New diagnostic criteria of adrenal subclinical Cushing's syndrome: opinion from the Japan Endocrine Society.

New diagnostic criteria and the treatment policy for adrenal subclinical Cushing's syndrome (SCS) are proposed on behalf of the Japan Endocrine Society. The Japanese version has been published, and the essential contents are presented in this English-language version. The current diagnostic criteria for SCS have elicited two main problems: (i) the relatively low reliability of a low range of serum cortisol essential for the diagnosis by an overnight 1-mg dexamethasone suppression test (DST); (ii) different cutoff values for serum cortisol after a 1-mg DST compared with those of other countries. Thus, new criteria are needed. In the new criteria, three hierarchical cortisol cutoff values, 5.0, 3.0 and 1.8 µg/dL, after a 1-mg DST are presented. Serum cortisol ≥5 µg/dL after a 1-mg DST alone is considered sufficient to judge autonomous cortisol secretion for the diagnosis of SCS, and the current criterion based on serum cortisol ≥3 µg/dL after a 1-mg DST can continue to be used. Clinical evidence suggests that serum cortisol ≥1.8-2.9 µg/dL after a 1-mg DST is not always normal, so cases who meet the cutoff value as well as a basal adrenocorticotropic hormone (ACTH) level <10 pg/mL (or poor ACTH response to corticotropin-releasing hormone (CRH)) and nocturnal serum cortisol ≥5 µg/dL are proposed to have SCS. We suggest surgery if cases show serum cortisol ≥5 µg/dL after a 1-mg DST (or are disheartened by treatment-resistant problems) or suspicious cases of adrenal cancer according to tumor imaging.

Ectopic ACTH syndrome caused by desmopressin-responsive thymic neuroendocrine tumor.

A 32-year-old Chinese woman with rapid weight gain and progressive edema was found to have typical Cushingoid features. Her endocrine data were consistent with a diagnosis of ACTH-dependent Cushing's syndrome. To differentiate ectopic ACTH syndrome (EAS) from Cushing's disease (CD), various dynamic endocrine and imaging tests were performed. Her ACTH response was negative to corticotropin-releasing hormone (CRH) and positive to desmopressin. Magnetic resonance imaging of the pituitary showed no mass lesion. Computed tomography scan of the chest revealed a large mass (21 × 15 mm) in the anterior mediastinum, where positron emission tomography showed accumulation of [(18)F] fluorodeoxyglucose. Selective venous sampling showed marked step-up in ACTH level in the internal thoracic vein but not in the cavernous sinus after CRH stimulation. These data are compatible with the diagnosis of EAS. The resected tumor was pathologically consistent with thymic neuroendocrine tumor (NET) positive for ACTH by immunohistochemistry and abundant V1b receptor gene expression by RT-PCR. Postoperatively, her circulating ACTH/cortisol levels became normalized, and responded to stimulation with CRH but not with desmopressin. Her Cushingoid appearance gradually disappeared, and she was free from recurrence 5 years after surgery. This is a rare case of desmopressin-responsive EAS caused by thymic NET with predominant V1b gene expression, which was successfully localized by imaging modalities combined with selective venous sampling.

Evaluation of salivary cortisol measurements for the diagnosis of subclinical Cushing's syndrome.

Late-night salivary cortisol (NSC) has been recognized as a sensitive and easy-to-perform screening test for the diagnosis of overt Cushing's syndrome (CS). However, there have been few reports on the diagnostic utility of salivary cortisol (SC) measurement in the diagnosis of subclinical Cushing's syndrome (SCS). Therefore, the present study was designed to evaluate the usefulness of SC measurements at late-night and after overnight 1 mg dexamethasone suppression test (DST) for the diagnosis of SCS in 42 patients with adrenal incidentaloma. We evaluated 16 patients with SCS, 12 with nonfunctioning adenoma (NFA), 8 with primary aldosteronism (PA), and 6 with pheochromocytoma (Pheo). NSC levels in SCS patients (0.238 ± 0.106 µg/dL) were significantly (P < 0.05) higher than those in NFA patients (0.154 ± 0.104 µg/dL); the cutoff value (0.11 µg/dL) by ROC analysis gave high sensitivity (100%) with low specificity (50%). Post DST SC levels in SCS patients (0.238 ± 0.116 µg/dL) were significantly (P = 0.0081) higher than those in NFA patients (0.136 ± 0.110 µg/dL); the cutoff value (0.12 µg/dL) by ROC analysis gave high sensitivity (93.8%) with somewhat improved specificity (58.3%). Both NSC and post DST SC levels were comparable between NFA, PA, and Pheo patients. In conclusion, our study revealed that measurements of NSC and/or post DST SC among patients with adrenal incidentaloma prove to have high sensitivities, but low specificities for the diagnosis of SCS from NFA, suggesting its possible alternative option before the screening tests for SCS currently employed in Japan.

