33 results on '"Ilondo MM"'
Search Results
2. Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: Summary statement of the GH Research Society
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Israel, E, Attie, Km, Bengtsson, Ba, Blethen, Sl, Blum, W, Cameron, F, Carel, Jc, Carlsson, L, Chipman, Jj, Christiansen, Js, Clayton, P, Clemmons, Dr, Cohen, P, Drop, S, Fujieda, K, Ghigo, E, Hintz, Rl, Ho, K, Ilondo, Mm, Jasper, H, Jesussek, B, Kappelgaard, Am, Laron, Z, Lippe, Bm, Malozowski, S, Mullis, Pe, DE MUNICK KEIZER SCHRAMA, S, Nishi, Y, Parks, Js, Phelps, C, Ranke, M, Robinson, I, Rosenfeld, Rg, Rose, S, Saenger, P, Saggese, Giuseppe, Savage, M, Shalet, S, Sizonenko, Pc, Strasburger, C, Tachibana, K, Tanaka, T, Thorner, Mo, Wikland, Ka, and Zadik, Z.
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- 2000
3. Plasma-levels of Androgens and 17alpha-oh-progesterone As An Index of the Adequacy of Treatment in Congenital Adrenal-hyperplasia
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UCL, Ilondo, MM., Vanderschuerenlodeweyckx, M., Pizarro, M., Vlietinck, R., Malvaux, Paul, Eggermont, E., Eeckels, R., UCL, Ilondo, MM., Vanderschuerenlodeweyckx, M., Pizarro, M., Vlietinck, R., Malvaux, Paul, Eggermont, E., and Eeckels, R.
- Published
- 1983
4. Plasma Androgens in Children and Adolescents .1. Control Subjects
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UCL, Ilondo, MM., Vanderschuerenlodeweyckx, M., Vlietinck, R., Pizarro, M., Malvaux, Paul, Eggermont, E., Eeckels, R., UCL, Ilondo, MM., Vanderschuerenlodeweyckx, M., Vlietinck, R., Pizarro, M., Malvaux, Paul, Eggermont, E., and Eeckels, R.
- Published
- 1982
5. Plasma Androgens in Children and Adolescents .2. a Longitudinal-study in Patients With Hypopituitarism
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UCL, Ilondo, MM., Vanderschuerenlodeweyckx, M., Vlietinck, R., Pizarro, M., Malvaux, Paul, Eggermont, E., Eeckels, R., UCL, Ilondo, MM., Vanderschuerenlodeweyckx, M., Vlietinck, R., Pizarro, M., Malvaux, Paul, Eggermont, E., and Eeckels, R.
- Published
- 1982
6. Plasma Androgens and Growth Or Puberty Disorders
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UCL, Ilondo, MM., Pizarro, M., Vlietinck, R., Malvaux, Paul, Eggermont, E., Eeckels, R., Vanderschuerenlodeweyckx, M., UCL, Ilondo, MM., Pizarro, M., Vlietinck, R., Malvaux, Paul, Eggermont, E., Eeckels, R., and Vanderschuerenlodeweyckx, M.
- Published
- 1981
7. Plasma Androgens As An Index of Adequacy of Treatment in Cah
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UCL, Ilondo, MM., Vanderschuerenlodeweyckx, M., Pizarro, M., Vlietinck, R., Malvaux, Paul, Eggermont, E., Eeckels, R., UCL, Ilondo, MM., Vanderschuerenlodeweyckx, M., Pizarro, M., Vlietinck, R., Malvaux, Paul, Eggermont, E., and Eeckels, R.
- Published
- 1982
8. Plasma Androgens Before and Throughout Puberty
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UCL, Ilondo, MM., Pizarro, M., Vlietinck, R., Malvaux, Paul, Eggermont, E., Eeckels, R., Vanderschuerenlodeweyckx, M., UCL, Ilondo, MM., Pizarro, M., Vlietinck, R., Malvaux, Paul, Eggermont, E., Eeckels, R., and Vanderschuerenlodeweyckx, M.
- Published
- 1980
9. The utility of Gram stains and culture in the management of limb ulcers in persons with diabetes.
- Author
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Abbas ZG, Lutale JK, Ilondo MM, and Archibald LK
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- Adolescent, Adult, Aged, Aged, 80 and over, Diabetic Foot microbiology, Female, Gram-Negative Bacteria isolation & purification, Gram-Positive Bacteria isolation & purification, Humans, Male, Middle Aged, Diabetes Complications microbiology, Gentian Violet, Leg Ulcer microbiology, Phenazines
- Abstract
In Tanzania, limited laboratory services often preclude routine identification of microorganisms that cause infections in persons with diabetes. Thus, we carried out this study to determine the utility of a Gram stain alone versus culture in guiding appropriate antimicrobial therapy. During February 2006 to December 2007 (study period), deep tissue biopsies were obtained from persons with diabetes presenting to the Muhimbili National Hospital (MNH) with infected limb ulcers. Specimens were Gram-stained then cultured for bacteria and fungi. Biopsies were obtained from 128 patients. Of 128 cultures, 118 (92%) yielded bacterial or fungal growth; 59 (50%) of these 118 cultures yielded mixed growth (80% included Gram-negative organisms); 38 (32%) and 20 (17%) yielded Gram-negative and Gram-positive organisms alone, respectively. The predictive value positive of a Gram stain for bacterial growth was 93% (110/118); a Gram-positive stain was 75% (15/20) predictive of growth of Gram-positive organisms whereas a Gram-negative stain was 82% (31/38) predictive of growth of Gram-negative organisms. In regions with limited resources, a Gram stain of an ulcer biopsy that is carefully procured is largely predictive of the type of microorganism causing infection. Gram staining of deep tissue biopsies might have a potential role to play in the management of infected diabetic limb ulcers., (© 2012 The Authors. © 2012 Blackwell Publishing Ltd and Medicalhelplines.com Inc.)
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- 2012
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10. Oral administration of the growth hormone secretagogue NN703 in adult patients with growth hormone deficiency.
