Iacopo Chiodini

AME Position Statement on Adrenal Incidentaloma.

OBJECTIVE To assess currently available evidence on adrenal incidentaloma and provide recommendations for clinical practice. DESIGN A panel of experts (appointed by the Italian Association of Clinical Endocrinologists (AME)) appraised the methodological quality of the relevant studies, summarized their results, and discussed the evidence reports to find consensus. RADIOLOGICAL ASSESSMENT Unenhanced computed tomography (CT) is recommended as the initial test with the use of an attenuation value of ≤10 Hounsfield units (HU) to differentiate between adenomas and non-adenomas. For tumors with a higher baseline attenuation value, we suggest considering delayed contrast-enhanced CT studies. Positron emission tomography (PET) or PET/CT should be considered when CT is inconclusive, whereas fine needle aspiration biopsy may be used only in selected cases suspicious of metastases (after biochemical exclusion of pheochromocytoma). HORMONAL ASSESSMENT: Pheochromocytoma and excessive overt cortisol should be ruled out in all patients, whereas primary aldosteronism has to be considered in hypertensive and/or hypokalemic patients. The 1 mg overnight dexamethasone suppression test is the test recommended for screening of subclinical Cushings syndrome (SCS) with a threshold at 138 nmol/l for considering this condition. A value of 50 nmol/l virtually excludes SCS with an area of uncertainty between 50 and 138 nmol/l. MANAGEMENT Surgery is recommended for masses with suspicious radiological aspects and masses causing overt catecholamine or steroid excess. Data are insufficient to make firm recommendations for or against surgery in patients with SCS. However, adrenalectomy may be considered when an adequate medical therapy does not reach the treatment goals of associated diseases potentially linked to hypercortisolism.

Diagnosis and Treatment of Subclinical Hypercortisolism

CONTEXT Subclinical hypercortisolism (SH) is a condition of biochemical cortisol excess without the classical signs or symptoms of overt hypercortisolism. It is thought to be present in the 5-30% of patients with incidentally discovered adrenal mass (adrenal incidentalomas), which in turn are found in 4-7% of the adult population. Therefore, SH has been suggested to be present in 0.2-2.0% of the adult population. Some studies suggested that this condition is present in 1-10% of patients with diabetes or established osteoporosis. The present manuscript reviews the literature on diagnostic procedures and the metabolic effect of the recovery from SH. EVIDENCE ACQUISITION A PubMed search was used to identify the available studies. The most relevant studies from 1992 to November 2010 have been included in the review. EVIDENCE SYNTHESIS The available data suggest that SH may be associated with chronic complications, such as hypertension, diabetes mellitus, overweight/obesity, and osteoporosis. The available intervention studies suggest that the recovery from SH may lead to the improvement of hypertension and diabetes mellitus. A retrospective study suggests that this beneficial effect could be predicted before surgery. CONCLUSIONS SH is suggested to be associated with some chronic complications of overt cortisol excess. Recovery from this condition seems to improve these complications. However, a large, prospective, randomized study is needed to confirm this hypothesis and to establish the best diagnostic approach to identify patients with adrenal incidentalomas who can benefit from surgery.

Longitudinal Evaluation of Vitamin D Status in Healthy Subjects from Southern Italy: Seasonal and Gender Differences

Abstract: Vitamin D status is currently considered among the relevant determinants of skeletal integrity. Since vitamin D levels present seasonal variations, we longitudinally studied young healthy men and women in order to investigate the related physiologic modifications of both calcium homeostasis and bone remodeling. Thirty-two men (mean age 39.4 ± 7.8 years) and 58 premenopausal women (aged 36.9 ± 6.4 years) from southern Italy were studied. In all subjects the following parameters were measured both in winter and in summer: serum calcium, phosphorus, creatinine, total alkaline phosphatase activity, 25-hydroxyvitamin D (25OHD), parathyroid hormone (PTH), osteocalcin (BGP), together with urinary calcium (Ca/Cr), total pyridinoline (Pyr/Cr) and deoxypyridinoline (d-Pyr/Cr), corrected for creatinine excretion. In both sexes 25OHD levels were significantly higher in summer, while PTH values were lower, than in winter. The prevalence of hypovitaminosis D, defined by concentrations of 25OHD lower than 30 nmol/l, was 17.8% in winter and 2.2% in summer in the whole sample, while it was 27.8% and 3.4%, respectively, among female subjects. Indeed male subjects did not display hypovitaminosis D, having throughout the year significantly higher calcium and 25OHD levels together with lower PTH values, than the women. Moreover, alkaline phosphatase total activity was more elevated in men both in winter and in summer. In women, during winter, bone remodeling markers levels were higher while urinary calcium levels were lower than in summer. In the whole sample serum 25OHD correlated positively with serum calcium and inversely with PTH. The seasonal percentage variations in PTH were inversely correlated with those of Ca/Cr. Our results show a relatively high prevalence of subclinical vitamin D deficiency among young healthy women from southern Italy. Significant gender-specific differences have been demonstrated in both calcium homeostasis and skeletal remodeling indexes; the seasonal fluctuations in the vitamin D–PTH axis are accompanied by cyclical variations of bone turnover rate, which were more pronounced in women.

