Possible hyperaldosteronism and discrepancy in enzyme activity deficiency in adrenal and gonadal glands in Japanese patients with 17 alpha-hydroxylase deficiency

We reviewed the pathophysiology of our previously reported female patient who had glucocorticoid-responsive hyperaldosteronism and was treated successfully with daily dose of dexamethasone (Dex) for 21 years. In this present study, the possibility that the patient may have 17 alpha-hydroxylase deficiency (17-OH-D) mainly in the adrenal could not be ruled out. We therefore reviewed 31 Japanese patients diagnosed as having 17-OH-D with suppressed plasma renin activity reported in Japan. Among these patients, 9 were found to have a high plasma aldosterone (Ald) concentration (PAC) (group I). Twenty-one patients had either normal or low-normal PAC and the remaining patient had low urine Ald (group II). The slight cross-reactivity of the anti-Ald-antibodies used with 17-deoxy-steroids such as progesterone, 11-deoxycorticosterone and corticosterone which were increased in both groups did not explain the increased PAC in group I. In the patients in group I and group II with high-normal basal PAC, PAC further increased after ACTH and was suppressed by Dex. PAC in 2 group I patients, however, did not respond to angiotensin-II or angiotensin-III infusion. PAC in patients in group II with low or low-normal basal PAC responded equivocally to ACTH and Dex. The basal plasma cortisol in group I was lower than in group II, and plasma cortisol level after ACTH in group I appeared to remain at a lower level than that in group II patients. Among the study subjects, 28 showed a negative correlation between basal PAC and plasma cortisol. A possible discrepancy in the deficiency of 17 alpha-hydroxylase activity in adrenal and gonadal glands was also suggested in three 17-OH-D patients. The pathophysiology of Ald secretion and discrepancy in the deficiency of the enzyme activities in both glands in 17-OH-D patients was discussed.     

Mild adrenal 3 beta-hydroxysteroid dehydrogenase deficiency with hyperaldosteronism

The patient was admitted to our hospital at 19 and again at 22-yr of age for hirsutism and hypertension. Her baseline and ACTH-stimulated plasma 17-hydroxy pregnenolone, dehydroepiandrosterone and dehydroepiandrosterone sulfate were increased whereas plasma 17-hydroxy progesterone and androstenedione were normal and responded poorly to ACTH. Plasma deoxycorticosterone, corticosterone and cortisol baseline levels were normal, and they responded normally to ACTH. The plasma aldosterone concentration (PAC) was always high and responded well to ACTH, angiotensin III and furosemide-upright stimulation. However, plasma renin activity (PRA) was normal or slightly high, and responded normally to furosemide-upright stimulation and fluorohydrocortisone suppression. Dexamethasone (2 mg/day) for 1-2 weeks suppressed the androgens, cortisol and corticosterone levels. PRA and PAC were suppressed temporally, but PRA returned to normal and PAC to be a high level after 2 weeks of dexamethasone administration. Blood pressure was also reduced temporally but returned to a high level after 2 weeks of dexamethasone. These results indicate that primary aldosteronism and dexamethasone-suppressible hyperaldosteronism were not likely to be present, and unknown aldosterone stimulating factors which potentiated the action of endogenous angiotensin II or ACTH might be responsible for the hyperaldosteronism in this patient. We conclude that this patient had a mild and non-salt losing 3 beta-HSD deficiency in the zona reticularis with normal fasciculata and high glomerulosa function.     

New compound heterozygous mutation in the CYP17 gene in a 46,XY girl with 17 alpha-hydroxylase/17,20-lyase deficiency

