Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0338671 (Steroids)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The spontaneously hypertensive rat (SHR) has a Y chromosome locus that increases blood pressure. This locus requires an androgen receptor and testosterone for maximum expression. Steroid sulfatase (STS) catalyzes the conversion of steroid sulfates to their active nonconjugated form. In some mammals the steroid sulfatase locus (Sts) is on the Y chromosome, although the rat Sts is on the X chromosome. We measured STS activity levels in SHR and normotensive Wistar Kyoto (WKY) males. SHR had significantly higher STS activity in testes, adrenal gland, liver, and hypothalamus. The Km values for STS in the two strains were not significantly different; thus, activity differences were likely due to differences in enzyme amounts. STS activity was measured in the backcross strains SHR/y and SHR/a to test and/or confirm a Y chromosome influence on STS. STS activity levels in these strains were intermediate between those of SHR and WKY. Because the blood pressures of SHR/y and SHR/a were also intermediate between SHR and WKY, the STS activity could be a secondary response to the hypertension. An alternative hypotheses is that a regulatory locus in addition to the structural locus is responsible for STS activity levels, and this regulatory locus is on the rat Y chromosome. Further study is needed to discriminate between these possibilities, and until the second hypothesis can be eliminated, the Sts locus or its modifier loci remain a potential component of the Y chromosome hypertensive locus.
Steroids 1995 Oct
PMID:Steroid sulfatase and the Y chromosome hypertensive locus of the spontaneously hypertensive rat. 853 76

During our studies of the hepatic androgen receptor in cynomolgus monkeys, tritiated mibolerone +/- a 200-fold excess of unlabeled mibolerone has been used to determine specific binding in cytosol. During time-course studies, high-capacity, unsaturable binding of [3H]mibolerone was noted after short-term incubations (4 h, 4 degrees C). When hepatic cytosol from male monkeys was incubated for 18 h at 4 degrees C, the high-capacity binding disappeared; saturable, high-affinity binding with characteristics consistent with the androgen receptor then could be identified. The characterization of [3H]mibolerone binding in molybdate-stabilized hepatic cytosol using sucrose density gradients and gel filtration yielded an unstable binding peak in addition to that of the androgen receptor. This lower molecular weight protein identified by gel filtration did not bind other androgens, including methyltrienolone, and did not have characteristics of other binding proteins that have been identified previously. This protein was not precipitated from 30% ammonium sulfate, which allowed it to be separated from the androgen receptor. Binding to this protein in ovariectomized female monkeys did not disappear with extended incubation at 4 degrees C, suggesting greater stability or a higher capacity. The function of this protein is not known, but both triamcinolone acetonide and contraceptive progestins appeared to displace tritiated mibolerone that was bound to it. This high-capacity binding of mibolerone interferes in the assessment of androgen receptor levels in these females unless it is eliminated. The synthetic androgen methyltrienolone does not bind to this protein and is a better choice for defining binding to the androgen receptor in these tissues.
Steroids 1995 Nov
PMID:Characterization of a hepatic protein in nonhuman primates that binds mibolerone but not dihydrotestosterone or methyltrienolone. 858

Male sexual differentiation and development proceed under direct control of androgens. Androgen action is mediated by the intracellular androgen receptor, which belongs to the superfamily of ligand-dependent transcription factors. In the X-linked androgen insensitivity syndrome, defects in the androgen receptor gene have prevented the normal development of both internal and external male structures in 46, XY individuals. The complete form of androgen insensitivity syndrome is characterized by 46, XY karyotype, external female phenotype, intra-abdominal testes, absence of uterus and ovaries, blindly ending vagina, and gynecomastia. There is also a group of disorders of androgen action that result from partial impairment of androgen receptor function. Clinical indications can be abnormal sexual development of individuals with a predominant male phenotype with severe hypospadias and micropenis or of individuals with a predominantly female phenotype with cliteromegaly, ambiguous genitalia, and gynecomastia. Complete or gross deletions of the androgen receptor gene have not been frequently found in persons with the complete androgen insensitivity syndrome, whereas point mutations at several different sites in exons 2-8 encoding the DNA- and androgen-binding domain have been reported in both partial and complete forms of androgen insensitivity, with a relatively high number of mutations in two clusters in exons 5 and 7. The number of mutations in exon 1 is extremely low, and no mutations have been reported in the hinge region, located between the DNA-binding domain and the ligand-binding domain. The X-linked condition of spinal and bulbar muscle atrophy (Kennedy's disease) is characterized by a progressive motor neuron degeneration associated with signs of androgen insensitivity and infertility. The molecular cause of spinal and bulbar muscle atrophy is an expanded length (> 40 residues) of one of the polyglutamine stretches in the N-terminal domain of the androgen receptor.
Steroids 1996 Apr
PMID:Molecular basis of androgen insensitivity. 873 95

