130, when fetal adrenal steroid secretion is low; receptor concentrations decreased before term. Fetal hypophysectomy, which resulted in prolonged gestation, raised receptor concentrations in placenta, but not in fetal lung. In both tissues, apparent dissociation constants for [3H]dexamethasone binding to glucocorticoid receptors were in the range 0·5–7·1 nmol/l; these dissociation constants did not change consistently between day 100 and term. In whole-cell preparations of placenta and fetal lung incubated in vitro there was time-dependent specific binding of [3H]dexamethasone by nuclei, and binding of labelled cytosolic receptor to isolated nuclei occurred at all stages of gestation investigated. Binding of [3H]dexamethasone by cytosolic receptor from placenta and fetal lung was inhibited by progesterone and 17α-hydroxyprogesterone, as well as by cortisol, cortisone, 11-deoxycorticosterone and 11β-hydroxyprogesterone; 20α-hydroxyprogesterone and 17α,20α-dihydroxypregn-4-en-3-one were less effective. In experiments to evaluate the possible antagonistic action of progesterone in whole-cell preparations, uptake of [3H]dexamethasone by nuclei was increased up to twofold in placental minces incubated with aminoglutethimide or epostane, when progesterone synthesis was reduced by 98 and 92 per cent respectively. Nuclear uptake in minces of fetal lung was blocked by concentrations of progesterone found in placenta. The existence of a placental glucocorticoid receptor confirms that fetal cortisol may act directly on the placenta to induce the enzymatic changes controlling the onset of labour. Its availability early in pregnancy is consistent with the ability of administered glucocorticoid to induce labour at any time after day 90 of gestation. Progesterone in the placenta may act as a glucocorticoid antagonist, protecting the fetus against inappropriate induction of preterm labour resulting from high levels of glucocorticoids in the maternal circulation.
J. Endocr. (1984) 103, 31–42
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Glucocorticoids regulate corticotropin-releasing hormone (CRH) gene expression in the placenta and the brain. In both the placenta and two extrahypothalamic sites in the brain (the amygdala and the bed nucleus of the stria terminalis), glucocorticoids elevate CRH gene expression. One functional role of the elevation of CRH by glucocorticoids may be to signal adversity. When CRH is over-expressed in the placenta, it may indicate that the pregnancy is in danger, and preterm labor may result. When CRH is over-expressed in the brains of animals, they may become more fearful. Both situations possibly reflect allostatic mechanisms and vulnerability to allostatic overload, a condition in which biological tissue may be compromised.
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Glucocorticoids are known to have diverse effects on the uterus, generally believed to be mediated by the glucocorticoid receptor (GR). To date, two isoforms of the enzyme 11beta-hydroxysteroid dehydrogenase (11betaHSD) have been identified, namely 11betaHSD1 and 11betaHSD2, which interconvert active and inactive glucocorticoids and regulate local levels of hormones available to the GR in target tissues. The aim of the present study was to examine the uterine expression of 11betaHSD and GR mRNA. The interplay of these parameters is probably an important factor in determining actions of glucocorticoids on the uterus. Using Northern analysis we investigated the uterine expression of 11betaHSD1, 11betaHSD2 and GR mRNA in relation to serum levels of sex steroid hormones and uterine progesterone receptor mRNA expression in an animal model. Immature female rats were treated with 10 IU pregnant mare serum gonadotrophin (PMSG) followed by 10 IU human chorionic gonadotrophin (hCG) 48 h afterwards, and then killed at 0, 3, 6, 9, 12 and 24 h and 5 days after the hCG injection. Expression of both 11betaHSD1 and 11betaHSD2 mRNA in total uterine RNA was found to be up-regulated by more than 50% at 48 h after PMSG injection when oestradiol levels were also high. Following hCG treatment the expression of 11betaHSD1 and 11betaHSD2 further increased to reach maximal levels at 24 and 12 h respectively. GR mRNA expression was down-regulated by more than 50% by PMSG but gradually recovered after hCG injection. The results show that mRNA expression of 11betaHSD1, 11betaHSD2 and GR in the uterus is developmentally regulated, suggesting that these key determinants of glucocorticoid action may play an important role in uterine function.
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Adrenal and plasma glucocorticoids were determined in developing chick embryos of Gallus domesticus from days 8 to 19 of incubation, using a competitive protein-binding assay. At the same time, tyrosine transaminase activity in the liver was studied as an adrenal-dependent target function.