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Svensson J, Monson JP, Vetter T, Hansen TK, Savine R, Kann P, Bex M, Reincke M, Hagen C, Beckers A, Ilondo MM, Zdravkovic M, Bengtsson BA, and Korbonits M
- Subjects
- Administration, Oral, Adult, Area Under Curve, Blood Pressure physiology, Dipeptides adverse effects, Double-Blind Method, Fatty Acids, Nonesterified blood, Female, Human Growth Hormone blood, Humans, Insulin-Like Growth Factor Binding Protein 3 blood, Insulin-Like Growth Factor I analysis, Male, Middle Aged, Pituitary Function Tests, Pituitary Hormones blood, Dipeptides administration & dosage, Human Growth Hormone deficiency
- Abstract
Objective: Little is known of the usefulness of GH secretagogues (GHSs) in GH-deficient (GHD) adults. The objective of this study was to determine the number of responders to treatment with NN703 in GHD adults., Design: A multicentre, randomized, double-blind, and placebo-controlled study., Patients: Ninety-seven GHD adults were included., Measurements: The GH response before and after 1 week of oral treatment with NN703 (n = 83) or placebo (n = 14) was determined. The first and last dose of NN703 was 3 mg/kg, whereas the dose of NN703 was 1.5 mg/kg/day during the 6 days between the first and last doses. Furthermore, all 97 patients received 1 micro g/kg GH-releasing hormone (GHRH) 3 weeks after the last dose of NN703., Results: Serum GH peak and area under curve (AUC) values after the first NN703 administration were greater than those after placebo administration (P < 0.05). However, after correction for the lower body mass index (BMI) in the NN703 group, this difference lost statistical significance. After 1 week of therapy, GH peak and AUC values were similar following the final doses of NN703 and placebo. Serum peak and AUC values of other anterior pituitary hormones were similar between the NN703 and placebo groups both after the first and last administration of study drug. Nine of the 83 patients (11%) responded with a serum peak GH concentration >or= 5 micro g/l after the first and/or last NN703 administration, whereas no patient responded after placebo administration. Serum IGF-I was unaffected by 1-week NN703 treatment, whereas serum IGFBP-3 was increased (P < 0.05 vs. placebo) also after correction for BMI. Mean serum peak GH concentration after GHRH administration was 2.1 micro g/l (+/-0.3, SEM), which was higher than that after the first NN703 administration (1.32 +/- 0.3, P < 0.05)., Conclusion: NN703 administration was generally well tolerated. Eleven per cent of the GHD adult patients responded with a peak GH response >or= 5 micro g/l after the first and/or last administration of oral NN703. Although a majority of GHD adults will not respond to NN703, the present results suggest that oral NN703 treatment could be useful in some adult patients with moderately severe GHD. These patients may be identified by a test dose of GHS.
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- 2003
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11. IRS-4 mediated mitogenic signalling by insulin and growth hormone in LB cells, a murine T-cell lymphoma devoid of IGF-I receptors.
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Ursø B, Ilondo MM, Holst PA, Christoffersen CT, Ouwens M, Giorgetti S, Van Obberghen E, Naor D, Tornqvist H, and De Meyts P
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- Adaptor Proteins, Signal Transducing, Animals, Cattle, Enzyme Activation, Female, Humans, Insulin Receptor Substrate Proteins, Lymphoma, T-Cell, Mice, Mice, Inbred BALB C, Phosphoinositide-3 Kinase Inhibitors, Phosphorylation drug effects, Receptor, IGF Type 1 deficiency, Signal Transduction drug effects, Tumor Cells, Cultured drug effects, Tumor Cells, Cultured enzymology, Tyrosine metabolism, Growth Hormone pharmacology, Insulin pharmacology, Mitogens pharmacology, Phosphatidylinositol 3-Kinases metabolism, Phosphoproteins metabolism
- Abstract
Insulin and growth hormone (GH) induce mitogenic and metabolic signals in cells, GH either directly or indirectly via IGF-I production. We have studied a spontaneous murine T-cell lymphoma (LB cells) devoid of IGF-1 receptors in which proliferation is maintained by insulin [Int. J. Cancer 50 (1992) 80], and show that GH is more potent than insulin, with both GH and insulin dose-response curves for thymidine incorporation being bell-shaped. Binding showed somatogenic rather than lactogenic GH receptors. Insulin stimulated phosphorylation of the insulin receptor and of a 160-kDa protein, identified as the IRS-4 protein. This phosphorylated IRS-4 associated with PI3-kinase, which was activated along with the downstream p70(S6) kinase, whereas the Ras-MAPK pathway was not. Using selective inhibitors, the PI3-kinase, but not p70(S6) kinase or MEK, was found to be involved in insulin-stimulated DNA synthesis. GH induced tyrosine phosphorylation of IRS-4 and nuclear translocation of STAT5. The LB cells constitute a new model for studying GH and insulin signalling without interference of IGF-1 receptors.
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- 2003
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12. A clinical study investigating the pharmacokinetic interaction between NN703 (tabimorelin), a potential inhibitor of CYP3A4 activity, and midazolam, a CYP3A4 substrate.
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Zdravkovic M, Olsen AK, Christiansen T, Schulz R, Taub ME, Thomsen MS, Rasmussen MH, and Ilondo MM
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- Adjuvants, Anesthesia metabolism, Adult, Area Under Curve, Cytochrome P-450 CYP3A, Cytochrome P-450 Enzyme System metabolism, Dipeptides adverse effects, Drug Interactions, Half-Life, Humans, Male, Midazolam metabolism, Middle Aged, Time Factors, Adjuvants, Anesthesia pharmacokinetics, Cytochrome P-450 Enzyme Inhibitors, Dipeptides pharmacology, Midazolam analogs & derivatives, Midazolam pharmacokinetics
- Abstract
Objective: NN703 (tabimorelin) is an orally active growth hormone (GH) secretagogue intended for use as an alternative to daily injections of GH. In vitro studies in human liver microsomes have indicated that NN703 is a mechanism-based inhibitor of CYP3A4. The aim of the present study was to investigate in man the effects of NN703 on the pharmacokinetics of midazolam, a substrate of CYP3A4., Methods: Seventeen adult male subjects were enrolled in the study, and each received an oral dose of midazolam (7.5 mg) on four occasions: at baseline (day 1), after one dose of NN703 (day 3), after 7 days once daily NN703 treatment (day 9) and after a 7-day washout period (day 16). The pharmacokinetics of midazolam and its main metabolite, alpha-hydroxymidazolam, were investigated., Results: Following a single dose of NN703 (day 3), the AUC of both midazolam and alpha-hydroxymidazolam increased by 64% and 34%, respectively (P=0.0001 for both). After repeated NN703 dosing (day 9), NN703 levels reached steady state, and midazolam AUC further increased to 93% relative to baseline (P=0.0001), whereas alpha-hydroxymidazolam AUC decreased slightly and was 11% higher than baseline (n.s.). Following the washout period (day 16), midazolam AUC decreased to values lower than those on day 3 and day 9, but still significantly (45%) higher than baseline levels (P=0.0001). The C(max) values of midazolam and alpha-hydroxymidazolam demonstrated a pattern similar to the AUC, but the effect following repeated NN703 dosing was more pronounced. The t(1/2) of midazolam increased from day 1 to day 3 (P=0.0483) but was essentially unchanged at steady state on day 9., Conclusion: This study shows that administration of NN703 and midazolam, a CYP3A4 substrate, leads to a significant increase in exposure of midazolam. This is consistent with NN703 inhibition of CYP3A4 activity.
