Thursday, May 6, 2010

Adrenocortical Zonation in Humans under Normal and Pathological Conditions

Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2009-2010
The Journal of Clinical Endocrinology & Metabolism Vol. 95, No. 5 2296-2305
Copyright © 2010 by The Endocrine Society

Koshiro Nishimoto, Ken Nakagawa, Dan Li, Takeo Kosaka, Mototsugu Oya, Shuji Mikami, Hirotaka Shibata, Hiroshi Itoh, Fumiko Mitani, Takeshi Yamazaki, Tadashi Ogishima, Makoto Suematsu and Kuniaki Mukai

Departments of Urology (K.Ni., K.Na., T.K., M.O.), Biochemistry and Integrative Medical Biology (D.L., F.M., M.S., K.M.), and Internal Medicine (H.S., H.I.), School of Medicine, Keio University, and Division of Diagnostic Pathology (S.M.), Keio University Hospital, Tokyo 160-8582, Japan; Laboratory of Molecular Brain Science (T.Y.), Graduate School of Integrated Arts and Sciences, Hiroshima University, Higashi-Hiroshima 739-8521, Japan; Department of Chemistry (T.O.), Faculty of Sciences, Kyushu University, Fukuoka 812-8581, Japan; and Department of Urology (K.Ni.), Federation of National Public Service Personnel Mutual Aid Associations, Tachikawa Hospital, Tokyo 190-8531, Japan

Address all correspondence and requests for reprints to: Kuniaki Mukai, Department of Biochemistry and Integrative Medical Biology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail,

Context: Aldosterone synthase (CYP11B2) and steroid 11β-hydroxylase (CYP11B1) catalyze the terminal steps for aldosterone and cortisol syntheses, respectively, thereby determining the functional differentiation of human adrenocortical cells. Little is known, however, about how the cells expressing the enzymes are actually distributed in the adrenals under normal and pathological conditions.

Objective: The objective of the study was to determine the localization of CYP11B2 and -B1 in human adrenal specimens by using developed antibodies capable of distinguishing the two enzymes from each other.

Results: Under normal conditions, CYP11B2 was sporadically detected in the zona glomerulosa, whereas CYP11B1 was entirely detected in the zonae fasciculata-reticularis. Adrenocortical cells lacking both enzymes were observed in the outer cortical regions. In addition to conventional zonation, we found a variegated zonation consisting of a subcapsular cell cluster expressing CYP11B2, which we termed aldosterone-producing cell cluster, and a CYP11B1-expressing area. Aldosterone-producing adenomas differed in cell populations expressing CYP11B2 from one another, whereas CYP11B1-expressing and double-negative cells were also intermingled. Adenomas from patients with Cushing’s syndrome expressed CYP11B1 entirely but not CYP11B2, resulting in atrophic nontumor glands. The nontumor portions of both types of adenomas bore frequently one or more aldosterone-producing cell clusters, which sustained CYP11B2 expression markedly under the conditions of the suppressed renin-angiotensin system.

Conclusion: Immunohistochemistry of the human normal adrenal cortex for CYP11B2 and CYP11B1 revealed a variegated zonation with cell clusters constitutively expressing CYP11B2. This technique may provide a pathological confirmatory diagnosis of adrenocortical adenomas.



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