Serum Insulin-Like Growth Factor-1 (IGF-1) Age-Specific Reference Values for Healthy Adult Population of Serbia.

Context: Insulin-like growth factor-1 (IGF-1) is main serum surrogate marker of growth hormone (GH) secretion, used in diagnostics and treatment of GH deficiency (GHD) and acromegaly. Regional, ethnic, racial or nutritional factors obscure cross-population applicability of IGF-1 reference values. Establishment of population- and assay-specific reference values requires sizable representative cohort of healthy subjects. Subjects and Methods: In representative sample of healthy adult population of Serbia (N=1200, 21-80 years, 1:1 male:female) serum IGF-1 was analyzed by Siemens Immulite 2000 assay under uniform laboratory conditions. Upper and lower limit of reference range (5th - 95th percentile) were calculated for each of the 12 quinquennial age intervals. IGF-1 distribution was normalized and standard deviation score (SDS) calculated by Logarithmic and LMS methods. Results: IGF-1 and age correlated significantly, with most prominent decline at 21-50 years, followed by a plateau up to age of 70. Gender differences were not significant overall. Plateau in age-related IGF-1 decline was less prominent in women. Correlations of IGF-1 with body mass index (BMI) or waist to hip ratio (WHR) were insignificant. Superior IGF-1 SDS transformation was achieved with LMS method, while logarithmic method was simpler to use. Conclusions: Normative age-specific serum IGF-1 reference values were established on a representative cohort of healthy adults in Serbia. Our results support recommendations against necessity for gender-specific or BMI- and WHR-specific reference ranges. Population-based data serve to generate IGF-1 SDS, which is valuable in rational application of consensus guidelines, proper longitudinal follow-up, advancement in efficacy and safety and personalization of treatment targets.

Systolic right ventricular adaptive changes in athletes as predictors of the maximal functional capacity: a pulsed tissue Doppler study.

AIM: The aim of this study was to extend the analysis of the systolic right ventricular (RV) adaptation to combined endurance and strength training, to assess the utility of tissue Doppler imaging in detecting the degree of these changes and to find independent RV predictors of the maximal functional capacity. METHODS: Standard Doppler and TDI were used to assess cardiac parameters at rest in 37 elite male athletes (16 wrestlers, 21 water polo players) and 20 sedentary subjects of similar age. Progressive maximal test on treadmill was used to assess VO2max. The obtained parameters were adjusted for HR, FFM, and BSA. RESULTS: Wrestlers showed higher VO2max than controls, but lesser than water polo players. RV diameter was larger in athletes. Right atrial pressure (RVE/e) was higher in water polo players than in other groups. Systolic function assessed by tricuspid annular plane systolic excursion (TAPSE) and RVs' was the highest in wrestlers. Global RV systolic parameters myocardial performance index (MPI) and preejection time/ejection time index (PET/ET) were similar. On multivariate analysis systolic parameters were independent predictors of VO2max only in wrestlers: RVs' (beta=3.18, P=0.001) and RV ET (beta=2.32, P=0.001). RVE/e` correlated with RVs' (r=-0.57, P=0.000). TAPSE correlated with RV ET (r=0.32, P=0.015) and RVs` (beta=0.28, P=0.033). CONCLUSION: Systolic function assessed by TAPSE and RVs` has more improved in less endurance athletes. RVs`and TDI ejection time predict VO2max in wrestlers, and possibly in other athletes with lesser right atrial pressure. TDI enables quantifying RV adaptation degree in athletes, but complementary to M-mode technique.

ACTH and cortisol responses to ghrelin and desmopressin in patients with Cushing's disease and adrenal enlargement.

