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Query: UMLS:C0338671 (Steroids)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies demonstrate that primary (hereditary) abnormalities in the glucocorticoid receptor gene make 6.6% of the normal population relatively "hypersensitive" to glucocorticoids, while 2.3% are relatively "resistant." These abnormalities might explain why some individuals develop severe adverse effects during low dose glucocorticoid therapy, while others do not develop side effects even during long-term therapy with a much higher dose. Awareness of this heterogeneity in glucocorticoid sensitivity in the normal population might eventually allow the prediction of a "safe" dose of glucocorticoid in individual patients. "Resistance" to the beneficial clinical effects of glucocorticoid therapy in part of the patients with severe rheumatoid arthritis and asthma is probably rarely related to generalized primary (hereditary) glucocorticoid resistance. In the majority of patients this "resistance" seems to be acquired and localized to the sites of inflammation, where it reflects high local cytokine production, which interferes with glucocorticoid action. Recognition of localized, acquired glucocorticoid resistance is of great importance indicating as alternative drug therapy with other immune-modulating drugs like cyclosporin and methotrexate. Chronic high dose glucocorticoid treatment in such patients is ineffective in alleviating symptomatology, while generalized side effects occur, reflecting the patient's normal systemic sensitivity to these drugs.
Steroids 1996 Apr
PMID:Clinical aspects of glucocorticoid sensitivity. 873 92

Generalized inherited glucocorticoid resistance (GIGR) is a rare syndrome characterized by elevated levels of plasma cortisol but lacking the symptoms of Cushing's syndrome. Biochemically, the condition is characterized by a relative resistance to glucocorticoids that can be compensated for by the elevated levels of cortisol. The inheritance pattern of GIGR is incompletely understood, and one of the central questions is whether there is a correlation between genotype and phenotype. Analysis of mutations within the receptor resulting in relative glucocorticoid resistance has identified two regions of clustered mutations in the proximity of previously identified affinity-labeled residues, the putative steroid-binding site. In the majority of cases, the mutation affects steroid binding and transactivation to the same degree, with the exceptions suggesting an explanation for the variability of the clinical manifestations. From a clinical point of view, in addition to preexisting genetic resistance to glucocorticoids, it is important to consider acquired changes in glucocorticoid receptor (GR) gene structure and organization, including alterations of noncoding sequences, and the importance of the resultant mutations, deletions, and other changes affecting receptor function. Finally, studies of New World primates and cell lines derived from hematologic malignancies constitute animal and human models for the molecular basis of glucocorticoid resistance where a number of inherited and acquired mutations in the GR gene have been demonstrated.
Steroids 1996 Apr
PMID:Molecular basis of glucocorticoid-resistant syndromes. 873 4

Steroid and thyroid hormones act on nuclear gene transcription by activating protein receptors, which in turn bind to hormone response elements (HREs). Among these cell-specific processes regulated by steroid receptors is energy metabolism through increased synthesis of respiratory enzymes. As some of these enzymes are encoded by both nuclear and mitochondrial genes, coordination of their synthesis is probable, inter alia at the transcriptional level. We have postulated a direct effect of steroid hormones on mitochondrial gene transcription and here present the following evidence in support of this hypothesis. 1) The human and rodent mitochondrial genomes contain nucleotide sequences similar both to type I and type II HREs. 2) Glucocorticoid receptors (GR) rapidly translocate from the cytoplasm into mitochondria after administration of glucocorticoids. This process has been reproduced in vitro and deletion of the N-terminal part of the glucocorticoid receptor stops translocation into mitochondria. 3) Gel shift analysis has demonstrated binding of GR to putative mitochondrial GR elements. 4) In transfection experiments, mitochondrial HREs confer dexamethasone inducibility on hybrid reporter constructs, abolished in the presence of excess RU38486. 5) Similar results were obtained for thyroid hormone receptor (TR alpha) localization, import, and binding to TR elements. These findings, taken with the demonstrated effects of steroid (and thyroid) hormones on mitochondrial transcription and respiratory enzyme biosynthesis, strongly support the hypothesis of a direct effect of steroid (and thyroid) hormones on mitochondrial gene transcription.
Steroids 1996 Apr
PMID:Mitochondrial genes as sites of primary action of steroid hormones. 873 6

