肾上腺意外瘤中亚临床库欣综合征临床研究

目的探讨肾上腺意外瘤中亚临床库欣综合征的临床及危害性。方法2000~2005年对上海交通大学医学院附属瑞金医院的23例亚临床库欣综合征患者进行血糖、血脂、血尿皮质醇、血皮质醇昼夜节律、地塞米松抑制试验检测和观察,并与同期25例肾上腺腺瘤型库欣综合征患者的结果比较。结果(1)亚临床库欣综合征组年龄大于肾上腺腺瘤型库欣综合征组,两组肥胖、高血压、糖代谢异常及高血脂的发生率比较差异无显著性意义,两组体重指数(BMI)、腰臀比、血压、血脂、血糖及胰岛素比较差异均无显著性意义。(2)亚临床库欣综合征组血皮质醇、日平均血皮质醇、夜间皮质醇占清晨分泌量百分比及24h尿游离皮质醇均低于肾上腺腺瘤型库欣综合征组,2mg地塞米松抑制试验后血皮质醇及尿游离皮质醇亦低,两组晨8h血促肾上腺皮质激素(ACTH)比较差异无统计学意义。结论亚临床库欣综合征患者可导致肥胖、高血压、高血脂及糖代谢异常的发生,对患者造成一定的危害,且危害程度与肾上腺腺瘤型库欣综合征相近。     

A patient with preclinical Cushing's syndrome and excessive DHEA-S secretion having unilateral adrenal carcinoma and contralateral adenoma.

We report a case of preclinical Cushing's syndrome in a 54-year-old male associated with bilateral adrenocortical tumours. Physical findings and general laboratory data were unremarkable except for mild hypertension (158/90 mmHg) and impaired glucose tolerance. Endocrinological evaluation revealed the presence of autonomous cortisol secretion including unsuppressible serum cortisol by 8 mg dexamethasone test (11 microg/dl), high serum DHEA-S (3580 ng/ml, normal: 400-3500) and increased urinary 17-KS excretion (31.0-35.8 mg/day, normal: 5.8-21.3). CT scan demonstrated the presence of tumours in both adrenals and bilateral adrenalectomy was subsequently performed. Histological examination of the resected specimens revealed an adrenocortical carcinoma on the right side and an adenoma on the left side with noticeable cortical atrophy in non-neoplastic adrenals. Immunohistochemical study of steroidogenic enzymes demonstrated that all the steroidogenic enzymes involved in cortisol biosynthesis were expressed in both right and left adrenal tumours. Enzymatic activities of 21, 17alpha, 18, 11beta-hydroxylases were detected in both right and left adrenals except for the absence of 11beta-hydroxylase activity in the left adrenal adenoma. Results of in vitro tissue steroidogenesis examined in short-term tissue culture of the specimens revealed no significant differences between carcinoma and adenoma in cortisol production, but the production of adrenal androgens in carcinoma was significantly higher than that in adenoma, which may indicate the importance of evaluating adrenal androgen levels in patients with adrenocortical neoplasms.     

Analysis of cortisol secretion in hormonally inactive adrenocortical incidentalomas: study of in vitro steroid secretion and immunohistochemical localization of steroidogenic enzymes.

Adrenal incidentalomas have recently increased in incidence, and thus it has become important to establish clinical management of these patients. It is also important to evaluate whether these tumors are different from preclinical or overt Cushing's syndrome in their steroidogenesis. In this study, we therefore examined steroidogenesis of hormonally inactive adrenal incidentalomas via short-term culture of tumor specimens, in addition to an immunohistochemical study of steroidogenic enzymes. Five patients (two men and three women) diagnosed with adrenocortical incidentaloma without any clinical signs of adrenocortical hormonal excess except for hypertension and disturbed glucose tolerance, were recruited for this study. Hormonal findings, including circadian rhythms for cortisol and ACTH secretion, the response of ACTH to CRH infusion and results of dexamethasone suppression test were all within normal limits in these patients. Immunoreactivity for all steroidogenic enzymes involved in cortisol production was detected in tumor cells in all cases examined. Results of in vitro steroidogenesis analysis using short-term culture revealed that levels of cortisol secretion varied among the cases. There were no differences in the immunolocalization of steroidogenic enzymes and/or the levels of cortisol secretion between these hormonally inactive tumors and preclinical and/or overt Cushing's syndrome. Dehydroepiandrosterone-sulfotransferase (DHEA-ST) immunoreactivity in nonneoplastic regions was suppressed in one case in which the tumor secreted cortisol similar to preclinical and/or overt Cushing's syndrome. These results demonstrate that the levels of in vitro steroid production and/or the immunolocalization of steroidogenic enzymes in hormonally inactive adrenocortical tumors vary markedly and are not overtly different from those of preclinical and/or overt Cushing's syndrome.     