Androgen resistance in genetic males occurs when gonadotropins and testosterone are normal, but the physiological androgen response in androgen target organs is absent or decreased. In androgen-dependent target tissues two main defects may be found: 1) defective testosterone metabolism (5 alpha-reductase type 2 deficiency) and 2) anomalies in androgen receptors (androgen insensitivity syndrome (AIS)). The clinical manifestations of these defects vary from subjects with female external genitalia to subjects with mild forms of impaired masculinization. In particular, in the complete form of AIS (CAIS) the phenotype is feminine, and in the partial form (PAIS) the external genitalia are ambiguous with an extremely variable phenotype. The diagnosis requires clinical, hormonal, genetic, and molecular investigation for appropriate gender assignation and treatment. In AIS, cloning of androgen receptor cDNA using the polymerase chain reaction, denaturing gradient gel electrophoresis, and nucleotide sequencing have enabled a variety of molecular defects in the androgen receptor to be identified. The complexity of phenotypic presentation of AIS probably reflects the heterogeneity of androgen receptor gene mutations, but to date a relationship between genotype/phenotype has been difficult to establish, with the same point mutation reported to be associated with different phenotypic expressions. Other factors must therefore also contribute to the clinical presentation of AIS, although none have yet been identified. Establishing the functional consequences of androgen receptor mutations in vitro systems and correlating them with clinical presentation may ultimately provide an explanation for the variable clinical presentation of AIS and perhaps enable prediction of the response to androgen therapy in infants with PAIS.
Steroids 1996 Apr
PMID:A clinician looks at androgen resistance. 873 2

Androgens stimulate the growth of prostatic carcinoma, possibly by modulating the activity of locally expressed growth factors. Recently, we have shown that an LHRH (or LHRH-like) system exerting an inhibitory action on cell proliferation is present in the human androgen-dependent prostatic tumor cell lines LNCaP. The following experiments have been performed in LNCaP cells to clarify whether LHRH might inhibit cell proliferation by interfering with the two major mitogenic factors for these cells: (a) testosterone (T), the major exogenous stimulating factor, and (b) epidermal growth factor (EGF), one of the locally produced growth factors. (a) It has been shown that an LHRH agonist (LHRH-A, Zoladex) counteracts the proliferative action of T in a dose-dependent way. To clarify whether LHRH might interfere with the activity of T in prostate tumors, LNCaP cells were treated with LHRH agonist over different time intervals, and the effects of treatment evaluated in terms of expression of androgen receptor mRNA. The data obtained indicate that LHRH-A does not affect androgen receptor expression at any time interval examined. (b) LHRH-A inhibits the mitogenic action of EGF on LNCaP cells and significantly reduces the concentration of EGF receptors in these cells. Experiments have been performed to explore whether LHRH-A might alter intracellular signaling mechanisms mediating the activity of EGF. In LNCaP cells LHRH-A blocks EGF-induced expression of the c-fos proto-oncogene but does not modify EGF-induced tyrosine phosphorylation of the EGF receptor. These data suggest that, in androgen-dependent prostate tumors, LHRH might inhibit cell proliferation by interfering with some but not all of the mechanisms mediating the mitogenic action of EGF. Possible interactions between LHRH and T-activated events still remain to be elucidated.
Steroids 1996 Apr
PMID:Growth factors in steroid-responsive prostatic tumor cells. 873 5

Mammalian 3 alpha-hydroxysteroid dehydrogenases (3 alpha-HSDs) regulate steroid hormone levels. For example, hepatic 3 alpha-HSDs inactivate circulating androgens, progestins, and glucocorticoids. In target tissues they regulate access of steroid hormones to steroid hormone receptors. For example, in the prostate 3 alpha-HSD acts as a molecular switch and controls the amount of 5 alpha-dihydrotestosterone that can bind to the androgen receptor, while in the brain 3 alpha-HSD can regulate the amount of tetrahydrosteroids that can alter GABAa receptor function. Molecular cloning indicates that these mammalian 3 alpha-HSDs belong to the aldo-keto reductase superfamily and that they are highly homologous proteins. Using the three-dimensional structure of rat liver 3 alpha-HSD as a template for site-directed mutagenesis, details regarding structure function relationships, including catalysis and cofactor and steroid hormone recognition have been elucidated. These details may be relevant to all mammalian 3 alpha-HSDs.
Steroids 1996 Sep
PMID:Mammalian 3 alpha-hydroxysteroid dehydrogenases. 888 17