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- 2003
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13. The pharmacokinetics, pharmacodynamics, safety and tolerability following 7 days daily oral treatment with NN703 in healthy male subjects.
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Zdravkovic M, Christiansen T, Eliot L, Agersoe H, Thomsen MS, Falch JF, Søgaard B, Ynddal L, and Ilondo MM
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- Administration, Oral, Adrenocorticotropic Hormone metabolism, Adult, Area Under Curve, Body Weight, Dipeptides administration & dosage, Dose-Response Relationship, Drug, Double-Blind Method, Follicle Stimulating Hormone metabolism, Humans, Hydrocortisone metabolism, Luteinizing Hormone metabolism, Male, Placebos, Thyrotropin metabolism, Time Factors, Dipeptides pharmacokinetics, Dipeptides toxicity
- Abstract
The aim of the present study was to assess the safety, pharmacokinetics and pharmacodynamics (including specificity) of NN703 (tabimorelin), a growth hormone (GH) secretagogue, in healthy male subjects following treatment for 7 days once-daily. This was a randomized, double-blind and placebo-controlled study with four active dose levels: 1.71, 3.0, 4.5 and 6.86 mg/kg body weight. There was a dose-related increase for GH area under the curve (AUC) (0-12 h) and GH C(max)(0--12 h); these were significantly higher on both days 1 and 7 as compared with placebo treatment (P = 0.04 to P< 0.0001); however, an overall significant decrease in GH release was found from day 1 to day 7 (P< 0.001). Insulin-like growth factor-I (IGF-I) and IGF binding protein 3 (IGFBP-3) increased at all dose levels (including placebo); however, a significantly higher increase as compared with placebo treatment was observed at the three highest dose levels for IGF-I (P = 0.04--0.0006) and at the highest dose level for IGFBP-3 (P = 0.03). There was no statistically significant increase in AUC (0-5 h) for follicle-stimulating hormone, luteinizing hormone and cortisol between active and placebo treatment for day 1 or 7. On day 1 only, a statistically significant increase in AUC (0--5 h) was found for prolactin at 1.71 and 6.86 mg/kg (P< 0.05), for thyroid-stimulating hormone (TSH) at 3.0 mg/kg (P< 0.01) and for adrenocorticotrophic hormone (ACTH) at 4.5 mg/kg (P< 0.05); however, no dose--response relationship was observed for TSH or ACTH. In addition, a statistically significant decrease in AUC (0--5 h) for ACTH (3.0 and 6.86 mg/kg) and cortisol (1.71 mg/kg) was observed on day 7 (P< 0.05). Thus, NN703 is a promising candidate for treatment of absolute or relative GH deficiency., (Copyright 2001 Harcourt Publishers Ltd.)
- Published
- 2001
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14. The pharmacokinetics, pharmacodynamics, safety and tolerability of a single dose of NN703, a novel orally active growth hormone secretagogue in healthy male volunteers.
- Author
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Zdravkovic M, Søgaard B, Ynddal L, Christiansen T, Agersø H, Thomsen MS, Falch JE, and Ilondo MM
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- Administration, Oral, Adrenocorticotropic Hormone blood, Adult, Dipeptides administration & dosage, Dose-Response Relationship, Drug, Double-Blind Method, Drug Tolerance, Human Growth Hormone blood, Human Growth Hormone deficiency, Humans, Hydrocortisone blood, Insulin-Like Growth Factor I metabolism, Male, Prolactin blood, Safety, Dipeptides pharmacokinetics, Dipeptides pharmacology, Human Growth Hormone metabolism
- Abstract
The aim of the present study was to investigate the pharmacodynamics, pharmacokinetics, safety and tolerability of a single dose of NN703 (tabimorelin), a growth hormone secretagogue in healthy male subjects. The study design was double blind, randomized and placebo-controlled, with eight escalating dose levels (0.05-12 mg/kg bodyweight (BW)). NN703 was well tolerated by the subjects. The GH area under the curve (AUC) (0-24 h) was significantly higher when compared to placebo for the three highest dose levels (3.0 mg/kg: P = 0.027, 6.0 mg/kg: P = 0.0023, 12 mg/kg: P< 0.0001), and for GH maximal concentration C(max)the four highest dose levels were also significantly higher when compared to placebo (1.5 mg/kg: P = 0.04, 3.0 mg/kg: P = 0.0143, 6.0 mg/kg: P = 0.0053, 12 mg/kg: P = 0.0007). Furthermore, there was a significant increase in IGF-1 levels when compared to placebo for the 6.0 and 12.0 mg/kg BW dose levels (P< 0. 0001). Statistical analysis comparing the AUC (0-24 h) of the NN703 (four highest dose levels) and placebo-treated groups showed no significant increases following NN703 for ACTH, LH, FSH, TSH, prolactin, and cortisol, however, subtle individual changes were noted in ACTH, cortisol and prolactin at doses above 3.0 mg/kg. In conclusion, NN703 is a promising potential candidate for treatment of GH deficiency/insufficiency., (Copyright 2000 Harcourt Publishers Ltd.)
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- 2000
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15. Evaluation of the conformity of human growth hormone concentrations measured with the DPC Immulite and the Nichols Advantage assays.
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Zdravkovic M, Christiansen T, Grosch K, and Ilondo MM
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- Antibodies immunology, Dipeptides, Human Growth Hormone immunology, Humans, Luminescent Measurements, Male, Protein Isoforms blood, Protein Isoforms immunology, Reproducibility of Results, Human Growth Hormone blood, Immunoassay methods, Reagent Kits, Diagnostic
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- 2000
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16. Mitogenic and antiadipogenic properties of human growth hormone in differentiating human adipocyte precursor cells in primary culture.
