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PubMed1989

Studies on anabolic steroids. I. Integrated methodological approach to the gas chromatographic-mass spectrometric analysis of anabolic steroid metabolites in urine.

The analytical and methodological imperatives for large-scale and routine gas chromatographic-mass spectrometric screening of anabolic steroid urinary metabolites are described. Several aspects of their isolation, enzymatic hydrolysis, derivatization and metabolism in humans are discussed. Gas chromatographic-mass spectrometric data illustrating artifacts arising from enzymatic hydrolysis of 3 beta-ol-5-en steroids, and describing new metabolites of boldenone, methanedienone and stanozolol, as well as the conversion of norethisterone into 19-nortestosterone metabolites through de-ethylation at C-17, are presented. The analytical approach developed for gas chromatographic-mass spectrometric screening of anabolic steroids is based on the sequential selection-ion monitoring of specific and discrete ion groups characteristic to the steroids of interest under high-resolution chromatographic conditions. The major analytical and methodological requirements necessary to provide irrefutable evidence, in the case where the presence of a synthetic anabolic steroid or a testosterone to epitestosterone ratio higher than 6:1 is suspected in a given urine specimen, are also discussed.

Anabolic Agents↗
PubMedDate not supplied

A steroid-sparing effect of ketotifen in steroid dependent asthmatics.

The steroid-sparing effect of ketotifen was studied in 30 steroid-dependent patients with atopic asthma with a mean age of 44 years, using a protocol of 3 consecutive periods of 3 months each. In the first period the average daily consumption of steroids was established. During the second period the patients were given ketotifen, 2 mg daily, which was withdrawn in the third period. The mean daily steroid consumption (prednisolone equivalents) was 11.08 mg in the first period, 3.13 mg in the second and 5.12 mg in the third. During ketotifen treatment steroids could be withdrawn in 12 patients and reduced in another 14 without any deterioration of their clinical state or increase of consumption of symptomatic antiasthmatic drugs.

Adolescent↗
PubMed1979

Testicular steroid secretion and peripheral serum steroid concentrations in patients with prostatic carcinoma after short-term estrogen treatment.

The short-term effects of the administration of estradiol on testicular steroid production were assessed by measuring the serum concentrations of testosterone, and a number of its precursors and metabolites, in the spermatic and peripheral veins of five inguinal hernia patients and one untreated prostatic carcinoma patient, as well as in 18 patients with advanced prostatic carcinoma, treated for 1 to 9 days with a single injection of 80 mg of polyestradiol phosphate (Estradurin). With the exception of progesterone, the treatment resulted in a significantly decreased testicular production of all steroids measured in spermatic vein serum; the same finding holds true for concentrations of testosterone, 5 alpha-dihydrotestosterone, and 17 alpha-hydroxyprogesterone in peripheral vein serum before and after treatment. By comparing the steroid concentrations in the spermatic and peripheral veins it is evident that the testicular production of all steroids measured persisted, although at a decreased level, even 7 to 9 days after Estradurin administration; this was most pronounced in the case of testosterone and 17 alpha-hydroxyprogesterone. It is apparent that the effect of estradiol on testicular steroid production is a gradual process which takes several days before it is clearly evident.

Androgens↗
PubMedDate not supplied

Effects of steroid-free fetal serum and steroid supplementation on MUC1 gene expression in human breast cancer cell line MCF7.

MUC1 is a gene expressed by many normal epithelial tissues and aberrantly expressed by carcinomas. Studies regarding the expression of MUC1 in endometrial tissues and the constitution of its promoter region suggest a possible role for hormonal regulation of this gene. The aim of the present work was to evaluate the regulation of MUC 1 expression by 17 beta-estradiol (E2), progesterone (Pg) and by steroid-free fetal calf serum (FCS) in the hormone-sensitive cell line MCF7. MUC1 mRNA proved to be detectable by means of Northern-blot analysis in MCF7 cells, and its levels were strongly increased in cells grown with 10% steroid-free FCS. By contrast, the steady-state MUC1 mRNA levels of steroid-supplemented cells did not change compared to those of unsupplemented cells (controls). In conclusion, MUC1 expression is regulated by substances present in the steroid-stripped FCS (growth factors, e.g. Insulin-like Growth Factor). The lack of any observed MUC1 modulation by steroids could be due to: a) a low FCS concentration preventing the manifestation (permissive action) of possible gene regulation; b) an immediate stimulatory effect occuring in the first phases of the treatment, which could subsequently be lost.

