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Norio Wada, Mitsumasa Kubo, Hiromichi Kijima, Tatsuya Ishizuka, Tomoko Saeki, Takao Koike, and Hironobu Sasano

Wada N, Kubo M, Kijima H, Ishizuka T, Saeki T, Koike T, Sasano H. Adrenocorticotropin-independent bilateral macronodular adrenocortical hyperplasia: immunohistochemical studies of steroidogenic enzymes and post-operative course in two men. Eur J Endocrinol 1996;134:583–7. ISSN 0804–4643

We treated two men with Cushing's syndrome due to adrenocorticotropin (ACTH)-independent bilateral macronodular adrenocortical hyperplasia (AIMAH). In both patients, plasma ACTH was low and plasma cortisol was not suppressed by a high dose of dexamethasone (8 mg) but was remarkably responsive to exogenous ACTH. The adrenal glands were extremely enlarged and contained multiple nodules composed of large clear cells and small compact cells. The immunore-activity of P-45017α was predominant in the small compact cells, while that of 3β-hydroxysteroid dehydrogenase (3 β-HSD) was observed exclusively in the large clear cells. Among various adrenocortical disorders, differential expression of 3β-HSD and P-45017α in clear and compact cells has heretofore been demonstrated only in AIMAH. Total adrenalectomy was done for one patient, and partial adrenalectomy for the other. In the former patient, the normal diurnal rhythm of plasma ACTH was restored 11 months postoperatively. In the latter patient, the normal dynamics in the hypothalamic-pituitary-adrenal axis became evident 15 months after surgery. Thus AIMAH is apparently a primary adrenocortical disorder and is not due to abnormalities of the hypothalamus or pituitary.

Mitsumasa Kubo, Department of Medicine II, Hokkaido University School of Medicine, Kita-15, Nishi-7, Kita-Ku, Sapporo 060, Japan

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Tao Wang, Fumitoshi Satoh, Ryo Morimoto, Yasuhiro Nakamura, Hironobu Sasano, Richard J Auchus, Michael A Edwards, and William E Rainey


Primary aldosteronism (PA) is the most common form of endocrine hypertension affecting ∼8–10% of hypertensive subjects. Aldosterone production in PA occurs under low-renin conditions, and the mechanisms that maintain the production of aldosterone in PA remain unknown.


This study was designed to compare the transcript profiles between aldosterone-producing adenoma (APA) and their adjacent adrenal gland (AAG) from the same adrenal.


Total RNA was extracted from ten APA and ten AAG; and subsequently analyzed by microarray and real-time quantitative RT-PCR (qPCR). The microarray data were paired for each APA–AAG, and analyzed by GeneSpring GX 11 with paired t-test and fold change calculations for each transcript. Changes identified by microarray analysis were confirmed by qPCR.


Microarray analysis indicated that 14 genes had significantly up-regulated expression in APA compared to AAG. Among the elevated genes were aldosterone synthase (CYP11B2) as well as novel transcription factors, calmodulin-binding proteins, and other genes that have not been previously studied in APA. Selective analysis of 11 steroidogenic enzymes using microarray demonstrated that only CYP11B2 showed a significantly higher transcript level in APA compared to AAG (P<0.001). In contrast, AKR1C3 (17β-hydroxysteroid dehydrogenase type 5), CYP17 (17α-hydroxylase/17,20 lyase), and CYB5 (cytochrome b5) showed significantly lower transcript level in APA (P<0.05).


The transcriptome analysis of APA compared with AAG showed several novel genes that are associated with APA phenotype. This gene list provides new candidates for the elucidation of the molecular mechanisms leading to PA.

