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At least 73 records · Page 4Linked to original sources
PubMed1987

Progression to steroid insensitivity can occur irrespective of the presence of functional steroid receptors.

A major problem in treatment of cancers arising in steroid-sensitive cells is their inevitable progression to a steroid-insensitive state; current therapies are based on the assumption that hormone insensitivity is associated with loss of receptor. We demonstrate for the first time that breast tumor cells can progress to steroid insensitivity in spite of functional steroid receptors. Transfection of the steroid-inducible LTR-C3 gene into unresponsive S115 mouse mammary tumor cells results in full inducibility of that gene with both androgen and glucocorticoid. Thus, although all known endogenous inducible parameters are lost, the steroid sensitivity of a transfected exogenous gene demonstrates that the machinery for steroid responsiveness is still fully functional. Furthermore, these transfected genes retain steroid sensitivity only while steroid is present; on prolonged withdrawal of steroid, they lose responsiveness, implying an epigenetic mechanism is involved.

Androgen-Binding Protein↗
PubMed1992

Studies on anabolic steroids--12. Epimerization and degradation of anabolic 17 beta-sulfate-17 alpha-methyl steroids in human: qualitative and quantitative GC/MS analysis.

The epimerization and dehydration reactions of the 17 beta-hydroxy group of anabolic 17 beta-hydroxy-17 alpha-methyl steroids have been investigated using the pyridinium salts of 17 beta-sulfate derivatives of methandienone 1, methyltestosterone 4, oxandrolone 7, mestanolone 10 and stanozolol 11 as model compounds. Rearrangement of the sulfate conjugates in buffered urine (pH 5.2) afforded the corresponding 17-epimers and 18-nor-17,17-dimethyl-13(14)-enes in a ratio of 0.8:1. These data indicated that both epimerization and dehydration of the 17 beta-sulfate derivatives were not dependent upon the respective chemical features of the steroids studied, but were instead inherent to the chemistry of the tertiary 17 beta-hydroxy group of these steroids. Interestingly, in vivo studies carried out with human male volunteers showed that only methandienone 1, methyltestosterone 4 and oxandrolone 7 yielded the corresponding 17-epimers 2, 5 and 8 and the 18-nor-17,17-dimethyl-13(14)-enes 3, 6 and 9 in ratios of 0.5:1, 2:1 and 2.7:1, respectively. No trace of the corresponding 17-epimers and 18-nor-17,17-dimethyl-13(14)-enes derivatives of mestanolone 10 and stanozolol 11 was detected in urine samples collected after administration of these steroids. These data suggested that the in vivo formation of the 17-epimers and 18-nor-17,17-dimethyl-13(14)-enes derivatives of 17 beta-hydroxy-17 alpha-methyl steroids is also dependent upon phase I and phase II metabolic reactions other than sulfation of the tertiary 17 beta-hydroxyl group, which are probably modulated by the respective chemical features of the steroidal substrates. The data reported in this study demonstrate that the 17-epimers and 18-nor-17,17-dimethyl-13(14)-enes are not artifacts resulting from the acidic or microbial degradation of the parent steroids in the gut as previously suggested by other authors, but arise from the rearrangement of their 17 beta-sulfate derivatives. Unchanged oxandrolone 7 was solely detected in the unconjugated steroid fraction whereas unchanged steroids 1, 4 and 11 were recovered from the glucuronide fraction. These data are indirect evidences suggesting that the glucuronide conjugates of compounds 1 and 4 are probably enol glucuronides and that of compound 11 is excreted in urine as a N-glucuronide involving its pyrazole moiety. The urinary excretion profiles of the epimeric and 18-nor-17,17-dimethyl-13(14)-ene steroids are presented and discussed on the basis of their structural features.

Adult↗
PubMed1995

Enhanced risk of steroid-resistant acute rejection following pretransplant steroid therapy in liver graft recipients.