BACKGROUND: Overexpression of ghrelin and vasopressin (V3) receptors demonstrated on corticotrophe adenomas accounts for exaggerated ACTH and cortisol responses to ghrelin and desmopressin (DDAVP) in patients with Cushing's disease (CD). AIM: In this study we have compared ACTH and cortisol responsiveness to DDAVP and ghrelin in CD patients with and without adrenal enlargement. SUBJECTS AND METHODS: Ghrelin and DDAVP tests were performed in 15 patients with CD (7 with and 8 without signs of adrenal enlargement) with CRH test in 8 patients. In 7 age and sex-matched healthy subjects, ghrelin test was performed. Plasma ACTH and serum cortisol concentrations were measured after ghrelin, DDAVP and CRH. Growth hormone was measured after stimulation with ghrelin. RESULTS: Significantly higher baseline and peak ACTH and cortisol concentrations after ghrelin were observed in all patients with CD compared to healthy control subjects. Patients with CD and adrenal enlargement had significantly lower baseline and peak ACTH concentrations after stimulation with ghrelin compared to CD patients without adrenal enlargement, while cortisol levels at baseline and after ghrelin administration were similar. Three out of seven patients with CD and adrenal enlargement did not respond to DDAVP while they responded well to CRH and ghrelin. CONCLUSION: Patients with CD and adrenal enlargement pose special diagnostic problems. They may have lower baseline ACTH levels and may not respond to DDAVP while they respond to ghrelin and CRH. Despite increased endogenous cortisol levels in CD, cortisol responses to ghrelin and CRH are preserved in patients with CD and adrenal enlargement.

The utility of 99mTc-EDDA/HYNIC-TOC scintigraphy for assessment of lung lesions in patients with neuroendocrine tumors.

UNLABELLED: Our aim was to assess clinical utility of 99mTc-EDDA/HYNIC-TOC scintigraphy for evaluation of lung lesions in patients with neuroendocrine tumors (NETs). Single photon emission computed tomography (SPECT) of the thorax and whole body scintigraphy were performed in 34 patients using 99mTc-EDDA/HYNIC-TOC. Visual assessment was complemented by semiquantitative evaluation based on tumor to non-tumor (T/NT) ratio. Clinical, laboratory, and histological findings served as the standard for comparison. Enhanced tracer uptake was observed on both SPECT and whole body scintigraphy in 29 of 34 patients (88% sensitivity). T/NT ratios were significantly higher on SPECT than whole body images (2.96+/-1.07 vs.1.70+/-0.43, p KEYWORDS: 99mTc-EDDA/Hynic-TOC, lung involvement of NETs, T/NT ratio.

Germline VHL gene mutations in three Serbian families with von Hippel-Lindau disease.

Von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited cancer predisposition syndrome due to germline mutations in the VHL tumor suppressor gene which is associated with virtually complete penetrance. The VHL syndrome has a highly variable phenotypic expressivity including retinal and CNS haemangioblastomas, pheochromocytomas, renal clear cell carcinomas, and multifocal cysts. In order to establish VHL gene testing, we analyzed three families affected by VHL disease, using SSCP mutation screening and DNA sequencing. Among 18 family members with and without clinical manifestations, eight cases with germline VHL mutations were detected. In family A, a c.490G>T/ p.Gly93Cys substitution was found. In family B, with pheochromocytoma only phenotype, we detected a previously not described c.463G>A/p.Val84Met replacement. Within this family, a prenatal diagnosis was also performed. Affected members of the third family with a VHL type 1 disease carried a c.475T>C/p.Trp88Arg exchange. All these mutations were located in exon 1 of the VHL tumor suppressor gene. Alterations in this hydrophobic region of the core beta domain of the VHL protein are known to have a variety of phenotypic consequences. We observed also intrafamiliar variation in time of onset and severity of the disease.

The results of molecular genetic testing for RET proto-oncogene mutations in patients with medullary thyroid carcinoma in a referral center after the two decade period.

BACKGROUND: Medullary thyroid carcinoma (MTC) is a type of thyroid neoplasm which originates from parafollicular cells, and it is commonly diagnosed by calcitonin screening. Besides the sporadic form, the heritable form of MTC is characterized by constitutive activation of the RET (REarranged during Transfection) proto-oncogene caused by different mutations. METHOD: We collected data regarding RET genetic screening performed in the Center for Endocrine Surgery in Belgrade during a 20-year-period. The study group included 249 MTC patients who were genetically tested for RET mutations by Sanger's sequencing method. RESULTS: Genetic screening of the study population revealed nine different mutations of the RET gene in 42 carriers. The most common mutation was C634F, and it has been detected in 31 % (13/42) of individuals, while C618R, L790F, and S904S were present in only 2 % (1/42) each in the study group. Detected mutations were unequally distributed in different RET gene exons. Among MTC patients, 67 % (28/42) had mutation harbored in exon 11, while the rarest mutation was located in exons 10 and 15, each present in only 2 % (1/42) of patients. CONCLUSIONS: The RET gene mutation profile has a unique distribution in this study population when compared with the other European populations. The mutations in codon 634 are most common; therefore the cost-reducing genetic screening should primarily target this codon, and if the negative outcome appears, then other codons should be examined in the order that depends on their occurrence. Hippokratia 2016, 20(3): 187-191.