Clinical outcome of subclinical Cushing's syndrome after surgical and conservative treatment.

Subclinical Cushing's syndrome (SCS), a subtle cortisol hypersecretion from an adrenal tumor, may be a common adrenal disease. However, the cardiovascular prognosis and the optimal surgical and conservative treatment in SCS remain elusive. The present study was undertaken to evaluate the prevalence of cardiovascular risk factors in 16 SCS cases, their relationships to cortisol secretory activities, and the clinical outcome after surgical and medical treatment. The prevalence of hypertension, impaired glucose tolerance (IGT), diabetes mellitus (DM), dyslipidemia and obesity in our SCS cases were 56%, 50%, 50%, and 19%, respectively, and 75% of cases were associated with two or more cardiovascular risk factors. In our series, 24-h urinary free-cortisol excretion showed a significant positive correlation with HbA1c and a negative correlation with high-density lipoprotein-cholesterol, but no correlation with age, body mass index, blood pressure or glycemic and lipid profile was found. Eight cases underwent unilateral adrenalectomy (operated (OP) group); the remaining eight cases were a conservative-treatment group (non-OP group). The number of cardiovascular risk factors decreased significantly in the OP group, but not in the non-OP group. In terms of differential changes in risk factors between the groups, more significant improvements of hypertension, dyslipidemia and IGT/DM were observed in the OP group than in the non-OP group. In conclusion, the present study showed the increased prevalence of cardiovascular risk factors in SCS patients with mild hypercortisolism related to impaired glucose/lipid metabolism. Adrenalectomy decreased accumulated cardiovascular risk factors in certain SCS patients, suggesting the possible involvement of mild hypercortisolism in the development of cardiovascular risk factors in SCS.

Clinicopathological features of primary aldosteronism associated with subclinical Cushing's syndrome.

Primary aldosteronism (PA), an autonomous aldosterone hypersecretion from adrenal adenoma and/or hyperplasia, and subclinical Cushing syndrome (SCS), a mild but autonomous cortisol hypersecretion from adrenal adenoma without signs or symptoms of Cuhing's syndrome, are now well-recognized clinical entities of adrenal incidentaloma. However, the clinicopathological features of PA associated with SCS (PA/SCS) remain unknown. The present study was undertaken to study the prevalence of PA/SCS among PA patients diagnosed at our institute, and characterize their clinicopathlogical features. The prevalence of PA/SCS was 8 of 38 PA patients (21%) studied. These 8 PA/SCS patients were significantly older and had larger tumor, higher serum potassium levels, lower basal plasma levels of aldosterone, ACTH and DHEA-S as well as lower response of aldosterone after ACTH stimulation than those in 12 patients with aldosterone-producing adenoma without hypercortisolism. All 8 PA/SCS patients showed unilateral uptake by adrenal scintigraphy at the ipsilateral side, whereas the laterality of aldosterone hypersecretion as determined by adrenal venous sampling varied from ipsilateral (3), contralateral (2), and bilateral side (2). 6 PA/SCS patinets who underwent adrenalectomy required hydrocortisone replacement postoperatively. Histopathological analysis of the resected adrenal tumors from 5 PA/SCS patients revealed a single adenoma in 3, and double adenomas in 2, with varying degrees of positive immunoreactivities for steroidgenic enzymes (3ß-HSD, P450(C17)) by immunohistochemical study as well as CYP11B2 mRNA expression as measured by real-time RT-PCR. In conclusion, PA/SCS consists of a variety of adrenal pathologies so that therapeutic approach differs depending on the disease subtype.

Clinical features and management of ectopic ACTH syndrome at a single institute in Japan.