BACKGROUND: 17alpha-Hydroxylase/17,20-lyase deficiency is caused by a defect of P450c17 which catalyzes both 17alpha-hydroxylase and 17,20-lyase reactions in adrenal glands and gonads. RESULTS: In the present study, we analyzed the CYP17 gene in a Japanese patient with 17alpha-hydroxylase/17,20-lyase deficiency. The patient was a phenotypic girl and referred to us for right-sided inguinal hernia at the age of 4 years. Biopsy of the herniated gonad showed testicular tissue. The karyotype was 46,XY. At 6 years of age, hypertension was clearly recognized and the patient was diagnosed as having 17alpha-hydroxylase/17,20-lyase deficiency based on the clinical and laboratory findings. Analysis of the CYP17 gene revealed a compound heterozygous mutation. One mutation was an undescribed single nucleotide deletion at codon 247 in exon 4 (CTT to CT: 247delT) and the other was a missense mutation resulting in a substitution of His to Leu at codon 373 in exon 6 (CAC to CTC: H373L), which has been previously shown to abolish both 17alpha-hydroxylase and 17,20-lyase activities. The functional expression study of the 247delT mutant showed that this 247delT mutation completely eliminates both 17alpha-hydroxylase and 17,20-lyase activities. CONCLUSIONS: Together, these results indicate that the patient is a compound heterozygote for the mutation of the CYP17 gene (247delT and H373L) and that these mutations inactivate both 17alpha-hydroxylase and 17,20-lyase activities and give rise to clinically manifest 17alpha-hydroxylase/17,20-lyase deficiency.     

Dopaminergic control of aldosterone secretion in hypertensive patients chronically treated with an angiotensin converting enzyme inhibitor

To investigate whether dopamine plays a role in the regulation of aldosterone secretion during long-term blockade of the renin-angiotensin system, we studied the effect of metoclopramide, a competitive antagonist of dopamine, in 6 patients with essential hypertension chronically treated with the angiotensin converting enzyme inhibitor enalapril. All but one of these patients received a diuretic in addition to enalapril. Six hours after the daily morning dose of enalapril (10-40 mg p.o.) a 10 mg bolus dose of metoclopramide was injected intravenously. In one patient a hypotensive episode developed following metoclopramide administration. In the 5 other patients plasma aldosterone significantly rose within 30 min after metoclopramide from 51 +/- 8.7 to 128.2 +/- 29.2 pg/ml. This metoclopramide-induced release of aldosterone occurred in the absence of concomitant changes in circulating angiotensin 11, potassium and ACTH levels. Metoclopramide given during chronic blockade of the renin-angiotensin system caused anxiety and agitation in 2 patients. The increase in plasma aldosterone following competitive dopamine blockade in the face of chronic angiotensin converting enzyme inhibition, unchanged plasma potassium and ACTH levels strongly suggests that in hypertensive patients, dopamine exerts a direct inhibitory effect on aldosterone secretion.     

Reversible hypertension caused by calcium overloading in a patient with postoperative hypoparathyroidism

A 37-year-old woman with postoperative hypoparathyroidism had hypertension, and elevated plasma renin activity (PRA) and subsequent hyperaldosteronism during a two-month hypercalcemic period caused by vitamin D and excessive calcium supplements. The hypertension with elevated PRA, however, was resistant to the angiotensin II (AII) analog [Sar1, Ile8] ALL. PRA further increased and plasma aldosterone decreased in response to the [Sar1, Ile8] ALL. When the patient became normocalcemic, normotensive and normoreninemic, calcium gluconate (5 mg calcium/kg/h) was infused for one hour. The calcium infusion reproduced hypercalcemic hypertension mediated by an increase in total peripheral resistance. These observations suggest that the hypertension observed while taking vitamin D and excessive calcium supplements may be caused by a direct effect of calcium on peripheral blood vessels and the renin-angiotensin system may play a negligible role.     

Testicular adrenal-like tissue in a patient with 17 alpha-hydroxylase deficiency.

Testicular adrenal-like tissue (TALT) have been observed in patients with congenital adrenal hyperplasia, and is usually associated with 21-hydroxylase deficiency; in 3 cases with 11 beta-hydroxylase deficiency. We report a case of male pseudohermaphroditism with 17 alpha-hydroxylase deficiency (17OHD) who also had TALT. To our knowledge, this is the first report about the association of 17OHD and TALT. Also, the patient had high levels of serum aldosterone--an unusual finding in patients with 17OHD. A possible pathogenic mechanism is discussed.     