Modifications of rat liver glucocorticoid receptor by insulin-induced hypoglycemia.

Stability-, equilibrium- and kinetic binding parameters, transformation rate and sedimentation properties of liver cytosol glucocorticoid receptor from insulin-treated rats were studied. 40% elevation of cytosolic glucocorticoid binding and a lower affinity of the receptor for ligand were observed in hypoglycemic rats as compared to the controls. A small but significant decrease of [3H]triamcinolone acetonide-receptor complexes association rate and an increase of dissociation rate were also found. The rate and the extent of activation of the complexes from insulin-treated rats were somewhat higher compared to the controls, and the complexes from both groups showed higher affinity for the nuclei isolated from insulin-treated animals. Mixing experiments suggested that insulin treatment lead to alterations at the level of both the receptor protein and the nuclear binding sites. Sedimentation properties of transformed and untransformed receptor remained unchanged upon insulin treatment. The physiological relevance of the data was confirmed by hypoglycemia-related stimulation of tyrosine aminotransferase induction by dexamethasone.

Blocked growth hormone-releasing peptide (GHRP-6)-induced GH secretion and absence of the synergic action of GHRP-6 plus GH-releasing hormone in patients with hypothalamopituitary disconnection: evidence that GHRP-6 main action is exerted at the hypothalamic level.

GH-releasing peptide (GHRP-6; His-D Trp-Ala-Trp-D Phe-Lys-NH2) is a synthetic compound that releases GH in a specific and dose-related manner through mechanisms and a point of action that are mostly unknown but different from those of GHRH. In man, GHRP-6 is more efficacious than GHRH, and a striking synergistic action on GH release is observed when GHRP-6 and GHRH are administered simultaneously. Based on such a synergistic action, it has been hypothesized that GHRP-6 acts through a double mechanism by actions exerted both at the pituitary and hypothalamic levels. The aim of the present study was 2-fold: 1) to further characterize the mechanism of action and synergistic effects of GHRP-6; and 2) to study its action in patients with hypothalamopituitary disconnection. Twelve patients with different neuroendocrine pathologies leading to a state of hypothalamopituitary disconnection (functional stalk section) and 11 age- and sex-matched normal controls were studied. Each subject underwent 3 tests on separate occasions, being challenged with GHRH (100 micrograms, i.v.), GHRP-6 (90 micrograms, i.v.), or GHRH plus GHRP-6. GH was analyzed as the area under the curve (mean +/- SE, micrograms per L/120 min). In normal subjects GH secretion was 483.7 +/- 99.2 after GHRH, 1434.8 +/- 393.0 after GHRP-6, and 3771.5 +/- 399.6 after GHRH plus GHRP-6; the level of GH secreted after GHRH plus GHRP-6 treatment was significantly (P < 0.05) higher than after the arithmetic sum of GH levels after both compounds administered separately. In the group of patients with hypothalamopituitary disconnection, the level of GH secreted after GHRH was similar to that in controls (423.4 +/- 62.8); however, a complete blockade was observed after GHRP-6 (97.3 +/- 7.9), significantly (P < 0.05) lower than after GHRH as well as lower than the GHRP-6-induced GH release in control subjects (P < 0.01). After GHRH plus GHRP-6, the patients with hypothalamopituitary disconnection showed severely reduced secretion (745.3 +/- 67.6; P < 0.01 vs. controls), a value that was not significantly different from the arithmetic addition of levels produced by both compounds administered separately.(ABSTRACT TRUNCATED AT 400 WORDS)

Growth hormone (GH) secretion in active acromegaly after the combined administration of GH-releasing hormone and GH-releasing peptide-6.

