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Characterization of Urinary Steroids in Adrenal

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CHARACTERIZATION OF URINARY STEROIDS IN ADRENAL HYPERPLASIA: ISOLATION OF METABOLITES OF CORTISOL, COMPOUND S, AND DESOXYCORTICOSTERONE FROM A NORMOTENSIVE PATIENT WITH ADRENOGENITAL SYNDROME Hortense M. Gandy, … , E. Henry Keutmann, Anthony J. Izzo J Clin Invest. 1960;39(2):364-377. https://doi.org/10.1172/JCI104047. Research Article Find the latest version: https://jci.me/104047/pdf CHARACTERIZATION OF URINARY STEROIDS IN ADRENAL HYPERPLASIA: ISOLATION OF METABOLITES OF CORTI- SOL, COMPOUND S, AND DESOXYCORTICOSTERONE FROM A NORMOTENSIVE PATIENT WITH ADRENOGENITAL SYNDROME * By HORTENSE M. GANDY,t E. HENRY KEUTMANN AND ANTHONY J. IZZO (From the Departmtent of Medicine, the University of Rochester, School of Medicine anld Dentistry, Rochester, N. Y.) (Submitted for publication August 25, 1958; accepted October 8, 1959) Congenital virilizing adrenal hyperplasia miiay corroborated by Bartter and associates (13). present a varied clinical picture. Patients have Dorfman (14) postulated that there is a deficiency been described who have only excessive virilization in the C-21 hydroxylation mechanism. Eberlein (1); others have an associated Addison-like elec- and Bongiovanni (15) then found that some pa- trolyte disturbance (2, 3), with hypoglycemia (4), tients with congenital virilizing adrenal hyper- or with hypertension (5-9). Recent studies (10- plasia excreted C-21 hydroxylated compounds in 12) indicate that the manifestation of virilism may approximately the same quantities as did normal result from defects in the biosynthesis of cortisol.' individuals. Tetrahydrocortisone in small amounts The first suggestion regarding the nature of the was found. The present authors (16) have stud- error was made by Lewis and Wilkins (12), and ied six patients with virilizing adrenal hyperplasia in addition to the one reported here. Each of these * This study was supported by a grant (C-1003) from was found to be excreting C-21 hydroxylated com- the National Cancer Institute, Bethesda, Md. pounds in amounts equal to those found in nor- t Postdoctoral Research Fellow, United States Public Health Service. Present address: New York Hospital, mals of com)parable age. Tetrahydrocortisol was New York, N. Y. one of the a-ketols present. More recently, both 1 The following trivial names are used in the text: Hy- tetrahydrocortisone and tetrahydrocortisol have drocortisone (Compound F) is 1l11, 17a, 21-trihydroxy- been found in the urine of patients with this dis- 4-pregnene-3,20-dione. Tetrahydrocortisol (tetrahydro F) is 3a, llp, 17a, 21-tetrahydroxy-pregnane-20-one. Corti- order (17-20). sone (Compound E) is 17a, 21-dihydroxy-4-pregnene-3,11,- Abnormally high excretion of precursors of cor- 20-trione. Tetrahydrocortisone (tetrahydro E) is 3a, 17a, tisol, metabolites of precursors, and androgens are 21-trihydroxy-pregnane-11,20-dione. 11-Desoxyhydrocor- well recognized consequences of the derangement tisone (Compound S) is 17a, 21-dihydroxy-4-pregnene-3,- in the pathway for synthesis of normial corti- 20-dione. Tetrahydro S is 3a, 17a, 21-trihydroxy-preg- Further of the amounts nane-20-one. Dihydro S is 17a, 21-dihydroxy-pregnane- costeroids. augmentation 3,20-dione. Corticosterone (Compound B) is 11,, 21-dihy- of such products is to be expected fromii the over- droxy-4-pregnene-3,20-dione. Tetrahydrocorticosterone stimulation by excess corticotropin. The identi- (tetrahydro B) is 3a, lip, 21-trihydroxy-pregnane-20-one. fication of some of the abnormal metabolites has Desoxycorticosterone (DOC) is 21-hydroxy-4-pregnene- led to the clarification of the probable location of 3,20-dione. Tetrahydrodesoxycorticosterone is 3a, 21-di- errors in the process Lab- hydroxy-pregnane-20-one. Dihydrodesoxycorticosterone is the synthetic (7-22). 21-hydroxy-pregnane-3,20-dione. Allo-dihydrodesoxycor- oratory and clinical data reported by many work- ticosterone acetate is 21 acetoxy-allo-pregnane-3,20-dione. ers favor the concept that the defect in some cases Twenty-one desoxycortisone is 17a-hydroxy-4-pregnene-3,- may be at two or more steps of the steroid svn- 11,20-trione. Pregnanetriol is pregnane-3a, 17a, 20a-triol. thesis. Pregnanediol is pregnane-3a, 20a-diol. Androsterone is Eberlein and (7-9) studied an un- 3a-hydroxyandrostane-17-one. Etiocholanolone is 3a-hy- Bongiovanni droxy-etiocholane-17-one. 11-Keto androsterone is 3a-hy- treated patient who had congenital adrenal hyper- droxy-androstane-11,17-dione. 11 Ketoetiocholanolone is plasia associated with hypertension. The plasma 3a-hydroxy-etiocholane-11,17-dione. 