Adrenal renin: a possible local regulator of aldosterone production

Extrarenal renin has been identified in a number of tissues, including the brain, the submaxillary gland, uterus, ovary, vascular endothelium, testes, pituitary gland, and the adrenal cortex. In some tissues, including the adrenal cortex, all of the components of the renin-angiotensin system have been identified; however, no specific physiologic role has been clearly demonstrated for these extrarenal renin-angiotensin systems. We have studied the role of the renin-angiotensin system in the adrenal cortex of the rat and have found that renin is localized and synthesized in the zona glomerulosa cells. Its production can be influenced by alterations in electrolyte balance, as well as the genetic background of the rat. In adrenal capsular explant cultures, a converting enzyme inhibitor can lower angiotensin II production and reduce the stimulation of aldosterone by potassium, suggesting that this system is involved in the aldosterone response to potassium. In addition to rat adrenals, renin has been identified in human adrenal tissue and human adrenal tumors, including aldosteronomas, and a patient with hypertension has been reported to have an adrenal tumor that appeared to be secreting renin into the circulation.     

Hypertension in a Patient with Aldosterone Deficiency

ObjectiveTo describe a patient with aldosterone synthase deficiency, who presented with failure to thrive, hypovolemic hyponatremia, and the unexpected finding of hypertension.MethodsWe present a case report, review the related literature, and outline a possible mechanism for the concomitant occurrence of high blood pressure and hyponatremia in this patient.ResultsA 5-month-old infant with unambiguous female genitalia was admitted to our hospital with failure to thrive and hyponatremia. Her blood pressure was 115/88 mm Hg (> 95% for age). The serum sodium concentration was 123 mEq/L (normal for age, > 130), and the potassium level was 5.3 mEq/L (normal, 3.5 to 5.3). A direct renin measurement by immunochemiluminescence assay was 11,400 μU/mL (normal, < 5), and the aldosterone level was 4 ng/dL (normal, 2 to 70). These findings indicated a diagnosis of aldosterone synthase deficiency. Treatment with fludrocortisone and sodium chloride was begun, but the hypertension worsened. Therapy with an angiotensin-converting enzyme inhibitor was transiently required.ConclusionAngiotensin II, a potent vasoconstrictor, is an intermediate in the renin-angiotensin system. We believe that this protein was the cause of the hypertension in the setting of aldosterone deficiency in our patient. (Endocr Pract. 2005;11:104-107)     

Disorders of the aldosterone synthase and steroid 11beta-hydroxylase deficiencies

The most potent corticosteroids are 11beta-hydroxylated compounds. In humans, two cytochrome P450 isoenzymes with 11beta-hydroxylase activity, catalysing the biosynthesis of cortisol and aldosterone, are present in the adrenal cortex. CYP11B1, the gene encoding 11beta-hydroxylase (P450c11), is expressed on high levels in the zona fasciculata and is regulated by ACTH. CYP11B2, the gene encoding aldosterone synthase (P450c11Aldo), is expressed in the zona glomerulosa under primary control of the renin-angiotensin system. Aldosterone synthase has 11beta-hydroxylase activity as well as 18-hydroxylase activity and 18-oxidase activity. The substrate for CYP11B2 is 11-deoxycorticosterone, that of CYP11B1 is 11-deoxycortisol. Mutations in CYP11B1 cause congenital adrenal hyperplasia (CAH) due to 11beta-hydroxylase deficiency. This disorder is characterized by androgen excess and hypertension. Mutations in CYP11B2 cause congenital hypoaldosteronism (aldosterone synthase deficiency) which is characterized by life-threatening salt loss, failure to thrive, hyponatraemia and hyperkalaemia in early infancy. Both disorders have an autosomal recessive inheritance. Classical and nonclassical forms of 11beta-hydroxylase deficiency can be distinguished. Studies in heterozygotes for classical 11beta-hydroxylase deficiency show inconsistent results with no or only mild hormonal abnormalities (elevated plasma levels of 11-deoxycortisol after ACTH stimulation). In infants with congenital hypoaldosteronism, a comparable frequency of 18-hydroxylase deficiency (aldosterone synthase deficiency type I) and of 18-oxidase deficiency (aldosterone synthase deficiency type II) can be found. Molecular genetic studies of the CYP11B1 and CYP11B2 genes in 11beta-hydroxylase deficiency or aldosterone synthase deficiency have led to the identification of several mutations. Transfection experiments showed loss of enzyme activity in vitro. In some of the patients with 18-oxidase deficiency (aldosterone synthase deficiency type II) no mutations in the CYP11B2 gene were identified. Refined methods for steroid determination are the basis for the diagnosis of inborn errors of steroidogenesis. Molecular genetic studies are complementary; on the one hand, they have practical importance for the prenatal diagnosis of virilizing CAH forms and on the other hand, they are of theoretical importance in terms of our understanding of the functioning of cytochrome P450 enzymes. Copyrightz1999S.KargerAG, Basel     