Beneficial Metabolic Effects of Prompt Surgical Treatment in Patients with an Adrenal Incidentaloma Causing Biochemical Hypercortisolism

CONTEXT In patients with adrenal incidentalomas, subclinical hypercortisolism (SH) is associated with an increased prevalence of the metabolic syndrome. The effect of surgical/conservative approach is debated. OBJECTIVE The objective of the study was to determine the effect of the surgical and conservative approaches on the metabolic syndrome in patients with adrenal incidentalomas. DESIGN This was a retrospective longitudinal study (18-48 months follow-up). SETTING The study was conducted on an in- and outpatient basis. PATIENTS One hundred eight patients with adrenal incidentalomas were studied for the presence of SH, which was diagnosed in the presence of more than two of the following: urinary free cortisol greater than 70 microg per 24 h (193 nmol per 24 h), cortisol after 1 mg dexamethasone suppression test greater than 3.0 microg/dl (83 nmol/liter), ACTH less than 10 pg/ml (2.2 pmol/liter). INTERVENTIONS Surgery was performed in 25 patients with SH (group TrSH+) and 30 without SH (group TrSH-), whereas the conservative approach was chosen by 16 patients with SH (group UntrSH+) and 37 without SH (group UntrSH-). MAIN OUTCOME MEASURES During the follow-up, the improvement/worsening of body weight, blood pressure, or glucose and cholesterol levels was defined in the presence of a greater than 5% weight decrease/increase and following the European Society of Cardiology or the Adult Treatment Panel III criteria, respectively. RESULTS In group TrSH+, weight, blood pressure, and glucose levels improved (32, 56, and 48%, respectively) more frequently than in group UntrSH+ (12.5%, P = 0.05; 0.0%, P < 0.0001; 0.0%, P = 0.001; and 0.0%, P = 0.0014, respectively). In group UntrSH+, blood pressure, glucose, and low-density lipoprotein levels worsened more frequently (50.0, 37.5, and 50.0%, respectively) than in group TrSH+ (0.0%, P < 0.0001; 0.0%, P = 0.001; and 20.0%, P = 0.05, respectively). CONCLUSIONS Regarding the various components of the metabolic syndrome, in patients with adrenal incidentalomas and SH, surgery is beneficial.

