Non-functioning Adrenal Adenoma Research Articles

Retroperitoneoscopic partial adrenalectomy for small adrenal tumours (≤1 cm): the Ruijin clinical experience in 88 patients

Therapy (case series). 4. To present our experience of retroperitoneoscopic partial adrenalectomy (RPA) for small adrenal tumours, as with modern imaging methods small adrenal lesions are being diagnosed more commonly, and retroperitoneoscopic adrenal surgery for small adrenal tumours (< or =1 cm) can be challenging. We retrospectively reviewed the records of 389 consecutive retroperitoneoscopic adrenalectomies from September 2005 to December 2008, 88 of which were small adrenal tumours and treated by RPA. Ultrasonography and computed tomography (CT) were used in all patients before RPA, and magnetic resonance imaging or positron emission tomography/CT in some patients. We used RPA for adrenal tumours and total adrenalectomy for adrenal cancer. During the surgery, the internal part of the adrenal gland close to the retroperitoneum was freed first, and the whole adrenal tissue was dissected completely. The preoperative imaging was important in these procedures. There were no deaths; conversions to open surgery were necessary in four patients (4.5%), the reasons being a missing target in two, massive haemorrhage caused by central adrenal vein injury in one, and severe adhesion in one. The mean (range) size of the adrenal tumours was 0.7 (0.5-1.0) cm, including 69 aldosterone-producing adenomas, 11 nonfunctional adrenal adenomas, three Cushing syndrome, two phaeochromocytomas, two myelolipomas and one melanoma. The operative duration in the initial 38 cases was significantly longer than that in the subsequent 50 (P < 0.01). However, there was no significant correlation between estimated blood loss and the number of procedures. Tumour size did not correlate with estimated blood loss and operative duration. There was no significant correlation between body mass index and operative duration. RPA is a safe, effective and minimally invasive therapeutic option for patients with small adrenal tumours. With improved operative technique the RPA has been completed in more quickly. Freeing the internal part of the adrenal gland close to the retroperitoneum first, and exploring the whole adrenal tissue during surgery are the key points of RPA. The location of the small adrenal tumour can be different from that shown on imaging before surgery, and the abnormality of the adrenal gland should be considered.

Adrenal incidentaloma, clinical, metabolic, follow-up aspects: single centre experience

To investigate clinical characteristics, metabolic parameters and follow-up findings of subjects with incidentally discovered adrenal tumors. 376 consecutive subjects who have been evaluated since 2002 were included. Initial radiological examination was CT. Hormonal evaluation included 8.00 a.m. cortisol, DHEA-S, ACTH and in hypertensive subjects, plasma renin activity, and serum aldosterone. Urinary free cortisol (UFC), urinary normetanephrine, and metanephrine were measured. Overnight 1 mg dexamethasone suppression test was performed. Radiological evaluation was performed at 6th and 12th months and annually in subsequent visits. Hormonal evaluation was performed 6 months after the initial visit and annually in subsequent visits. Additionally, patients were evaluated for the development of Type 2 diabetes mellitus, hypertension, hyperlipidemia, and metabolic syndrome in 6-month intervals. Mean age of the participants was 54.7 ± 13.1. Female subjects were more commonly affected (70%). CT was the most frequent radiological intervention that discovered adrenal masses (57%). The vast majority of the participants (85.6%) had benign adrenal adenomas. Primary adrenocortical malignancy was detected in 4 subjects (1.1%). Subjects with adrenal adenomas had significantly smaller tumor diameters (P ≤ 0.001 vs. other tumors). Sensitivity and specificity of 40 mm as a cut-off value in the differentiation of adrenal gland malignancies from benign tumors was 73.3 and 54.8%, respectively. Most of the adrenal adenomas were non-functioning (73.5%). Subclinical Cushing syndrome (sCS) was detected in 12.5%. The overall prevalence of Type 2 diabetes mellitus, hypertension, hyperlipidemia, and metabolic syndrome was 18.4, 54.9, 59.6, and 48.1%, respectively. They were significantly more common in middle-aged and elderly subjects. During 24 months follow-up 10.2% of adenomas featured increase in tumor diameter and 2.06% developed sCS. Young subjects featured more stable tumor diameter and hormonal status. Most of the incidentally discovered adrenal tumors were non-functioning adrenal adenomas. Clinically overt hormone hypersecretion syndromes were mainly shown in young subjects, while adrenal gland malignancies and sCS were more common in older ages. Mass enlargement and development of subclinical cortisol secretion were not rare and observed especially in middle-aged and elderly subjects. Metabolic derangements were common; however, a possible independent association between adrenal adenoma and metabolic problems need to be elucidated with prospective studies.