Ectopic ACTH syndrome (EAS) is a diagnostic challenge because it is often indistinguishable from Cushing's disease. We describe our series of EAS patients referred to us during 1992-2009. Among 16 cases (9 females / 7 males), with mean age of 58.4 ± 19.0yr, the ectopic source was identified in ten (proven EAS), whereas unidentified in six (occult/unknown EAS). Their salient clinical manifestations included Cushingoid feature (88%), skin pigmentation (88%), profound hypokalemia (88%), hypertension (75%), diabetes/impaired glucose tolerance (75%), hyperlipidemia (69%), and severe infection (44%). Dynamic endocrine tests revealed markedly elevated plasma ACTH levels (211 ± 116pg/mL) and cortisol levels (60.9 ± 30.1µg/dL) which showed resistance to overnight high-dose (8mg) dexamethasone suppression test in 15 (94%) and unresponsiveness to CRH stimulation in 12 (75%). No ACTH gradient during inferior petrosal sampling was noted in 13 of 15 (87%). Imaging tests by CT/MRI identified the tumors in 8 of 16 (50%), in 4 of 11 (36%) and 4 of 6 (66.7%) octreotide-responders by somatostatin receptor scintigraphy, but in only one of 9 (11.1%) by FDG-PET scan. Six cases deceased, including small cell carcinoma (2) and adenocarcinoma (1) of lung, neuroendocrine carcinoma of pancreas (1) and stomach (1), and olfactory neuroblastoma (1), whereas 4 cases survived after removal of the tumors, including bronchial carcinoid tumor (3) and thymic hyperplasia (1). Six occult/unknown EAS patients survived for 67.5 months after medical treatment with metyrapone to control hypercortisolism. Thus, various endocrine tests combined with imaging studies are required to correctly localize the tumors. Control of hypercortisolemia by metyrapone, even if tumor is unrecognized, is critical for better prognosis, and the long-term follow-up by repeated endocrine and imaging tests is mandatory.

[Case of ruptured multiple cerebral aneurysms associated with primary aldosteronism].

Primary aldosteronism (PA) has been recognized as a relatively benign form of hypertension associated with a low incidence of vascular complications. Recent reports, however, indicate that cerebrovascular accidents are common in PA. We report a case of multiple aneurysms with PA in a middle-aged woman who presented with subarachnoid hemorrhage. A 47-year-old woman with a history of untreated hypertension was referred to our hospital for subarachnoid hemorrhage. Cerebral angiography showed multiple small aneurysms. The initial intervention was aneurysm clipping for a ruptured aneurysm at the bifurcation of the right middle cerebral artery. Despite medication, she continued to suffer from uncontrolled hypertension and hypokalemia. She was diagnosed with PA on the basis of elevated plasma aldosterone, suppressed plasma rennin, and a right adrenal tumor detected by abdominal CT scanning. She underwent several more neck clippings for the remaining aneurysms (unruptured), followed by a total right adrenectomy. Histological examination revealed an adrenal adenoma. After the operation, her blood pressure returned to normal without any vasodepressors. Recent studies have demonstrated that hyperaldosteronism might have direct vasculo-toxic actions, including remodeling, fibrosis, and proliferation. Cerebrovascular accidents caused by PA are reported to have high rates of mortality and recurrence when the PA is overlooked or untreated. Physicians must be alert to the possibility of PA in patients with hypertension and persistent hypokalemia, especially in those who are young or middle-aged. We also recommend screening for intracranial aneurysms by low-invasive magnetic resonance angiography.

Development and validation of a 0.5 mg dexamethasone suppression test as an initial screening test for the diagnosis of ACTH-dependent Cushing's syndrome.

