John C. Laidlaw

CONCURRENT OBSERVATIONS OF BEHAVIOR CHANGES AND OF ADRENOCORTICAL VARIATIONS IN A CYCLOTHYMIC PATIENT DURING A PERIOD OF 12 MONTHS

Excerpt I. REVIEW OF LITERATURE II. PSYCHOLOGIC BACKGROUND The Patient Overactivity Depression Projection Family Previous Episodes Hospitalization for Depression Interval Between Hospitalization fo...

BIOLOGICAL EFFECTS OF FLUORINATED DERIVATIVES OF HYDROCORTISONE AND PROGESTERONE IN MAN

The biological effects of halogenated steroids in animals have been reviewed in this monograph by Doctor Fried and his collaborator^.^-^ The high degree of potency which these compounds demonstrated in the animal assays clearly indicated the desirability of a clinical evaluation of their biological activity in I t has been possible to test a number of these derivatives of hydrocortisone and to compare their metabolic effects with those of the nonfluorinated parent compounds. Among them, 9-alpha-fluorohydrocortisone appeared to be the most promising from a clinical point of view and was made available in amounts sufficient for adequate clinical testing. The results obtained with other derivatives are to be considered, at present, as preliminary. These studies have been carried out on the Metabolic Ward of the Peter Bent Brigham Hospital, Boston, Mass. The high degree of activity of 9-alpha-fluorohydrocortisone acetate is illustrated in FIGURE 1. The effects of 100 mg. of hydrocortisone acetate and of 5 mg. of fluorohydrocortisone acetate on urinary electrolyte excretion were compared in an Addisonian patient maintained on a constant diet. The two compounds were administered as a single dose by mouth. I t is apparent that both sodium retention and potassium diuresis were considerably more marked with the fluorinated compound, indicating a t least a twentyfold increase in sodium-retaining activity. Furthermore, when the urinary sodium-to-potassium ratio was followed (FIGURE 2), it appeared that both hydrocortisone and fluorohydrocortisone produced a marked and rapid decrease in this ratio, but that the effects of 5 mg. of fluorohydrocortisone were considerably prolonged as compared to those of 100 mg. of hydrocortisone. The marked effects of 9-alpha-fluorohydrocortisone on organic metabolism are illustrated in FIGURE 3. A patient with Addison’s disease maintained on a constant diet was given 25 mg. of the compound as an eight-hour intravenous infusion. The steroid was dissolved in 10 ml. of absolute ethanol and diluted in 500 ml. of saline containing 5 grams of albumin. The metabolic effects obtained were compared with those of a control infusion of saline with alcohol and albumin. A maximal and prolonged eosinopenia, a marked increase in urinary glucose excretion, and a definite rise in the urinary excretion of nitrogen, uric acid, and potassium were observed with fluorohydrocortisone. Urinary glucose was measured by a specific, enzymatic method based on the oxidation of glucose by glucose oxidase.6 Employing this method with a patient main-

Comparison of the metabolic effects of cortisone and hydrocortisone in man.

The metabolic effects of cortisone and hydrocortisone in man are qualitatively similar.’ This is evidenced by the ability of both hormones to produce such changes as sodium chloride and water retention, potassium diuresis, increased excretion of nitrogen and uric acid, and a rise in the level of blood and urinary glucose. There are, however, quaiztitatire differences in the metabolic actions of cortisone and hydrocortisone which vary according to the route of administrationand state of esterification of the compounds. Early studies i n animals by Ingle et ul.?, :j and Olson and his associates4 demonstrated that hydrocortisone administered by intramuscular or subcutaneous injection possessed greater metabolic activity than cortisone. ‘The criteria used were work performance of adrenalectomized rats, glycogen deposition activity in adrenalect omized rats, and diabetogenic effect in force-fed normal rats. That the difference in potency between hydrocortisone and cortisone was not due t o a difference in either rate of absorption or speed of inactivation was unequivocally demonstrated by the studies of Ingle el ul.,” in which the hormones were administered by continuous intravenous infusion and assayed by the muscle work test. Hydrocortisone was found to be approximately twice as effective as cortisone. Comparative studies in man, w i t h the free alcohol of cortisone and hydrocortisone administered intravenously, have confirmed the superior potency of hydrocortisone.6 This is illustrated in F I G U R E 1, which shows the eosinopenic effect of hydrocortisone to be greater than that of cortisone. I n addition to the demonstration of its greater potency when administered intravenously, hydrocortisone in the form of either the acetate or the free alcohol has been shown by C‘ond and ‘Thorn et ~ 1 . ~ to be more effective than cortisone acetate when the compounds are given by mouth. In contrast to these findings, Salassa and his associates,!’ C ~ n n , ~ and others’ have shown that when the hormones are given in the form of the acetate ester by intramuscular injection the metabolic effects of hydrocortisone are slower in onset, less intense, and more Imlonged than those of cortisone. This difference would appear to be due to a slower rate of absorption of hydrocortisone acetate from the intramuscular depot. Thus, while hydrocortisone acetate by intramuscular injection is of no value in situations where a rapid and intense hormone effect is required, i t may prove useful in the long-term treatment of patients with virilism due to bilateral adrenal hyperplasia where satisfactory adrenal inhibition may be achieved by injection of the hormone every one to three weeks.’”