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Wabitsch M, Braun S, Hauner H, Heinze E, Ilondo MM, Shymko R, De Meyts P, and Teller WM
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- Adipocytes cytology, Adolescent, Adult, Cell Differentiation drug effects, Cell Division drug effects, Cells, Cultured, Child, Child, Preschool, Female, Glucose metabolism, Human Growth Hormone metabolism, Humans, Infant, Iodine Radioisotopes, Lipolysis drug effects, Middle Aged, Mitogens metabolism, Protein Binding, Stem Cells drug effects, Adipocytes drug effects, Human Growth Hormone pharmacology, Mitogens pharmacology
- Abstract
Children with GH deficiency have enlarged fat cells but a reduced number of fat cells compared with healthy children. After treatment with human GH (hGH) both fat cell volume and number are shifted toward normal. To clarify the role of hGH in fat cell formation in human adipose tissue, we investigated the effect of hGH on the proliferation and the differentiation of cultured human adipocyte precursor cells obtained from five children and 10 adults. In a chemically defined serum-free medium treatment of adipocyte precursor cells with hGH led to an increase in IGF-I production and a stimulation of cell proliferation, which could be blocked by a MAb raised against human IGF-I. hGH dose-dependently reduced the number of differentiating cells and suppressed the expression of glycerol-3-phosphate dehydrogenase (GPDH), a marker of adipose differentiation. No significant differences in the hGH effects on proliferation and differentiation capacities were seen between cultures obtained from children and adults. In newly differentiated adipocytes, hGH inhibited glucose uptake and lipogenesis, and stimulated lipolysis. Scatchard analysis of hGH competition experiments using 125I-labeled hGH yielded a linear plot with an apparent Kd of 1.08 nM and an estimated number of 7000 hGH receptors per cell. These data suggest that hGH is able to enlarge the human adipocyte precursor pool via induction of IGF-I synthesis but exhibits a direct antiadipogenic activity. hGH is also able to reduce fat cell volume by reducing lipogenesis and increasing lipolysis.
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- 1996
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17. Biological effects of human growth hormone in rat adipocyte precursor cells and newly differentiated adipocytes in primary culture.
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Wabitsch M, Heinze E, Hauner H, Shymko RM, Teller WM, De Meyts P, and Ilondo MM
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- Adipocytes cytology, Adipocytes enzymology, Animals, Antibodies, Monoclonal immunology, Antibodies, Monoclonal pharmacology, Cell Differentiation drug effects, Cell Differentiation physiology, Cell Division drug effects, Cell Division physiology, Cells, Cultured, Corticosterone pharmacology, Dose-Response Relationship, Drug, Glucose pharmacokinetics, Glycerolphosphate Dehydrogenase analysis, Humans, Insulin-Like Growth Factor I immunology, Iodine Radioisotopes, Lipid Metabolism, Lipolysis physiology, Male, Rats, Rats, Wistar, Stem Cells cytology, Stem Cells enzymology, Thymidine metabolism, Tritium, Adipocytes drug effects, Growth Hormone pharmacology, Stem Cells drug effects
- Abstract
The effects of human growth hormone (hGH) on proliferation and differentiation of primary adipocyte precursor cells isolated from rat epididymal fat pads were studied under serum-free culture conditions. hGH markedly reduced the formation of new fat cells and the expression of glycerophosphate dehydrogenase activity, a marker enzyme of adipose differentiation, in a dose-dependent manner. To find an explanation for this inhibitory effect, we investigated the action of GH on (1) cell proliferation and on (2) lipid accumulation, the latter in the absence and presence of corticosterone. In undifferentiated cells, 5 nmol/L hGH increased both cell number and [3H]-thymidine incorporation (1.3- and 2.6-fold over basal, respectively). This effect was mediated by insulin-like growth factor-I (IGF-I), since hGH stimulated IGF-I production in undifferentiated cells by 12-fold and addition of an anti-IGF-I monoclonal antibody (IGF-I MAb) abolished the mitogenic effect of hGH but did not prevent hGH-induced suppression of adipose differentiation. In developing fat cells, hGH significantly reduced cellular 2-deoxyglucose uptake and glucose incorporation into lipids. In addition, hGH exhibited a lipolytic action in the presence of insulin and triiodothyronine. These effects were not prevented by IGF-I MAb. Specific binding of [125I]-hGH to precursor cells increased significantly during adipose conversion. In differentiated cells Scatchard analysis yielded linear plots with an apparent Kd of 0.16 nmol/L and 8,400 sites per cell. Taken together, these data show that hGH reduces adipose conversion in primary cultures of rat adipocyte precursor cells while promoting cell proliferation through an increase in IGF-I production.
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- 1996
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18. Human growth hormone increases cytosolic free calcium in cultured human IM-9 lymphocytes: a novel mechanism of growth hormone transmembrane signalling.
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Ilondo MM, De Meyts P, and Bouchelouche P
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- Alkaloids pharmacology, Benzoquinones, Catechols pharmacology, Cell Line, Cyclic AMP metabolism, Cytosol drug effects, Cytosol metabolism, Dose-Response Relationship, Drug, Humans, Inositol 1,4,5-Trisphosphate metabolism, Insulin pharmacology, Insulin-Like Growth Factor I pharmacology, Kinetics, Lactams, Macrocyclic, Lymphocytes drug effects, Nitriles pharmacology, Protein-Tyrosine Kinases antagonists & inhibitors, Quinones pharmacology, Rifabutin analogs & derivatives, Staurosporine, Calcium metabolism, Cell Membrane physiology, Growth Hormone pharmacology, Lymphocytes physiology, Signal Transduction drug effects, Tyrphostins
- Abstract
Cytosolic free calcium ions concentration ([Ca2+]i) was measured in cell suspensions of cultured human IM-9 lymphocytes by dual wavelength fluorescence spectrometry using the calcium probe fura-2. Human GH (0.2-50 nM) induced a slow, progressive and sustained increase in [Ca2+]i. The GH effect was specific and exhibited a biphasic pattern, presumably reflecting GH receptor dimerization, typical of some other GH actions. The hGH effect depended on extracellular calcium, suggesting that at least part of the [Ca2+]i increase was due to a stimulation of calcium influx. GH did not increase IP3. Somatostatin-14 in the range 10(-10) to 10(-8) M, while having no effect of its own on [Ca2+]i, inhibited the effect of hGH. This inhibition by somatostatin was prevented by pretreatment of the cells with pertussis toxin. The hGH-induced [Ca2+]i increase was not related to either protein tyrosine phosphorylation or protein kinase C activation, thus suggesting a novel mechanism of GH transmembrane signalling.
