Summary
The effect of ketoconazole on adrenal androgen secretion was examined in 15 patients with elevated serum androgens. In a dose of 600 mg per day orally ketoconazole inhibited the biosynthesis of all measured androgens. The mean reduction in serum levels of dehydroepiandrosterone sulfate was 32%, of dehydroepiandrosterone 54%, of androstenedione 52%, and of testosterone 43%; mean serum levels of cortisol only fell by 19%. The reduction in serum androgen levels was first significant 24 h after beginning of treatment and persisted as long as the drug was administered. We conclude that ketoconazole inhibits adrenal androgen biosynthesis more pronouncedly than cortisol biosynthesis. This might be of clinical benefit in the treatment of hirsutism and other states of androgen hypersecretion.
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Abbreviations
- CV:
-
coefficient of variation
- MV:
-
mean value
- SEM:
-
standard error of the mean
- f:
-
female
- m:
-
male
- K:
-
ketoconazole
- ACTH:
-
adrenocorticotropic hormone
- DHEA:
-
dehydroepiandrosterone
- DHEAS:
-
dehydroepiandrosterone sulfate
- A:
-
androstenedione
- T:
-
testosterone
- F:
-
cortisol
- P:
-
progesterone
- H:
-
hirsutism
- C:
-
Cushing's disease
- EAS:
-
ectopic ACTH syndrome
- ATU:
-
adrenal tumor
References
Baulieu EE, Corpechot C, Dray F, Emiliozzi R, Lebeau MC, Mauvais-Jarvis P, Robel P (1965) An adrenal secreted “androgen”: dehydroisoandrosterone sulfate. Its metabolism and tentative generalization of the metabolism of other steroid conjugates in man. Recent Progr Hormone Res 21:411–500
Carvalho D, Pignatelli D, Resence C (1985) Ketoconazole for hirsutism. Lancet 2:560 letter
Contreras P, Altieri E, Liebermann C, Gac A, Rojas A, Ibarra A, Ravanal M, Seron-Ferre M (1985) Adrenal rest tumor of the liver causing Cushing's syndrome: treatment with ketoconazole preceding an apparent surgical cure. J Clin Endocrinol Metab 60:21–28
Couch RM, Müller J, Perry YS, Winter JSD (1987) Kinetic analysis of inhibition of human adrenal steroidogenesis by ketoconazole. J Clin Endocrinol Metab 65:551–554
De Coster R, Caers I, Haeltermann C, Debroye M (1985) Effect of a single administration of ketoconazole on total and physiologically free plasma testosterone and 17β-oestradiol levels in healthy male volunteers. Eur J Clin Pharmacol 29:486–493
De Coster R, Caers I, Coene MC, Amery W, Beerens D, Haeltermann C (1986) Effects of high dose ketoconazole therapy on the main plasma testicular and adrenal steroids in previously untreated prostatic cancer patients. Clin Endocrinol 24:657–664
De Coster R, Mahler C, Denis L, Coene MC, Caerts I, Amery W, Haeltermann C, Beerens D (1987) Effects of high-dose ketoconazole in dexamethasone on ACTH-stimulated adrenal steroid genesis in orchiectomized prostatic cancer patients. Acta Endocrinol 115:265–271
Denis L, Chaban M, Mahler C (1985) Clinical applications of ketoconazole in prostatic cancer. Prog Clin Biol Res 185A:319–326
Engelhardt D, Abedinpour F (1987) Inhibition of androgen biosynthesis in human adrenal tissue by ketoconazole. J Steroid Biochem 28 [Suppl]:335
Feldmann LD (1986) Ketoconazole for male metastatic breast cancer (letter). Ann Intern Med 104:123–124
Glass AR (1986) Ketoconazole-induced stimulation of gonadotropin output in men: basis for a potential test of gonadotropin reserve. J Clin Endocrinol Metab 63:1121–1125
Heyns W, Drochmans W, van der Schueren E, Verhoeven G (1985) Endocrine effects of high-dose ketoconazole therapy in advanced prostatic cancer. Acta Endocrinol 110:276–283
Holland FJ, Kirsch SE, Selby R (1987) Gonadotropin-independent precocious puberty (“testotoxicosis”): influence of maturational status on response to ketoconazole. J Clin Endocrinol Metab 64:328–333