To understand the role of glucocorticoid and mineralocorticoid signalling during development and in whole animal physiology, we have disrupted the mouse glucocorticoid and mineralocorticoid receptor gene by gene targeting. Most of the mice with a disrupted glucocorticoid receptor gene die within the first hours after birth due to severe lung atelectasis. Perinatal induction of gluconeogenic enzymes in the liver is impaired. Regulation of the glucocorticoid synthesis via the hypothalamic-pituitary-adrenal axis is perturbed, leading to increased plasma levels of corticosterone and adrenocorticotrophic hormone. Activation of the hypothalamic-pituitary-adrenal axis results in extensive hypertrophy and hyperplasia of the cortical zones of the adrenal and induction of genes involved in steroid biosynthesis. The adrenal medulla is disorganized and severely reduced in size; no cells capable of adrenaline synthesis can be detected. Mineralocorticoid receptor deficient mice die mainly at day 9/10 after birth. Weightloss precedes death of homozygous mutant mice and is correlated with an increase in the haematocrit. As a consequence of this mutation, plasma levels of renin and aldosterone are high elevated.
Steroids 1996 Apr
PMID:Molecular genetic analysis of glucocorticoid and mineralocorticoid signaling in development and physiological processes. 873 8

Glucocorticoid hormones convert the glucocorticoid receptor (GR) from an inactive cytosolic complex to a nuclear form that regulates transcription. Binding of GR to palindromic DNA-recognition sites (hormone response elements) leads to activated target gene transcription. GR also exerts negative actions on transcription, e.g., by interfering with the function of several other transcription factors such as AP-1, NK-kappa B, CREB, and Oct-1. Physical interactions of GR with AP-1 subunits are readily detectable but do not seem sufficient since nonrepressing GR mutants still interact in vitro, so that specific conformational changes and/or interactions with additional partner proteins may be required for negative action. In an attempt to find such partner proteins, we defined regions of c-Jun and GR essential for mutual interference and used in those a yeast two-hybrid screen for interacting proteins. Repeatedly we isolated overlapping cDNA sequences of one protein interaction with both c-Jun and GR. This protein does not interact with c-Fos or a non-repressing GR mutant and expressed in mammalian cells does not substantially affect AP-1 or GR activity. Interestingly, however, the protein rescues yeast cells from the toxic effects of the GR fragment used for screening. The protein represents the human homologue of the yeast E2 ubiquitin-conjugating enzyme, Ubc9; its specific interactions with both GR and c-Jun, but not mutant GR, suggest that it may exert physiologic regulatory functions.
Steroids 1996 Apr
PMID:Interaction of the Ubc9 human homologue with c-Jun and with the glucocorticoid receptor. 873 11