Adrenal incidentaloma: a new cause of the metabolic syndrome?

A number of patients with adrenal incidentaloma are exposed to a slight degree of cortisol excess resulting from functional autonomy of the adrenal mass (usually a cortical adenoma). At present, there are only scant data on the unwanted effects of this endocrine condition referred to as subclinical Cushing's syndrome. The aim of the present study was to look for some features of the metabolic syndrome in patients with incidental adrenal adenoma. Forty-one patients (9 men and 32 women) bearing adrenal incidentaloma with typical computed tomography features of cortical adenoma were studied. For both patients and controls, exclusion criteria were age equal to 70 yr or greater, previous history of fasting hyperglycemia, or impaired glucose tolerance (IGT), severe hypertension, current use of medication or concomitant relevant illnesses, and body mass index (BMI) equal to 30 kg/m(2) or greater. Forty-one patients with euthyroid multinodular goiter accurately matched for sex, age, and BMI served for a 1:1 case-control analysis. The study design included an oral glucose tolerance test (75 g) and an endocrine workup aimed at the study of the hypothalamic-pituitary-adrenal axis. Age and BMI were fully comparable between patients (54.0 +/- 10.7 yr, 23.8 +/- 2.4 kg/m(2)) and controls (52.2 +/- 11.6 yr, 23.5 +/- 2.8 kg/m(2)). Fasting glucose and fasting insulin levels were not different between the two groups (4.96 +/- 0.61 mmol/liter vs. 4.88 +/- 0.58 mmol/liter; 67 +/- 34 pmol/liter vs. 59 +/- 32 pmol/liter), but the 2-h postchallenge glucose was significantly higher in patients than in controls (7.43 +/- 2.49 mmol/liter vs. 6.10 plus minus 1.44 mmol/liter, P = 0.01). Fifteen patients (36%) reached the World Health Organization criteria for IGT and two other patients (5%) reached those for diabetes, and 14% of the controls qualified for IGT (P = 0.01). No difference in the lipid pattern was seen between the two groups, but either systolic or diastolic blood pressure were higher in patients (135.4 +/- 15.5 mm Hg vs. 125.0 +/- 15.6 mm Hg, P = 0.003; 82.9 +/- 9.1 mm Hg vs. 75.3 +/- 6.6 mm Hg, P < 0.0001). We calculated the whole-body insulin sensitivity index derived from the oral glucose tolerance test that was significantly reduced in the patients (4.3 +/- 1.7 vs. 5.7 +/- 2.5, P = 0.01). In a multiple regression analysis, 2-h glucose was associated with BMI and midnight cortisol values (r(2) = 0.36, P = 0.002). The comparison of the patients with nonfunctioning adenoma (n = 29) with those with subclinical Cushing's syndrome (n = 12) yielded significant differences as to 2-h glucose and triglyceride levels, which were significantly higher in the second group (7.02 +/- 1.76 mmol/liter vs. 8.72 +/- 3.17 mmol/liter, P = 0.03; 1.06 +/- 0.4 mmol/liter vs. 1.73 +/- 0.96 mmol/liter, P = 0.002), but the insulin sensitivity index was conversely reduced (5.2 +/- 1.4 vs. 2.9 +/- 1.2, P < 0.0001). In conclusion, many patients with incidental adrenal adenoma display altered glucose tolerance, that may be explained by reduced insulin sensitivity, and increased blood pressure levels in comparison with carefully age- and BMI-matched controls. The slight hypercortisolism observed in some such patients may significantly contribute to this state of insulin resistance. Midnight serum cortisol appears as a sensitive marker of the metabolic effects of subclinical Cushing's syndrome.     

