Is pasireotide-induced diabetes mellitus predictable? A pilot study on the effect of a single dose of pasireotide on glucose homeostasis.

INTRODUCTION: Pasireotide (PAS) is an effective treatment for Cushing's disease (CD) but its use is burdened by an associated high incidence of diabetes mellitus (DM). The aim of this study was to examine the effect of a single subcutaneous injection of PAS on glucose metabolism in CD, and to identify predictors of DM onset. METHODS: Fifteen patients with CD (13 females, 2 males; median age 43 years [IQR 34-50]) were submitted to an acute PAS test (600 µg s.c.), measuring glucose, insulin, C-peptide, GIP, glucagon, GLP-1, ACTH, and cortisol at the baseline and every 30 min for 2 h. Then they were treated twice daily with PAS 600 µg, and followed up with clinical and hormone assessments for a median of 6 months [2-13]. RESULTS: PAS prompted a significant decrease in all hormonal parameters considered except for glycemia, which increased (as expected), reaching the highest value at 120' (p < 0.0001). Overall, 9/15 patients developed DM within 2 months of starting PAS therapy. There were no differences in age, weight, visceral adiposity, HOMA index, fasting glucose or severity of CD between patients who developed DM and those who did not. Baseline fasting glucagon levels were higher in the DM patients (17.95 [12.45-20.54] vs. 10.53 [8.11-12.33] pmol/L, p = 0.0256), and so were GIP and HbA1c levels (37 [5.5-39.5] vs. 29 [27-31.8] mmol/mol, p = 0.0008). Glucose at 120' was also significantly higher in the DM patients (9.5 [8.65-11.95] vs. 6.85 [4.48-9] mmol/L, p = 0.012). CONCLUSIONS: PAS was rapidly able to suppress insulin and incretin secretion, with a subsequent rise in glucose levels into the diabetic range. It also induced a significant inhibition of glucagon production. The patients at higher risk of DM during PAS therapy were those with higher glucagon levels, HbA1c > 34.5 mmol/mol, and a glucose peak after PAS administration > 9 mmol/L. CD patients with these features given PAS therapy should therefore be monitored more carefully.

Cushing's syndrome: Overview of clinical presentation, diagnostic tools and complications.

Cushing's syndrome (CS) is a severe condition that results from chronic exposure to elevated circulating cortisol levels; it is a rare but potentially life-threating condition, especially when not timely diagnosed and treated. Even though the diagnosis can be straightforward in florid cases due to their typical phenotype, milder forms can be missed. Despite the availability of different screening tests, the diagnosis remains challenging as none of the available tools proved to be fully accurate. Due to the ubiquitous effect of cortisol, it is easy understandable that its excess leads to a variety of systemic complications including hypertension, metabolic syndrome, bone damages and neurocognitive impairment. This article discusses clinical presentation of CS with an eye on the most frequent cortisol-related comorbidities and discuss the main pitfalls of first- and second-line tests in endogenous hypercortisolism diagnostic workup.

Approach to patients with pseudo-Cushing's states.

The distinction between pseudo-Cushing's states (PCS) and Cushing's syndrome (CS) poses a significant clinical challenge even for expert endocrinologists. A patient's clinical history can sometimes help to distinguish between them (as in the case of alcoholic individuals), but the overlap in clinical and laboratory findings makes it difficult to arrive at a definitive diagnosis. We aim to describe the most common situations that can give rise to a condition resembling overt endogenous hypercortisolism and try to answer questions that physicians often face in clinical practice. It is important to know the relative prevalence of these different situations, bearing in mind that most of the conditions generating PCS are relatively common (such as metabolic syndrome and polycystic ovary syndrome), while CS is rare in the general population. Physicians should consider CS in the presence of additional features. Appropriate treatment of underlying conditions is essential as it can reverse the hormonal abnormalities associated with PCS. Close surveillance and a thorough assessment of a patient's hormone status will ultimately orient the diagnosis and treatment options over time.

