cortodoxone and Hypertension

The terminal stages in the synthesis of aldosterone and cortisol are catalysed by the enzymes aldosterone synthase and 11beta-hydroxylase respectively. We have previously reported that polymorphic variation in the 5' promoter region (-344C/T) of the gene encoding aldosterone synthase (CYP11B2) is associated with increased aldosterone metabolite excretion and with hypertension associated with a raised aldosterone to renin ratio (ARR). Additionally, basal and ACTH-stimulated plasma levels of 11-deoxycortisol, the precursor of cortisol, are higher in subjects carrying the T-allelic variant. We have now identified in a family study (573 individuals from 105 extended families ascertained through a hypertensive proband) that excretion of the main metabolite of this steroid (tetrahydro-11-deoxycortisol, THS) is heritable (19.4%) and that the T-allele of CYP11B2 is more strongly associated with higher THS levels than the C-allele. Raised plasma and urinary levels of 11-deoxycortisol suggest that there is relative inefficiency of 11beta-hydroxylation in the zona fasciculata; the P450 enzyme responsible for this step is encoded by the gene CYP11B1, which is highly homologous with and adjacent to CYP11B2. The association of genetic variation in the promoter of CYP11B2 which, in the adrenal cortex, is only expressed in zona glomerulosa, and zona fasciculata 11beta-hydroxylation function is paradoxical. There may be linkage dys-equilibrium between this polymorphism and a quantitative trait locus (QTL) in CYP11B1. Chronic alteration of 11beta-hydroxylase activity may increase ACTH drive to the adrenal cortex, altering the regulation of aldosterone synthesis. This may explain, at least partly, the association between CYP11B2 polymorphisms and hypertension.

Topics: Adrenocorticotropic Hormone; Aldosterone; Blood Pressure; Cortodoxone; Cytochrome P-450 CYP11B2; Genetic Predisposition to Disease; Haplotypes; Humans; Hydrocortisone; Hypertension; Point Mutation; Polymorphism, Genetic; Promoter Regions, Genetic; Quantitative Trait Loci; Steroid 11-beta-Hydroxylase; Zona Fasciculata

The aim of this study was to determine the validity of our previous hypothesis of adrenal 11 beta-hydroxylase (11-OH) dysregulation in "essential" low-renin hypertension.. A comparison was made between 30 hypertensive patients and 30 age-matched controls (NC) in basal conditions and after ACTH stimulation (ACTH 1-17) test. The 11-deoxycortisol (S) and deoxycorticosterone (DOC) integrated areas under the curve (AUCs) of stimulus were significantly higher in the hypertensives (p < 0.001) and pointed to adrenal 11-OH dysregulation.. The ACTH 1-17 test detects impairment of 11-OH activity of probable genetic origin. The relative mineralocorticoid excess thus provoked could be an additional cause of "essential" low-renin hypertension.

Topics: Adrenal Cortex; Adrenal Cortex Function Tests; Adrenocorticotropic Hormone; Adult; Area Under Curve; Cortodoxone; Desoxycorticosterone; Female; Humans; Hypertension; Male; Peptide Fragments; Steroid 11-beta-Hydroxylase

The present study aimed to investigate the associations of cortisol-to-cortisone ratio (F/E) and 11-deoxycortisol (S) in hypertension and blood pressure among Chinese rural population.. A total of 6233 participants from the Henan Rural Cohort Study were included. Serum cortisol (F), cortisone (E), and S were assessed using liquid chromatography-tandem mass spectrometry. Generalized linear model (GLM) and logistic regression model were performed to assess the associations of F, E, F/E, and S with blood pressure and hypertension. Moreover, the sex specificity of the associations was assessed.. Serum F, F/E, and S were positively associated with systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP), while E was negatively associated with SBP and PP. There were no statistically significant associations of F and E with the prevalence of hypertension, while F/E and S were positively associated with hypertension [odds ratios (ORs) and 95% confidence intervals (CIs)] of F/E and S were 1.28 (1.13, 1.44) and 1.10 (1.04, 1.17), respectively. Also, the combination of high F/E and S was significantly associated with hypertension. The blood pressure indicators and the prevalence of hypertension increased with an incremental in the serum concentration of F, F/E, and S (all Ptrend < 0.05). In addition, the positive association between F/E and SBP was stronger in women than that in men, and F/E was strongly positively associated with hypertension only in women (all Pinteraction < 0.05).. Serum F/E and S were positively associated with hypertension and blood pressure. Additionally, their combination has a synergistic effect on hypertension. Moreover, the associations of F and F/E with hypertension and blood pressure were in a sex-specific manner.

