Miscellaneous endocrine causes of hypertension

Aldosterone is the principal circulating mineralocorticoid in humans, and aldosterone synthesis normally occurs in the face of volume depletion and renin stimulation. In primary and secondary aldosteronism, aldosterone synthesis continues despite volume expansion and causes hypertension. Other steroid hormones that are aldosterone and cortisol precursors also activate the mineralocorticoid receptor and cause hypertension when overproduced. Mineralocorticoid synthesis in these pathologic states can be constitutive or driven by pituitary adrenocorticotropic hormone (ACTH), due to genetic defects that cause disordered steroid synthesis or catabolism. This review focuses on uncommon forms of ACTH-dependent mineralocorticoid excess states associated with hypertension.     

Deoxycorticosterone inactivation by AKR1C3 in human mineralocorticoid target tissues

Aldosterone is the principal endogenous mineralocorticoid in humans and regulates salt and water homeostasis. Cortisol, the major glucocorticoid, has high affinity for the mineralocorticoid receptor; however, 11beta-hydroxysteroid dehydrogenase type 2 converts cortisol to the inactive steroid cortisone in aldosterone target cells of the kidney, thus limiting the mineralocorticoid action of cortisol. Deoxycorticosterone (DOC) binds to the mineralocorticocoid receptor with high affinity and circulates at concentrations comparable to aldosterone. Severe DOC excess as is seen in 17alpha- and 11beta-hydroxylase deficiencies causes hypertension, and moderate DOC overproduction in late pregnancy is associated with hypertension. Here, we demonstrate that DOC is inactivated by the 20-ketosteroid reductase activity of the human AKR1C3 isozyme. Immunohistochemical analyses demonstrate that AKR1C3 is expressed in the mineralocorticoid-responsive epithelial cells of the renal cortical and medullary collecting ducts, as well as the colon. Our findings suggest that AKR1C3 protects the mineralocorticoid receptor from activation by DOC in mineralocorticoid target cells of the kidney and colon, analogous to cortisol inactivation by 11beta-hydroxysteroid dehydrogenase type 2.     

Aldosterone and Mineralocorticoid Receptors in the Cardiovascular System

Aldosterone is currently thought to exert its physiologic effects by activating epithelial mineralocorticoid receptors, and its pathologic effects on the cardiovascular system via mineralocorticoid receptors in the heart and blood vessels. Recent studies have extended this understanding to include a reevaluation of the roles of aldosterone and mineralocorticoid receptor activation in blood pressure control; the rapid, nongenomic effects of aldosterone; the role of cortisol as a mineralocorticoid receptor agonist under conditions of redox change/tissue damage/reactive oxygen species generation; the growing consensus that primary aldosteronism accounts for approximately 10% of all essential hypertension; recent new insights into the cardioprotective role of spironolactone; and the development of third- and fourth-generation mineralocorticoid receptor antagonists for use in cardiovascular and other inflammatory disease. These findings on aldosterone action and mineralocorticoid receptor blockade are analyzed in the context of the prevention and treatment of cardiovascular disease.     

17 alpha-hydroxylase deficiency: mineralocorticoid hormone profiles in an affected family

The plasma concentrations of mineralocorticoid hormones, basal and after stimulation and suppression with ACTH, can identify the heterozygotes in a family with two siblings with 17 alpha-hydroxylase deficiency. Both parents and one sibling had elevated levels of plasma deoxycorticosterone, corticosterone, 18-hydroxydeoxycorticosterone, and 18-hydroxycorticosterone, but normal cortisol and aldosterone concentrations. Stimulation with ACTH effected additional increases in the elevated steroid and cortisol levels, but not in aldosterone, further increasing the discrepancy and the ratio between 18-hydroxycorticosterone and aldosterone. One sibling had normal steroid patterns and an 18-hydroxycorticosterone to aldosterone ratio. Suppression of ACTH restored the steroids to low normal levels. In addition, the ratio of the gas chromatographic analysis of the total major urinary metabolites of corticosterone to total metabolites of cortisol was greater, and the sum of urinary androsterone and etiocholanolone to total corticosterone and cortisol metabolites was less in the heterozygotes than in normal subjects. This identifies deficient 17-hydroxylation, which is required for the production of cortisol and C-19 steroids. These criteria appear unique for the 17 alpha-hydroxylase defect in the heterozygote.     

