I Case Report
Preoperative ketoconazole therapy for adrenocortical carcinoma
Linda J.E. Sinnaeve, MD, FRCPC Gregory P. Becks, MD, FRCPC
K etoconazole, an imidazole derivative, is a broad-spectrum antifungal agent. The de- velopment of gynecomastia in some men receiving ketoconazole fostered research into the drug’s inhibitory effects on the production of testosterone1,2 and, subsequently, other steroid hormones.3-5 Ketoconazole has been used in the treatment of adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome (Cush- ing’s disease and ectopic ACTH syndromes), but there has been little experience with its use in Cushing’s syndrome of primary adrenal origin.6 We report a case of adrenocortical carcinoma in which preoperative ketoconazole therapy resulted in short-term clinical improvement.
Case report
A 60-year-old woman with a 4-month history of hypertension presented to hospital comatose. The hypertension had been treated with a diuretic and prazosin until 2 days before presentation, when hydralazine was substituted. The blood pres- sure on admission was 230/130 mm Hg and the pulse rate 80 beats/min. No focal neurologic abnormalities were detected. Initial laboratory in- vestigation revealed mild hyponatremia (serum sodium level 129 mmol/L) and respiratory alkalo- sis. Toxicology test results were negative.
The hypertension responded to intravenous hydralazine therapy. The patient resisted opening of her eyes but was otherwise unresponsive. Com- puted tomography (CT) of the head revealed normal findings. Episodes of catatonic behaviour occurred, and haloperidol therapy was started because of suspected hysteria.
From the Section of Endocrinology and Metabolism, Depart- ment of Medicine, St. Joseph’s Health Centre and University of Western Ontario, London
Reprint requests to: Dr. Gregory P. Becks, Section of Endocri- nology and Metabolism, St. Joseph’s Health Centre, 268 Gros- venor St., London, Ont. N6A 4V2
By the third hospital day the patient was conscious and related a 2-month history of easy bruising, thin skin, hirsutism, facial plethora and puffiness, and muscle weakness. Her blood pres- sure was 120/75 mm Hg after antihypertensive therapy was stopped. Subsequently it increased to 210/120 mm Hg, and prazosin, 6 mg/d, was given.
The catecholamine levels in a 24-hour urine collection were normal before prazosin therapy was started. The serum cortisol level was 790 (normally 170 to 580) nmol/L at 8 am and 849 (normally 50 to 300) nmol/L at 4 pm. The serum aldosterone level was 598 (normally 80 to 280) pmol/L at 8 am. The plasma level of ACTH was 9 (normally less than 22) pmol/L, of testosterone 6.7 (normally less than 2.3) nmol/L and of dehydro- epiandrosterone sulfate (DHEA-S) 18 (normally less than 1.7) umol/L. The urine level of 17-ketosteroids was 250 (normally less than 52) umol/d. The free cortisol level in a 24-hour collection of urine was markedly elevated, did not respond to low-dose dexamethasone administra- tion and failed to decrease by 50% or more with high-dose dexamethasone administration (Fig. 1). The plasma cortisol levels at 4 pm on the second day of low-dose and high-dose dexamethasone administration were 850 and 687 nmol/L respec- tively.
Ultrasonography revealed a solid mass 9 × 5 X 7 cm in the left adrenal gland; CT showed a well-defined encapsulated mass with radiolucent areas. The liver appeared normal. Bone scanning revealed increased uptake in the third, fourth and fifth ribs on the left side, and x-ray films confirmed the presence of rib fractures.
Adrenocortical carcinoma was suspected on the basis of a large adrenal mass, rapidly progres- sive signs and symptoms, and biochemical evi- dence of increased secretion of androgens (testos- terone, DHEA-S and 17-ketosteroids), cortisol and aldosterone. In preparation for surgery the patient was given ketoconazole, the dosage being gradual- ly increased from 200 mg once daily to 200 mg three times daily. The free cortisol level in a
24-hour collection of urine returned to normal (Fig. 1). The blood pressure was normal after the withdrawal of prazosin therapy, and the plethora was alleviated.
Twelve days after the institution of ketocona- zole therapy the tumour was resected under gluco- corticoid coverage, with incidental splenectomy. No metastases were noted. The tumour weighed 291 g and measured 14 × 8 × 6 cm. Histologic study confirmed the clinical diagnosis of adreno- cortical carcinoma and revealed vascular invasion and areas of hemorrhage and necrosis. After sur- gery the plasma levels of aldosterone, testosterone and androstenedione and the urine level of 17-ketosteroids were normal with the use of dex- amethasone, 1 mg/d. Ketoconazole therapy was stopped.
Three months after surgery the patient pre- sented with a recurrence of her original symptoms. The free cortisol level in a 24-hour collection of urine was again markedly elevated, and hepatic metastases were present. Mitotane therapy was ineffective, and she died shortly thereafter.