Topics: Blood Pressure; China; Cohort Studies; Cortisone; Cortodoxone; Cross-Sectional Studies; Female; Humans; Hydrocortisone; Hypertension; Male; Rural Population

Aldosterone is an important cardiovascular hormone; 15% of hypertensive subjects have alteration in aldosterone regulation, defined by a raised ratio of aldosterone to renin (ARR). Studies of the aldosterone synthase gene (CYP11B2) have focused on a single nucleotide polymorphism in the 5'promoter region (-344 C/T). In normotensive subjects, the T allele associates with raised levels of the 11-deoxysteroids, deoxycorticosterone and 11-deoxycortisol which are substrates for 11beta-hydroxylase, encoded by the adjacent and homologous gene, CYP11B1. We have speculated that this altered 11beta-hydroxylase efficiency leads to increased ACTH drive to the adrenal gland to maintain cortisol production and reported herein the association between the -344 C/T single nucleotide polymorphism (SNP) and adrenal steroid production in subjects with essential hypertension.. The CYP11B2-344 C/T polymorphism was genotyped and urinary excretion of adrenal steroid metabolites was measured (by GCMS) in 511 unrelated hypertensives from the Medical Research Council (MRC) British Genetics of Hypertension (BRIGHT) study.. Thirty-five per cent of subjects were homozygous for the -344T allele whilst 16% were CC homozygotes. There was no difference in cortisol excretion rate between the two genotype groups but the index of adrenal 11beta-hydroxylation (ratio of tetrahydrodeoxycortisol/total cortisol) was significantly higher in the TT group (P < 0.005) than in the CC group. Excretion rates of the major urinary metabolite of aldosterone (tetrahydroaldosterone) correlated strongly with the ACTH-regulated steroids, cortisol (r = 0.437, P < 0.0001) and total androgen metabolites (r = 0.4, P < 0.0001) in TT but not CC subjects.. Hypertensives homozygous for the -344 T allele of CYP11B2 demonstrate altered 11beta-hydroxylase efficiency (CYP11B1); this is consistent with the hypothesis of a genetically determined increase in adrenal ACTH drive in these subjects. The correlation between excretion of aldosterone and cortisol metabolites and suggests that, in TT subjects, ACTH exerts an important common regulatory influence on adrenal corticosteroid production in subjects with hypertension.

Topics: Adrenocorticotropic Hormone; Aged; Aldosterone; Alleles; Cortodoxone; Cytochrome P-450 CYP11B2; Female; Genotype; Humans; Hypertension; Male; Middle Aged; Polymorphism, Single Nucleotide; Steroid 11-beta-Hydroxylase

