The regulation of plasma 18-hydroxy 11-deoxycorticosterone in man.

18-hydroxy 11-deoxycorticosterone (18-OH DOC), a weak mineralocorticoid, was estimated by a radioimmunoassay procedure after purification in 49 patients with hypertension and 38 normal control subjects. The sensitivity of the method was 2-4 pg; there was no detectable blank, and the precision was 9-10%. In normal subjects the absolute plasma levels were similar to those of aldosterone. ACTH administration produced a 23-fold increase, and sodium restriction resulted in a 4-fold increase (5.4+/-0.7-20.5+/-3.0 ng/dl). On the other hand, the plasma levels of 18-OH DOC declined by nearly 50% with upright posture or angiotensin II infusion. During both of these procedures, plasma aldosterone levels significantly increased. Patients with normal and low renin hypertension had similar changes in plasma 18-OH DOC levels with sodium restriction. However, the mean high sodium level in the normal renin essential hypertension group (11.6+/-1.6 ng/dl) was significantly greater (P is less than 0.001) than in the control group (5.4+/-0.7 ng/dl). In addition, at least 22% and perhaps as high as 37% of the hypertensive subjects had levels greater than the upper limits of normal on a high sodium intake. Differences between the groups were less impressive in the sodium-restricted studies. There were no significant differences in age, duration of hypertension, sodium balance, serum sodium, potassium, or blood urea nitrogen in those patients who had elevated levels of plasma 18-OH DOC. Patients with primary aldosteronism had levels within the normal range on both dietary intake. However, in contrast to the other groups there were no significant changes in the plasma levels with sodium restriction. Thus, a significant number of patients with essential hypertension presumably have an alteration in 18-OH DOC secretion.

Effect of aminoglutethimide on blood pressure and steroid secretion in patients with low renin essential hypertension.

An inhibitor of adrenal steroid biosynthesis, aminoglutethimide, was administered to seven patients with low renin essential hypertension, and the antihypertensive action of the drug was compared with its effects on adrenal steroid production. In all patients aldosterone concentrations in plasma and urine were within normal limits before the study. Mean arterial pressure was reduced from a pretreatment value of 117+/-2 (mean+/-SE) mm Hg to 108+/-3 mm Hg after 4 days of aminoglutethimide therapy and further to 99+/-3 mm Hg when drug administration was stopped (usually 21 days). Body weight was also reduced from 81.6+/-7.2 kg in the control period to 80.6+/-7.0 kg after 4 days of drug treatment and to 80.1+/-6.7 kg at the termination of therapy. Plasma renin activity was not significantly increased after 4 days of treatment but had risen to the normal range by the termination of aminoglutethimide therapy. Mean plasma concentrations of deoxycorticosterone and cortisol were unchanged during aminoglutethimide treatment whereas those of 18-hydroxydeoxycorticosterone, progesterone, 17alpha-hydroxyprogesterone, and 11-deoxycortisol were increased as compared to pretreatment values. In contrast, aminoglutethimide treatment reduced mean plasma aldosterone concentrations to about 30% of control values. Excretion rates of 16beta-hydroxydehydroepiandrosterone, 16-oxo-androstenediol, 17-hydroxycorticosteroids and 17-ketosteroids, and the secretion rate of 16beta-hydroxydehydroepiandrosterone were not significantly altered by aminoglutethimide treatment whereas the excretion rate of aldosterone was reduced from 3.62+/-0.5 (mean+/-SE) in the control period to 0.9+/-0.2 mug/24 h after 4 days and to 1.1+/-0.3 mug/24 h at the termination of aminoglutethimide treatment. The gradual lowering of blood pressure and body weight during aminoglutethimide therapy is consistent with the view that the antihypertensive effect of the drug is mediated through a reduction in the patients' extracellular fluid volume, probably secondary to the persistent decrease in aldosterone production. The observation that chronic administration of aminoglutethimide lowered blood pressure in these patients and elevated their plasma renin activity to the normal range without decreasing production of the adrenal steroids, deoxycorticosterone, 18-hydroxydeoxycorticosterone, and 16beta-hydroxydehydroepiandrosterone, makes it unlikely that these steroids are responsible either for the decreased renin or the elevated blood pressure in patients with low renin essential hypertension.

