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Role of Local 11ß-Hydroxysteroid Dehydrogenase Type 2 Expression in Determining the Phenotype of Adrenal Adenomas

Third Department of Internal Medicine (T.M., Y.I., T.T., H.D., K.Y.), Department of General Medicine (H.M.), and Department of Urology (Y.T., T.D.), Gifu University School of Medicine, Gifu 500-8705, Japan; Matsunami General Hospital (N.Y.), Gifu 501-6062, Japan; Department of Pathology, Tohoku University School of Medicine (T.S., H.S.), Sendai 980-8575, Japan; and Division of Pediatric Endocrinology, University of Texas Southwestern Medical Center (P.C.W.), Dallas, Texas 75235-9063

Address all correspondence and requests for reprints to: Dr. Tomoatsu Mune, Third Department of Internal Medicine, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu 500-8705, Japan. E-mail: mune{at}cc.gifu-u.ac.jp.

It is not understood why some adrenal adenomas are nonfunctional and others with similar histopathology cause preclinical or overt Cushing’s syndrome. Two isozymes of 11ß-hydroxysteroid dehydrogenase, types 1 and 2 (HSD11B1 and HSD11B2), are known to modulate glucocorticoid levels in other tissues and might influence circulating levels of active and inactive glucocorticoids if they were expressed in adrenal adenomas. We determined levels of expression of these isozymes in normal adrenals and 61 adrenal adenomas by quantitative competitive RT-PCR and immunohistochemistry. There were no differences in HSD11B1 mRNA levels among adrenal tumor groups. HSD11B2 mRNA levels were high in nonfunctioning adenomas and preclinical Cushing’s adenomas compared with levels in control adrenals or in adenomas causing overt Cushing’s syndrome. HSD11B2 immunoreactivity was not detected in control adrenals, but was observed in more than half of these tumors. When nonfunctioning adenomas and those causing preclinical and overt Cushing’s syndrome were considered as a single group, HSD11B2 mRNA levels were strongly correlated with the ratio of plasma cortisone to cortisol, and a simple model incorporating adrenal HSD11B2 expression and tumor size as variables could predict more than 50% of the interindividual variation in plasma cortisol levels (r² = 0.54; P < 0.0001).

Adrenal HSD11B2 may regulate levels of active and inactive glucocorticoids in the systemic circulation under these conditions, presumably by acting in an autocrine or paracrine manner. Nonfunctioning adenomas and those causing preclinical and overt Cushing’s syndrome may represent a continuum with clinical manifestations depending mainly on tumor size and HSD11B2 expression levels.

This work was supported by grants for Disorders of the Adrenal Gland (1996–1998, 1999–2001) from the Ministry of Health, Labor, and Welfare, Japan, and by NIH Grant DK-42169 (to P.C.W.). There was a preliminary presentation of this work at the 81st Annual Meeting of The Endocrine Society, San Diego, California, June 14, 1999.

Abbreviations: E, Cortisone; F, cortisol; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HSD11B1, 11ß-hydroxysteroid dehydrogenase type 1; pE/F, ratio of plasma E to F.

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