For the diagnosis of Cushing' s syndrome (CS), the overnight 1 mg dexamethasone suppression test (DST) has been widely used as a standard low-dose DST. However, it is evident that 1 mg DST may not be sensitive enough to detect CS when the cortisol cut-off concentration is 5 microg/dL. Therefore, we developed and validated 0.5 mg DST as a new screening method for diagnosis of ACTH-dependent CS. To compare 0.5 mg DST with 1 mg DST, 110 patients with ACTH-dependent CS were enrolled, including 88 with Cushing' s disease (CD), 8 with subclinical CD and 14 with ectopic ACTH syndrome, as well as 134 control subjects. Subjects were given either 0.5 mg or 1 mg dexamethasone orally at 23:00 on different days, with blood samples collected the following morning between 8:00 and 9:00 to determine plasma cortisol concentration. The area under the receiver operator characteristics curve observing the 0.5 mg DST was higher than that of the 1 mg DST. The most sensitive and specific cut-off value of plasma cortisol concentration using 0.5 mg DST was found to be 3.05 microg/dL with 99.1% sensitivity and 98.4% specificity, identical to the 3 microg/dL cut-off currently used in the Japanese guideline for diagnosis of subclinical CD. In conclusion, 0.5 mg DST is a sensitive and specific screening test for diagnosis of ACTH-dependent CS. We recommend 0.5 mg DST with a cortisol cut-off concentration of 3 microg/dL to be used as the initial step in diagnosing ACTH-dependent CS.

Improvement of congestive heart failure after octreotide and transsphenoidal surgery in a patient with acromegaly.

A 59-year-old man was admitted because of congestive heart failure. He was suspected to have acromegaly, and magnetic resonance imaging revealed a pituitary macroadenoma. Endocrine examination revealed elevated plasma levels of growth hormone (GH) and insulin-like growth factor (IGF)-1, and an oral glucose tolerance test failed to suppress plasma GH levels, consistent with the diagnosis of GH-producing pituitary tumor. Treatment with octreotide, followed by transsphenoidal surgery resulted in normalization of plasma GH/IGF-1 levels, accompanied by the improvement of cardiac function. Thus, it is suggested that excess GH/IGF-1 axis is involved in the development of acromegaly-related cardiomyopathy in the present case.

Defective expression of prohormone convertase 4 and enhanced expression of insulin-like growth factor II by pleural solitary fibrous tumor causing hypoglycemia.

A 75-year-old man was admitted to our hospital because of unconsciousness. His plasma glucose was very low, but his serum levels of insulin and IGF-I were also low. He was found to have a giant solitary pleural tumor, which was completely resected, after which his hypoglycemia ameliorated postoperatively. Histologically, the tumor was consistent with the pathological diagnosis of a solitary fibrous tumor derived from the pleura. Immunohistochemical study revealed positive immunostaining for IGF-II in tumor cells. The presence of high molecular weight (HMW) form of IGF-II in the tumor tissue and patient's serum was confirmed by Western blot analysis. Steady-state mRNA levels of IGF-II and prohormone convertases (PC) 4, a potential protease responsible for IGF-II processing, as determined by RT-PCR were about 14-fold greater and 5-fold less in the tumor tissue than those in normal placental tissue, respectively. Therefore, it is suggested that biologically active, unprocessed HMW form of IGF-II generated from the impaired processing of IGF-II precursor by the defective PC4 expression in the tumor was responsible for the non-islet cell tumor hypoglycemia (NICTH) in the present case.

Improvement of endothelial dysfunction in acromegaly after transsphenoidal surgery.

Flow-mediated vasodilatation (FMD) is a vascular functional test to detect endothelial dysfunction at the early stage of cardiovascular diseases. Patients with active acromegaly have higher morbidity and mortality due to cardiovascular events. To determine whether active acromegaly is associated with endothelial dysfunction, we studied 17 patients with active acromegaly for measurements of FMD, carotid intima-media thickness (IMT) and brachial-ankle pulse wave velocity (baPWV), and other biochemical parameters before and 3 months after transsphenoidal surgery (TSS). Baseline %FMD in patients with active acromegaly was significantly lower than that in age- and sex-matched control subjects. After TSS, the mean %FMD in acromegaly significantly increased from 5.3% to 7.4%; 12 patients had increased %FMD (responders), whereas 5 patients had decreased or unchanged %FMD (non-responders). However, neither carotid IMT nor baPWV changed after TSS. Serum levels of GH, insulin-like growth factor (IGF)-1, total cholesterol, low-density lipoprotein cholesterol (LDL-C), hemoglobin HA(1C), fasting plasma glucose and insulin levels, and homeostasis model assessment (HOMA)-R significantly decreased, whereas high-density lipoprotein cholesterol significantly increased. Responders had significantly lower baseline %FMD than did non-responders and both insulin levels and HOMA-R significantly decreased in responders, but not in non-responders after TSS. Simple regression analysis revealed that the change of %FMD showed a significant negative correlation with that of LDL-C, but not of IGF-1 or GH, in responders. In conclusion, it is suggested that endothelial dysfunction associated with active acromegaly improves soon after TSS, which is related to LDL-C and/or insulin resistance, but not to excess GH and/or IGF-1 itself.