Variant of pre-clinical Cushing's syndrome: hypertension and hypokalemia associated with normoreninemic normoaldosteronism.

The case of a 48-year-old woman with a left adrenocortical adenoma and showing hypokalemia, hypertension and normoreninemic normoaldosteronism is reported. Basal plasma adrenocorticotrophic hormone (ACTH) and cortisol levels were within the reference ranges. The patient's plasma cortisol level decreased insufficiently at night, and was insufficiently decreased by nighttime administration of dexamethasone. She showed no Cushingnoid stigmata. Iodocholesterol scintigraphy revealed tumor-sided uptake alone. The plasma dehydroepiandrosterone-sulfate level was low-to-normal for her age. Metabolic alkalosis and increased potassium clearance after sodium thiosulfate loading were revealed. The plasma aldosterone level was within the normal range, but it was statistically higher than the range for patients with pre-clinical Cushing's syndrome. However, peripheral plasma renin activity (PRA) increased normally after the patient resumed an upright posture following furosemide administration. After adenomectomy the hypokalemia and hypertension were resolved, and the plasma ACTH, cortisol, and PRA remained within the reference ranges. The plasma aldosterone level decreased slightly, but also remained within the reference range after adenomectomy. Paradoxical hyperplasia in the non-neoplastic adrenal glomerulosa zone, which indicates primary aldosteronism, and slight atrophy of the non-neoplastic adrenal cortex, which indicates pre-clinical Cushing's syndrome, were demonstrated. These findings satisfied the criteria of pre-clinical Cushing's syndrome, but did not completely satisfy those of primary aldosteronism. However, the level of CYP11 B2 mRNA in the tumor was in the lower-limit of the range for adenomas associated with primary aldosteronism and was higher than the ranges for adenomas associated with pre-clinical Cushing's syndrome and overt Cushing's syndrome. Based on these results, this case was suspected to constitute a variant of pre-clinical Cushing's syndrome with slight hypersecretion of aldosterone.     

Clinical and histopathological evaluation of the adrenal incidentaloma

Clinically silent adrenal masses (incidentaloma) are incidentally discovered lesions, when noninvasive imaging methods (USG, CT, MRI) are performed for reasons other than known or suspected adrenal disease. Most studies report on a prevalence of adrenal incidentaloma range between 1% and 10% in radiological series. Between 1994 and 1999 we observed in our Department 57 patients with incidentalomas of adrenal glands. After endocrinological evaluation silent Cushing's syndrome was found in 2 cases (3.5%). Fifty two patients were qualified for surgery. Adrenocortical adenoma was diagnosed in 73.1%; adrenocortical carcinoma in 7.7%; pheochromocytoma in 7.7% and less frequent adrenal lesions in 11.5%. All adrenal carcinomas and malignant pheochromocytomas (11.5%) were found in tumors with diameter over 4 cm.     

Aberrant adrenal sensitivity to multiple ligands in unilateral incidentaloma with subclinical autonomous cortisol hypersecretion: a prospective clinical study

BACKGROUND: Incidentally discovered adrenal tumours are frequently associated with subclinical autonomous cortisol hypersecretion of unknown origin. Aberrant hormone receptors have been observed in case reports of overt Cushing's syndrome. The question arises as to whether such receptors may be present in the functioning adrenal incidentaloma, which is common and might be a subclinical stage of Cushing's syndrome. PATIENTS AND METHODS: Twenty-one consecutive patients with a unilateral incidentaloma, the biochemical features of subclinical cortisol hypersecretion and/or the scintigraphic features of an autonomously functioning adrenal adenoma were investigated for plasma cortisol responses to various stimuli: upright posture, meal, combined hypothalamic-hormones, the vasopressin analogue terlipressin, glucagon, angiotensin II, the serotonin 5-HT4 agonist cisapride, and ACTH. Six normal controls were similarly investigated. All subjects were studied during 8 mg per day dexamethasone in order to avoid any ACTH-dependent variation of plasma cortisol. RESULTS: The most constant responses in adrenal incidentalomas were observed after stimulation by terlipressin (18/20 patients, 28-415% cortisol increase) and cisapride (17/21 patients, 25-364% cortisol increase). Eighteen out of 21 patients responded to several stimuli (cortisol increase >or= 25%), and all responded to at least one stimulus other than ACTH, while such responses were absent in the controls. Plasma ACTH remained suppressed in all subjects throughout the study. CONCLUSIONS: Aberrant membrane receptors detected by in vivo stimulation tests appear to be common in autonomously functioning unilateral adrenocortical adenomas. These receptors may be involved in the modulation of cortisol secretion in adrenal incidentaloma, with potential therapeutic consequences for the control of subclinical cortisol hypersecretion.     