Retroperitoneal laparoscopic partial adrenalectomy for adrenal micro-lesions WANG Xino-jing,

Objective To discuss the experience and key points of laparoscopic partial adrenalectomy for adrenal micro-lesions(≤1.5 cm). Methods Fifty-two patients underwent laparoscopic partial adrenalectomy for adrenal micro-lesions,including 46 cases of primary hyperaldosteronism(10 cases of adrenal cortical hyperplasia,36 cases of adenomas),3 cases of nonfunctional adrenal adenomas,1 case of adrenal metastasis,1 case of myelopiloma,1 case of mixed adenoma).Tumor size was measured Via Ultrasonography and CT scanning(mean 1.2 cm,range 0.8 to 1.5 cm). Results All operations were successful without perioperative or postoperative complications.The micro-lesion of one aldosteronoma was disagreemeat with preoperatiVe imagings.The falselesionfound was atually the fused intumescence of the internal and external part of the adrenal gland. After dissecting the whole gland carefully,the true adenoma closing to the renal hilum was discovered.One micro-1esion of aldosteronoma can not be found.After fully dissecting the gland,the micro-lesion was discovered in the head of internal part of the gland ultimately,which was deformed.The mean operative time was 92 (35-240)min.The estimated blood loss was 150(30-260)ml.No patient required blood transfusion. Eight Patients required analgesia after operation.The mean postoperative intesfinal recoverv was 16(12-24)h.The mean postoperative hospital stay was 4.6(3-9)d.The diagnosis accurate rate of Ultrasonography was 71%(37/52),CT 96%(50/52). Conclusions The diagnosis accuracv of CT scanning is superior to Ultrasonography under these circumstances.Liberating the internal part of the adrenal gland closing to the retroperitoneum firstly and exploring the whole adrenal tissue with the guidance of laparoscopy are the key points of the operations. Key words: Laparoscopes; Adrenal micro-lesion

American Association Of Clinical Endocrinologists And American Association Of Endocrine Surgeons Medical Guidelines For The Management Of Adrenal Incidentalomas

American Association Of Clinical Endocrinologists And American Association Of Endocrine Surgeons Medical Guidelines For The Management Of Adrenal Incidentalomas

Adrenal incidentaloma: a diagnostic challenge

The widespread application of abdominal imaging procedures has resulted in an increased frequency of clinically silent adrenal masses. Adrenal incidentaloma (AI) is a term applied to an accidentally discovered adrenal mass on imaging performed for the investigation of an unrelated complaint. Adrenal incidentalomas (AIs) are a cluster of different pathologies, the majority of which are benign and non-functioning adrenal adenomas. However, mild hormonal alterations as well as metabolic abnormalities may be present in patients with AIs. Thus, a multidisciplinary approach with biochemical and radiologic evaluation is needed to characterize these lesions and identify patients who are at high risk for hormonal or malignant evolution. Significant new information has helped resolve controversies regarding the most reliable approach to this clinical problem. The present review considers the prevalence, pathology and natural history of AIs. We also discuss the reliability of available screening methods and localization techniques and consider optimal management and follow-up strategies.

