Svetozar Damjanovic

Increased incidence of neoplasia in patients with pituitary adenomas

The goal of our study was to determine the rate of neoplasms in patients with other pituitary adenomas (non‐functioning and prolactinomas) in comparison with acromegaly which is known to favour the development of neoplasia.

Risk Profiles and Penetrance Estimations in Multiple Endocrine Neoplasia Type 2A Caused by Germline RET Mutations Located in Exon 10

Multiple endocrine neoplasia type 2 is characterized by germline mutations in RET. For exon 10, comprehensive molecular and corresponding phenotypic data are scarce. The International RET Exon 10 Consortium, comprising 27 centers from 15 countries, analyzed patients with RET exon 10 mutations for clinical‐risk profiles. Presentation, age‐dependent penetrance, and stage at presentation of medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism were studied. A total of 340 subjects from 103 families, age 4–86, were registered. There were 21 distinct single nucleotide germline mutations located in codons 609 (45 subjects), 611 (50), 618 (94), and 620 (151). MTC was present in 263 registrants, pheochromocytoma in 54, and hyperparathyroidism in 8 subjects. Of the patients with MTC, 53% were detected when asymptomatic, and among those with pheochromocytoma, 54%. Penetrance for MTC was 4% by age 10, 25% by 25, and 80% by 50. Codon‐associated penetrance by age 50 ranged from 60% (codon 611) to 86% (620). More advanced stage and increasing risk of metastases correlated with mutation in codon position (609→620) near the juxtamembrane domain. Our data provide rigorous bases for timing of premorbid diagnosis and personalized treatment/prophylactic procedure decisions depending on specific RET exon 10 codons affected. Hum Mutat 31:1–8, 2010.

Pituitary adenomas secreting large amounts of prolactin may give false low values in immunoradiometric assays. The hook effect

Immunoradiometric assay (IRMA) for serum prolactin (PRL) measurement can give falsely low values, leading to unnecessary surgery in patients with prolactinomas. We studied clinical and biochemical features of patients with pituitary macroprolactinomas in whom plasma PRL levels had been underestimated due to the so-called “high dose PRL hook effect”. This phenomenon was observed in four (14.2%) out of 28 patients with pituitary macroadenomas (13 macroprolactinomas and 15 non-functioning macroadenomas) reffer during one-year period. Undiluted median (range) PRL levels were 11.3 (3.0–48.7), 983.9 (194.4–1959.4), and 96.9 (66.6–147.7) µg/l in patients with non-functioning macroadenomas, macroprolactinomas and the hook effect adenomas, respectively. In all patients assay was performed after serum dilution, and only in patients with the hook effect the median PRL levels increased significantly to 5795.0 (2097.2–12722.2) µg/l. The mean age at diagnosis was 38±6.5, 45±6, and 53±3 yr, for the patients with the hook effect, macroprolactinoma and non-functioning adenoma, respectively. Males were predominant (75%) in the hook effect adenoma group. Patients with the hook effect macroprolactinomas were all treated successfully with dopamine agonists, and all patients had significant shrinkage of the tumor mass (more than 50% shrinkage). In conclusion, this study suggests that patients with high dose PRL hook effect are generally younger, more frequently males with very large pituitary adenomas (grade III–IV according to Hardy). It is necessary, whenever performing IRMA for serum prolactin measurement, to dilute samples routinely (1:1 and 1:10 dilutions) in every patient with pituitary tumor.

High output heart failure in patients with newly diagnosed acromegaly

PURPOSE We sought to determine the prevalence and characteristics of heart failure in patients with newly diagnosed acromegaly. SUBJECTS AND METHODS We assessed 102 consecutive patients who had acromegaly (44 men; age range, 22 to 71 years) for signs and symptoms of heart failure. We included a control group of 33 nonobese healthy subjects (13 men; age range, 26 to 70 years). Cardiac morphologic parameters, left ventricular mass index, ejection fraction, end-systolic wall stress, and cardiac index were measured by echocardiography. Endocrinological assessment was performed in all participants. RESULTS Of the 102 patients, 10 (10%) had overt heart failure at the time of diagnosis of acromegaly, 9 of whom were men (P <0.01). Patients with acromegaly and heart failure had an increased mean (+/- SD) left ventricular end-diastolic diameter (76 +/- 11 mm) compared with those without heart failure (53 +/- 6 mm, P <0.001) and control subjects (49 +/- 5 mm, P <0.001). Patients with heart failure had higher left ventricular mass index (230 +/- 56 g/m2 vs. 118 +/- 40 g/m(2), P <0.001) and end-systolic wall stress (237 +/- 79 x 10(3) dyn/cm2 vs. 111 +/- 42 x 10(3) dyn/cm2, P <0.001), but lower ejection fraction (42% +/- 17% vs. 66% +/- 9%, P <0.001), in comparison with patients without heart failure. The mean cardiac index was significantly higher in patients with heart failure (4.3 +/- 1.8 L/min-m2) than in those without heart failure (3.5 +/- 0.8 L/min-m2, P = 0.04) or in control subjects (3.1 +/- 0.6 L/min-m2, P = 0.002). Two factors were independently associated with heart failure in acromegalic patients: cardiac index (odds ratio [OR] per SD of 1.0 L/min-m2 = 16; 95% confidence interval [CI]: 1.8 to 135) and ejection fraction (OR per SD of 12% = 0.7; 95% CI: 0.6 to 0.9). CONCLUSION High output heart failure with a modest decline in ejection fraction is frequently detected at the time of diagnosis of acromegaly. Left ventricular hypertrophy in these patients is characterized by a dilated ventricle and an increased left ventricular mass that is primarily due to the enlarged chamber diameter.