Recent studies have demonstrated that the interconversion of active and inactive glucocorticoids plays a key role in determining the specificity of the mineralocorticoid receptor and controlling local tissue glucocorticoid receptor activation. Two distinct isoforms of the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) have been identified. 11 beta-HSD1 is NADPH-dependent and at its major site of action (the liver) is a reductase, converting cortisone to cortisol (11-dehydrocorticosterone to corticosterone in the rat). 11 beta-HSD2 is NAD-dependent, is present in tissues such as the kidney and placenta, and converts cortisol to cortisone (corticosterone to 11-dehydrocorticosterone in the rat). Congenital or acquired deficiency of 11 beta-HSD2 produces the syndrome of apparent mineralocorticoid excess (SAME) in which cortisol gains access to the unprotected nonspecific mineralocorticoid receptor. The congenital deficiency is associated with mutations in the gene encoding the kidney isoform of 11 beta-HSD2; the acquired form results from inhibition of the enzyme by licorice, carbenoxolone, ACTH-dependent steroids in the ectopic ACTH syndrome, and possibly circulating inhibitors of the enzyme. This paper focuses on recent evidence, which suggest that low levels of placental 11 beta-HSD2 result in increased exposure of the fetus to maternal glucocorticoid and low birth weight. In animal studies using the rat we have shown that birth weight is correlated positively and placental weight negatively with the level of placental 11 beta-HSD. Thus animals with low birth weight and large placentae were those likely to be exposed to the highest level of maternal glucocorticoid. In man a similar relationship was found with birth weight being significantly correlated either with placental 11 beta-HSD activity or with the extent of cortisol inactivation by isolated perfused placental cotyledons. Administration of dexamethasone (which is poorly metabolized by placental 11 beta-HSD2) to pregnant rats resulted in decreased birth weight and the development of hypertension in the pups when adult. The same results were obtained when pregnant rats were given carbenoxolone, an inhibitor of placental 11 beta-HSD2. Low protein diet during pregnancy in the rat resulted in low birth weight of the pups, increased placental weight but decreased placental 11 beta-HSD activity, and adult hypertension. Thus increased glucocorticoid exposure of the fetus secondary to a failure of the normal inactivation of maternal glucocorticoid by the placental may be an important mechanism linking changes in the in utero environment and common adult diseases.
Steroids 1996 Apr
PMID:11 beta-Hydroxysteroid dehydrogenases: key enzymes in determining tissue-specific glucocorticoid effects. 873 12

The use of the synthetic progestin medroxyprogesterone acetate (MPA) for estrus prevention in the dog can result in overproduction of growth hormone, suppression of plasma glucocorticoid levels, and the induction of mammary tumors. Proligestone (PROL) was claimed to be devoid of these unwanted side effects. In the present study, the binding characteristics of MPA and PROL for the canine progesterone receptor (PR) and glucocorticoid receptor (GR) were investigated. The apparent inhibition constants for the PR and GR of MPA and PROL were compared with those of progesterone, ORG 2058, and a number of corticosteroids. MPA and PROL had high affinities for both the PR and the GR. The rank order for displacement of the binding of the PR ligand [3H]ORG 2058 from the canine uterine receptor was: MPA approximately ORG 2058 > PROL > progesterone >> cortisol, dexamethasone, and spironolactone. The rank order for displacement of the specific binding of the GR ligand [3H]dexamethasone from the canine liver receptor was: dexamethasone > cortisol > MPA > PROL > progesterone >> aldosterone approximately spironolactone. The apparent inhibition constants of PROL for both the PR and the GR were approximately 10 times higher than those of MPA. The ratios of the inhibition constants for the GR and PR appeared to be equal for PROL and MPA. It is concluded that although MPA has higher affinities for the PR and GR than PROL, both progestins have a similar in vitro binding specificity, which is less than that of progesterone. These findings are consistent with suppression of the adrenal cortex and the induction of growth hormone secretion in the mammary gland after MPA and PROL treatment in dogs.
Steroids 1996 Mar
PMID:Binding specificity of medroxyprogesterone acetate and proligestone for the progesterone and glucocorticoid receptor in the dog. 885 30

