Abstract
The in vivo influence of metyrapone (M) on different adrenal enzymes has been studied by simultaneous measurement of serum progesterone (P), 17-hydroxyprogesterone (17-OHP), deoxycorticosterone (DOC), corticosterone (B), deoxycortisol (S), 18-hydroxydeoxycorticosterone (18-OHDOC), aldosterone and cortisol (F) as well as by the measurement of plasma ACTH before and after oral administration of 40 mg of M/kg at 08:15 in four healthy male subjects. The well known inhibitory effect of M on adrenal 11-hydroxylase is demonstrated by a decrease of serum F and B and a synchronous increase of serum S and DOC after administration of M. The additional inhibition of 18-hydroxylase by M is documented by a decrease of serum 18-OHDOC in spite of a marked increase of serum DOC after M. The moderate increase of serum P and 17-OHP soon after drug administration, although plasma ACTH is highly elevated at this time, as well as the marked increase of these steroids in the afternoon synchronously to a rise of serum F and B suggest a further inhibitory effect of M on an enzyme prior to the total corticosteroid biosynthesis. This effect of M should be taken into account if ACTH activity is monitored in terms of adrenal steroid output in the metyrapone test.
Similar content being viewed by others
References
Liddle G.W., Island D., Lance E.M., Harris A.P. Alterations of adrenal steroid patterns in man resulting from treatment with a chemical inhibitor of 11-β-hydroxylation. J. Clin. Endocrinol. Metab. 18: 906, 1958.
Liddle G.W., Estep H.L., Kendall J.W., Williams W.C., Townes A.W. Clinical application of a new test of pituitary reserve. J. Clin. Endocrinol. Metab. 19: 875, 1959.
Child D.F., Burke C.W., Burley D.M., Rees L.H., Fraser T.R. Drug control of Cushing’s syndrome. Combined aminoglutethimide and metyrapone therapy. Acta Endocrinol. (Kbh.) 82: 330, 1976.
Jeffcoate W.J., Rees L.H., Tomlin S., Jones A.E., Edwards C.R., Besser G.M. Metyrapone in long-term management of Cushing’s disease. Brit. Med. J. 2: 215, 1977.
Doe R.P., Gold E.M. The metyrapone test of pituitary function. Postgrad. Med. 46: 157, 1969.
Carballeira A., Fishman L.M., Jacobi J.D. Dual sites of inhibition by metyrapone of human adrenal steroidogenesis: correlation of in vivo and in vitro studies. J. Clin. Endocrinol. Metab. 42: 687, 1976.
Carballeira A., Cheng S.C., Fishman L.M. Site of metyrapone inhibition of steroid biosynthesis by rat adrenal mitochondria. Acta Endocrinol. (Kbh.) 76: 703, 1974.
Cheng S.C., Harding B.W., Carballeira A. Effect of metyrapone on pregnenolone biosynthesis and on cholesterol cytochrome P-450 interaction in the adrenal. Endocrinology 94: 1451, 1974.
Erickson R.E., Ertel R.J., Ungar F. Effect of SU-4885 on steroid 18-hydroxylation in the mouse adrenal in vitro. Endocrinology 78: 343, 1966.
Kraulis I., Birmingham M.K. Inhibition of the biosynthesis of 18-hydroxy-11-deoxycorticosterone by SU-4885. Can. J. Biochem. 43: 1471, 1965.
De Nicola A.F., Dahl V. Acute effects of SU-4885 and its reduced derivative (SU-5236) on the adrenocortical secretion in the rat. Endocrinology 89: 1236, 1971.
Traikov H., De Nicola A.F., Birmingham M.K. Effects of 2 methyl-1, 2-bis, (3’-pyridyl)-1-propanol (reduced metopirone) on the formation of 18-hydroxylated steroids by quartered rat adrenals. Steroids 13: 457, 1969.
Schneider P.B. Falsely abnormal responses of normal subjects to the metopirone (SU-4885) test for pituitary ACTH reserve. J. Clin. Endocrinol. Metab. 24: 218, 1964.
Schöneshöfer M. Simultaneous determination of eight adrenal steroids in human serum by radioimmunoassay. J. Steroid Biochem. 8: 995, 1977.
Voigt K.H., Fehm H.L., Pfeiffer E.F. Radioimmunoassay of adrenocorticotropic hormone (ACTH) in plasma. In: Breuer H., Hamel D., Kruskemper H.L. (Eds.), Methods of hormone analysis. Thieme-Verlag, Stuttgart, 1976, p. 12.
Schöneshöfer M. Computer program for evaluation, physico-chemical characterization and optimization of competitive protein binding assays: comparison of four curve-fitting models in peptide and steroid radioimmunoassays. Clin. Chim. Acta 77: 101, 1977.
Hildebrandt A.G. The binding of metyrapone to cytochrome P-450 and its inhibitory action on microsomal hepatic mixed function oxidation reactions. Biochem. Soc. Symp. 34: 79, 1972.