Dissociation between kallikrein and aldosterone in Cushing's disease with periodic hormonogenesis

It has been suggested that the renal kallikrein-kinin system is dependent on mineralocorticoid activity. This hypothesis was studied in a patient with cyclic Cushing's syndrome combined with cortisol suppressible, dexamethasone non-suppressible ACTH secretion. The 24-h urinary excretions of sodium, potassium, cortisol, active and inactive kallikrein, aldosterone, and prostaglandin E2 (PGE2) were studied during normal and excessive cortisol secretion and after bilateral adrenalectomy. Kallikrein, PGE2 and potassium rose during cortisol overproduction while aldosterone and sodium decreased. Kallikrein, PGE2 and potassium were positively related to cortisol excretion, whereas urinary aldosterone and sodium showed a negative relationship to cortisol. Kallikrein was inversely related to aldosterone. Excretion of inactive kallikrein followed closely the changes of active kallikrein. During cortisol excess, as in our patient, the mineralocorticoid activity of cortisol will exceed that of aldosterone. This suggests that the alterations in kallikrein, aldosterone and PGE2 during cortisol excess in the present study were due to the mineralocorticoid potency of the steroid.     

Mineralocorticoid receptors and pathophysiological roles for aldosterone in the cardiovascular system

For almost 40 years since its discovery in 1953, the mineralocorticoid hormone, aldosterone, was considered to affect blood volume, and thus blood pressure, by its action to retain sodium at epithelial tissues. Over the past decade, direct effects of aldosterone on the heart and blood vessels, and on the cerebral control of blood pressure, have been established in experimental animals. Simultaneously, the incidence of primary aldosteronism in essential hypertension is now acknowledged to be 10-20%, rather than 相似文献   

Steroid hormones and disease activity during pregnancy in systemic lupus erythematosus

OBJECTIVES: To analyze the variation of steroid hormone levels during pregnancy in patients with systemic lupus erythematosus (SLE). Moreover, to investigate whether, during gestation, there is any relationship between steroid concentration and SLE activity. METHODS: Seventeen consecutive pregnant SLE patients and 8 matched healthy pregnant controls were studied prospectively. Disease activity was evaluated by European Consensus Lupus Activity Measure (ECLAM) score modified for pregnancy. The following hormones were evaluated: testosterone, 17beta-estradiol (estradiol), cortisol, dehydroepiandrosterone sulfate (DHEAS), and progesterone. RESULTS: Disease activity score significantly varied during pregnancy and postpartum (P< 0.05), being decreased in the third trimester and increased in the second trimester and postpartum. Serum levels of all steroids varied significantly during pregnancy and the postpartum period both in patients and in healthy subjects. In SLE patients, estradiol, progesterone, and DHEAS concentrations were found to be significantly reduced compared with controls. Serum level profiles of estradiol and progesterone were different from those observed in controls. No differences in the steroid levels were observed between patients taking prednisone 5 mg/day, apart from cortisol, which was, as expected, lower in the latter group. CONCLUSIONS: The major hormonal alteration observed during pregnancy in SLE patients was an unexpected lack of estrogen serum level increase, and, to a lesser extent, progesterone serum level increase, during the second and-even more-the third trimester of gestation. This lack of increase probably was due to placental compromise. Therefore, these steroid hormone variations may result in a lower humoral immune response activation, probably related to a change in the estrogen/androgen balance, that in turn could account for the decrease in disease activity observed during the third trimester in pregnant SLE patients.     

The new biology of aldosterone

Classically, aldosterone is synthesised in the adrenal zona glomerulosa and binds to specific mineralocorticoid receptors located in the cytosol of target epithelial cells. Translocation of the resulting steroid receptor complex to the cell nucleus modulates gene expression and translation of specific 'aldosterone-induced' proteins that regulate electrolyte and fluid balance. However, non-epithelial and rapid non-genomic actions of aldosterone have also been described that account for a variety of actions of aldosterone that contribute to blood pressure homeostasis. These include key actions on endothelial cells and on cardiac tissue. There is also evidence that aldosterone can be synthesised in other tissues; the most convincing evidence relates to the central nervous system. However, suggestions that aldosterone is produced in the heart remain controversial, and adrenal derived aldosterone is the principal source of circulating and locally available hormone. Recent studies have shown major therapeutic benefits of mineralocorticoid receptor antagonism in cardiac failure, which emphasise the importance of aldosterone in causing adverse cardiovascular pathophysiological effects. Additional evidence demonstrates that aldosterone levels predict development of high blood pressure in normotensive subjects, while it is now clear that increased aldosterone action contributes to hypertension and cardiovascular damage in approximately 10% of patients with established hypertension. These new findings highlight the role of aldosterone as a key cardiovascular hormone and extend our understanding of its role in determining adverse cardiovascular outcomes.     

