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Objective: Gamma Knife radiosurgery (GKS) is typically used after failed resection in patients with Cushing's disease (CD) and acromegaly. Little is known about the upfront role of GKS for patients with CD and acromegaly. In this study, the authors examine the outcome of upfront GKS for patients with these functioning adenomas., Methods: An international group of 7 Gamma Knife centers sent pooled data from 46 patients (21 with CD and 25 with acromegaly) undergoing upfront GKS to the coordinating center of the study for analysis. Diagnosis was established on the basis of clinical, endocrine, and radiological studies. All patients were treated on a common radiosurgical platform and longitudinally followed for tumor control, endocrine remission, and hypopituitarism. Patients received a tumor median margin dose of 25 Gy (range 12-40.0 Gy) at a median isodose of 50%., Results: The median endocrine follow-up was 69.5 months (range 9-246 months). Endocrine remission was achieved in 51% of the entire cohort, with 28% remission in acromegaly and 81% remission for those with CD at the 5-year interval. Patients with CD achieved remission earlier as compared to those with acromegaly (p = 0.0005). In patients post-GKS, the pituitary adenoma remained stable (39%) or reduced (61%) in size. Hypopituitarism occurred in 9 patients (19.6%), and 1 (2.2%) developed third cranial nerve (CN III) palsy. Eight patients needed further intervention, including repeat GKS in 6 and transsphenoidal surgery in 2., Conclusions: Upfront GKS resulted in good tumor control as well as a low rate of adverse radiation effects in the whole group. Patients with CD achieved a faster and far better remission rate after upfront GKS in comparison to patients with acromegaly. GKS can be considered as an upfront treatment in carefully selected patients with CD who are unwilling or unable to undergo resection, but it has a more limited role in acromegaly.

Background: Surgery is the definitive treatment of Cushing's syndrome (CS) but medications may also be used as a first-line therapy. Whether preoperative medical treatment (PMT) affects postoperative outcome remains controversial., Objective: (1) Evaluate how frequently PMT is given to CS patients across Europe; (2) examine differences in preoperative characteristics of patients who receive PMT and those who undergo primary surgery and (3) determine if PMT influences postoperative outcome in pituitary-dependent CS (PIT-CS)., Patients and Methods: 1143 CS patients entered into the ERCUSYN database from 57 centers in 26 countries. Sixty-nine percent had PIT-CS, 25% adrenal-dependent CS (ADR-CS), 5% CS from an ectopic source (ECT-CS) and 1% were classified as having CS from other causes (OTH-CS)., Results: Twenty per cent of patients took PMT. ECT-CS and PIT-CS were more likely to receive PMT compared to ADR-CS ( P  < 0.001). Most commonly used drugs were ketoconazole (62%), metyrapone (16%) and a combination of both (12%). Median (interquartile range) duration of PMT was 109 (98) days. PIT-CS patients treated with PMT had more severe clinical features at diagnosis and poorer quality of life compared to those undergoing primary surgery (SX) ( P  < 0.05). Within 7 days of surgery, PIT-CS patients treated with PMT were more likely to have normal cortisol ( P  < 0.01) and a lower remission rate ( P  < 0.01). Within 6 months of surgery, no differences in morbidity or remission rates were observed between SX and PMT groups., Conclusions: PMT may confound the interpretation of immediate postoperative outcome. Follow-up is recommended to definitely evaluate surgical results., (© 2018 European Society of Endocrinology.)

