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Short term suppression of ACTH by dexamethasone effects limited reduction in plasma deoxycorticosterone (DOC) while cortisol levels are almost completely suppressed in normal control subjects. The zona fasciculata (ZF) microsomal cytochrome P-450(21) appeared less influenced by lack of ACTH than mitochondrial cytochrome P-450(11 beta-18). Eleven patients with hypopituitarism were studied to quantitate basal ZF microsomal and mitochondrial derived steroids and their acute and extended responses to ACTH. Basal levels of 11-deoxycortisol (S) and DOC were modestly reduced (70% and 53%, respectively), while other ZF steroids were almost completely absent. Acute and prolonged ACTH treatment amplified the discrepancy in both plasma levels and production rates. DOC and S demonstrated prompt and sustained increases similar to those in normal controls, while cortisol, 18-hydroxydeoxycorticosterone, and corticosterone showed a slow subnormal recovery of steroid production. The preservation of microsomal cytochrome P-450(21) and P-450(17 alpha) to maintain DOC and S levels contrasts the reduced and delayed responses of steroids dependent on mitochondrial cytochrome P-450(11 beta-18), cortisol, corticosterone, and 18-hydroxydeoxycorticosterone. A greater effect of ACTH deficiency on mitochondrial over microsomal cytochrome P-450 activity is demonstrated, and in addition, the possibility is raised that other non-ACTH regulators sustain microsomal cytochrome P-450(21) and P-450(17 alpha) in a setting of reduced ACTH-stimulated factors.

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.

The 0800 h plasma concentrations of the mineralocorticoid hormones, 18-hydroxydeoxycorticosterone (18-OHDOC), deoxycorticosterone (DOC), corticosterone, 18-hydroxycorticosterone (18-OHB), and aldosterone, in six patients with nonsalt-losing congenital adrenal hyperplasia revealed two groupings of these steroids: in one group, DOC, 18-OHB, and aldosterone were significantly elevated (P less than 0.001) at 51.7 +/- 18.0, 70.8 +/- 14.2, and 22.7 +/- 3.0 ng/dl, respectively; in the other group, corticosterone and 18-OHDOC were normal at 363.6 +/- 76.0 and 7.8 +/- 1.1 ng/dl, respectively. No significant increases in response to upright posture were observed in DOC, 18-OHB, or aldosterone. After a 1-h Cortrosyn stimulation test, the already elevated levels of DOC, 18-OHB, and aldosterone showed slight additional increases, but the normal levels of corticosterone and 18-OHDOC changed little within the normal unstimulated range. In these patients certain mineralocorticoid hormone patterns permit the identification of the zonal origins of steroids. The normal and fixed levels of 18-OHDOC and corticosterone, zona fasciculata steroids, are similar to those of cortisol and imply deficiency of formation and of their precursor, zona fasciculata DOC, a 21-hydroxylated steroid. Both the mineralocorticoid and glucocorticoid pathways distal to 21-hydroxylation are impaired in the zona fasciculata. However, the elevated and partially responsive levels of DOC, 18-OHB, and aldosterone imply that there is greater activation of 21-hydroxylation in the zona glomerulosa than in the zona fasciculata, with its normal fixed steroid levels, and that the elevated level of DOC is primarily from this zone.

In 12 obligate heterozygotes for the simple virilizing form of congenital adrenal hyperplasia (21-hydroxylase deficiency), basal and ACTH-stimulated levels of aldosterone, corticosterone, deoxycorticosterone, 18-hydroxycorticosterone, and 18-hydroxydeoxycorticosterone were examined. The responses to ACTH were significantly impaired (P less than 0.025 less than 0.001) compared with those of normal subjects. In addition to the often exaggerated stimulation by ACTH of the immediate precursor to 21-hydroxylation, 17 alpha-hydroxyprogesterone, the heterozygotes can now be characterized further by the impaired ACTH responses of mineralocorticoids distal to the block in the zona fasciculata; the ACTH-stimulated 17 alpha-hydroxyprogesterone/18-hydroxydeoxycorticosterone ratio was greater than normal in 94% of the heterozygotes. A limitation of 21-hydroxylation may also exist in the zona glomerulosa.

Superphysiological doses of ACTH were administered for 3 consecutive days to nine patients with CAH, five with the classical simple virilizing (CSV) type and four with nonclassical simple virilizing type (NCSV; late onset), receiving a sodium-restricted diet. In the CSV patients, cortisol levels were lower [4.9 +/- 2.2 (+/- SEM) micrograms/dl] than in the NCSV patients (10.9 +/- 3.8; P less than 0.005) and normal subjects (10.7 +/- 4.0; P less than 0.05). ACTH produced a subnormal increase to only 14.5 micrograms/dl by day 3. In the NCSV patients, cortisol rose slowly during the first 24 h, but reached normal response levels by 48 h (42.5 +/- 11.5 micrograms/dl). In all patients, basal plasma corticosterone and 18-hydroxydeoxycorticosterone (18-OHDOC) levels were normal, but deoxycorticosterone (DOC) was elevated at 25.3 +/- 5.0 ng/dl (P less than 0.05). ACTH failed to increase plasma levels of DOC, corticosterone, and 18-OHDOC. Aldosterone and 18-hydroxycortisol were elevated in both groups [29.1 +/- 5.8 (P less than 0.02) and 83.8 +/- 15.3 (P less than 0.01) ng/dl, respectively] and increased briskly after the first 24 h of ACTH. However, neither steroid returned to normal levels in the CSV group, but both did in the NCSV group. Paired values of stimulated cortisol and aldosterone in normal subjects and CSV and NCSV patients (n = 76) were significantly negatively correlated (r = -0.63; P less than 0.001), suggesting that cortisol inhibits aldosterone biosynthesis. Prolonged ACTH administration after initial increases returned aldosterone and 18-hydroxycortisol levels from the zona glomerulosa to baseline values in the NCSV type, but not in the CSV type. The capacity to increase cortisol levels, which occurred only in NCSV patients, is linked to the reduction of aldosterone in the zona glomerulosa. In contrast, in both types of 21-hydroxylase deficiency, sustained impairment of both the 17-hydroxy pathway (cortisol) and the 17-deoxy pathway of the zona fasciculata (DOC, corticosterone, and 18-OHDOC) was demonstrated.

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.