Adrenal adenoma with bilateral adrenocortical nodular change in a patient with Cushing's syndrome

We report a 57-year-old male patient with adrenocorticotrophin (ACTH)-independent Cushing's syndrome and long-standing hypertension. Both abdominal computed tomographic scan and magnetic resonance imaging revealed bilateral adrenal enlargement with the presence of a tumour in the left adrenal. Marked uptake of ¹³¹I-6β-iodomethyl-19-norcholesterol was observed only in the left adrenal gland. Left adrenalectomy and biopsy of the right adrenal gland were subsequently performed. Histological examination revealed the presence of an adrenocortical adenoma in the left adrenal with multiple adrenocortical nodules in both left and right non-neoplastic adrenals. Peri- and intraadrenal arteries and arterioles demonstrated marked arteriosclerotic vascular changes. Immunoreactivity for several steroidogenic enzymes was present in the tumour and markedly diminished in the non-neoplastic adrenals. This patient with Cushing's adenoma is considered to have developed adrenocortical nodules in the non-neoplastic adrenal possibly as a result of localized compensatory overgrowth of adrenocortical cells in response to ischaemic changes due to arteriopathy. When examining patients with Cushing's syndrome and bilateral adrenal enlargement, the possibility of concomitant adenoma and adrenocortical nodule formation should also be considered in the differential diagnosis.     

A case of acromegaly accompanied by adrenal preclinical Cushing's syndrome.

We encountered a 58-year-old woman with acromegaly accompanied by a cortisol-secreting adrenal tumor without clinical features of hypercortisolism. The simultaneous occurrence of these two endocrinopathies in one individual is extremely rare. She was diagnosed as having diabetes mellitus 8 years ago. Afterwards, in spite of insulin therapy, her hyperglycemia could not be well controlled. Her acromegaly and preclinical Cushing's syndrome were histopathologically proven to be due to a pituitary adenoma and an adrenocortical adenoma, respectively. Successful treatment for these endocrinopathies resulted in greatly improved blood sugar control because of a reduction in insulin resistance. In this case of preclinical Cushing's syndrome, replacement therapy with glucocorticoid was able to be discontinued at only 8 weeks after adrenalectomy, so that the period of necessary replacement was much shorter than that for overt Cushing's syndrome. This is the first report describing insulin resistance before and after treatment in a case of acromegaly accompanied by adrenal preclinical Cushing's syndrome.     

Improvement of insulin resistance in essential hypertension by long-acting Ca antagonist benidipine

To investigate whether the long-acting Ca channel blocker, benidipine improves insulin resistance in patients with essential hypertension, insulin sensitivity was measured using the steady state plasma glucose (SSPG) method in 11 or 14 nonobese and nondiabetic hypertensive subjects before and after treatment with benidipine or placebo, respectively, and 11 healthy control subjects. SSPG level was significantly higher in two hypertensive groups, indicating reduced insulin sensitivity than in controls. SSPG level significantly decreased after benidipine treatment, with a decrease of blood pressure. SSPG level and blood pressure did not change in the placebo group. As for oral glucose tolerance test, the area under the curve of insulin diminished significantly after benidipine treatment. SSPG level significantly correlated with intra-platelet Ca2+ concentrations in 9 hypertensive subjects. The long-acting Ca channel blocker benidipine has partially improved insulin resistance in essential hypertension, contributing to the prevention of atherosclerosis associated with insulin resistance.     

