Suppression of Tumorous Adrenal Hyperfunction by Aminoglutethimide
By RENATA P. SMILO, JERRY M. EARLL AND PETER H. FORSHAM
Six patients with Cushing’s syndrome were treated with aminoglutethimide in doses ranging from 1000 to 1500 mg./ day. Two had adrenocortical adenomas, 1 carcinoma and 3 bilateral hyperplasia. The 3 with tumors responded with a marked decrease in cortisol secretion rates, urinary 17-hydroxycorticosteroids (17-OHCS), and 17-ketosteroids (17- KS) after the initial 2 days of treat- ment and showed no rebound for a further 8 days of therapy. This suppres-
sion was achieved with doses less than those recommended for maximal anti- convulsant therapy. In contrast, the 3 cases of bilateral hyperplasia showed incomplete suppression of steroid secre- tion even at higher dose levels. There were no unfavorable reactions to the drug. Aminoglutethimide is a promising agent for the control of excess steroid secretion in adrenocortical tumors. (Metabolism 16: No. 4, April, 374-377, 1967)
S TUDIES CONDUCTED at the Children’s Hospital in Ann Arbor, Michi- gan in 1965 suggested that adrenal insufficiency and abnormal adrenal histology may result from the administration of the anticonvulsant amino- glutethimide“ (AG) in man.1 This drug was recently withdrawn from the market.
To date, chemotherapy of adrenocortical cancer with ortho, para’ DDD (o,p’DDD) had been used and accomplished with a moderate degree of success.3,4 The drug’s toxicity, however, although generally reversible by dose reduction still presents problems. Treatment of tumorous adrenocortical hyper- activity with metyrapone could conceivably decrease the cortisol production by 11-hydroxylase inhibition but the 17-KS would remain essentially un- changed. We have attempted to elucidate the effect of AG on adrenal function in Cushing’s syndrome as a possible therapeutic agent.
MATERIALS AND METHODS
Six female patients with documented Cushing’s syndrome were studied in the General
From the Metabolic Research Unit and Department of Medicine, University of California Medical Center, San Francisco.
This work was done in the General Clinical Research Center maintained by Grant FR-79 from the Division of Research Facilities and Resources, National Institutes of Health, U. S. Public Health Service. Supported in part by a grant-in-aid from the Ciba Pharmaceutical Company, Summit, New Jersey.
Elipten® was kindly supplied by Dr. F. G. McMahan of the Ciba Pharmaceutical Company, Summit, New Jersey.
Received for publication Dec. 1, 1966.
RENATA P. SMILO, M.D .: Assistant Research Physician, Metabolic Research Unit. JERRY M. EARLL, M.D .: Research Fellow, Metabolic Research Unit. Present address: Department of Medicine, Tripler General Hospital, Oahu, Hawaii. PETER H. FORSHAM, M.D .: Professor of Medicine and Pediatrics; Director, Metabolic Research Unit and General Clinical Re- search Center.
“Elipten®, Ciba Pharmaceutical Company, Summit, New Jersey.
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Clinical Research Center. Two had benign adrenocortical adenomas, a third had an adre- nal carcinoma with extensive metastasis, and the remaining 3 had bilateral adrenocortical hyperplasia of hypothalamic-pituitary origin. Patients ranged in age from 30 to 52 years. Studies consisted of base-line plasma and urinary 17-OHCS, cortisol secretion rates, an 8-hour intravenous ACTH infusion, metyrapone, 500 mg. given every hour for 6 doses .? and dexamethasone suppression tests, 2 mg./day for 2 days and 8 mg./day for 2 days.
The urinary 17-OHCS were estimated by a modified method of Reddy” and the urinary 17-KS by the method of Drekter et al.7 Cortisol secretion rates were done as described by Copes and modified by Biglieri et al.9
The 2 patients with benign adrenocortical tumors received AG for a total of 8 days with a maximum dose of 1,000 mg./day reached on the third day of treatment. continued for 3 days thereafter and then withdrawn. Since these patients reduced their cortisol secretion rates and urinary 17-OHCS to nearly undetectable levels soon after treatment was begun they were given supplementary dexamethasone in doses previously shown not to affect the adrenocortical activity in this type of patient.
The patients with hyperplasia were given AG in slowly increasing doses starting with 250 mg. daily until the fourth treatment day when a maximal dose of 1500 mg. daily was reached and maintained until the eighth day. The AG was slowly withdrawn until medica- tion was discontinued on the twelfth day of treatment.