Late-night salivary cortisol as a screening test for the diagnosis of Cushing's syndrome in Japan.

Measurement of late-night and/or midnight salivary cortisol currently used in US and European countries is a simple and convenient screening test for the initial diagnosis of Cushing's syndrome (CS). Unfortunately, this test has not been widely used in Japan. The purpose of this study was to evaluate the usefulness of the measurement of late-night salivary cortisol as a screening test for the diagnosis of CS in Japan. We studied 27 patients with various causes of CS, consisting of ACTH-dependent Cushing's disease [5] and ectopic ACTH syndrome [4] and ACTH-independent adrenal CS [11] and subclinical CS [7]. Eleven patients with type 2 diabetes and obesity and 16 normal subjects served as control group. Saliva samples were collected at late-night (23:00) in a commercially available device and assayed for cortisol by radioimmunoassay. There were highly significant correlations (P<0.0001) between late-night serum and salivary cortisol levels in normal subjects (r = 0.861) and in patients with CS (r = 0.788). Late-night salivary cortisol levels in CS patients (0.975 +/- 1.56 microg/dl) were significantly higher than those in normal subjects (0.124 +/- 0.031 microg/dl) and in obese diabetic patients (0.146 +/- 0.043 microg/dl), respectively. Twenty-five out of 27 CS patients had late-night salivary cortisol concentrations greater than 0.21 microg/dl, whereas those in control group were less than 0.2 microg/dl. Receiver operating characteristic curve (ROC) analysis showed that the cut-off point of 0.21 microg/dl provides a sensitivity of 93% and a specificity of 100%. Therefore, it is concluded that the measurement of late-night salivary cortisol is an easy and reliable noninvasive screening test for the initial diagnosis of CS, especially useful for large high-risk populations, such as diabetes and obesity.

Differential gene expression in ACTH -secreting and non-functioning pituitary tumors.

OBJECTIVE: Differential expression of several genes between ACTH-secreting pituitary tumors causing Cushing' disease (CD), silent corticotroph adenoma (SCA), and non-functioning pituitary tumors (NFT) was investigated. DESIGN AND METHODS: We used tissue specimens from 35 pituitary tumors (12 CD, 8 SCA, and 15 NFT). Steady-state mRNA levels of the genes related to proopiomelanocortin (POMC) transcription, synthesis, processing, and secretion, such as neurogenic differentiation 1 (NeuroD1), T-box 19 (Tpit), corticotropin releasing hormone receptor (CRHR), vasopressin receptor 1b (V1bR), prohormone convertase (PC) 1/3 and PC2, 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 1 and type 2, glucocorticoid receptor alpha (GRalpha), annexin A1, histone deacetylase 2 (HDAC2), and BRM/SWI2-related gene 1, were determined by real-time RT-PCR. RESULTS AND CONCLUSION: POMC and Tpit mRNA levels were greater in CD and SCA than those in NFT. NeuroD1 mRNA levels were less in CD than those in NFT, but almost comparable between SCA and NFT. PC1/3 mRNA levels were greater in CD, but less in SCA than those in NFT. PC2 mRNA levels in CD and SCA were less than those in NFT. CRHR, V1bR, and 11beta-HSD2 mRNA levels in CD were greater than those in SCA and NFT. HDAC2 mRNA levels in CD and SCA were lower than those in NFT. In conclusion, our study demonstrated that the genes related to transcription, synthesis, processing, and secretion of POMC are differentially regulated in ACTH-secreting pituitary tumors causing CD and SCA compared with those in NFT. This may partly explain the development of clinically active and inactive CD.

Defective expression of prohormone convertase 1/3 in silent corticotroph adenoma.