Exogenous estrogen and endogenous sex hormones.

Estrogen replacement therapy is widely used to treat menopausal symptoms and prevent osteoporosis. The mechanism of these and other estrogen effects is currently under investigation. We studied the plasma steroid hormone and sex hormone binding globulin levels in frozen plasma obtained from 977 women aged 50 to 79 years from 1972 to 1974. Almost all of the 301 women who reported current use of noncontraceptive estrogen were taking conjugated estrogen by mouth; none reported use of a progestin. Women taking estrogen were significantly younger, thinner, and more likely to smoke cigarettes than women not taking estrogen. Sex hormone binding globulin and all endogenous hormones except testosterone were negatively correlated with age; estradiol was positively and cortisol and sex hormone binding globulin were negatively associated with obesity. After adjusting for age and obesity, dehydroepiandrosterone sulfate, androstenedione, and free testosterone were significantly lower in women currently taking estrogen than in women not using estrogen. These differences were independent of cigarette smoking. As expected, estrogens (including free estradiol), sex hormone binding globulin, and cortisol levels were higher in treated than untreated women. The possibility that some of the benefits and risks of replacement estrogen are secondary to altered adrenal steroid metabolism and androgen levels needs further evaluation.     

The use of aldosterone receptor blockers in the treatment of hypertension

The emerging role of aldosterone in hypertension and cardiovascular diseases has prompted a renewal of interest in therapeutic approaches designed to interfere with the action of this mineralocorticoid hormone. While spironolactone has long been used for this purpose, side effects, largely attributable to the interaction of this agent with non-mineralocorticoid steroid receptors, has reduced the enthusiasm for its use. Eplerenone, a specific aldosterone receptor blocker with a lower incidence of the sex hormone-related side effects than spironolactone, has been used in several recent clinical trials in hypertension and congestive heart failure. This review will highlight the major findings from these studies.     

Glucocorticoid and mineralocorticoid receptors in gut mucosa.

Both glucocorticoid and mineralocorticoid hormones are known to be involved in the physiology and pathophysiology of the gastrointestinal tract. Studies on the mechanism of action of steroid hormones indicate an initial obligatory step of binding to stereospecific receptor proteins in the cytoplasm of target tissue cells. Mucosal cells from the gastrointestinal tract of adrenalectomized, gonadectomized rats contain cytoplasmic glucocorticoid receptors which bind tritiated dexamethasone with an affinity (Kdiss4C) of approximately 10(-8)M. The concentration of glucocorticoid receptors per unit cytoplasmic protein is in order duodenum greater than jejunum greater than ileum=stomach greater than colon, and their affinity for steroid hormones is in order dexamethasone greater than corticosterone greater than deoxycorticosterone=aldosterone. No glucocorticoid receptors could be demonstrated in esophageal mucosal cells. Binding sites for tritiated aldosterone, with affinity characteristics appropriate for physiological mineralocorticoid receptors, were demonstrated in duodenum, jejunum, ileum and colon. No similar sites could be shown in the mucosa of the gastric antrum.     

Interactions of high salt intake and the response of the cardiovascular system to aldosterone