Role of adrenal steroidogenesis in etiology of hypertension in the spontaneously hypertensive rat.

We measured peripheral adrenal steroid levels in spontaneously hypertensive rats (SHR), killed by nitrogen suffocation, at different ages during the development of hypertension. SHR became hypertensive by 8 weeks of age. Circulating plasma aldosterone (Aldo) levels of SHR gradually declined with age compared to their male Wistar-Kyoto (WKY) normotensive controls. On the other hand, corticosterone (B) concentrations rose relatively as the rats grew older, however, they were significantly lower in SHR at 16 weeks of age. Deoxycorticosterone (DOC) levels were significantly lower at 8 weeks and 18-hydroxy-11-deoxycorticosterone (18-OH-DOC) were lower at 16 weeks of age. Steroid ratios at age 4 weeks showed significantly higher B to 18-OH-DOC and lower B to DOC, 18-OH-DOC to Aldo, and 18-OH-DOC to DOC values in SHR. Furthermore, the B to 18-OH-DOC ratio remained significantly higher at 12 weeks and the B to DOC ratio remained lower at 16 weeks. These data imply the possibility of the secretion of an unknown steroid(s) and the existence of another, fourth pathway of Aldo biosynthesis in young SHR. Thus, major alterations of adrenal steroidogenesis exist in young SHR which may be causative in the development of hypertension. After the onset of hypertension, steroidogenesis tends to return to normal, by which time, however, SHR may have developed metacorticoid hypertension.

Regulation of 18-hydroxydeoxycorticosterone in the rat.

Simultaneous measurements of plasma 18-hydroxydeoxycorticosterone (18 OH-DOC), corticosterone, and aldosterone were performed in the rat by using RIA. Under basal conditions, 18 OH-DOC levels averaged 11.3 +/- 3.7 (SE) ng/ml. Plasma concentrations were increased 8-fold (86.8 +/- 8.0 ng/ml) 1 h after 1 U sc ACTH. Dexamethasone suppressed 18 OH-DOC to less than 1.5 ng/ml, irrespective of Na+ intake. Neither Na+ depletion nor Na+ loading had any influence on 18 OH-DOC levels. Excellent correlation between 18 OH-DOC and corticosterone (r = 0.90, P less than 0.001) was observed, whereas there was none between 18 OH-DOC and aldosterone (r = 0.061, P greater than 0.6). In the rat, 18 OH-DOC is an ACTH-dependent steroid which does not appear to be under the influence of the renin-angiotensin system.

Mineralocorticoid response to low dose adrenocorticotropin infusion.

The adrenocorticoid responses to low dose ACTH of plasma aldosterone (aldo), corticosterone (B), 11-deoxycorticosterone (DOC), 18-hydroxycorticosterone (18-OHB), 18-hydroxycorticosterone (18-OH-DOC), and cortisol (F) were compared. Alpha ACTH-)1-24) was infused beginning at 0800 h at increasing rates from 12.5-200 mIU/30 min in supine normal subjects under the following conditions: 1) regular Na (120 meq) diet, 2) low Na (10 meq) diet, 3) dexamethasone preadministration (0.5 mg every 6 h for 48 h), and 4) night study (2000 h; 120 meq Na intake). Plasma 18-OH-DOC and B demonstrated quantitatively the greatest responses to ACTH, while DOC and 18-OHB responses were intermediate. Increments in aldo and F were least after ACTH and were maximum at 50 mIU/30 min ACTH, whereas other corticosteroids demonstrated linear responses up to infusion rates of 200 mIU/30 min. All corticosteroids, however, were similar in their threshold responses to ACTH which were at infusion rates of approximately 7-9 mIU/30 min. Na restriction enhanced aldo and 18-OHB responses to ACTH 2- to 3-fold but did not alter the other corticosteroid responses. Dexamethasone pretreatment augmented aldo, 18-OHB, and F responses but did not change the responsitivity of the other corticosteroids to ACTH. Adrenal corticosteroid responses to ACTH were not significantly different between 0800 and 2000 h in subjects on 120-meq Na intake. Thus, corticosteroids show markedly different responses to physiological doses of ACTH, which may have more importance in their regulation than heretofore proposed. Dexamethasone pretreatment enhances aldo, 18-OHB, and F responses to ACTH but does not affect the responses of other corticosteroids. Contrary to reports in experimental animals, corticosteroid responses to ACTH in man do not differ from day to night.

