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Query: UMLS:C0338671 (Steroids)
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Adrenal uptake and metabolism of circulating low density lipoprotein (LDL) was examined in female guinea pigs. [H3]LDL was prepared by exchange labeling with [H3]cholesteryl linoleate. After its injection plasma [H3]sterol ester concentration declined rapidly. This decline was slower in those animals pretreated with dexamethasone than in untreated controls. At 120 min after [H3]LDL administration [H3]-cholesteryl esters and [H3]cholesterol were detected in the adrenal gland. The levels of both radioactive and radioinert esters were lower in animals given dexamethasone. In contrast no difference in radioactive or radioinert cholesterol concentration was evident. In a second experiment [H3]LDL was prepared by reconstitution of the LDL-core with [H3]cholesteryl linoleate. After administration its disappearance from the circulation was similar to that observed in the first experiment. Other organs also took up [H3]LDL including the liver and kidney. Free and esterified [H3]cholesterol concentrations were greater in the liver than in the adrenal gland at 120 min after injection. The results from these two experiments were interpreted to mean that th adrenal cortex is capable of taking up LDL and metabolizing its cholesteryl esters. Uptake may be stimulated by ACTH.
Steroids 1981 May
PMID:In vivo uptake and metabolism of low density lipoprotein in the guinea pig adrenal. 725 15

Glucocorticoid resistance results from incomplete but apparently generalized inability of glucocorticoids to exert their effects on their target tissues. The condition is associated with compensatory elevation of circulating ACTH and cortisol, with the former causing excess secretion of both adrenal androgens and adrenal steroid biosynthesis intermediates with salt-retaining activity. The manifestations of glucocorticoid resistance vary from asymptomatic to different degrees of hypertension and/or hypokalemic alkalosis and/or hyperandrogenism, caused by elevation cortisol and other salt-retaining steroids, and of adrenal androgens, respectively. In women, hyperandrogenism can result in acne, hirsutism, male type baldness, menstrual irregularities, oligoanovulation, and infertility; in men, it may lead to infertility; and in children to precocious puberty. Different molecular defects, such as point mutations or microdeletions of the highly conserved glucocorticoid receptor gene, alter the functional characteristics or concentrations of the intracellular receptor and cause glucocorticoid resistance. The extreme variability in the clinical manifestations of glucocorticoid resistance and its mimicry of many common diseases can be explained by different degrees of glucocorticoid resistance, differing sensitivity of target tissues to mineralocorticoids and/or androgens or both, and perhaps different biochemical defects of the glucocorticoid receptor. Mineralocorticoid resistance results from the inability of aldosterone to exert its effect on target tissues. The syndrome is associated with salt loss, hypotension, and hyperkalemic acidosis. We have cloned and sequenced the cDNA of five unrelated patients with this syndrome and have not found any mutations of pathophysiological significance that would explain the resistance of these patients to aldosterone.(ABSTRACT TRUNCATED AT 250 WORDS)
Steroids 1995 Jan
PMID:Syndromes of glucocorticoid and mineralocorticoid resistance. 779 8

In comparison with the glucocorticoids cortisol and corticosterone, the mineralocorticoid aldosterone is a minority hormone of the mammalian adrenal cortex, and its proper function is dependent upon protective physiological mechanisms. These include a particular site of aldosterone synthesis in zona glomerulosa cells as well as a complex multifactorial control system, which adapts aldosterone production to acute and chronic changes in body sodium and potassium contents, irrespective of pituitary ACTH secretion. In the course of the last few years, an important element of these mechanisms has been identified in the form of the enzyme involved in the final steps of aldosterone biosynthesis. In species such as the human, rat, and mouse, the conversion of deoxycorticosterone to aldosterone is catalyzed by an isozyme (CYP11B2) of cytochrome P450(11 beta) (CYB11B1). The gene encoding this enzyme is expressed only in the zona glomerulosa. Its transcription is enhanced by sodium deficiency and potassium intake, but is suppressed by long-term administration of high doses of ACTH. In contrast, the gene encoding CYP11B1, i.e., the major (non-aldosterone-producing) type of the enzyme, is expressed mainly in the zona fasciculata, and its expression depends on physiological concentrations of ACTH. In other animal species (cattle, pig), the major forms of cytochrome P450(11) beta have an inherent aldosterone-synthesizing activity, which is, however, selectively suppressed in mitochondria of zona fasciculata cells by yet unknown mechanisms.
Steroids 1995 Jan
PMID:Aldosterone: the minority hormone of the adrenal cortex. 779 10