Silent corticotroph adenoma (SCA) is defined as an ACTH-producing pituitary tumor not associated with clinical and endocrine feartures of Cushing's syndrome, but its underlying molecular mechanism(s) remains unknown thus far. We tested the hypothesis that reduced expression of prohormone convertase (PC) 1/3 responsible for proteolytic processing of proopiomelanocortin (POMC) in SCA may lead to production of unprocessed, biologically inactive POMC and/or precursor of ACTH. Among 30 non-functioning pituitary macroadenomas (NFA) examined, we found 6 SCAs by immunohistochemical study using anti-ACTH antibody. Preoperative endocrine and diagnostic image tests did not reveal any differences between SCA and the remaining NFA except for the higher recurrence rate of SCA. While steady-state PC1/3 mRNA levels determined by RT-PCR were almost comparable between SCAs and NFAs, immunohistochemical study showed negative immunostaining for PC1/3 in all 6 SCAs. Our data suggest that defective PC1/3 expression may lead to preferential production of unprocessed, biologically inactive ACTH variants in SCA.

[Problems of cortisol assay: confusion in the diagnosis of preclinical Cushing's syndorme].

Cortisol assay is used for the diagnosis of hypothalamo-pituitary adrenal disorders. The Incidence of adrenal incidentaloma has been increasing with advances in imaging tools. The criteria for the diagnosis of preclinical Cushing's syndrome in Japan was made by the Nawata group supported by the Ministry of Health and Welfare in 1995. The presence of adrenal adenoma, a lack of overt signs of Cushing's syndrome and autonomic cortisol secretion are essential for the diagnosis of preclinical Cushing's syndrome. For the diagnosis of autonomy of cortisol secretion, cortisol should not be suppressed by either low dose dexamethasone (DEX) of 1 mg (cortisol > or =3 microg/dl) or high dose DEX of 8 mg (cortisol > or =1 microg/dl). We have reported that two doses of DEX suppression tests revealed a discrepancy in several cases of adrenal incidentaloma; therefore, we studied the cortisol values of DEX suppression tests in 47 cases with adrenal incidentaloma using four different cortisol kits (TFB, SPAC, TDX and TOSOH). Correlation between the kits was good; however, correlation coefficient in the low range (< or =5 microg/dl) among kits declined. In the inter assay, discrepant results of the cortisol level were seen in six cases after 1 mg of DEX and 18 cases after 8 mg of DEX. In the intra assay, discrepant results of cortisol after 1 mg of DEX and 8 mg of DEX were seen in 31 in TFB, 23 in SPAC, 24 in TDX and 25 in TOSOH. These results revealed that the clinical diagnosis varies according to the cortisol kit used. It is suggested that standardization of the cortisol assay is necessary for the accurate diagnosis of adrenal incidentaloma.

Subclinical Cushings disease with amelioration of metabolic comorbidities after removal of pituitary tumor.

A 49-year-old woman with hypertension, obesity and impaired glucose tolerance (IGT) was admitted for evaluation of pituitary incidentaloma. Although she presented no Cushingoid feature, endocrine examination of hypothalamo-pituitary-adrenal (HPA) axis showed elevated basal plasma ACTH and cortisol levels, their lack of circadian rhythm, non-suppressibility to low-dose (1 mg) dexamethasone, and responsiveness to CRH, suggesting autonomous ACTH secretion from a pituitary tumor. She underwent transsphenoidal surgery, and was diagnosed as chromophobe adenoma with positive ACTH immunoreactivity. Postoperatively, her abnormal HPA axis was resolved, along with improvement of hypertension, obesity and IGT. Thus, her metabolic comorbidities are likely due to subclinical Cushings disease.

A Case of acromegaly associated with subclinical Cushing's disease.

A 54-year-old man with type 2 diabetes was referred to our hospital for endocrine evaluation of acromegaly. Physical examination showed typical acromegalic features without Cushingoid features. Magnetic resonance imaging of the brain revealed the presence of a pituitary macroadenoma. Basal plasma levels of GH and insulin-like growth factor-I under fasting hyperglycemia (202 mg/dl) were markedly elevated. Plasma GH levels paradoxically increased after stimulation with TRH and LH-RH, and decreased after bromocriptine and octreotide administration. Endocrine examination of the hypothalamo-pituitary-adrenal (HPA) axis showed a lack of circadian rhythm of ACTH and cortisol, non-suppressibility to low-dose (1 mg), but suppressibility to high-dose (8 mg) dexamethasone, and normal response to CRH stimulation. The tumor resected by transsphenoidal surgery was histopathologically consistent with the diagnosis of eosinophilic adenoma: positive immunoreactivities of GH, PRL and ACTH were demonstrated, but negative immunoreactivities of prohormone convertase (PC) 1/3 by immunohistochemical method. After surgery, plasma GH and IGF-I levels decreased along with normalization of HPA axis. Metabolic co-morbidities such as diabetes and hypertension disappeared after removal of the pituitary tumor. This is a very rare case of GH-producing pituitary adenoma causing typical acromegaly with concomitant production of ACTH causing subclinical Cushing's disease.