Subclinical Hypercortisolism among Outpatients Referred for Osteoporosis

Context The Cushing syndrome is a well-recognized secondary cause of osteoporosis. Contributions The researchers looked for hypercortisolism in asymptomatic patients referred for osteoporosis testing. They identified 7 patients with the condition. Six had functioning adrenal masses and 1 had an adrenocorticotropic hormonesecreting pituitary adenoma. The prevalence of subclinical hypercortisolism among patients with T-scores of 2.5 or less and vertebral fractures was 10.8%. Caution The findings come from a referral setting and might not apply to patients in the community. Implication Subclinical hypercortisolism may be more common than is generally recognized in patients with osteoporosis. The Editors Hypercortisolism is a frequent cause of secondary osteoporosis (1). Overt endogenous hypercortisolism (Cushing syndrome) is a well-recognized cause of osteoporosis (2), but because its prevalence in the general population is low (1 per 500000 persons) (2), its contribution to osteoporosis in general populations is trivial. The terms subclinical Cushing syndrome and subclinical hypercortisolism describe altered adrenocorticotropic hormone (ACTH)cortisol homeostasis without the classic signs or symptoms of the Cushing syndrome (3). Subclinical hypercortisolism is more common than overt hypercortisolism, with an estimated prevalence of about 0.8 per 1000 individuals in the general population (3); however, this prevalence is probably underreported because of the lack of symptoms or signs in these patients (37). Several cross-sectional and longitudinal studies have suggested that these patients are at high risk for complications of hypercortisolism, such as diabetes and osteoporosis (816). Recent studies have indicated that subclinical hypercortisolism is more prevalent than previously thought in patients with type 2 diabetes (1719). However, studies on the prevalence of subclinical hypercortisolism in patients with osteoporosis are lacking. Some evidence suggests that osteoporotic fractures may be the presenting manifestations of otherwise-asymptomatic hypercortisolism (20). Moreover, a recent paper showed a difference in cortisol secretion between healthy participants and patients with established osteoporosis, possibly due to mild autonomous cortisol hypersecretion in some individuals (21). Thus, the prevalence of subclinical hypercortisolism in patients with osteoporosis may be underestimated. We therefore designed a study to assess the prevalence of subclinical hypercortisolism in patients referred to our outpatient clinics for evaluation of osteoporosis. Methods Setting and Participants The study was done at the Casa Sollievo della Sofferenza Scientific Institute, San Giovanni Rotondo, Foggia, Italy, and the San Giuseppe-Fatebenefratelli Hospital, Fatebenefratelli Research Association, Milan, Italy, from January 2005 to December 2005. We recruited 219 consecutive patients (200 women and 19 men) referred to our outpatient clinics for prevention or diagnosis and treatment of osteoporosis and who met the following inclusion criteria: 1) absence of any known secondary causes of osteoporosis (that is, past or current thyrotoxicosis, bowel disease, precocious or surgical menopause, chronic renal failure, chronic hepatic disease, eating disorders, or rheumatologic or hematologic disease); 2) absence of depression and alcoholism, which may enhance cortisol secretion; 3) no administration of drugs influencing bone, cortisol, and dexamethasone metabolism or cortisol secretion; and 4) no signs or symptoms of cortisol excess, including moon facies, striae rubrae, skin atrophy, or buffalo hump. All participants signed consent forms, and local ethical committees approved the study in accordance with the second Declaration of Helsinki. Testing Sequence The Figure shows the study flow diagram. All patients had spinal and femoral dual-energy x-ray absorptiometry and spinal radiography. They had outpatient testing for secondary causes of osteoporosis (general chemistry profile, calcium homeostasis measurements [serum calcium, phosphorus, alkaline phosphatase total activity, 24-hour urinary calcium], thyroid-stimulating hormone, antigliadin antibodies, and serum testosterone in men) and blood for cortisol measurement drawn at 8:00 a.m. after a 1-mg overnight dexamethasone suppression test. Participants with altered thyroid-stimulating hormone levels were tested for free thyroxine, antithyroglobulin, and antithyroperoxidase antibodies; those with high serum calcium levels were tested for serum parathyroid hormone. In patients with normal antigliadin antibodies but clinical suspicion of celiac disease, antiendomysial antibodies were also measured. Figure. Study flow diagram. All patients were subdivided on the basis of bone mineral density (BMD) (T-score of 2.5 or less [low BMD] or greater than 2.5 [normal BMD]) and vertebral fractures. ACTH = adrenocorticotropic hormone; Fx+ = presence of vertebral fractures; Fx = absence of vertebral fractures. Participants with serum cortisol levels greater than 50.0 nmol/L after the 1-mg overnight dexamethasone suppression test were hospitalized for further diagnostic investigations (case participants). Those with cortisol levels less than 50.0 nmol/L had no further evaluation, but antiosteoporotic therapy was started in those with osteoporosis. Among hospitalized patients, catheters were inserted in the forearm vein on the day of admission, and blood testing began the day after to avoid stress-related hypopituitaryadrenal axis activation due to venipuncture. Because inpatient status can in theory increase cortisol secretion (19), a control group of inpatients was recruited to estimate the prevalence of subclinical hypercortisolism in hospitalized participants (control participants). This group comprised 56 age- and sex-matched inpatients without diabetes, osteoporosis, or vertebral fractures who were consecutively hospitalized from January 2005 to December 2005. All hospitalized participants had serum cortisol levels measured at 9:00 a.m. after 2 days of low-dose (0.5 mg every 6 hours) dexamethasone suppression and at midnight, 2 measurements of 24-hour urinary free cortisol, and measurement of ACTH at 8:00 a.m. Subclinical hypercortisolism was diagnosed if participants had incomplete suppression of cortisol (>50.0 nmol/L) after the low-dose dexamethasone suppression test and a 24-hour urinary free cortisol level greater than 165.6 nmol/d (normal range, 22.2 to 165.6 nmol/d) and/or midnight cortisol level greater than 207 nmol/L (normal range, 0.0 to 138.5 nmol/L) (3, 7, 8, 2123). The cutoff value of 165.6 nmol/d for urinary free cortisol corresponds to the 97th percentile value of 70 healthy control participants (20 men and 50 women; age, 35 to 65 years; body mass index, 20 to 40 kg/m2) who were recruited in our center as a reference population for urinary free cortisol. The cutoff value of 207.0 nmol/L for midnight cortisol is the standard for diagnosing hypercortisolism when overt Cushing syndrome is clinically suspected (2). Terzolo and colleagues (24) proposed a cutoff value of 148.8 nmol/L for diagnosing subclinical hypercortisolism, but we used the greater value because we lack reference midnight cortisol values in our center and wanted to increase specificity. Participants with subclinical hypercortisolism and an ACTH level of 2.2 pmol/L or less (normal range, 1.1 to 11.0 pmol/L) had abdominal computed tomography. Patients with subclinical hypercortisolism and ACTH levels greater than 2.2 pmol/L had abdominal computed tomography, nuclear magnetic resonance of the pituitary region, and additional biochemical tests (serum cortisol measurement after 8-mg overnight dexamethasone suppression and serum ACTH and cortisol measurement after stimulation with corticotropin-releasing hormone). Whole-body computed tomography was done when an ectopic source of ACTH hypersecretion was suspected (25). Subclinical hypercortisolism in patients with type 2 diabetes can be attributed mainly to adrenal masses (19). Because incidentally discovered adrenal lesions (adrenal incidentalomas) are frequently found in otherwise-healthy persons (4), we performed abdominal computed tomography in a subset of patients who tested positive after the 1-mg overnight dexamethasone suppression test but were classified as having no subclinical hypercortisolism. Testing Procedures In all patients, bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (Hologic Discovery, Bedford, Massachusetts) at the spine (in vivo precision at L1 to L4, 1.0%) and total and femoral neck (in vivo precision, 1.8% and 2.3%, respectively). Individual BMD values were expressed as SD units (T-scores) relative to the reference population of our center, which included 382 healthy female participants (26). Conventional spinal radiographs in lateral (T4 to L4) and anteroposterior (L1 to L4) projections were obtained in all participants by using a standard technique. Two trained radiologists who were blinded to BMD and hormonal data independently reviewed the radiographs. Vertebral fractures were diagnosed on visual inspection by using the semiquantitative method described by Genant and colleagues (27), in which fractures assessed on lateral thoracolumbar spine radiographs were defined as a reduction of more than approximately 20% in anterior, middle, or posterior vertebral height. Fractures were graded by severity and were graded as I, II, or III on the basis of the height reduction (20% to 25%, 25% to 40%, or >40%, respectively). The radiologists discussed questionable cases for consensus on a diagnosis; the interrater reliability between the 2 radiologists was good (= 0.85). The 2-day, low-dose dexamethasone suppression test was done after ACTH, 24-hour urinary free cortisol, and midnight cortisol levels were measured. Every 6 hours, 0.5 mg of dexamethasone was administrated orally, and serum cortisol was measured at 9:00 a.m., 4