The expression of the androgen receptor (AR) gene is regulated by androgens. Although androgens down-regulate AR mRNA in most cell lines and tissues, including the prostate, up-regulation occurs in some tissues. Androgen-mediated reduction in AR mRNA is reproduced in COS1 cells and in the androgen-sensitive human prostate cancer cell line LNCaP when each expresses the AR cDNA. We have previously established that the AR cDNA contains the requisite sequences for this down-regulation. Here we shown that androgen promoted up-regulation of AR mRNA in two androgen-independent human prostate cancer cell lines, PC3 and DU145, when each was transfected with a human AR cDNA. This effect was due to the AR cDNA and not to the heterologous promoter driving AR expression. In addition to up-regulation of AR mRNA, androgen induced comparable increases in AR protein levels in PC3 cells stably expressing an AR cDNA (PC3/AR). Up-regulation of AR in PC3/AR cells was accompanied by failure of these cells to undergo desensitization or inactivation of AR following prolonged (96 h) androgen administration, whereas the same conditions resulted in desensitization of AR transactivation in LNCaP cells and in CVl cells that stably express the AR cDNA. Androgen treatment of PC3/AR cells resulted in induction of an androgen-regulated reporter gene (MMTV-CAT) as well as the native prostate-specific antigen gene, which is silent in untransfected PC3 but is androgen up-regulated in LNCaP and in the prostate. These results suggest that ectopic expression of AR in androgen-independent prostate cancer cell lines establishes both typical and atypical androgenic responses in a target gene-specific manner. Androgenic up-regulation of AR cDNA expression may be due to distinct signaling mechanisms that influence androgen action in androgen-independent prostate cancer cells.
Steroids 1996 Sep
PMID:Androgenic up-regulation of androgen receptor cDNA expression in androgen-independent prostate cancer cells. 888 19

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

The rat androgen-binding protein/sex hormone-binding globulin (ABP/SHBG) gene is regulated by promoters P1 and PA. P1 regulates the mRNA encoding secreted ABP/SHBG, whereas PA regulates an alternate mRNA which encodes a modified protein that is targeted to the nucleus. Promoter PA is GC rich, consisting of 70-80% GC residues. During routine BLAST sequence analysis it was discovered that this GC-rich region is highly related to the human fragile X-related protein 2 (FXR-2) 5'-untranslated RNA sequence. Furthermore, the nucleotide coding sequence of the initial 14 FXR-2 amino acid residues was identical in the ABP/SHBG gene. The 5'-untranslated FXR-2 sequence contains triplet (CGG) repeats, which are also present in the rat ABP/SHBG gene. The meiotic instability of CGG repeats in the human fragile X (FMR1) gene causes the fragile X mental retardation syndrome. The data presented here suggest that the ABP/SHBG and FXR-2 genes overlap with each gene transcribed in the opposite direction. In support of this structure, the human ABP/SHBG and the FXR-2 genes map to the same site on chromosome 17. Thus, the ABP/SHBG gene contains triplet repeats in the alternate promoter PA. It will be of particular interest to determine if triplet instability affects ABP/SHBG gene expression. A triplet instability in the X-linked androgen receptor gene causes spinal and bulbar muscular atrophy.
Steroids 1998 Jan
PMID:The rat androgen-binding protein (ABP/SHBG) gene contains triplet repeats similar to unstable triplets: evidence that the ABP/SHBG and the fragile X-related 2 genes overlap. 943 88

We have previously found that the androgen receptor gene is expressed both in normal and adenomatous human adrenal cortex and in the NCI-H295 human adrenocortical cancer cell line. Furthermore, we have observed that dihydrotestosterone (DHT) at physiological concentrations (10(-11) M) inhibits human adrenocortical cell growth in vitro and slightly decreases c-myc RNA levels in NCI-H295 cells. As c-myc is probably not the main mechanism mediating DHT-induced inhibition of cell growth, other genes controlling cell proliferation may be involved. Transforming Growth Factor beta (TGF beta) is a regulatory peptide that acts by both autocrine and paracrine mechanisms to control proliferation and differentiation, and there is previous evidence that TGF beta may exert an antimitotic effect on human fetal adrenal cells in vitro. This study examines a possible role for TGF beta 1 in mediating the DHT-induced reduction of human adrenocortical cell growth. TGF beta 1 and its receptor (TGF beta RII) are expressed in DHT-treated and nontreated NCI-H295 cells; on Northern blot analysis 24-h treatment with DHT (10(-11) M) produced a small increase in TGF beta RII RNA, and quantitative RT-PCR showed a 1.5-fold increase in TGF beta 1 RNA levels. These findings suggest that TGF beta 1 and its receptor may be involved in DHT-induced inhibition of human adrenocortical cell growth.
Steroids
PMID:Role of transforming growth factor beta 1 (TGF beta 1) in mediating androgen-induced growth inhibition in human adrenal cortex in vitro. 961 78


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