Breast Neoplasms↗
PubMed1979

Steroid receptors and steroid response in cultured L1210 murine leukemia cells.

Murine L1210 leukemia cells were cultured in the presence of various steroid hormones to determine their growth response. Cells maintained in medium containing glucocorticoids such as dexamethasone exhibit a 10--20% inhibition of growth, whereas progesterone of 17 beta estradiol produce a 40--50% inhibition of growth. The response is due to growth inhibition and not to any cytolytic effect of the steroids. L1210 cytoplasmic and nuclear extracts contain high affinity binding sites for [3H]dexamethasone, [3H]progesterone and [3H]17 beta-estradiol. Competition with various steroids indicate that estrogens bind to one class of cytoplasmic binding sites, while glucocorticoids and progestins bind to a second class of receptor sites. These receptors appear not be be completely responsible for growth inhibition since there is no correlation between the magnitude of growth inhibition and the intracellular concentration of receptor sites, and since the concentration of steroid required to cause significant growth inhibition exceeds those concentrations required to saturate the cytoplasmic receptors.

Animals↗
PubMed2006

Design of an Escherichia coli system for whole cell mediated steroid synthesis and molecular evolution of steroid hydroxylases.

The 15beta-hydroxylase (CYP106A2) from Bacillus megaterium, one of the few bacterial steroid hydroxylases, which has been isolated and characterized so far, catalyses the 15beta-hydroxylation of a variety of steroids. The enzyme can be supported in its activity with adrenodoxin (Adx) and adrenodoxin reductase (AdR) from bovine adrenals, supplying this enzyme with the reducing equivalents necessary for steroid hydroxylation activity. This three-component electron transfer chain was implemented in Escherichia coli by coexpression of the corresponding coding sequences from two plasmids, containing different selection markers and compatible origins of replication. The cDNAs of AdR and Adx on the first plasmid were separated by a ribosome binding sequence, with the reductase preceding the ferredoxin. The second plasmid for CYP106A2 expression was constructed with all features necessary for a molecular evolution approach. The transformed bacteria show the inducible ability to efficiently convert 11-deoxycorticosterone (DOC) to 15beta-DOC at an average rate of 1 mM/d in culture volumes of 300 ml. The steroid conversion system was downscaled to the microtiter plate format and a robot set-up was developed for a fluorescence-based conversion assay as well as a CO difference spectroscopy assay, which enables the screening for enzyme variants with higher activity and stability.

Adrenodoxin↗
PubMed2002

Genomics of steroid hormones: in silico analysis of nucleotide sequence variants (polymorphisms) of the enzymes involved in the biosynthesis and metabolism of steroid hormones.

Alterations of steroid hormone biosynthesis and metabolism are suspected to be involved in the pathogenesis of several diseases. Several polymorphisms of the enzymes involved in these processes have already been described and some could be associated with certain diseases. We attempted to examine the sequence variants of these genes in order to find novel variants by an in silico analysis. We analyzed the known human nucleotide sequences of the enzymes p450 side-chain cleavage enzyme, steroid 17-alpha-hydroxylase/17,20-lyase, 3-beta-hydroxysteroid dehydrogenase types 1 and 2, 21-hydroxylase, 11-beta-hydroxylase, aldosterone synthase, aromatase, 11-beta-hydroxysteroid dehydrogenase types 1 and 2, steroid 5-alpha-reductase types 1 and 2, steroid 5-beta-reductase, dehydroepiandrosterone sulfotransferase, 17-beta-hydroxysteroid dehydrogenase types 1-3. The analysis was performed using the National Center for Biotechnology Information Database by the search tool blastn. We found numerous sequence variants in both coding and non-coding sequences. The majority of these sequence variants have already been described, nevertheless, some appear as novel variants. Some of these may also have functional significance. We hypothesize over the possible significance of these findings and briefly review the available literature.

