Aminoglutethimide in the Treatment of Cushing’s Syndrome
R. I. MISBIN, M.D., J. CANARY, M.D., and D. WILLARD, M.D. Summit, N.J.
A MINOGLUTETHIMIDE, the para-amino derivative of the sedative glutethimide (Doriden), was introduced as an anticon- vulsant in the United States in 1960. Be- cause of endocrine abnormalities observed in children taking aminoglutethimide, the drug was withdrawn in 1966. Subsequent work established that aminoglutethimide inhibits the conversion of cholesterol to pregnenolone and hence the production of all adrenocorticol hormones. A detailed review of the history and mechanism of action of aminoglutethimide has been re- ported by Hughes and Burley.1 Schtein- gart et al.2 were the first to report on the use of aminoglutethimide in a patient with Cushing’s syndrome due to metastatic adrenal carcinoma. The efficacy of amino- glutethimide in the treatment of various forms of Cushing’s syndrome was soon confirmed.3-10 More recently, “medical adrenalectomy” with aminoglutethimide has been shown to be effective therapy for patients with metastatic carcinoma of the breast11,12 and prostate18,14 and to normal- ize blood pressure in patients with low- renin hypertension.15
In the ten years since aminoglutethi- mide was withdrawn from general use in
From the Division of Endocrinology, Depart- ment of Medicine of The New Jersey College of Medicine and Dentistry, Rutgers Medical School, The Research Department, Pharmaceuticals Divi- sion, Ciba-Geigy Corporation, Summit, N.J .; Georgetown University, Washington, D.C .; and The Medical Center at Princeton, Princeton, N.J.
the United States, 168 patients with Cush- ing’s syndrome have been treated with aminoglutethimide on an investigational basis. The purpose of this report is to re- view the efficacy and tolerability of aminoglutethimide in this condition. Three recently treated cases are presented to illustrate the role of aminoglutethimide in the various forms of Cushing’s syndrome, i.e., metastatic adrenal carcinoma, adrenal adenoma, and bilaterial hyperplasia.
Case 1 (Fig. 1)
Three months prior to her admission to Georgetown University Hospital, this 28- year-old white woman developed amenorrhea associated with progressive muscle weakness and masculinization. At the time of admis- sion, she was noted to have increased pubic and axillary hair, thickened dorsal and supraclavicular fat pads, and easy bruis- ability. Her blood pressure was 160/120. Her liver was enlarged with a nodular con- sistency. Abnormal laboratory values in- cluded (in mEq/liter) K, 2.0-2.4; CO2, 38-42; C1, 69-79; FBS, 180-200 mg/100 ml. Liver scan showed filling defects consistent with metastatic carcinoma. IVP showed displace- ment of the right kidney with flattening of the superior pole. Plasma cortisols ranged from 75 to 115 ug/100 ml (10-24 in A.M.) without diurnal variation. Urinary 17-keto- genic steroids and 17-ketosteroids ranged, respectively, from 150 to 250 mg/day (7-22 in A.M.) and from 26 to 36 mg/day (4-14 in A.M.). Neither plasma cortisol nor urinary ketogenic or ketosteroids responded to intra- venous corticotropin or to 2 or 8 mg dexame- thasone. After 72 hours of 4 mg dexame-
MISBIN, CANARY, AND WILLARD
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Upon resumption of aminoglutethimide, plasma cortisol fell to 22 ug/100 ml and 17- ketogenic steroids to 21 mg/day. The patient was treated at home for three weeks with 8 Gm o,p’-DDD and 750 mg aminoglutethimide. She was readmitted because of extensive hepatic metastases with inferior vena cava obstruction and expired two days later. Her plasma cortisol the day of readmission was 42 µg/100 ml.