Most episodes of acute rejection will resolve after steroid therapy without detrimental consequences on the liver allograft. However, steroid-resistant acute rejection may induce irreversible lesions of the graft and is associated with an increased risk of chronic rejection. The aim of this study was to determine whether there were predictive factors for steroid-resistant acute rejection after liver transplantation. A total of 108 adult liver recipients with a follow-up of at least 2 years have been analyzed; sixty-two (57%) patients had at least one episode of acute rejection. The rates of steroid resistance were 35%, 52% and 83% after a first (n = 62), second (n = 25), or third (n = 7) episode of acute rejection, respectively. Steroid resistance of acute rejection was significantly associated with a past history of pretransplant steroid therapy (P = 0.004). High levels of ALT (P = 0.03) and serum bilirubin (P = 0.002) were also predictive of steroid-resistant acute rejection. Eight (7%) patients eventually developed chronic rejection. Predictive factors for chronic rejection included steroid-resistant acute rejection (P = 0.01), recurrent acute rejection (P = 0.03), and CMV infection (P = 0.01). In conclusion, this study suggests that pretransplant steroid administration or high levels of ALT and bilirubin in rejecting patients are risk factors for steroid resistance and should lead to aggressive antirejection therapy without delay.

Adolescent↗
PubMed2001

Risk of steroid withdrawal in pediatric renal transplant patients with suspected steroid toxicity.

BACKGROUND: Glucocorticoids are still a cornerstone in immunosuppressive regimens in pediatric patients after renal transplantation (Tx). Due to the side effects, steroid withdrawal may significantly improve the appearance and growth of children with renal grafts, but bears a substantial risk for late rejections. AIM OF THE STUDY: To investigate whether exclusion of subclinical acute rejection by renal histology in combination with a prolonged steroid withdrawal period is predictive of a successful outcome. PATIENTS AND METHODS: Ten children (5 females) with a median age of 12.3 (range 7.9-20.9) years and 1.8 (0.7-7.5) years after Tx with a stable graft function and a median calculated creatinine clearance (C(Cr)) of 71 (60.5-99.7) ml/min/1.73 m2 were included. All patients showed steroid toxicity signs. Immunosuppressive regimen included low-dose steroids (median 2.72 mg/m2) in all patients, in addition to cyclosporin A (CsA) and azathioprine in 8, CsA on its own and CsA combined with mycophenolate mofetil in one patient each. A graft biopsy was performed in 8 patients prior to the start of steroid withdrawal, which was done over a median period of 6 months. Renal function was calculated as creatinine clearance using the Schwartz formula. RESULTS: None of the biopsied grafts showed histologic signs of rejection. Cyclosporin A dosage and trough levels were not significantly different before and after steroid withdrawal. While steroid side effects improved in most of the patients after withdrawal, C(Cr) decreased significantly within a median observation time of 42 (11.4-49.3) months. This decrease was due to loss of renal function in 4 patients who had biopsy-proven rejection episodes at 21.6 (8.1-29.9) months after the start of steroid withdrawal. CONCLUSION: Slow steroid withdrawal in pediatric Tx patients using conventional immunosuppression reduces side effects, but bears a high risk of late rejection. A pre-withdrawal renal biopsy was not useful for the prediction of successful steroid withdrawal.

Acute Disease↗
PubMed1996

Steroid receptor-mediated effects of neuroactive steroids: characterization of structure-activity relationship.

Neuroactive steroids rapidly alter neuronal excitability through their action via the cell surface. The 3 alpha-hydroxy ring A-reduced pregnane steroids enhance gamma-aminobutyric acid (GABA)-mediated Cl- currents while pregnenolone sulfate and dehydroepiandrosterone sulfate may exert functional antagonistic properties. Based on our previous findings that the 3 alpha-hydroxy ring A-reduced pregnane steroids allotetrahydroprogesterone and allotetrahydrodeoxycorticosterone may regulate gene expression via the progesterone receptor after intracellular oxidation, we have characterized the effects of a series of natural and synthetic neuroactive steroids at the genomic level using a cotransfection system with various steroid receptor expression vectors and a reporter gene in a human neuroblastoma cell line. Pregnanolone and pregnenolone were able to activate both the chicken and the human progesterone receptor while the synthetic 3 alpha-hydroxylated derivative alphaxalone and dehydroepiandrosterone were active via the chicken progesterone receptor but devoid of transcriptional activity via the human progesterone receptor. Moreover, the antiglucocorticoid activity of dehydroepiandrosterone reported at the systemic level could not be reconstituted in the cellular cotransfection system. None of the neuroactive steroids bound directly to steroid receptors. Thus, their genomic activity appears to be mediated via intracellular metabolization. This study provides evidence for differential genomic effects of neuroactive steroids in a structure-specific and species-specific way that may have impact on the development of these steroids for therapeutic application.

Animals↗
PubMed1994

Steroid-binding and dimerization domains of human sex hormone-binding globulin partially overlap: steroids and Ca2+ stabilize dimer formation.