The medical treatment with pasireotide in Cushing's disease: an Italian multicentre experience based on "real-world evidence".

A phase III study has demonstrated that 6-month pasireotide treatment induced disease control with good safety in 15-26% of patients with Cushing's disease (CD). The aim of the current study was to evaluate the 6-month efficacy and safety of pasireotide treatment according to the real-world evidence. Thirty-two CD patients started pasireotide at the dose of 600 µg twice a day (bid) and with the chance of up-titration to 900 µg bid, or down-titration to 450 or 300 µg bid, on the basis of urinary cortisol (UC) levels or safety. Hormonal, clinical and metabolic parameters were measured at baseline and at 3-month and 6-month follow-up, whereas tumour size was evaluated at baseline and at 6-month follow-up. At baseline, 31 patients had very mild to moderate disease and 1 patient had very severe disease. Five (15.6%) patients discontinued treatment for adverse events; the remaining 27 patients (26 with very mild to moderate disease and 1 with very severe disease), reached 6-month follow-up. Considering the group of patients with very mild to moderate disease, responsiveness, defined by the normalization (<1 the upper limit of normal range, ULN) or near normalization (>1 and ≤1.1 ULN) of UC levels, was registered in 21 patients (full control in 19 and near control in 2), corresponding to 67.7% and 80.8% according to an "intention-to-treat" or "per-protocol" methodological approach, respectively. Weight, body mass index, waist circumference, as well as total and LDL-cholesterol significantly decreased, whereas fasting plasma glucose and glycated haemoglobin significantly increased. Hyperglycaemia was documented in 81.2%, whereas gastrointestinal disturbances in 40.6% of patients. In conclusion, in the real-life clinical practice, pasireotide treatment normalizes or nearly normalizes UC in at least 68% of patients with very mild to moderate disease, with consequent improvement in weight, visceral adiposity and lipid profile, despite the occurrence or deterioration of diabetes in the majority of cases, confirming the usefulness of this treatment in patients with milder disease and without uncontrolled diabetes.

Effects of pasireotide treatment on coagulative profile: a prospective study in patients with Cushing's disease.

INTRODUCTION: Cushing's disease (CD) is characterized by procoagulative profile. Treatment with cortisol-reducing medications might normalize the coagulation impairment potentially eliminating the risk of thromboembolic complications. AIM: The aim of this prospective study is to evaluate the effectiveness of 6-12 months of treatment with pasireotide (Signifor®, Novartis) 600 µg twice daily on coagulative factors in 21 patients (16 females, mean age 46 ± 12.2 years) with CD. Biochemical, hormonal (urinary free cortisol, UFC; late night salivary cortisol, LNSC; ACTH) and coagulative parameters as Protrombin time (PT), aPTT, factors VIII, IX and XI, antithrombin III, protein C, protein S, fibrinogen, were evaluated at baseline and during therapy. RESULTS: UFC showed a significant reduction from baseline (3.2 ± 1.8 vs. 1.0 ± 0.8, p < 0.0001) with normalization in 13/21 (61.9%) and in 7/16 (43.8%) at 6 and 12 months, respectively. On the same way LNSC returned to normal in 5/11 at 6 months, showing a trend to reduction (8.6 ± 5 vs. 4.1 ± 2.9), even though without statistical significance (p = 0.07). Throughout the treatment period there was an increase in serum glycaemia (5.5 ± 2.3 vs. 6.8 ± 2.3 mmol/L, p = 0.09), with a concomitant significant increase in HbA1c after 6 months (40.7 ± 8.4 vs. 50.7 ± 12.3 mmol/mol, p = 0.006). Regarding coagulative parameters, no differences were found neither in clotting nor in anticoagulant factors during therapy. No patients developed thrombotic complication during treatment. CONCLUSIONS: Pasireotide resulted an effective treatment in controlling hypercortisolism in more than half of CD patients with partial restoration also of circadian cortisol secretion. No significant improvements were observed on clotting factors; this fact might depend on persistence of typical alteration of CD, such as obesity and hypertension, and reflects also on the worsening in glucide metabolism induced by the drug. Clinical implications of persistent procoagulative impairment while on medical therapy should be considered.

