Diagnostic and prognostic value of 99mTc-Tektrotyd scintigraphy and 18F-FDG PET/CT in a single-center cohort of neuroendocrine tumors.

Introduction: The aim was to assess the diagnostic value of 99mTc-Tektrotyd scintigraphy (TCT) and positron emission tomography/computed tomography using F-18 fluorodeoxyglucose (18F-FDG PET/CT) in the detection and follow-up of neuroendocrine tumors (NETs), and their predictive value for disease progression. Material and methods: In this retrospective cohort, TCT and 18F-FDG PET/CT were performed in 90 patients (37 men, 53 women, mean age 52.7 ±15.1), with NET. Correlation of Ki67 and tumor grade versus Krenning score and SUVmax was assessed, Kaplan-Meier analysis was used for progression-free survival (PFS), and Cox regression analysis was performed to identify the association between progression-related factors and PFS. Results: Out of 90, true positive TCT was detected in 56 (62.2%) patients, true negative in 19 (21.1%), false positive in 4 (4.4%), false negative in 11 (12.2%), while 18F-FDG PET/CT was true positive in 69 (76.7%) patients, true negative in 10 (11.1%), false positive in 5 (5.5%), false negative in 6 (6.7%). Mean 18F-FDG PET/CT SUVmax was 6.8 ±6.2. Diagnostic sensitivity of TCT was 83.6%, specificity 82.6%, accuracy 83.3% vs. 18F-FDG PET/CT sensitivity was 92.0%, specificity 66.7%, accuracy 87.8%. A significant correlation between Ki67 and SUVmax was found in positive 18F-FDG PET/CT findings, unlike the correlation between Ki67 and Krenning score. Median PFS was 25 months (95% CI: 18.2-31.8), in 18F-FDG PET/CT positive patients 23 months (95% CI: 16.3-29.7) and 18F-FDG PET/CT negative 26 months (p = 0.279). Progression-free survival predictors were SUVmax and Krenning score. Conclusions: In our study, TCT and 18F-FDG PET/CT have high diagnostic accuracy in detection of NET. Higher Krenning score on TCT and SUVmax in positive 18F-FDG PET/CT findings are predictors of disease progression. 99mTc-Tektrotyd scintigraphy and 18F-FDG PET/CT can be useful complementary tools in management of patients with NETs and in predicting patients' outcome.

The association of glucocorticoid receptor polymorphism with metabolic outcomes in menopausal women with adrenal incidentalomas.

OBJECTIVES: To investigate whether BclI polymorphism in the glucocorticoid receptor gene influences hypothalamic-pituitary-adrenal (HPA) axis regulation, body composition and metabolic parameters in women with adrenal incidentalomas (AIs). STUDY DESIGN: A cross-sectional study. MAIN OUTCOME MEASURES: We analyzed 106 women with AIs. Insulin resistance was assessed using a homeostasis model while HPA activity was assessed using dexamethasone suppression tests (DST), basal ACTH, urinary free cortisol, and midnight serum cortisol level. Body composition was analyzed using dual-energy X-ray absorptiometry. DNA was obtained from peripheral blood leucocytes and BclI polymorphism was detected using PCR, RFLP and DNA sequencing. RESULTS: BclI carriers in comparison with those with wild-type BclI had less suppressed cortisol after DST-0.5 mg (126.4 ± 111.4 vs 80.9 ± 75.7 nmol/l, p = 0.026) and had a lower prevalence of impaired glucose tolerance and of type 2 diabetes mellitus (T2DM). BclI carriers had a higher percentage of leg fat mass (FM), lower left-sided limb muscle mass and a decline in total lean body mass. Duration of menopause remained a strong predictor of appendicular lean mass index (ALMI) (ß=-0.125, p = 0.034). BclI polymorphism was significantly associated with sum of legs FM percentage (ß=0.327, p = 0.048). T2DM was negatively associated with BclI polymorphism, after adjusting for age, truncal FM, ALMI, and sum of legs FM (OR=0.158, 95%CI 0.031-0.806, p = 0.027). CONCLUSIONS: BclI polymorphism is associated with tissue-specific glucocorticoid sensitivity, relative glucocorticoid resistance of the HPA axis and peripheral adipose tissue, and glucocorticoid hypersensitivity at the muscle level. By modulating glucocorticoid and insulin sensitivity, BclI polymorphism appears to reduce the risk of T2DM in women with AIs.