Impaired mineralocorticoid hormone responses to adrenocorticotropin stimulation: additional characterization of heterozygosity for the 21-hydroxylase deficiency type of congenital adrenal hyperplasia.

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.

Relationship of 19-nor-deoxycorticosterone to other mineralocorticoids in low-renin hypertension.

A number of mineralocorticoids have been proposed as etiologic factors in low-renin hypertension. In this study, urinary free 19-nor-deoxycorticosterone (UF 19-nor-DOC) was compared to other mineralocorticoids--aldosterone, deoxycorticosterone (DOC), and 18-OH-DOC, in 11 low-renin hypertensive patients on a controlled diet in a metabolic unit. Results demonstrated that both UF 19-nor-DOC and tetrahydro-DOC (TH-DOC) excretion were elevated (2086 +/- 926, nl = 339-579 ng/day, and 18 +/- 7, nl = 5-15 mcg/day, respectively), and positively correlated (r = 0.95). Neither 18-OH-DOC nor aldosterone secretion rates were elevated, and neither of these hormones correlated with UF 19-nor-DOC, with exception of the supine plasma aldosterone (SPA) (r = 0.86). In conclusion, both UF 19-nor-DOC and TH-DOC were increased and positively correlated in the present series of hypertensives. This association is possibly indicative of a precursor-product relationship between DOC and 19-nor-DOC. 19-Nor-DOC, furthermore, correlated with supine plasma aldosterone (SPA), which could, in part, reflect their shared adrenocorticotropic hormone (ACTH) dependence.

Sex differences in corticosteroids in man.

The serum concentrations of progesterone (P), 17-OH-progesterone (17-OHP), 11-deoxycorticosterone (DOC), corticosterone (B), 11-deoxycortisol (S), 18-OH-11-deoxycorticosterone (18-OH-DOC), aldosterone (Aldo) and cortisol (F) were measured in 18 normal men (M), 14 normal women in the folicular phase (FF) and 14 normal women in the luteal phase (FL) of menstrual cycle from blood samples obtained between 0800 and 0900 h. Steroids were estimated by a sensitive and specific radioimmunoassay allowing the simultaneous determination of all steroids studied from one 3 ml serum sample. The mean steroid concentrations (ng/1dl) in FF were found to be as follows: P, 20.3; 17-OHP, 58; DOC, 3.8; B, 241; S, 20.7; 18-OH-DOC, 12.3; Aldo, 8.8; F, 9860. Apart from P, steroid concentrations in FF were significantly lower than in M. Serum 17-OHP, DOC, B and Aldo in FF were significantly lower than in FL. With the exception of P, there were no significant differences of mean steroid concentrations between M and FL.

Radioimmunoassay of 18-hydroxy-11-deoxycorticosterone in plasma.

A method is described for the radioimmunoassay of 18-OH-DOC using antibodies generated in rabbits against the carboxymethoxime derivative coupled to bovine serum albumin. The procedure uses 4 ml of plasma with intra and interassay variations of 8 and 9% respectively. Standard 18-OH-DOC added to plasma from an adrenalectomized patient gave a regression equation, Y=0.974X+/-2.210 and a correlation coefficient of 0.999. The only cross reacting steroid, 18-OH-B which may lead to falsely high levels is removed by a single thin layer chromatographic step. Blood levels in normal subjects agree closely with those calculated indirectly by metabolic clearance and secretion rate measurements. ACTH stimulation produced an 18-fold increase in plasma concentration while dexamethasone suppression decreased levels 3-fold. Four hours in the upright position resulted in a decreased plasma concentration while aldosterone increased. No significant response to dietary sodium restriction could be demonstrated.

The zonal origins of the mineralocorticoid hormones in the 21-hydroxylation deficiency of congenital adrenal hyperplasia.

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.

Urinary free 18-hydroxy-11-desoxycorticosterone excretion in normal and hypertensive patients.