Subclinical Cushing's Syndrome

Clinically inapparent adrenal masses, or adrenal incidentalomas, are discovered inadvertently in the course of workup or treatment of unrelated disorders. Cortical adenoma is the most frequent type of adrenal incidentaloma accounting for approximately 50% of cases in surgical series and even greater shares in medical series. Incidentally discovered adrenal adenomas may secrete cortisol in an autonomous manner, that is not fully restrained by pituitary feed-back, in 5 to 20% of cases depending on study protocols and diagnostic criteria. A number of different alterations in the endocrine tests aimed to assess the function of the hypothalamic-pituitary-adrenal axis has been demonstrated in such patients. This heterogeneous condition has been termed as subclinical Cushing's syndrome, a definition that is more accurate than preclinical Cushing's syndrome since the evolution towards clinically overt hypercortisolism does occur rarely, if ever. The criteria for qualifying subclinical cortisol excess are controversial and we presently do not have sufficient evidence to define a gold standard for the diagnosis of subclinical Cushing's syndrome. An increased frequency of hypertension, central obesity, impaired glucose tolerance, diabetes and hyperlipoproteinemia has been described in patients with subclinical Cushing's syndrome; however, there is not evidence-based demonstration of its long-term complications and, consequently, the management of this condition is largely empirical. Either adrenalectomy or careful observation associated with treatment of metabolic syndrome has been suggested as treatment options because data are insufficient to indicate the superiority of a surgical or nonsurgical approach to manage patients with subclinical hyperfunctioning adrenal cortical adenomas. This work was partially supported by grants of the University of Turin (ex-60% funds).     

Subclinical Cushing's syndrome

Subclinical Cushing's syndrome (CS) is attracting increasing interest since the serendipitous discovery of an adrenal mass has become a rather frequent event owing to the routine use of sophisticated radiologic techniques. Cortical adenoma is the most frequent type of adrenal incidentaloma accounting for approximately 50% of cases in surgical series and even greater shares in medical series. Incidentally discovered adrenal adenomas may secrete cortisol in an autonomous manner that is not fully restrained by pituitary feedback, in 5 to 20% of cases depending on study protocols and diagnostic criteria. The criteria for qualifying subclinical cortisol excess are controversial and presently there is no consensus on a gold standard for the diagnosis of this condition. An increased frequency of hypertension, central obesity, impaired glucose tolerance, diabetes and hyperlipemia has been described in patients with subclinical CS; however, there is still no clear demonstration of the long-term complications of this condition whose management remains largely empirical. Either adrenalectomy or careful observation associated with treatment of the metabolic syndrome have been suggested as treatment options.     

Anthropometric,haemodynamic, humoral and hormonal evaluation in patients with incidental adrenocortical adenomas before and after surgery

OBJECTIVE: To compare clinical and humoral parameters before and after surgery in patients with incidental adrenocortical adenomas. DESIGN: Six patients with subclinical Cushing's syndrome and nine with non-functioning adenomas were investigated before and 12 Months after removal of the mass. METHODS: Anthropometric (body weight, body mass index and waist to hip ratio), haemodynamic (blood pressure and heart rate), metabolic (lipids and oral glucose tolerance test (OGTT)), hormonal (cortisol, plasma renin activity, aldosterone, androgens and catecholamines) and bone metabolism (hydroxyproline, parathyroid hormone, osteocalcin and ostase) parameters were evaluated. RESULTS: In the whole group, a significant decrease in body weight (69.7+/-3.5 vs 70.8+/-3.5 kg, P<0.03), in systolic (135.3+/-5.1 vs 145.6+/-4.9 mmHg, P<0.009) and diastolic (83.7+/-1.9 vs 91.0+/-3.5 mmHg, P<0.03) blood pressure and in glucose levels in response to OGTT (106.4+/-9.6 vs 127.5+/-6.5 mg/dl, P<0.05) was observed after surgery. All other parameters examined did not change significantly. This trend was also found in both groups separately. Analytical data showed a high frequency of overweight/obesity (66.6%), hypertension (66.6%) and impaired glucose profile (26.6%) in our patients, with a greater prevalence of these cardiovascular risk factors in the subclinical Cushing's syndrome group. After surgery, values normalized or improved in eight out of ten hypertensive patients and in three out of four patients with impaired glucose profile. CONCLUSIONS: Solid adrenocortical incidentalomas are associated with some cardiovascular risk factors which may be corrected after removal of the mass. Therefore, surgery may be an appropriate choice in patients with subclinical Cushing's syndrome but also in those with solid non-functioning adenomas and coexistent cardiovascular risk factors.     