Can primary hyperaldosteronism be considered as a specific form of diabetes mellitus?

Aldosterone-producing adenoma (aldosteronoma)--the most frequent form of primary hyperaldosteronism (PH)--is considered a specific form of diabetes mellitus (DM). In a previous study we demonstrated insulin resistance in patients with PH. We have therefore undertaken a study to evaluate the incidence of abnormalities of glucose metabolism in patients with PH (36 subjects) compared to control subjects with essential hypertension (EH) (21 patients). The following parameters were measured in all studied subjects: office blood pressure (by mercury sphygmomanometer in the sitting position), body mass index (BMI), plasma potassium, plasma glucose and insulin levels during oral glucose tolerance test (OGTT) (0, 60, 120 min), plasma renin activity and plasma aldosterone. Although patients with PH tended to have higher stimulated plasma glucose levels after 60 and 120 min compared to EH, these differences did not attain statistical significance. Patients with EH tended to have higher insulin levels at each measured interval, but due to a high variability these differences were again not significant. There were no significant differences between PH and EH in the proportion of diabetics (20% vs. 14%) or patients with impaired glucose tolerance (18% vs. 10%). In conclusion, we have found the absence of significant differences in the frequency of diabetes mellitus, impaired glucose tolerance and insulin resistance in patients with EH and PH. Our data thus do not support the idea of primary hyperaldosteronism as a specific type of diabetes mellitus. Furthermore, our results indicate that glucose metabolic characteristics in essential hypertension and primary hyperaldosteronism tend to be similar. The definitive conclusion with respect to the possible causal relationship between DM and PH, however, can be obtained only on larger groups of subjects, in particular after the evaluation of the effect of surgical/pharmacological treatment of primary hyperaldosteronism.     

Hypokalemia and alkalosis in adipsic hypernatremia are not associated with hyperaldosteronism

Idiopathic adipsic hypernatremia (AH) is a rare disorder associated with hypokalemia and alkalosis. Hypokalemic alkalosis has been presumed to be secondary to hyperaldosteronism. We evaluated plasma renin activity, serum aldosterone, serum and urine electrolytes in a 17-year-old patient with AH on several occasions. Despite evidence of mild dehydration, serum Na >160 and K <3.2, aldosterone levels were suppressed and plasma renin activity was not elevated. Urine Na and K were not conserved. We also examined electrolyte and hormone levels in previously reported cases of AH. Aldosterone levels were not increased in any of the cases when measured. Renin secretion was increased in 2 patients. Among the compiled cases serum K was inversely correlated with serum Na (r = -0.73, p < 0.002, n = 15). Hypokalemia and alkalosis occurring in AH are not associated with secondary hyperaldosteronism. Patients with AH may have chronic renal losses of potassium leading to hypokalemia and alkalosis.     

Recent aspects of steroid biosynthesis in male sex differentiation. Clinical studies.