Cortisol Secretion in Patients With Type 2 Diabetes Relationship with chronic complications

OBJECTIVE—The presence of an enhanced cortisol secretion in patients with type 2 diabetes is debated. In type 2 diabetic subjects, cortisol secretion was found to be associated with the complications and metabolic control of diabetes. We evaluated cortisol secretion in 170 type 2 diabetic subjects and in 71 sex-, age-, and BMI-matched nondiabetic subjects. RESEARCH DESIGN AND METHODS—In all subjects, we evaluated ACTH at 8:00 a.m. in basal conditions and serum cortisol levels at 12:00 p.m. (F24) and at 9:00 a.m. after a 1-mg overnight dexamethasone suppression test and 24-h urinary free cortisol (UFC). In diabetic patients, we evaluated the presence of chronic complications (incipient nephropathy, asymptomatic neuropathy, background retinopathy, and silent macroangiopathy). Patients were subdivided according to the absence (group 1, n = 53) or presence (group 2, n = 117) of diabetes complications. RESULTS—In group 2, UFC (125.2 ± 4.6 nmol/24 h) and F24 (120.6 ± 4.1 nmol/l) were higher than in group 1 (109.2 ± 6.8 nmol/24 h, P = 0.057, and 99.7 ± 6.1 nmol/l, P = 0.005, respectively) and in nondiabetic patients (101.7 ± 5.9 nmol/24 h, P = 0.002, and 100.3 ± 5.3 nmol/l, P = 0.003, respectively). In diabetic patients, the number of complications was associated with F24 (R = 0.345; P < 0.0001) and diabetes duration (R = 0.39; P < 0.0001). Logistic regression analysis showed that the presence of diabetes complications was significantly associated with F24, sex, duration of diabetes, and glycated hemoglobin. CONCLUSIONS—In type 2 diabetic subjects, hypothalmic-pituitary-adrenal activity is enhanced in patients with diabetes complications and the degree of cortisol secretion is related to the presence and number of diabetes complications.