CYP11B1 (11 beta-hydroxylase) and CYP11B2 (aldosterone synthase) are steroidogenic enzymes which mediate the final step (11 beta-hydroxylation) in cortisol synthesis and the final three steps (11 beta-hydroxylation, 18-hydroxylation, and 18-oxidation) in aldosterone synthesis, respectively. The enzymes share 93% identity in amino acid sequence and are encoded by two structurally similar genes which are located in tandem on chromosome 8q22, approximately 40 kb apart. Expression of the aldosterone synthase gene (CYP11B2) is limited to the zona glomerulosa of the adrenal cortex, thereby limiting the synthesis of aldosterone to that zone, where it is principally regulated by plasma levels of angiotensin II and potassium. The 11 beta-hydroxylase gene (CYP11B1) is expressed in the zona fasciculata, the zone which also expresses a 17-hydroxylase activity, where it mediates cortisol synthesis under the control of ACTH. Genetic recombination involving a mispairing of the two CYP11B genes can lead to duplications and deletions of the genes, creation of hybrid genes of several forms, or transfer of coding and regulatory sequences from one gene to the other. Since the two genes have related but different activities, are normally expressed in different zones, and respond to different physiological signals, such recombination has the potential to generate a variety of inherited disorders of steroid production. In this paper we review the range of mutations which can occur and the resulting disorders of steroid biosynthesis, and suggest some novel mutations which might be sought in variants of these endocrinological syndromes.
Steroids 1995 Jan
PMID:Genetic recombination as a cause of inherited disorders of aldosterone and cortisol biosynthesis and a contributor to genetic variation in blood pressure. 779 11

The present study was designed to clarify the transcriptional regulation of the human type 1 angiotensin II receptor (AT1) gene and its pathophysiological roles in steroidogenesis by adrenal tumors. A cDNA encoding type 1 angiotensin II receptor (AT1) was isolated from a human liver cDNA library encoding a protein of 359 amino acids with seven transmembrane segments. It is very likely that human has only one type of AT1 receptor, in contrast with rodents. A genomic clone containing 217 bp of exon 1 and 2558 bp of the 5'-flanking region of human AT1 receptor gene was isolated. Its proximal promoter region contained putative TATA and GC boxes, CRE and AP1 sites. Aldosterone-producing adenoma (APA) contained significantly higher levels of mRNA for AT1 and ACTH receptors than normal tissues adjacent to APA. There were no mutations within the cytoplasmic third loops of AT1 and ACTH receptors in APAs examined. APA showed increased expression of the mRNA for P450c11 and decreased expression of the mRNA for P450c17. These results suggest that renin-independent overproduction and clinically observed ACTH-dependent production of aldosterone in APAs may results from the enhanced transcription of P450c11 and ACTH receptor genes. The mechanism of the discordantly increased expression of AT1 receptor in APA remains to be clarified.
Steroids 1995 Jan
PMID:Type 1 angiotensin II receptors of adrenal tumors. 779 12