Case 2 (Fig. 2)
This 31-year-old female had an 8-year his- tory of obesity, amenorrhea, and hyperten- sion. On two occasions, 17-hydroxysteroid levels were reported “at the upper limit of normal.” She was treated with methyldopa and a thiazide diuretic. At age 30, she de- veloped internuclear ophthalmoplegia. Physi- cal examination at the Medical Center at Princeton showed a weight of 154 pounds with trunkal obesity. The arms and legs were strikingly thin. Striae were present. Blood pressure was 140/100. Routine laboratory tests were within normal limits except for a
thasone every six hours, the plasma cortisol dropped to 19 ug/100 ml and the 17-keto- genic steroids to 15 mg per day. A 70-Gm right adrenocortical carcinoma was removed at laparotomy. Biopsies of metastatic lesions in the liver showed similar histology. Because of the persistence of hypercorticism, the pa- tient was started on o,p’-DDD in increasing doses from 3 to 6 Gm/day on the 14th post- operative day. After ten days with no change in steroid excretion, the dose of o,p’-DDD was increased to 10 Gm, and 750 mg aminoglutethimide was added. A rapid fall in steroid excretion was noted. Both drugs were stopped because of upper gastrointestinal symptoms, but were reinstituted after three days. The patient was treated for the next 18 days with 8 Gm o,p’-DDD and 1000 mg aminoglutethimide. The persistent fall in steroid levels was associated with improve- ment of hyperglycemia, hypokalemia, and the physical stigmata of hypercorticism. In order to determine which of the two drugs was primarily responsible for this improvement, aminoglutethimide was discontinued for five days. The plasma cortisol rose to 139 g/100 ml and 17-ketogenic steroids to 382 mg/day.
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The Journal of Clinical Pharmacology
AMINOGLUTETHIMIDE IN CUSHING’S SYNDROME
BUN of 24, WBC of 12,900, and moderate hy- perlipemia (noted previously). Serum cor- tisol was 31.4 ug/100 ml at 8 A.M., 33.9 µg/ 100 ml at 8 P.M., and 33.9 ug/100 ml at 8A.M. after 1.0 mg dexamethasone. Urinary 17- hydroxysteroids of 11.3 mg/day fell to 10.0 during the second day of dexamethasone, 0.5 mg 6-hourly. Nine hours after oral adminis- tration of 2.5 Gm metyrapone, the 8 A.M. plasma cortisol was 15 µg/100 ml and 11- deoxycortisol was 1.6 ug/100 ml (normal re- sponse is 10 µg/100 ml). Adrenal venography revealed a 3.7-cm oval mass on the right and normal venous pattern on the left. Amino- glutethimide was started at 250 mg per day and increased after seven days to 250 mg twice daily. Dexamethasone was admin- istered at a dose of 0.5 mg daily. After one week, her blood pressure had fallen to 114/ 88. Serum cortisol was 14.8 ug/100 ml and remained in the range of 10-13 ug/100 ml for the duration of therapy. The patient lost ap- proximately 1 pound per week. On day 88 of therapy, regular menses resumed after nine years of amenorrhea. After 111 days of therapy, aminoglutethimide was discontinued. Serum cortisol rose to 32 g/100 ml within one week. The patient was taken to surgery where a 25-Gm right adrenal adenoma was excised. The patient continued to be asymptomatic six months after surgery.
Case 3 (Fig. 3)
This 30-year-old female was admitted to Princeton Medical Center for evaluation of back pain. She was found to have extensive osteoporosis with a vertebral compression fracture and was referred for endocrine evaluation. Delivery of her second child (15 months previously) was followed by irregular spotting, hirsutism, and progressive weight gain. A history of purple striae over the flanks was also obtained. The patient had been treated with oral contraceptives until her admission. Physical examination revealed a blood pressure of 150/96, prominent facial hair, and very prominent striae over the ab- domen, flanks, and arms. Serum cortisol was 45 µg/100 ml at 8 A.M. and 20.5 µg/100 ml at 8 P.M. while on Ovulen* and was 29 g/100 ml at 8 A.M. and 14.7 ug/100 ml at 8 P.M. two months later. Following 1 mg of dexametha- sone, 8-A.M. cortisol was 29 ug/100 ml. Metyrapone, 2.75 Gm at bedtime, increased
the 8-A.M. 11-deoxycortisol from 0.7 to 14 µg/ 100 ml. On the second day of dexamethasone, 2 mg every 6 hours, serum cortisol was sup- pressed to 2 µg/100 ml. With a presumptive diagnosis of Cushing’s disease, the patient was treated with aminogluthethimide, 250 mg q.i.d. A fall in morning cortisol to 3 µg/100 ml was noted after two and three weeks of therapy and was associated with normaliza- tion of blood pressure (120/80), improved sense of well being, and increased physical activity. After 10 to 12 weeks of treatment, the patient had lost 20 pounds, but morning cortisols had climbed to 18 ug/100 ml and diastolic blood pressure to 88 mm Hg. Bi- lateral adrenalectomy was performed without difficulty. The right adrenal weighed 8 Gm, the left, 7 Gm. Neither contained nodules. The signs of Cushing’s syndrome had dis- appeared six months later.