One hundred fourteen hypertensives and 20 normal controls were examined using a new clinical technique of measuring 24-h urinary free 18-hydroxy-11-desoxycorticosterone (18-OH-DOC) excretion in response to dietary salt manipulations and ACTH injections. The object was to avoid potential errors of random plasma sampling. Mean urinary free 18-OH-DOC in normals on 110 milliequivalent sodium diet was 1.84 +/- 0.69 microgram (mean +/- SD) and represented about 2% of the daily secretion rate of this steroid. Both in normals and hypertensives, urinary free 18-OH-DOC approximately doubled on low salt (P less than 0.01 for each) and rose about 10 times in response to ACTH injection (P less than 0.05 and P less than 0.01, respectively). Plasma and urinary free 18-OH-DOC showed good correlation in patients with essential hypertension on a low salt diet (r = 0.45, P less than 0.01). Suppressed renin patients showed no propensity toward excess 18-OH-DOC excretion and hypertensives with elevated 18-OH-DOC could not be distinguished by their aldosterone levels, cortisol levels, nor their responses to various stimuli. These data suggest 18-OH-DOC is predominantly secreted under ACTH control and, to a smaller extent, in response to salt changes. Hypertension characterized by chronic overproduction of 18-OH-DOC forms only a small percentage of the hypertensive population. It is proposed that measuring 24-h urinary free 18-OH-DOC excretion may be the best method of assessing its rate of secretion without resorting to injection of radiolabeled material.

Diurnal 18-hydroxy-11-deoxycorticosterone pattern in human stable hypertension.

Diurnal 18-hydroxy-11-deoxycorticosterone (18-OH-DOC) pattern was studied with RIA technique in 33 hypertensive patients in supine position and on normal sodium diet. The compound was evaluated every 2 h from 0800-2000 h. Simultaneously, plasma aldosterone and cortisol were measured. Abnormal 18-OH-DOC behavior was observed in only 2 out of 4 patients with Cushing's disease, while sporadic and slight elevations, synchronous with F, were seen in 5 out of 24 stable essential hypertensive patients [1 with normal plasma renin activity (PRA), 1 with low PRA, and 3 with high PRA]. 18-OH-DOC was normal in 2 cases of hypertension due to renal artery stenosis, in 1 patient with nephrosclerosis, and in 1 patient with horseshoe kidney. From these results, 18-OH-DOC does not seem to play an important pathogenetic role in stable essential hypertension, considering also the low mineralocorticoid activity of the compound.

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.

Diagnostic performance of basal free cortisol/18-hydroxy-11-deoxycorticosterone (18-OH-DOC) ratio in endogenous depression: comparison with the dexamethasone suppression test.

We assessed the 8:00 AM ratio of free cortisol/18-hydroxy-11-deoxycorticosterone (18-OH-DOC) in 56 endogenous depressive inpatients and in 22 normal volunteers. A ratio higher than 40 was associated with a diagnostic sensitivity for endogenous depression of 75%, a specificity of 95.5%, and a diagnostic confidence of 97.7%. These diagnostic results were at least equivalent to the Dexamethasone Suppression Test (DST) using a cortisol cut-off limit of 5 micrograms/dl. This may thus represent a simpler procedure than the DST in the diagnostic analysis of endogenous depression.

Distinctive plasma aldosterone, 18-hydroxycorticosterone, and 18-hydroxydeoxycorticosterone profile in the 21-, 17 alpha-, and 11 beta-hydroxylase deficiency types of congenital adrenal hyperplasia.

Forms of congenital adrenal hyperplasia resulting from deficient steroid hydroxylation at positions 21, 17 alpha, and 11 beta have several similar clinical and biochemical characteristics. Biochemical diagnosis has been dependent on the demonstration of elevated plasma or urinary concentrations of metabolites of the immediate biosynthetic precursor before the enzymatic block, especially after stimulation with adrenocorticotropin. Aldosterone, 18-hydroxycorticosterone, and 18-hydroxydeoxycorticosterone are not closely involved nor are they immediate precursors of any of these enzymatic defects. However, simultaneous determination of the baseline plasma levels of these steroids in patients with nonsodium-losing 21-hydroxylase deficiency (n = 12), 17 alpha-hydroxylase deficiency (n = 6), and 11 beta-hydroxylase deficiency (n = 2) revealed a consistent and distinct pattern (mean +/- SEM in nanograms per deciliter): aldosterone (28.1 +/- 2.8) and 18-hydroxycorticosterone (84.5 +/- 9.2) levels were elevated and 18-hydroxydeoxycorticosterone (8.0 +/- 0.8) levels were within normal limits in 21-hydroxylase deficiency; 18-hydroxycorticosterone (327.2 +/- 73.9) and 18-hydroxydeoxycorticosterone (236.0 +/- 33.8) levels were elevated and aldosterone (3.5 +/- 0.6) levels were reduced in 17 alpha-hydroxylase deficiency; levels of all three steroids (aldosterone 2.6 +/- 0.4, 18-hydroxycorticosterone 5.1 +/- 3.1, 18-hydroxydeoxycorticosterone 0.9 +/- 0.1) were reduced in 11 beta-hydroxylase deficiency. It is suggested that simultaneous measurement of these three steroids can be useful in identifying and further characterizing each of these forms of congenital adrenal hyperplasia.