Base Sequence↗
PubMed2004

Depot differences in steroid receptor expression in adipose tissue: possible role of the local steroid milieu.

Sex hormones play an important role in adipose tissue metabolism by activating specific receptors that alter several steps of the lipolytic and lipogenic signal cascade in depot- and sex-dependent manners. However, studies focusing on steroid receptor status in adipose tissue are scarce. In the present study, we analyzed steroid content [testosterone (T), 17beta-estradiol (17beta-E2), and progesterone (P4)] and steroid receptor mRNA levels in different rat adipose tissue depots. As expected, T levels were higher in males than in females (P = 0.031), whereas the reverse trend was observed for P4 (P < 0.001). It is noteworthy that 17beta-E2 adipose tissue levels were higher in inguinal than in the rest of adipose tissues for both sexes, where no sex differences in 17beta-E2 tissue levels were noted (P = 0.010 for retroperitoneal, P = 0.005 for gonadal, P = 0.018 for mesenteric). Regarding steroid receptor levels, androgen (AR) and estrogen receptor (ER)alpha and ERbeta densities were more clearly dependent on adipose depot location than on sex, with visceral depots showing overall higher mRNA densities than their subcutaneous counterparts. Besides, expression of ERalpha predominated over ERbeta expression, and progesterone receptor (PR-B form and PR-A+B form) mRNAs were identically expressed regardless of anatomic depot and sex. In vitro studies in 3T3-L1 cells showed that 17beta-E2 increased ERalpha (P = 0.001) and AR expression (P = 0.001), indicating that estrogen can alter estrogenic and androgenic signaling in adipose tissue. The results highlighted in this study demonstrate important depot-dependent differences in the sensitivity of adipose tissues to sex hormones between visceral and subcutaneous depots that could be related to metabolic situations observed in response to sex hormones.

3T3-L1 Cells↗
PubMed1989

Rat P450(17 alpha) from testis: characterization of a full-length cDNA encoding a unique steroid hydroxylase capable of catalyzing both delta 4- and delta 5-steroid-17,20-lyase reactions.

A cDNA clone encoding the complete rat 17 alpha-hydroxylase (P450(17 alpha] from testis has been identified and sequenced. The deduced amino acid sequence is found to have 69% similarity with human P450(17 alpha), 64% similarity with bovine P450(17 alpha), and 47% similarity with chicken P450(17 alpha). The protein contains 507 amino acids being one amino acid shorter than the human P450(17 alpha) as the result of a codon being absent at the position of amino acid 139 in the human sequence. The cDNA hybridizes to a single mRNA (approximately 2.0 kilobases) in rat testis RNA and Southern analysis indicates the presence of a single CYP17 gene in the rat genome. Expression of this cDNA in COS1 cells leads to production of a steroid hydroxylase which is capable of converting both 17 alpha-hydroxypregnenolone and 17 alpha-hydroxyprogesterone into C19 steroids, dehydroepiandrosterone, and androstenedione, respectively. This activity profile is distinct from that of either the human or bovine forms of P450(17 alpha) which are unable to catalyze 17,20-lyase conversion of delta 4-C21 steroids to delta 4-C19 steroids at significant rates.

Amino Acid Sequence↗
PubMed1994

Gonadal steroid control of preprocholecystokinin mRNA expression in the limbic-hypothalamic circuit: comparison of adult with neonatal steroid treatments.

