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Previous studies in the rat have demonstrated that 11-deoxycortisol [compound S (pregn-4-ene-17α,21-diol-3,20-dione)], a competitive glucocorticoid antagonist in vitro, fails to behave as an antagonist in growth and adrenal suppression bioassays in nonadrenalectomized animals. This is probably explained by conversion of 11-deoxycortisol to cortisol by the adrenal glands. Δ1,9(11)-ll-Deoxycortisol (pregn-l,4,9(11)-triene-17α,21-diol-3,20 dione) has been shown to resist 11-hydroxylation because of the double bond at the 9–11 position and, hence, should be a more effective antiglucocorticoid in vivo. This hypothesis was tested by comparing the in vivo antiglucocorticoid activity of Δ1,9(11)-11-deoxycortisol with that of 11-deoxycortisol. The affinity of both compounds for the rat thymus glucocorticoid receptor was similar (equilibrium dissociation constant, 3 × 10-7 M). Both compounds antagonized dexamethasone-induced liver glycogen accumulation in nonadrenalectomized rats, Δ1,9(11)-11-deoxycortisol being 3-...

A detailed analysis of 12 samples of human adrenal vein blood, collected from patients with mammary carcinoma, is reported. Cortisol has been isolated from every sample and identified. The isolation and identification of corticosterone in 6 instances, Compound S in 5 instances, and llj8-hydroxy-A4- androstene-3,17-dione in 10 instances is also reported. The isolation of 17ahydroxyprogesterone from 5 samples and dehydroepiandrosterone from 1 sample and their identification is reported for the first time.

A method utilizing the steroid-binding properties of corticosteroid-binding globulin (CBG, transcortin) was described in 1963 for the routine determination of corticoids in 1 ml of plasma (J Clin Endocr 23: 293, 1963) and later modified to reduce the time required (J Clin Endocr 24: 919, 1964). A 100-fold increase in sensitivity has now been achieved by using tritiated steroids in place of 14C-labeled steroids, by utilizing the CBG's of species other than man, and by using adsorption in place of dialysis or gel filtration. The use of several insoluble adsorbing agents (Fuller's earth, Florisil, coated charcoal) to separate protein-bound and unbound steroids was investigated and their effects on specificity were studied. The use of these techniques in plasma, urine and cerebrospinal fluid was vindicated. With these methods, cortisol can be measured routinely in 0.01 ml of plasma or 0.1 ml of cerebrospinal fluid, and progesterone in 0.3 ml of plasma. Compound S (11-desoxycortisol), corticosterone, ...

SU-4885 inhibits 11β-hydroxylation of steroids by the human adrenal cortexand leads to a decrease in cortisol secretion, a “compensatory” rise in ACTH secretion, and the secretion of large quantities of 11-desoxycorticosteroids such as compound S. Compound S and its metabolites are readily measurable in biologic fluids as 17-hydroxycorticoids. In normal subjects, therefore, SU-4885 induces a rise in total blood and urinary 17-hydroxycorticoids. Since this response to SU-4885 is dependent upon a rise in ACTH secretion it affords, in patients who do not have frank adrenal insufficiency, a sensitive means of testing the reserve capacity of the pituitary gland to secrete ACTH. Of 9 patients with chromophobe adenomas tested in this manner, 6 were found to have “limited pituitary reserve.” This was true also of 2 out of 5 patients with acromegaly, 3 out of 6 patients with cachexia, and 1 patient with post-traumaticdiabetes insipidus. Of 7 patients with active Cushing's disease due to adrenal hyperplasi...

The results of a preliminary study on the biosynthesis of adrenocortical hormones by the human adrenal gland in vitro are presented. The substrates investigated were 3β-hydroxy-Δ5-pregnene-20-one, progesterone, 17α-hydroxyprogesterone, compound S (17α21-dihydroxy-Δ4-pregnene-3,20-dione) and deoxycorticosterone. The results have led to the proposal of the following tentative scheme of adrenocortical biosynthesis by the human adrenal

The “hyalinosis syndrome” is the name applied, by Selye (1946, 1950), to the cardiovascular-renal changes which occur in salt-treated, unilaterally nephrectomized rats administered such steroids as desoxycorticosterone acetate (DCA) or Reichstein’s Compound S (desoxocortisone) for prolonged periods. The characteristic changes of this syndrome are hypertension, renal and cardiac hypertrophy, nephrosclerosis, glomerular hyalinization, “rheumatic-like” cardiac nodules and frequently periarteritis nodosa. Up to the present time such changes have been observed only after treatment with steroids known to possess appreciable mineralocorticoid activity. This fact, plus the observation that certain stresses, as well as the administration of lyophilized anterior pituitary powder (LAP) or alkaline pituitary extract (APE) also produced the hyalinosis syndrome, led Selye to postulate (1946, 1950) that similar pathological conditions in the human might be pathogenetically related to hyperfunction of the anterior pituit...

