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Biomedical subjects

C J Strasburger

Publications and source records attributed to C J Strasburger.

At least 73 records · Page 4Linked to original sources
PubMed1998

Activation of chimeric and full-length growth hormone receptors by growth hormone receptor monoclonal antibodies. A specific conformational change may be required for full-length receptor signaling.

Signal transduction by the growth hormone receptor (GHR) occurs through growth hormone (GH)-induced dimerization of two GHRs to form a trimeric complex. It is thought that dimerization alone is sufficient for signaling, since monoclonal antibodies (mAbs) against the extracellular domain of the GHR elicit proliferation of FDC-P1 cells transfected with a chimeric receptor comprising the extracellular domain of the GHR and the fibronectin and cytoplasmic domains of the murine granulocyte colony-stimulating factor receptor. We have screened 14 GHR mAbs for proliferative activity against characterized FDC-P1 and BaF-B03 cell lines stably expressing the full-length human, rabbit, or rat GHR, or the chimeric human GHR/granulocyte colony-stimulating factor receptor, and for transactivation of the c-fos promoter and STAT activation. With the chimeric receptor, eight mAbs were able to elicit proliferation, although there was no correlation between inhibition of hormone binding and agonist activity. In contrast, no mAbs were able to act as agonists with the full-length GHR FDC-P1 cell lines, although nine competed with GH for binding. A weak proliferative response was observed in the BaF-B03 cell lines with two of the mAbs (263 and 1C9), and the addition of anti-mouse F(ab)2 resulted in increased signaling in the hGHR BaF-B03 cell line to a plateau of 28 +/- 4% of the GH maximum for mAb 263. These data could indicate considerable stringency in the ability of mAbs to correctly dimerize the full-length GHR. However, the ability of mAb 263 to stimulate a mutant hGHR altered in the F'-G' loop of domain 2 was nearly abolished, concurrent with an increased affinity of this mAb for the receptor. Since the F'-G' loop undergoes a conformational change on GH binding and is necessary for full proliferative signaling, we propose that in addition to promoting receptor dimerization, mAb 263 may induce specific changes in receptor conformation similar to GH, which are required for the biological response.

Animals↗
PubMed1998

[A 35-year old male patient with fever and painful swelling of the pectoral glands following a short visit to Sri Lanka].

HISTORY AND CLINICAL FINDINGS: One week after returning from a two-week holiday in Sri Lanka a 35-year-old man started to have recurrent bouts of fever, up to 39.2 degrees C, as well as pain over the left upper abdomen, the back of the right thorax and bilateral pain on pressure with swelling of both breasts. He went to the Tropical Institute in Munich to have malaria excluded. There signs of cholestasis were noted and sonography revealed multiple round foci in the liver. As he had lost 10 kg in 3 weeks he was admitted to a medical unit for further tests. Physical examination now showed bilateral gynaecomastia and marked pressure resistance in the upper abdomen. Proprioceptor reflexes were greatly increased but equal bilaterally. INVESTIGATIONS: Inflammatory parameters were raised (C-reactive protein 22.6 mg/dl, ferritin level 2674 micrograms/l, erythrocyte sedimentation rate 50/82 mm), there also were a leucocytosis (20,600 WBC/mm3) and a raised lactate dehydrogenase level of 613 U/l. In addition, thyroid stimulating hormone was reduced to < 0.03 microU/ml, while free thyroxine was raised to 2.7 ng/dl. The pregnancy test was positive. On quantitative analysis the human beta-chorionic gonadotropin (hCG) level was markedly raised to 193,200 mIU/ml. Abdominal and thoracic computed tomography revealed multiple round metastasis-like masses in the liver and in the lung, and a thickened cardia. Serology for malaria, amoebiasis and echinococciasis was negative, sonography of the testes and thyroid was unremarkable. Endoscopy revealed a polypoid tumour at the gastro-oesophageal junction which histologically was an undifferentiated hCG-positive choriocarcinoma. TREATMENT AND COURSE: The neoplasm at first responded with partial remission (hCG minimally 39 mIU/ml) to chemotherapy (PEI schema: cisplatin, etoposide, ifosfamide) but then progressed, also under treatment of recurrences with paclitaxel, ifosfamide and cisplatin. The patient has since received high-dosage chemotherapy with autologous stem-cell transplantation.

Adult↗
PubMed1998

Deficient insulin-like growth factor I in chronic heart failure predicts altered body composition, anabolic deficiency, cytokine and neurohormonal activation.

