Quantitative Urinary 17-Hydroxycorticoid Patterns: Effect of Acth and “Operative Stress”*

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Variations have been shown to occur in the quantitative urinary excretion pattern of the metabolites of cortisol in a variety of traumatic events such as surgery, bone fracture and burns (1). The compounds evaluated were THF, allo-THF and THE,' and it was demonstrated that the relative proportion of THF: THE excreted during and after a "traumatic event" was markedly increased. In addition almost complete absence of allo-THF was observed in a chronically ill individual and it reappeared upon convalescence. The rate of secretion of cortisol was one factor involved in producing the increase in urinary THF: THE, since following the administration of adrenocorticotropin (ACTH) to normal individuals the relative proportion of urinary THF as compared with THE was observed to rise (1)(2)(3)(4)(5) factors other than the rate of adrenal secretion were involved in altering the rates of excretion of the numerous metabolites of cortisol. It became clear that knowledge concerning the pathways of metabolism, the pool sizes of the metabolites and the relative rates of formation of the individual metabolites from cortisol would prove valuable in interpreting the urinary excretion patterns of these compounds.2 Consequently these studies were undertaken to determine the extent of the reaction THF = THE in volunteer subjects with and without the administration of ACTH; the pathways for the formation of THF, allo-THF, THE and cortolone from cortisol; the miscible pool size of THF, allo-THF, THE and cortolone; and the possibility of determining the overall rates of formation of THF, allo-THF and THE. This work was performed in volunteer subjects with cortisol-4-C14 as a tracer. METHODSGeneral plan. Tracer doses of cortisol4-C' (1 puc., about 250 ,ug.) were administered intravenously to normal volunteer subjects and urine samples were collected every 15 minutes. The specific activity of cortisol and its metabolites was determined as a function of time, and pool sizes and pathways were determined by isotope dilution procedures after the intravenous administration of small amounts of unlabeled cortisol metabolites. The rates of formation of these metabolites were computed in several instances using the criteria described by Zilversmit, Entenman and Fishler (6

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confidence: 99%

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confidence: 99%

Cortisol Metabolism in Man: Observations of Pathways, Pool Sizes of Metabolites and Rates of Formation of Metabolites*

Gold

Smith²,

Moore³

1959

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“…Their results indicated increased excretion of these metabolites after surgery but did not show any other definite pattern of alteration of the metabolism of cortisol, although they state that "a tendency can be observed for tetrahydro-compound F excretion to rise more than does tetrahydrocortisone." In a preliminary report, Gold, Macfarlane, and Moore (31) showed that the relative proportions of the two urinary cortisol metabolites, THF and THE, were related to situations of "stress" and adrenocorticotropin (ACTH) administration. It is the purpose of this current report to supply additional evidence for alterations in the excretion of certain cortisol metabolites in the human in a variety of "stress" situations, such as surgery, bone trauma, burns and prolonged illness, and to compare the proportion of metabolites in these cases with normal individuals and with the urine of individuals receiving ACTH.…”

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confidence: 99%

Quantitative Determination of the Urinary Cortisolc Metabolites, “Tetrahydro F,” “Allo-Tetrahydro F” and “Tetrahydro E”: Effects of Adrenocorticotropin and Complex Trauma in the Human1

Gold¹,

Singleton²,

Macfarlane³

et al. 1958

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Methods for the quantitative estimation of plasma cortisol concentration have been devised by Nelson and Samuels (1), Silber and Porter (2), and Peterson and Wyngaarden (3) who used the sulfuric acid-induced fluorescence developed by Sweat (4). Together with urinary procedures (5, 6) these techniques have been employed to determine the secretion of cortisol by the adrenal in normal and pathological conditions (7-9) and to evaluate the factors involved in the "removal" of cortisol from the plasma in surgery (10-13) and liver disease (14-16).Although a considerable amount of work has been done in isolating and identifying such urinary metabolites of cortisol as THF8 and THE (17-22) and their interconversions (23-25), much less has been done to relate the quantitative transformations of these urinary metabolites from cortisol under normal and pathological conditions. In 1953, deCourcy, Bush, Gray, and Lunnon (26) reported daily excretion values for two chromatographically separated urinary steroids corresponding in migration rates to THF and THE, in 10 1 This work was suported in part by a grant from the Atomic Energy Commission. It was sponsored and supported in part by the Subcommittee on Metabolism in Trauma, Advisory Committee on Metabolism, Office of the Surgeon General, Department of the Army, through a contract (DA-49-MD472) with Harvard University.The assistance of Winthrop Laboratories, Inc., and The Upjohn Co. is gratefully acknowledged.2 Present address: The Medical College of St. Bartholomew's Hospital, London. 3 Compounds referred to are the following: THF, tetrahydrocortisol (3a,11p,17a,21-tetrahydroxypregnan-20-one ); allo-THF (3a,1 1,l17a,21-tetrahydroxyallopregnan-20-one); THE, tetrahydrocortisone (3a,17a,21-trihydroxypregnan-11,20-dione); F, cortisol (llfi,17a,21-trihydroxypregnan-3,20-dione); E, cortisone (17a,21-dihydroxypregnan-3,11,20-trione).normal men. The mean values were 212 tg. per 24 hours for THF and 1.5 mg. per 24 hours for THE, giving a ratio for THF: THE of 0.14. Romanoff, Seelye, Rodriquez, and Pincus (27) have recently published quantitative data on the excretion of THF and THE combined with allo-THF (28, 29) in one group of normal men and in a group of schizophrenic men. There was no essential difference in the ratio of THF:(THE plus allo-THF) between the two groups of men, and the ratio was reported as approximately 1: 2. Cope and Hurlock (30) published data on the excretion of urinary THF and THE in several normal and surgical cases. Their results indicated increased excretion of these metabolites after surgery but did not show any other definite pattern of alteration of the metabolism of cortisol, although they state that "a tendency can be observed for tetrahydro-compound F excretion to rise more than does tetrahydrocortisone." In a preliminary report, Gold, Macfarlane, and Moore (31) showed that the relative proportions of the two urinary cortisol metabolites, THF and THE, were related to situations of "stress" and adrenocorticotropin (ACTH) administration. It is the purpo...