Bone Mineral Density, Prevalence of Vertebral Fractures, and Bone Quality in Patients with Adrenal Incidentalomas with and without Subclinical Hypercortisolism: An Italian Multicenter Study

CONTEXT In patients with adrenal incidentalomas and subclinical hypercortisolism (SH), the factors influencing bone and the prevalence of vertebral fractures are debated. Spinal deformity index (SDI), which reflects bone quality, has never been evaluated. OBJECTIVE The objective of the study was to investigate in these patients SDI and factors influencing the prevalence of fractures. DESIGN This was a retrospective, multicenter study. SETTING The study was conducted on an in- and outpatient basis. PATIENTS Patients included 287 adrenal incidentaloma patients (111 eugonadal males, 31 premenopausal, 145 postmenopausal females) and 194 controls (90 eugonadal males, 29 premenopausal, 75 postmenopausal females). MAIN OUTCOME MEASURE Bone mineral density (BMD) was measured by dual X-ray absorptiometry at lumbar spine and femoral neck. By radiograph each vertebra was assessed as intact (grade 0) or grade 1 (20-25%), 2 (25-40%), or 3 (>40%) deformity; SDI was calculated by summing the grade of deformity for each vertebra. SH was diagnosed in the presence of at least two of the following: urinary free cortisol greater than 70 microg per 24 h (193.1 nmol/liter), cortisol after 1-mg dexamethasone test greater than 3.0 microg/dl (>82.8 nmol/liter), ACTH less than 10 pg/ml (<2.2 pmol/liter). RESULTS BMD was significantly lower in SH+ than SH- patients and controls (lumbar spine -0.73 +/- 1.43, 0.17 +/- 1.33, 0.12 +/- 1.21, respectively; femoral neck -0.37 +/- 1.06, 0.07 +/- 1.09, 0.17 +/- 1.02). Patients with SH had higher fracture prevalence and SDI than those without SH and controls (70.6, 22.2, 21.8%, respectively, P < 0.0001; 0.31 +/- 0.68, 0.39 +/- 0.93, 1.35 +/- 1.27, respectively, P < 0.0001). Fractures and SDI were associated with SH (odds ratio 7.27, 95% confidence interval 3.94-13.41, P = 0.0001; beta = 0.352, t = 6.241, P = 0.0001, respectively) regardless of age, BMD, menopause, and gender. CONCLUSION SH is associated with low BMD, high fracture prevalence, and reduced bone quality as measured by SDI.

Differential expression of microRNAs in human parathyroid carcinomas compared with normal parathyroid tissue

Parathyroid carcinoma (PaC) is a rare cause of primary hyperparathyroidism. Though the loss of the oncosuppressor CDC73/HRPT2 gene product, parafibromin, has been involved in the hyperparathyroidism-jaw tumor syndrome and in a consistent set of sporadic PaCs, parathyroid carcinogenesis remains obscure. MicroRNAs are a new class of small, non-coding RNAs implicated in development of cancer, since their deregulation can induce aberrant expression of several target genes. The aim of the present study was to identify differentially expressed microRNAs in parathyroid cancers compared with normal tissues. We performed a TaqMan low-density array profiling of four parathyroid cancers harboring CDC73 inactivating mutations and negative for parafibromin immunostaining. Their microRNA profiling was compared with that of two normal parathyroid biopsies. Out of 362 human microRNAs assayed, 279 (77%) were successfully amplified. Fourteen and three microRNAs were significantly down- and over-expressed in parathyroid cancers respectively. Of these, miR-296 and miR-139 were down-regulated, and miR-503 and miR-222 were over-expressed with a null false discovery rate. Carcinomas could be discriminated from parathyroid adenomas by a computed score based on the expression levels of miR-296, miR-222, and miR-503 as miR-139 was similarly down-regulated in both cancers and adenomas. Finally, miR-296 and miR-222 levels negatively correlated with mRNA levels of the hepatocyte growth factor receptor-regulated tyrosine kinase substrate and p27/kip1 levels respectively. These results suggest the existence of an altered microRNA expression pattern in PaCs together with a potential role of miR-296 as novel oncosuppressor gene in these neoplasia.

