Glucose-dependent insulinotropic peptide receptor overexpression in adrenocortical hyperplasia in MEN1 syndrome without loss of heterozygosity at the 11q13 locus

BACKGROUND: The molecular mechanisms involved in the genesis of the adrenocortical lesions seen in MEN1 syndrome (ACL-MEN1) remain poorly understood; loss of heterozygosity at 11q13 and somatic mutations of MEN1 are not usually found in these lesions. Thus, additional genes must be involved in MEN1 adrenocortical disorders. Overexpression of the glucose-dependent insulinotropic peptide receptor has been shown to promote adrenocortical tumorigenesis in a mice model and has also been associated with ACTH-independent Cushing syndrome in humans. However, to our knowledge, the status of glucose-dependent insulinotropic peptide receptor expression in adrenocortical lesions in MEN1 has not been previously investigated. OBJECTIVE: To evaluate glucose-dependent insulinotropic peptide receptor expression in adrenocortical hyperplasia associated with MEN1 syndrome. MATERIALS/METHODS: Three adrenocortical tissue samples were obtained from patients with previously known MEN1 germline mutations and in whom the presence of a second molecular event (a new MEN1 somatic mutation or an 11q13 loss of heterozygosity) had been excluded. The expression of the glucose-dependent insulinotropic peptide receptor was quantified by qPCR using the DDCT method, and b-actin was used as an endogenous control. RESULTS: The median of glucose-dependent insulinotropic peptide receptor expression in the adrenocortical lesions associated with MEN1 syndrome was 2.6-fold (range 1.2 to 4.8) higher than the normal adrenal controls (p = 0.02). CONCLUSION: The current study represents the first investigation of glucose-dependent insulinotropic peptide receptor expression in adrenocortical lesions without 11q13 loss of heterozygosity in MEN1 syndrome patients. Although we studied a limited number of cases of MEN1 adrenocortical lesions retrospectively, our preliminary data suggest an involvement of glucose-dependent insulinotropic peptide receptor overexpression in the etiology of adrenocortical hyperplasia. New prospective studies will be able to clarify the exact role of the glucose-dependent insulinotropic peptide receptor in the molecular pathogenesis of MEN1 adrenocortical lesions.

A study on clinical features of ACTH-independent bilateral macronodular adrenal hyperplasia / 中华内分泌代谢杂志

Objective To study the clinical features of patients with ACTH-independent bilateral macronodular adrenal hyperplasia(AIMAH).Methods Eighteen cases with AIMAH diagnosed in Chinese PLA General Hospital from 1998 to 2010 were analyzed retrospectively.Results ( 1 ) AIMAH was equally distributed between genders,mean age at diagnosis was ( 51.4 ± 10.7 ) years,and average course was ( 9.9:t:2.7 ) years.( 2 )Most patients visited hospital because of adrenal incidentaloma; hypertension and impaired glucose tolerance/diabetes mellitius were the most common clinical presentations; typical signs of Cushing′s syndrome (CS) such as moon face and central obesity were less frequent.( 3 ) All cases′ laboratory findings met the diagnostic criteria of ACTH-independent CS,some cases with the features of subclinical CS.24 h dynamic plasma ACTH and cortisol monitoring had the advantage of revealing the features of subclinical CS for some AIMAH cases; there was remarkable elevation of plasma cortisol after exogenous ACTH stimulation in AIMAH patients.(4) Bilateral adrenal macronodular changes could be visualized on CT scan.( 5 ) Pathology identified bilateral macronodular adrenal hyperplasia.( 6 ) Bilateral adrenalectomy was the most useful treatment.Conclusions AIMAH is an infrequent cause of CS,and some patients present subclinical CS.Its marked clinical feature is ACTH-independent bilateral macronodular adrenal hyperplasia.