RESULTS AND DISCUSSION
The results indicate (Fig. 1) that AG is most effective in suppressing adren- ocortical function in tumors where secretion is independent of ACTH. In con- trast, suppression was only partial in the 3 cases of hyperplasia, presumably because ACTH compensated for the reduced cortisol secretion. No ill effects were noted. No excessive sedation was encountered. The patient with metasta- tic adrenal carcinoma developed a mild fever on the second day of therapy when her adrenal function was already acutely reduced, and the drug was discontinued. She was probably sensitive to an intravenous urogram done at this time, since after the AG therapy was discontinued it was successfully reinstituted.
Dexter et al.1º reported that the normal increase in adrenal venous corti- costerone in response to ACTH was abolished in hypophysectomized rats and decreased in intact rats given AG. Preliminary studies suggested that the block in biosynthesis is prior to 4-5-pregnenolone; 2 patients with Cushing’s syndrome showed normalization of plasma and urinary corticosteroids when treated for a brief period. Fishman et al.11 gave large doses of AG to 3 normal subjects for 3 days and demonstrated a variable fall in cortisol secretion rates and plasma 17-OHCS, but a more than fivefold increase in plasma ACTH, indicating an ACTH-compensated inhibition of cortisol production. Pittman and Brown12 have recently reported thyroid and adrenal inhibition in rats.
It is concluded that in functioning tumors of the adrenal cortex, AG is an effective agent for blocking steroid secretion and is of low general toxicity. In contrast, in cases of functional hyperplasia, it can serve only as a temporary expedient for lowering adrenocortical secretion to varying degrees.
AG may also be beneficial in adrenocortical overactivity due to extrapitui- tary ACTH-like stimulation from other tumors18 since their ACTH-like output appears to be fixed.
REFERENCES
1. Personal communication (Dr. G. McMahon, Ciba). Studies by Alvro M. Camacho, Children’s Hospital. Michigan.
2. Bergenstal, D. M., Hertz, R., Lipsett, M. B., and Moy, R. H .: Chemotherapy of adrenocortical cancer with o,p’DDD. Ann. Int. Med. 53:672. 1960.
3. Lipsett, M. B., Hertz, R., and Ross, G. T .: Clinical and pathophysiologie as- pects of adrenocortical carcinoma. Amer. J. Med. 35:374, 1963.
4. Hwtter, A. M., Jr., and Kaynoe, D. E .: Adrenal cortical carcinoma: results of treatment with o,p’DDD in 138 pa- tients. Amer. J. Med. 41:581-592. 1966.
5. Smilo, R. P., Sparks, L. L., Pavlatos, F. Ch., and Forsham, P. H .: Rapid oral
metyrapone test to determine the etiology of Cushing’s syndrome. J.A.M.A. (to be submitted).
6. Reddy, W. J .: Modification of the Reddy-Jenkins-Thorn method for the estimation of 17-hydroxycorticoids in urine. Metabolism 3:489, 1954.
7. Drekter, I. J., Heisler, A., Scism, G. R., Stern, S., Pearson, S., and McGavack. T. H .: The determination of urinary steroids. I. The preparation of pig- ment-free extracts and a simplified procedure for the estimation of total 17-ketosteroids. J. Clin. Endocrinol. 12:55, 1952.
8. Cope, C. L., and Black, E. G .: The be- haviour of 14,,-cortisol and estimation of cortisol production rate in man. Clin. Sci. 17:147, 1958.
9. Biglieri, E. G., Hane, S., Slaton, P. E., and Forsham, P. H .: In vivo and in vitro studies of adrenal secretions in Cushing’s syndrome and primary al- dosteronism. J. Clin. Invest. 42:516. 1963.
10. Dexter, R. N .. Fishman. L. M., Black. A. C., Jr., and Ney, R. L .: Inhibition of adrenal corticosteroid synthesis by aminoglutethimide. Clin. Res. 14:61, 1966.
11. Fishman, L. M .. and Dexter, R. N .: Effects of aminoglutethimide on adre-
nal function in rats and man. Endo- crine Society Program. 48th Meeting. p. 64. 1966.
12. Pittman, J. A., and Brown, R. W .: Anti- thyroid and antiadrenocortical activity of aminoglutethimide. J. Clin. Endo- crinol. 26:1014. 1966.
13. Liddle. G. W., Island. D. P .. Ney, R. I … Nicholson, W. E., and Shimuzu, N .: Nonpituitary neoplasma and Cush- ing’s syndrome. Arch. Int. Med. 111: 471, 1964.