We previously described an association between the -344C/T 5'-untranslated region (UTR) polymorphism in the CYP11B2 (aldosterone synthase) gene and hypertension with a raised aldosterone to renin ratio (ARR); the same genetic variant is also associated with impaired adrenal 11beta-hydroxylase efficiency. The -344 polymorphism does not seem to be functional, so is likely to be in linkage with variants in CYP11B1 that determine the associated variation in 11beta-hydroxylase efficiency. We therefore aimed to determine whether there is an association between CYP11B1 variants and hypertension and/or an altered ARR.. We screened 160 subjects divided into four groups, normotensive controls, unselected hypertensive subjects, and hypertensive subjects with either a high (> or = 750) or low ARR (< or = 200), for variants in the coding region of CYP11B1 by single-stranded conformation polymorphism (SSCP) and direct sequencing. The effects of these variants on enzyme function were assessed by conversion of 11-deoxycortisol to cortisol and 11-deoxycorticosterone (DOC) to corticosterone.. Eight novel missense mutations were identified in the CYP11B1 gene that alter the encoded amino acids: R43Q, L83S, H125R, P135S, F139L, L158P, L186V and T196A. In each case they were heterozygous changes. However, no mutations were identified that could account for hypertension and/or a raised ARR. The variants L158P and L83S severely impaired enzyme function while R43Q, F139L, P135S and T196A enzymes resulted in product levels that were approximately 30-50% that of wild-type levels. The variant enzymes H125R and L186V resulted in substrate-specific alterations in enzyme function. H125R decreased conversion of 11-deoxycortisol to cortisol and L186V increased 11-deoxycortisol conversion. Neither had an effect on the conversion of DOC to corticosterone.. No variants were identified in the coding region of CYP11B1 that could account for hypertension and/or a raised ARR. However, this in vitro study identifies the importance of these affected residues to enzyme function and will inform subsequent studies of structure-function relationships.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aldosterone; Animals; Biological Assay; Case-Control Studies; Corticosterone; Cortodoxone; Desoxycorticosterone; Humans; Hydrocortisone; Hyperaldosteronism; Hypertension; Middle Aged; Mutation, Missense; Polymorphism, Single Nucleotide; Rats; Renin; Sequence Analysis, DNA; Steroid 11-beta-Hydroxylase

Left ventricular mass (LVM) is under the control of aldosterone and angiotensin II in experimental hypertension, but the effect of aldosterone on LVM is controversial in essential hypertension (EH). Some EH patients show a mild impairment of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) activity without clinical features of the syndrome of apparent mineralocorticoid excess, where the incomplete cortisol-to-cortisone conversion leads to glucocorticoid-mediated mineralocorticoid effects. The mineralocorticoid receptor and 11beta-HSD2 are co-expressed in human heart. We investigated whether LVM may be regulated by glucocorticoids in EH patients.. The ratio between 24 h urinary tetrahydro derivatives of cortisol and cortisone (THFs/THE), plasma renin activity, 24 h urinary aldosterone, blood pressure, and LVM indexed for height(2.7) (LVMh(2.7)) were analysed in 493 never-treated hypertensives and 98 normotensives. THFs/THE was associated with LVMh(2.7) in hypertensives and normotensives (r=0.32, P<0.001, and r=0.17, P=0.04, respectively) and persisted after adjusting for confounders (multiple regression analysis). Body mass index, sex, recumbent plasma renin activity, and THFs/THE accounted for 26.1% of LVMh(2.7) variation. Urinary aldosterone was not correlated with LVMh(2.7).. We suggest that glucocorticoids may take part in the regulation of LVM in EH patients as a function of 11beta-HSD2 activity, and contribute to the target organ damage associated with essential hypertension.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 2; Aldosterone; Blood Pressure; Cohort Studies; Cortodoxone; Echocardiography; Female; Glucocorticoids; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Renin; Tetrahydrocortisol; Tetrahydrocortisone

In glucocorticoid-remediable aldosteronism (GRA), there is a large interfamily variation of phenotype. We report three subjects with GRA in a single family (parents, two brothers and two sisters), of whom only one (proband) displayed classical features of the mineralocorticoid excess. The proband was a man found to be hypertensive and hypokalaemic at the age of 24 years. Plasma renin activity was suppressed and plasma aldosterone was repeatedly elevated. Blood pressure and aldosterone levels normalized within 5 days of dexamethasone therapy. The presence of a chimaeric CYP11B1/CYP11B2 gene was demonstrated by long-PCR and Southern blotting (crossover site at the end of intron 3) in the proband, in the younger sister (sibling 1) and in the father. In these patients, sequencing of the chimaeric portion of CYP11B1 did not reveal any mutation, while sequencing of the chimaeric portion of CYP11B2 showed a V386A polymorphism in exon 7, known to cause only a minimal impairment of enzymatic activity. Sibling 1 was normotensive, normokalaemic and had normal PRA and aldosterone. The father had normal blood pressure and potassium, low-normal PRA and normal aldosterone. All three subjects had elevated levels of urinary 18-hydroxycortisol and 18-oxocortisol. Baseline 11-deoxycorticosterone (DOC), corticosterone (B) and aldosterone were high in the proband and normal in the father and sibling 1; 11-deoxycortisol (S) and cortisol (F) were normal. ACTH induced a normal increase of B, DOC, S and F, and an excessive aldosterone increase in all three patients. Abnormalities in the chimaeric portions of CYB11B1 or CYP11B2 genes did not account for the phenotypic disparity of the different members in a single GRA family. Altered regulation of the chimaeric gene may be responsible for differences in its activity.