Metabolic Syndrome and Myocardial Infarction in Women.

Metabolic syndrome (MetS) represents a cluster of metabolic disorders that arise from insulin resistance (IR) and adipose tissue dysfunction. As a consequence, there is an increased risk for type 2 diabetes mellitus and atherosclerotic cardiovascular disease (CVD). MetS is associated with a 2-fold increase in cardiovascular outcomes. Earlier population analyses showed a lower prevalence of MetS in women (23.9%) in comparison to men (27.8%), while later analyses suggest significantly reduced difference due to an increase in the prevalence in women aged between 20 and 39. However, the prevalence of MetS in specific populations of women, such as in women with polycystic ovary syndrome, ranges from 16% to almost 50% in some geographical regions. Abdominal fat accumulation and IR syndrome are recognized as the most important factors in the pathogenesis of MetS. After menopause, a decline in insulin sensitivity corresponds to an increase in fat mass, circulating fatty acids, low-density lipoproteins, and triglycerides. Prevalence of MetS in acute coronary syndrome (ACS) is significantly more present in women (55.9%-66.3%) than in men (40.2%-47.3%) in different cohorts. Younger women with ACS had a higher mortality rate than younger men. Acute myocardial infarction (AMI) remains a leading cause of death in aging women. Women with AMI had significantly higher rates of prior congestive heart failure, hypertension history, and diabetes. The role of androgens in CVD pathogenesis in women has not yet been clarified. The current review aims to provide an insight into the role of MetS components and inflammation for the development of atherosclerosis, CVD, and AMI in women.

Somatostatin receptor scintigraphy in the follow up of neuroendocrine neoplasms of appendix.

BACKGROUND: Neuroendocrine tumors of appendix (ANETs) known as carcinoids, are rare endocrine neoplasms originated from enterochromaffin cells of gastrointestinal tract. ANETs are the third most frequent (16.7%) gastrointestinal neuroendocrine tumors, with the incidence of 0.08-0.2 cases/100000 during one year. Incidental ANETs occur in 0.2%-0.7% of emergency surgical resections because of suspected appendicitis which is usually the first manifestation of ANET. Although there are a lot of papers about application of somatostatin receptor scintigraphy in gastrointestinal neuroendocrine tumors, there are very rare sporadic cases described about ANETs particularly. AIM: To establish the role of somatostatin receptor scintigraphy (SRS) in the management of patients with neuroendocrine tumors of appendix (ANET). METHODS: The total of 35 patients was investigated, 23 females and 12 males, average age (43.7 ± 17.3 years). All patients had histological diagnosis of ANET (34 carcinoids of appendix and one tubular carcinoid). Majority of tumors have been found incidentally during surgery of: Acute appendicitis (n = 15), perforated appendicitis (n = 2), ileus (n = 3), hysterectomy (n = 3), ruptured ovarian cyst (n = 2), caecal volvulus (n = 1), while 9 patients had diagnosis of appendiceal tumor before the surgery. Seventeen patients had tumor grade (G) G1, 12 G2 and 6 G3. The right hemicolectomy was performed in 13, while the rest of the patients had appendectomy only. SRS was done early (2 h) and late (24 h) after i.v. application of 740 MBq technetium-99m ethylenediamine-N, N'-diacetic acid Hydrazinonicotinyl-Tyr3-Octreotide (technetium-99m-Tektrotyd, Polatom, Poland). SRS was performed for restaging in all the patients after surgery. RESULTS: There were 12 true positive (TP), 19 true negative, 3 false positive and 1 false negative SRS result. Sensitivity of the method was 92.31%, specificity was 86.36%, positive predictive value was 80.00%, negative predictive value was 95.00% and accuracy 88.57%. Receiver operating characteristics analysis showed that SRS scintigraphy is a good test for detection TP cases [area under the curve of 0.850, 95% confidence interval (CI): 0.710-0.990, P < 001]. Single photon emission computed tomography contributed diagnosis in 7 TP findings. In 10 patients Krenning score was 4 and in 2 was 3. In 8 patients SRS significantly changed the management of the patients (in two surgery was repeated, in 4 somatostatin analogues and in two peptide receptor radionuclide therapy). Median progression-free survival in SRS positive patients was 52 months (95%CI: 39.7-117.3 mo) while in SRS negative patients it was 60 months (95%CI: 42.8-77.1 mo), without statistically significant difference between the two groups (P = 0.434). CONCLUSION: In conclusion, our results confirmed the value of SRS in the follow-up of the patients with ANET after surgery, if recurrences or metastases are suspected.