Diagnosis and surgical management of adrenocortical hyperplasia disease (report of 180 cases) / 中华泌尿外科杂志

Objective To review the diagnosis and surgical therapeutic methods of adrenocorti-cal hyperplasia disease. Methods One hundred and eighty adrenocortical hyperplasia patients (74 males and 106 females with a mean age of 40 years) were retrospectively analyzed. The patients were divided into hypereortisolism (n=152) and aldosteronism (n=28) according to secretion. Data of clinical characteristic, endocrine and image examination were collected. All patients were treated by operation. Results Of these patients, 107 had Cushing disease (CD), 28 had adrenocorticotropin independent macronodular adrenal hyperplasia (AIMAH), 19 had ectopic adrenocorticotropin adrenal hyperplasia (EAAH), 4 had primary pigmented nodular adrenocortical hyperplasia (PPNAH), 28 had DOI: 10.3760/cma.j.issn. 1000-6702.2009.05.002idiopathic hyperaldosteronism (IHA). 24 h urinay free cortisol (24hUFC) excretion of CD, AIMAH, EAAH and PPNAH were 95.2-535.7 μg (mean, 287.6 μg), 24.8-808.2 μg (mean, 307.9 μg), 102.5-3127.0 μg (mean, 852.5 μg), 243.8-1124.6 μg (mean. 564.3 μg). The proportion loss of the serum cortisol circadian rhythm were 99% (102/103), 92% (11/12), 100% (17/17), 100% (4/ 4), respectively. Low- and high-dose dexamethasone suppression tests (DDST) failed to suppress cor-tisol secretion in AIMAH, PPNAH and EAAH groups, but HDDST was suppressed in CD group. Of the 28 IHA cases, 17 had hypokalemia and 15 had high urine kalium (>30 mmol/24 h). The results of plasma renin activity and serum aldosterone accorded with the diagnosis. Unilateral adrenalectomy were operated in 102 hypercortisolism cases, and 24hUFC of CD, AIMAH, EAAH and PPNAH were 56.2-233.5 μg (mean, 157.4 μg), 22.5-418.5 μg (mean, 117.9 μg), 116.5-1137.0 μg (mean, 756.7 μg), 124.6-422.6 μg (mean, 164.3 μg) 1 week after operation. The blood pressure was nor-mal in 8 paitents and droped in 13 patients for IHA after unilateral adrenalectomy. 24hUFC were nor-mal in 55 patients after bilateral adrenalectomy for hypercortisolism. One hundred and six patients were followed up for 4-158 months, the Cushing syndrome ameliorated and blood pressure dropped. Conclusions Unilateral adrenalectomy is the first choice for adrenocortical hyperplasia disease which needs operation. The operation mode of the contralateral adrenal gland is based on the hyperplasia types and clinical observation.

Primary pigmented nodular adrenocortical disease and Cushing's syndrome

Primary pigmented nodular adrenocortical disease (PPNAD) is a form of bilateral adrenocortical hyperplasia that is often associated with corticotrophin (ACTH)-independent Cushing's syndrome (CS) and is characterized by small to normal-sized adrenal glands containing multiple small cortical pigmented nodules (1,2). PPNAD may occur in an isolated form or associated with a multiple neoplasia syndrome, the complex of spotty skin pigmentation, myxomas, and endocrine overactivity, or Carney complex, in which Cushing's syndrome is the most common endocrine manifestation (3). Molecular studies have led to the identification of several genes, defects in which may predispose PPNAD formation; all of these molecules play important role for the cAMP signaling pathway. This review intends to present the most recent knowledge of the pathology and molecular genetics of the benign bilateral adrenocortical lesions, as well as to discuss the modern tools for diagnostics and treatment of this condition.

A doença adrenocortical nodular pigmentada primária (PPNAD) é uma forma de hiperplasia adrenocortical bilateral que está freqüentemente associada com a síndrome de Cushing (SC) ACTH-independente, sendo caracterizada por glândulas adrenais de tamanho pequeno ou normal contendo múltiplos nódulos corticais pigmentados pequenos. PPNAD pode ocorrer de forma isolada ou associada com uma síndrome de neoplasia múltipla, o complexo de manchas pigmentadas na pele (lentigíneas), mixomas e hiperatividade endócrina, ou complexo de Carney, no qual a SC é a manifestação endócrina mais comum. Estudos moleculares levaram à identificação de vários genes que, quando mutados, podem predispor à formação da PPNAD; todas essas moléculas têm um papel importante na via de sinalização do AMPc. Esta revisão pretende apresentar os conhecimentos mais recentes sobre a patologia e a genética molecular das lesões adrenocorticais benignas bilaterais e discutir os modernos instrumentos para diagnóstico e tratamento dessa condição.

