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)

11 alpha-Hydroxytestosterone (1a), 11 beta-hydroxytestosterone (1b), 11 alpha-methoxytestosterone (1c), 11 beta-methoxytestosterone (1d), 11-ketotestosterone (1e), and delta 9(11)-testosterone (1f) were synthesized from hydrocortisone (4b) or 11-epi-hydrocortisone (4a). The six target compounds, together with 11 alpha-methoxyandrostenedione (2c), 11 beta-methoxyandrostenedione, (2d) and their lead compound, testosterone (1), were found to effectively inhibit the growth and differentiation of human decidual cells in culture. There is no observable binding of these compounds to estrogen receptor of rabbit uterus. The introduction of a polar group (e.g., hydroxyl and carbonyl) to C-11 of androstenes decreases both the relative binding affinities to progesterone receptor and the inhibitory effects on human decidual cell growth, while the methylation of 11-hydroxyl group minimizes these effects. The similar effects of a polar group at C-11 of testosterone (1) on the inhibitory effects on human decidual cell growth and the relative binding affinities to progesterone receptor of rabbit uterus may suggest that one of the mechanisms of human decidual cell growth inhibition by these compounds is the anti-progestational activity of these androgens.
Steroids 1994 Mar
PMID:Synthesis of 11-substituted androstenediones and testosterones as human decidual cell growth inhibitors. 804 51

16 alpha-Ethyl-21-hydroxy-19-norpregn-4-ene-3,20-dione (ORG 2058) is a ligand widely used in progesterone receptor assays. An improved synthesis of the compound is reported, starting from norethisterone acetate. The preparation of the tritiated radioligand [3H]ORG 2058 is also described.
Steroids 1993 Mar
PMID:Steroids 51. An improved synthesis of ORG 2058 and the synthesis of [3H]ORG 2058. 847 15

Two 11 beta-derivatives of estradiol (E2) were tested for their potential antiestrogenic activity in the MCF-7 breast cancer model: one contained a phenoxydimethylaminoethyl side-chain (RU 39,411), the other a pentafluoropentylsulfinyl side-chain (RU 58,668). The former compound displayed mixed estrogenic/antiestrogenic properties, while the latter indicated only an antiestrogenic activity. Both the compounds produced a growth inhibition of MCF-7 cells at doses related to their binding affinity for the estrogen receptor (ER); E2 suppressed this inhibition. The compounds also down-regulated the estrogen binding capacity of the cells but failed to reduce ER mRNA levels, indicating that the grafting of their side-chains prevented this antagonistic effect usually observed with steroidal estrogens. Assessment of ER levels by enzyme immunoassay revealed a marked increase with RU 39,411 and a decrease with RU 58,668; different mechanisms of action should, therefore, be considered. Finally, the estrogenic activity of RU 39,411 was demonstrated by its strong ability to induce synthesis of the progesterone receptor; RU 58,668 failed to display this agonistic activity.
Steroids 1995 Aug
PMID:Antiestrogenic activity of two 11 beta-estradiol derivatives on MCF-7 breast cancer cells. 853 93

The aim of this study was to evaluate the effect of several abeopregnane, steroidal heterocycles (A/B-transandrostano [2,3-d]isoxazole, and 17-spiroandrostano[2,3-c]furazan), and 6 alpha, 11 beta, 16 alpha-trisubstituted 19-norpregnadienedione on the influx of extracellular Ca2+ in human sperm. These steroidal compounds had minimal genomic progestational, androgenic, or estrogenic activity with the exception of 16 alpha-ethyl-6 alpha-methyl-11 beta-(4-N,N-dimethylaminophenyl)-19- norpregna-4,9-diene-3,20-dione which was four times more progestational than progesterone. Some of the steroidal compounds, e.g., 16 alpha-ethyl-6 alpha-methyl-11 beta-(4-N,N-dimethylaminophenyl)-19-nor- pregna-4,9-diene-3,20-dione and 2',3',4',5'-tetrahydrospiro[furan-2' beta, 17-androstano] [2,3-c]furazan produced an influx of Ca2+ into human spermatozoa. These studies indicate that high (10 microM) concentrations of certain steroidal compounds are selective for the sperm membrane progesterone receptor, since most of them have minimal genomic activity. The steroidal compounds that elicited an influx of Ca2+ caused an initial high influx but were not as potent as progesterone, since no effects were observed below 1 microM, whereas progesterone at 1 microM produced a maximum effect. Progesterone as well as the steroidal compounds caused a modest increase in the number of acrosome-reacted spermatozoa. Molecular modeling revealed that 5 alpha-dihydro-2,3-fused and 4,4-dimethyl-5-ene-2,3-fused steroidal heterocycles possessing different conformations compared to that of progesterone are responsible for elevation of Ca2+. In conclusion, a unique non-genomic progesterone receptor is present on human spermatozoa and several steroidal compounds that do not have progestational effects may activate this sperm membrane receptor, resulting in Ca2+ influx.
Steroids 1996 Mar
PMID:Steroid specificity of the human sperm membrane progesterone receptor. 885 28