Lamberts SWJ, Bons EG, Bruining HA, de Jong FH (1986) Differential effects on the imidazole derivatives etomidate, ketoconazole and miconazole and of metyrapone on the secretion of cortisol and its precursors by human adrenocortical cells. J Pharmacol Exp Therap 240:259–264
Loli P, Berselli ME, Tagliaferri M (1986) Use of ketoconazole in the treatment of Cushing's syndrome. J Clin Endocrinol Metab 63:1365–1371
Martikainen H, Heikkinen J, Ruokonen A, Kaupilla A (1988) Hormonal and clinical effects of ketoconazole in hirsute women. J Clin Endocrinol Metab 66:987–991
McCance DR, Hadden DR, Kennedy L, Shewridan B, Atkinson AB L (1987) Clinical experience with ketoconazole as a therapy for patients with Cushing's syndrome. Clin Endocrinol 27:593–599
Pepper GM, Poretsky L, Gabrilove JL, Ariton MM (1987) Ketoconazole reverses hyperandrogenism in a patient with insulin resistance and acanthosis nigricans. J Clin Endocrinol Metab 65:1047–1052
Pont A, Williams PL, Azhar S, Reitz RE, Bochra C, Smith ER, Stevens DA (1982) Ketoconazole blocks testosterone synthesis. Arch Intern Med 142:2137–2140
Pont A, Graybill JR, Craven PC, Galgiani JN, Dismukes WE, Reitz RE, Stevens DA (1984) High dose ketoconazole therapy and adrenal and testicular function in humans. Arch Intern Med 144:2150–2153
Rajfer J, Sikka SC, Rivera F, Handelsmann DJ (1986) Mechanism of inhibition of human testicular steroid genesis by oral ketoconazole. J Clin Endocrinol Metab 63:1193–1198
Santen RJ, Van den Bosche H, Symoens J, Brugmans J, DeCoster R (1983) Site of action of low dose ketoconazole on androgen biosynthesis in men. J Clin Endocrinol Metab 57:732–736
Schürmeyer T, Nieschlag E (1984) Effect of ketoconazole and other imidazole fungicides on testosterone biosynthesis. Acta Endocrinol 105:275–280
Sikka SC, Swerdloff RS, Rajfer J (1985) In vitro inhibition of testosterone biosynthesis by ketoconazole. Endocrinology 116:1920–1925
Sonino N, Boscaro M, Merola G, Mantero F (1985) Prolonged treatment of Cushing's disease by ketoconazole. J Clin Endocrinol Metab 61:718–722
Sonino N (1987) The use of ketoconazole as an inhibitor of steroid production. N Engl J Med 317:812–818
Tapazoglou E, Subramanian MG, Al-Sarraf M, Kresge C, Decker DA (1986) High-dose ketoconazole therapy in patients with metastatic prostate cancer. Am J Clin Oncol 9:369–375
Trachtenberg J, Halpern N, Pont A (1983) Ketoconazole: a novel and rapid treatment for advanced prostatic cancer. J Urol 130:152–153
Trachtenberg J, Pont A (1984) Ketoconazole therapy for advanced prostate cancer. Lancet 2:433–435
Van Tyle JH (1984) Ketoconazole. Mechanism of action, spectrum of activity, pharmacokinetics, drug interactions, adverse reactions and therapeutic use. Pharmacotherapy 4:343–373
Weber MM, Abedinpour F, Luppa P, Engelhardt D (1989) Inhibition of adrenal androgen biosynthesis by ketoconazole in vivo and in vitro. Acta Endocrinol 120 [Suppl 1]:114
Williams G, Kerle DJ, Ware H, Doble A, Dunlop H, Smith C, Allen J, Yeo T, Bloom SR (1986) Objective response to ketoconazole therapy in patients with relapsed progressive prostatic cancer. Br J Urol 58:45–51
Zeller M, Engelhardt D (1985) Inhibition of C17,20-desmolase, 17α-hydroxylase and 16α-hydroxylase activity in human testis by ketoconazole. Acta Endocrinol 108 [Suppl 267]:99
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Weber, M.M., Luppa, P. & Engelhardt, D. Inhibition of human adrenal androgen secretion by ketoconazole. Klin Wochenschr 67, 707–712 (1989). https://doi.org/10.1007/BF01721288
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DOI: https://doi.org/10.1007/BF01721288