Objective: To evaluate which tests are performed to diagnose hypercortisolism in patients included in the European Registry on Cushing's syndrome (ERCUSYN), and to examine if their use differs from the current guidelines., Patients and Methods: We analyzed data on the diagnostic tests performed in 1341 patients with Cushing's syndrome (CS) who have been entered into the ERCUSYN database between January 1, 2000 and January 31, 2016 from 57 centers in 26 European countries. Sixty-seven percent had pituitary-dependent CS (PIT-CS), 24% had adrenal-dependent CS (ADR-CS), 6% had CS from an ectopic source (ECT-CS) and 3% were classified as having CS from other causes (OTH-CS)., Results: Of the first-line tests, urinary free cortisol (UFC) test was performed in 78% of patients, overnight 1 mg dexamethasone suppression test (DST) in 60% and late-night salivary cortisol (LSaC) in 25%. Use of LSaC increased in the last five years as compared with previous years ( P  < 0.01). Use of HDDST was slightly more frequent in the last 5 years as compared with previous years ( P  < 0.05). Of the additional tests, late-night serum cortisol (LSeC) was measured in 62% and 48-h 2 mg/day low-dose dexamethasone suppression test (LDDST) in 33% of cases. ACTH was performed in 78% of patients. LSeC and overnight 1 mg DST supported the diagnosis of both PIT-CS and ADR-CS more frequently than UFC ( P  < 0.05)., Conclusions: Use of diagnostic tests for CS varies across Europe and partly differs from the currently available guidelines. It would seem pertinent that a European consensus be established to determine the best diagnostic approach to CS, taking into account specific inter-country differences with regard to the availability of diagnostic tools., (© 2017 European Society of Endocrinology.)

The objective of this study was to measure plasma fibroblast growth factor 21 and 19 (FGF21 and FGF19) levels in patients with Cushing's syndrome (CS) and to compare it with those of lean control subjects (C) and patients with obesity (OB). Fourteen untreated patients with CS, 19 patients with OB and 36 controls were included in the study. Plasma FGF21 and FGF19 levels were measured by ELISA kits, other hormonal and biochemical parameters were measured by standard laboratory methods. Plasma FGF19 did not significantly differ among the studied groups. Plasma FGF21 levels were significantly higher in both CS and OB groups relative to C group but they did not differ between CS and OB groups. In a combined population of all three groups FGF21 levels positively correlated with BMI, waist circumference and percentage of total and truncal fat mass. Less prominent inverse relationship with these parameters was found for FGF19. Neither FGF21 nor FGF19 were significantly related to cortisol concentrations. Increased FGF21 concentrations in both patients with CS and OB relative to lean subjects suggest that excessive body fat and/or related metabolic abnormalities rather than direct effects of cortisol are responsible. In contrast neither obesity nor hypercortisolism significantly affected FGF19 concentrations.

The aim of the study was to evaluate skin microvascular reactivity (MVR) and possible influencing factors (fibrinolysis, oxidative stress, and endothelial function) in patients with Cushing's syndrome. Twenty-nine patients with active Cushing's syndrome (ten of them also examined after a successful operation) and 16 control subjects were studied. Skin MVR was measured by laser Doppler flowmetry during post-occlusive (PORH) and thermal hyperemia (TH). Malondialdehyde and Cu,Zn-superoxide dismutase were used as markers of oxidative stress. Fibrinolysis was estimated by tissue plasminogen activator (tPA) and its inhibitor (PAI-1). N-acetyl-beta-glucosaminidase, E-selectin, P-selectin, and ICAM-1 were used as markers of endothelial function. Oxidative stress and endothelial dysfunction was present in patients with hypercortisolism, however, increased concentration of ICAM-1 was also found in patients after the operation as compared to controls (290.8+/-74.2 vs. 210.9+/-56.3 ng.ml(-1), p<0.05). Maximal perfusion was significantly lower in patients with arterial hypertension during PORH and TH (36.3+/-13.0 vs. 63.3+/-32.4 PU, p<0.01, and 90.4+/-36.6 vs. 159.2+/-95.3 PU, p<0.05, respectively) and similarly the velocity of perfusion increase during PORH and TH was lower (3.2+/-1.5 vs. 5.2+/-3.4 PU.s(-1), p<0.05, and 0.95+/-0.6 vs. 1.8+/-1.1 PU.s(-1), p<0.05, respectively). The most pronounced impairment of microvascular reactivity was present in patients with combination of arterial hypertension and diabetes mellitus.