Coronary artery disease risk predicted by insulin resistance, plasma lipids, and hypertension in people without diabetes

BACKGROUND: It has been shown that insulin resistance syndrome, including glucose intolerance, dyslipidemia, and hypertension, is frequently associated with coronary artery disease (CAD). However, their relative contributions and predictive power in the development of CAD are still unclear, particularly in persons without diabetes. METHOD: We examined these risk factors between 96 patients without diabetes but with angiographically documented CAD and 96 age-, sex-, and body mass index-matched healthy control subjects. Fasting plasma lipoprotein, glucose, and insulin concentrations in response to a 75-g oral glucose tolerance test were determined, and insulin sensitivity was measured by the insulin suppression test. RESULTS: Patients with CAD had significantly higher values of fasting glucose, glucose and insulin responses to oral glucose tolerance test, total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride and decreased high-density lipoprotein (HDL) cholesterol concentrations compared with those of healthy people (P < 0.02-0.001). Although the steady-state plasma insulin values were similar in both groups, the steady-state plasma glucose (SSPG) concentrations were significantly higher in patients with CAD (12.2+/-0.4 versus 8.1+/-0.4 mmol/L, P < 0.001) compared with healthy subjects. When HDL < 0.9 mmol/L, LDL cholesterol > or = 4.1 mmol/L, triglyceride > or = 2.3 mmol/L, SSPG > or = 10.5 mmol/L, and presence of hypertension were defined as separate risk factors for CAD, significantly higher odds-ratio values were observed in patients with CAD compared with healthy people. From logistic multiple regression analysis, SSPG was the strongest risk, followed by lowered HDL cholesterol, elevated triglyceride and LDL cholesterol, and hypertension, to predict CAD. These 5 factors accounted for 36% of total risk for development of CAD in persons without diabetes. CONCLUSIONS: Patients without diabetes with CAD have abnormal glucose metabolism, hyperinsulinemia, and insulin resistance. Degree of insulin resistance (SSPG values), plasma lipid values, and history of hypertension together accounted for one third of all risk for CAD, although degree of insulin resistance was the strongest risk factor.     

Forty-one cases of Cushing's syndrome: a comparison between Cushing's syndrome (adrenal adenoma) and Cushing's disease (adrenal hyperplasia)]

We experienced 41 cases of Cushing's syndrome (12 males and 29 females, 15 years old - 65 years old) during the last 20 years. These included 20 patients with unilateral adrenal adenoma (Cushing's syndrome), 19 patients with bilateral adrenal hyperplasia (Cushing's disease), one patient with adrenal carcinoma and one patient with primary adrenocortical nodular dysplasia (PAND). Moreover, these cases included some special ones, i.e. 5 cases with destructive thyroiditis after treatment, 2 cases with aggravation of arthritis after treatment, a case of Carney's complex with PAND, one case with paradoxical response to dexamethasone, and one case combined with empty sella syndrome. The most specific clinical signs were moon face (95% occurrence), hypertension (95%) and subcutaneous bruising (80%). Other significant signs were eye edema (66%), buffalo hump (68%), subcutaneous purpura (63%) and osteoporosis (49%). Skin striae was not a common sign in our cases (41%). Renal stone was observed in only 20% of our patients but was a significant sign in this syndrome. There was no difference in the occurrence of each clinical sign between Cushing's syndrome and Cushing's disease. The elevation of white blood cell count (WBC) and serum sodium, a decrease of serum potassium, and a decrease of reabsorption of phosphate (%TRP) were observed. Thyroid-stimulating hormone (TSH) and human growth hormone (HGH) were suppressed in patients with Cushing's syndrome and patients with Cushing's disease. These results were consistent with those of previous reports. However, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and prolactin (PRL) were high in those patients with Cushing's syndrome and those with Cushing's disease. Oral glucose tolerance test was carried out in 34 patients before and after treatment. Thirty-one percent of those had diabetes mellitus and 26% had impaired glucose tolerance (IGT). The response of IRI in this test was high in patients with Cushing's syndrome and patients with Cushing's disease, and decreased 4 weeks after treatment in those with Cushing's syndrome but remained high in those with Cushing's disease. Plasma ACTH level and urinary 17-OHCS excretion were significantly higher in Cushing's disease than in Cushing's syndrome. During an 8mg-high-dose dexamethasone suppression test, urinary 17-OHCS excretion in 13 of 14 patients with Cushing's disease (93%) was suppressed by more than 50% of baseline on the second day of testing. However, all of 18 patients with Cushing's syndrome, who had an 8mg-dexamethasone suppression test, failed to suppress urinary 17-OHCS by 50% of baseline.(ABSTRACT TRUNCATED AT 400 WORDS)     