Recent discoveries in molecular biology have much clarified the regulation and function of steroid-converting enzymes. Most progress has been made in the area of cytochromes, which regulate the side chain cleavage of cholesterol (P-450 SCC) and the 17 alpha-hydroxylase and 17,20-desmolase (or 17,20-lyase) activities (P-450 17 alpha), as well as in 3 beta-hydroxysteroid dehydrogenase. Nevertheless, there are some discrepancies between fundamental knowledge and clinical experience, which are difficult to understand: why is it for example possible that cases with 'pure' 17 alpha-hydroxylase or 17,20-desmolase deficiency exist, when there is only one cytochrome regulating both steps? After a brief review of clinical and biochemical findings in the various defects of testosterone biosynthesis, a case is discussed, which is of interest in this respect. This XY patient with female external genitalia, who has been shown to have compound heterozygous mutations, had 'pure' 17,20-desmolase deficiency up to adolescence, but additional 17 alpha-hydroxylase deficiency with hypertension developed thereafter. From this observation, it has to be concluded that as yet unknown, possibly age-dependent modulating factors exist, which influence the activity of the cytochrome. Also the estrogen replacement given to the patient might have played a role in this change.     

Recurrent Hyperkalaemia due to Selective Aldosterone Deficiency: Correction by Angiotensin Infusion

A patient with recurrent weakness and blurring of consciousness associated with hyperkalaemia due to aldosterone deficiency is reported. The plasma concentrations of renin, angiotensin II, and aldosterone were low and did not increase during sodium deprivation. Blood angiotensin I was also low while renin-substrate concentration was normal. Infusion of angiotensin produced a distinct rise in plasma aldosterone. The patient was treated successfully with fludrocortisol.The results support the concept that the renin-angiotensin system is an important regulator of aldosterone secretion and that in the syndrome of acquired selective hypoaldosteronism the primary abnormality may be a deficiency of renin. It is suggested that a selective lack of aldosterone should be considered in all cases of otherwise unexplained hyperkalaemia.     

Steroids and hypertension

Primary aldosteronism is the principal disorder of zona glomerulosa and a number of subsets have been identified: unilateral adenoma; bilateral micro- or macro-nodular hyperplasia (idiopathic aldosteronism); primary hyperplasia and aldosterone-producing carcinoma either adrenal or ectopic. The diagnostic criteria for a correct differential diagnosis of these subsets are now quite reliable and our experience is presented in detail. Unfortunately the pathogenesis of most of these forms is still poorly recognized and requires further investigation. An extreme sensitivity to angiotensin II is present in patients with idiopathic aldosteronism, and a role for adrenal renin is now being advocated. A peculiar form of hyperaldosteronism is the glucocorticoid-remediable subtype. An unusual sensitivity of aldosterone to ACTH is present in this form. A qualitative biochemical abnormality in this disorder consists of marked over-production of products of the cortisol C18-oxidation pathway, 18-hydroxycortisol and 18-oxocortisol, which are more abundant than aldosterone and 18-hydroxycorticosterone. A family with three affected sibs has been studied by our group. In other clinical situations, classical zona fasciculata mineralocorticoids [deoxycorticosterone (DOC), corticosterone and their 18-hydroxy compounds] are secreted in excess. The hypertensive diseases of this zone are rare DOC-secreting tumors and two forms of congenital adrenal hyperplasia (CAH), the 11 beta-hydroxylase (11-OHDS) and the 17 alpha-hydroxylase deficiency syndromes (17-OHDS), which are identified by the presence of hypokalemia and suppressed renin activity. DOC is the only mineralocorticoid hormone (MCH) oversecreted in the 11-OHDS, while all ACTH-dependent MCH are very high in the 17-OHDS. The molecular basis of gene abnormalities of this disorder are currently under investigation, and preliminary data obtained in some of our patients are presented. Finally a syndrome of apparent mineralocorticoid excess, which is not a primary disorder of the adrenal cortex, describes the association of an unexplained hypermineralocorticoid state with a decreased rate of peripheral 11 beta-hydroxy dehydrogenation of cortisol to cortisone. Studies on this syndrome have led to the hypothesis that peripheral cortisol inactivation is the normal mechanism permitting specific mineralocorticoid recognition. The syndrome exists in two forms both characterized by a decreased turnover of a normal level of plasma cortisol, but in the type I variant an elevated cortisol/cortisone metabolite ratio is found, whereas in the type II variant this ratio is normal. Three patients of the latter form have recently been described by us and are shortly illustrated.(ABSTRACT TRUNCATED AT 400 WORDS)     

Adrenal aldosterone-producing adenoma: use of colonic potential in diagnosis and subtraction scanning technique for localisation.