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- 1994
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19. Receptor dimerization determines the effects of growth hormone in primary rat adipocytes and cultured human IM-9 lymphocytes.
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Ilondo MM, Damholt AB, Cunningham BA, Wells JA, De Meyts P, and Shymko RM
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- Adipocytes metabolism, Animals, Cell Line, Computer Simulation, Down-Regulation, Growth Hormone metabolism, Humans, Lipids biosynthesis, Lymphocytes metabolism, Macromolecular Substances, Male, Mathematics, Models, Biological, Rats, Rats, Wistar, Receptors, Somatotropin metabolism, Adipocytes drug effects, Growth Hormone pharmacology, Lymphocytes drug effects, Receptors, Somatotropin chemistry
- Abstract
Binding of GH to its cell surface receptors is thought to result in the formation of a complex comprised of one molecule of hormone per two molecules of receptor. It has been proposed that this hormone-induced receptor dimerization is important for the mechanism of signal transduction. We have developed a mathematical model for quantitative evaluation of the biological responses associated with sequential receptor dimerization. Based on these predictions, we have investigated whether GH-induced receptor dimerization plays a role in two classical effects of GH, i.e. stimulation of lipogenesis in primary rat adipocytes and GH receptor down-regulation in cultured human IM-9 lymphocytes. Model predictions of biological responses linked to dimer formation yielded a bell-shaped pattern, with self-antagonism at high GH concentrations when monomeric GH-receptor complexes become predominant. The GH lipogenic bioactivity curve was indeed biphasic and first increased in a concentration-dependent manner between 10(-10)-10(-8) M GH (ED50, 0.5 nM), up to a maximum of 1.7-fold stimulation above basal. Then, the response decreased continuously above 5 x 10(-8) M GH, returning to basal levels around 10(-5) M GH. Incubation of IM-9 cells with wild-type human GH resulted in a dose-dependent loss of their surface receptors. In contrast, a human GH analog (G120R), mutated in the second binding surface of the hormone and, therefore, unable to induce GH receptor dimerization, failed to induce receptor down-regulation in the IM-9 cells. Furthermore, when added together with wild-type human GH, human GH(G120R) inhibited, in a concentration-dependent manner, the down-regulation induced by wild-type human GH. Taken together, these data support the hypothesis that receptor dimerization is critical for the stimulation by GH of both lipogenesis in primary rat adipocytes and receptor down-regulation in cultured human IM-9 lymphocytes.
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- 1994
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20. The insulin-like growth factor-I receptor. Structure, ligand-binding mechanism and signal transduction.
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De Meyts P, Wallach B, Christoffersen CT, Ursø B, Grønskov K, Latus LJ, Yakushiji F, Ilondo MM, and Shymko RM
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- Animals, Binding Sites, Calcium-Calmodulin-Dependent Protein Kinases metabolism, Humans, Kinetics, Ligands, Models, Molecular, Molecular Structure, Protein Structure, Tertiary, Protein-Tyrosine Kinases metabolism, Receptor, IGF Type 1 metabolism, Receptor, Insulin chemistry, Receptor, Insulin metabolism, Signal Transduction, ras Proteins metabolism, Receptor, IGF Type 1 chemistry
- Abstract
The nonclassical binding kinetics of IGF-I and insulin to their respective receptors, suggestive of negative cooperativity, can be readily explained by our recently proposed novel binding mechanism whereby the bivalent ligand bridges the two receptor alpha-subunits alternatively at opposite sites in a symmetrical receptor structure. The bivalent binding mechanism also explains bell-shaped bioactivity curves. The possible role of different binding modes versus differences in downstream signaling by insulin and IGF-I in producing specific mitogenic or metabolic responses is discussed.
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- 1994
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21. Cellular processing of growth hormone in IM-9 cells: evidence for exocytosis of internalized hormone.
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Ilondo MM, Vanderschueren-Lodeweyckx M, Courtoy PJ, and De Meyts P
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- Cell Line, Computer Simulation, Electrophoresis, Polyacrylamide Gel, Humans, Receptors, Somatotropin metabolism, Exocytosis, Growth Hormone metabolism, Lymphocytes metabolism
- Abstract
IM-9 cells extensively internalize [125I]human (h) GH at physiological temperatures, yet little is known regarding the final destination of internalized hormone and its receptor. We studied this by first binding [125I]hGH to the cell surface at 4 C, and then following its fate during a subsequent incubation at 30 C in isotope-free medium. Cell-associated radioactivity decreased with time at 30 C, with a biphasic pattern suggestive of a rapid (but minor) and a slow component. The kinetics of the latter were critically influenced by NH4Cl and were abolished at 20 C. Intracellular (acid-resistant) [125I]hGH first increased with time at 30 C until it reached a maximum after 1 h, then declined continuously upon prolonged incubation. The radioactivity released by the cells was recovered in the medium as both trichloroacetic acid-precipitable material and trichloroacetic acid-soluble fragments. After sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing conditions, one major band migrating with an estimated mol wt of 22,000 was identified, presumably corresponding to intact [125I]hGH. These data suggest exocytosis of intact hormone via recycling endosomes and degradation in the lysosomes, respectively. Computer modelling was consistent with two intracellular compartments acting partially in series and probably corresponding to these two organelles. When analyzed by computer curve fitting, this model accurately described the kinetics of [125I]hGH internalization. So, receptor-mediated endocytosis and subsequent exocytosis are part of the GH pathway in IM-9 cells. In as much as they reflect pathways of GH receptors, these processes contribute to receptor down-regulation and could provide an explanation for release into the medium of the high affinity GH-binding protein.
- Published
- 1992
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22. Comparison of the effects of hypertonic sucrose and intracellular potassium depletion on growth hormone receptor binding kinetics and down-regulation in IM-9 cells: evidence for a sequential block of receptor--mediated endocytosis.