A case of preclinical Cushing's disease,accompanied with thyroid papillary carcinoma and adrenal incidentaloma

A 75-year-old woman had tumors in her pituitary, thyroid and left adrenal gland. Plasma ACTH and cortisol levels were both mildly elevated. Both plasma ACTH and cortisol concentrations were partially suppressed by 1 mg of overnight dexamethasone suppression test, while both were inhibited with a dosage of 8 mg dexamethasone. Plasma ACTH and cortisol levels were increased in response to human CRH and desmopressin. Together with the observation of pituitary microadenoma, the patient had a pituitary ACTH-producing tumor. The patient, however, had no typical Cushingoid features, hypertension, or impaired glucose tolerance, suggesting that the tumor had an autonomic ACTH secretion that was insufficient for expressing clinical symptoms, the so-called preclinical Cushing's disease. A case of preclinical Cushing's disease is extremely rare. Further, the patient had thyroid papillary carcinoma and non-functioning adrenal tumor. Molecular genetic analysis demonstrated a polymorphism of the menin gene in the patient. Even without Cushingoid features in pituitary incidentaloma, we concluded that the elevated ACTH and cortisol levels should be followed up by CRH, desmopressin and dexamethasone suppression tests. This patient with preclinical Cushing's disease would be observed whether the physical conditions in the patient develop to overt Cushing's disease.     

Plasma 18-oxocortisol levels in the patients with adrenocortical disorders

OBJECTIVES 18-Oxocortisol (18oxoF) shares structural characteristics with cortisol and aldosterone and is secreted from the adrenal cortex. It has been reported that 18oxoF has weak gluco and mineralo-corticoid activities and increases blood pressure when administered to animals. We tried to clarify the characteristics of the production of 18oxoF in patients with adrenocortical disorders compared with the control subjects.
DESIGN AND PATIENTS In patients with primary aldosteronism due to aldosterone producing adenoma (APA) ( n = 21) and Cushing's disease or syndrome (Cushing's disease n = 13; adrenocortical adenoma n = 10), plasma 18oxoF level early in the morning following an overnight fast was evaluated as well as plasma cortisol and aldosterone levels.
RESULTS The plasma 18oxoF levels were significantly higher in the patients with adrenocortical disorders than in control subjects. The ratios of 18oxoF/cortisol and 18oxoF/ aldosterone were high in APA and in Cushing's disease and syndrome patients, respectively. In the control subjects and combined group of patients with Cushing's disease and syndrome, plasma 18oxoF level significantly correlated with plasma cortisol level but not with aldosterone level. However, in APA patients plasma 18oxoF level correlated significantly with both cortisol and aldosterone levels.
CONCLUSION The production of 18oxoF was elevated as a result of the hyperactivity of 18-hydroxylase and excess cortisol production in APA patients and in patients with Cushing's disease and syndrome, respectively. An excess 18oxoF production could be playing a role in the pathogenesis of hypertension in these patients. The correlation of plasma 18oxoF levels with plasma cortisol and aldosterone levels suggests that the production of 18oxoF is more dependent on the supply of cortisol than on 18-hydroxylase activity in normal subjects and patients with Cushing's disease and syndrome.     