Topics: Adult; Aged; Aldosterone; Cortodoxone; Cytochrome P-450 CYP11B2; Dexamethasone; Female; Genotype; Glucocorticoids; Humans; Hydrocortisone; Hyperaldosteronism; Hypertension; Male; Middle Aged; Pedigree; Phenotype; Renin; Steroid 11-beta-Hydroxylase

CYP11B1 (11beta-hydroxylase) and CYP11B2 (aldosterone synthase) are 93% identical mitochondrial enzymes that both catalyze 11beta-hydroxylation of steroid hormones. CYP11B2 has the additional 18-hydroxylase and 18-oxidase activities required for conversion of 11-deoxycorticosterone to aldosterone. These two additional C18 conversions can be catalyzed by CYP11B1 if serine-288 and valine-320 are replaced by the corresponding CYP11B2 residues, glycine and alanine. Here we show that such a hybrid enzyme also catalyzes conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol, and 18-oxocortisol. These latter two steroids are present at elevated levels in individuals with glucocorticoid suppressible hyperaldosteronism (GSH) and some forms of primary aldosteronism. Their production by the recombinant CYP11B enzyme is enhanced by substitution of further amino acids encoded in exons 4, 5, and 6 of CYP11B2. A converted CYP11B1 gene, containing these exons from CYP11B2, would be regulated like CYP11B1, yet encode an enzyme with the activities of CYP11B2, thus causing GSH or essential hypertension. In a sample of 103 low renin hypertensive patients, 218 patients with primary aldosteronism, and 90 normotensive individuals, we found a high level of conversion of CYP11B genes and four cases of GSH caused by unequal crossing over but no gene conversions of the type expected to cause GSH.

Topics: Case-Control Studies; Catalysis; Cortodoxone; Cytochrome P-450 CYP11B2; Gene Conversion; Genetic Code; Genetic Testing; Humans; Hydrocortisone; Hyperaldosteronism; Hypertension; Renin; Steroid 11-beta-Hydroxylase

Corticosteroid 11 beta-hydroxylation is catalysed by 11 beta-hydroxylase and aldosterone synthase. Using plasma steroid ratios, the level of this process in patients with glucocorticoid-suppressible hyperaldosteronism (GSH) was compared with that in unaffected control subjects and in patients with Conn's syndrome. Based on both 11-deoxycortisol:cortisol (S:F) and 11-deoxycorticosterone:corticosterone (DOC:B) ratios, patients with GSH showed impaired resting 11 beta-hydroxylase activity. In GSH, but not in the other groups, the S:F ratio was significantly correlated with basal plasma aldosterone concentration. ACTH infusion increased the S:F ratio in all these patient groups, suggesting a common partial deficiency. The results also indicate that 11 beta-hydroxylation may be rate-limiting in normal subjects. In control subjects and patients with Conn's syndrome, the DOC:B ratio was not affected by ACTH. However, in GSH patients, this ratio fell markedly, indicating an increased efficiency of 11 beta-hydroxylation of DOC (but not S). This may be due to the activation by ACTH of the zona fasciculata chimaeric aldosterone synthase characteristic of this disease. Plasma aldosterone, corticosterone and DOC concentrations, appeared to be more sensitive to ACTH in GSH than the other groups. The defect in 11 beta-hydroxylation in GSH accounts for the increased levels of DOC reported in the condition, and may contribute to the phenotypic variability.