Cushing's syndrome is associated with typical central redistribution of adipose tissue. The aim of the study was to assess lipolysis and catecholamines and their metabolites in subcutaneous abdominal adipose tissue using an in-vivo microdialysis technique. Nine patients with Cushing's syndrome and nine age-, gender- and body mass index (BMI)-matched control subjects were included in the study. Local glycerol concentrations were significantly increased in subcutaneous adipose tissue of patients with Cushing's syndrome (p<0.001). Plasma noradrenaline, dihydroxyphenylglycol and dihydroxyphenylalanine were decreased in patients with Cushing's syndrome (p<0.02, p<0.05, and p<0.02, respectively). Adrenaline, noradrenaline, dihydroxyphenylglycol and dihydroxyphenylalanine concentrations in subcutaneous abdominal adipose were non-significantly higher in patients with Cushing's syndrome. In conclusion, we showed that lipolysis in subcutaneous adipose tissue of patients with Cushing's syndrome is significantly increased as compared to healthy subjects. This finding together with non-significantly increased local catecholamine concentrations in these patients suggests a possible link between increased lipolysis and catecholaminergic activity in subcutaneous adipose tissue.

Background: Cushing's syndrome (CS) is associated with central adiposity, insulin resistance and impaired glucose homeostasis. Adipose tissue is thought to regulates glucose homeostasis via circulating adipokines, such as resistin, leptin and adiponectin, although their role in the insulin resistance associated with CS has not been established., Design: We examined the relationship between insulin resistance and adipokine levels in CS patients. We compared plasma levels of resistin, leptin and adiponectin in 10 women and four men patients with CS, with 14 health subjects matched for age, gender and body mass index. A subgroup of three women and four men with pituitary-dependent CS were re-examined at least 9 months after curative surgery., Results: CS patients had significantly more truncal fat and less lean body mass as assessed by DEXA compared to control subjects. Total cholesterol, triglycerides and insulin resistance, as calculated using the homeostasis model assessment of insulin resistance (HOMA-R), was significantly increased in CS patients. Of the adipokines measured, only resistin was significantly different between female CS patients and female control subjects (5.05 +/- 0.56 vs. 2.91 +/- 0.39 micro g/l, P = 0.015). Curative surgery significantly reduced total body fat and truncal fat, leptin, total and low-density lipoprotein (LDL) cholesterol, glucose and HOMA-R. A reduction in both resistin and adiponectin was also observed but the differences between pre- and post-treatment levels did not achieve statistical significance., Conclusion: Here we report for the first time that resistin levels are significantly elevated in CS patients and may be important in the insulin resistance associated with glucocorticoid excess.

Unlabelled: Hypercortisolism is associated with a high risk of sickness rate and death rate particularly in view of facilitated arteriosclerotic processes. It is most frequently induced by drug therapy, but endogenous hypercortisolism (Cushing's syndrome) may serve as a suitable model of the effect of hypercortisolism on vascular wall. Our cohort included the following groups of patients and control individuals: 1. a group of patients with florid so far untreated Cushing's syndrome--14 patients, 2. a control group to these patients--16 individuals, 3. a group recently operated on and healed-up patients with Cushing's syndrome--8 patients, 4. a group of previous of previous cured-up patients with Cushing's syndrome--27 subjects, 5. a control group to those patients of group 4--17 persons. The following differences were found between the respective groups: 1. the ultrasonographic examination of carotid arteries demonstrated sclerotic plates or carotid stenosis in 21.3% of patients with florid Cushing's syndrome and 41.4% in patients with corticolism having been cured-up against 11.7% in the relevant control group; 2. the examination of skin microcirculation by the laser-doppler method revealed a lower velocity of perfusion increase during examination of postocclusion hyperemia in patients with florid Cushing's syndrome and hypercortisolism having been cured-up against a control group (CUSH., P < 0.04; previous cured-up, P < 0.02) as well as thermally-induced hyperemia (CUSH., P < 0.03; formerly cured-up, P < 0.04); 3. the laboratory examination of patients with florid Cushing's syndrome revealed higher values of LDL-cholesterol (P < 0.05) and total cholesterol (P < 0.001), malonyldialdehyde as an indicator of increased formation of oxygen radicals (P < 0.05) and oromucoid, the protein of acute phase, signaling a chronic inflammation (P < 0.05); 4. in patients who previously suffered from hypercortisolism increased levels of fibrinogen (P < 0.03) and the cytoadhesive molecule ICAM-1 (P < 0.05) were accompanied by decreased levels of the growth factor of vascular endothelia (VEGF) (P < 0.05) against patients with florid Cushing's syndrome., Conclusion: The findings of the examinations performed indicate that increased incidence of arteriosclerotic processes is present in patients with the florid Cushing's syndrome as well as in those who have suffered from Cushing's syndrome before.