Influence of an enriched dietary sodium chloride regime during gestation and suckling and post-natally on the ontogeny of hypertension in the rat.

Brattleboro rats without diabetes insipidus were subjected to sodium chloride enrichment (20-fold increase in dietary salt) at various stages of their development. Salt supplementation in the adult rat produced higher systolic blood pressure (SBP), particularly in males (142 +/- 3 versus 110 +/- 3 mmHg in control. The blood pressures of females on salt-supplemented diets during pregnancy decreased from 136 +/- 1 to 121 +/- 2 mmHg, although throughout this period the blood pressures for these rats were greater than for the control pregnant rats. Pregnant females on salt-supplemented diets also showed higher sodium concentrations in the amniotic fluid compared with controls (155 +/- 3.4 versus 134.1 +/- 6.0 mmol/l). Salt supplemented lactating mothers produced milk with similar sodium concentrations to those of the controls, but the urinary sodium concentrations of pups suckling on the former were greater than in the controls. It is concluded that the suckling pups were also salt-enriched. Rats were submitted to salt-enriched regimes in utero, during suckling, post-weaning and post-pubertally, or permutations thereof. Salt supplementation post-weaning led to consistent elevation in arterial blood pressure with males being more susceptible than females. The degree of elevation was increased if the salt-supplement was present during suckling (132 +/- 1 versus 112 +/- 1 mmHg) and was greatest when the salt-supplemented regime was administered both in utero and during the post-weaning period (154 +/- 2 versus 112 +/- 1 mmHg).(ABSTRACT TRUNCATED AT 250 WORDS)

New mineralocorticoids and adrenocorticosteroids in hypertension.

Alterations in steroidogenesis have been demonstrated in experimental and human hypertension. It is highly likely that increased secretion of the nonaldosterone mineralocorticoid deoxycorticosterone (DOC) and 18-hydroxy-11-deoxycorticosterone (18-OH-DOC) may initiate or perpetuate hypertension, or both. It is possible that 16 beta-hydroxydehydroeplandrosterone (16beta-OH-DHEA) directly induces the hypertensive process in animals. The significance of the findings of increased secretion of 16 alpha, 18-dihydroxy-11-deoxycorticosterone (16alpha, 18-diOH-DOC) and dehydroepiandrosterone sulfate (DHEA-S) cannot now be appreciated. Neither has been examined experimentally for its ability to induce hypertension, and the former compound is not a mineralocorticoid. It does possess the curious property of increasing mineralocorticoid activity of other steroids, by altering either their metabolism or mode of action. Variations in the mineralocorticoid hypertensive syndrome or, more aptly, the steroid hypertensive syndrome could account for the hypertension in a substantial portion of patients with reduced plasma renin activity.

Adrenocortical hormones, ageing and mental condition: seasonal and circadian rhythms of plasma 18-hydroxy-11-deoxycorticosterone, total and free cortisol and urinary corticosteroids.