Topics: Adrenocorticotropic Hormone; Aldosterone; Chimera; Corticosterone; Cortodoxone; Cytochrome P-450 CYP11B2; Desoxycorticosterone; Glucocorticoids; Humans; Hydrocortisone; Hyperaldosteronism; Hypertension; Steroid 11-beta-Hydroxylase; Zona Fasciculata

Based on the concept of glucocorticoid-receptor induction of angiotensin-converting enzyme (ACE), approaches to inhibiting enzyme induction with drugs that suppress the function of type II cytoplasmic glucocorticoid receptors, (genuine glucocorticoid receptors), are suggested. Three types of inhibiting the function of type II glucocorticoid receptors by drugs were distinguished. Type I is characterized by competition of the drugs with natural and synthetic glucocorticoids for interaction with glucocorticoid receptors (cortexolone, progesterone); type II is determined by irreversible inactivation of type II glucocorticoid receptors (aminazine, tisercin); type III is related to an increase of interaction of transcorticoid receptors with natural glucocorticoids which is accompanied by a reduction of the interaction of natural glucocorticoids with genuine glucocorticoid receptors (analgin, amidopyrine). It has been established that the drugs that provoke irreversible inactivation of the function of type II glucocorticoid receptors decrease ACE activity in blood plasma and in the lungs, that may serve the main reason for their high hypotensive effect in arterial hypertension. A concept is advanced, providing evidence for the use of the classical ACE inhibitors and of type II glucocorticoid receptor inhibitors.

Topics: Aminopyrine; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Chlorpromazine; Cortodoxone; Dipyrone; Glucocorticoids; Humans; Hypertension; Methotrimeprazine; Peptidyl-Dipeptidase A; Progesterone; Receptors, Glucocorticoid

1. Previous studies demonstrated that the combined infusion of cortisol (F), aldosterone (ALDO), deoxycorticosterone (DOC), corticosterone (B), 11-deoxycortisol (S), 17 alpha-hydroxyprogesterone (17 alpha OHP) and 17 alpha, 20 alpha- dihydroxy-4-pregnane-3-one (17 alpha 20 alpha OHP), at rates equivalent to their production during adrenocorticotrophic hormone (ACTH) treatment, reproduced the pressor and metabolic responses to ACTH administration in sheep. 2. This study examined which of these adrenocortical steroids were necessary for the initiation of the hypertension produced by these steroids in sheep. 3. Infusion of F, ALDO, 17 alpha OHP and 17 alpha 20 alpha OHP together, increased MAP by 19 mmHg, similar to both complete steroid cocktail (+25 mmHg) or ACTH administration (+21 mmHg). Infusion of F, 17 alpha OHP and 17 alpha 20 alpha OHP increased MAP by +7 mmHg. Infusion of ALDO, 17 alpha OHP and 17 alpha 20 alpha OHP had no effect on MAP. Thus F and ALDO were essential for the pressor effects of the steroid infusion. 4. To determine the role of glucocorticoid activity in the MAP rise, prednisolone, a non-pressor glucocorticoid, was substituted for cortisol. Combined prednisolone, ALDO, 17 alpha OHP and 17 alpha 20 alpha OHP infusion did not raise blood pressure. This suggested that the mineralocorticoid component rather than glucocorticoid component of cortisol's activity was involved in the pressor response. 5. Aldosterone (7 micrograms/h) was substituted for cortisol, giving a total of 10 micrograms/h aldosterone. High dose ALDO (10 micrograms/h), 17 alpha OHP and 17 alpha 20 alpha OHP infusion raised blood pressure by 18 mmHg. Thus, the essential role of cortisol appeared to be due to its occupancy of mineralocorticoid receptors, rather than glucocorticoid receptors. 6. Given that ACTH produces a transient initial increase in aldosterone secretion of up to 10 micrograms/h, it appears that aldosterone and not cortisol is essential for the pressor effects of ACTH. 7. Hypertension resulting from the combined steroid infusion in the sheep appears to be produced by a mechanism which involves a complex interaction between ALDO, F, 17 alpha OHP and 17 alpha 20 alpha OHP. Therefore, the putative 'hypertensinogenic' receptor may be multivalent with binding sites for F, ALDO and 17 alpha 20 alpha OHP, or is a site of single interactive receptors for these steroids and that F exerts its permissive action by occupying the same site as ALDO on the hypertensin

