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Unilateral adrenal hyperplasia with primary aldosteronism is very rare and shows similar endocrine features to aldosterone-producing adenoma and bilateral adrenal hyperplasia. In this study, the mRNA expression of steroidogenic enzymes in unilateral adrenal hyperplasia was examined by in situ hybridization. We found subcapsular micronodules composed of spironolactone body-containing cells, which showed intense expression for 3beta-hydroxysteroid dehydrogenase, 11beta-hydroxylase, 18-hydroxylase, and 21-hydroxylase but not 17alpha-hydroxylase, indicating aldosterone production. This expression pattern was the same as that in unilateral multiple adrenocortical micronodules, reported recently. Additionally, it was noted that a nodule with active aldosterone production was closely adjacent to one showing intense 17alpha-hydroxylase expression. In the adrenal cortices adhering to aldosterone-producing adenoma, the majority of hyperplastic zona glomerulosa and hyperplastic nodules demonstrated a decreased steroidogenic activity. However, minute nodules indicative of active aldosterone production were found at high frequency. These results suggest that the subcapsular micronodules observed might be the root of aldosterone-producing adenoma. Furthermore, we emphasize the need for long-term follow-up after unilateral adrenalectomy or enucleation of the adenoma because of the possibility that buds with autonomous aldosterone production may still be present in the contralateral or remaining adrenal tissue.

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We present a case of unilateral adrenal medullary hyperplasia in a 63-year-old woman with clinical signs and symptoms of pheochromocytoma unassociated with multiple endocrine neoplasia. The surgically removed adrenal gland revealed diffuse medullary hyperplasia with multiple micronodules measuring up to 2 mm. The micronodules were composed of enlarged chromaffin cells with atypia, histologically similar t o those of pheochromocytoma, forming small solid alveolar patterns separated by a fibrovascular stroma. Removal of the hyperplastic adrenal gland resulted in disappearance of paroxysmal nocturnal hypertension and palpitation. These results suggest that diffuse and nodular medullary hyperplasia is the precursor of pheochromocytoma. Acta Pathol Jpn 40 : 683-686,1990.A-63-year-old woman presented with a 3-year history of paroxysmal nocturnal hypertension and palpitation. Because she was a nurse, she had examined her own blood pressure during the nocturnal attack, and found it had risen to 200 mmHg. She had no positive family history of MEN. Ultrasonography and computed tomography (CT) revealed no morphological abnormalities of the thyroids and parathyroids, except for a small adenomatous goiter. The normal blood values of calcium (4.6 mEq/l), calcitonin (80 pg/ml) and carcinoembryogenic antigen (CEA) (3.3 ng/ml) also ruled out the possibility of MEN.Laboratory data under asymptomatic conditions were as follows: slight elevation of plasma norepinephrine