- Author
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Ilondo MM, Smal J, de Meyts P, and Courtoy PJ
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- Cell Line, Down-Regulation, Growth Hormone metabolism, Humans, Hypertonic Solutions, Kinetics, Receptors, Somatotropin physiology, Temperature, Time Factors, Endocytosis physiology, Intracellular Membranes metabolism, Lymphocytes metabolism, Potassium Deficiency metabolism, Receptors, Somatotropin metabolism, Sucrose pharmacology
- Abstract
To better understand the complex kinetics of human GH (hGH) binding to its receptors, we have further investigated, in IM-9 cultured human lymphocytes, the cellular locus corresponding to the slowly dissociating component of hormone binding, and to the homologous down-regulation of hGH receptors. First, we have detailed the biphasic kinetics of dissociation of bound hormone in control cells at 30 C. When the association at 30 C was extended from 0.5 to 3 h, the time required for half-dissociation of the fast component was slightly decreased (from 30 to 15 min) but that of the slow component increased considerably (from 6 h to 30 h). Concomitantly, the size of the slowly dissociating component increased from 50 to 80% of total. This indicates a maturation of bound hormone, from a rapidly to a slowly dissociating pool and, in the latter, an increase in the apparent affinity that may reflect a molecular rearrangement. Next, we have compared the effect of two procedures reported to inhibit receptor-mediated endocytosis at the level of coated pits. As previously reported, depletion of intracellular K+ abolished the slowly dissociating component and the down-regulation of hGH receptors. In contrast, upon incubation with 0.4 M sucrose, which like K+ depletion virtually abrogated hGH internalization, the dissociation kinetics remained non-first order, and the down-regulation of hGH-receptor was only slightly reduced. Thus, these procedures appear to block receptor-mediated endocytosis at two successive compartments of the cell surface. In conclusion, we propose that some conformational change of hGH-receptor at the cell surface (possibly associated with clustering) may considerably slow down their dissociation and may be sufficient for down-regulation.
- Published
- 1991
- Full Text
- View/download PDF
23. Measuring growth hormone activity through receptor and binding protein assays.
- Author
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Ilondo MM, Vanderschueren-Lodeweyckx M, and De Meyts P
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Humans, Lymphocytes metabolism, Receptors, Somatotropin chemistry, Receptors, Somatotropin genetics, Receptors, Somatotropin physiology, Carrier Proteins blood, Carrier Proteins genetics, Growth Hormone blood, Radioligand Assay
- Abstract
In most of the children with short stature, no organic basis can be found, which has led to the suggestion that some cases of growth failure may be due to an immunoreactive but bioinactive growth hormone (GH). In order to compare GH immunoreactivity and bioactivity (measured as receptor binding ability), a radioreceptor assay allowing the measurement of GH levels in human serum was developed using cultured human lymphocytes and 125I-labeled human GH purified by high-performance liquid chromatography. Serum samples were obtained after pharmacological stimulation with either insulin, glucagon or GRF from 19 healthy control subjects and 114 patients with various growth disturbances, aged 2.3-24.8 years. In general, there was a good correlation between the GH levels measured by the two methods, the RRA-GH levels being lower than the RIA-GH levels at all times irrespective of the stimulation test. In all the groups studied, most of the individual RRA/RIA ratios were within normal limits. It is concluded that the presence of an abnormal (bioinactive) GH molecule is extremely rare in patients with short stature.
- Published
- 1991
- Full Text
- View/download PDF
24. Serum growth hormone levels measured by radioimmunoassay and radioreceptor assay: a useful diagnostic tool in children with growth disorders?
- Author
-
Ilondo MM, Vanderschueren-Lodeweyckx M, De Meyts P, and Eggermont E
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Chromatography, High Pressure Liquid, Dwarfism, Pituitary blood, Dwarfism, Pituitary drug therapy, Female, Glucagon administration & dosage, Growth Disorders diagnosis, Growth Hormone administration & dosage, Growth Hormone deficiency, Humans, Insulin administration & dosage, Male, Radioimmunoassay, Radioligand Assay, Turner Syndrome blood, Growth Disorders blood, Growth Hormone blood
- Abstract
Serum GH levels were measured by RIA and RRA in 133 subjects (19 healthy controls and 114 patients with various growth disturbances, aged 2.3-24.8 yr). Serum samples obtained from 147 stimulation tests representing a total of 1065 samples were analyzed by both methods, and the results compared. The data are expressed in absolute values and in RRA/RIA ratios. The area under the curve after a stimulation test (area GH) was calculated by planimetry. RIA was performed by the classical double antibody method using a polyclonal anti-serum. For the RRA, human cultured lymphocytes (IM-9 cells) were used, and 125I-labeled human GH was purified by high performance liquid chromatography. The same human GH standard was used in both assay systems. In control subjects a significant (P less than 0.0001) positive correlation was found at all ages between GH levels measured by RIA and RRA (r = 0.69 after insulin and r = 0.77 after glucagon). The RRA/RIA ratio (mean +/- SEM) for the peak GH level was 0.88 +/- 0.05, and the area under the GH curve was 0.85 +/- 0.05. The peak mean RRA/RIA ratios were significantly lower (P less than 0.05 and P = 0.03, respectively). No relationship was found with the absolute value of either peak or area GH. In patients with growth delay and Turner's syndrome, lower GH levels were found than in control subjects in both assay systems. The RRA/RIA ratios were also lower. In the other patients with some growth disorder, normal GH levels and ratios were found. In patients with renal failure, high levels of RIA-GH and RRA-GH were found, with a normal RRA/RIA ratio. In patients with documented pituitary GH deficiency, GH-releasing factor administration resulted in an increase in GH levels that was identical in both assays. The RRA/RIA ratio remained constant throughout the test. No correlation was found between the ratio and the absolute value of either RIA-GH or RRA-GH regardless of the stimulation test used. It is concluded that the presence of an abnormal GH molecule is extremely rare in patients with short stature. Thus, the presence of a bioinactive hormone is not a common cause of growth failure. During provocative testing some changes in the ratio may occur that do not appear after GH-releasing factor, further illustrating the different mechanisms involved in GH secretion.
- Published
- 1990
- Full Text
- View/download PDF
25. Plasma levels of androgens and 17 alpha-OH-progesterone as an index of the adequacy of treatment in congenital adrenal hyperplasia.