Long-term follow-up in adrenal incidentalomas: an Italian multicenter study

CONTEXT The long-term consequences of subclinical hypercortisolism (SH) in patients with adrenal incidentalomas (AIs) are unknown. SETTING AND PATIENTS In this retrospective multicentric study, 206 AI patients with a ≥5-year follow-up (median, 72.3 mo; range, 60-186 mo) were enrolled. INTERVENTION AND MAIN OUTCOME MEASURES Adrenocortical function, adenoma size, metabolic changes, and incident cardiovascular events (CVEs) were assessed. We diagnosed SH in 11.6% of patients in the presence of cortisol after a 1 mg-dexamethasone suppression test >5 μg/dL (138 nmol/L) or at least two of the following: low ACTH, increased urinary free cortisol, and 1 mg-dexamethasone suppression test >3 μg/dL (83 nmol/L). RESULTS At baseline, age and the prevalence of CVEs and type 2 diabetes mellitus were higher in patients with SH than in patients without SH (62.2 ± 11 y vs 58.5 ± 10 y; 20.5 vs 6%; and 33.3 vs 16.8%, respectively; P < .05). SH and type 2 diabetes mellitus were associated with prevalent CVEs (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.1-9.0; and OR, 2.0; 95% CI, 1.2-3.3, respectively), regardless of age. At the end of the follow-up, SH was diagnosed in 15 patients who were without SH at baseline. An adenoma size >2.4 cm was associated with the risk of developing SH (sensitivity, 73.3%; specificity, 60.5%; P = .014). Weight, glycemic, lipidic, and blood pressure control worsened in 26, 25, 13, and 34% of patients, respectively. A new CVE occurred in 22 patients. SH was associated with the worsening of at least two metabolic parameters (OR, 3.32; 95% CI, 1.6-6.9) and with incident CVEs (OR, 2.7; 95% CI, 1.0-7.1), regardless of age and follow-up. CONCLUSION SH is associated with the risk of incident CVEs. Besides the clinical follow-up, in patients with an AI >2.4 cm, a long-term biochemical follow-up is also required because of the risk of SH development.

The limited role of midnight salivary cortisol levels in the diagnosis of subclinical hypercortisolism in patients with adrenal incidentaloma

OBJECTIVE The criteria for defining subclinical hypercortisolism (SH) are debated and a real gold standard test or combination of tests is lacking. Recently, late-night salivary cortisol (MSC) has been described as a sensitive and easy-to-perform marker for diagnosing overt hypercortisolism. No data are available on the role of MSC in the diagnosis of SH. The aim of this study was to evaluate the sensitivity and specificity of MSC levels in the diagnosis of SH in patients with adrenal incidentalomas (AI). METHODS In 103 (females/males, 69/34) patients with AI, MSC levels were studied. One milligram overnight dexamethasone suppression test (DST), urinary-free cortisol (UFC), and ACTH plasma levels were also evaluated. Patients were defined as affected by SH if they showed two of the following criteria: DST>83 nmol/l, ACTH <2.2 pmol/l, and UFC >193 nmol/24 h. RESULTS No difference in MSC levels in patients with SH (3.1+/-3.1 nmol/l) compared with patients without SH (2.2+/-2.8 nmol/l) was observed. In patients with SH, MSC levels were significantly correlated with DST (r=0.4, P<0.05). Using the cut-off of 5.1 nmol/l, the sensitivity and specificity of MSC levels for diagnosis of SH is 22.7 and 87.7% respectively. CONCLUSION In patients with AI, normal levels of MSC do not exclude SH, whereas high levels may suggest the presence of SH identified by conventional tests. Thus, MSC is not suitable as a screening test, although it may be used in conjunction with other tests as the confirming test in selected patients.