Metyrapone treatment in Cushing's syndrome: a real-life study.

INTRODUCTION AND AIM: Medical treatment is increasingly used in patients with Cushing's syndrome (CS). Metyrapone (MET) is an inhibitor of 11ß-hydroxylase: retrospective studies reported a decrease of cortisol secretion in 50% of cases. We evaluated the effectiveness of MET in an observational study, considering the normalization of urinary-free cortisol (UFC) and late-night salivary cortisol (LNSC) levels. MATERIALS AND METHODS: We enrolled 31 patients with CS, treated with MET for at least 1 month (16 for primary treatment and 15 after surgical failure). A planned dose-titration regimen considering baseline UFC levels was adopted; MET dose was uptitrated until UFC normalization, surgery, or side effect occurrence. UFC and LNSC levels were routinely measured by liquid chromatography-tandem mass spectrometry. RESULTS: Patients were treated with a median dose of 1000 mg for 9 months. UFC and LNSC decreased quickly after the first month of treatment (-67 and -57% from baseline), with sustained UFC normalization up to 12 and 24 months (in 13 and 6 patients, respectively). UFC and LNSC normalized later (after 3-6 months) in patients with severe hypercortisolism (>5-fold baseline UFC). Regarding the last visit, 70 and 37% of patients normalized UFC and LNSC, respectively. Body weight reduction (-4 kg) was observed after UFC normalization. Severe side effects were not reported, half of the female patients complained of hirsutism, and blood pressure was not increased. CONCLUSIONS: MET therapy is a rapid-onset, long-term effective, and safe medical treatment in CS patients, achieving UFC normalization (in 70% of patients) more than cortisol rhythm recovery (in 37% of subjects).

Daily salivary cortisol and cortisone rhythm in patients with adrenal incidentaloma.

BACKGROUND AND AIM: Impaired cortisol rhythm is a characteristic feature of Cushing's Syndrome, nevertheless late night salivary cortisol (LNSC) is not suitable to detect subclinical hypercortisolism in patients with adrenal incidentaloma (AI). We studied daily salivary cortisol (F) and cortisone (E) rhythm in patients with AI. MATERIALS AND METHODS: Six saliva samples were collected from awakening to night in 106 patients with AI and 40 controls. F and E were measured with LC-MS/MS and daily F exposure was calculated with the area under the curve (AUC). RESULTS: Patients with serum cortisol after dexamethasone suppression test (DST) > 50 nmol/L showed higher morning F (15.5 ± 14.5 vs. 8.6 ± 5.5 nmol/L, p = 0.001), suppressed corticotropin levels (76 vs. 35%, p < 0.001) and increased daily F exposure (3795 ± 1716 vs. 2898 ± 1478, p = 0.012), especially in the morning (2035 ± 1267 vs. 1365 ± 777, p = 0.003), otherwise LNSC levels were similar. Salivary E and AUC levels were higher in patients with DST > 50 nmol/L. AUC was not correlated with urinary cortisol levels or adenoma size. F and E levels were similar among patients with unilateral or bilateral adenoma, or considering the presence of hypertension, dyslipidemia, diabetes, or cardiovascular events. CONCLUSION: Daily cortisol exposure, evaluated with AUC from multiple saliva collections, is increased in AI patients with serum cortisol > 50 nmol/L after DST, especially in the morning, leading to reduced corticotropin levels. Cortisol rhythm is preserved in patients with AI, remarking that LNSC is not a screening test for subclinical hypercortisolism.

Cardiovascular autonomic dysfunction in patients with idiopathic diabetes insipidus.