Studies of ACTH release from rat pituitary tissue incubates were performed in an effort to determine if glucocorticoids act directly on the pituitary to influence ACTH secretion. The spontaneous release of ACTH from pituitary halves or quarters incubated in Krebs-Ringer bicarbonate was not altered by the addition of 5 μg/ml of dexamethasone-21-PO4. Synthetic lysine or arginine vasopressin (10–100 mU/ml) induced release of ACTH into the incubation media. The addition of dexamethasone-21-PO4 to the incubation media in concentrations of 0.05 μg/ml or greater inhibited vasopressin-induced ACTH release. Another glucocorticoid, methylprednisolone, also inhibited vasopressin-induced ACTH release. Compound S and desoxycorticosterone, which are not glucocorticoids, in concentrations of 100 μg/ml, and thyroxine in a concentration of 2 μg/ml did not affect vasopressin-induced ACTH release. These studies are consistent with the concept that glucocorticoids act directly at the pituitary to inhibit activation of ACTH s...

The effect of DHEA in vivo on the biosynthesis of the adrenal steroids, with special consideration of the 11β-hydroxylation, has been studied in dogs. The biosynthesis of cortisol, corticosterone and aldosterone from deoxycorticosterone and compound S of Reichstein by the dog adrenal gland has been investigated after perfusion with a solution of 5 % glucose saturated with DHEA. The results indicate a decreasedconversion of deoxycorticosterone and compound S of Reichstein (11-deoxycortisol) to corticosterone and cortisol, respectively, as shown by plasma levels, following perfusion with DHEA. Total production of aldosterone by the adrenal tissue was also decreased following perfusion with DHEA, as is evident from the incubation studies. (Endocrinology 84: 98, 1969)

A CONSIDERABLE volume of investigation in man as well as in animals has indicated that the adrenal cortex might be involved in hypertensive disease, either in a causal or supportive r61e (Soffer, 1948; Perera, 1950). Some impetus to these studies has been given by the exploration of the hypertensive properties of desoxycorticosterone acetate (DCA) (Selye, Hall and Rowley, 1943; Friedman, Polley and Friedman, 1948). In view of these findings, it seemed of importance to us to determine whether any compounds, either by reason of their structural or physiological properties, might oppose the known cardiovascular-renal effects of DCA. To this end we have set up a simple screening test and have thus far explored the action of progesterone, testosterone, estradiol, 21-acetoxy pregnenolone, “12-keto DCA,” Compound S (11-desoxy-17-hydroxycorticosterone acetate), Compound A (11-dehydrocorticosterone), cortisone, hyaluronidase, Lipo-Adrenal Cortex (Upjohn) and pitressin. Of these, only Lipo-Adrenal Cortex, in large ...

In short termexperimentsinthedog2-methyl–l,2-bis(3-pyridyl)-l-propanonc (SU 4885) in high dosage totally suppressed the secretion of steroids by the adrenal gland. In low dosage there was a shift from cortisol and corticosterone to 11-desoxycortisol (Reichstein's Compound S) and desoxycorticosterone suggesting a selective inhibition of hydroxylation at C11. In contrast amphenone suppressed total steroid secretion (i.e., of cortisol and corticosterone) with no evidence for a selective action on 11-hydroxylation.

To evaluate the possible effect of ACTH upon circulating growth hormone levels, various forms of ACTH and metyrapone have been administered to 7 groups of 8 or more normal adults as well as to 37 children including 27 hypopituitary patients. In normal adults, significant increases in plasma corticoids occurred after all ACTH preparations were administered while growth hormone concentrations were significantly elevated after 100 and 25 U of synthetic ACTH iv and after 100 U porcine ACTH iv, but not after 100 U synthetic ACTH im or bovine ACTH iv. In contrast, the children, whether normal or hypopituitary, showed no growth hormone increase following administration of any of the ACTH preparations mentioned above. Neither oral (750 mg) nor iv (7.5 mg/kg/hr) metyrapone administration was followed by growth hormone release in adult subjects with increased compound S concentrations indicative of endogenous ACTH release. The lack of GH rise after endogenous ACTH release produced by metyrapone would indic...

DESPITE recent advances in the treatment of the collagen diseases in man, their pathogenesis remains obscure. Pathologic lesions strikingly similar to those found in humans have been produced in animals by a wide variety of technics (1–21). Selye has claimed the production of typical lesions in animals following the administration of desoxycorticosterone acetate (DCA) (1–7), lyophilized anterior pituitary (LAP) (6, 8), compound S of Reichstein (10) and growth hormone (11, 12). He has concluded (7) that the collagen disorders in man result from a maladaptation to stress in which adrenocortical hyperactivity occurs, in response to excessive stimulation by the anterior pituitay. On the other hand, studies in this laboratory (22, 23) indicate that the administration of DCA to the rat induces a relative state of adrenocortical insufficiency by inhibiting the output of pituitary adrenocorticotropic hormone (ACTH) and by antagonizing, at a target-cell level, the action of the ACTH-induced secretion of the adrena...