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

Abstract

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...

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

“…Only 2 to 4 per cent of the total THF, allo-THF, and THE excreted is represented by allo-THF in both the control and post-operative periods. This is in marked contrast to the 15 to 30 per cent proportion of allo-THF reported for normal adults (8,9,12,25).…”

“…In Table I, f, the ratios of THF: THE, 3.1 in the post-operative and 2.1 in the control period, are both highly elevated when compared with the values (2 1.0) in normal adults (8,9,12,25) and those (approximately 1.0) in adults stimulated with ACTH (11,12,26). The higher value of the THF: THE ratio in the post-operative as compared with the control period of Table I is consistent with previous findings (12) that a variety of "stress" situations, surgery included, produce elevations in the THF: THE ratio and that this phenomenon involves alterations in the metabolism of cortisol.…”

“…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.…”

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

“…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.…”

“…(Submitted for publication July 23, 1959; accepted August 31, 1959) 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.…”