INTRODUCTION: Central diabetes insipidus (DI) is a rare disease characterized by the excretion of excessive volumes of dilute urine due to reduced levels of the antidiuretic hormone arginine vasopressin (AVP), caused by an acquired or genetic defect in the neurohypophysis. The aim of this study was to identify any autonomic dysfunction (AD) in patients with DI as a possible cofactor responsible for their reportedly higher mortality. METHODS: The study involved 12 patients (6 females) with central idiopathic DI and a well-controlled electrolyte balance, and 12 controls matched for age, sex and cardiovascular risk factors, who were assessed using the tilt, lying-to-standing, hand grip, deep breath, Valsalva maneuver and Stroop tests. RESULTS: The tilt test showed a significantly more pronounced decrease in both systolic (- 20.67 ± 18 vs. - 1.92 ± 6.99 mmHg, p = 0.0009) and diastolic blood pressure (- 10.5 ± 14.29 vs. - 1.5 ± 5 mmHg, p = 0.012) in patients than in controls. Three patients with DI had to suspend the test due to the onset of syncope. The lying-to-standing test also revealed a marked reduction in blood pressure in patients with DI (1.05 ± 0.13 vs. 1.53 ± 0.14, p = 0.0001). Similar results emerged for the Valsalva maneuver (Valsalva ratio, 1.24 ± 0.19 vs. 1.79 ± 0.11, p < 0.0001) and deep breath test (1.08 ± 0.11 vs. 1.33 ± 0.08, p < 0.0001). CONCLUSIONS: All the principal autonomic tests performed in the study were concordant in indicating that patients with central DI have an impaired autonomic nervous system function despite a normal hydroelectrolytic balance under desmopressin therapy. This impairment may reflect damage to the autonomic system per se and/or the absence of any vasoactive effect of AVP on vascular smooth muscle. In our opinion, patients with central DI should be educated on how to prevent orthostatic hypotension, and pharmacological treatment should be considered for patients with a more marked impairment.

Body Composition is Different After Surgical or Pharmacological Remission of Cushing's Syndrome: A Prospective DXA Study.

Patients with active Cushing's syndrome (CS) exhibit an increase of the visceral adipose tissue, increasing the risk of cardiovascular events. Until now, it is not yet clear whether remission of CS leads to a normalization of body composition, or if different strategies to control hypercortisolism could result in a different clinical outcome concerning adipose tissue distribution. Therefore, we analyzed body composition changes using dual-energy X-ray absorptiometry (DXA) in patients with CS in a prospective and controlled study. We considered 23 patients with CS, whose remission was achieved after surgery in 14 or gained with pharmacological treatment in 9 subjects. Clinical and DXA data (lean and fat mass in total body, trunk, and R1 box) were collected during active hypercortisolism and after sustained remission, defined as the normalization of both late night salivary and 24-h urinary cortisol levels, at least for 6 consecutive months. Healthy subjects, matched with CS for gender, age, and BMI, were considered as controls (n=25). After remission of hypercortisolism, body compositions of patients were similar to matched controls; fat mass in total body (-7.53%), trunk (-3.24%), and R1- box (-12.82%, all p<0.01) were decreased from baseline levels. Dividing patients by type of treatment, fat mass reduction was higher in those that achieved surgical remission of CS (total body -17.26%, trunk -22.73%, and R1 box -21.21%, all p<0.05). Surgical remission of hypercortisolism is characterized by improvement of body composition, particularly fat reduction, easily detectable with DXA during routine clinical practice.

Glucose Metabolism Abnormalities in Cushing Syndrome: From Molecular Basis to Clinical Management.

An impaired glucose metabolism, which often leads to the onset of diabetes mellitus (DM), is a common complication of chronic exposure to exogenous and endogenous glucocorticoid (GC) excess and plays an important part in contributing to morbidity and mortality in patients with Cushing syndrome (CS). This article reviews the pathogenesis, epidemiology, diagnosis, and management of changes in glucose metabolism associated with hypercortisolism, addressing both the pathophysiological aspects and the clinical and therapeutic implications. Chronic hypercortisolism may have pleiotropic effects on all major peripheral tissues governing glucose homeostasis. Adding further complexity, both genomic and nongenomic mechanisms are directly induced by GCs in a context-specific and cell-/organ-dependent manner. In this paper, the discussion focuses on established and potential pathologic molecular mechanisms that are induced by chronically excessive circulating levels of GCs and affect glucose homeostasis in various tissues. The management of patients with CS and DM includes treating their hyperglycemia and correcting their GC excess. The effects on glycemic control of various medical therapies for CS are reviewed in this paper. The association between DM and subclinical CS and the role of screening for CS in diabetic patients are also discussed.

