Biomedical subjects

Vera Popovic

Publications and source records attributed to Vera Popovic.

27 records · Page 2Linked to original sources

PubMed2003

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. PATIENTS: Fifty patients presenting with long-standing hypopituitarism and two control groups consisting of 50 healthy subjects in each group [age-, sex- and body mass index (BMI)-matched] participated in a multicentre study. All underwent two provocative tests on different days within 3 months apart: (i) a combined GHRH + GHRP-6 test and (ii) arginine + GHRH test. Main outcome measures were sensitivity, specificity and areas under receiver operating characteristic curves (ROC) for GHRH + GHRP-6 and arginine + GHRH tests in the diagnosis of GH deficiency in adults. RESULTS: A peak GH level after GHRH + GHRP-6, under 15.0 microg/l had a sensitivity of 94.4% and specificity of 98.8% for diagnosing GHD and area under the ROC curve was 0.99 (95% confidence interval 0.95-0.99). For peak GH levels after arginine + GHRH, a level under 9.6 microg/l had a sensitivity of 88.4% and specificity of 95% and area under the ROC curve of 0.96 (95% confidence interval 0.91-0.98). The relationship between the increment in serum GH following GHRH + GHRP-6 and arginine + GHRH test was positive, i.e. r = 0.749, P = 0.001.Thus, there was high concordance between both tests. CONCLUSION: Both GHRH + GHRP-6 and/or arginine + GHRH test may serve as an alternative to the ITT in diagnosing GHD in adults.

Adult↗

PubMed2002

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.

Acromegaly↗

PubMed2002

Physical activity or food intake prior to testing did not affect the reproducibility of GH secretion elicited by GH releasing hormone plus GH-releasing hexapeptide in normal adult subjects.

OBJECTIVE: Growth hormone deficiency (GHD) in adults is a defined syndrome of which the adverse effects on different areas of body function are reversed under replacement therapy with GH. The diagnosis of GHD is controversial in adults, relying on the GH secretion elicited by the so-called provocative tests of GH reserve. Most of the tests in use, including the widely employed insulin tolerance test, have been shown to be blunted after daily activities, such as mild exercise, heat or food intake, which makes stringent testing conditions mandatory in order to assure reproducibility. The combined administration of GH releasing hormone (GHRH) and GH-releasing hexapeptide (GHRP-6) is a very effective test for the diagnosis of GH deficiency in adults. In the present study, the perturbatory action of mild physical activity and food intake on the reproducibility of this combined test was assessed. METHODS: Seventeen healthy volunteers of both sexes were tested twice on separate occasions with the sequential administration of GHRH (90 microg i.v.) plus GHRP-6 (90 microg i.v.) as bolus. Eleven subjects underwent the first combined test in the morning under basal conditions and the second test was performed in the afternoon of the same day after a morning of habitual working activity and after a standard lunch. Another group of six subjects underwent similar double testing in the morning and in the afternoon after morning activity followed by lunch; however, both tests were separated by a period of 6 months. MEASUREMENTS: GH levels were analysed by time-resolved fluoroimmunoassay, with sampling every 15 minutes. RESULTS: The reproducibility of the GHRH + GHRP-6 test performed on the same day was high, with the mean GH peak being 65.4 +/- 8.0 microg/l in the basal state and 51.2 +/- 9.6 microg/l after lunch, while the area under the curve (AUC) was 2287 +/- 288 microg/l per 45 minutes in the morning and 1759 +/- 350 after lunch. When a period of 6 months had elapsed between the first and the second test, the reproducibility was well maintained with a mean GH peak of 42.7 +/- 6.2 microg/l in the basal state and 34.3 +/- 3.6 microg/l in the after lunch test, with the AUC 1463 +/- 209 and 1164 +/- 106 microg/l per 45 minutes in the morning and after lunch, respectively. When analysed individually, physical activity, lunch or time elapsed between the two tests did not significantly change the GH peak in the subjects tested. CONCLUSIONS: The GHRH + GHRP-6 test of GH reserve is a highly reproducible test in adult subjects over time, and is not perturbed by common daily activities, such as mild physical exercise or food intake. Considering that stringent testing conditions are not required and the whole test may be performed in 30 minutes, it may be useful in the clinical setting for the diagnosis of GH deficiency in adults.

Adult↗

PubMed2002

The impact of cranial irradiation on GH responsiveness to GHRH plus GH-releasing peptide-6.