High salt intake contributes to the risk of hypertension, and this effect is in part mediated by the physiologic action of aldosterone on renal mineralocorticoid receptors. However, the actions of aldosterone are not restricted to the kidneys, because aldosterone can bind to mineralocorticoid receptors in the heart, vasculature, and brain to produce structural and functional changes that lead to target organ damage. Experimental and clinical studies show that, in the setting of high salt intake, blocking aldosterone at the mineralocorticoid receptor reduces progression to target organ damage and preserves vascular function. In many cases, these benefits are independent of changes in blood pressure. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have short-term effects on reducing aldosterone levels, but frequently aldosterone levels return to pretreatment levels during long-term therapy. Aldosterone blockade may be more completely achieved with mineralocorticoid receptor antagonists. Spironolactone has been shown to have substantial and significant benefits in experimental and clinical studies of cardiac dysfunction. Eplerenone is a selective aldosterone blocker with a greater binding affinity for mineralocorticoid receptors than for androgen and progesterone receptors. Eplerenone has similarly demonstrated significant benefits in experimental animals and in patients with left ventricular dysfunction after myocardial infarction. Thus, aldosterone blockade with mineralocorticoid receptor antagonists offers target organ protection and may blunt some of the adverse effects of chronic high salt intake.     

Diagnosis and therapy surveillance in Addison's disease: rapid adrenocorticotropin (ACTH) test and measurement of plasma ACTH, renin activity, and aldosterone.

The rapid ACTH injection test is an indirect screening test for adrenocortical insufficiency. As a supplement to this test, we evaluated the practicability of single measurements of plasma cortisol, ACTH, aldosterone, and PRA as a definitive diagnostic test of primary adrenocortical insufficiency (PAI). We also tested the value of PRA measurements during treatment with hydro- and fludrocortisone (HC and FC) as a guide for correct mineralocorticoid substitution. In 45 patients with PAI, results of the rapid ACTH test and single measurements of the four hormones (all tests between 0800-0900 h) were compared. Single hormone measurements were also made in 55 normal subjects and 46 patients with pituitary disease (cortisol and ACTH only), most of them with mild to severe secondary adrenocortical insufficiency (SAI). The rapid ACTH test was abnormal in 100% of 41 patients with PAI tested. Plasma ACTH, PRA, and the ratios of ACTH/cortisol and PRA/plasma or urinary aldosterone were clearly elevated in 100% of the patients with PAI. The ACTH/cortisol ratio also distinguished 100% of patients with PAI from those with SAI, but not always control subjects from those with SAI. Thus, dynamic tests (CRH or insulin tests) are indicated if SAI is suspected. PAI and involvement of zona fasciculata and glomerulosa function can be diagnosed with high reliability by measuring cortisol, ACTH, aldosterone, and PRA either together with the rapid ACTH test or later, after a short interval of steroid substitution. PRA measurements during treatment with HC and FC correlated better with the mineralocorticoid dose than plasma potassium and sodium levels. PRA measurement is a valuable guide for FC replacement therapy. It should be titrated into the upper normal range to avoid under- and overtreatment.     

Vascular type I aldosterone binding sites are physiological mineralocorticoid receptors

In vitro, Type I receptors have high and equivalent affinity for aldosterone, corticosterone and cortisol: in vivo, physiological mineralocorticoid target tissues (kidney, colon, parotid) are highly aldosterone-selective, in contrast with hippocampus and heart. In the present study we show that the mesenteric vascular arcade is similarly highly aldosterone-selective in vivo, and in vitro shows considerable levels of 11 beta OH steroid dehydrogenase activity, previously postulated as the mechanism whereby glucocorticoids are excluded from physiological mineralocorticoid receptors.     

Administration of glycyrrhetinic acid: significant correlation between serum levels and the cortisol/cortisone-ratio in serum and urine.