Prospective evaluation of tumor size and hormonal status in adrenal incidentalomas

Because of the increased use of imaging interventions, more subjects have been diagnosed with adrenal incidentaloma in recent years. To evaluate the risk of mass enlargement, hormone hypersecretion and development of adrenal carcinomas during short-term followup. There were 317 subjects with incidentally discovered adrenal tumors in the registry. Forty subjects were excluded because of clinically overt hormone secretion at diagnosis and subjects with complete data were included in radiological (no.=150) and hormonal (no.=150) follow- up. Radiological evaluation was performed with computed tomography (CT) and/or magnetic resonance imaging (MRI). There were 143 subjects with adrenal adenomas and 7 subjects with other tumor types (cyst or myelolipoma). Median follow-up duration was 24 months. Increase in tumor size was detected in 25 subjects (17.4%) with adenomas and 1 subject with adrenal myelolipoma (14.3%). Decrease in tumor size was found in 7 subjects (4.8%) with adrenal adenomas. One patient was diagnosed with adrenocortical carcinoma during follow-up. In subjects with non-functioning adrenal adenoma (NFA, no.=120) or subclinical Cushing syndrome (sCS) (no.=30), no subject developed clinically overt hormone hypersecretion, while 8 (6%) subjects in the NFA group developed sCS. Tumor diameter and follow-up duration were significantly higher in subjects who developed sCS. In conclusion, we demonstrated that, despite being infrequent, adrenal tumors may increase in size, develop overt or subclinical hormone secretion or feature malignant transformation. Therefore, radiological and hormonal follow-up should be recommended to the patients. More investigations are needed for the establishment of long-term follow-up protocols.

Evaluation of Two Methods of Endoscopic Adrenalectomy

The aim of this study was to analyse the results of minimally invasive adrenalectomy and to compare the advantages and weaknesses of two methods of operation. The outcomes of 70 patients operated on between 2000 and 2006 because of lesions of the adrenal glands were analysed. The patients were allocated to two groups: 40 patients underwent laparoscopic adrenalectomy (group A), and 30 patients underwent retroperitoneal endoscopic adrenalectomy (group B) (1 patient had bilateral lesions of the adrenals). Blood loss during the operation, incidence of complications and conversions, duration of operation, size of tumour and patient's body mass index (BMI) were analysed. Median tumour size was 3.49 +/- 1.27 cm (range: 2-7 cm) in group A, and 3.9 +/- 1.38 cm -(range: 1.4-6 cm) in group B. More than half of all patients (n = 38; 54.3 %) were operated on because of a non-functional adrenal adenoma. Conversion was performed on 5 patients (12.5 %) in group A and on 1 patient (3.3 %) in group B. Operation time in group A was 122 +/- 30.42 min, and in group B 135 +/- 57.05 min. The training period for laparoscopic adrenalectomy was shorter. There were no significant differences in blood loss during operation or incidence of complications. The size of the tumour and the patient's BMI did not have a statistically significant impact on the duration of operation. Laparoscopic and retroperitoneal endoscopic adrenalectomies are of the same value in most aspects. However, the training period for laparoscopic adrenalectomy was shorter.

Síndrome de Cushing: situaciones especiales

The present article reviews: Corticotrophin (ACTH) independent bilateral macronodular adrenal hyperplasia, which is characterized by aberrant adrenal receptors due to either ectopic expression or to overexpression (eutopic expression). Micronodular adrenal hyperplasia, which provokes small pigmented nodules in the adrenal gland with atrophy of the internodal tissue. These nodules may not be visible on imaging tests. The term subclinical Cushing's syndrome, coined in 1981, should be used in patients with clinically non-functioning adrenal adenomas but who show autonomous cortisol production that is insufficient to generate overt Cushing's syndrome. This entity must be distinguished from preclinical Cushing's syndrome, given that the subclinical form does not necessarily herald the development of symptoms of hypercortisolism. Cushing's syndrome is uncommon in children and adolescents. Regarding the general incidence of the disease, only 10% of cases are diagnosed in this age group. The most common cause of endogenous Cushing's disease in children older than 7 years is ACTH-dependent Cushing's disease (85%). The association of Cushing's syndrome and pregnancy is highly uncommon, since hypercortisolism usually causes amenorrhea, oligomenorrhea and infertility due to inhibition of gonadotropin secretion. One hundred thirty-six pregnancies have been described in 122 women, with a gestational age at diagnosis of 18.4+/-1 weeks.