His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (called GHRP-6) is a synthetic compound that releases GH in a dose-related, specific, and nonspecies-specific manner, through mechanisms different from those of GHRH. Being, normally, more potent than GHRH, GHRP-6 shows a striking synergistic action when administered simultaneously with GHRH, although the mechanisms and point of action of such a potentiating effect are unknown. The aim of the present study was 2-fold: 1) to further characterize the actions and mechanisms of GHRP-6 as well as its synergistic effects, and 2) to study its actions in acromegalic patients. Eleven acromegalic patients and 12 normal subjects, age and sex matched as controls, underwent 3 tests each on separate occasions, being challenged with GHRH (100 micrograms, iv), GHRP-6 (90 micrograms, iv), or GHRH plus GHRP-6. GH was analyzed as the area under the curve (mean +/- SE; micrograms per L/120 min). In normal subjects, GH secretion was 686 +/- 227 after GHRH, 1787 +/- 510 after GHRP-6, and 4111 +/- 671 after GHRH plus GHRP-6; the level of GH secreted after GHRH plus GHRP-6 treatment was significantly (P < 0.05) higher than the arithmetic sum of GH levels after both compounds administered separately. In acromegalic patients, the level of GH secreted after GHRH was 1468 +/- 499, that after GHRP-6 was 2595 +/- 762, and that after GHRH plus GHRP-6 was 4949 +/- 1043; this last value was not significantly different from the arithmetical addition of levels produced by both compounds administered separately. These results indicate that GH-secreting pituitary adenomas respond surprisingly well to either GHRH or GHRP-6 despite being deprived for long periods (even years) of the physiological regulation exerted by the hypothalamus. In addition, the synergistic action of GHRH plus GHRP-6 was observed in normal subjects, but not in acromegalic patients. These results suggest that GHRP-6 does not need to operate through hypothalamic factors to exert its GH-releasing action, even for eliciting a greater response than GHRH. On the other hand, the synergistic effect of GHRH plus GHRP-6 appears to need the cooperation of the hypothalamus, but how this occurs is still undetermined.

Serum leptin levels in patients with acromegaly before and after correction of hypersomatotropism by trans-sphenoidal surgery.

It has been shown that GH excess is associated with decreased leptin levels and decreased body fat mass. Reports regarding the effect of GH on serum leptin levels are inconsistent. We studied leptin secretion in 20 acromegalics before and 2 months after trans-sphenoidal surgery and in 20 gender-, age-, and body mass index (BMI)-matched control subjects. The mean 8-h leptin concentration for each subject was measured from a pool formed of samples collected hourly beginning at 2200 h until 0600 h the next morning. In a subgroup of 10 acromegalics, leptin pulsatility was assessed for the same period of time in 10-min sampling intervals. Basal GH, insulin-like growth factor-I (IGF-I), insulin, glucose, and lipids levels were measured. Area under the curve for insulin (AUCins) during oral glucose tolerance test was calculated. Control subjects and acromegalics had similar BMI, but patients with active acromegaly had significantly lower mean leptin level (mean +/- SEM; in men, 2.6+/-0.4 vs. 7.1+/-1.1 microg/L, P = 0.003; in women, 16.0+/-3.4 vs. 23.5+/-3.1 microg/L; P = 0.036). Mean 8-h leptin correlated with BMI (r = 0.57, P = 0.007, in controls; r = 0.70, P = 0.001, in patients). In stepwise regression analysis with mean 8-h leptin as a dependent variable, BMI (P<0.001) and gender (P = 0.01) in acromegalics entered the equation, whereas in control subjects gender, free fatty acids, insulin, and age accounted for 99.3% in leptin variability. After surgery, BMI did not change significantly; and glucose (P = 0.014), GH (P<0.001), and IGF-I (P<0.001) levels together with AUCins (P = 0.002) decreased, whereas mean leptin concentration rose significantly and attained normal levels (4.1+/-0.8 microg/L, P = 0.028) in acromegalic men and (23.6+/-4.7 microg/L, P = 0.003) in acromegalic women. Correlation between leptin level and BMI was preserved after surgery (r = 0.62, P = 0.005). In stepwise regression analysis, free fatty acids (P = 0.04) contributed to 26.8% of the variance in corrected-leptin (for BMI and gender). Leptin concentration peak height and interpeak nadir level rose significantly (P = 0.033 and P = 0.037) after surgery by Cluster analysis, without significant changes in leptin pulse frequency and incremental peak amplitude. Nocturnal rise of leptin (mathematically described by a cubic curve) was characterized by an acrophase just after midnight, before and after surgery. The amplitude and the average leptin concentration of the cubic fit increased significantly after surgery (P = 0.028 and P< 0.001). In conclusion in acromegalic patients: 1) leptin secretion maintains the pulsatility and nocturnal rise; 2) the gender-based leptin differences are preserved; 3) GH-IGF-I normalization leads to a rise in leptin that is not related to changes in BMI; and 4) the possible role of rise in leptin levels when assessing clinical and metabolic outcome of therapy in acromegalic patients deserves additional studies.