- Author
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Ilondo MM, Vanderschueren-Lodeweyckx M, Pizarro M, Vlietinck R, Malvaux P, Eggermont E, and Eeckels R
- Subjects
- 17-alpha-Hydroxyprogesterone, Adolescent, Adrenal Hyperplasia, Congenital blood, Androstenedione blood, Child, Child, Preschool, Dehydroepiandrosterone analogs & derivatives, Dehydroepiandrosterone blood, Dehydroepiandrosterone Sulfate, Female, Humans, Hydrocortisone therapeutic use, Infant, Male, Testosterone blood, Adrenal Hyperplasia, Congenital drug therapy, Androgens blood, Hydroxyprogesterones blood
- Abstract
Plasma levels of dehydroepiandrosterone-sulfate (DHEA-S), dehydroepiandrosterone (DHEA), delta 4-androstenedione (delta 4), testosterone and 17 alpha-OH-progesterone (17-OH-P) were studied in 58 samples collected in 18 patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency, during long-term ambulatory treatment with hydrocortisone. At each visit the patients were classified as being either in good control (GC) or in poor control (PC), based on well-defined clinical, auxological and biochemical criteria. The results were analyzed in relation to the degree of control and to chronological age (CA), bone age (BA), body surface (BS) and pubertal development. The most clear distinction between the children with GC and those with PC is found for DHEA-S (p less than 0.001 for BA). The majority of the DHEA-S values in the children with GC are closely grouped and significantly below the normal limits for CA, BA, BS and pubertal stage (p less than 0.001). In contrast, the PC children have wide-spread values, most of them being within or above the normal limits. The difference between GC and PC is also significant for testosterone (p less than 0.01) and delta 4 (p less than 0.05), but not for DHEA. Of the five steroids studied, DHEA-S is the most specific, whereas testosterone is the most sensitive and especially useful in girls and in prepubertal boys. delta 4 and 17-OH-P are almost as sensitive as DHEA-S, but they are less specific. DHEA is the less valid criterium.
- Published
- 1983
- Full Text
- View/download PDF
26. Intracellular potassium depletion in IM-9 lymphocytes suppresses the slowly dissociating component of human growth hormone binding and the down-regulation of its receptors but does not affect insulin receptors.
- Author
-
Ilondo MM, Courtoy PJ, Geiger D, Carpentier JL, Rousseau GG, and De Meyts P
- Subjects
- Cell Line, Coated Pits, Cell-Membrane metabolism, Humans, Lymphocytes ultrastructure, Receptors, Somatotropin, Growth Hormone metabolism, Insulin metabolism, Lymphocytes metabolism, Potassium physiology, Receptor, Insulin metabolism, Receptors, Cell Surface metabolism
- Abstract
We have investigated whether the slowly dissociating component of insulin and human growth hormone (hGH) binding and the homologous down-regulation of their receptors in IM-9 cultured human lymphocytes are due to distinct conformations of the receptor or, rather, to a redistribution within the cell. To do so, we used intracellular K+ depletion, which has been shown to inhibit reversibly coated-pit formation and ligand internalization in some cell lines. IM-9 cells incubated in K+-free buffer after a hypotonic shock rapidly lost their K+, which was stabilized at +/- 50% of control by incubation in K+-free binding assay buffer. In K+-depleted cells, the hGH dissociation kinetics became monoexponential and, in contrast with control cells, compatible with the equilibrium constant derived from saturation and association data using a simple model. The loss of hGH receptors during competition studies was abolished. The down-regulation by unlabeled hGH was decreased by 80%. In contrast, insulin receptor kinetics remained unchanged (non-first-order) in the K+-depleted cells; the negative cooperativity and the down-regulation (60%) were identical to those of control cells. Quantitative electron microscopic autoradiography showed a decrease of +/- 50% in the fraction of 125I-labeled hGH internalized. The number of visible coated pits in the membrane was reduced by 80%. Thus, in IM-9 cells, association with coated pits and endocytosis appear to play a major role in the kinetics of hGH binding and in the down-regulation of its receptors, but not in insulin-receptor binding kinetics and down-regulation.
- Published
- 1986
- Full Text
- View/download PDF
27. [Acute hepatitis in children with drepanocytemia. Apropos of 61 cases].
- Author
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Omanga U, Ntihinyurwa M, Ilondo MM, and Tady M
- Subjects
- Anemia, Sickle Cell therapy, Child, Child, Preschool, Cholestasis complications, Democratic Republic of the Congo, Female, Hepatitis, Viral, Human etiology, Humans, Infant, Infant, Newborn, Male, Transfusion Reaction, Anemia, Sickle Cell complications, Hepatitis etiology
- Published
- 1977
28. Plasma androgens in children and adolescents. Part II. A longitudinal study in patients with hypopituitarism.
- Author
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Ilondo MM, Vanderschueren-Lodeweyckx M, Vlietinck R, Pizarro M, Malvaux P, Eggermont E, and Eeckels R
- Subjects
- Adolescent, Adrenocorticotropic Hormone deficiency, Adult, Androstenedione blood, Child, Child, Preschool, Dehydroepiandrosterone analogs & derivatives, Dehydroepiandrosterone blood, Dehydroepiandrosterone Sulfate, Female, Growth Hormone deficiency, Humans, Longitudinal Studies, Male, Pituitary Hormones deficiency, Puberty, Testosterone blood, Androgens blood, Hypopituitarism blood
- Abstract
In this prospective longitudinal study, plasma androgen levels were determined during 1-7 years in 45 patients aged 5.6-23.8 years with either isolated growth hormone (GH) deficiency or multiple pituitary hormone deficiencies. Dehydroepiandrosterone sulfate, dehydroepiandrosterone, delta 4-androstenedione and testosterone were measured by RIA in 339 blood samples collected during the study period. Mean plasma androgen levels are normal in isolated GH deficiency. Patients with multiple pituitary hormone deficiencies, but normal ACTH reserve, have mean levels lower than normal. Patients with multiple deficiencies including ACTH deficiency have still lower plasma androgen levels. Longitudinal analysis of the data, however, shows that patients with either isolated GH deficiency or multiple pituitary deficiencies without ACTH deficiency constitute a heterogeneous population, with either normal or low to very low plasma androgen levels. Treatment with human GH as such does not have any effect on the adrenal androgen secretion. A dissociation is found in some patients between adrenarche and gonadarche, which indicates that the two events are not controlled by the same mechanisms. Our results support the existence of a specific hypothalamic-pituitary adrenal androgen-stimulating hormone (AASH). ACTH, although not identical to AASH, is essential for normal adrenarche. Induced puberty with estrogens in girls does not influence plasma androgen levels, and pubic and axillary hair growth is not achieved. It is suggested that replacement treatment with dehydroepiandrosterone sulfate should be administered to girls with hypopituitarism and very low plasma androgen levels at the time of the induction of puberty. Finally, it appears from this study that, to interpret the plasma androgens in hypopituitarism, body surface is as good as bone age.