Carotid intima media thickness is increased and associated with morning cortisol in subjects with non-functioning adrenal incidentaloma

Data regarding cardiovascular risk in subjects with non-functioning adrenal adenoma are limited. The objectives of this study are to investigate carotid intima media thickness (IMT) as an indicator of atherosclerosis in subjects with non-functioning adrenal incidentaloma (AI) and to evaluate the factors that could be associated with IMT. Forty-nine subjects without findings of hypercortisolism or other adrenal gland disorders, 34 body mass index (BMI)-unmatched controls (C) and 18 BMI-matched controls (BC) were enrolled. Participants underwent hormonal evaluation including morning cortisol, adrenocorticotrophic hormone (ACTH), post dexamethasone suppression test cortisol (DST), dehydroepiandrosterone sulfate (DHEAS), and urinary free cortisol. Anthropometric and metabolic parameters and carotid IMT were measured. AI group had increased BMI, blood pressure, waist circumference, post DST cortisol, uric acid, and homeostasis model assessment (HOMA) levels when compared with C. Blood pressure, uric acid and, post DST cortisol remained significantly elevated in AI versus BC. Average IMT was increased significantly in AI versus C (0.74 mm vs. 0.68 mm, P = 0.029) and insignificantly elevated in AI versus BC (0.74 mm vs. 0.67 mm, P = 0.086). In all participants, IMT was correlated with age, BMI, HOMA, waist circumference, morning cortisol, and uric acid. Morning cortisol was independently associated with HOMA levels in both AI group and all participants. Increased IMT in non-functioning AI was a consequence of insulin resistant state associated with subtle cortisol autonomy rather than a direct effect of cortisol. The correlation between morning cortisol and IMT may be associated with the effect of hypothalamus-pituitary-adrenal axis disturbances on vasculature.

Atherosclerotic risk factors and complications in patients with non-functioning adrenal adenomas treated with or without adrenalectomy: a long-term follow-up study

Despite the increased prevalences of hypertension, type 2 diabetes mellitus (T2DM), hyperlipidemy, and obesity in patients with non-functioning adrenal adenomas (NFAAs), there is a paucity of data on long-term atherosclerotic morbidity as well as the long-term cardiovascular effects of adrenalectomy in these patients. This retrospective study includes the results of baseline and follow-up investigations of 125 patients (29 males and 96 females; mean age 60.1 years) with NFAAs referred for endocrine evaluation between 1990 and 2001. Of the 125 patients, 47 underwent unilateral adrenalectomy, while 78 patients were followed conservatively. These patients were reinvestigated after a mean follow-up time of 9.1 (5-16) years in 2006, with special emphasis on laboratory and other atherosclerotic risk factors (ARF), vascular events, and interventions. The prevalences of hypertension, impaired glucose tolerance or T2DM, hyperlipidemy, and obesity were 82, 43, 58, and 50%, and 89, 58, 82, and 50% at baseline and follow-up, respectively. None of the investigated ARF prevalences were different between patients treated and not treated with adrenalectomy, and between patients with and without subclinical Cushing's syndrome. The prevalences of angina pectoris, acute myocardial infarction, coronary, and peripheral arterial interventions or cerebrovascular stroke did not differ significantly between patients treated and not treated with adrenalectomy. Our study confirms previous investigations reporting markedly increased prevalences of various ARF in patients with NFAAs. Adrenalectomy performed in these patients failed to decrease the prevalence of ARF and atherosclerotic morbidity.

