ACTA ENDOCRINOLOGICA (BUC)

In acromegalic patients growth hormone (GH) excess induces insulin resistance (IR) but whether this is sufficient for pre-diabetes to occur is a matter of debate.\r\nAim. To assess the relative role of IR and insulin secretion in the pre-diabetes of acromegaly.\r\nMethods. 126 patients with acromegaly (79 women, 47 men) were included. Plasma glucose, GH and insulin levels were measured basal and 30, 60 and 120 minutes during a 75 g oral glucose tolerance test (OGTT). Basal and stimulated IR was assessed by homeostasis model assessment (HOMA), insulin resistance index (HOMA-IR) and insulin sensitivity index (ISI) derived from OGTT (OGTTISI) respectively. Basal and stimulated insulin secretion was assessed using HOMA-B% index and insulinogenic index (IGI), respectively. The local Ethic Committee approved the study.\r\nResults. There were 51 subjects with pre-diabetes and 75 subjects with normal glucose tolerance (NGT). Pre-diabetes group had a significantly higher HOMA-IR index (4.8?3.3 vs 2.5?1.6, p<0.001) and nadir GH in OGTT (9.4 (4.3, 22.2) vs. 4.8 (2.2, 14.5) ng/mL, p=0.02) than NGT group. HOMA-IR did not correlate with nadir GH serum level in pre-diabetes group (r =0.22, p=0.12) but correlated significantly in NGT group (r= 0.5, p<0.001). In contrast, the pre-diabetes group had a lower HOMA-B% index than NGT group (165.4?15.7 vs 228.5?29, p<0.001). HOMA-B% did not correlate with nadir GH in both groups. Unadjusted IGI did not differ between the two groups (0.40?0.07 vs. 0.48?0.05, p=0.34) but became statistically significant after adjusting for both basal IR (HOMA-IR) (0.31?0.06 vs. 0.54?0.05, p=0.01) and stimulated IR (OGTTISI) (0.30?0.06 vs. 0.54?0.05, p=0.005). There were no significant differences between pre-diabetes and NGT groups regarding age, duration of acromegaly and sex.\r\nConclusions. Our data suggest that reduced basal and stimulated insulin secretion express the failure of &#946;-cells adaptation to increased GH-induced-insulin resistance and is the pathogenic mechanism of pre-diabetes in acromegaly.

Introduction: The necessity to determine the levels of pituitary hormones in the cerebrospinal fluid is motivated both by difficulties in the diagnosis of different neuroendocrine disorders, as well as by research purposes such as understanding the transport mechanisms of hormones through the blood brain barrier.\r\nObjective: The aim of this study was to compare the results obtained with different immunometric methods for some pituitary hormones in the serum and CSF in patients with neuroendocrine tumors.\r\nMaterials and methods: The levels of LH, FSH, PRL and TSH were determined simultaneously in the serum and CSF with 3 different immunometric methods using commercial kits: IRMA, FIA and Chemiluminescence for 36 patients. The validation of IRMA method on CSF samples was performed using the dilution test.\r\nResults: The dilution test - as one of validation criteria of an immunoassay - proved that the results obtained in the CSF using the commercially available kits were correct. This enables the use of this sensitive method to accurately demonstrate abnormal levels of pituitary hormones beyond the blood-brain barrier. The correlation between IRMA and FIA: Hormonal concentrations values obtained by IRMA correlate well with those measured by FIA for serum with no significant differences of the mean concentration value for FSH (r=0.93, p: NS) and LH (r=0.99, p: NS), but with a significant difference for PRL (r=0.88, p=0.002). In CSF, mean concentrations values correlate well and we found no differences for TSH (r =0.97, p: NS) and LH (r = 0.94, p: NS), but significant differences for PRL (r= 0.98, p=0.001) and FSH (r=0.98, p=0.001). Statistically significant differences were also found for the CSF/serum ratio for PRL (p=0.08), FSH (p=0.001) and LH (p=0.001). The ratios CSF/serum are significantly higher with IRMA method than with FIA for all the hormones. Except for one patient for all the others we found the ratio CSF/serum less than 1 showing that the pathologic significance of this parameter is not modified due to the type of immunometric assay. A statistically significant difference (p<0.001) was found for mean FSH concentration in CSF with FIA and Chemiluminescent assays .\r\nConclusions: Any immunometric method currently used for the determination of hormones in the serum or plasma has to be validated accordingly in order to be used on CSF. For obtaining results that can be interpreted and compared it is preferred that the same immunometric method is used on both serum and CSF, inside one group of patients. The presence of a control group for the results determined with that method is strongly recommended.