Long-term glucocorticoid effect on bone mineral density in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

INTRODUCTION: Patients with 21-hydroxylase deficiency (21OHD) assume a lifelong glucocorticoid (GC) therapy. Excessive GC treatment increases the risk of osteoporosis and bone fractures, even though the role of substitutive therapy is not fully established: we analyzed the effect of GC dose on bone metabolism and bone mineral density (BMD) over time in patients with 21OHD. METHODS: We studied bone metabolism markers and BMD in 38 adult patients with 21OHD (19-47 years, 24 females and 14 males) and 38 matched healthy control. In 15 patients, BMD data were available at both baseline and after a long-term follow-up. RESULTS: BMD was lower in patients than in controls at lumbar spine (0.961±0.1g/cm(2) vs 1.02±0.113g/cm(2), P=0.014) and femur neck (0.736±0.128g/cm(2) vs 0.828±0.103g/cm(2), P=0.02); otherwise, after height correction, only femoral neck BMD was lower in patients (0.458±0.081g/cm(2) vs 0.498±0.063g/cm(2), P=0.028). In those 21OHD subjects with at least 10 years follow-up, we observed an increase in lumbar BMD (P=0.0429) and a decrease in femur neck BMD values (P=0.004). Cumulative GC dose was not related to bone metabolism or BMD. No patient experienced clinical fragility fractures. CONCLUSIONS: BMD values are decreased in patients with 21OHD, which are in part explained by decreased height, but not by the dose of glucocorticoids. Nevertheless, bone status should be carefully monitored in patients with 21OHD.

Second-line tests in the differential diagnosis of ACTH-dependent Cushing's syndrome.

INTRODUCTION: Diagnosing Cushing's syndrome (CS) can be a challenge, especially in ACTH-dependent CS, when it comes to detecting the origin of ACTH secretion. MATERIALS AND METHODS: Retrospective data were collected on 170 patients with ACTH-dependent CS (149 CD, 21 EAS) referring to two endocrinology units, focusing on three non-invasive tests: dexamethasone 8 mg overnight challenge (HDDST); corticotrophin-releasing hormone (CRH) assay and the desmopressin (DDAVP) test. RESULTS: Patients with EAS were slightly older and had higher ACTH, serum and urinary cortisol levels than patients with CD (p < 0.01). CD patients had a stronger ACTH and cortisol response after CRH injection (p < 0.0001), and a more pronounced reduction in cortisol levels after HDDST (p < 0.0001). A threshold percentage ACTH increase after CRH stimulation of 72.4 % was able to identify CD with a sensitivity (SE) of 76 % (95 % CI 68-83) and a specificity (SP) of 100 % (95 % CI 83-100). As for HDDST, a cortisol suppression >52.7 % below the basal level suggested a pituitary origin with a SE of 88 % (95 % CI 81-93) and a SP of 90 % (95 % CI 68-99). There were no cases of EAS with positive responses to both these tests. Increases in ACTH and cortisol levels after the DDAVP test were also higher in CD than in EAS (p < 0.01), though the SE and SP were lower. CONCLUSIONS: Patients with CD showed a stronger response to HDDST and CRH, and the adopted cut-offs showed a good SE and SP in discriminating them from patients with EAS. Concordant tests indicated CD when positive, whereas no response to either test was highly suggestive of EAS. The DDAVP test was of limited utility in the diagnostic phase. In conclusion, the choice of tests may play an important part in the differential diagnosis of ACTH-dependent CS.

