Bruno Ambrosi

Corticotropin tests for hypothalamic-pituitary- adrenal insufficiency: a metaanalysis.

CONTEXT The diagnostic value of tests for detecting hypothalamic-pituitary adrenal insufficiency (HPAI) is controversial. OBJECTIVE Our objective was to compare standard-dose and low-dose corticotropin tests for diagnosing HPAI. DATA SOURCES We searched the PubMed database from 1966-2006 for studies reporting diagnostic value of standard-dose or low-dose corticotropin tests, with patient-level data obtained from original investigators. STUDY SELECTION Eligible studies had more than 10 patients. All subjects were evaluated because of suspicion for chronic HPAI, and patient-level data were available. We excluded studies with no accepted reference standard for HPAI (insulin hypoglycemia or metyrapone test) if test subjects were in the intensive care unit or if only normal healthy subjects were used as controls. DATA EXTRACTION We constructed receiver operator characteristic (ROC) curves using patient-level data from each study and then merged results to create summary ROC curves, adjusting for study size and cortisol assay method. Diagnostic value of tests was measured by calculating area under the ROC curve (AUC) and likelihood ratios. DATA SYNTHESIS Patient-level data from 13 of 23 studies (57%; 679 subjects) were included in the metaanalysis. The AUC were as follows: low-dose corticotropin test, 0.92 (95% confidence interval 0.89-0.94), and standard-dose corticotropin test, 0.79 (95% confidence interval 0.74-0.84). Among patients with paired data (seven studies, 254 subjects), diagnostic value of low-dose corticotropin test was superior to standard-dose test (AUC 0.94 and 0.85, respectively; P<0.001). CONCLUSIONS Low-dose corticotropin test was superior to standard-dose test for diagnosing chronic HPAI, although it has technical limitations.

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.

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.

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.

Risk of new vertebral fractures in patients with adrenal incidentaloma with and without subclinical hypercortisolism: a multicenter longitudinal study

In patients with adrenal incidentalomas (AIs), cross‐sectional studies suggested the presence of an association between subclinical hypercortisolism (SH) and an increased prevalence of vertebral fractures (VFx) and spinal deformity index (SDI), which is a clinical index of bone quality. No longitudinal studies investigated the incidence of VFx and SDI changes over time in SH. The aim of this study was to evaluate VFx risk and SDI changes in SH over time. One‐hundred‐three consecutive AI patients were studied at baseline and after 12 and 24 months. Patients were divided into SH+ (n = 27) and SH– (n = 76) groups on the basis of the presence of two or more among urinary free cortisol greater than 70 µg/24 hours, serum cortisol after 1‐mg dexamethasone suppression test greater than 3.0 µg/dL, and adrenocorticotropic hormone (ACTH) less than 10 pg/mL in 2 or more of the 3 evaluations. At baseline and after 24 months, bone mineral density (BMD) by dual‐energy X‐ray absorptiometry and the presence of VFx and SDI by summing the grade of deformity for each vertebra were evaluated. At the end of follow‐up, the SH+ group showed a higher prevalence of VFx (81.5%) as compared with baseline (55.6%, p = .04) and a worsening of SDI (2.11 ± 1.85 versus 1.11 ± 1.47, p = .032) associated with SH regardless of age, gender, body mass index , BMD, baseline SDI, menopause duration [odds ratio (OR) = 12.3, 95% confidence interval (CI) 4.1–36.5, p = .001]. The incidence of new vertebral fractures was higher in the SH+ group (48%) than in the SH– group (13%; p = .001). It is concluded that subclinical hypercortisolism is associated with an increased risk of VFx and a possible deterioration of bone quality.

Subclinical hypercortisolism: correlation between biochemical diagnostic criteria and clinical aspects.

Objective  Subclinical hypercortisolism (SH) has been associated with increased prevalence of hypertension, type 2 diabetes mellitus, dyslipidaemia, central obesity, osteoporosis and vertebral fractures. We aimed to investigate the accuracy of different SH diagnostic criteria in predicting the presence of complications.

Failure of somatostatin and octreotide to acutely affect the hypothalamic-pituitary-adrenal function in patients with corticotropin hypersecretion

Although somatostatin inhibits a variety of pituitary and non-pituitary hormones, not univocal data on its effects on ACTH release have been reported so far. In this study we investigated the effects of somatostatin or octreotide on ACTH levels of patients with corticotropin hypersecretion: 7 patients with Addison’s disease, 2 patients previously adrenalectomized for Cushing’s disease, 4 patients with Cushing’s disease and 3 patients with ectopic ACTH syndrome. Plasma ACTH and Cortisol levels were determined after somatostatin (500μg over 60 min) infusion or octreotide (100μg sc) injection. In 5 other patients with Cushing’s disease ACTH and Cortisol responses to CRH (1 μ/kg iv) were evaluated in basal conditions and after octreotide acute administration. In no patients with Addison’s disease any inhibitory influence of somatostatin (Δ % = −21, −25) or octreotide (Δ % = −38 ± 12 vs −39 ± 12 after saline) on plasma ACTH was found. Somatostatin did not significantly inhibit plasma ACTH in the two patients previously adrenalectomized for Cushing’s disease and in 3 patients with Cushing’s syndrome; in other 4 patients with Cushing’s syndrome octreotide did not affect plasma ACTH levels. In 5 patients with Cushing’s disease the plasma ACTH and Cortisol responses to CRH were similar both before (ACTH from 9.9 ± 1.7 pmol/L to 19.4 ± 6.1 pmol/L; Cortisol from 496 ± 43.9 nmol/L to 923 ± 355 nmol/L) and after octreotide injection (ACTH from 8.8 ± 2.4 pmol/L to 19.1 ± 8.2 pmol/L; Cortisol from 510 ± 54.6 nmol/L to 735 ± 220 nmol/L). In conclusion, the acute administration of somatostatin or octreotide is not able to modify ACTH levels in patients with corticotropin hypersecretion either due to hypo-cortisolemic state or consequent to ACTH-secret-ing pituitary or ectopic tumors; moreover, octreotide does not affect the pituitary-adrenal responsiveness to CRH in patients with Cushing’s disease.

Effect of desmopressin on ACTH and cortisol secretion in states of ACTH excess.

To assess the ability of desmopressin administration to stimulate ACTH/cortisol secretion in patients with Cushings disease, either before or after surgery, and in patients with other states characterized by ACTH hypersecretion, and to compare the results with those obtained after CRH testing.