Acute Response to Endurance Exercise Stress: Focus on Catabolic/anabolic Interplay Between Cortisol, Testosterone, and Sex Hormone Binding Globulin in Professional Athletes.

BACKGROUND: Endocrine system plays a major role in both permissive and regulatory activities in order to adequately respond to physical stress of exercise. But level and direction of activation depend on many factors and are not easily interpreted. METHODS: We tested a group of male professional athletes (21 water polo players and 15 wrestlers), together with 20 sedentary controls matched by age. All participants took a continuous progressive exercise stress test on a treadmill until exhaustion and plateau of oxygen consumption (VO2). Blood samples for cortisol, sex hormone binding globulin (SHBG) and testosterone were drawn in four time points: baseline (B), start of the test (S), point of maximal strain (MAX) and in the 3rd minute of recovery period (R). RESULTS: Cortisol levels significantly increased in both groups, but the response between S and MAX was more pronounced in controls (p=0.036). The athletes had significantly higher levels of cortisol in all points in test, except during R (p=0.118), when their cortisol levels gradually started to decline. Significant increase in total testosterone was in great deal a consequence of increase in SHBG level (p<0.01 for both). Consequently, calculated free testosterone significantly decreased during test (p=0.008), and the drop was more pronounced in athletes. This was in concordance with significant correlation between SHBG and cortisol level demonstrated in athletes, but not in controls. CONCLUSIONS: It seems that high intensity endurance exercise favors catabolic response, but the level of response highly depends on a previous level of training.

Novel Mutations in Serbian MEN1 Patients: Genotype-phenotype Correlation.

BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant cancer syndrome characterized by the occurrence of primary hyperparathyroidism (PHPT), pituitary adenoma (PA) and pancreatic neuroendocrine tumor (pNET). Whether the underlying mutations in MEN1 gene predict clinical presentation of affected heterozygotes or not, is still a matter of a debate. METHODS: Clinical and genetic analysis of 90 consecutive MEN1 patients was performed in a retrospective, single - center study. RESULTS: MEN1 mutation was found in 67 (74.4%) patients belonging to 31 different families. Twenty nine different heteozygous mutations were found, including 6 novel point mutations (W220G, 941delG, 1088del7, 1184insA, 1473del10, 1602del17) and one large deletion of exon 8. Truncating mutations predicted development of pNETs (OR=5.8, 95% CI 1.7 - 19.7%) and PHPT (OR=4.3, 95% CI 1.5 - 12.4%). CONCLUSIONS: Large number of novel mutations among MEN1 patients confirmed previously reported data. PNETs and PHPT were more frequent in patients with truncating mutations.

The Occurrence of Subclinical Hypercortisolism and Osteoporosis in Patients with Incidentally Discovered Unilateral and Bilateral Adrenal Tumors.