Glucose-responsive and octreotide-sensitive insulinoma.

Insulinoma is the most common cause of fasting hypoglycemia resulting from autonomous insulin hypersecretion. We describe herein a unique case with paradoxical hypoglycemic episodes induced by hyperglycemia. A 55-year-old female had repeated hypoglycemic episodes after meal or during increased physical activity. Although fasting (10 hr) failed to provoke hypoglycemia, oral glucose tolerance test (GTT) caused an exaggerated insulin response (885 microU/ml) at 30 min, followed by hypoglycemia (36 mg/dl) after 90 min. Moreover, intravenous GTT also induced an exaggerated insulin response (>2900 microU/ml) at 10 min, followed by hypoglycemia (34 mg/dl) after 40 min. Although MRI and CT scan of the abdomen failed to detect any mass lesions in the pancreas, Octreoscan revealed increased radioactive uptake around the pancreatic head region. Treatment with a daily injection of octreotide (100 microg) alleviated her hypoglycemic episodes. At surgery, two islet cell adenomas were identified in the pancreas and resected. Postoperatively, she was free from hypoglycemic episodes after meal. Postoperative oral and intravenous GTT did not induce hypoglycemia. Thus, this is a very rare case of glucose-responsive and octreotide-sensitive insulinoma in whom GTT and octreotide proved to be a useful provocation and treatment for hypoglycemic episodes.

A case of factitious adrenal insufficiency after vascular graft surgery caused by spurious immunometric assays.

A 70-year-old man with abdominal aortic aneurysm underwent surgical repair with Hemashield vascular graft. Postoperatively, he was found to have very low plasma cortisol levels, which failed to increase after stimulation with ACTH. A tentative diagnosis of adrenal insufficiency was made despite the lack of its clinical manifestations and a replacement therapy with hydrocortisone was started. He had also elevated plasma levels of TSH, thyroid hormones and estrogen without any clinical manifestations. Such abnormal hormone levels were spontaneously normalized three months after operation, which was later proven to be factitious by different immunometric assays (IMA). Since the vascular graft coated with bovine type I collagen has been reported to induce a transient immune response in some patients after surgery, we speculated that certain antibodies generated against heterologous collagen and/or yet-unknown components derived from the graft may have caused such factitious data; exogenous addition of bovine type I collagen and albumin to patient's serum, however, failed to affect the assay results. Whatever the cause, caution must be paid that some patients with surgical repair using heterologous materials may have such factitious hormone data by IMAs.

A case of estrogen-secreting adrenocortical carcinoma with subclinical Cushing's syndrome.

A 25-year-old man was found to have a large right adrenal mass detected by abdominal echography and computed tomography, and presented with a mild gynecomastia. Endocrine study showed increased serum concentrations and urinary excretion of estrogens and dehydroepiandorosterone sulfate (DHEA-S). The patient had no Cushingoid features but autonomous cortisol secretion, compatible with the diagnosis of subclinical Cushing's syndrome. Surgical removal of the adrenal tumor led to normalization of serum and urinary excretion of estrogens and DHEA-S. Histopathological examination revealed a high-grade adrenocortical carcinoma (ACC). The disorganized expression of all the steroidogenic enzymes in individual tumor cells was demonstrated by immunohistochemical analysis, and the abundant expression of both aromatase mRNA and insulin-like growth factor (IGF)-II mRNA was shown by RT-PCR. These data suggest the excessive secretion of estrogen as well as the ineffective steroidogenesis by the adrenal tumor. This is a very rare case of estrogen-secreting ACC associated with subclinical Cushing's syndrome.