Lipid and lipoprotein profile in women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by obesity-related risk factors for cardiovascular disease. The objective of our study was to determine values of key lipid and lipoprotein fractions in PCOS, and their possible relation to insulin resistance. A total of 75 women with PCOS (aged 23.1 +/- 5.1 years, BMI 24.9 +/- 4.7 kg/m(2)), and 56 age- and BMI-matched controls were investigated. In all subjects, basal glucose, cholesterol (total, HDL, and LDL), oxidized LDL (OxLDL), triglycerides, apolipoprotein (apo)A1, apoB, and apoE, nonesterified fatty acids, insulin, testosterone, sex hormone-binding globulin, homeostasis model assessment (HOMA) index, and free androgen index were determined in the follicular phase of the cycle. PCOS patients compared with controls had increased indices of insulin resistance, basal insulin (p < 0.001), and HOMA index (p < 0.001), and worsened insulin resistance-related dyslipidemia with decreased HDL cholesterol (p < 0.01), elevated triglycerides (p = 0.010), and pronounced LDL oxidation (p < 0.001). In conclusion, characteristic dyslipidemia of insulin resistance and unfavorable proatherogenic lipoprotein ratios were present only in women with PCOS and not in controls. Elevated OxLDL and the relation of apoE and nonesterified fatty acids with insulin resistance suggest that women with PCOS are at increased risk for premature atherosclerosis.

Lymphocyte glucocorticoid receptor expression level and hormone-binding properties differ between war trauma-exposed men with and without PTSD.

OBJECTIVE Posttraumatic stress disorder (PTSD) has been shown to be associated with altered glucocorticoid receptor (GR) activity. We studied the expression and functional properties of the receptor in peripheral blood mononuclear cells (PBMCs) from non-traumatized healthy individuals (healthy controls; n=85), and war trauma-exposed individuals with current PTSD (n=113), with life-time PTSD (n=61) and without PTSD (trauma controls; n=88). The aim of the study was to distinguish the receptor alterations related to PTSD from those related to trauma itself or to resilience to PTSD. METHODS Functional status of the receptor was assessed by radioligand binding and lysozyme synthesis inhibition assays. The level of GR gene expression was measured by quantitative PCR and immunoblotting. RESULTS Current PTSD patients had the lowest, while trauma controls had the highest number of glucocorticoid binding sites (Bmax) in PBMCs. Hormone-binding potential (Bmax/KD ratio) of the receptor was diminished in the current PTSD group in comparison to all other study groups. Correlation between Bmax and KD that normally exists in healthy individuals was decreased in the current PTSD group. Contrasting Bmax data, GR protein level was lower in trauma controls than in participants with current or life-time PTSD. CONCLUSIONS Current PTSD is characterized by reduced lymphocyte GR hormone-binding potential and by disturbed compensation between Bmax and hormone-binding affinity. Resilience to PTSD is associated with enlarged fraction of the receptor molecules capable of hormone binding, within the total receptor molecule population in PBMCs.

Clinical indicators of biochemical remission in acromegaly: does incomplete disease control always mean therapeutic failure?

Objective  Correction of GH and IGF‐I levels are associated with improvements in insulin secretion, cardiac performance and body composition in patients with acromegaly, but whether these parallel post‐treatment levels of GH–IGF‐I axis activity is undefined. We investigate whether various biochemical outcomes after transsphenoidal pituitary surgery (TSS) in these patients are associated with clinically relevant differences in cardiac performance, insulin resistance and body composition.

Hypothalamic-pituitary-adrenocortical axis hypersensitivity and glucocorticoid receptor expression and function in women with polycystic ovary syndrome.

INTRODUCTION Molecular mechanisms underlying pathophysiology of polycystic ovary syndrome (PCOS), especially those related to cortisol signaling, are poorly understood. We hypothesized that modulation of glucocorticoid receptor (GR) expression and function, may underlie possible PCOS-related impairment of feedback inhibition of hypothalamic-pituitary-adrenocortical (HPA) axis activity and thus contribute to increased adrenal androgen production in women with PCOS. MATERIALS AND METHODS 24 normal-weight and 31 obese women with PCOS were compared to 25 normal-weight controls. Fasting blood samples were collected for measurements of serum concentrations of dehydroepiandrosterone sulfate, testosterone, sex hormone-binding globulin, insulin, basal cortisol and cortisol after oral administration of 0.5 mg dexamethasone. Concentrations of GR mRNA, GR protein, mineralocorticoid receptor (MR) protein and heat shock proteins (Hsps), as well as the number of GR per cell (B(max)) and its equilibrium dissociation constant (K(D)) were measured in isolated peripheral blood mononuclear cells. RESULTS An increase in HPA axis sensitivity to dexamethasone, an elevation of the GR protein concentration, and unaltered receptor functional status were found in both normal-weight and obese women with PCOS vs. healthy controls. Lymphocyte MR, Hsp90 and Hsp70 concentrations, and MR/GR ratio were similar in all groups. Correlation between B(max) and K(D) was weaker in the group of obese women with PCOS than in the other 2 groups. CONCLUSIONS The results did not confirm the initial hypothesis, but imply that PCOS is associated with increased GR protein concentration and HPA axis sensitivity to dexamethasone.

The effectiveness of arginine + GHRH test compared with GHRH + GHRP‐6 test in diagnosing growth hormone deficiency in adults

objective The objective of this study is to investigate the performance of two novel tests in diagnosing growth hormone deficiency in adults.

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 9β) 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 9β (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 iso-forms, 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 9β, are associated with Als. 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.