Stimulation and suppression of the mineralocorticoid hormones in normal subjects and adrenocortical disorders.

In summary, maneuvers that affect the RAS stimulate or suppress solely aldosterone and 18-OHB and have little, if any, effect on DOC, 18-OHDOC, B, or cortisol. The magnitude of aldosterone response seems to be of equal magnitude for all stimulatory or suppressive maneuvers as used in the present protocols. Although primarily originating in the ZG, some secretion of 18-OHB from the ZF is evident by its disproportionate responses (in relation to aldosterone) to maneuvers challenging ACTH. The prompt and marked increases the 18-OHDOC and B after ACTH make them the most sensitive "markers" of the ZF steroid activity. The application of those maneuvers and MCH measurements to adrenal disorders should help to further characterize their pathophysiology.

Circadian rhythm and effect of posture on plasma aldosterone concentration in primary aldosteronism.

The effect of circadian rhythm and alterations in posture on plasma aldosterone concentration was studied in 13 patients with primary aldosteronism (six adenoma, five idiopathic hyperplasia, two carcinoma) to define the regulatory mechanism in each of these pathologic subtypes. Blood samples for aldosterone, cortisol, renin, and potassium concentrations were obtained every 4 h during prolonged recumbency (32 h) and upright posture (16 h). During recumbency, aldosterone and cortisol followed a normal circadian pattern in patients with adenoma and hyperplasia, with peak values at 0400-0800 h and the nadir at 1600-2400 h. Normalized aldosterone and cortisol values correlated significantly in both groups (adenoma r=+0.66, P less than 0.001; hyperplasia r=+0.42, P less than 0.01). With upright posture, aldosterone levels declined parallel to the normal circadian fall in cortisol in patients with adenoma (r=+0.68, P less than 0.001); whereas aldosterone levels increased in patients with hyperplasia parallel to small increments in renin (r=+0.65, P less than 0.001) and potassium (r=+0.64, P less than 0.001). During the administration of dexamethasone, aldosterone no longer correlated with cortisol in patients with adenoma but continued to correlate with renin during upright studies in patients with hyperplasia (r=+0.77, P less than 0.01). Aldosterone circadian rhythm was abnormal in patients with carcinoma and no effect of posture was noted. Unilateral adrenalectomy restored the normal postural relationship in four patients with adenoma. These studies suggest that aldosterone secretion is under continuous ACTH control regardless of posture in patients with adenoma, whereas persistent adrenal responsiveness to small increments in renin and/or potassium mediate the postural increase in plasma aldosterone in patients with hyperplasia. True adrenal autonomy occurs only in patients with adrenal carcinoma and when ACTH is suppressed in those with adenoma.

The constant plasma 18-hydroxycorticosterone to aldosterone ratio: an expression of the efficacy of corticosterone methyloxidase type II activity in disorders with variable aldosterone production.

Aldosterone and 18-hydroxycorticosterone (18-OHB) are produced by the adrenocortical zona glomerulosa. Under normal conditions, plasma 18-OHB levels parallel and are influenced by the same trophic factors that regulate aldosterone production. To evaluate corticosterone-methyl-oxidase II activity, the final step of aldosterone biosynthesis, in conditions associated with chronic derangements of the pituitary-adrenal and/or renal-adrenal axis, we measured the plasma 18-OHB to aldosterone ratio, cortisol, PRA or plasma renin concentration, and potassium (K) in 104 such patients and 15 normal subjects. The 18-OHB to aldosterone ratios in the pituitary-adrenal group were not significantly different from normal regardless of elevated or reduced ACTH and/or cortisol levels [patients with Cushing's syndrome, 3.55 +/- 0.68 (+/-SE); ACTH deficiency, 2.03 +/- 0.34; 21-hydroxylase deficiency, 3.09 +/- 0.23; normal subjects, 2.50 +/- 0.15]. The renal-adrenal group also had normal ratios regardless of plasma renin concentration and K levels [patients with aldosterone-producing adenomas, 2.85 +/- 0.15; idiopathic hyperaldosteronism, 2.14 +/- 0.19; salt-losing nephropathy, 3.06 +/- 0.54; Bartter's syndrome, 2.89 +/- 0.20; isolated (hyporeninemic) hypoaldosteronism, 3.20 +/- 0.39]. Only in patients with 17 alpha-hydroxylase deficiency (230.1 +/- 118.6) was the ratio abnormally high. Chronic perturbations of aldosterone production by ACTH, the renin-angiotensin system, and/or K did not alter this last step of aldosterone biosynthesis (corticosterone-methyloxidase II), as defined by their plasma concentrations. Any influence of these trophic factors must be proximal to the site of 18-OHB production.