The neuropeptide cholecystokinin (CCK) is involved in the regulation of female, but not male, reproductive behavior. In both sexes, estrogen regulates the expression of CCK in adulthood within the bed nucleus of the stria terminalis and medial amygdaloid nucleus. These areas are parts of an interconnected limbic system-hypothalamic circuit, the development of which is influenced by estrogen during the early postnatal period. This is the same period during which central nervous system (CNS) expression of CCK is dramatically increased, suggesting that the male and female patterns of CCK expression may be the result of early postnatal exposure to estrogen. In the present experiment, the expression of preprocholecystokinin (pCCK) mRNA was determined by in situ hybridization with an isotopically labeled pCCK complementary RNA and emulsion autoradiography in animals whose neonatal and adult gonadal steroid levels had been manipulated. The number of pCCK-expressing cells in animals that were gonadectomized as adults was determined by neonatal estrogen, but stimulation with steroids in adulthood induced a similar number of pCCK-expressing cells in both sexes in the medial amygdala and bed nucleus of the stria terminalis. Neonatal treatment of females with estrogen or testosterone, followed by ovariectomy in adulthood, eliminated the sex difference in pCCK mRNA expression. Males treated neonatally with the aromatase inhibitor androstenedione (to block metabolism of testosterone to estrogen) and orchidectomized in adulthood had a level of pCCK mRNA expression that was similar to that of ovariectomized females. These data suggest that, during neonatal development, estrogen determines the constitutive expression of pCCK mRNA in the medial amygdala and bed nucleus of the stria terminalis, resulting in higher levels of pCCK mRNA expression in males than in females. However, exogenous gonadal steroids induce the same levels of pCCK mRNA expression in adult females, indicating that the levels of gonadal steroids and the patterns of their secretion are the predominant influences on the sexually dimorphic adult levels of pCCK mRNA expression.

Aging↗
PubMed1997

Identification of the nonsubstrate steroid binding site of rat liver glutathione S-transferase, isozyme 1-1, by the steroid affinity label, 3beta-(iodoacetoxy)dehydroisoandrosterone.

3beta-(Iodoacetoxy)dehydroisoandrosterone (3beta-IDA), an analogue of the electrophilic substrate, Delta5-androstene-3,17-dione, as well as an analogue of several other steroid inhibitors of glutathione S-transferase, was tested as an affinity label of rat liver glutathione S-transferase, isozyme 1-1. A time-dependent loss of enzyme activity is observed upon incubation of 3beta-IDA with the enzyme. The rate of enzyme inactivation exhibits a nonlinear dependence on 3beta-IDA concentration, yielding an apparent Ki of 21 microM. Upon complete inactivation of the enzyme, a reagent incorporation of approximately 1 mol/mol of enzyme subunit or 2 mol/mol of enzyme dimer is observed. Protection against inactivation and incorporation is afforded by alkyl glutathione derivatives and nonsubstrate steroid ligands such as 17beta-estradiol-3,17-disulfate but, surprisingly, not by Delta5-androstene-3,17-dione or any other electrophilic substrate analogues tested. These results suggest that the site of reaction is within the nonsubstrate steroid binding site of the enzyme, which is distinguishable from the electrophilic substrate binding site, near the active site of the enzyme. Two cysteine residues, Cys17 and Cys111, are modified in nearly equal amounts, despite an average reagent incorporation of 1 mol/mol enzyme subunit. Isolation of enzyme subunits indicates the presence of unmodified, singly labeled, and doubly labeled subunits, consistent with mutually exclusive modification of cysteine residues across enzyme subunits; i.e., modification of Cys111 on subunit A prevents modification of Cys111 on subunit B and similarly for Cys17. Molecular modeling analysis suggests that Cys17 and Cys111 are located in the nonsubstrate steroid binding site, within the cleft between the subunits of the dimeric enzyme.

Affinity Labels↗
PubMed1984

Changes in the activities of microsomal enzymes involved in hepatic steroid metabolism in the rat after administration of androgenic, estrogenic, progestational, anabolic and catatoxic steroids.

Several steroids (5 beta-dihydrotestosterone, 19-nortestosterone, methyltrienolone, norethisterone, medroxyprogesterone acetate, cyproterone acetate, chlormadinone acetate and 16 alpha-cyanopregnenolone) were tested for their ability to influence the activities of three sexually differentiated hepatic microsomal enzymes (3 alpha- and 3 beta-hydroxysteroid dehydrogenase and 5 alpha-reductase) in male and female gonadectomized and intact female rats. Of the steroids tested only 5 beta-dihydrotestosterone was completely ineffective. The other tested steroids elicited varying degrees of "masculinization" with a distinct gradation of effect according to the enzyme activity measured and animal model used. 5 alpha-Reductase was the most sensitive enzyme activity and 3 alpha-hydroxysteroid dehydrogenase the least. Male castrates responded better than female castrates, and these in turn better than intact females. The mechanism of action of three of the steroids (methyltrienolone, medroxyprogesterone acetate and norethisterone) was examined. Both flutamide and estradiol were able to block the action of methyltrienolone and medroxyprogesterone acetate, but not that of norethisterone. It is concluded that methyltrienolone and medroxyprogesterone acetate probably masculinize the enzyme activities by the same mechanisms as androgens, whereas the repression of 5 alpha-reductase activity elicited by norethisterone administration involves a different route.