Prevalence of subclinical Cushing's syndrome in 70 patients with adrenal incidentaloma: clinical, biochemical and surgical outcomes

Subclinical Cushing's syndrome (SCS) is being detected with increased frequency in patients with adrenal incidentaloma. In the current study, we evaluated the prevalence of SCS in 70 patients with adrenal incidentaloma and compared the main findings on them with other patients with nonfunctional adrenal incidentaloma (NFA). Overnight 3 mg dexamethasone (DXM) suppression test to exclude cortisol hypersecretion, and high dose DXM suppression test to find out patients with SCS, were applied to all subjects. Afterwards, biochemical and clinical findings of patients with SCS were compared with the other patients with NFA. Four of the 70 patients with adrenal incidentaloma were found to have SCS, with a prevalence of 5.7%. Basal ACTH and DHEA-S levels were significantly lower (p < 0.05 and p < 0.01, respectively), and midnight cortisol and 24-hour urinary free cortisol levels were significantly higher in patients with SCS (p < 0.001 and p < 0.05, respectively). Biochemical and metabolic bone parameters were similar in patients with SCS and in patients with NFA. Hypertension, diabetes mellitus, and obesity were more common in patients with SCS. One of the patients with SCS developed adrenocortical insufficiency following unilateral adrenalectomy which lasted for about 6 months. Suppressed ACTH and DHEA-S levels, and high midnight cortisol levels may be some clues for SCS in patients with adrenal incidentaloma. Since patients with SCS frequently have risk factors for atherosclerosis such as hypertension, diabetes, and obesity, and the surgical management of SCS with adrenalectomy may offer an advantage. Patients undergoing adrenalectomy should be followed for the development of adrenal insufficiency.     

Exacerbations of Graves' disease after unilateral adrenalectomy for Cushing's syndrome

Cushing's syndrome is characterized by endogenously increased production of glucocorticoids. The activity of immune system is regulated mainly by two systems in the body. Glucocorticoids and NF-kappaB counteract the effects of each other on the immune system. It has been reported that immune response is exaggerated after the amelioration of Cushing's syndrome. We report a rare case of exacerbation of Graves' disease after unilateral adrenalectomy for Cusing's syndrome. A 50-yr-obese woman with hypertension, dyslipidemia, impaired glucose tolerance and insulin resistance wasadmitted to outpatients clinic of endocrinology. The results of evaluation of glucocorticoids metabolism and adrenal magnetic resonance imaging revealed the Cusing's syndrome. We also assessed thyroid function tests because of the diagnosis of goiter and thyroid hormone replacement in her medical history, and the presence of exophthalmia and tachycardia in examination. Althoug TSH level was detected at the lower border of normal range, free T4 and free T3 were in normal range and autoantibody of thyroidal peroxidase and thyroglobulin was higer than normal reference range. An operation was performed and a mass was removed from her left adrenal gland. The pathologic examination confirmed adrenal adenoma. She was re-admitted to the outpatient clinic 9 months after with complaints of palpitation, malaise and weight loss. Tests carried out to determine the thyroid function revealed Graves' disease. We prescribed propylthiouracil and beta-blocker treatment.     

Normalization of Insulin Resistance in Non-Obese Essential Hypertension by Cilazapril Treatment

To determine whether ACE inhibitor other than captopril improves insulin sensitivity in patients with essential hypertension, we measured insulin sensitivity to glucose utilization using SSPG method in 10 lean hypertensive subjects before and after chronic cilazapril treatment (1.5±0.2 mg/day, 15.6±2.1 weeks). The results were compared with those obtained in 10 healthy control subjects. SSPG obtained by insulin sensitivity test was significantly higher in hypertensive subjects, indicating a lower insulin sensitivity than in controls. After cilazapril treatment, SSPG reduced significantly to the level which was statistically not different from control subjects. Hyperinsulinemia diminished after treatment, while no significant change of blood glucose was observed during oral glucose tolerance test in hypertensive subjects. Plasma HDL cholesterol increased by cilazapril treatment. Cilazapril treatment has beneficial effect in the reversal of insulin resistance in patients with essential hypertension.