The circannual rhythms of plasma 18-hydroxy-11-deoxycorticosterone (18-OH-DOC), total and free cortisol have been documented on a circadian basis in January, March, June and October in seven young men (24 years old), six elderly men, six elderly women and six elderly demented subjects, both men and women, in their eighties. Blood samples were drawn every 4 h over a 24-h period at each sampling session and urine samples were collected at 4-h intervals only from the young men. A circadian rhythm of 17-hydroxy-corticosteroids (17-OH-CS), 17-ketosteroids (17-KS), urinary free cortisol and 18-OH-DOC was defined for each of the four seasons with stable acrophases throughout the year and the same excretory profiles. A circannual rhythm was validated in young men for 17-OH-CS, urinary free cortisol and 18-OH-DOC but not for 17-KS. A circadian rhythm of plasma free cortisol, the active form of the hormone, plasma total cortisol and plasma 18-OH-DOC was validated in all groups and at all the seasons at which samples were taken. The secretory profiles of 18-OH-DOC, free and total cortisol were very similar, with no differences attributable to age, sex or mental condition except for the levels of plasma free cortisol and 18-OH-DOC which were higher and lower respectively in the elderly subjects. Whereas a circannual rhythm of plasma 18-OH-DOC was validated for all groups, a circannual rhythm of both free and total cortisol in the plasma was validated in young men but not in any group of elderly subjects. This loss of the circannual rhythmicity of cortisol in the elderly may reflect the decrease with age of the capacity to adapt to seasonal external factors.

Adrenal circadian system in young and elderly human subjects: a comparative study.

Circadian changes in plasma 18-hydroxy-11-deoxycorticosterone (18-OH-DOC), total and unbound cortisol were studied in four groups: seven healthy young men, six elderly men, six elderly women and six elderly demented patients of both sexes. The daily activities of the subjects were synchronous; blood samples were taken every 4 h and 4 hourly urine samples were collected only from the young men. A circadian rhythm was defined for plasma 18-OH-DOC, total and unbound cortisol in all groups; the secretory patterns of these steroids were parallel, as were the profiles of urinary 18-OH-DOC and unconjugated cortisol. When compared with respect to sex, the 24-h mean level of total cortisol was higher in women; that of unbound cortisol was higher in the three groups of elderly patients than in the young men. No major changes in plasma steroids were observed between elderly demented patients (mainly women) and healthy elderly women. The phasing of total and unbound cortisol showed no major modifications with age, sex or senile dementia. Acrophases of 18-OH-DOC were earlier in elderly patients than in young men. Amplitudes were not modified with sex in elderly patients but were always lower in the demented patients. A circadian rhythm was defined for 18-OH-DOC, unconjugated cortisol, 17-hydroxycorticosteroids (17-OH-CS) and 17-ketosteroids in the urine of the young men. The acrophases of 18-OH-DOC and unbound cortisol were close, as were those of 17-OH-CS and 17-ketosteroids. The lag was short between the acrophases of 18-OH-DOC in plasma and urine and between those of plasma unbound cortisol and urinary unconjugated cortisol; it was much larger between the acrophases of plasma total cortisol and 17-OH-CS. Thus, the process of ageing, and the possible alterations in the central nervous system which are often seen in normal ageing, induced no major modifications in the temporal organization of adrenocortical function, even in subjects who were very advanced in age.

Role of 18-hydroxy-11-deoxycorticosterone and 16 alpha, 18-dihydroxy-11-deoxycorticosterone in hypertension.

Excess secretion of 18-hydroxy-11-deoxycorticosterone (18-OH-DOC) occurs in more than 10% of hypertensive patients with suppressed plasma renin activity, but it also is reported to occur in essential hypertension without impairment of the renin system. Preliminary studies measuring plasma 18-OH-DOC by radioimmunoassay support the idea that 18-OH-DOC secretion is elevated in some patients with essential hypertension. Interpretation of these data must take into account endogenous ultradien and circadian variations in plasma 18-OH-DOC, however. 18-OH-DOC serves as a precursor of another steroid secretory product. Conversion of labeled 18-OH-DOC to a new structure, 16alpha, 18-dihydroxy-11-deoxycorticosterone (16alpha, 18-diOH-DOC), was demonstrated to be greatly accelerated by the adrenal tissue in low-renin patients as compared with those with normal adrenal tissue (70 to 80% versus 15% conversion). Hypersecretion of 16alpha, 18-diOH-DOC occurred in each. This steroid exerted no effect on sodium metabolism in adrenalectomized rats or in the toad bladder assay, but it markedly enhanced activity of subthreshold doses of aldosterone in reducing sodium excretion in urine of adrenal-ectomized rats. Because of the unique activity of this steroid, we have concluded that excessive 16alpha, 18-diOH-DOC secretion may be important in the genesis of suppressed renin in some patients with hypertension.