A venous thromboembolism risk assessment model for patients with Cushing's syndrome.

Cushing's syndrome (CS) is associated with an incidence of venous thromboembolism (VTE) about ten times higher than in the normal population. The aim of our study was to develop a model for identifying CS patients at higher risk of VTE. We considered clinical, hormonal, and coagulation data from 176 active CS patients and used a forward stepwise logistic multivariate regression analysis to select the major independent risk factors for thrombosis. The risk of VTE was calculated as a 'CS-VTE score' from the sum of points of present risk factors. VTE developed in 20 patients (4 pulmonary embolism). The group of CS patients with VTE were older (p < 0.001) and had more cardiovascular events (p < 0.05), infections and reduced mobility (both p < 0.001), higher midnight plasma cortisol levels (p < 0.05), and shorter APTT (p < 0.01) than those without. We identified six major independent risk factors for VTE: age ≥69 years and reduced mobility were given two points each, whereas acute severe infections, previous cardiovascular events, midnight plasma cortisol level >3.15 times the normality and shortened APTT were given one point each. A CS-VTE score <2 anticipated no risk of VTE; a CS-VTE score of two mild risk (10 %); a CS-VTE score of three moderate risk (46 %); a CS-VTE score ≥4 high risk (85 %). Considering a score ≥3 as predictive of VTE, 94 % of the patients were correctly classified. A simple score helps stratify the VTE risk in CS patients and identify those who could benefit from thromboprophylaxis.

Screening Tests for Cushing's Syndrome: Urinary Free Cortisol Role Measured by LC-MS/MS.

INTRODUCTION AND AIM: As initial screening for Cushing's syndrome (CS), The Endocrine Society guidelines recommend one of the following: the 1-mg dexamethasone suppression test (DST) or late-night salivary cortisol (LNSC) or urinary free cortisol (UFC) measurement. We examined the diagnostic performance of the above-mentioned tests in a series of patients. MATERIALS AND METHODS: We retrospectively analyzed 137 patients with clinical conditions suggestive of hypercortisolism: 38 with confirmed CS diagnosis and 99 without (termed non-CS). UFC was measured by liquid chromatography tandem-mass spectrometry, whereas LNSC by the radioimmunometric method and serum cortisol were measured by a chemiluminescence immunoassay. RESULTS: Comparing CS vs non-CS, a cutoff of 138 nmol/L after 1-mg DST revealed the best specificity (SP; 97%), whereas the 50-nmol/L cutoff confirmed the best sensitivity (SE; 100%); the SE and SP for LNSC greater than 14.46 nmol/L were, respectively, 84% and 89%, whereas the SE and SP for UFC greater than 170 nmol per 24 hours, they were 97% and 91%. Overall, UFC revealed both a combined higher positive and a lower negative likelihood ratio among first-line tests (respectively 10.7 and 0.03). Computing a receiver-operating curve -contrast analysis to compare the power of each single test with that of the others, alone or combined (DST+LNSC, DST+UFC, and LNSC+UFC) or with that of all the tests together (DST+LNSC+UFC), the UFC assay was at least as good as all the other possible combinations. CONCLUSIONS: Measuring UFC by liquid chromatography tandem-mass spectrometry achieves the best accuracy in diagnosing CS among patients presenting with suspected hypercortisolism.

Age and the metabolic syndrome affect salivary cortisol rhythm: data from a community sample.