Ghrelin main action on the regulation of growth hormone release is exerted at hypothalamic level.

Ghrelin, a recently isolated hormone, seems to participate in the physiological regulation of GH secretion. Exogenously administered ghrelin stimulates GH discharge in all species so far tested including man, but whether this action is exerted at pituitary or alternatively at hypothalamic level is not known at present. To understand the point of ghrelin action a group of patients with organic lesion mainly in the hypothalamic area and matched controls were studied. Patients showed a severe GH deficiency after hypothalamic stimulation (ITT), but partial response after GHRH administration. Cases and controls were tested on three separate days by either ghrelin; GHRH; and ghrelin plus GHRH; always at 1 micro g/Kg iv. The mean GH peak after stimulation in the patients were: 0.4 +/- 0.1 micro g/L by ITT; 3.1 +/- 0.5 micro g/L after GHRH; 2.0 +/- 0.8 micro g/L after ghrelin; and 9.6 +/- 2.9 micro g/L after the combination of GHRH plus ghrelin. In the controls GHRH induced a GH peak of 21.2 +/- 7.5 micro g/L, and 75.1 +/- 16.0 micro g/L after ghrelin with a peak after GHRH + ghrelin of 103.5 +/- 26.4 micro g/L. These data indicate that when hypothalamic structures are not operative ghrelin, either alone or in combination with GHRH, is not able to significantly release GH. In addition to postulating a hypothalamic point of action for the ghrelin-induced GH secretion, these results suggests that ghrelin will not have significant clinical utility in patients with GH deficiency due to organic lesion.

The effect of thyrotropin-releasing hormone on gonadotropin and free alpha-subunit secretion in patients with acromegaly and functionless pituitary tumors.

UNLABELLED: Paradoxical response of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and alpha-subunits (alpha-SU) to thyrotropin-releasing hormone (TRH) have previously been reported in individuals with clinically nonfunctioning pituitary tumors (NFT). In the present study, we assessed the in vivo responses of LH, FSH, alpha-SU to TRH in 34 patients with NFT and 29 patients with agromegaly. Twenty-three clinically NFT were postoperatively analyzed by immunocytochemistry and 21 stained positive for beta-FSH and/or beta-LH. Two patients with NFT had elevated basal circulating levels of FSH (41.5 IU/L) and thus were characterized as FSH-secreting adenomas. TRH in these patients increased LH from basal 1.6 IU/L to 32.6 IU/L. In other patients with NFT, circulating levels of glycoprotein peptides were not elevated. TRH induced significant rise of LH in 8 (23.5%), FSH in 5 (14.7%), and alpha-SU in 10 (29.4%) patients with NFT. Thus, a bolus dose of TRH elicited a notable increment in FSH, LH or alpha-SU in 23 of 34 patients with NFT. Among 29 patients with acromegaly, LH rose in 6 (20.7%), FSH in 5 (17.2%), and alpha-SU in 3 (10.3%) patients. IN CONCLUSION: (1) We confirm that most NFTs are capable of synthesizing gonadotropin hormones and subunits (beta-FSH, beta-LH). (2) Most patients in our study responded by either FSH, LH or alpha-SU secretion after TRH, independent of basal hormone levels. Furthermore, recent studies show that by measurement of TRH stimulated beta-FSH and beta-LH one might further improve the diagnostic tools. (3) Gonadotropin response and possibly alpha-SU to TRH are also found in some patients with acromegaly. This could be a marker of a plurihormonal pituitary tumor.

Epidemiology of Trichinella infection in the horse: the risk from animal product feeding practices.

