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Journal Article 2014; 35(8): 724-732 PubMed PMID: 25702302 Citation  Keywords:  Animals, Calcium Channels, L-Type:drug effects, Cells, Cultured, Cerebral Cortex:cytology, Estradiol:pharmacology, Female, Insulin-Like Growth Factor I:pharmacology, Ion Channel Gating:drug effects, Neurons:drug effects, Patch-Clamp Techniques, Rats.Rats.   

INTRODUCTION: Calcium transport pathways are key factors for understanding how changes in the cytoplasmic calcium concentration are associated with neuroprotection because calcium is involved in the onset of death signaling in neurons.

OBJECTIVES: This study characterized the effects of 17β-estradiol and IGF-1 on voltage-activated and stretch-activated calcium channels in rat cultured cortical neurons.

METHODS: The whole-cell patch-clamp technique, using a voltage steps protocol or by applying positive pressure into the micropipette, was used on 7-10 day cultured neurons from a Wistar rat cortex, and pharmacological characterization was performed on these neurons.

RESULTS: Both 17β-estradiol and IGF-1 inhibited the currents mediated by L-type voltage-activated calcium channels, although the IGF-1 effects were lower than those of 17β-estradiol. The effect of both hormones together was greater than the sum of the effects of the individual agents. Unlike IGF-1, 17β-estradiol decreased the current mediated by stretch-activated channels. The inhibition of the classical receptors of these hormones did not affect the results.

CONCLUSION: Both hormones regulate voltage-activated calcium channels in a synergistic way, but only 17β-estradiol has an inhibitory effect on stretch-activated calcium channels. These effects are not mediated by classical receptors and may be relevant to the neuroprotective effects of both hormones because they diminish calcium entry into the neuron and decrease the possibility for the onset of apoptotic signaling....

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Journal Article 2013; 34(7): 624-634 PubMed PMID: 24464002 Citation  Keywords:  Animals, Animals, Newborn, Brain:drug effects, Brain-Derived Neurotrophic Factor:genetics, Dexamethasone:toxicity, Disease Models, Animal, Drug Interactions, Female, Glucocorticoids:toxicity, Hormone Antagonists:pharmacology, Insulin-Like Growth Factor I:.   

OBJECTIVES: Dexamethasone (Dex) causes neurodegeneration in developing brain. Insulin-like growth factor-I (IGF-I) and -II (IGF-II) are potent neurotrophic and differentiation factors and play key roles in the regulation of growth and development of CNS. Current project evaluated the effects of Dex on IGF-I and -II in developing rat brains.

MATERIAL AND METHODS: Sprague-Dawley rat pups in each litter were divided into vehicle (n=230) or Dex-treated (n=234) groups. Rat pups in the Dex group received one of the 3 different regimens of i.p. Dex: tapering doses (DexTD) on postnatal days (PD) 3 to PD 6 or repeated doses on PD 4 to PD 6 or single dose on PD 6. To quantify the glucocorticoid receptor (GR) blockade effect, rat pups in the DexTD group on PD 3 and 5 received vehicle or RU486 (GR blocker, 60 mg/kg) s.c., twenty minutes prior to Dex treatment.

RESULTS: Dex decreased the gain of body and brain weight while RU486 inhibited these effects. RU486 also prevented the DexTD-induced increase in caspase-3 activity and reduction in IGF-I and -II proteins. Compared to the vehicle, the expression of mRNA of IGF-I and -II decreased at 24 h after DexTD treatment, while RU486 prevented this decrease on IGF-II but not IGF-I.

CONCLUSIONS: Our findings indicate that Dex via GR decreases IGF-I and -II and causes neurodegeneration in the neonatal rat brain....

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Clinical Trial 2013; 34(3): 222-228 PubMed PMID: 23685421 Citation  Keywords:  Adolescent, Body Height:drug effects, Child, Drug Monitoring:methods, Female, Growth Disorders:drug therapy, Human Growth Hormone:blood, Humans, Insulin-Like Growth Factor Binding Protein 3:blood, Insulin-Like Growth Factor I:metabolism, Male, Predictive.   

BACKGROUND: Insulin-like growth factor-I (IGF-I) generation test has been introduced for the assessment of growth hormone (GH) sensitivity, however, its significance in predicting growth response to GH therapy has also been brought up. The molar ratio of IGF-I to its binding protein-3 (IGFBP-3) determines IGF-I bioavailability.

AIMS: Evaluation of usefulness of IGF-I and IGFBP-3 generation test in predicting the effectiveness of rhGH therapy in children with short stature.

PATIENTS AND METHODS: The analysis comprised 60 children with short stature, normal results of GH stimulating tests but decreased IGF-I secretion. In all the patients, GH insensitivity was excluded on the basis of IGF-I and IGFBP-3 generation test. Next, GH therapy was administered and height velocity (HV), together with IGF-I and IGFBP-3 secretion, was assessed every year, during 3 years. The comparative group consisted of 30 children with partial GH deficiency (pGHD).