Primary aldosteronism is the commonest cause of potentially curable hypertension when diagnosed in both florid and less florid forms. Genetic screening, so far available only for glucocorticoid-suppressible hyperaldosteronism, permits diagnosis from birth, before any biochemical or clinical abnormalities appear. Biochemical screening using the aldosterone-to-renin ratio permits diagnosis in the absence of raised aldosterone or of hypokalemia. Primary aldosteronism occurs in several familial forms. As well as the variety described in 1966 which is ACTH-dependent and glucocorticoid-suppressible, and not so far associated with tumors, another variety described in 1991 is not glucocorticoid-suppressible and is frequently associated with aldosterone-producing adenomas (APAs). Primary aldosteronism due to adrenocortical hyperplasia, adenoma, or carcinoma can also occur as part of the multiple endocrine neoplasia syndromes, where normoplasia, hyperplasia, benign neoplasia, and malignant neoplasia can exist in the same patient in the same endocrine gland(s) at the same time. The morphology of adrenocortical hyperplasia causing primary aldosteronism ranges from glomerulosa-like (idiopathic hyperplasia of the adrenals) to fasciculata-like (glucocorticoid-suppressible hyperaldosteronism). The morphology of adrenocortical neoplasia causing primary aldosteronism can also be either predominantly glomerulosa-like or fasciculata-like, in our experience equally often. Varying morphology of APAs is associated with varying responses of aldosterone to angiotensin II. Tumors predominantly fasciculata-like are unresponsive to angiotensin II, whereas those predominantly glomerulosa-like are responsive to angiotensin II. Both subtypes can be seen in a single family. Primary aldosteronism represents a spectrum of genetic disorders resulting in hyperplasia or neoplasia, but all are associated with some degree of autonomy of aldosterone production, independent of the renin-angiotensin system.
Steroids 1995 Jan
PMID:Primary aldosteronism--some genetic, morphological, and biochemical aspects of subtypes. 779 13

Glucocorticoid-remediable aldosteronism (GRA) is a hereditary cause of human hypertension in which aldosterone secretion is regulated by adrenocorticotropin (ACTH). A genetic mutation which causes GRA has recently been identified in our laboratory, a hybrid or chimeric gene fusing nucleotide sequences of the 11 beta-hydroxylase and aldosterone synthase genes. The finding that these chimeric gene duplications are sensitive and specific markers for GRA allows for a simple, direct genetic test for this disorder. In preliminary studies, we found a wide range of blood pressure levels (including normotension) in affected GRA subjects. Studies to data indicate that this is not related to environmental factors such as sodium intake. Another possibility is that chimeric gene expression is variable, with low blood pressure subjects having reduced gene expression. However, the data have not demonstrated differences in steroid levels in subjects with severe versus mild hypertension. In fact, it is likely that the wide range in blood pressure levels in affected subjects involves interaction of other systems which control blood pressure. Preliminary data in two kindreds suggest that blood pressure levels are reciprocally related to levels of urinary kallikrein excretion, supporting the notion that GRA is a hypertension-predisposing syndrome, with the resultant blood pressure the interaction of the gene mutation with other blood pressure regulatory systems. Although GRA is a mineralocorticoid excess state, as evidenced by profoundly suppressed levels of plasma renin activity, we have observed (contrary to the reported literature) that normokalemia is a typical finding. In one large normokalemic pedigree, preliminary findings indicate that these subjects have a normal capacity to excrete potassium.(ABSTRACT TRUNCATED AT 250 WORDS)
Steroids 1995 Jan
PMID:Glucocorticoid-remediable aldosteronism (GRA): diagnosis, variability of phenotype and regulation of potassium homeostasis. 779 15