Patients treated with cranial radiation are at risk of GH deficiency (GHD). We evaluated somatotroph responsiveness to maximal provocative tests exploring the GH releasable pool in relation to the impact of radiation damage to the hypothalamic-pituitary unit. The GH-releasing effect of GHRH plus GH secretagogue [GH-releasing peptide (GHRP)-6] (GHRH+GHRP-6) was studied in 22 adult patients (age, 23.2 +/- 1.4 yr; 8 female and 14 male; mean body mass index, 22.6 +/- 0.7 kg/m(2)) who received cranial radiation for primary brain tumor distant from hypothalamic-pituitary region 7.6 +/- 0.7 yr before GH testing. Two stimulatory tests for GH secretion were employed: insulin tolerance test (ITT, 0.15 IU/kg regular insulin i.v. bolus); and GHRH+GHRP-6 test: GHRH (Geref Serono, Madrid, Spain; l microg/kg) plus GHRP-6 (CLINALFA, Laufelingen, Switzerland; 1 microg/kg) as i.v. bolus. Serum GH was measured (Delphia; Perkin Elmer, Wallac, Turku, Finland) at -30, -15, 0, 15, 30, 45, 60, 90, and 120 min. Anterior pituitary function was normal in all except in 1 female with hyperprolactinemia. Twelve out of 22 irradiated patients were GH-deficient (GHD) with both tests. Eleven out of 22 (50%) irradiated patients were severely GHD, according to the ITT (GH < 3 microg/liter; mean GH peak, 1.5 +/- 0.5 microg/liter). In 9 irradiated patients, in whom ITT was performed as well, mean peak GH after the GHRH+GHRP-6 test was 6.2 +/- 0.8 microg/liter, which is considered as severe GHD, according to our own cut-off for the test (peak GH < 10 microg/liter). GH responses to both tests were highly concordant, but the differential in the GH peak concentrations between GHD and non-GHD irradiated patients was significantly larger for the GHRH+GHRP-6 test than that for the ITT. The 2 discordant responses, i.e. poor response to the ITT and good response to the GHRH+GHRP-6 test, were found in 1 hyperprolactinemic female patient and in 1 other female. One irradiated patient was diagnosed as GHD only with the combined test, because ITT was contraindicated because of epilepsy. PRL and cortisol responses to ITT were normal in all irradiated patients and did not depend on the GH status. IGF-I levels were not informative or discriminative between the GHD and non-GHD irradiated adult patients. In conclusion, the use of GH secretagogues plus GHRH is an easy, reliable and accurate way of assessing GH secretion in cranially irradiated patients. Impairment of the GH releasable pool in the irradiated patients, with a maximal provocative test, reflects alterations in the hypothalamic-pituitary unit caused by radiotherapy.

Adolescent↗

PubMed2002

Dopaminergic tone and obesity: an insight from prolactinomas treated with bromocriptine.

OBJECTIVE: It has recently been shown that increased body weight is associated with prolactinomas and that weight loss occurs with normalization of prolactin levels. On the other hand, decreased dopaminergic tone in humans is well correlated with obesity. The objective of this study was to correlate changes in prolactin levels with leptin and body mass index (BMI) in patients with prolactinomas treated with the long-acting dopamine agonist bromocriptine (BC). METHODS: Eleven female and twelve male patients, aged 36.7+/-2.6 years with BMI in males of 30.4+/-1.7 kg/m(2) and in females of 24.4+/-1.2 kg/m(2), were evaluated after 1 and 6 months and 11 patients were further evaluated after 2 years of BC therapy. Plasma prolactin is presented as the mean of four samples taken daily. Serum leptin was determined in the pooled serum from three samples taken at 15-min intervals at 0800 h after an overnight fast. Multivariate linear regression and repeated measures analysis of covariance were used. RESULTS: In males, pretreatment prolactin levels were 71 362+/-29 912 mU/l while leptin levels were 14.9+/-1.8 microg/l. In females, pretreatment prolactin levels were 11 395+/-5839 mU/l and leptin levels were 16.7+/-2.5 microg/l. The sexual dimorphism of serum leptin levels at initial presentation was preserved after adjusting for BMI and prolactin-induced hypogonadism. After 1 month of therapy, prolactin levels significantly decreased (males: 17 618+/-8736 mU/l, females: 3686+/-2231; P<0.05), BMI did not change (males: 30.2+/-1.7 kg/m(2), females: 24.1+/-1.2 kg/m(2); P>0.05), while serum leptin levels decreased (males: 12.5+/-1.5 microg/l, females: 13.6+/-2.1 microg/l; P<0.05). After 6 months of treatment, prolactin further decreased (males: 3456+/-2101 mU/l, females: 677+/-360 mU/l; P<0.05) as did BMI (males: 28.6+/-1.6 kg/m(2), females 23.1+/-1.0 kg/m(2); P<0.05). The difference was more pronounced in male patients. Leptin levels were 12.8+/-2.8 microg/l in males and 12.9+/-1.8 microg/l in females (P<0.05). After 2 years of BC treatment, prolactin levels were near normal (males: 665+/-439 mU/l, females 447+/-130 mU/l; P<0.05) and BMI remained 26.5+/-1.9 kg/m(2) for males and 23.6+/-0.8 kg/m(2) for females (P<0.05). Leptin levels were 9.5+/-2.2 microg/l in males and 18.7+/-3.1 microg/l in females (P<0.05). There was a gradual increase in the gender difference in serum leptin levels over time. Changes in serum leptin levels significantly correlated with changes in BMI (r=0.844, P<0.001) but did not correlate with changes in plasma prolactin levels after 1 month (r=0.166), 6 months (r=0.313) and 2 years (r=0.234, P>0.05). CONCLUSION: The long-acting dopamine agonist BC, by increasing dopaminergic tone, may influence body weight and likely body composition by mechanisms in addition to reducing hyperprolactinemia in patients with prolactinomas.