Primary hyperaldosteronism is a potentially curable cause of hypertension, and much interest has been shown in methods of diagnosing the associated hypokalaemic hypertension and localising the adrenal adenoma. In two patients the diagnosis of primary aldosteronism was confirmed by colonic potential measurement and the adenoma localised by a new subtraction technique for early adrenal imaging applied to the use of 131I-19-iodocholesterol. Both patients underwent adrenalectomy and in each case an adenoma was removed. Blood pressure and electrolyte levels returned to normal after operation. In one patient bilateral adrenal phlebography had failed to show the tumour, and sampling of aldosterone concentrations in the adrenal veins had been unsatisfactory.     

Missense mutation serine106----proline causes 17 alpha-hydroxylase deficiency.

Steroid 17 alpha-hydroxylase deficiency is caused by defects in cytochrome P450c17, the single enzyme that has 17-alpha hydroxylase and 17,20-lyase activities. We describe a rapid and efficient polymerase chain reaction tactic for identifying these genetic lesions and identify Ser106----Pro as the cause of 17 alpha-hydroxylase deficiency in two unrelated homozygous patients from Guam. We used site-directed mutagenesis of the normal P450c17 cDNA to construct the Pro106 mutant, and expressed both the normal and mutant sequences in monkey COS-1 cells and in yeast. Expression of the normal sequence permitted the cells to convert pregnenolone to 17-OH pregnenolone, progesterone to 17-OH progesterone, and 17-OH pregnenolone to dehydroepiandrosterone, showing the normal sequence conferred both 17 alpha-hydroxylase and 17,20-lyase activities. Expression of the mutant sequence generated P450c17 mRNA, but conferred none of these activities, proving that the Ser106----Pro mutation abolished the 17 alpha-hydroxylase and 17,20-lyase activities. An HhaI restriction site created by the mutation should permit screening of large populations.     

Enhanced response of plasma prolactin to metoclopramide during chronic converting enzyme inhibition

The effect of chronic converting enzyme inhibition with enalapril on the PRA, PRL and plasma aldosterone responses to metoclopramide was studied in 10 patients with mild to moderate essential hypertension. Enalapril reduced supine blood pressure and increased heart rate significantly. PRA and urinary sodium excretion rose significantly. PRA levels did not change after metoclopramide neither during placebo nor during enalapril. The aldosterone response to metoclopramide was not altered by enalapril, indicating that this response is independent of the renin-angiotensin system. The PRL response to metoclopramide was considerably enhanced after 4 weeks of treatment with enalapril. It is proposed that enalapril, by decreasing the formation of angiotensin II, increases the prolactin reserve.     

Angiotensin II and aldosterone regulation

The circulating renin-angiotensin system is a major regulator of the secretion of the adrenocortical hormone, aldosterone. This renin-angiotensin aldosterone system is important in the control of salt and water balance and blood pressure. This review describes the historical background leading to the discovery of aldosterone in the 1950s and the recognition in the 1960s that angiotensin II was involved in its control. Although angiotensin II is important in the regulation of aldosterone secretion, its action is influenced by multiple other factors, especially potassium and atrial natriuretic peptide. In addition to the circulating renin-angiotensin system, a local renin-angiotensin system is present in the zona glomerulosa cell. This local system also appears to be involved in the regulation of aldosterone production. The mechanism by which angiotensin II stimulates the adrenal zona glomerulosa cell is described in some detail. Angiotensin II interacts with the angiotensin receptor (AT1) membrane receptor that is coupled to cellular second messengers. Specific AT1 receptor antagonists are now clinically used to block angiotensin II's action on various target organs, including the adrenal gland.