In the course of my studies of patients with mineralocorticoid hypertensive disorders, unusual presentations led to unexpected findings, both clinically and in steroid etiologies and regulation. Unique circumstances permitted early studies in defining the autonomy of the aldosterone-producing adenoma. A chance referral brought the index case of 17 alpha-hydroxylase deficiency to the research center. New techniques were developed in unusual ways to measure the metabolites of deoxycorticosterone (DOC) using an anesthetic agent. Procedural delays were followed by the surreptitious transfer of a patient from one hospital to the research center after a benign DOC-secreting tumor had been removed. The delay of DOC and all 17-deoxysteroids to respond normally to ACTH stimulation suggested a possible second regulator of DOC. This observation led to studies that demonstrated divergent responses between DOC and cortisol in diverse conditions. An unexplained mineralocorticoid form of hypertension with suppression of renin and aldosterone, but normal DOC production, is seen in licorice intoxication. After licorice was discontinued we documented the delay in the recovery of the inhibited cortisol metabolism (14 days) and renin-angiotensin system (4 months). Licorice extract given to normal subjects on low sodium diets with and without ACTH suppression showed similar results. Other factors in licorice may thus be operative in terms of renin and aldosterone suppression.
Steroids 1995 Jan
PMID:My engagement with steroids: a review. 779 16

19-Acetylenic-deoxycorticosterone (19-A-DOC) is believed to be a competitive irreversible inhibitor of the synthesis of 19-nor-deoxycorticosterone (19-nor-DOC), a potent mineralocorticoid implicated in some forms of human and animal hypertension. It has been shown to inactivate 11 beta/19-hydroxylase in hamster adrenal mitochondria. Dispersed bovine zona fasciculata cells were incubated for one hour with 1.5 x 10(-8) M ACTH and 0, 1, 10, or 100 microM 19-A-DOC and tritiated deoxycorticosterone (DOC) substrate. Steroids were separated using two sequential thin-layer chromatography systems and their tritium content was counted and corrected for recovery. The 19-A-DOC decreased synthesis of 19-hydroxydeoxycorticosterone, the precursor of 19-nor-DOC. The inhibitor also impaired 11-hydroxylation of DOC to form corticosterone. The data suggest that 19-A-DOC is an effective inhibitor of 11 beta/19-hydroxylase activity in dispersed bovine adrenal cells.
Steroids 1995 Mar
PMID:19-Acetylenic-deoxycorticosterone inhibits 19-hydroxylase and 11 beta-hydroxylase activities in dispersed bovine zona fasciculata cells. 779 29

Previous reports have shown that 17 beta-N,N-Diethylcarbamoyl-4-methyl-4-aza- 5 alpha-androstan-3-one (4-MA), a synthetic inhibitor of 5 alpha-reductase, exerts an inhibitory effect on 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase (3 beta-HSD) activity. To characterize further the effects of 4-MA on steroidogenesis, guinea pig fasciculata-glomerulosa cells in primary culture were treated for 24 h with 4-MA. Our data indicate that 4-MA reduced 3 beta-HSD activity in cultured adrenal cells but had no effect on the activities of 11-hydroxylase, 21-hydroxylase, 17-hydroxylase, and 17,20-lyase. Be decreasing the conversion of pregnenolone into progesterone or 17-hydroxypregnenolone into 17-hydroxyprogesterone, 4-MA caused the steroidogenic pathway to shift toward the production of dehydroepiandrosterone. Despite the presence of 4-MA, androstenedione and 11 beta-hydroxyandrostenedione were produced at levels exceeding the control levels. In the presence of ACTH and 4-MA, cortisol production was inhibited by 90% whereas androstenedione and 11 beta-hydroxyandrostenedione were reduced by only 40%. The effect of the compound was reversed by washing the adrenal cells with medium, thus suggesting a direct action of 4-MA on the enzyme itself. In summary, our data indicate that 4-MA markedly reduces the production of cortisol in the adrenals and partially alters the formation of C-19 steroids. It is important to consider this finding in the use of 4-azasteroids in the treatment of prostate cancer, which was previously found to be sensitive to secretion of adrenal C-19 steroids.
Steroids 1994 Jun
PMID:Effects of 4-MA, a potent inhibitor of 5 alpha-reductase, on 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase activity in guinea pig adrenals. 794 Jun 15


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