BACKGROUND: Adrenal incidentalomas (AI) are clinically silent adrenal masses that are detected incidentally during imaging procedures performed for unrelated diseases. The aim of this study was to investigate the prevalence of sub-clinical hypercortisolism (SH) and associated co-morbidities in patients with unilateral AI (UAI) and bilateral AI (BAI). METHODS: We evaluated 152 patients, 105 (69.1%) with UAI and 47 (30.9%) with BAI. SH was diagnosed in the presence of serum cortisol levels after 1 mg dexamethasone suppression test (DST) or after 2-day low-dose DST (LDDST) > 50 nmol/L with at least one of the following parameters: midnight serum cortisol > 208 nmol/L, 24-h urinary free cortisol > 245 nmol/24 h, or ACTH < 10 ng/L. Bone mineral density (BMD) was measured at lumbar spine (LS) and femoral neck (FN). RESULTS: Age, BMI, and waist circumference were comparable, and diabetes, hypertension and dyslipidemia occurred with similar frequency in both groups. The overall prevalence of SH was 20.5% based on post-1 mg DST, and 20.0% based on post-LDDST cortisol levels, and it was more prevalent in BAI than UAI patients (31.1% vs 15.2%, respectively, p=0.026). LS BMD was lower in BAI than in UAI patients (0.96±0.14 vs 0.87±0.15, p=0.002). There were no differences in FN BMD. The prevalence of osteoporosis was higher in BAI compared to UAI patients (37.1% vs 15.9%, respectively, p=0.011). CONCLUSIONS: Patients with BAI had higher prevalence of SH and osteoporosis than those with UAI. Frequency of other co-morbidities was similar. This may be due to the higher degree of autonomous cortisol secretion or different tissue-specific sensitivity to glucocorticoids.

Recurrent spontaneous abortions, Hashimoto thyroiditis and alopecia totalis: response to anticoagulation and intravenous immunoglobulin therapy.

INTRODUCTION: Although numerous studies indicated a link between antithyroid antibodies and recurrent spontaneous abortions (RSA), consensus on the treatment of this condition is still lacking. CASE REPORT: We present a case of a 35-year-old pregnant woman (gestation week 4) with primary hypothyroidism, total alopecia, high level of positive antithyroid antibodies, and history of two recurrent spontaneous abortions in early pregnancy. Along with L-thyroxin substitution, intravenous human immunoglobulin (IVIg) combined with anticoagulation and antiaggregation therapy was introduced. During pregnancy her scalp hair completely re-grew, and following gestation week 39 she delivered healthy female child. CONCLUSION: Thyroid antibodies could contribute to previous recurrent abortions in our patient. It is suggested that in older primiparas with Hashimoto thyroiditis and history of RSA, a combined treatment with IVIg, anticoagulation and antiaggregation therapy should be considered.

Glucocorticoid receptor and molecular chaperones in the pathogenesis of adrenal incidentalomas: potential role of reduced sensitivity to glucocorticoids.

Glucocorticoid (GC) sensitivity depends on glucocorticoid receptor (GR) and heat shock proteins (Hsps). We investigated whether common GR genes (ER22/23EK, N363S, Bcl I, and 9ß) and adrenocorticotropin receptor promoter polymorphisms influence susceptibility for unilateral adrenal incidentaloma (AI), plus GR and Hsp expression in tumorous (n = 19), peritumorous (n = 13) and normal adrenocortical (n = 11) tissues. Patients (n = 112), population-matched controls (n = 100) and tumor tissues (n = 32) were genotyped for these polymorphisms. Postdexamethasone serum cortisol was higher in patients (p < 0.001). GR gene variants, larger allele of Bcl I (odds ratio [OR] 2.9; 95% confidence interval [CI] 1.7-5.1; p < 0.001] and minor allele of 9ß (OR 3.0; 95% CI 1.6-5.7; p < 0.001) were independent predictors of AI. In patients, the first allele is linked with larger tumors (p = 0.002) and the latter with higher postdexamethasone cortisol levels (p = 0.025). Both allele carriers had lesser waist circumference (p = 0.02), similar adrenocorticotropin and higher basal (p = 0.024) and postdexamethasone cortisol concentrations (p < 0.001). Tumorous and constitutional genotypes were similar. GR-D is the major receptor isoform in normal adrenal cortex by Western blotting. Loss of other receptor isoforms, decrease in immunostaining for GR (p < 0.0001), underexpression of chaperones (p ≤ 0.01) and the presence of inducible Hsp70 were found in adenomas. In conclusion, GR gene variants, C allele of Bcl I and minor allele of 9ß, are associated with AIs. Their concurrent presence in patients reduces GC sensitivity. Normal adrenal cortex preferentially expresses GR-D. In adenomas, the lack of other GR isoforms and underexpression of heat shock proteins perhaps permanently impair GC signaling, which could promote dysregulated cortisol production and tumor growth. The innate GC sensitivity probably modifies these effects.