BACKGROUND: Recent studies of growth hormone supplementation in chronic heart failure have been associated with variable results. Acquired abnormalities of biochemical parameters of the growth hormone insulin-like growth factor I axis have been associated with severe chronic heart failure. There are suggestions of an acquired growth hormone resistance with deficient insulin-like growth factor I in some patients. OBJECTIVES: Therefore, we set out to investigate the clinical and functional status and the degree of cytokine and neurohormonal alteration of chronic heart failure patients with deficient insulin-like growth factor I responses. METHODS: Patients with chronic heart failure were divided into two groups according to their insulin-like growth factor I levels (classified according to the manufacturer's assay range in normal controls): low insulin-like growth factor I <104 (n = 20; 89 +/- 9.6 ng/ml), and normal/high >104 ng/ml (n = 32; 169 +/- 52 ng/ml). Between groups there was no difference in age (low versus high: 65.3 +/- 12.1 versus 61.6 +/- 9.1 years, p = 0.21), body mass index, aerobic capacity (peak oxygen consumption: low versus high: 15.5 +/- 5.2 versus 17.3 +/- 6.3 mL/kg/min, p = 0.23), left ventricular ejection fraction, New York Heart Association classification. RESULTS: During quadriceps strength testing, patients with low insulin-like growth factor I had reduced absolute strength (-24%), and strength per unit area muscle (- 14%) than patients with normal/high insulin-like growth factor I. Leg muscle cross-sectional area was lower in the low insulin-like growth factor I group (-12% and -13% for right and left legs, respectively). These alterations were accompanied by increased levels of growth hormone (+145%), tumor necrosis factor-alpha (+46%), cortisol/ dehydroepiandrosterone ratio (+60%), noradrenaline (+49%) and adrenaline (+136%) (all at least p < 0.05). CONCLUSIONS: Patients with low insulin-like growth factor I levels show signs of altered body composition, cytokine and neuroendocrine activation, to a greater extent than patients with normal/high levels.

Adrenergic alpha-Agonists↗
PubMed1998

[Does the growth hormone pharmacokinetic profile help to predict the treatment response?].

Pharmacokinetics of subcutaneously administered recombinant growth hormone (rGH) were studied in nine GH deficient children at the time of the first rGH injection at the beginning of treatment. Serum GH levels were determined by four different methods: immunofunctional assay, immunofluorometric assay and two bioassays on Nb2 cells. The results showed similar profiles whatever the type of assay with a concentration peak reached 2 to 6 hours after subcutaneous injection; however, large individual variations in peak amplitude were observed. They were related to individual variations in the growth velocity during the first year of rGH treatment. These variations are possibly related to individual differences in rGH degradation at the site of injection. Study of rGH absorption profiles appears useful in the evaluation of rGH treatment in GH deficient patients.

Biological Assay↗
PubMed1998

A time-resolved fluoroimmunoassay for cortisol in unextracted bovine plasma or serum with optimized procedures to eliminate steroid binding protein interference and to minimize non-specific streptavidin-europium binding.

A time-resolved fluoroimmunoassay (TR-FIA) for human salivary cortisol was adapted for the measurement of cortisol in unextracted bovine blood plasma and serum. It has been demonstrated that the binding of cortisol binding plasma proteins (CBPP) to the cortisol-biotin primary probe cannot be eliminated by means of cortisol releasing agents. Complete inactivation of CBPP was achieved by heating water diluted samples for 30 min at 80 degrees C. The high non-specific binding (NSB) of the streptavidin-europium secondary probe, encountered during preliminary experiments, was shown to be caused by an interaction with bovine serum albumin (BSA) and could be reduced partly by the addition of heparin. It was also shown that the ability to bind streptavidin-europium nonspecifically is not a general property of proteins since bovine gamma-globulin and gelatin lack this behaviour. The advantage of a highly reduced NSB, resulting from the use of a BSA free assay buffer, is not limited to this particular assay but is also beneficial for other procedures based on specific measurement of streptavidin-europium fluorescence. The detection limit for a 20 microl sample was 0.5 ng/ml. The intra-assay coefficients of variation for control samples with cortisol concentrations of 71.1, 39.2 and 10.3 ng/ml were 8.2, 7.9 and 11.3% (n = 16). The corresponding inter-assay coefficients of variation were 7.3, 9.0 and 11.2% (n = 73). Correlation with a commercially available radioimmunoassay, preceded by diethylether extraction of the sample, was 0.97 (n = 88).