Comments
Ketoconazole has been shown to be a potent inhibitor of mitochondrial enzymes of the cyto- chrome P450 system.7 In healthy male volunteers a single 600-mg dose given orally resulted in a statistically significant reduction in testosterone levels for up to 8 hours.2 Higher doses, 800 to 1200 mg/d, resulted in persistently low testosterone levels in some patients. This effect is thought to be due to inhibition of the 17-20 lyase enzyme. In addition, gynecomastia, decreased libido, impo- tence and oligospermia have been noted.4 Another study demonstrated a reduction in 1,25-dihydroxy- vitamin D3 levels in male volunteers receiving ketoconazole, 600 to 1200 mg/d, for 1 week.5
In-vitro studies have suggested several actions of ketoconazole within the adrenal gland;7 these include (a) inhibition of desmolase activity in the side-chain cleavage of cholesterol to pregnenolone, (b) inhibition of 11-hydroxylase catalyzation of deoxycorticosterone to corticosterone and of 18- hydroxydeoxycorticosterone to 18-hydroxycortico- sterone and (c) inhibition of 18-hydroxylase cataly- zation of deoxycorticosterone to 18-hydroxydeoxy- corticosterone and of corticosterone to 18-hydroxy- corticosterone. Studies involving isolated rat adrenal cells demonstrated no inhibition by keto- conazole of noncytochrome P450 enzymes.8
Ketoconazole has been used as primary or adjunctive treatment in patients with ACTH- dependent Cushing’s syndrome (Cushing’s dis- ease) before or after transsphenoidal pituitary sur- gery9-11 and in those with metastatic small cell carcinoma of the lung associated with ectopic ACTH production.12
In addition, ketoconazole has been used to treat benign and malignant adrenal tumours.
Contreras and associates13 reported a case in which a 21-year-old woman with an adrenal rest tumour of the liver causing Cushing’s syndrome was treated for 42 days preoperatively with ketocona- zole, up to 1000 mg/d. In another case a patient with adrenal carcinoma and metastases in the liver and lungs responded to treatment with ketocona- zole, 1200 mg/d, with an apparent reduction in the size of the metastases.14 Oeklers and col- leagues15 reported on the effects of ketoconazole on adrenocortical micronodular adenomatosis in vivo and in vitro.
The case we have described demonstrates the clinical effectiveness of short-term preoperative ketoconazole treatment in Cushing’s syndrome due to adrenocortical carcinoma. Although acute adrenal insufficiency has been associated with ketoconazole therapy,16 it did not develop in this patient. Ketoconazole appears to be useful as adjunctive therapy for the many causes of in- creased production of adrenal steroid hormones.6
References
1. DeFelice R, Johnson DG, Galgiani JN: Gynecomastia with ketoconazole. Antimicrob Agents Chemother 1981; 19: 1073-1074
2. Pont A, Williams PL, Azhar S et al: Ketoconazole blocks testosterone synthesis. Arch Intern Med 1982; 142: 2137- 2140
3. Pont A, Williams PL, Loose DS et al: Ketoconazole blocks adrenal steroid synthesis. Ann Intern Med 1982; 97: 370- 372
4. Pont A, Graybill JR, Craven PC et al: High-dose ketocona- zole therapy and adrenal and testicular function in humans. Arch Intern Med 1984; 144: 2150-2153
Dexamethasone 2 mg/d | 8 mg/d
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Ketoconazole 200 mg/d | 400 mg/d | 600 mg/d
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5. Glass AR, Eil C: Ketoconazole-induced reduction in serum 1,25-dihydroxyvitamin D. J Clin Endocrinol Metab 1986; 63: 766-769
6. Sonino N: The use of ketoconazole as an inhibitor of steroid production. N Engl J Med 1987; 317: 812-818
7. Nagai K, Miyamori I, Ikeda M et al: Effect of ketoconazole (an imidazole antimycotic agent) and other inhibitors of steroidogenesis on cytochrome P450 catalyzed reactions. J Steroid Biochem 1986; 24: 321-323
8. Loose D, Kan P, Hirst M et al: Ketoconazole blocks adrenal steroidogenesis by inhibiting cytochrome P450-dependent enzymes. J Clin Invest 1983; 71: 1495-1499
9. Sonino N, Boscaro M, Merola G et al: Prolonged treatment of Cushing’s disease by ketoconazole. J Clin Endocrinol Metab 1985; 61: 718-722
10. Loli P, Berselli ME, Tagliaferri M: Use of ketoconazole in the treatment of Cushing’s syndrome. J Clin Endocrinol Metab 1986; 63: 1365-1371
11. McCance DR, Hadden DR, Kennedy L et al: Clinical experience with ketoconazole as a therapy for patients with
Cushing’s syndrome. Clin Endocrinol 1987; 27: 593-599
12. Shepherd FA, Hoffert B, Evans WK et al: Ketoconazole: use in the treatment of ectopic adrenocorticotropic hormone production and Cushing’s syndrome in small-cell lung cancer. Arch Intern Med 1985; 145: 863-864
13. Contreras P, Altieri E, Liberman C et al: Adrenal rest tumour of the liver causing Cushing’s syndrome. Treatment with ketoconazole preceding an apparent surgical cure. J Clin Endocrinol Metab 1985; 60: 21-28
14. Contreras P, Rojas A, Biagini L et al: Regression of metastatic adrenal carcinoma during palliative ketoconazole treatment [C]. Lancet 1985; 2: 151-152
15. Oeklers W, Bahr V, Heusen J et al: Primary adrenocortical micronodular adenomatosis causing Cushing’s syndrome. Effects of ketoconazole on steroid production and in-vitro performance of adrenal cells. Acta Endocrinol (Copenh) 1986; 113: 370-377
16. Tucker WS, Snell BB, Island DP et al: Reversible adrenal insufficiency induced by ketoconazole. JAMA 1985; 253: 2413-2414
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