A Case of Bilateral Macronodular Adrenocortical Hyperplasia Accompanied by Hyperresponsiveness to Vasopressin / 대한내분비학회지

Cushing's syndrome associated with nodular adrenal hyperplasia glands is divided into 4 main categories: adrenal adenoma, adrenal carcinoma, primary pigmented nodular adrenal dysplasia and macronodular adrenal hyperplasia(MAH). The mechanism of bilateral MAH, when ACTH is suppressed, was previously unknown, and referred to as being "autonomous". Recently, several reports have shown MAH to be under the control of ectopic or eutopic membrane hormone. Here, a case of Cushing's syndrome, caused by bilateral MAH, is reported. A 62-year-old woman presented with Cushingoid features, hypertension and diabetes mellitus. In her case, abnormal adrenal stimulation of cortisol secretion in response to exogenous vasopression stimulation was shown. Her urine free cortisol was 726.0microgram/dL, which was not suppressed after administration of high-dose dexamethasone. Her plasma cortisol level was elevated, but without circadian rhythm. ACTH was undetectable. An abdomen CT scan demonstrated bilaterally enlarged multinodular adrenal glands. A Sella MRI revealed no alteration of the pituitary gland. The patient underwent a laparoscopic bilateral adrenalectomy. Histological examination revealed bilateral macronodular hyperplasia. After having recovered, the patient showed progressive regression of the Cushingoid status.

Relationship between ACTH expression in adrenal cortical tissue and plasma ACTH level in patients with adrenal cortical hyperplasia / 中华内分泌代谢杂志

Objective To investigate the expression of ACTH in normal and hyperplastic adrenal cortical tissue, and to explore the relationship between plasma ACTH concentration and expression level of ACTH in adrenal cortical tissue of patients with adrenal cortical hyperplasia. Methods The expression of ACTH in adrenal cortical tissue was examined by immunohistochemical technique, and the result was analyzed by computer-assisted image analyzing system. Besides, plasma ACTH concentration was measured by RIA. The correlation between plasma ACTH concentration and expression level of ACTH in adrenal cortical tissue of patients with adrenal cortical hyperplasia was studied. Results The expression of ACTH was significantly higher in adrenal cortical tissue of patients with ACTH-independent adrenal cortical hyperplasia than those with ACTH-dependent adrenal cortical hyperplasia and normal adrenocortical tissue (both P0.05). Conclusion ACTH expression exists in normal adrenal cortical tissue. Local ACTH overproduction appears to participate in the pathogenesis of ACTH-independent adrenal cortical hyperplasia.The raised concentration of plasma ACTH influences the expression of ACTH in cortical tissue of patients with ACTH-dependent adrenal hyperplasia.

A Case of Bilateral Macronodular Adrenocortical Hyperplasia / 대한내분비학회지

Cushing's syndrome associated with nodular adrenal glands will be divided into four main categories: adrenal adenoma, adrenal carcinoma, primary pigmented nodular adrenal dysplasia (PPNAD) and macronodular adrenal hyperplasia(MAH). The term macronodular adrenal hyperplasia is restricted to the presence of multiple nodules visible to the naked eye, ranging in size from 0.5 to 7.0 cm. We report a case of Cushings syndrome caused by bilateral macronodular adrenal hyperplasia (MAH). A 45-year-old man presented with Cushingoid features, hypertension and diabetes mellitus. Urine free cortisol was 449.9 mmol/day(27-276) and were not suppressed after administration of low-dose and high-dose dexamethasone. Plasma ACTH was very low(1.87 pmol/L(18)) and was not stimulated by administration of ovine CRH. In abdominal CT, both adrenal glands were markedly enlarged and nodular in appearance. Pituitary MRI showed no abnormal finding. Bilateral adrenalectomy was done. Histologic examination revealed multiple nodules and internodular hyperplasia. This case and other reports suggested that because of variable biochemical, radiologic and pathologic findings, macronodular adrenal hyperplasia represents a heterogeneous group of patients with varying degrees of adrenal autonomy.