RADIOLOGICAL OBSERVATION OF THE GROWTH OF NONFUNCTIONING ADRENAL TUMORS

42 RADIOLOGICAL OBSERVATION OF THE GROWTH OF NONFUNCTIONING ADRENAL TUMORS Gaku Tamaki*, Yuji Kato, Tatsuhiko Kura, Yuji Saga, Hidehiro Kakizaki. Asahikawa, Japan. INTRODUCTION AND OBJECTIVE: Improvement in abdominal imaging techniques has increased the detection of adrenal incidentaloma. When the adrenal mass is less than 4cm in diameter and nonfunctioning, usually it can be followed with a regular radiological examination. However, if the tumor growth is observed, we must decide whether it should be removed with the possibility of malignant potential in mind. To elucidate the frequency and velocity of tumor growth among nonfunctioning adrenal masses, we performed a retrospective analysis of chronological changes in diameter of clinically nonfunctioning adrenal tumors. METHODS: From January 2000, 138 patients with adrenal mass visited our hospital. All the patients underwent a diagnostic workup that included computed tomography (CT) and endocrinological function of the adrenal gland. CT was taken twice or more in 47 patients (23 males and 24 females) with nonfunctioning adrenal tumor. These 47 patients (mean age 62.7 years) had 55 tumors (unilateral in 39 and bilateral in 8) and were followed for 1-116 months (median 20.8 months). We examined chronological changes in tumor diameter and the velocity of tumor growth by CT. RESULTS: Clinical diagnosis of 55 tumors was adenoma in 44, metastatic tumor in 5, cyst or hematoma in 4, myelolipoma and uncertain nature in one each. Among the 55 tumors, 7 (12.7%) showed 5 mm or greater increase in diameter and the velocity of tumor growth in the 7 tumors was 39.6 mm per year. Adrenalectomy was performed for 2 of the 7 tumors with growth and pathological diagnosis was cyst and gastrointestinal stromal tumor (GIST) of the stomach in one each. Suspected diagnosis of the other 5 tumors with growth was metastatic tumor in 2, adenoma in 2 and cyst in 1. Four of the 55 tumors showed 5 mm or greater decrease in diameter and the remaining 44 tumors showed no change in diameter. Suspected diagnosis of the 5 tumors with regression was adenoma in 3 and cyst and hematoma in one each. If only nonfunctioning adenoma is taken into account, the frequency and velocity of tumor growth was 4.5% (2/44) and 7.3mm per year, respectively. Regarding adrenal tumors other than adenoma, the frequency and velocity of tumor growth was 45.5% (5/11) and 52.5mm per year, respectively. CONCLUSIONS: When a diagnostic workup suggests nonfunctioning adrenal adenoma, the frequency of tumor growth is very low and thus repeating imaging studies at a short interval is not warranted. However, if the radiological feature of adrenal adenoma is lacking, close followup is mandatory to detect tumor growth and to treat without undue delay.

Hiperaldosteronismo primário causado por aldosteronoma: problemas no diagnóstico etiológico

Primary aldosteronism (PA) represents an important cause of secondary hypertension, potentially curable, and it has been receiving particular attention due to its increasing prevalence, after the beginning of the use of plasma aldosterone concentration to plasma renin activity ratio as a screening method. We present a case of PA caused by an aldosteronoma associated with a contralateral nonfunctioning adrenal adenoma, which resulted in difficulties in the final diagnosis. We discuss the most appropriated tests to screen, confirm the diagnosis of PA and define the etiology of the disorder, especially the adrenal veins sampling to distinguish the aldosteronoma and idiopathic hyperaldosteronism and to guide successful treatment.

Metabolic syndrome in patients with adrenocortical adenoma

To investigate the prevalence and characteristics of metabolic syndrome (MS) in patients of adrenocortical adenoma. MS-related indexes, including waist circumference (WC), blood pressure, triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), fasting plasma glucose, plasma and urinary aldosterone, plasma potassium, basic and upright plasma renin activity (PRA), plasma and urinary cortisol, and plasma ACTH, were examined among 61 patients of aldosterone producing adenoma (APA, Group 1), 23 patients of cortisol-secreting adenoma (CSA, Group 2), 24 patients of nonfunctional adrenal adenoma (NAA, Group 3), and 26 healthy controls (Group 4). As defined by the National Cholesterol Education Program Adult Treatment Panel III criteria, the prevalence rates of MS were 27.9%, 39.1%, 16.7%, and 11.5% in Groups 1, 3, 3, and 4. The abdominal obesity rate was 26.2% in Group 1 and 9.1% in Group 2, both significantly higher than those of Group 3 and 4 (20.8% and 15.4% respectively). The prevalence rates of hypertension and systolic blood pressure were the highest in Group 1, followed by Group 2, 3, and 4 t. The diastolic blood pressure in patients of Group 1 was also higher than those of the other three groups. The prevalence rates of hypertriglyceride were 24.6%, 52.2%, 21.7%, and 23.1% in Group 2 1 approximately 4. The prevalence rates of low HDL-C was 32.8%, 47.8%, 30.4%, and 26.9% respectively. The prevalence rates of hyperglycemia were 13.1%, 26.1%, 8.7%, and 7.7% respectively. Patients with adrenocortical adenoma have a significantly high prevalence of metabolic syndrome, especially the patients of CSA and NAA.