OBJECTIVE: Measurement of cortisol levels in saliva is a marker of free hormone. How salivary cortisol rhythm is affected by age, gender, the metabolic syndrome and estrogen-progestin therapy was evaluated in a community sample of adults. SUBJECTS AND METHODS: One hundred twenty volunteers recruited from the Hospital staff and family members of the Endocrinology Unit were instructed to collect 7 salivary samples: the first on awakening (F(0)) and 6 more (F(1.5), F(5), F(6), F(10), F(11.5) and F(14)) over the next 14 hours. Each volunteer also underwent a complete physical evaluation and a comprehensive medical history was taken. Salivary cortisol was measured using a radioimmunometric assay. Daily cortisol secretion was evaluated computing the Area Under the Curve (AUC(F0)(→)(F14)); the F(14)/F(0) ratio was calculated as a marker of cortisol rhythm. RESULTS: Median F(14) levels were higher in the subjects in the third tertile of age than in those falling in the second or in the first age tertile (respectively, 2.09 vs 1.33 vs 1.25 ng/mL, p=0.023 and p=0.006), in the hypertensive volunteers (2.44 vs 1.44 ng/mL, p=0.030) and in those with the metabolic syndrome (2.95 vs 1.4 ng/mL, p=0.002), with an elevated median F(14)/F(0) ratio (0.48 vs 0.19, p=0.006). According to the Kruskal-Wallis analysis of variance, the most important factor affecting F(14) value was age (p=0.001). AUC(F0)(→)(F14) was not influenced by gender, age, metabolic syndrome or estrogen-progestin therapy. CONCLUSIONS: While it did not affect the daily cortisol rate, late-night salivary cortisol levels were found to be increased in the subjects in the higher age tertile and in those with the metabolic syndrome.

Perioperative thromboprophylaxis in Cushing's disease: What we did and what we are doing?

PURPOSE: Cushing's disease (CD) is associated with an increased risk of thrombotic events, particularly after surgery. No guidelines are available on the management of patients with CD undergoing pituitary transsphenoidal surgery (TSS). We aimed to compare the effectiveness of different prophylactic procedures on the prevention of thrombotic events after surgery in CD. METHODS: We retrospectively collected data on 78 consecutive patients who underwent TSS for CD between 2001 and 2012 at Padova's Neurosurgical Unit, recording their hemostatic, hormonal and anthropometric parameters. Patients were divided into two groups according to their perioperative management. Group A (34 patients) received fractionated heparin for a maximum of 14 days after surgery. Patients in group B (44 patients) were given no early glucocorticoid replacement therapy, and treated with subcutaneous enoxaparin 4,000-8,000 U/daily (depending on their weight) for 30 days plus graduated elastic stockings until mobilization, and early ambulation. RESULTS: The whole cohort of patients had clotting and anticoagulant factors significantly higher than the normal range. The two groups were comparable for age, BMI, ACTH, urinary free cortisol levels, outcome of surgery, and main clotting parameters. The surgical procedure did not change during the study period. Three venous thrombotic events [venous thromboembolic events (VTE), 2 associated with pulmonary embolism] were recorded in group A, none in group B (p = 0.079). No hemorrhagic events were reported. CONCLUSIONS: Provoked thrombotic events pose a major problem in the management of CD patients after surgery, regardless of the procedure's outcome. The prophylactic regimen proposed in this paper afforded an efficacy prophylaxis against postoperative VTE in patients with CD. Due to the rarity of CD, a multicenter study on a larger sample of cases would be warranted in order to collect more thrombotic events.

The diagnostic performance of urinary free cortisol is better than the cortisol:cortisone ratio in detecting de novo Cushing's syndrome: the use of a LC-MS/MS method in routine clinical practice.

OBJECTIVE: The Endocrine Society Clinical Guidelines recommend measuring 24-h urinary free cortisol (UFF) levels using a highly accurate method as one of the first-line screening tests for the diagnosis of Cushing's Syndrome (CS). We evaluated the performance of UFF, urinary free cortisone (UFE), and the UFF:UFE ratio, measured using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. SUBJECTS AND METHODS: The LC-MS/MS was used to analyze UFF and UFE levels in 43 surgically confirmed CS patients: 26 with Cushing's disease (CD, 16 de novo and ten recurrences), 11 with adrenal CS and six with ectopic CS; 22 CD patients in remission; 14 eu-cortisolemic CD patients receiving medical therapy; 60 non-CS patients; and 70 healthy controls. Sensitivity and specificity were determined in the combined groups of non-CS patients, healthy controls, and CD in remission. RESULTS: UFF>170 nmol/24 h showed 98.7% specificity and 100% sensitivity for de novo CS, while sensitivity was 80% for recurrent CD patients, who were characterized by lower UFF levels. The UFF:UFE and UFF+UFE showed lower sensitivity and specificity than UFF. Ectopic CS patients had the highest UFF and UFF:UFE levels, which were normal in the CD remission patients and in those receiving medical therapy. CONCLUSIONS: Our data suggest high diagnostic performance of UFF excretion measured using LC-MS/MS, in detecting de novo CS. UFF:UFE and UFF+UFE assessments are not useful in the first step of CS diagnosis, although high levels were found to be indicative of ectopic CS.