As the kits used in routine for assessment of human growth hormone (hGH) status in CSF are originally designed for the serum and plasma, the specifications and limitations imposed by some environmental factor are important to be known. The aim of study was to\r\ninvestigate the influence of different protein concentrations on an immunometric assay to design a suitable and reproducible method for hGH measurement in different matrices, particularly in CSF-like environment.\r\nMaterial and methods. Experiments were performed using an in-house protocol for the determination of hGH by Time Resolved Immunofluorometric method. Standard curves were prepared in different biological matrices (sheep, human or fetal calf serums and CSFlike matrix). The concentrations of albumin and gamma-globulins were the variable parameters. The gold standard was the standard curve in sheep serum.\r\nResults. Constantly high background signal values were obtained at different albumin concentrations, in the absence of IgG, indicating intense non-specific binding and a low sensitivity. This fact allows accurate hGH measurement at over 5-10 ng/ml. Using a reaction environment enriched in IgG with a standard albumin concentration, background signal decreases while increasing IgG concentration. The highest sensibility is obtained for 5 g/l and 2.5 g/l IgG environments, allowing the sample signal to be measured accurately at hGH concentrations of 0.2 ng/ml or 0.5 ng/ml respectivly. This is observed in all biological matrices used.\r\nConclusions. The variation of protein concentration influences hGH determination. A standard curve with high sensibility for low values and a reduction in the influences of the reaction environment by minimising non-specific binding were obtained by enriching the environment with IgG.

Endogenous Cushing’s syndrome is rare, with an incidence of 0.7–2.4 per a million people a year. Clinical presentation of Cushing syndrome can be pleomorphic, and establishing diagnosis can be difficult. Early recognition and rapid control of hypercortisolaemia are necessary to decrease morbidity and mortality in these patients. We report a series of 6 endogenous Cushing’s syndromes of different etiologies (4 Cushing’s disease and 2 adrenal Cushing’s syndrome) assessed in our endocrine department over a decade (2009-2019). In order to highlight the diversity of clinical forms, diagnostic tools and specific management of this condition we labelled each case suggestively: the typical Cushing’s disease, the Pseudo Cushing’s, the elusive Cushing’s disease, the mild autonomous cortisol hypersecretion, Cushing’s syndrome in pregnancy and Cushing’s disease with thromboembolism. We discussed their particularities which were revelatory for the diagnosis, such as dermatologic, cardiovascular, musculoskeletal, neuropsychiatric, or reproductive signs, reviewing literature for each manifestation. We also discuss the commonalities and differences in laboratory and imagistic findings. Therapeutic approach can also differ with respect to the particular condition of each patient and the multiple choices of therapy will be reviewed.

Glycemic control can be impaired in active acromegaly and insulin sensitivity (IS) decreases with rising growth hormone (GH) levels.\r\nAim. To assess the short-term impact of transsphenoidal surgery for acromegaly on glycemic control. Methods. 11 patients with native active acromegaly due to pituitary macroadenoma were assessed before and after (2-3 months) transsphenoidal hypophysectomy. Serum glucose, GH and insulin levels were measured by immunoradiometric assay at 0, 30, 60 and 120 minutes during a 75 g OGTT before and after surgery. IGF-1 levels were measured by ELISA. Basal hepatic IS was assessed using HOMA-S% and QUICKI indexes and stimulated IS using OGTTISI. Basal and stimulated insulin secretion was assessed using HOMA-B% index and IGI respectively. Results. All patients had their acromegaly improved (mean?SD pretreatment nadir GH 34?24.7 ng/mL vs. 4.6?3.5 ng/mL postsurgery; p<0.001) but only one was cured (nadir GH<1 ng/mL, normal IGF- 1 level). Mean fasting serum glucose was lowered by 7.9 mg/dL (95% CI 1.3-14.4, p=0.03) and fasting serum insulin by 9.6 mU/mL (95% CI 1.0-18.1, p=0.02). IS increased after surgery as shown by HOMA-S% index which rose 0.25?0.18 to 0.5?0.36 (p<0.01), QUICKI which rose form 0.31?0.03 to 0.33?0.03 (p=0.001) and OGTTISI index which rose from 2.5?1.6 to 5.1 ? 3.5 (p=0.002). Insulin secretion was unchanged as shown by HOMA-B% index (313?229 presurgery vs. 227?139 postsurgery, p=NS) and IGI index (0.96 ? 0.86 presurgery vs. 0.55 ? 0.49, p=NS). Conclusions. Partial removal of the pituitary adenoma by transsphenoidal surgery in patients with acromegaly induces a significant increase in insulin sensitivity and an improvement in glycemic control at 3 months after surgery. This suggests that transsphenoidal surgery should be indicated even if complete removal of the pituitary adenoma is not achieved.