A discovery in 2002 of a Trichinella spiralis-infected horse in Serbia offered an opportunity to conduct needed epidemiological studies on how horses, considered herbivores, acquire a meat-borne parasite. This enigma has persisted since the first human outbreaks from infected horse meat occurred in then 1970s. The trace back of the infected horse to a farm owner was carried out. Interviews and investigations on the farm led to the conclusion that the owner had fed the horse food waste in order to condition the horse prior to sale. Further investigations were then carried out to determine the frequency of such practices among horse owners. Based on interviews of horse producers at local horse markets, it was revealed that the feeding of animal products to horses was a common practice. Further, it was alleged that many horses, particularly those in poor nutritional condition would readily consume meat. A subsequent series of trials involving the experimental feeding of 219 horses demonstrated that 32% would consume meat patties. To confirm that horses would eat infected meat under normal farm conditions, three horses were offered infected ground pork balls containing 1100 larvae. All three became infected, and at necropsy at 32 weeks later, were still positive by indirect IFA testing, but not by ELISA using an excretory-secretory (ES) antigen. This result indicates that further study is needed on the nature of the antigen(s) used for potential serological monitoring and surveillance of horse trichinellosis, especially the importance of antigenic diversity. The experimentally-infected horses also had very low infection levels (larvae per gram of muscle) at 32 weeks of infection, and although the public health consequences are unknown, the question of whether current recommended inspection procedures based on pepsin digestion of selected muscle samples require sufficient quantities of muscle should be addressed. It is concluded that horses are more willing to consume meat than realized and that the intentional feeding of animal products and kitchen waste is a common occurrence among horse owners in Serbia (and elsewhere?). This is a high risk practice which demands closer scrutiny by veterinary and food safety authorities, including the implementation of rules and procedures to ensure that such feeds are rendered safe for horses, as is now required for feeding to swine.

Pituitary enlargement due to primary hypothyroidism: growth hormone response to GHRH, GHRP-6 and GHRH plus GHRP-6.

GH secretion after growth hormone-releasing hormone (GHRH), growth hormone releasing peptide-6 (GHRP-6) and after combined administration of both peptides was studied in a patient with lactotrope and thyrotrope hyperplasia due to primary hypothyroidism. Pituitary pseudotumor disappeared after thyroid hormone replacement; this was evidenced by magnetic resonance imaging (NMR). There was no difference between areas under the curve (AUCzero-120 min) during GHRH test before and after thyroid hormone replacement (136.5 vs 129.0 micrograms/l min). Maximal GH increases over basal values (delta GH) did not change (1.5 and 1.9 micrograms/l). GH secretion induced by GHRP-6 increased after treatment (AUCzero-120 min 197.2 vs 650.4 micrograms/l min). delta GH increments were 4.0 and 18.3 micrograms/l before and after therapy respectively. When the peptides were administered together a synergistic effect on GH secretion was observed but GH release was much more powerful after pituitary pseudotumor disappearance (AUCzero-120 min 1043.2 vs 2046.7 micrograms/l min). This was accompanied by increased delta GH (22.7 vs 35.5 micrograms/l). The synergic action of peptides normalized in euthyroid condition and after the resolution of pituitary pseudotumor mainly due to improved GH response to GHRP-6. Blunted response of GH to GHRP-6 and GHRP-6 plus GHRH were in part due to known effects of hypothyroidism on GH secretion. Hypothalamopituitary disconnection and/or decrease in the synthesis of an unknown factor in the hypothalamus which mediates the effects of GHRP-6 may have participated in the GH responsiveness of this patient. This case adds to in vivo evidence that GHRP-6 operates through a non-GHRH dependent mechanism.

Evaluation of pituitary GH reserve with GHRP-6.

GH releasing peptides (GHRPs) were developed before the isolation and identification of GH releasing hormone (GHRH) in 1982 yet the clinical era of the GHRPs began in 1988. Since then clinical studies have been greatly extended. We studied the effects of GHRPs on GH release as a function of age, metabolic status and in different neuroendocrine pathologies. The different mechanism of action of GHRPs versus GHRH and the site of action have been addressed. There is a large variability in the stimulatory action of GHRH contrasted with the reproducibility of action of GHRPs. In different metabolic states GH response after GHRH is more impaired than after GHRP-6. On the other hand in different neuroendocrine pathologies GH response after GHRP-6 is more impaired than after GHRH. Each secretagogue provides separate information on GH secretion, necessary not only for linear growth but for general metabolism.

Growth hormone secretagogues in pathological states: diagnostic implications.