MEN1 family with a novel frameshift mutation

Multiple endocrine neoplasm type 1 (MEN1) syndrome predisposes to the development of endocrine and non-endocrine tumors with an autosomal dominant pattern of inheritance. Different mutations have been found throughout the gene with a variable phenotype expression. The proband, a Caucasian man, was admitted to our department in 2001, at the age of 51 because of a 1-yr history of diarrhoea and hypertension. He reported a previous intestinal resection for bowel occlusion with a histological diagnosis of unspecified mesenchymal neoplasia. He had also undergone a left adrenalectomy for a large nonfunctioning adrenal adenoma. Subsequently, he had suffered from gastralgia and melena; a gastroduodenoscopy showed an erosive gastritis. His family history was negative for endocrine disorders. On physical examination, multiple abdominal cutaneous lipomas and facial angiofibromas were observed. Biochemical screening revealed a primary hyperparathyroidism and an increase in circulating levels of PRL, chromogranin-A, gastrin and glucagon. The whole body computed tomography (CT) scan, the 111In-octreotide scan and the pituitary magnetic resonance imaging (MRI) did not reveal any abnormality. The presence of small neuroendocrine tumors was suspected by a positron emission tomography uptake in the epigastric region. The endoscopic ultrasound revealed a pancreatic lesion sized 1.1 cm that is under evaluation. Direct DNA sequencing analysis of the proband MEN1 gene revealed the 579delG frameshift mutation in the exon 3. The genetic screening of the family revealed the same mutation in 3 out of 5 offspring. The biochemical screening revealed some features of the MEN1 syndrome in all three of them. In conclusion, a novel frameshift MEN1 mutation was found in kindred with an apparently negative family history. Our experience confirms that MEN1 syndrome is a complex and underestimated condition, unless specifically investigated by trained specialists.

Asociación de feocromocitoma con adenoma suprarrenal contralateral no funcionante

A 52-year-old woman complaining of abdominal pain, headaches and palpitations was admitted to our hospital for investigation of a bilateral adrenal tumor. Bilateral adrenalectomy was subsequently performed. The definitive diagnosis was right pheochromocytoma and left adrenocortical adenoma. Only four cases of pheochromocytoma associated with nonfunctioning adrenal adenoma have previously been reported. The coexistence of both entities is currently believed to be coincidental. Further examination of cases similar to ours might reveal the underlying mechanisms for the coexistence of these tumors.

Risk Assessment in 457 Adrenal Cortical Carcinomas: How Much Does Tumor Size Predict the Likelihood of Malignancy?

Laparoscopic adrenalectomy for tumors > 6 cm is controversial because of the risk of malignancy, but data to support this position are mostly from small series. The recent NIH consensus conference did not make a definitive recommendation about management of 4- to 6-cm nonfunctioning incidentalomas. Adrenocortical carcinomas (ACC) recorded in the Surveillance, Epidemiology, and End Results (SEER) database (1988 to 2000) were compared with benign functional or nonfunctional adrenal cortical adenomas (excluding aldosteronomas) operated on at our institution between January 1, 1993, and July 1, 2003. Data were compared using t-tests, chi-square tests, likelihood ratios, and receiver operating characteristic (ROC) curves. We identified 457 patients with ACC and 47 patients with adrenal cortical adenomas; 376 and 44 neoplasms, respectively, had tumor size data available. Tumor size was larger in ACC (12.0 +/- 5.6 versus 4.2 +/- 1.9 cm, mean +/- SD, p < 0.05). For ACC presenting with local disease, the sensitivity, specificity, and likelihood ratios of tumor size to predict malignancy were 96%, 52%, and 2.0, respectively, for tumors > or = 4 cm; 90%, 80%, and 4.4 for tumors > or = 6 cm; 77%, 95%, and 16.9 for tumors > or = 8 cm; and 55%, 98%, and 24.4 for tumors > or = 10 cm. Assuming a pretest probability of malignancy of 5%, the likelihood ratios derived from this study yield a posttest probability of 10%, 19%, and 47% for cancer in adrenal cortical tumors > or = 4 cm, > or = 6 cm, and > or = 8 cm, respectively. These data suggest that size is useful for predicting malignancy, and that at a size threshold of > or = 4 cm, the likelihood of malignancy doubles (to 10%) and it is more than ninefold higher for tumors > or = 8 cm (47%).