Relationship between basal metabolic rate and cortisol secretion throughout pregnancy.

The role of cortisol in mediating basal metabolic rate (BMR) changes that accompany the adjustment of maternal body weight (BW) and body composition during pregnancy is unknown. We tested whether increase in BMR during pregnancy is explained by variations in cortisol secretion. Longitudinal changes in BW, fat mass (FM), fat-free mass (FFM), BMR, hormonal, and metabolic parameters in 31 parous Caucasian women at gestational weeks 12, 26, and 36 were examined. Individual differences (Delta) between the last and the first measurement occasions for each variable were calculated. By gestational week 36, BW and BMR increased while both FFM/FM and BMR/BW ratio decreased (P < 0.001 for all) suggesting higher proportion of FM accretion. Cortisol, leptin, and insulin-like growth factor-1 (IGF-1) concentration rose, whereas non-placental growth hormone (GH) and thyroid hormones declined (P < 0.001 for all). Insulin resistance changed; basal glucose (P < 0.001) and ghrelin (P < 0.014) declined, whereas insulin (P < 0.001), homeostatic model index (HOMA-IR) (P = 0.041), and free fatty acid (FFA) concentration (P = 0.007) increased. The elevation in BMR showed inverse correlations with DeltaBW (r = 0.37, P = 0.047) and Deltacortisol (r = -0.53, P = 0.004). Significant portion (51.6%) of the variation in BMR change was explained by increases of cortisol (27.1%), FFA (13.4%), and free triiodothyronine (11.1%). In conclusion, the changes in maternal cortisol concentration are in relationship with changes in BMR and BW, further suggesting that increased cortisol secretion during pregnancy could be linked with the maintenance of maternal BW and body composition.

Conductive hearing loss in patients with active acromegaly.

OBJECTIVE: There have been rare conflicting results reported concerning possible higher frequency of hearing loss in acromegalic patients. Our goal was to determine whether there is higher frequency of conductive hearing loss in acromegalics and what may cause it if there is any. STUDY DESIGN: Prospective study. SETTING: Tertiary referral center. PATIENTS: Thirty previously untreated patients with acromegaly were compared with 20 age- and sex-matched healthy control subjects. INTERVENTIONS: In all subjects: Otomicroscopy, tuning fork tests, audiometry tympanometry, cochleostapedial reflex, otoacoustic emissions. In acromegalics: endocrinologic assessment, MRI and if necessary, epipharyngoscopy. MAIN OUTCOME MEASURES: We searched for: 1) Signs of ossicle fixation: absence of stapedial reflex in the presence of normal tympanogram, conductive hearing loss, and absence of or grossly disturbed OAE; 2) Disturbances of middle ear ventilation: excessive negative pressure (tympanogram type C), or middle ear effusion (tympanogram type B). RESULTS: The only statistically significant difference between untreated acromegalics and healthy subjects was the presence of middle ear ventilation problem: 7/30 acromegalics (23%) in comparison to none out of 20 healthy controls (0%), p = 0.033. The acromegalics with middle ear ventilation problem were significantly older, had longer duration of the disease, and lower mean growth hormone (GH) levels in comparison with acromegalics without this problem (51.6 +/- 1.7 vs. 44.4 +/- 2.5 years, 11.6 +/- 2.4 vs. 7.7 +/- 0.4 years, 21.68 +/- 4.89 vs. 49.98 +/- 12.54 microg/L respectively). CONCLUSION: Patients with active acromegaly have more frequent middle ear ventilation problem than normal population, especially those with longer duration of the disease. Possible causes are discussed.

[Disorder of adrenal gland function in chronic fatigue syndrome]. / Poremecaj funkcije nadbubrega u sindromu hronicnog zamora.