Discussion
In the United States between 1966 and 1976, 168 patients with Cushing’s syn- drome were treated with aminoglutethi-
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MISBIN, CANARY, AND WILLARD
| Improvement (%) | |||
|---|---|---|---|
| Etiology | Clinical and biochemical | Biochemical only | No improvement |
| Metastatic adrenocortical carcinoma (N=21) | 62 | 14 | 24 |
| Ectopic ACTH | 67 | 0 | 33 |
| production from metastatic carcinoma (N=6) | |||
| Adrenal adenoma (N=6) | 100 | 0 | 0 |
| Bilateral adrenal hyperplasia (N=33) | 42 | 15 | 42 |
| Total (N=66) | 56 | 12 | 32 |
* Clinical improvement =amelioration of such signs of Cushing’s syndrome as muscle weakness, bruisability, hypokalemia, and hyperglycemia. Biochemical improvement=50 per cent reduction in steroid levels or a return to within normal limits.
mide on an investigational basis. In many, the efficacy and tolerability of aminoglutethimide could not be ade- quately assessed because of insufficiency of data, inadequacy of the trial, or con- comitant use of other adrenal blocking agents such as metyrapone and o,p’-DDD. In order to assess the effectiveness of aminoglutethimide itself, data were ex- amined from 66 patients who fulfilled each of the following criteria: (1) uninter- rupted treatment with aminoglutethimide for at least 14 days; (2) documentation of adrenocortical function (plasma corti- sol, cortisol secretion rate, and/or 24- hour urinary cortisol or 17-ketosteroids) before, during, and after (where possible) treatment with aminoglutethimide; (3) no concomitant use of metyrapone, o,p’-DDD, or cytotoxic agents except (as in case 1) where the pharmacologic activity of aminoglutethimide could be clearly dis- tinguished from these agents.
Patients were scored as having had bio- chemical improvement if steroid levels fell by at least 50 per cent or returned to
normal limits after initiation of amino- glutethimide. Improvement in such stig- mata of Cushing’s syndrome as muscle weakness, hypokalemia, and hyperglycemia was taken as evidence of clinical improve- ment. As shown in Table I, 50 per cent of patients showed clinical and biochemi- cal improvement on aminoglutethimide therapy. Particularly impressive was the high rate of successful palliation of Cush- ing’s syndrome due to malignant causes. The improvement rate of 42 per cent of patients with bilaterial adrenal hyper- plasia (Cushing’s disease) is less than that reported by Jones et al.16 and Child et al.17 who used a combination of amino- glutethimide and metyrapone. The greater efficacy of combination therapy can be ex- plained by the observation that the block- ade of steroid synthesis produced by aminoglutethimide can be overcome by high levels of ACTH.18,19 While amino- glutethimide alone suppresses autonomous steroid production, overproduction due to excessive ACTH stimulation is only par- tially suppressed. Since metyrapone acts
AMINOGLUTETHIMIDE IN CUSHING’S SYNDROME
at a point in glucocorticoid synthesis (11- hydroxylation) beyond that of amino- glutethimide, the activity of these agents in cases of excessive ACTH stimulation may be additive. Case 3 is typical of pa- tients with Cushing’s disease who respond initially to aminoglutethimide, but who relapse because of ACTH overriding the blockade. While several patients with Cushing’s disease in this series experi- enced prolonged remission, all had had a previous history of pituitary irradia- tion. Aminoglutethimide alone, therefore, cannot be considered definitive therapy for Cushing’s disease.