Free access

Fumitoshi Satoh, Ryo Morimoto, Kazumasa Seiji, Nozomi Satani, Hideki Ota, Yoshitsugu Iwakura, Yoshikiyo Ono, Masataka Kudo, Masahiro Nezu, Kei Omata, Yuta Tezuka, Yoshihide Kawasaki, Shigeto Ishidoya, Yoichi Arai, Kei Takase, Yasuhiro Nakamura, Keely McNamara, Hironobu Sasano, and Sadayoshi Ito

Objective and design

Adrenal venous sampling (AVS) is critical to determine the subtype of primary aldosteronism (PA). Central AVS (C-AVS) – that is, the collection of effluents from bilateral adrenal central veins (CV) – sometimes does not allow differentiation between bilateral aldosterone-producing adenomas (APA) and idiopathic hyperaldosteronism. To establish the best treatment course, we have developed segmental AVS (S-AVS); that is, we collect effluents from the tributaries of CV to determine the intra-adrenal sources of aldosterone overproduction. We then evaluated the clinical utility of this novel approach in the diagnosis and treatment of PA.


We performed C-AVS and/or S-AVS in 297 PA patients and assessed the accuracy of diagnosis based on the results of C-AVS (n=138, 46.5%) and S-AVS (n=159, 53.5%) by comparison with those of clinicopathological evaluation of resected specimens.


S-AVS demonstrated both elevated and attenuated secretion of aldosterone from APA and non-tumorous segments, respectively, in patients with bilateral APA and recurrent APA. These findings were completely confirmed by detailed histopathological examination after surgery. S-AVS, but not C-AVS, also served to identify APA located distal from the CV.


Compared to C-AVS, S-AVS served to identify APA in some patients, and its use should expand the pool of patients eligible for adrenal sparing surgery through the identification of unaffected segments, despite the fact that S-AVS requires more expertise and time. Especially, this new technique could enormously benefit patients with bilateral or recurrent APA because of the preservation of non-tumorous glandular tissue.

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Takuya Kitamura, Amy R Blinder, Kazutaka Nanba, Mika Tsuiki, Mutsuki Mishina, Hiroshi Okuno, Koki Moriyoshi, Yuto Yamazaki, Hironobu Sasano, Keisuke Yoneyama, Aaron M Udager, William E Rainey, Akihiro Yasoda, Noriko Satoh-Asahara, and Tetsuya Tagami

Although excess production of androgens and glucocorticoids has often been observed in adrenocortical carcinomas, adrenocortical adenoma with such hormonal activity is rare. Herein, we report a 41-year-old woman who presented with hyperandrogenemia and mild autonomous cortisol secretion with an undetectable level of adrenocorticotropic hormone. Imaging demonstrated a 6 cm left adrenal tumor. The histologic diagnosis of the resected adrenal tumor was adrenocortical adenoma. Pre- and post-operative serum samples were used for steroid profiling with liquid chromatography-tandem mass spectrometry (LC-MS/MS). LC-MS/MS analysis of pre-operative serum revealed an abnormal buildup of steroid precursors and androgens. Importantly, circulating levels of 11-oxygenated androgens, including 11β-hydroxytestosterone (11OHT) and 11-ketotestosterone (11KT), were highly elevated. Both androgen and glucocorticoid levels significantly decreased post-operatively. Immunohistochemical analysis of steroidogenic enzymes and cofactor protein supported the tumor’s ability to directly produce 11OHT and 11KT. This study is the first to describe and characterize an adrenocortical adenoma that co-secretes glucocorticoids and 11-oxygenated androgens.

Significance statement

Due to its rarity, biochemical and histologic characteristics of androgen and glucocorticoid co-secreting adrenocortical adenomas are largely unknown. Herein, we report a case of adrenocortical adenoma that caused marked hyperandrogenemia and mild autonomous cortisol secretion. In this study, we investigated serum steroid profiles using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and histologic characteristics of the resected tumor. LC-MS/MS revealed highly elevated levels of 11-oxygenated androgens which have not been well studied in adrenal tumors. The expression patterns of steroidogenic enzymes determined by immunohistochemistry supported the results of steroid profiling and suggested the capacity of the tumor cells to produce 11-oxygenated androgens. Measurement of 11-oxygenated steroids should facilitate a better understanding of androgen-producing adrenocortical neoplasms.