11 Hydroxyandro- and urinary 17-hydroxycorticosteroids were imiark- sterone is 3a, 11-dihydroxy-androstane-17-one. 11 Hy- The contained S droxyetiocholanolone is 3a. 1 lp-dihydroxy-etiocholane-17- edly elevated. plasma Comlpound one. and tetrahydro S. The predomiiinant compound in 364 \IETABOLITES OF COMPOUND S AND DOC IN AN ADRENOGENITAL PATIENT 365 the urine was tetrahydro S. Tetrahydrodesoxy- amination were limited to a penis measuring 9 cm in corticosterone was also identified. length and small testes and prostate. The bone age, ac- two cording to Todd's "Atlas of Skeletal Maturation," corre- Three nonketonic C,1 steroids and C19-17- sponded to that of 11 years and 9 months. The neutral ketosteroids were isolated and identified by infra- 17-ketosteroids ranged from 15.7 to 21.7 mg per day red spectroscopy. None of the compounds iso- for 4 successive days before this investigation began. lated had oxygen functions at the 11-carbon. The Urinary a-ketol excretion, measured as blue tetrazolium authors proposed that these findings were evidence reducing substances (23), ranged from 18.6 to 27.7 mg for in C-11 hydroxylation. They also per 24 hours. The normal range for children 5 to 7 years deficiencv of age was found to be 2.5 to 3.5 mg per 24 hours in our suggested that the hypertension may be attributed laboratory. Excretion of pregnanetriol and pregnanediol, to accumulation of desoxycorticosterone, and this determined according to the method of Bongiovanni (24) type of defect has been considered characteristic was 4.5 and 1.5 mg per day, respectively. Serum electro- of congenital adrenal hyperplasia when hyperten- lytes, hemogram, blood sugar anid urinalysis were normal. sion is a complication (21). One week after the administration of 25 mg of cortisone acetate orally every 12 hours, the urinary neutral 17- Later Dyrenfurth and associates (19) reported ketosteroid excretion and total corticoid excretion had de- finding large amounts of tetrahydro S in the urine creased to 2.5 and 12.4 mg per 24 hours, respectively. The of two lpatients with congenital adrenal hyper- excretion of both types of steroids rose to pretreatment l)lasia: one had hypertension and the other did levels 48 hours after the cortisone was discontinued. not. Both of them excreted metabolites of cortisol. The patient was then placed on 37.5 mg of cortisone orally per day in divided doses for the next 9 months. -More recently Birke and colleagues (20) studied During that time the 17-ketosteroid excretion ranged be- the steroid patterns in the urine of two siblings tween 1.2 and 2.5 mg per 24 hours. Urinary pregnanetriol with congenital adrenal hyperplasia. Both pa- and pregnanediol were found to be 1.7 and 0.8 mg, re- tients excreted tetrahydro S, tetrahydrocortisone spectively, per day. No change in the range of systolic and 11-oxygenated 17-ketosteroids. Neither pa- or diastolic blood pressure was noted during the trial of cortisone, when the drug was stopped, or during mainte- tient had hypertension. nance therapy. The study reported here concerns a normoten- sive patient with the adrenogenital syndrome with METHODS a corticoid pattern characterized by the presence Corticosteroids. A 3 day pool of urine was collected of the metabolites of Compound S and of desoxy- before treatment and again a week after cortisone therapy corticosterone as well as of cortisol. had been started. Twenty-four hour aliquots from each pool were buffered at pH 4.8, hydrolyzed for 48 hours at 470 C with p-glucuronidase (250 units per ml of urine), CASE REPORT and then continuously extracted xith ether for 48 hours D.(., a white male, was first seen at 5.5 years of age after the pH had been readjusted to 6.8. The extracted \hen he was admitted to the Pediatric Service of this urine was put aside and the ether extracts were dried and hospital for evaluation of sexual precocity. The parents washed in chloroform by the procedure described by related that he weighed 3.5 kg at birth. Acceleration of Burton, Zaffaroni and Keutmann (25). The number of growth was noted during the first year of life. At 3 washings was reduced to 3 alkali, 1 acid, and 1 water months the patient weighed 4.6 kg, at 6 months 9.6 kg, wash, together with their appropriate back washings. and at 10.5 months 12.0 kg. Acne was noted on his face Preliminary fractionation and identification were done and chest at one year of age. The history was not re- on one of the 24 hour aliquots, the other two were used markable otherwise. for more definite and confirmatory information both as OIi admission the patient had the physical develop- to identity and quantitation. ment of an adolescent; his voice was deeply pitched. The total a-ketol content of the neutral extracts was A papular rash was present on the face and over the measured with blue tetrazolium according to the method shoulders. There was a moderate amount of hair on the described by Izzo, Keutmann and Burton (23) prior to upper lip and in the axillae; pubic hair was abundant. and after chromatographic fractionation on paper. The He weighed 35 kg; his height was 142 cm. total C-21, 17-hydroxyglycol content was determined by The blood pressure was recorded by 3 different ex- the method of Wilson and Fairbanks (26), and total 17- aminers to be 100/65, 105/70 and 120/80, respectively.
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