Aminopyrine N-Demethylase↗
PubMed1988

Quantitative analysis of steroids and steroid glucuronides in the seminal vesicle fluid of feral spawning and feral and cultivated nonspawning African catfish, Clarias gariepinus.

The seminal vesicles of African catfish, Clarias gariepinus, can produce at least seven different steroid glucuronides, especially during the breeding season. In the present experiments quantification of the seven compounds and their free steroids was carried out by means of gas chromatography-mass spectrometry in particular by selected ion monitoring, using seminal vesicle fluid of African catfish collected in the Hula nature reserve (Israel) and from a nearby fish farm. Some of the feral fish were in spawning condition; the others and the pond fish were in nonspawning condition. Compared to the nonspawning groups, in the feral spawning animals a significantly higher level was found especially of 5 beta-pregnane- 3 alpha,17 alpha-diol-20-one-glucuronide, but also of 5 beta-androstane-3 alpha,17 beta-diol-glucuronide, 5 beta-androstane-3 alpha,17 beta-diol-11-one-glucuronide, and 5 beta-pregnane-3 alpha,17 alpha-diol-20-one. The feral and pond nonspawning groups mainly differed in a signficantly higher concentration of 5 beta-pregnane-3 alpha,17 alpha-diol-20-one-glucuronide in the feral nonspawning fish. For the levels of etiocholanolone, testosterone, 5 beta-androstane-3 beta,17 beta-diol, and their glucuronides no significant differences were observed between the three groups, and 5 beta-dihydrotestosterone and its glucuronide could not be detected in the seminal vesicle fluid of any of the animals. The increase in the concentration of three 5 beta-reduced steroid glucuronides may point to a pheromonal function of one or more of these compounds, as demonstrated for the entire steroid glucuronide fraction of the seminal vesicle fluid. Experiments are being carried out to verify this hypothesis.

Androstane-3,17-diol↗
PubMed1985

Stimulation of the synthesis of steroids and steroid sulphates in human testicular tissue in vitro by hCG and by 8-bromo-cyclic AMP.

Small pieces (10-20 mg) of human testis tissue were incubated for 4 h in the presence or absence of hCG and 8-bromo-cAMP and the concentrations of testosterone, some of its steroidal precursors, and their sulphates were measured by radioimmunoassays. The results showed, we believe for the first time, that the production of steroid sulphates as well as of unconjugated steroids can be stimulated in human testis tissue in vitro and they confirm earlier observations in vivo which suggested that testicular production of steroid sulphates can be stimulated by hCG.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1989

Specificity of steroid binding to testicular microsomal cytochrome P-450. Relation of steroid structure to type-I spectral responses after correction for hydrophobic association with the membrane.

On the basis of the concept that steroids accumulate in the lipid phase of endoplasmic reticulum membranes and approach the active sites of steroidogenic cytochromes P-450 from a hydrophobic environment, we describe a procedure that allows calculation of spectral dissociation constants Ks for steroid interaction with testicular microsomal cytochrome P-450 after correction for hydrophobic association of ligand with the membrane. Maximal type-I spectral responses, apparent Ks, and partition into microsomal lipids were determined for 36 steroids, and corrected Ks values were derived from these primary data. Partition coefficients range from 60 to 62,000, and corrected Ks range from 60 microM to 25 mM steroid concentration in the lipid phase. Full spectral properties depend on a side-chain (1-3 carbon atoms) at the C17-position which may be hydrophobic or may bear a 20-oxo or 20 beta-hydroxy, but not a 20 alpha-hydroxy group. Binding constants are especially sensitive towards modifications of ring A structure (aromatization or 5 beta-, but not 5 alpha-reduction) and of the side-chain length. Androgens, with the exception of those bearing a 17 beta-acetoxy or 17 beta-propionyloxy group, are poorly accommodated by this cytochrome P-450.