Diagnosis and complications of Cushing's disease: gender-related differences.

OBJECTIVE: Cushing's disease (CD) presents a remarkable preponderance in female gender, with a female-to-male ratio of 3-8:1. The aim of this study was to evaluate gender-related differences in the presentation of CD, as regards: biochemical indices of hypercortisolism; sensitivity of diagnostic tests; clinical features and complications of disease. METHODS: We retrospectively studied 84 adult patients with CD, 67 women and 17 men, evaluated at diagnosis. We compared the features of the disease between the sexes and analysed the effect of gender on CD complications, adjusted for potential confounders (age, gonadal status, BMI, urinary free cortisol values). RESULTS: We observed no differences between males and females as regards age at diagnosis, disease duration and BMI. Men, compared with women, presented higher urinary free cortisol values (P < 0·001) and ACTH values (P < 0·05). As regards diagnostic tests, men presented a lower ACTH response to DDAVP stimulation (P < 0·05). The pituitary tumour itself was less easily visualized by pituitary MRI in males compared with females (P < 0·05). Furthermore, some complications of disease were more frequent or more severe in men, in particular hypokalaemia (P < 0·05), hypercoagulable state and osteoporosis at lumbar spine (P < 0·01), with consequent higher risk of vertebral fractures. Male gender was found to be an independent risk factor for dyslipidaemia, severity of hypertension, lumbar osteoporosis and fractures. CONCLUSIONS: Although CD is less frequent in male patients, in this gender, it presents with more florid clinical manifestations and may imply more diagnostic difficulties.

Performance of salivary cortisol in the diagnosis of Cushing's syndrome, adrenal incidentaloma, and adrenal insufficiency.

OBJECTIVE: Salivary cortisol has recently been suggested for studies on the hypothalamic-pituitary-adrenal (HPA) axis. The lack of circadian rhythm is a marker of Cushing's syndrome (CS), and some authors have reported that low salivary cortisol levels may be a marker of adrenal insufficiency. The aim of our study was to define the role of salivary cortisol in specific diagnostic settings of HPA axis disease. SUBJECTS AND METHODS: We analyzed morning salivary cortisol (MSC) and late-night salivary CORTISOL (LNSC) levels in 406 SUBJECTS: 52 patients with Cushing's disease (CD), 13 with ectopic CS, 17 with adrenal CS, 27 with CD in remission (a mean follow-up of 66±39 months), 45 with adrenal incidentaloma, 73 assessed as having CS and then ruled out for endogenous hypercortisolism, 75 with adrenal insufficiency, and 104 healthy subjects. RESULTS: A LNSC value above 5.24  ng/ml differentiated CS patients from controls with high sensitivity (96.3%) and specificity (97.1%); we found higher LNSC levels in ectopic CS patients than in CD patients. We found no difference in MSC and LNSC levels between patients with CD in remission and healthy subjects. Both MSC and LNSC levels were higher in patients with adrenal incidentaloma than in healthy controls. A MSC value below 2.65 ng/ml distinguished patients with adrenal insufficiency from controls with high sensitivity (97.1%) and specificity (93.3%). CONCLUSIONS: Salivary cortisol is a useful tool to assess endogenous cortisol excess or adrenal insufficiency and to evaluate stable CD in remission.