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

The review deals with the clinically important aspects of the basic mechanisms of sex steroid hormones. Steroids can act through two basic mechanisms: genomic and non-genomic. The classical genomic action is mediated by specific intracellular receptors, whereas the primary target for the non-genomic one is the cell membrane. Many clinical symptoms seem to be mediated through the non-genomic route. Furthermore, membrane effects of steroid and other factors can interfere with the intranuclear receptor system inducing or repressing steroid-and receptor-specific genomic effects. These signalling pathways may lead to unexpected hormonal or anti-hormonal effects in patients treated with certain drugs. Steroid receptors (SRs) are members of a large family of nuclear transcription factors that regulate gene expression by binding to their cognate steroid ligands, to the specific enhancer sequences of DNA (steroid response elements) and to the basic transcription machinery. SRs are phosphoproteins, which are further phosphorylated after ligand binding. The role of phosphorylation in receptor transaction is complex and may not be uniform to all SRs. However, phosphorylation/dephosphorylation is believed to be a key event regulating the transcriptional activity of steroid receptors. SR activities can be affected by the amount of SR in the cell nuclei, which is modified by the rate of transcription and translation of the SR gene as well as by proteolysis of the SR protein. There is an auto- and heteroregulation of receptor levels. Some of the SRs appear to bind specific protease inhibitors and exhibit protease activity. The physiological significance of this weak proteolytic activity is not clear. Some SRs are expressed as two or more isoforms, which may have different effects on transcription. Receptor isoforms are different translation or transcription products of a single gene. Isoform A of the progesterone receptor is a truncated form of PR isoform B originating from the same gene, but it is able to suppress not only the gene enhancing activity of PR-B but also that of other steroid receptors. From the clinical point of view, it is important to note that the final hormonal effect in a target tissue is dependent on the cross talk between different nuclear steroid receptors and on expression of receptor isoforms.
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PMID:Mechanisms of action of sex steroid hormones: basic concepts and clinical correlations. 886 32

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.
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PMID:Identification of steroid receptors in human adipose tissue. 901 78

Estradiol secreted by growing ovarian follicle(s) has been considered classically to be the neural trigger for the preovulatory surge of gonadotropins. The observation that the estradiol-induced gonadotropin surge in ovariectomized rats is of lesser magnitude and duration than that found in the cycling rat at proestrus has resulted in a search for other steroid regulators. Progesterone is a major regulator of the preovulatory gonadotropin surge. It can only act in the presence of an estrogen background, which is necessary for the synthesis of progesterone receptors. In the estrogen-primed ovariectomized rat, progesterone is able to initiate and enhance the gonadotropin surge to the magnitude observed on the day of proestrus and limit it to 1 day. The physiological role of progresterone in the induction of the preovulatory gonadotropin surge has been demonstrated by the attenuation of the progesterone-induced surge and the endogenous proestrus surge by progesterone receptor antagonist RU486 and the progesterone synthesis inhibitor trilostane. The promoter region of the follicle-stimulating hormone (FHS)-beta gene contains multiple progesterone response elements and progesterone brings about FSH release as well. The reduction of progesterone in the 5 alpha-position appears to be important for the regulation of progesterone secretion. Corticosteroids appear to play a significant role in the secondary FSH surge on late proestrus and early estrus.
Steroids 1998 Dec
PMID:Regulation of the preovulatory gonadotropin surge by endogenous steroids. 987 Feb 58

In addition to the well-known genomic effects of steroid molecules via intracellular steroid receptors, certain steroids rapidly alter neuronal excitability through interaction with neurotransmitter-gated ion channels. Several of these steroids accumulate in the brain after local synthesis or after metabolism of adrenal steroids. The 3alpha-hydroxy ring A-reduced pregnane steroids allopregnanolone and tetrahydrodeoxycorticosterone have been thought not to interact with intracellular receptors, but enhance gamma-aminobutyric acid (GABA)-mediated chloride currents, whereas pregnenolone sulfate and dehydroepiandrosterone (DHEA) sulfate display functional antagonistic properties at GABA(A) receptors. We demonstrated that these neuroactive steroids can regulate also gene expression via the progesterone receptor after intracellular oxidation. Thus, in physiological concentrations these neuroactive steroids regulate neuronal function through their concurrent influence on transmitter-gated ion channels and gene expression. When administered in animal studies, memory-enhancing effects have been shown for pregnenolone sulfate and DHEA. The 3alpha-hydroxy ring A-reduced neuroactive steroids predominantly display anxiolytic, anticonvulsant, and hypnotic activities. Sleep studies evaluating the effects of progesterone as a precursor molecule for these neuroactive steroids revealed a sleep electroencephalogram pattern similar to that obtained by the administration of benzodiazepines. These findings extend the concept of a "cross-talk" between membrane and nuclear hormone effects and provide a new role for the therapeutic application of these steroids in neurology and psychiatry.
Steroids
PMID:Neuropsychopharmacological properties of neuroactive steroids. 1032 76

The progestin dienogest (17alpha-cyanomethyl-17beta-hydroxy-estra-4,9-dien-3-one) was metabolized by the nitrile hydratase-containing microorganism Rhodococcus erythropolis. An enzymatic hydrolysis of the nitrile group at the 17alpha-side chain was intended to obtain novel derivatives and to test them for progesterone receptor affinity. In contrast to the rapid enzymatic hydrolysis of nonsteroidal nitriles, the nitrile group of dienogest was cleaved very slowly. The dominant reaction was an aromatization of ring A. After prolonged fermentation, the 17alpha-acetamido derivatives of estradiol and of 9(11)-dehydroestradiol were formed. Three of the metabolites were also prepared synthetically. They were tested for hormonal activity by assessing their binding to progesterone and estrogen receptors in vitro. Neither the aromatized 17alpha-acetamido derivatives nor the dienogest derivative 17alpha-acetamido-17beta-hydroxy-estra-4,9-dien-3-one, which was prepared synthetically only, exhibited affinity for the progesterone receptor.
Steroids 1999 Aug
PMID:Nitrile hydratase from Rhodococcus erythropolis: metabolization of steroidal compounds with a nitrile group. 1049 99


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