Animals↗
PubMed1989

Biotransformation, estrogenicity, and steroid structure as determinants of dysmorphogenic and generalized embryotoxic effects of steroidal and nonsteroidal estrogens.

A series of nine chemicals of varying structure and estrogenicity was investigated for biochemical determinants of their relative capacities to alter normal embryonic growth and developmental patterns during organogenesis in rats. In order to circumvent the potentially confounding influences of maternal factors, the direct effects of steroidal and nonsteroidal estrogens on cultured whole embryos were compared at concentrations producing readily measurable embryotoxicity but low embryolethality (2-20%). Nonsteroidal estrogens included were diethylstilbestrol (DES), hexestrol (HES), E,E-dienestrol (alpha-DIES), and tamoxifen (TAM). Steroidal estrogens were estradiol 17 beta (E2), estrone (E1), and 17 alpha-ethinylestradiol 17 beta (EE). For comparative purposes, the effects of two essentially nonestrogenic phenols, Z,Z-dienestrol (beta-DIES) and phenol, were also studied. TAM, a weak estrogen which also exhibits antiestrogenic properties, was studied for possible interactive effects with potent estrogens. Prosencephalic hypoplasia was the abnormality most consistently observed and was elicited by each of the chemicals investigated. Embryotoxicity was neither attenuated by TAM nor related to estrogenic potency or steroidal structure, but was strongly and unpredictably influenced by biotransformational determinants. Presence of a cytochrome P450-dependent oxidizing system in the culture medium resulted in marked increases in embryotoxicity of E1, E2, and phenol, only minor increases for beta-DIES and alpha-DIES, but in strikingly decreased effects of EE, TAM, and HES. It produced no statistically significant differences in effects of DES. The results obtained were compatible with the concept that effects of these agents on growth and development during the earlier stages of organogenesis are independent of steroid structure or estrogenic activity but strongly dependent upon pathways and rates of biotransformation of some (but not all) of the parent chemicals.

Abnormalities, Drug-Induced↗
PubMed1982

Some theoretical questions of the peptide and steroid hormone regulation. Part III.: The RLVC hypothesis as a possible mode for the interaction of the peptide and steroid hormone regulation.

My previous models for peptide and steroid hormone actions, in accordance with their biological and molecular-informational requirements, suggested possible mechanisms for the subcellular interactions of the two regulatory systems. In my hypothesis the homogeneous or heterogeneous multiligand binding-proteins (receptors, characterized previously) have the ability to bind both steroids and (cyclic) nucleotide phosphates in a unique distribution and sequence. The specificity of such a Receptor-Ligand Variable Complex (RLVC), the pattern of the steroid and/or (cyclic) nucleotide phosphate ligands, is determined by the equilibrium between the actually acting steroids and peptides on the one hand and by the binding possibilities of the receptor on the other.

Animals↗
PubMed1990

Studies on the mechanism of steroid 5 alpha-reductase inhibition by 3-carboxy A-ring aryl steroids.

The mechanism of interaction between two 3-carboxy A-ring aryl steroids, 17 beta-(N,N-diisopropylcarboxamide)-estra-1,3,5(10)-triene-3-carboxy lic acid (1) and 17 beta-(N-t-butylcarboxamide)-estra-1,3,5(10)-triene-3-carboxylic acid (2), with rat hepatic and human prostatic steroid 5 alpha-reductases has been investigated. Dead-end inhibition plots with 1 and 2 versus both substrates (testosterone and NADPH) were linear-uncompetitive using either enzyme, while double-inhibition analyses indicated cooperative binding to enzyme between NADP+ and 1 or 2. These results were interpreted within the ordered kinetic mechanism of steroid 5 alpha-reductase to result from the preferential association of 3-carboxy A-ring aryl steroids to the enzyme-NADP+ complex. The direct displacement by 2 of a radioligand known to associate to this same enzyme form provides further support for these conclusions.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