C a 2+ is a critical signal for adrenal and gonadal steroid synthesis 1 acting within 2 cellular compartments; Ca 2+ is generated in the cytosol 2,3 and transferred to the mitochondria 4-7 where it activates matrix dehydrogenases to generate reducing equivalents (NAD(P)H) that are essential cofactors for steroid hydroxylation. 8 In aldosterone-producing zona glomerulosa (ZG) cells of the adrenal cortex, the dominant pathway for extra-cellular Ca 2+ entry into the cytoplasmic compartment is plasma membrane voltage-gated Ca 2+ channels, 9 whereas the principal pathway for mitochondrial Ca 2+ uptake is via the mitochon-drial uniporter, a Ca 2+-selective channel. 10 Membrane voltage across each of these compartments regulates Ca 2+ transport and thus the rate of steroid production. Because other ion channels resident in each membrane (plasma and mitochondrial) can change membrane voltage, they too are capable of altering Ca 2+ uptake by mitochondria. 11 Accordingly, it is not surprising that genetic variation in genes encoding ion channels and transporters is now considered central to the pathophysiology of 1 common subtype of primary hyperaldosteronism, unilateral aldosterone-producing adenoma. 12 In aldosterone-producing adenoma, aldosterone synthesis is not strictly controlled by the renin-angiotensin II system and thus is characterized by a large increase in the aldosterone/renin ratio. 13 Yet, the cause of other common endocrine hypertensive disorders in which aldosterone production is inappropriate for the level of renin, such as bilateral adrenal hyperplasia and low renin essential hypertension, 14,15 still remains poorly understood. Our laboratory and that of Barhanin et al have generated mouse models of aldosterone overproduction evoked by deletion of leak potassium channels that generate background currents to establish a negative resting cell membrane voltage. 16-20 The combined deletion of TASK-1 and TASK-3 channels (tandem pore domain acid-sensitive K + channels) leads to excessive aldosterone overproduction and low renin in mice. By contrast, deletion of TASK-3 alone evokes mild hyperal-dosteronism and low renin, 19 whereas that of TASK-1 elicits mild hyperaldosteronism without an accompanying suppression of renin. 21 Genetic variations in the human TASK-1 gene (KCNK3) 21-23 are associated with measures of hypertension (rs1275988, rs13394970) and elevated plasma aldosterone (rs2586886), and KCNK3 mRNA is abundantly expressed in mouse and human adrenal cortex. 24 By contrast, the KCNK9 gene product, TASK-3, is principally expressed in the rodent adrenal cortex, 25 although low levels of message are detected in the human adrenal cortex. 26 The function of TASK-3 in adrenal cortical cells remains unknown. We previously reported that global deletion of TASK-3 in mice produces a mild hyperaldosteronism even though the cell Abstract-Ca 2+ drives aldosterone synthesis in the cytosolic and mitochondrial compartments of the adrenal zona glomerulosa cell. Membrane potential across each of these compartments regu...

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Design and methods:We have recently demonstrated that the adrenal cortices attached to aldosteroneproducing adenoma (APA) contained microscopic subcapsular micronodules suggestive of active aldosterone production. In this study, we used in situ hybridization to investigate the mRNA expression of steroidogenic enzymes in the adrenal cortices attached to cortisol-producing adenoma (CPA) and clinically silent adenoma (non-functioning adenoma; NFA), in addition to APA. Results: Microscopic subcapsular micronodules, which were several hundreds of micrometers in size and spheroid in shape, were observed in the cortices attached to CPA and NFA, as well as APA, at high frequency. Most of the cortical nodules in zona fasciculata to zona reticularis showed a suppressed steroidogenesis in the cortices attached to adenoma, but some expressed intensely all necessary steroidogenic enzyme mRNAs for cortisol synthesis. Conclusions: It is thus necessary to keep in mind, on the occasion of subtotal adrenalectomy, that lesions with the potential to later develop into functional adrenocortical nodules may be present in other parts of the ipsilateral or contralateral adrenal cortices.European Journal of Endocrinology 158 867-878

In addition to the morphological examination, the measurement of the content of corticosteroids was done in aldosterone-producing adenoma. Histologically, the adenoma consists of four types of cells. The major component of the adenoma was clear-type cells. In this type of cells, the activities of 38hydroxysteroid dehydrogenase and glucose-6-phosphate dehydrogenaee showed weakly positive. The Ane structure was characterized by numerous lipid vacuoles and poor organellae. On the contrary, intermediate-and compact-type cells revealed higher than moderate activities of these enzymes. Moreover, marked development of smooth endoplasmic reticulum and mitochondria was noted. Zona glomerulosa-type cells were observed only in a small part. The content of aldosterone and corticosterone in aldosterone-producing adenoma was signiflcantly larger than those of the other type of adenoma. A tendency of positive correlation between the increase of compact-type cells and content of aldosterone was found. The cell origin of this aldosterone-producing adenoma and functional role of clear-and compact-type cells were also discussed. ACTA PATHOL. JPN. 30: 961-976, 1980. IntraEuctionAldosterone-producing tumors have been shown to have considerable macroscopic and histological characteristics. Such reports, however, were either limited to histological observations alonelo or a t the level of case reports including electron microscopic o b~e r v a t i o n s~~,~~.In the present study, the morphology of aldosterone-producing tumor was studied by histological, enzyme histochemical and electron microscopic methods. At the same time, further analysis was attempted from the viewpoint of functional pathology utilizing quantitative procedure of corticosteroid hormones in the tumor. -~ ___--*:Crr %9& W e BLP, E[B1 S& #ah, I%% FIT All communication and reprint requests to: Prof. Hideo TSUCHIYAMA,