Adolescent↗

PubMed2002

Ghrelin-induced GH secretion in normal subjects is partially resistant to homologous desensitization by GH-releasing peptide-6.

OBJECTIVE: GH secretagogues and GH-releasing hormone (GHRH) exert a complex cross-talk at the somatotrope cell, and undertake homologous and heterologous desensitization. On the other hand, the discovery of ghrelin as a new factor implicated in the regulation of GH secretion makes a thorough assessment of its properties and cell biology processes mandatory. In order to implement this, three different testing schedules were devised using the administration, on the same day, of two GH stimuli administered in sequential order 120 min apart. The two aims of the study were (a) to evaluate the relative potency of ghrelin in comparison with other GH stimulants and (b) to assess the presence of homologous or heterologous desensitization between these compounds. DESIGN: The different testing days performed in random order were (a) on one day, saline was administered at time 0 min and ghrelin at time 120 min, (b) on another testing day, GHRH was administered at 0 min followed by ghrelin at 120 min and (c) on the last testing day, GH-releasing peptide-6 (GHRP-6) and ghrelin were injected at 0 and 120 min respectively. Ghrelin, GHRH and GHRP-6 were always administered at 1 microg/kg i.v., and plasma GH was measured. PATIENTS: Six normal subjects participated in the study after providing informed consent, and each was assessed on three different testing days, at least 1 week apart. RESULTS: Saline did not modify peak GH (means+/-s.e.) values (1.5+/-0.6 microg/l), and ghrelin administered 120 min later induced a significant GH rise (39.9+/-2.8 microg/l). On a different testing day, GHRH induced a GH peak (9.4+/-2.8 microg/l) lower than that of ghrelin injected 120 min later (26.8+/-4.7 microg/l). On the last testing day, GHRP-6 at time 0 induced a GH peak of 18.4+/-5.9 microg/l and ghrelin 120 min later a peak of 19.8+/-2.9 microg/l. The ghrelin-mediated GH secretion after GHRP-6 was significantly lower than the GH elicited by ghrelin when the preceding administration was saline. This demonstrated that ghrelin was partially affected by GHRP-6 and was not affected by GHRH. CONCLUSIONS: Calculated at equal mass doses or in molecular terms, ghrelin appears to be a more potent stimulus than GHRP-6 and GHRH. Ghrelin was completely insensitive to the previous administration of GHRH as well as relatively resistant to the homologous desensitization exerted by GHRP-6.

Adult↗

PubMedDate not supplied

The influence of serum cortisol levels on growth hormone responsiveness to GH-releasing hormone plus GH-releasing peptide-6 in patients with hypocortisolism.

The aim of this study was to evaluate the influence of circulating cortisol levels on the somatotroph responsiveness to the most potent stimuli of growth hormone (GH) secretion, the GHRH+GHRP-6 test. We studied 12 patients with hypocortisolism (10 with Addison's disease and 2 with isolated ACTH deficiency) before and after glucocorticoid (GC) replacement therapy and compared them with 14 healthy subjects. In the 10 patients with Addison's disease, GH responses (GH peak, microg/L) to GHRH+GHRP-6 were similar both during GC, (68.2+/-12.8) and off GC (60.3+/-14.1) therapy and did not differ from those in controls (61.5+/-6.0). In a subgroup of 4 patients with newly diagnosed Addison's disease, GH responsiveness to GHRH+GHRP-6 prior to GC replacement (26.4+/-4.1) was significantly lower than in the 6 patients with long-standing Addison's disease after short-term GC withdrawal (82.9+/-18.2). In the newly diagnosed Addison's patients, after one month of GC replacement, mean GH peak value increased to 40.7+/-11.8. In the 2 patients with isolated ACTH deficiency, GH responses to GHRH+GHRP-6 did not differ off and on GC therapy (60.3+/-14.1 and 41.5+/-2.0, respectively). Our data suggest that short-term GC deprivation does not have a major impact on GH responsiveness to GHRH+GHRP-6. However, in patients with long-standing hypocortisolism, GH response is blunted but still within normal range (> 15 microg/L).