Clinical manifestation of adrenocorticotropin-determined plasma concentrations of mineralocorticoid hormones.

Chronic oversecretion of adrenocorticotropin (ACTH) in Cushing's disease and partial adrenal insufficiency results in a plasma pattern of mineralocorticoid hormones (MCHs) in which deoxycorticosterone, 18-hydroxycorticosterone and aldosterone remain within normal limits. In patients with deficiencies of 17 alpha- and 21-hydroxylation, the entire MCH pathway may be initially stimulated by ACTH alone in the presence of reduced cortisol production. An ACTH-induced intra-adrenal factor reflected by levels of cortisol production, or cortisol itself, may determine MCH levels by its inhibition (high) or lack of inhibition (low) of 11 beta- and 18-hydroxylation.

Adrenocorticotropin inhibition of mineralocorticoid hormone production.

1. Adrenocorticotropin (ACTH)-induced steroidogenesis, obtained by continuous administration of ACTH for 3 days, produces in man (a) sustained elevations of plasma deoxycorticosterone and cortisol concentrations, (b) transient elevations of plasma aldosterone and 18-hydroxycorticosterone concentrations that return to near-control values, and (c) brisk initial increases in plasma 18-hydroxydeoxycorticosterone and corticosterone concentrations that fall to 20-68% of peak values 30 h thereafter. 2. Dexamethasone (8 mg/day, orally) treatment for 2 days in man permits a greater postural increase in plasma aldosterone and 18-hydroxycortisone concentrations. A dampening effect of ACTH is suggested. 3. An ACTH-initiated inhibition of 11 beta- and 18-hydroxylation is proposed to be operative in regulation of mineralocorticoid hormones.

The mineralocorticoid hormone pathways in hypertension with hyperaldosteronism.

Simultaneous measurement of the 0800-hr plasma concentrations of deoxycorticosterone (DOC), corticosterone (B), 18-hydroxycorticosterone (18-OHB), aldosterone, 18-hydroxydeoxycorticosterone (18-OHDOC) and cortisol (F) in four types of primary aldosteronism provides evidence for primary adrenal disease. Elevated DOC with normal F concentrations in the presence of elevated 18-OHB and aldosterone, and suppressed renin concentration suggests a primary adrenal abnormality of the zona glomerulosa (ZG). Steroid production by the zona fasciculata (ZF), F, 18-OHDOC, and most often B, is normal. These patterns exist only for primary adrenal hyperplasia, aldosterone-producing adenoma (APA), and aldosterone-producing adrenocortical carcinoma (AP-Ca). Elevated DOC levels are rarely found in patients with idiopathic hyperaldosteronism (IHA or adrenal hyperplasia) and suggest that IHA is not a primary adrenal disorder and should be excluded from the syndrome of primary aldosteronism as they have been heretofore.

Regulation of the mineralocorticoid hormones in adrenocortical disorders with adrenocorticotropin excess.

Chronic stimulation by adrenocorticotropin (ACTH) of the adrenal cortex produces different plasma mineralocorticoid hormone (MCH) patterns, depending on the amount of glucocorticoid hormones (cortisol) concurrently generated and the degree of activation of the renin angiotensin system (RAS). Patients with Cushing's disease or the ectopic ACTH-excess syndrome have normal or low production of the MCHs, aldosterone and 18-hydroxycorticosterone (18-OHB), by the zona glomerulosa (ZG), elevated cortisol and deoxycorticosterone (DOC) levels, and high-normal to elevated production of the MCHs corticosterone (B) and 18-hydroxydeoxycorticosterone (18-OHDOC) by the zona fasciculata (ZF). Prolonged administration of superphysiologic doses of ACTH to normal subjects yields similar patterns. Patients with simple virilizing 21-hydroxylase deficiency (21-OHD) have impaired ZF production of B and 18-OHDOC and elevated DOC, 18-OHB, and aldosterone secretion secondary to the superimposed RAS stimulation of the ZG. Patients with 17 alpha-hydroxylase deficiency (17 alpha-OHD) have elevated levels of the ZF MCHs DOC, B, 18-OHDOC, and 18-OHB and a functionally suppressed ZG. Patients with 11 beta-hydroxylase deficiency (11 beta-OHD) have only elevated production of DOC by the ZF and suppressed RAS and aldosterone. A significant negative correlation between cortisol and aldosterone concentrations suggests that cortisol is involved in the ACTH-mediated inhibition of aldosterone formation.