- Published
- 1982
- Full Text
- View/download PDF
29. Growth hormone deficiency: clinical appearance and results of treatment.
- Author
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Vanderschueren-Lodeweyckx M, Dooms L, Vanacker G, Snoeys M, Ilondo MM, Corbeel L, Eggermont E, and Eeckels R
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Female, Growth Disorders drug therapy, Growth Hormone therapeutic use, Hormones therapeutic use, Humans, Infant, Male, Growth Disorders diagnosis, Growth Hormone deficiency
- Published
- 1981
30. Plasma androgens and growth or puberty disorders.
- Author
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Ilondo MM, Pizarro M, Vlietinck R, Malvaux P, Eggermont E, Eeckels R, and Vanderschueren-Lodeweyckx M
- Subjects
- Adolescent, Child, Child, Preschool, Female, Humans, Hypopituitarism blood, Infant, Male, Puberty, Delayed blood, Puberty, Precocious blood, Androgens blood, Endocrine System Diseases blood, Growth Disorders blood, Puberty
- Published
- 1981
31. A boy with Leydig cell tumour and precocious puberty: ultrasonography as a diagnostic aid.
- Author
-
Ilondo MM, van den Mooter F, Marchal G, Vereecken R, Wynants P, Lauweryns JM, Eeckels R, and Vanderschueren-Lodeweyckx M
- Subjects
- Child, Humans, Leydig Cell Tumor diagnosis, Male, Testicular Neoplasms diagnosis, Ultrasonography, Leydig Cell Tumor complications, Puberty, Precocious etiology, Testicular Neoplasms complications
- Abstract
A 7 1/2 year-old boy developed pseudoprecocious puberty. The diagnosis of Leydig cell tumour was suggested by clinical and hormonal findings and greatly facilitated by ultrasonographic investigation of the testes. Surgical exploration was in keeping with the diagnosis and the tumour was removed. Orchidectomy was not necessary. It appears that ultrasonography may be very useful in diagnosing a testicular tumour. It facilitates surgical intervention since it permits localization of the lesion which is usually very small and limited to a small part of the testis, as in this case.
- Published
- 1981
- Full Text
- View/download PDF
32. A rapid method for the preparation of 125I-labelled human growth hormone for receptor studies, using reverse-phase high performance liquid chromatography.
- Author
-
Ilondo MM, Dehart I, and De Meyts P
- Subjects
- Chromatography, High Pressure Liquid, Growth Hormone immunology, Humans, Iodine Radioisotopes, Iodoproteins immunology, Iodoproteins isolation & purification, Receptors, Somatotropin, Growth Hormone isolation & purification, Receptors, Cell Surface metabolism
- Abstract
Human growth hormone was labelled with 125 Iodine by the stoichiometric modification of the chloramine-T method to a specific activity of 50-80 microCi/microgram, and the iodinated mixture was purified by reverse-phase high performance liquid chromatography using a C18 column (SynChropak RP-P) and a linear gradient. Compared with the usual Sephadex G-100 chromatography, HPLC gave a much better separation, with a higher yield and a considerably reduced analysis time (30 min vs 5 h). The [125I]-labelled preparation had normal binding to IM-9 lymphocyte receptors. The maximum bindability of the HPLC-purified preparation approximated 90%, which is the best value so far reported for human growth hormone. It is concluded that HPLC is a fast, convenient and reproducible method for obtaining an improved [125I]-labelled human growth hormone for receptor studies.
- Published
- 1986
- Full Text
- View/download PDF
33. Plasma androgens in children and adolescents. Part I: control subjects.
- Author
-
Ilondo MM, Vanderschueren-Lodeweyckx M, Vlietinck R, Pizarro M, Malvaux P, Eggermont E, and Eeckels R
- Subjects
- Adolescent, Adult, Androstenedione blood, Body Surface Area, Child, Child, Preschool, Cross-Sectional Studies, Dehydroepiandrosterone analogs & derivatives, Dehydroepiandrosterone blood, Dehydroepiandrosterone Sulfate, Female, Humans, Infant, Infant, Newborn, Male, Puberty, Sex Factors, Testosterone blood, Aging, Androgens blood
- Abstract
In this cross-sectional study, plasma levels of dehydroepiandrosterone sulfate (DHEA-S), dehydroepiandrosterone (DHEA), delta 4-androstenedione (delta 4) and testosterone (T) were measured by RIA in 232 normal subjects of both sexes, aged 2 weeks to 20 years. The results were analyzed in relation to chronological age, body surface and pubertal stage. High levels of plasma androgens were found in newborn infants of both sexes. After 3 months of age, androgen levels were uniformly low and rose with increasing chronological age and body surface. The first significant increase in mean androgen levels was found for DHEA-S. It occurred after 6 years of age in girls and after 8 years in boys. DHEA and T rose in both sexes after 8 years of age. delta 4 increased steadily with chronological age and body surface in both sexes. When androgen levels were related to body surface, a first significant increase was observed above 1.00 m2 for the four androgens, in both boys and girls. Above 1.20 m2 and 12 years of age, girls had higher mean levels of DHEA-S, DHEA and delta 4, but lower mean T levels than boys of the same body surface and chronological age. Before puberty, a positive correlation was found in both sexes between the plasma androgen levels on the one hand, and both chronological age and body surface on the other. Plasma androgen levels markedly increased at stage P2 in both sexes, and further increased with pubertal development. During puberty, girls had higher plasma delta 4, but lower plasma T levels than boys of the same pubertal stage. Plasma DHEA-S and DHEA levels were similar in both sexes. In contrast to the plasma androgens, plasma cortisol levels did not show any change in relation either to chronological age or to body surface or pubertal development. Body surface appears to be as good a discriminating factor as chronological age, at least in young children. It also appears from this study that DHEA-S is a good guide for the clinical evaluation of adrenal maturation and may be very useful in evaluating patients with growth or pubertal disturbances.
- Published
- 1982
- Full Text
- View/download PDF
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