Simon S., Kahl G.G., Netter K.J. Beeinflussung von Redoxstatus und Sauerstoffverbrauch isoliert perfundierter Rattenlebern durch Metyrapon. Naunyn Schmiedebergs Arch. Pharmacol. 226: 454, 1970.
Bruno O.D., Leclerq R., Virasoro E., Copinschi G. Extraadrenal actions of metyrapone in man: Effects on plasma cortisol disappearance, growth hormone secretion and glucose metabolism. J. Clin. Endocrinol. Metab. 32: 260, 1971.
Takahara J., Ogawa N., Ofuji T. Etraadrenal action of metyrapone upon human growth hormone secretion in man. Endocrinol. Jpn. 19: 197, 1972.
Levin J., Zumoff P., Fukushima D.K. Extraadrenal effects of metyrapone in man. J. Clin. Endocrinol. Metab. 47: 845, 1978.
Blichert-Toft M., Folke K., Nielsen M.L. Effect of metyrapone and corticotrophin infusion on cortisol disappearance rate in man. J. Clin. Endocrinol. Metab. 35: 59, 1972.
Hellmann, L., Nakada F., Curti J., Weitzman E.D., Kream J., Roffwarg H., Ellman S., Fukushima D.K., Gallagher T.F. Cortisol is secreted episodically by normal man. J. Clin. Endocrinol. Metab. 30: 411, 1970.
Berson S.A., Yalow R.S. Radioimmunoassay of ACTH in plasma. J. Clin. Invest. 47: 2725, 1968.
Voigt K.H., Fehm H.L., Reck R., Pfeiffer E.F. Spontaneous and stimulated secretion of QUSO-extractable immunoassayable ACTH in man. Klin. Wochenschr. 52: 516, 1974.
Schöneshöfer M., L’age M. Oelkers W. Short time kinetics of deoxycorticosterone, deoxycortisol, corticosterone and cortisol during single dose metyrapone test. Acta Endocrinol. (Kbh.) 85: 109, 1977.
Sawano S., Saito T., Shizume K., Takebe K. Simultaneous determinations of plasma ACTH and GH levels after an oral metyrapone dose. Endocrinol. Jpn. 19: 477, 1972.
Meikle A.W., West S.C., Weed J.A., Tyler F.H. Single-dose metyrapone test. 11-β-hydroxylase inhibition by metyrapone and reduced metyrapone assayed by radioimmunoassay. Nature 253: 290, 1975.
Williamson D.G., O’Donnel V.J. Mechanism of metopirone inhibition of a soluble adrenal steroid 11-beta-hydroxylase. Can. J. Biochem. 45: 153, 1967.
Williamson D.G., O’Donnel V.J. The interaction of metopirone with adrenal mitochondrial cytochrome P-450. A mechanism for the inhibition of adrenal steroid 11-beta-hydroxylation. Biochemistry 8: 1306, 1969.
Dale S.L., Komanicky P., Pratt J.H., Melby J.C. Radioimmunoassay of 18-hydroxy-11-deoxycorticosterone in plasma. J. Endocrinol. Metab. 43: 803, 1976.
Björkhem I., Karlmar K.E. Common characteristics of the cytochrome P-450 system involved in 18- and 11-β-hydroxylation of deoxycorticosterone in rat adrenals. J. Lipid. Res. 18: 592, 1977.
Watanuki M., Riley B.E., Hall P.F. Cytochrome P-450 for 11-β- and 18-hydroxylase activities of bovine adrenocortical mitochondria: one enzyme or two? Biochemistry 17: 127, 1978.
Jenkins J.S., Meakin J.W., Nelson D.H. A comparison of the inhibitory effects of 2-methyl-1,2-bis (3-pyridyl)-1 -propanone and amphenone B on adrenal cortical secretion in the dog. Endocrinology 64: 572, 1959.
Meikle A.W., Jubiz W., Hutchings M.P., West C.D., Tyler F.H. A simplified metyrapone test with determination of plasma 11-deoxycortisol (metyrapone test with plasma S). J. Clin. Endocrinol. Metab. 29: 985, 1969.
Leisti S. Evaluation of 3 hour metyrapone test in children and adolescents. Clin. Endocrinol. (Oxf). 6: 305, 1977.
Author information
Authors and Affiliations
Additional information
The paper includes parts of the thesis of B. Schefzig and was in part presented to the 23rd Symposium of the Deutsche Gesellschaft für Endokrinologie, Ulm 1978, the abstracts of which are published in Acta Endocrinologica (Kopenhagen), (Suppl.) 215, 1978.
Rights and permissions
About this article
Cite this article
Schöneshöfer, M., Schefzig, B. & Arabin, S. Short-term kinetics of serum adrenal steroids and plasma ACTH after a single dose of metyrapone in man. J Endocrinol Invest 3, 229–236 (1980). https://doi.org/10.1007/BF03348268
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/BF03348268