Steroids have the ability to alter adipose tissue distribution. Controversy exists as to whether these effects of sex hormones (oestrogen, progesterone and testosterone) on human adipose tissue are indirect or direct, as only very few studies have focused on steroid receptor status in human adipose tissue. In the present study, we reinvestigated steroid receptor status in human mature adipose tissue and human preadipocytes. Oestrogen, glucocorticoid and androgen receptors were found in human mature adipocytes from both women and men. The receptors were detected by ligand binding. Furthermore, the existence of the receptors was confirmed by demonstrating that adipocytes contained mRNA encoding the receptors. cDNA was generated using reverse transcriptase (RT) followed by polymerase chain reaction (PCR) amplification using specific primers (RT-PCR) for the specific steroid receptors. Adipocytes did not contain mRNA encoding the progesterone receptor (PR), and no progesterone binding was detectable in human adipocytes. Human preadipocytes contained glucocorticoid receptor (GR) mRNA and androgen receptor (AR) mRNA, whereas we were unable to detect oestrogen receptor (ER) mRNA and progesterone mRNA in human preadipocytes. In conclusion, oestrogen glucocorticoid and androgen receptors are present in mature adipocytes from subjects of both sexes, whereas adipocytes do not contain progesterone receptors. In preadipocytes, only glucocorticoid receptors and androgen receptors are present, whereas oestrogen receptors and progesterone receptors are not present.
 ...
PMID:Identification of steroid receptors in human adipose tissue. 901 78

11 beta-hydroxyprogesterone (HOP) and 11-ketoprogesterone (KP) are reversible components of a shuttle pair whose interconversion in rat liver is catalyzed by isoform-1 of 11 beta-hydroxysteroid dehydrogenase. Kidneys also produce this interconversion. The present study was carried out to investigate the shuttle pair and its components in the rat. As in corticosterone/11-dehydrocorticosterone, oxidation is more effective at an alkaline pH, while reduction prevails at a neutral pH. Moreover, both reactions are inhibited by the detergent 3-[(3-cholamido propyl)-dimethylammonio]-1-propane-sulphonate (CHAPS). However, at variance with the 11-ketosteroids cortisone (E) and 11-dehydrocorticosterone (A) thought to be "inactive," KP has slight direct Na(+)-retaining properties, and it, as well as HOP, induces glucocorticoids (11 beta-hydroxycorticoids) to retain sodium. 11-ketoprogesterone exhibits 17 times better affinity for native type 1 mineralocorticoid receptor than HOP and a 3-fold affinity for partially purified (transcortin free) mineralocorticoid receptor. However, KP, in contrast to HOP, binds only weakly to transcortin, not at all to glucocorticoid receptor, and requires reduction at C11 for tyrosine aminotransferase (TAT) induction.
Steroids 1997 Apr
PMID:Features of the shuttle pair 11 beta-hydroxyprogesterone-11-ketoprogesterone. 909 Jul 96

Carbenoxolone potentiates the mineralocorticoid activity of endogenous glucocorticoid hormones by inhibiting the enzyme 11 beta-hydroxysteroid dehydrogenase, which converts cortisol and corticosterone to inactive 11-oxo-derivatives. We addressed the question of whether glucocorticoid activity is also affected by carbenoxolone. Using a rat model involving low dose corticosterone treatment, we found that carbenoxolone neither potentiated nor inhibited the modest increases in blood pressure or reductions in weight gain caused by steroid treatment. Other indices of glucocorticoid activity including white blood cell number, thymus weight, and down regulation of the glucocorticoid receptor were unaffected. In vitro studies with liver and kidney cytosol preparations indicated that carbenoxolone did compete for 3H-dexamethasone binding sites. Carbenoxolone was 5-10 times more effective than glycyrrhetinic acid, 20-30 thousand times less effective than dexamethasone, and is therefore, approximately 1000 times less effective than corticosterone. Analysis of dexamethasone-binding curves indicated a single class of receptor. We conclude that carbenoxolone at the dose tested does not have intrinsic glucocorticoid activity in vivo, nor does it modulate the activities of corticosterone. Carbenoxolone binds weakly to the glucocorticoid receptor. It is not clear whether this weak affinity accounts for some or any of the direct in vitro effects of high concentrations of carbenoxolone that others have described.
Steroids 1997 Apr
PMID:In vivo and in vitro effects of carbenoxolone on glucocorticoid receptor binding and glucocorticoid activity. 909 Aug


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