Topics: 17-alpha-Hydroxyprogesterone; Adrenal Cortex Hormones; Adrenocorticotropic Hormone; Aldosterone; Animals; Corticosterone; Cortodoxone; Desoxycorticosterone; Female; Hydrocortisone; Hydroxyprogesterones; Hypertension; Prednisolone; Sheep

The case was a 33-year-old woman with hypertension and hypokalemia, who presented depression of renin activity and the abnormal elevation of plasma deoxycorticosterone (DOC) and 11-deoxycortisol on laboratory tests. After admission, abdominal CT scan, 131I-adosterol scintigram and adrenal venogram revealed a tumor in the left adrenal, which histologically seemed to be benign. When the tumor was resected, blood pressure and all the biochemical data returned to normal range. DOC and 11-deoxycortisol levels in the tumor were abnormally elevated as compared with those in the normal adrenal tissue. These findings suggested that the abnormal elevation of hormone levels resulted from depression of 11 beta-hydroxylase. Though numerous adrenal tumors have been documented, we rarely encounter an apparently benign adrenal tumor that produces 2 kinds of hormones. This seemed to be the first case of benign adrenal tumor in which both DOC and 11-deoxycortisol were elevated.

Topics: 17-Hydroxycorticosteroids; Adenoma; Adrenal Gland Neoplasms; Adult; Cortodoxone; Desoxycorticosterone; Female; Humans; Hypertension; Hypokalemia

The function of the adrenal zona glomerulosa was studied in two pubertal siblings with the hypertensive virilizing form of congenital adrenal hyperplasia who had never been treated. Initially, their plasma 11-deoxycortisol and 11-deoxycorticosterone (DOC) levels were very high, PRA was suppressed, and plasma aldosterone and 18-hydroxycorticosterone (18-OHB) were undetectable. To selectively study zona glomerulosa function, the patients and five normal subjects were given dexamethasone (2 mg/day; thus suppressing zona fasciculata function), and their sodium intake was restricted to 10 mmol/day. After 3-5 days, the zona glomerulosa was stimulated with either angiotensin II or potassium chloride. The same protocol was repeated in the patients at various intervals up to 39 months after beginning maintenance therapy with dexamethasone (0.25 mg twice daily). PRA, plasma aldosterone, and 18-OHB remained low during the first 6 months of treatment. After the first year, PRA recovered, and the zona glomerulosa began to respond. Plasma aldosterone and 18-OHB levels reached normal basal and stimulated values in one of the patients after 2 yr of treatment, but remained subnormal after 39 months of treatment in the other patient. Both patients, however, had persistently elevated plasma DOC concentrations, suggesting slight but definite impairment of 11 beta-hydroxylation in the zona glomerulosa. We conclude that in spite of a severe and persistent 11 beta-/18-hydroxylation deficiency in the zona fasciculata, the zona glomerulosa can recover almost completely after prolonged treatment. Appropriate stimulation, however, discloses a minor 11 beta-hydroxylation impairment also in the zona glomerulosa. In addition, the lack of parallelism in zona glomerulosa 11 beta- and 18-hydroxylation of DOC provides evidence for the concept of different 18-hydroxylating systems in the adrenal cortex.

Topics: 18-Hydroxycorticosterone; Adolescent; Adrenal Cortex; Adrenal Hyperplasia, Congenital; Aldosterone; Angiotensin II; Child; Cortodoxone; Cytochrome P-450 CYP11B2; Desoxycorticosterone; Female; Humans; Hypertension; Male; Potassium Chloride; Renin; Steroid 11-beta-Hydroxylase; Steroid Hydroxylases

Analysis of urinary steroids excreted by a 7-year old girl with low renin hypertension following ACTH treatment revealed several unknown steroids, which have been analysed by gas chromatography-mass spectrometry. It is proposed that these steroids are monohydroxylated derivatives of cortisol, cortisone, either or both tetrahydro and allo-tetrahydrocortisol and either or both tetrahydro and allo-tetrahydro-11-deoxycortisol. Further analysis indicated that there are two likely positions for the additional hydroxyl group, either on the A or B ring.