Comparison of adrenal vein sampling value between aldosterone producing adrenal adenoma and non-functioning adrenal adenoma: evaluation using receiver operating characteristic analysis

To evaluate adequate criteria for adrenal vein sampling values in patients with aldosterone producing adrenal adenoma (APA), retrospectively. Between 1988 and 2002, 59 hypertensive patients (15 M and 44 F, aged 47.58 +/- 9.45 years) were referred to our hospital and diagnosed with APA based on established criteria. During the same period, 23 patients with non-functioning adrenal adenoma (11 M and 12 F aged 53.56 +/- 11.76 years) were diagnosed based on computed tomography and laboratory data. All 82 patients were enrolled in the present study. Bilateral adrenal vein sampling (AVS) for measurement of plasma aldosterone (A) and cortisol (C) was performed, and a receiver operating characteristics (ROC) analysis was conducted to establish the best criteria from the AVS-derived index in patients with APA. A (APA side)/A (contralateral side) was confirmed to provide the best diagnostic accuracy {(>2.5: right APA, sensitivity 83.3%, specificity 79.5%), (> 3: left APA, sensitivity 84.2%, specificity 76.9)}. The Az values for A (APA side)/A (contralateral side) were 0.8948 and 0.9260 for right and left APA, respectively. The A (APA side)/A (contralateral side) value was the best compromise for sensitivity and false-positive rate for lateralization of APA.

Clinical and molecular evidence for DAX-1 inhibition of steroidogenic factor-1-dependent ACTH receptor gene expression

The ACTH receptor (ACTH-R) is a member of the seven transmembrane domain receptor super-family. In non-functional adrenal adenomas and adrenocortical carcinomas, ACTH-R expression is low. However, no inhibitory factor for ACTH-R expression has been defined to date. DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia congenita, critical region on the X chromosome, gene-1) is a general repressor of steroid production, inhibiting steroidogenic factor-1 (SF-1)-dependent expression of multiple steroidogenic enzymes. The aim of this study was to investigate whether ACTH-R gene transcription is affected by DAX-1 and whether this mechanism is involved in down-regulation of ACTH-R expression in adrenocortical tumors. We screened 22 adrenocortical tumors for ACTH-R and DAX-1 mRNA expression by Northern blot. For in vitro analyses we co-transfected mouse Y1 adrenocortical carcinoma cells with the luciferase reporter gene vector pGL3 containing full-length constructs of human (h) or mouse (m) ACTH-R promoter together with a DAX-1 expression plasmid. These experiments were also performed using ACTH-R promoter 5'-deletion constructs and constructs mutated at the SF-1-binding sites. We found a negative correlation between DAX-1 and ACTH-R mRNA expression (R=-0.47, P<0.02). Accordingly, in vitro expression of DAX-1 significantly reduced hACTH-R and mACTH-R promoter activity by 89 and 55% respectively. DAX-1 inhibition was also present in the shortest construct of a series of 5'-deletion constructs of the human promoter extending from -64 to +40 bp relative to the transcription start site. Mutation of the SF-1-binding sites within the hACTH-R promoter resulted in reduced or abolished DAX-1 inhibition, arguing for a mechanism that involves SF-1 for DAX-1 inhibition. These data support the concept that DAX-1 is a major repressor of ACTH-R gene expression in vitro and in vivo.

Dopamine receptor expression and function in human normal adrenal gland and adrenal tumors.