In this study we aimed to assess amiodarone&#8217;s effects on thyroid hormones, C reactive protein (CRP), interleukin 6 (IL-6) and tumor necrosis factor (TNF-&#945;) profile in amiodarone-induced thyrotoxicosis (AIT) and their relationship with arrhythmias. In 60 patients with AIT (29M/31F), aged 59.7 ? 1.5 years and 105 hyperthyroid patients (25M/80F), aged 59.4 ? 1 years, TSH, total T3, total T4, free T4 were measured by IRMA or microenzymatic immunoassay. In 11 AIT patients and 26 patients with common hyperthyroidism, without significant Graves&#8217; ophthalmopathy, CRP, IL-6 and TNF-&#945; were measured by chemiluminescent immunoassays. AIT patients showed significantly lower T3 levels (273.82 ? 18.76 ng/dL) as compared to common thyrotoxicosis (361.89 ? 13.47 ng/dL), p<0.001, while T4 and FT4 were similar. AIT patients showed similar CRP, IL-6 and TNF-&#945; levels to common hyperthyroidism (10.22 ? 3.03 mg/L vs. 6.31 ? 2.33 mg/L, p=0.11, for CRP, 17.46 ? 13.09 pg/mL vs. 6.46 ? 1.14 pg/mL, p=0.65, for IL-6, and 9.9 ? 1.76 pg/mL vs. 12.85 ? 2.22 pg/mL, p=0.22, for TNF-&#945;, respectively. Patients with arrhythmias (n=19) showed significantly higher CRP, IL-6 and TNF-&#945; levels as compared to patients without arrhythmias (n= 18): 10.81 ? 3.35 mg/L vs. 3.96 ? 1.08 mg/L, p=0.05, for CRP, 15.15 ? 7.52 pg/mL vs. 4.02 ? 0.74 pg/mL, p=0.007 for IL-6, and 15.16 ? 3.33 pg/mL vs. 9.2 ? 0.82 pg/mL, p=0.037 for TNF-&#945;. In conclusion, AIT showed a similar pattern of proinflammatory cytokines to common hyperthyroidism. Increased CRP, IL-6 and TNF-&#945; are found only in patients with thyrotoxicosis associated with atrial fibrillation or other arrhythmias.

The aim of the study was to evaluate the prevalence of hyperhomocysteinemia in hypothyroid patients and the effect of folic acid supplementation when serum homocysteine\r\n(Hcy) was over risk level.\r\nPatients and methods. Patients with moderate (Group1) and severe hypothyroidism (Group 2) were evaluated before any therapy and after 6 months of combined folic acid and\r\nlevothyroxine substitution, versus control subjects. Hcy, folic acid, thyroid hormones and lipids were measured for all subjects. Thyroglobulin and antithyroglobulin antibodies were measured only for Group 2.\r\nResults. Only 17 % of the cases had basal Hcy at non risk level (<10 mmol/L). Both groups had higher Hcy levels than control (p <0.0001). In Group 1 basal folic acid was lower\r\nthan in control and group 2 (p<0.001). No correlation was found between high levels of Hcy (> 12 mmol/L ) and positive thyroglobulin. After 3 months of combined therapy, significant decrease of Hcy (p<0.0001) was observed compared with the basal level. Normalization of\r\nHcy appears during next 3 months even with reducing the folic acid supplementation.\r\nConclusion. Our results report moderate hyperhomocysteinemia in hypothyroid patients. This may exacerbate the cardiovascular risk traditionally attributed to lipid changes. Six months of combined therapy (L-thyroxine and folic acid) corrected hyperhomocysteinemia excluding the additional risk.