“…This suggests a partial inhibition in the rate of transformation of cortisol to cortisone in the Cushing's patient.9 The relatively small THE pool sizes, however, found in the face of rates of THE formation almost equivalent to those in the two normal subjects, with rates of 72 and 81 mg 10 Correlation of the infusion rate of cortisol-hemisuccinate with the turnover of cortisol calculated from the miscible cortisol pool demonstrates not only the rapid rate of hydrolysis of the hemisuccinate to "free" cortisol but also the lack of transformation of any significant amount of the steroid nucleus while the compound was still in the hemisuccinate form. Had the latter occurred to a measurable extent, the rate of dilution of the cortisol pool would have been diminished accordingly.…”

Section: Kinetic Aspects Of Cortisol-4-c4 Metabolism In Cushing's Synmentioning

confidence: 98%

“…Although the major urinary metabolites of cortisol 1 have been identified (1)(2)(3)(4)(5)(6)(7)(8)(9) and quantitatively estimated (1,(10)(11)(12)(13) in man, kinetic aspects related to the formation of these metabolites have been less clearly defined. In a previous publication (14) the pathways of formation, metabolite pool sizes, and the rates of formation of the metabolites of cortisol in two normal humans have been reported.…”

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confidence: 99%

Kinetic Aspects of Cortisol-4-C14 Metabolism in a Patient After Subtotal Adrenalectomy for Cushing's Syndrome Associated With Bilateral Adrenal Hyperplasia*

Gold¹

1962

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Although the major urinary metabolites of cortisol 1 have been identified (1-9) and quantitatively estimated (1, 10-13) in man, kinetic aspects related to the formation of these metabolites have been less clearly defined. In a previous publication (14) the pathways of formation, metabolite pool sizes, and the rates of formation of the metabolites of cortisol in two normal humans have been reported. The general method was the administration of a small quantity of cortisol-4-C14 during a steady-state condition (with reference to cortisol turnover) and the determination of the specific activities of cortisol and its metabolites in consecutive 15-minute urine samples. Equations expressing turnover of cortisol and rates of metabolite formation (15) were subsequently applied to these data. * Work supported in part by U. S. Public Health Service grant A-3164 to Harvard University; in part by grants from the Medical Foundation, Inc. and the American Legion Child Welfare Foundation to the Children's Hospital; in part by a contract with the Advisory Committee on Metabolism, Office of the Surgeon General, Department of the Army; and in part by a contract with the Atomic Energy Commission to the Peter Bent Brigham Hospital, Boston, Mass.I The compounds referred to are: cortisol or F, 11p3,-17a,21-trihydroxy-4-pregnene-3,20-dione; THF, 3a,11f,-17a,21-tetrahydroxy-5p8-pregnane-20-one; allo-THF, 3a,-1l,,17a,21-tetrahydroxy-5a-pregnane-20-one; THE, 3a, cortol, 3a,,17a,20a or p, cortolone, 3a,17a,20a or ,3,21-tetrahydroxy-5j3-pregnane-11-one; cortisone or E, 17a,21-dihydroxy-4-pregnene-3,11,20-trione; 6p-hydroxycortisol or 6,-OH-F, 6fl,11,6,17a,21-tetrahydroxy-4-pregnene-3,20-dione; 6,8-hydroxycortisone or 6#- 6,p,17a,11,11,,17ca,20a,11,,17a,20,8,17a, 1lfl-OH-Etio or llfl-hydroxyetiocholanolone, 3a,11,8-dihydroxy-5,8-androstane-17-one; and 11-0-Etio or li-ketoetiocholanolone, 3a-hydroxy-5,8-androstane-11,17-dione.To aid in the interpretation and applicability of such kinetic measurements, it seemed advisable to carry out further studies in man using similar techniques in which cortisol turnover was fixed by administration of a continuous infusion so that the calculated kinetic parameters could be compared with the known turnover rate. The patient chosen for study was a 23-year-old woman who, 6 weeks before the initial study, had had a subtotal adrenalectomy as treatment for Cushing's syndrome associated with adrenal hyperplasia. From the time of subtotal adrenalectomy to the time of the studies reported, the patient required cortisone as adrenal maintenance therapy. The initial observations of cortisol metabolism were obtained 24 hours after a surgical procedure, cholecystectomy. A similar study was repeated 4 months later when the patient appeared totally recovered from the cholecystectomy. In this paper, a comparison of kinetic parameters is made with reference to the low recovery of urinary cortisol metabolites, and attention is called to the low excretion of the 5a isomer, allo-THF, which we have reported to occur in Cus...