Animals↗
PubMed1998

Laboratory assessment of GH.

The diagnosis of growth hormone (GH) deficiency is based primarily on clinical criteria. In paediatric endocrinology, auxological evaluation leads to the diagnosis, while in adult endocrinology evidence of severe pituitary disease is associated with GH deficiency. Final proof of the diagnosis, however, is sought by measurement of GH levels in serum after dynamic provocative testing of GH secretion. Although arbitrary cut-off levels exist, below which the maximum GH peak should be found in different provocative tests, these recommendations have to be considered vague in the light of the considerable heterogeneity between results from different commercially available GH assays. Factors influencing the results of GH measurement by immunoassay are the heterogeneity of molecular isoforms of circulating GH, assay design, standard matrix, choice of reference preparation for calibration and, to a considerable extent, the epitope specificity of the antibodies used. Ideally, GH should be measured by a true somatogenic bioassay. Such assays are too cumbersome for routine use, however, and in most instances are only suitable for investigation of purified GH preparations rather than quantification of GH levels in serum samples. Significant progress was made recently with the concept of immunofunctional measurement of GH levels, in which only GH molecules having both receptor interaction sites necessary for initiation of the signal transduction process in target cells are translated into an assay signal. Immunofunctionally measured GH levels are, therefore, closer to the results from bioassays than the determination of arbitrary immunoreactivity of GH isoforms with a given antibody or set of antibodies in conventional immunoassays. In the context of establishing a diagnosis of GH deficiency, it is mandatory that techniques for GH measurement are standardized more rigidly before recommendations on meaningful cut-off levels for different provocative tests are made.

Adult↗
PubMed1998

Development of a highly sensitive nonisotopic immunoassay for the determination of salivary 17-hydroxyprogesterone: reference ranges throughout childhood and adolescence.

A sensitive nonisotopic immunoassay for the determination of 17-hydroxyprogesterone (17-OHP) levels in saliva was developed. The new time-resolved fluorometric immunoassay employs a specific polyclonal anti-17-OHP antiserum immobilized onto microtiter plates, a 17-OHP-biotin conjugate as a tracer, and streptavidin-europium a as secondary probe. The lower detection limit of the assay is 23.6 pmol/L (mean -3 s of a 22-fold zero determination) corresponding to 0.39 pg/well. The coefficients of intraassay variation are 8.8, 5.3, and 8.3% at the respective concentrations of 90.9, 454.5, and 1363.5 pmol/L. The coefficients of interassay variation are 8.8, 5.3, and 8.3% at the respective concentrations. Saliva was collected in commercially available devices. Reference ranges were established using 394 saliva samples from 132 healthy children, adolescents, and adults. Morning, midday, and evening levels of 17-OHP levels in saliva varied significantly in all age groups with morning levels being higher than midday and evening levels. Saliva samples (n = 57) were also obtained from 18 children with congenital adrenal hyperplasia (CAH). Salivary 17-OHP levels in the limited number of CAH patients studied ranged from 121 to 106,050 pmol/L. In conclusion 1) a new, sensitive nonisotopic immunoassay for measurement of 17-OHP in saliva has been developed; 2) reference ranges for healthy children, adolescents, and adults have been established; 3) there is a circadian pattern of 17-OHP levels in saliva at all ages; and 4) measurement of 17-OHP in saliva should be further evaluated over a longer period of time as a potentially reliable and powerful technique to monitor metabolic control in patients with CAH. As 17-OHP levels in saliva are stable for > 10 wk at 4 degrees C, the technique is ideally suited for outpatient sampling.

17-alpha-Hydroxyprogesterone↗
PubMed1998

Growth hormone and its receptor are expressed in human thymic cells.

GH has been shown to modulate various functions of the thymus. We now demonstrate the production of human GH (hGH) by human thymic cells, and the expression of GH receptors in thymic epithelial cells (TEC) and in thymocytes at different stages of differentiation. The presence of hGH messenger RNA was shown by RT-PCR in both human thymocytes and in primary cultures of TEC. Moreover, immunoreactive hGH material was detected in culture media of thymocytes and TEC with the use of a sensitive immunoradiometric assay. GH receptor gene expression was shown in TEC in primary cultures and in fetal and postnatal TEC lines as well as in thymocytes. By immunocytochemistry, the presence of GH receptors in the various TEC preparations was confirmed. In cytofluorometric studies with the use of a biotinylated anti-GH receptor monoclonal antibody, we could show that GH receptors are predominantly expressed by immature thymocytes: over 90% of CD3- CD4- CD8- CD19- CD34+ CD2- cells (a phenotype characterizing the most immature T cell progenitors in the thymus) were GH receptor positive. Our results provide a molecular basis for an autocrine/paracrine mode of action of GH in the human thymus.