The identification and cloning of the receptor for synthetic growth hormone (GH) secretagogues, even before the endogenous ligand has been identified or its precise physiological role established, suggests that there is a novel target of action for this class of drug. In an attempt to select patients who will benefit from GH treatment, GH secretagogues are being evaluated for their usefulness in diagnosing GH deficiency. The effects of GH-releasing peptides (GHRPs) on GH release as a function of age and metabolic status, and in different neuroendocrine pathologies, are described, as are the different mechanisms of action, potency and reproducibility of the response to GHRPs compared with GH-releasing hormone (GHRH). GHRPs offer the advantage over GHRH in natural models of deranged GH secretion in that, in various metabolic states (e.g. obesity, anorexia nervosa and non-insulin-dependent diabetes mellitus), the GH response to GHRH is more impaired than it is to GHRPs. However, in some neuroendocrine pathologies, the reverse is true. Thus, both secretagogues provide separate information on the physiological status of somatotrophs.

Cepstral distance measures of hormone concentration time series.

In this paper we present a class of time series distance measures based on the difference of their cepstral transformations. We emphasise the convenience of the proposed distance measure in the cases when the time series can be treated as output of a linear system driven with a quasi-periodic stochastic signals. In order to illustrate the cepstral time series distance measure we applied them in cluster and multidimensional scaling analysis of daily hormonal secretion fluctuation series taken from a group of patients before and after surgery.

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.

Cardiac autonomic control in patients with myasthenia gravis and thymoma.

OBJECTIVE: To evaluate cardiac autonomic control in patients with myasthenia gravis (MG) and thymoma. MATERIALS AND METHODS: The study was performed on 21 patients with MG and thymoma and the same number of matched healthy volunteers. Standard cardiovascular reflex tests according to Ewing and baroreflex sensitivity (BRS) at rest was applied. Spectral analysis of heart rate variability (HRV) at rest was assessed using a 20-minute ECG recording (normalized low- and high-frequency bands-LFnu-RRI, HFnu-RRI and LF/HF-RRI) Time-domain analysis of HRV was derived from 24-hour ECG monitoring. RESULTS: Overall autonomic score according to Ewing was significantly increased in patients with MG and thymoma (p<0.05), mostly due to parasympathetic dysfunction. Time-domain parameters representing the overall and long-term sympathetic activity of HRV did not differ significantly between the two groups (p>0.05), but there was a significant decrease in measures of the short-term vagal variations in HRV (p<0.01). HFnu-RRI was lower, while LFnu-RRI and LF/HF-RRI were higher in patients with MG and thymoma in comparison to healthy controls but these differences were not of statistical significance (p>0.05). BRS at rest was highly significantly reduced in patients group (p<0.01). CONCLUSIONS: Our results showed mainly parasympathetic cardiac impairment in patients with myasthenia gravis and thymoma. Since autonomic dysfunction may lead to cardiac conduction abnormalities and sudden death, the investigation of autonomic nervous system function in these patients may be significant in everyday clinical practice.

Canadian Physicians' Use of Antiobesity Drugs and Their Referral Patterns to Weight Management Programs or Providers: The SOCCER Study.

Antiobesity pharmacotherapy and programs/providers that possess weight management expertise are not commonly used by physicians. The underlying reasons for this are not known. We performed a cross-sectional study in 33 Canadian medical practices (36 physicians) examining 1788 overweight/obese adult patients. The frequency of pharmacotherapy use and referral for further diet, exercise, behavioral management and/or bariatric surgery was documented. If drug treatment or referral was not made, reasons were documented by choosing amongst preselected categories. Logistic regression models were used to identify predictors of antiobesity drug use. No single antiobesity management strategy was recommended by physicians in more than 50% of patients. Referral was most common for exercise (49% of cases) followed by dietary advice (46%), and only 5% of eligible patients were referred for bariatric surgery. Significant predictors of initiating/continuing pharmacotherapy were male sex (OR 0.70; 95% CI 0.52-0.94), increasing BMI (1.02; 95% CI 1.01-1.03), and private drug coverage (1.78; 95% CI 1.39-2.29). "Not considered" and "patient refusal" were the main reasons for not initiating further weight management. We conclude that both physician and patient factors act as barriers to the use of weight management strategies and both need to be addressed to increase uptake of these interventions.