Topics: Adrenocorticotropic Hormone; Child; Corticosterone; Cortisone; Cortodoxone; Female; Humans; Hydrocortisone; Hydroxycorticosteroids; Hypertension; Isomerism; Renin; Tetrahydrocortisol

Adrenal vein catheterizations were done in rats made hypertensive by administration of methylandrostenediol (MAD; 17alpha-methyl-5-androstene-3beta,-17beta-diol), and in control rats at intervals during treatment. All MAD-treated rats were hypertensive by 7 weeks. Secretion of corticosterone was consistently decreased at all times in MAD-treated rats. 18-Hydroxy-11-deoxycorticosterone secretion and 11-deoxycorticosterone (DOC) secretion decreased and increased, respectively, compared to controls at 2, 4, and 6 weeks. Aldosterone secretion was decreased at 2 and 4 weeks. This study shows an in vivo block of adrenal 11- and 18-hydroxylation. Transient DOC accumulation by treatment with MAD produced hypertension, though DOC oversecretion and other changes in steroidogenesis were waning by the time hypertension developed.

Topics: 18-Hydroxydesoxycorticosterone; Adrenal Glands; Animals; Blood Pressure; Body Weight; Corticosterone; Cortodoxone; Female; Hypertension; Methandriol; Rats; Steroids

Topics: 18-Hydroxydesoxycorticosterone; Adrenal Cortex Hormones; Aldosterone; Cortodoxone; Dehydroepiandrosterone; Humans; Hydrocortisone; Hypertension; Kidney Failure, Chronic; Middle Aged; Renin

Plasma concentrations of progesterone (P), deoxycorticosterone (DOC), 17-hydroxyprogesterone (17-OH P), corticosterone (B), deoxycortisol (S), cortisol (F), and aldosterone were measured in 8 control subjects and in 10 patients with low and normal renin essential hypertension (EH) before and 4 and 8 h after an iv infusion of 25 units of ACTH. Secretion rates of 18-hydroxy-11-deoxycorticosterone (18-OH DOC) were measured for the 24 h prior to and the day of the ACTH infusions. The hypertensive patients had significantly higher plasma levels of aldosterone, DOC and S after ACTH than the controls, whereas plasma B levels were significantly lower. The low renin subgroup considered separately had significantly higher plasma levels of aldosterone and DOC than controls, and higher levels of B and lower levels of F than the normal renin subgroup in response to ACTH. Although not significantly different, the plasma levels of P and the secretion rate of 18-OH DOC tended to be higher, and plasma 17-OH P and F levels lower after ACTH in patients with EH than in controls. The low renin subgroup tended to have the highest plasma S levels and 18-OH DOC secretory rates and lowest F levels. Estimations of adrenal 11beta-hydroxylating efficiency in response to ACTH in patients and controls by plasma steroid ratios revealed significantly lower B/DOC ratios in both low and normal renin patients compared to controls, supported by somewhat lower F/S ratios in these patients, especially those in the low renin subgroup. Altered 17-hydroxylating efficiency seen by significantly lower 17-OH P/P ratios were also found in those with EH, supported by somewhat lower F/B and S/DOC ratios in these patients, agian especially in the low renin subgroup. These data are compatible with a pattern of altered adrenocortical steroid biosynthesis in essential hypertension bearing features similar to adrenal 11beta and 17alpha-hydroxylation deficiencies.