RESULTS: Both IGF-I secretion and IGF-I/IGFBP-3 molar ratio increased significantly during generation test (p<0.05) and - further - during GH therapy (however insignificantly), together with at least doubling of pretreatment HV. There was no significant difference between the studied group of patients and children with pGHD.

CONCLUSIONS: Significant increase of IGF-I in generation test speaks for GH therapy effectiveness in short children, despite normal results of GH stimulating tests.

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Comparative Study 2013; 34(1): 18-26 PubMed PMID: 23524620 Citation  Keywords:  Adolescent, Adult, Age Factors, Aging:blood, Alanine Transaminase:blood, Aspartate Aminotransferases:blood, Biomarkers:blood, Female, Human Growth Hormone:blood, Humans, Insulin-Like Growth Factor I:metabolism, Male, Middle Aged, Opioid-Related Disorders:.   

OBJECTIVE: To compare IGF1 levels in opiate dependent and general patients both absolutely and by age.

DESIGN: A naturalistic observational study was undertaken of opiate dependent and general medical patients.

SETTING: Primary care.

PATIENTS: 74 opiate substance use dependent (SUD) patients were compared with 262 non-SUD (NSUD) patients.

RESULTS: (1) Comparative IGF1 levels; (2) age and sex corrected IGF1 levels; (3) IGF1 levels corrected for age, sex, and hepatic and immune biomarkers.

MAIN FINDINGS: The SUD patients were younger (32.60+0.89 vs. 42.49+0.96 years, mean+S.E.M., p<0.0001) and had more males (72.9% and 39.3%, p<0.0001) than the NSUD patients. Restriction of the age range to 15-45 years (70 vs. 153 patients) made the difference in ages non-significant (31.27+0.71 vs. 32.32+0.61 years, p=0.47) but IGF1 remained elevated in SUD (26.56+1.21 vs. 22.65+0.57nmol/L, p=0.0039). When multiple regression was used to correct for the age and sex disparities, the age: addiction interaction remained significantly elevated (p=0.0003). In an additive model opiate dependence showed a 23.8% elevation in IGF1. When the interactive model was further adjusted by the inclusion of ALT and CRP as indices of hepatic inflammation and immune activation respectively, addictive status remained significant both alone (p=0.0134) and in 2-, 3- and 4-way interactions with age, male sex, and ALT (all p<0.0255).

CONCLUSION: These data demonstrate that serum IGF1 is elevated in opiate dependence both absolutely and after adjustment for age, sex, and markers of immune and hepatic activation....

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Comparative Study 2012; 33(4): 412-418 PubMed PMID: 22936258 Citation  Keywords:  Adolescent, Age Factors, Child, Child, Preschool, Female, Ghrelin:blood, Growth Disorders:blood, Human Growth Hormone:deficiency, Humans, Insulin-Like Growth Factor Binding Protein 3:blood, Insulin-Like Growth Factor I:metabolism, Male,.   

OBJECTIVES: In children with growth hormone deficiency (GHD) and neurosecretory dysfunction (NSD) ghrelin concentrations are significantly higher than in children with idiopathic short stature (ISS), however the correlation between serum ghrelin and growth hormone (GH) is not observed. The aim of the study was to compare ghrelin concentrations with IGF-I/IGFBP3 molar ratio in children with short stature due to different etiology.

MATERIAL: Analysis comprised 136 children (58 girls and 78 boys), aged 3.86-16.82 years with short stature (below -2.0 SD); in 21 of them GHD was diagnosed, in 23 - NSD and 92 - ISS. In each child, fasting ghrelin, insulin-like growth factor type I (IGF-I) and its binding protein type 3 (IGFBP-3) concentrations were measured. The results were analysed separately in younger and in older children. Depending on IGF-I/IGFBP-3 molar ratio, children were divided into two (2) groups: with lower IGF-I/IGFBP-3 and with higher IGF-I/IGFBP-3 ratio value.

RESULTS: Both in younger and in the older age groups, ghrelin concentration was significantly higher in children with lower IGF-I/IGFBP-3 ratio than in children with higher IGF-I/IGFBP-3 value (1937.3±1232.4 vs 1365.3±632.1 pg/ml in younger children and 1205.4±548.8 vs 867.4±282.9 pg/ml in older children). The negative correlation between ghrelin and IGF-I/IGFBP-3 ratio was observed in both age groups. Not only children with GHD and NSD, but also as much as 39% out of all children with ISS were qualified into the subgroups with lower IGF-I/IGFBP-3 ratio.

CONCLUSIONS: Ghrelin secretion is elevated in children with lower IGF-I/IGFBP-3 ratio. It seems that lower bioactivity of IGF-I is stimulating factor for ghrelin synthesis....

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Journal Article 2012; 33(2): 138-148 PubMed PMID: 22592194 Citation  Keywords:  Animals, Body Weight:drug effects, Estradiol:blood, Female, Follicle Stimulating Hormone:blood, Gonadotrophs:drug effects, Gonadotropin-Releasing Hormone:blood, Growth Hormone:blood, Hypothalamus:drug effects, Insulin-Like Growth Factor I:metabolism, Lept.   