Chronic fatigue syndrome (CFS) is defined as constellation of the prolonged fatigue and several somatic symptoms, in the absence of organic or severe psychiatric disease. However, this is an operational definition and conclusive biomedical explanation remains elusive. Similarities between the signs and symptoms of CFS and adrenal insufficiency prompted the research of the hypothalamo-pituitary-adrenal axis (HPA) derangement in the pathogenesis of the CFS. Early studies showed mild glucocorticoid deficiency, probably of central origin that was compensated by enhanced adrenal sensitivity to ACTH. Further studies showed reduced ACTH response to vasopressin infusion. The response to CRH was either blunted or unchanged. Cortisol response to insulin induced hypoglycaemia was same as in the control subjects while ACTH response was reported to be same or enhanced. However, results of direct stimulation of the adrenal cortex using ACTH were conflicting. Cortisol and DHEA responses were found to be the same or reduced compared to control subjects. Scott et al found that maximal cortisol increment from baseline is significantly lower in CFS subjects. The same group also found small adrenal glands in some CFS subjects. These varied and inconsistent results could be explained by the heterogeneous study population due to multifactorial causes of the disease and by methodological differences. The aim of our study was to assess cortisol response to low dose (1 microgram) ACTH using previously validated methodology. We compared cortisol response in the CFS subjects with the response in control and in subjects with suppressed HPA axis due to prolonged corticosteroid use. Cortisol responses were analysed in three subject groups: control (C), secondary adrenal insufficiency (AI), and in CFS. The C group consisted of 39 subjects, AI group of 22, and CFS group of nine subjects. Subject data are presented in table 1. Low dose ACTH test was started at 0800 h with the i.v. injection of 1 microgram ACTH (Galenika, Belgrade, Serbia). Blood samples for cortisol determination were taken from the i.v. cannula at 0, 15, 30, and 60 min. Data are presented as mean +/- standard error (SE). Statistical analysis was done using ANOVA with the Games-Howell post-hoc test to determine group differences. ACTH dose per kg or per square meter of body surface was not different between the groups. Baseline cortisol was not different between the groups. However, cortisol concentrations after 15 and 30 minutes were significantly higher in the C group than in the AI group. Cortisol concentration in the CFS group was not significantly different from any other group (Graph 1). Cortisol increment at 15 and 30 minutes from basal value was significantly higher in C group than in other two groups. However, there was no significant difference in cortisol increment between the AI and CFS groups at any time of the test. On the contrary, maximal cortisol increment was not different between CFS and other two groups, although it was significantly higher in C group than in the AI group. Maximal cortisol response to the ACTH stimulation and area under the cortisol response curve was significantly larger in C group compared to AI group, but there was no difference between CFS and other two groups. Several previous studies assessed cortisol response to ACTH stimulation. Hudson and Cleare analysed cortisol response to 1 microgram ACTH in CFS and control subjects. They compared maximum cortisol attained during the test, maximum cortisol increment, and area under the cortisol response curve. There was no difference between the groups in any of the analysed parameters. However, authors commented that responses were generally low. On the contrary Scott et al found that cortisol increment at 30 min is significantly lower in the CFS than in the control group. Taking into account our data it seems that the differences found in previous studies papers are caused by the methodological differences. We have shown that cortisol increment at 15 and 30 min is significantly lower in CFS group than in C group. Nevertheless, maximum cortisol attained during the test, maximum cortisol increment, and area under the cortisol response curve were not different between the C and CFS groups. This is in agreement with our previous findings that cortisol increment at 15 minutes has the best diagnostic value of all parameters obtained during of low dose ACTH test. However, there was no difference between CFS and AI group in any of the parameters, although AI group had significantly lower cortisol concentrations at 15 and 30 minutes, maximal cortisol response, area under the cortisol curve, maximal cortisol increment, and maximal cortisol change velocity than C group. Consequently, reduced adrenal responsiveness to ACTH exists in CFS. In conclusion, we find that regarding the adrenal response to ACTH stimulation CFS subjects present heterogeneous group. In some subjects cortisol response is preserved, while in the others it is similar to one found in secondary adrenal insufficiency.