Topics: Adrenal Cortex Hormones; Adrenal Glands; Adrenocorticotropic Hormone; Adult; Aldosterone; Corticosterone; Cortodoxone; Desoxycorticosterone; Female; Humans; Hydrocortisone; Hydroxyprogesterones; Hypertension; Kinetics; Male; Middle Aged; Potassium; Progesterone; Sodium

The case of a young boy who had Cushing's syndrome and severe hypertension in association with metastatic adrenal carcinoma is described. Marked elevation of the mineralocorticoid 11-deoxycorticosterone was demonstrated in the plasma. 11-Deoxycortisol, 17alpha-hydroxyprogesterone, and urinary tetrahydro-11-deoxycortisol and pregnanetriol were also elevated. Aldosterone excretion was low. The data implicate defective 11beta hydroxylation and suggest that excessive 11-deoxycorticosterone production may have been responsible for the hypertension.

Topics: 17-Hydroxycorticosteroids; 17-Ketosteroids; Adrenal Cortex Hormones; Adrenal Gland Neoplasms; Aldosterone; Carcinoma; Child; Cortodoxone; Desoxycorticosterone; Humans; Hydrocortisone; Hydroxyprogesterones; Hypertension; Male; Pregnanetriol

One of the first described cases of hypertensive virilizing adrenal hyperplasia (VAH) (Pediatrics 8: 805, 1951) has been followed from age 2 1/2 until age 26. Blood pressure as an infant was 150/90, and at age 25 was 220/160. During childhood the patient was lost to follow-up for prolonged periods, and received no therapy from age 20 to 25. At this time 24 h urinary excretion of 17-ketosteroids was 89 mg; tetrahydro 11-deoxycortisol (tetrahydro S), 47 mg and pregnanetriol 5.7 mg. Hourly measurements of several plasma steroids utilizing sephadex LH 20 chromatography and competitive protein binding were made during 24 h; concentration ranges were made during 24 h; concentration ranges were as follows (mug/100 ml): 11-deoxycortisol 8-40; cortisol 0-48; corticosterone 0-15; deoxycorticosterone 1-18. Plasma cortisol, especially showed a significiant morning impairment, but reached normal and even markedly elevated levels during the day and early evening. Urinary cyclic AMP per 24 h ranged from 5.3 to 11.6 n mol/mg creatinine before therapy, and was 1.9 n mol after therapy. The results suggest either the formation of an alternate pathway to cortisol synthesis, or the existence of a form of VAH with two independent 11-B hydroxylating systems, exhibiting only minimal impairment of the synthetic route to cortisol. The latter would support the presence of two independent 11-B hydroxylating systems in the normal human adrenal. This has been suggested by Zachmann et al. (J Clin Endocrinol Metab 33: 501, 1971) to be true in infancy. Our observations on an adult indicate that these two systems may not be transitory, but persist into adulthood.

Topics: Adrenocortical Hyperfunction; Adult; Child, Preschool; Circadian Rhythm; Corticosterone; Cortodoxone; Cyclic AMP; Desoxycorticosterone; Follow-Up Studies; Humans; Hydrocortisone; Hypertension; Male

Results from the examinations of 20 hypertonics treated with methtopyron 4.5 g/24 h are presented. The values of S, THS, THF, THE and aldosterone in urine are determined, parallelly with plasma cortisol prior to and post hydroxilase blocker. An elevation of urinary THS and DOK was found, with depressed levels of aldosterone in urine and plasma cortisol. Those four indices permit a considerably precise assessment of involving and notinvolving of the different links of hypothalamo-hypophyseal-suprarenal system and the eventual location of the disturbance. Three of the hypertonics did not elevate THS and DOK in urine after methopyron, in spite of the inhibition of the urinary aldosterone and plasma cortisol. That was admitted to be a manifestation of a disturbance in the hypothalamo-hypophyseal functional reserves which might participate in the development and maintenance of the hypertensive disease.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aldosterone; Circadian Rhythm; Cortodoxone; Desoxycorticosterone; Female; Humans; Hydrocortisone; Hypertension; Male; Metyrapone; Middle Aged; Tetrahydrocortisone

Topics: Acetates; Adrenal Cortex; Adrenal Cortex Hormones; Cardiovascular System; Corticosterone; Cortodoxone; Desoxycorticosterone; Desoxycorticosterone Acetate; Hypertension