About 15-20% of adults with Down?s syndrome have autoimmune hypothyroidism. Among patients with Down?s syndrome, prevalence of Graves disease (1-2%) may not be increased compared with the general population. About 15% of the patients with Turner?s syndrome have autoimmune hypothyroidism. Until 2006, only 15 cases of Graves disease have been reported among patients with Turner?s syndrome. We present two adult patients with chromosomial disorders (Down?s syndrome, Turner?s syndrome) with Graves? disease without clinical Graves ophthalmopathy. Clinical picture of thyrotoxicosis was oligosymptomatic in the patient with Down?s syndrome, probably because Down?s syndrome represents a syndrome of accelerated ageing. Both were pretreated with antithyroid drugs before radioiodine therapy. Both patients developed postradioiodine hypothyroidism: after 8 months in the case with Turner?s syndrome and after 11 years in the patient with Down?s syndrome. Adults with these two chromosomial disorders should be screened annually for autoimmune thyroid dysfunction.

Glucose intolerance (impaired fasting glucose [IFG], impaired glucose tolerance [IGT] or diabetes mellitus) due to insulin resistance is a frequent complication of acromegaly due to excessive growth hormone (GH) production. Long-acting somatostatin analogs are known to reduce the GH and IGF-1 serum levels, and to inhibit at the same time the pancreas insulin release. The effect upon acromegalic patients who express IFG before therapy is controversial. We here present two male patients, 66 and 36 years old, with active acromegaly and IFG who were submitted to a treatment with long-acting somatostatin analog lanreotide. After being diagnosed with active acromegaly with high nadir serum GH levels along oral glucose tolerance test (OGTT), i.e. 149 ng/mL and 43 ng/mL respectively, the patients underwent complex therapy (surgery and radiotherapy) which reduced the GH serum levels (20.7 ng/mL and 3.5 ng/mL respectively) without curing the disease. The patients developed IFG with fasting serum glucose levels of 113 mg/dL and 101 mg/dL, respectively. The treatment with the long-acting somatostatin analog lanreotide (30 mg i.m., every two weeks) decreased the GH serum levels close to normal limits (1.5 ng/mL and 1.6, ng/mL respectively). The treatment with lanreotide normalised the fasting serum glucose levels (91 mg/dL and 81 mg/dL, respectively) together with a reduction of serum insulin levels from 14.2 mU/mL to 8.7 mU/mL and from 25.4 mU/mL to 11.5 mU/mL, respectively (HOMA decreased form 3.96 to 1.97 and 6.33 to 2.3, respectively). We discuss the mechanisms by which lanreotide can improve glucose tolerance in patients with active acromegaly despite lowering the serum insulin levels through a direct effect on insulin secretion.

Introduction. Acromegaly is a chronic disease associated with high mortality rate if untreated. The aim of the study is to evaluate mortality ratio in Romanian patients with acromegaly in latest years, with new therapeutic options. Patients and Methods. This retrospective study analyzed 336 (111M/225F, mean age 48.13±12.40 years) consecutive patients with acromegaly between 1st January 2001 and 31 December 2014, median follow-up 7.36 years (0.48-13.99 years). PAMCOMP computation program assessed standardized mortality ratio (SMR). Kaplan Meier curve was used for comparison between of different cut-off levels of the last GH level on survival. Serum GH levels were measured by IRMA (sensitivity 0.1 ng/mL). Results. During follow-up 2596.34 person-years, 41 patients died, with a SMR of 1.34 (CI 0.96-1.82). Mean age at death was 63.19±11.66 years. Females with acromegaly died 83% more frequently than women in general population: SMR-1.83 (CI 1.21-2.67). Females were older at diagnosis (p=0.006), and were less probable to receive substitution of gonadotrophic failure than males (p<0.001). Independent factors correlated with mortality were age at baseline (p<0.001, HR=1.07), last GH level (p=0.003, HR=1.01) and systolic blood pressure (p=0.029, HR=1.02). Patients with last GH level ≤ 1 ng/mL had a better survival than patients with GH>1 ng/mL (p Log Rank=0.002). SMR of patients with last GH >1 ng/mL was 1.59 (CI 1.08-2.26) for the entire group, 2.2 (CI 1.32-3.44) for females and 1.3 (CI 0.67-2.29) for males. Conclusion. Patients with acromegaly have a high mortality ratio compared to general population, especially in women and those with post-therapeutic serum GH levels over 1 ng/mL. Longer follow-up is needed for the evaluation of the effect of new therapies on mortality.