Thirty-eight of the 66 patients in this series experienced an adverse reaction that was attributed to aminoglutethimide (Table II). Sedation occurred in 30 per cent of cases and was generally mild or transient at the usual dose of 250 mg four times daily. A rash developed in 21 per cent of patients (associated with fever in 3 per cent) one to two weeks after initia- tion. In some cases, the rash disappeared within a few days despite continuation of
| Number of patients | % of total | |
|---|---|---|
| Adverse reaction absent | 28 | 42 |
| Adverse reaction present | 38 | 58 |
| Adverse Reactions | ||
| Central nervous system* | 20 | 30 |
| Rash without fever | 12 | 18 |
| Rash with fever | 2 | 3 |
| Upper gastrointestinalt | 8 | 12 |
| Headache | 3 | 5 |
| Myalgia and malaise | 4 | 6 |
* Includes lethargy, sedation, dizziness, blurred vision, and depression.
t Includes nausea, vomiting, and anorexia.
therapy. In cases where aminogluthethi- mide was discontinued, resumption of therapy after the rash had cleared was not associated with its reappearance.
The widespread effects of cortisol ex- cess on body tissues have been reviewed extensively, as have their interplay with a number of systems involved in tissue injury and the response thereto.20-22 Vari- ous authors have recommended prompt surgical therapy as the therapy of choice in those patients demonstrating the great- est degrees of cortisol excess even though operative morbidity which is increased in Cushing’s syndrome would be even more significant in that subclass of patients. Body compositional studies have, in gen- eral, confirmed varying degrees of pro- tein depletion, potassium depletion, adi- pose tissue excess, calcium and phosphorus depletion, and abnormalities of total body water and sodium in such patients.28,24 We concur with the recommendations of others that aminoglutethimide can be used as a significant part of the preoperative preparation of such patients to reduce operative morbidity by inhibition of adrenal steroidogenesis.26,26 Aminoglu- tethimide would also be useful in shorten- ing the total recovery time of patients with Cushing’s disease selected for treat- ment with pituitary irradiation and in those patients where prior adrenal or pituitary ablation was not successful.
Summary
The efficacy and tolerability of amino- glutethimide for the treatment of Cush- ing’s syndrome was assessed in 66 cases three of which are described in the present paper. Aminoglutethimide provided pal- liation from the signs and symptoms of hypercorticism in 13 of 21 patients with metastatic adrenocortical carcinoma and four of six patients with ectopic ACTH production due to metastatic carcinomas. All six of the patients with adrenal adenomas showed clinical and biochemi-
cal improvement, while 14 of the 33 pa- tients with bilateral adrenal hyperplasia of pituitary origin improved. Adverse re- actions attributed to aminoglutethimide such as drowsiness, rash, and nausea oc- curred in 58 per cent of cases.
These data suggest that aminoglutethi- mide has a place in controlling the signs and symptoms of adrenocorticoid excess in patients with Cushing’s syndrome due to malignancy and is effective preopera- tive therapy for patients with adrenal adenomas and bilateral hyperplasia.
Acknowledgments
The authors are indebted to Dr. Frank Vinci, Mrs. Annette Gompels, Mrs. Anne Le Sher, and Ms. Barbara White for valuable assistance in the preparation of this manu- script and to the following physicians whose cases are included in this series: R. H. Bot- tomley, E. D. Bransome, Jr., H. Brown, V. W. Cole, D. M. Cook, R. L. Eddy, D. T. Elder, J. B. Field, J. Geller, R. D. Gittler, J. R. Givens, P. Gorden, C. V. Hodges, J. W. Holli- field, A. H. Janoski, N. M. Kaplan, M. A. Kirschner, D. T. Krieger, G. W. Liddle, J. A. Linfoot, J. G. Lodmell, J. Lord, J. R Man- nino, E Miller, P. J. Murlow, O. H. Pearson, W. J. Pendergast, R. E. Peterson, D. E. Schteingart, P. J. Snyder, J. Swift, H. D. Weiss, E. Werk, R. H. Williams, and N. M. Zetterstraund. These studies were supported in part by the facilities of the GCRC, RR 60 at Georgetown University Hospital, Grant awarded by the National Institutes of Health.
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Reprint requests to Dr. R. I. Misbin, 556 Morris Avenue, Summit, N.J. 07901.