Journal Article↗

PubMedDate not supplied

Changes in prothrombin and activated partial thromboplastin time during replacement therapy with human recombinant growth hormone in growth hormone deficient adults.

BACKGROUND: In rodents, Growth Hormone (GH) has been shown to stimulate coagulation parameters, including Prothrombin Time (PT), activated Partial Thromboplastin Time (aPTT) and vitamin K dependent coagulation factors. However, there are no reports on the influence of GH replacement therapy on global coagulation tests in Growth Hormone Deficiency (GHD). OBJECTIVE: The aim of this study was to investigate the effects of GH administration on basic coagulation parameters: PT, aPTT and fibrinogen concentrations in adult GHD patients before and during one year of GH replacement. DESIGN: Twenty-one adult patients with severe GHD (mean age +/- SE: 38.6 +/- 2.8 years) were included in this hospital based, prospective, interventional study. All patients were treated with rhGH for 12 months (GH dose: 0.4 mg/day for male and 0.6 mg/day for female patients). IGF-1 concentrations were determined using RIA-INEP kits. Basic coagulation tests, i.e. aPTT and fibrinogen concentrations, were measured before and after 3, 6 and 12 months of treatment with rhGH. Control values were obtained from fourteen "healthy" subjects matched by age, sex and body mass index (BMI). RESULTS: At baseline, we observed no significant differences in PT, aPTT and fibrinogen values between GHD and healthy subjects. IGF-1 concentrations increased significantly within 3 months of GH therapy (8.2 +/- 1.5 vs. 24.2 +/- 2.9 nmol/l, p <0.05) and remained stable thereafter. A significant increase in PT values, which was more pronounced in female subjects, was noted after 6 and 12 months of treatment with GH. aPTT values increased significantly after 12 months of treatment only in male patients (28.8 +/- 4.6 vs. 39.7 +/- 2.1 s.; p <0.05). No significant changes in fibrinogen concentrations were found during the study. CONCLUSIONS: Twelve months of GH replacement therapy led to a significant increase in PT and aPTT values in adult GHD patients, while fibrinogen concentrations did not change. Changes in PT were more pronounced in female GHD patients, while an increase in aPTT values was observed only in male patients with GHD. The clinical significance of these changes needs further evaluation.

Adult↗

PubMedDate not supplied

Leptin, nutrition and reproduction: new insights.

Recent data suggest that in addition to leptin's role in conveying signals of the amount of energy stores to the central nervous system, this adipocyte secreted hormone interacts with the endocrine system to provide critical information about the size of fat stores, acting as a permissive factor that allows the triggering of energy demanding situations as the onset of puberty and reproduction. Animal and human data are concordant with the concept that leptin plays an important permissive role in the initiation of puberty and in maintenance of reproductive function thereafter. Leptin regulates the gonadotropin-gonadal axis at a central level. The hypothalamus is an important site of leptin's action where a complex network of neuropeptides is involved in leptin's effect on GnRH. In addition, leptin plays a role during pregnancy and lactation as it is produced by the placenta and is present in milk. Plasma leptin levels are elevated during pregnancy and this hyperleptinemia is not accompanied by a reduction in food intake, suggesting a state of leptin resistance. Leptin is also detected in the amniotic fluid and its levels are high in venous cord blood at delivery correlating positively with weight at birth which suggests a potential role in intrauterine growth. The fact that in females leptin levels are higher than in males, even when corrected for body fat, suggests that the reproductive system is modulated by leptin in a different way in males and females estrogens. In hypoleptinemia resulting from specific genetic causes, leptin levels may still be adequate for the function of the reproductive system in humans, a phenomenon which differs from the findings in leptin-deficient animals which are infertile. Due to species differences in the role of leptin, it is difficult to extrapolate data from rodents to human physiology. However hypoleptinemia due to non-genetic causes such as anorexia nervosa and exercise leads to loss of reproductive function. Genetic/developmental factors influence the threshold required to turn off the behavioral, metabolic and endocrine responses to perceived caloric deprivation.

Journal Article↗