Total amounts of glucocorticoids in the adrenal gland increased from day 11 and reached 7 ng/pair of glands on day 19. This increase was related to growth of the adrenal since concentrations remained constant at about 380 pg/μg dry weight from days 9 to 18. Glucocorticoids appeared in the plasma on day 12 and their concentrations rose to 10 ng/ml on day 19, with a marked peak on day 13. This peak was not reflected in the tyrosine transaminase activity which appeared and developed independently of the variations in the circulating glucocorticoids.
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ABSTRACT
The distribution of 1α,25-dihydroxyvitamin D3 (1,25-(OH)2D3) receptors in isolated jejunal villous and crypt cells was investigated in normal and adrenalectomized male rats, and also in animals treated with the synthetic glucocorticoid, dexamethasone, and/or the glucocorticoid antagonist, 11-deoxycortisol. Adrenalectomy caused an increase in 1,25-(OH)2D3 receptors whilst dexamethasone treatment led to a reduction in receptor number. 11-Deoxycortisol was able to reverse the 'down-regulation' effect caused by glucocorticoids. In all cases, the changes in receptor numbers were more pronounced in crypt cells. The data suggest that, in the small intestine, glucocorticoids may control the synthesis of 1,25-(OH)2D3 receptors via the mediation of a glucocorticoid receptor, and that the adrenal hormones mainly express their effect in crypt cells. It is proposed that this phenomenon may, in part, explain the reduction in calcium absorption which occurs in man after chronic glucocorticoid treatment.
J. Endocr. (1984) 103, 295–300
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Glucocorticoids represent one of the most effective clinical treatments for a range of inflammatory conditions, including severe acute inflammation. Although glucocorticoids are known to affect processes involved in the initiation of inflammation, the influence of glucocorticoids on the mechanisms by which acute inflammation normally resolves have received less attention. Apoptosis of granulocytes present at inflamed sites leads to their rapid recognition and internalisation by macrophages, a process which may be important for resolution of inflammation. However, if clearance of either eosinophils or neutrophils is impaired, these cells rapidly undergo secondary necrosis leading to release of pro-inflammatory mediators from the phagocyte, potentially prolonging inflammatory responses. Physiologically relevant concentrations of glucocorticoids accelerate eosinophil apoptosis whilst delaying neutrophil apoptosis during in vitro culture. Here we discuss key pathways regulating the granulocyte apoptotic programme and summarise the effects of glucocorticoids on monocyte differentiation and the consequent changes to apoptotic cell clearance capacity. Definition of the mechanisms underlying resolution of inflammatory responses following glucocorticoid treatment may unveil new targets for modulation of inflammatory disease, allowing co-ordinated augmentation of granulocyte apoptosis together with increased macrophage capacity for clearance of apoptotic cells.
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Regulation of mammary prolactin receptors by steroid hormones was investigated in ovariectomized mid-pregnant mice. Ovariectomy increased the number of mammary prolactin receptors per cell with no effect or a slight decrease in dissociation constant (K d). The simultaneous removal of adrenals prevented this increase in numbers. A single injection of glucocorticoid (corticosterone or cortisol) in ovariectomized–adrenalectomized mice restored the number of prolactin receptors in mammary glands to the same level as that in ovariectomized controls without changing the K d. Aldosterone, deoxycorticosterone and oestradiol did not affect the number of mammary prolactin receptors after ovariectomy–adrenalectomy. Serum concentration of prolactin was not influenced by the hormone manipulation except with injections of oestradiol or cortisol and apparently did not correlate with the number of prolactin receptors. These results indicated that glucocorticoids are required for the increase in the number of mammary prolactin receptors induced by ovariectomy in mid-pregnant mice.
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SUMMARY
The effects of single and continuous administrations of a synthetic gluco-corticoid (dexamethasone) on eosinophil numbers and distribution have been studied. Absolute blood eosinophil counts were made, and the turnover of the eosinophils was examined by continuous infusion of tritiated thymidine to label the deoxyribonucleic acid of all newly formed cells.
Dexamethasone equivalent to less than 200 μg. cortisone/100 g. rat/day produced disappearance of eosinophils from the blood and the normal output of glucocorticoids is therefore probably less than this.
Single administrations of dexamethasone produced a blood eosinopenia within 2 hr. due to removal and destruction of eosinophils by the reticulo-endothelial system. Continuous dexamethasone administration reduced the number of proliferating eosinophil cells in the marrow, with a consequent reduction in the number of eosinophils in the tissues.