Background: Osteoporosis is one of the most serious consequences of Cushing's syndrome. Only a small number of longitudinal observations on bone mineral density (BMD) in patients with treated Cushing's syndrome have been reported so far. To evaluate changes in bone mass in patients with Cushing's syndrome after surgical cure of the disease, BMD was evaluated cross-sectionally., Methods and Results: BMD (DPX-L, Lunar) was measured in the lumbar spine and femoral neck (i.e. in skeletal areas with high proportion of trabecular and cortical bone, respectively) in 72 patients after successful surgical cure of Cushing's syndrome (8 men, 34 women before menopause and 30 women after menopause who were not on hormone replacement therapy). No other drug's interfering with skeletal metabolism were used. The reference group consisted of young healthy Czech women and/or men. The mean lumbar spine and femoral neck BMD increased to normal values within 3 and 5 years after surgery, respectively. In women after menopause, however, the significant positive relationship between BMD and time after surgery was negatively influenced by time after menopause. It is likely that several other factors contributed to the increase in bone mass in the patients (cure of hypercortisolism, recovery from hypogonadism and restoration of muscle strength)., Conclusions: After surgical cure of Cushing's syndrome in premenopausal women and in men, BMD rapidly and substantially increases. The recovery is negatively affected by estrogen deficiency in postmenopause.

Background: Differential diagnosis of the etiology of ACTH-dependent hypercortisolism is very difficult in some cases. The uncertainty, whether there is a central or ectopic etiology, is also strengthened by the fact that even nuclear magnetic resonance (MR) sometimes does not prove the pituitary adenoma. A more precise differential diagnosis under these conditions has been made, over the last years, by selective determination of ACTH levels bilaterally in sinus petrosi inferiores (SPI) and by their comparison with the level in peripheral blood. The confirmation of central etiology makes a decision about neurosurgical intervention easier. This intervention, due to the present microsurgery technique, makes it possible to detect otherwise undetectable microadenoma and enables its selective excision with maintaining healthy hypophysis tissue and all its functions., Methods and Results: In the last two years the authors indicated 11 patients (10 women, one man at the age of 17-54 years, mean age 33.5 year) with proved ACTH-dependent hypercortisolism to the determination of ACTH in SPI. Their CT or NMR examination did not prove a hypophysis tumour unequivocally. Only in one female patient the catheterization was not possible for anomalous vascular bed with aplasia of internal jugular vein on the left and hypoplasia of internal jugular vein on the right. In 8 patients the determination of the ratio of ACTH levels between SPI and periphery (7.78 +/- 1.54, mean +/- S.E.) has shown that even the basal levels indicated central etiology of hypercortisolism. This has been confirmed by the ratio of the values of ACTH after stimulation with corticotrophin releasing hormone (CRH). The diagnosis was confirmed in all patients by surgery, by histology and post-operation course. In two female patients the ratio of basal levels of ACTH, SPI/periphery did not prove useful for the diagnosis of the Cushing's disease. In the first patient the CRH stimulation was not yet performed routinely and the ratio of basal levels of ACTH, SPI/periphery gave a false negative result, as shown by the finding of adenoma of hypophysis during the operation. The operation was indicated on the basis of hormonal examinations and repeated MR with a finding of suspected microadenoma and the diagnosis was then confirmed by further clinical development. The determination of the levels of ACTH after CRH stimulation would give more precision in this case, as shown by analysis of the results of large cohorts in literature, which we perform at present as well. In the other patient the CRH stimulation test was done, changing the ratio from 1.1 to 5.7 and thus confirmed central etiology of the Cushing's syndrome. In agreement with literature this method did not contribute to lateral localization of the tumour., Conclusions: The determination of basal levels of ACTH in SPI and levels after CRH stimulation enables to differentiate between central and ectopic overproduction of ACTH in the ACTH-dependent Cushing's syndrome.