In vitro, cortisol and aldosterone have a similar affinity to the mineralocorticoid receptor. The 11beta-hydroxysteroid dehydrogenase catalyzes the interconversion of cortisol to its inactive 11-oxo-metabolite cortisone. This interconversion is responsible for the in vivo specificity of the mineralocorticoid receptor. A defect of this enzyme leads to a pseudohyperaldosteronism with hypertension and hypokalemia, the so-called apparent mineralocorticoid excess syndrome. Glycyrrhetinic acid, a compound of licorice, also leads to pseudohyperaldosteronism by an inhibition of the 11beta-hydroxysteroid dehydrogenase. We studied the pharmacokinetics of glycyrrhetinic acid and its effect on the 11beta-hydroxysteroid dehydrogenase. Ten healthy students, aged 24 to 38 years, were included in the study. On the first day 500 mg glycyrrhetinic acid were given orally at 08.00 h. Blood and urine samples were taken prior to and 2, 4, 7, 10 and 24 hours after ingestion of glycyrrhetinic acid. We measured the serum level of cortisol, cortisone and glycyrrhetinic acid and the urinary excretion rates of cortisol, cortisone and their 20-dihydrometabolites. For determination of glycyrrhetinic acid and steroid levels we used a fully automated liquid chromatographic analyzer which allows the highly specific and simultaneous determination of steroid profiles even in the matrix of urine. Ratios of the 11-hydroxy- and 11-oxo-metabolites were calculated and correlated to the serum level of glycyrrhetinic acid. We found a significant correlation of the steroid-ratios to the serum levels of glycyrrhetinic acid. Coefficients of correlation were 0.9873, 0.7812, 0.7396 and 0.5844 between the serum level of glycyrrhetinic acid and the cortisol/cortisone-ratio in serum (p < 0.0001), the cortisol/cortisone-ratio in urine (p = 0.0279), the 20alpha-dihydrocortisol/20alpha-dihydrocortisone-ratio in urine (p = 0.0119) and the 20beta-dihydrocortisol/20beta-dihydrocortisone-ratio in urine (p = 0.0419), respectively. We conclude that the ratios of cortisol to cortisone and of the 20-dihydrometabolites of cortisol to the 20-dihydrometabolites of cortisone provide a simple noninvasive tool for monitoring the in-vivo activity of the 11beta-hydroxysteroid dehydrogenase.     

The mislabelling of deoxycorticosterone: making sense of corticosteroid structure and function

Over the 70 or so years since their discovery, there has been continuous interest and activity in the field of corticosteroid functions. However, despite major advances in the characterisation of receptors and coregulators, in some ways we still lack clear insight into the mechanism of receptor activation, and, in particular, the relationship between steroid hormone structure and function remains obscure. Thus, why should deoxycorticosterone (DOC) reportedly be a weak mineralocorticoid, while the addition of an 11β-hydroxyl group produces glucocorticoid activity, yet further hydroxylation at C18 leads to the most potent mineralocorticoid, aldosterone? This review aims to show that the field has been confused by the misreading of the earlier literature and that DOC, far from being relatively inactive, in fact has a wide range of activities not shared by the other corticoids. In contrast to the accepted view, the presence of an 11β-hydroxyl group yields, in corticosterone or cortisol, hormones with more limited functions, and also more readily regulated, by 11β-hydroxysteroid dehydrogenase. This interpretation leads to a more systematic understanding of structure-function relationships in the corticosteroids and may assist more rational drug design.     

Adrenocortical dysfunction in paracoccidioidomycosis: comparison between plasma β-lipotrophin/adrenocorticotrophin levels and adrenocortical tests

OBJECTIVE: Paracoccidioidomycosis is an important cause of Addison's disease in South America. We have carried out an extensive and prospective study on paracoccidioidomycosis comparing glucocorticoid, mineralocorticoid and androgen function with adrenal regulators, ACTH/beta-LPH and plasma renin activity (PRA). PATIENTS AND METHODS: Forty-seven male patients with active paracoccidioidomycosis were studied consecutively together with 20 healthy controls. On day 1, plasma aldosterone and PRA levels were measured in blood samples obtained from patients in the supine and erect position. On day 2 at 0900 h, baseline plasma samples were taken for ACTH, beta-lipotrophin (beta-LPH), cortisol, corticosterone, aldosterone, androstenedione (delta 4-A) and dehydroepiandrosterone sulphate (DHEA-S). ACTH 1-24 (250 micrograms) was given i.v. and blood samples for these steroid assays were taken at 1 and 2 hours. RESULTS: Five patients (10%) had Addison's disease with high basal plasma ACTH and beta-LPH, and low cortisol levels after the ACTH test. In the remaining 42 patients, baseline ACTH and beta-LPH levels and plasma cortisol after ACTH were within the normal range. A high percentage of patients presented with reduced corticosterone (21% of patients) and aldosterone (23%) secretion and increased PRA (31%). Plasma delta 4-A (19%) and DHEA-S (50%) levels were also reduced. CONCLUSIONS: The frequency of Addison's disease among our patients with paracoccidioidomycosis was 10%. In addition, a subset of patients presented with adrenal dysfunction detected by mineralocorticoid or androgen tests. In parallel to pathological lesions a functional adaptation may occur during adrenal involvement in paracoccidioidomycosis.