OBJECTIVE: Available data suggest that estrogens and leptin play a role in the control of the pubertal process. In humans and some mammal species the increase of the activity of gonadotropic axis accompanies the decrease in the rate of growth at puberty. The effect of 17β-estradiol and/or leptin administration on the somatotropic and gonadotropic axes was studied using prepubertal female rats as an animal model.

MATERIAL AND METHODS: Prepubertal female rats received estradiol/saline, estradiol/leptin, oil/leptin or oil/saline (vehicles) respectively. The changes of growth rate, and serum 17β-estradiol, leptin, GH, IGF-I and gonadotropins levels as well as LHRH and estrogen receptor (ER) concentrations in the medial basal hypothalamus (MBH) and the pituitary were determined. All hormones concentrations were measured by radioimmunoassay and ER by radioligand methods .

RESULTS: In estradiol and/or leptin treated animals noticeable reduction of rate of growth was found. The decrease of growth in response to estradiol treatment accompanied the increase GH level and the decrease of IGF-I concentration in the circulation. Both hormones operating together activated reproductive axis, what was manifested by a significant increase of LHRH abundant in the hypothalamus as well as elevated LH and FSH levels in the circulation. In these rats a significant decrease of the estrogen receptor concentrations in the pituitary was observed.

CONCLUSION: The role of estradiol and leptin in the control of growth and reproduction seems to overlap only partially. Estradiol plays a significant role in the activation of the reproductive axis, and leptin takes part as a permissive factor in pubertal process....

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Case Reports 2012; 33(2): 103-106 PubMed PMID: 22592188 Citation  Keywords:  Adenoma:blood, Adult, Female, Growth Hormone:adverse effects, Growth Hormone-Secreting Pituitary Adenoma:blood, Humans, Insulin-Like Growth Factor I:adverse effects, Moyamoya Disease:blood,.   

: We report a case of Moyamoya syndrome developing in association with growth hormone-secreting pituitary adenoma. A 31-year-old female presented with acromegalic features. Magnetic resonance imaging revealed a 1 × 2 cm tumor in the sella turcica and MR angiography demonstrated unremarkable findings. Blood growth hormone and insulin-like growth factor I levels were elevated to 74.1 ng/ml and over 1 575 ng/ml, respectively. The diagnosis was growth hormone-secreting pituitary adenoma, and the tumor was removed through a transsphenoidal approach. Four years after surgery, she visited the outpatient department due to left side weakness for 2 months. Magnetic resonance images showed acute and old infarcted lesions in the basal ganglia and subcortical area and residual small pituitary adenoma in the sellar area. MR angiography demonstrated stenosis of the bilateral distal internal carotid arteries with basal collateral vessels. Conventional cerebral angiography showed complete obstruction in the right internal carotid artery and severe stenosis of the left internal carotid artery, middle cerebral artery, and anterior cerebral artery with basal collateral vessels. Her blood growth hormone and insulin-like growth factor I levels were 15.3 ng/ml and 1 055 ng/ml, respectively. We believe that excess systemic exposures of growth hormone and insulin-like growth factor I may participate in the development of Moyamoya syndrome....

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Journal Article 2012; 33(1): 37-41 PubMed PMID: 22467110 Citation  Keywords:  Child, Growth Disorders, Growth Hormone, Human Growth Hormone:deficiency, Humans, Insulin-Like Growth Factor I:secretion, Sleep,.   

OBJECTIVE: Growth hormone (GH) secretion is characterized by a pulsatile, circadian rhythm, with the highest concentrations at night hours. Evaluation of nocturnal GH secretion may be truncated to 6 hours. Growth hormone stimulating tests are the standard method of assessment of GH secretion. In Poland, the assessment of GH peak during 2 hours after falling asleep was introduced as a screening procedure in children, suspected for GH deficiency. The aim of current study was to compare the results of a screening test with GH secretion during 6-hour nocturnal profile and with the results of GH stimulating tests, as well as with IGF-I secretion in children with short stature.

METHODS: In 72 short children, GH concentrations were measured every 30 minutes during first 6 hours after falling asleep and in two GH stimulating tests (the cut-off level of GH peak for all the tests was 10.0 ng/ml). Also, IGF-I concentrations were measured and expressed as IGF-I SDS for age and sex.

RESULTS: The screening test results correlated significantly with both GH peak in 6-hour profile and mean GH concentration, and the area under the curve (AUC) in 6 hour profile (r= 0.94, r=0.90 and r=0.89, respectively, p<0.05) but not with GH peak in stimulating tests (r=0.07, NS). There was no correlation between IGF-I secretion and any of the analyzed parameters of spontaneous and stimulated GH secretion.

CONCLUSIONS: The results of screening test seem to reflect overnight GH secretion in short children, remaining, however, discordant with the results of GH stimulating tests and with IGF-I secretion....

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