Human sex hormone-binding globulin (SHBG) is a homodimeric plasma glycoprotein with a single steroid-binding site for biologically active sex steroids, and a methionine at position 139 (M139) interacts with the photoaffinity ligand, delta 6-testosterone. We have introduced amino acid substitutions into this and other locations in the SHBG molecule and have examined their impact on steroid binding and dimerization. As a result, substitutions at residues 134-139 generate alterations steroid-binding specificity. In particular, substitutions at residues 134-138 were characterized by altered binding affinities for estradiol relative to 5 alpha-dihydrotestosterone (DHT), and one of them (R135L) also showed a 2-fold increase in affinity for C19 steroids with a 3 beta-hydroxy group. Unlike all of the other mutants we have examined, the M139W mutant has a 5-fold lower affinity for DHT, and its affinities for testosterone, 5 alpha-androstane-3 beta, 17 beta-diol, and estradiol also appear to be reduced to a similar extent. By contrast, M139W appears to bind androst-5-ene-3 beta, 17 beta-diol with only 2-fold less affinity than wild-type SHBG, while its affinity for 19-nortestosterone remains unaffected. Substitutions at other positions, including those immediately C-terminal to M139, had no effect on steroid-binding affinity and/or specificity. These data provide evidence that residues 134-139 influence the recognition of specific A/B ring conformations of steroid ligands and may constitute part of the steroid-binding domain. We have also found that substitutions at residues 138-148 impair dimerization and that this defect may be abrogated by occupancy of the steroid-binding site.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding Sites↗
PubMed1996

Levels of plasma C19 steroids and 5 alpha-reduced C19 steroid glucuronides in primates, rodents, and domestic animals.

In this study, a comparison of circulating levels of androsterone glucuronide and androstane-3 alpha, 17 beta-diol glucuronide in the male and female of several mammalian species was performed. Glucuronidated steroids were not detected in the circulation of the dog, bovine, swine, and rodent. High levels of circulating glucuronidated steroids were measured in the cynomolgus monkey and found to be 10-fold higher than in humans. The determination of tissue levels of unconjugated and conjugated C19 steroids was then performed in intact and castrated rats treated with androgens. Steroid glucuronides were not detected in the plasma, skin, prostate, or liver of either intact or treated rats, although the levels of unconjugated steroids in the plasma and tissues were increased after steroid treatments. Significant levels were detected in the bile, thus suggesting hepatic formation of steroid glucuronides in the rat. It is suggested that the monkey represents the best animal model to date to study the contribution of diphosphoglucuronosyltransferases present in steroid target peripheral tissues to circulating levels of steroid glucuronides.

Aging↗
PubMed1992

Effect of chronic ACTH treatment on guinea-pig adrenal steroidogenesis: steroid plasma levels, steroid adrenal levels, activity of steroidogenic enzymes and their steady-state mRNA levels.

We report here the effects of a 7-day treatment of guinea-pigs with ACTH on adrenal mRNA levels for steroid-transforming enzymes. Adrenal 3 beta-hydroxysteroid dehydrogenase 4-ene-5-ene-isomerase (3 beta-HSD), 17-hydroxylase, 17,20-lyase, 21-hydroxylase and 11-hydroxylase activities were also examined as well as plasma and adrenal steroid levels. Our data reveal that chronic ACTH-treatment stimulated all post-pregnenolone enzyme activities in glomerulosa-fasciculata cells. Plasma steroid levels increased 8 h after the last injection of ACTH and returned to the control levels 24 h later whereas, in the adrenal, the content in steroids in the group sacrificed 8 h after the last injection of ACTH were similar to the values of the control group and decreased markedly 24 h later. It is suggested that the steroid turn-over in the adrenal may be affected by the chronic ACTH-treatment. On the other hand, despite the significant stimulation in steroid-transforming enzyme activities, our data reveal that chronic ACTH administration caused a decrease in mRNA levels for P450c21 and P450c17 while P450scc, 3 beta-HSD and P450c11 remained unchanged. Taken together, these results suggest that in vivo chronic ACTH-treatment of guinea-pigs increases adrenal steroidogenic capacity by increasing steroid secretion and steroid enzyme activity. Moreover, the chronic treatment with ACTH may have a post-transcriptional effect on steroidogenic enzymes gene expression by affecting the half-life of their mRNAs.

3-Hydroxysteroid Dehydrogenases↗