Dopamine is known to play a role in the modulation of aldosterone and catecholamine secretion from the adrenal gland, where dopamine receptors (DR), in particular the DR type 2 (D(2)), have been found to be expressed. DR expression has also been demonstrated in some types of benign adrenal tumors. The aims of the current study were to evaluate DR expression and D(2) localization in the normal adrenal gland and in different types of benign and malignant adrenal tumors, as well as to evaluate the in vitro effects of the dopamine agonists bromocriptine and cabergoline on hormone secretion in nontumoral adrenal cells. Adrenal tissues from 25 patients, subjected to adrenal surgery for different diseases, were studied. These included three normal adrenals; five adrenal hyperplasias; four aldosterone-secreting, two cortisol-secreting, and two clinically nonfunctioning adrenal adenomas; two aldosterone-secreting, two cortisol-secreting, and two androgen-secreting adrenal carcinomas; and three pheochromocytomas. In all tissues, DR and D(2) isoform (D(2long) and D(2short)) expression was evaluated by RT-PCR. D(2) localization was also evaluated by immunohistochemistry using a specific polyclonal antibody, whereas D(2)-like receptor expression was evaluated by receptor-ligand binding study, using the radiolabeled D(2) analog (125)I-epidepride. The effects of bromocriptine and cabergoline on baseline and ACTH and/or angiotensin II-stimulated aldosterone, cortisol, and androstenedione secretion were evaluated in cell cultures derived from five different adrenal hyperplasia. At RT-PCR, both D(1)-like and D(2)-like receptors were expressed in all normal and hyperplastic adrenals. D(2) and D(4) were expressed in aldosterone- and cortisol-secreting adenomas, cortisol-secreting carcinomas, and clinically nonfunctioning adenomas, whereas no DR was expressed in aldosterone- and androgen-secreting carcinomas. D(2), D(4), and D(5) were expressed in pheochromocytomas. In all D(2)-positive tissues, both D(2) isoforms were expressed, with the exception of one case of aldosterone-secreting adenoma and the cortisol-secreting carcinomas, in which only the D(2long) isoform was expressed. D(2)-like receptor expression was confirmed at receptor-ligand binding study. At immunohistochemistry, D(2) was mainly localized in the zona glomerulosa and reticularis of the adrenal cortex and, to a lesser extent, in the zona fasciculata and medulla of normal and hyperplastic adrenal tissue. In the positive tumors, D(2) was localized in the tumoral cells. At the in vitro study, a significant inhibition of both baseline and ACTH-stimulated aldosterone secretion was found after high-dose cabergoline, but not bromocriptine, administration; and a significant inhibition of angiotensin-II-stimulated aldosterone secretion was found after both bromocriptine and cabergoline administration in the adrenal hyperplasias. In conclusion, the current study demonstrated that both D(1)-like and D(2)-like receptors are expressed in the normal adrenal gland and in a percentage of adrenal adenomas or carcinomas. Bromocriptine and cabergoline induce only a minor inhibition of the secretion of adrenal hormones in the nontumoral adrenal gland in vitro, not excluding, however, the possible effective use of dopamine agonists in vivo in the treatment of adrenal tumors.

Assessing the presence of abnormal regulation of cortisol secretion by membrane hormone receptors: in vivo and in vitro studies in patients with functioning and non-functioning adrenal adenoma.

Regulation of cortisol secretion by aberrant hormone receptors may play a role in the pathogenesis of ACTH-independent Cushing's syndrome. In this study, the topic was evaluated by combining in vivo and in vitro approaches. Cortisol responses to various stimuli (standard meal, GnRH + TRH, cisapride, vasopressin, glucagon) were assessed in 6 patients with clinical or subclinical adrenal Cushing's syndrome, and non-functioning adrenal adenoma in two cases. Abnormal responses were observed in three patients with Cushing's syndrome; one patient showed a gastric inhibitory polypeptide (GIP)-dependent cortisol rise after meal, together with responses after GnRH and cisapride; the second patient showed an LH-dependent cortisol response to GnRH, and in the third cortisol rose after cisapride. The pattern of receptor expression performed by RT-PCR showed that while GIP-R was only expressed in tumor from the responsive patient, 5-hydroxytryptamine type 4 receptor and LH-R were also present in normal adrenal tissues and tissues from non-responsive patients. Interestingly, an activating mutation of Gsalpha gene was identified in one of these tumors. Therefore, cortisol responses to agents operating via Gs protein coupled receptors (in one case associated with Gsalpha mutation) were found in Cushing's patients, while these responses were absent in the others. The finding of receptor expression in normal and non-responsive tumors suggests that different mechanisms are probably involved in inducing in vivo cortisol responses.