Cells, Cultured↗
PubMed1998

Interleukin-1 beta enhances interleukin-1 receptor antagonist content in human somatotroph adenoma cell cultures.

In addition to the well-known modulation of immune and inflammatory responses, the interleukin-1 (IL-1) system has been shown to be involved in the regulation of anterior pituitary hormone secretion and growth. We previously demonstrated that IL-1 receptor antagonist (IL-1ra) is expressed in human pituitary adenomas cultured in vitro. In the present study, we investigated the regulation of IL-1ra protein by IL-1 beta (1-100 U/mL) in human somatotroph adenomas (n = 9) cultured for 12-48 h. IL-1 beta significantly enhanced the concentration of IL-1ra dose dependently in the somatotroph adenoma cell lysates, whereas IL-1ra concentrations remained unchanged in the culture supernatants. Furthermore, basal IL-1ra concentrations were significantly higher in the cell lysates compared with the corresponding culture supernatants. The regulation of IL-1ra in somatotroph adenoma cells is different from human cultured monocytes, in which IL-1 beta significantly stimulated IL-1ra secretion into the culture supernatants, and no change of intracellular IL-1ra content was observed. Incubation of the somatotroph adenoma cells with 100 U/mL IL-1 beta did not result in a change of GH concentrations in the culture supernatants. Enhancement of intracellular IL-1ra protein by IL-1 beta may represent a mechanism intrinsic to somatotroph adenoma cells to counterregulate the response to IL-1 beta on hormone secretion or cellular growth.

Adenoma↗
PubMed1998

A time-resolved fluorescence immunoassay for the measurement of testosterone in saliva: monitoring of testosterone replacement therapy with testosterone buciclate.

Monitoring of testosterone replacement therapy requires a reliable method for testosterone measurement. Determination of salivary testosterone, which reflects the hormone's biologically active plasma fraction, is a superior technique for this purpose. The aim of the present study was to establish a new sensitive time-resolved fluorescence immunoassay for the accurate measurement of testosterone levels in saliva and to validate it by monitoring testosterone replacement therapy in eight hypogonadal men. A clinical phase I-study with the new ester testosterone buciclate was performed to search for new testosterone preparations to produce constant serum levels in the therapy of male hypogonadism. After two control examinations eight male patients with primary hypogonadism were randomly assigned to two treatment groups (n = 2 x 4) and given single doses of either 200 mg (group I) or 600 mg (group II) testosterone buciclate intramuscularly. Saliva and blood samples were obtained 1, 2, 3, 5 and 7 days post injection and then weekly for three months. The time-resolved fluorescence immunoassay for salivary testosterone shows a detection limit of 16 pmol/l, an intra-assay CV of 8.9% (at a testosterone concentration of 302 pmol/l), an inter-assay CV of 8.7% (at a testosterone concentration of 305 pmol/l) and a good correlation with an established radioimmunoassay of r = 0.89. The sample volume required by this method is only 180 microliters for extraction and duplicate determination. The assay procedure requires no more than three hours. In group I (200 mg) testosterone did not increase to normal levels either in saliva or in serum. However, in group II, androgen levels increased significantly and were maintained in the normal range for up to 12 weeks with maximal salivary testosterone levels of 303 +/- 18 pmol/l (mean +/- SE) and maximal testosterone levels of 13.1 +/- 0.9 nmol/l (mean +/- SE) in serum in study week 6 and 7. The time-resolved fluorescence immunoassay for salivary testosterone provides a useful tool for monitoring androgen status in men and women and is well suited for the follow-up of testosterone replacement therapy on an outpatient basis. The long-acting ester testosterone buciclate is a promising agent for substitution therapy of male hypogonadism and in combination with testosterone monitoring in saliva offers an interesting new perspective for male contraception.

Adult↗
PubMed1998

A five day treatment with daily subcutaneous injections of growth hormone-releasing peptide-2 causes response attenuation and does not stimulate insulin-like growth factor-I secretion in healthy young men.

The synthetic hexapeptide growth hormone-releasing peptide (GHRP)-2 specifically stimulates GH release in man. To determine the effects of prolonged treatment and whether response attenuation occurs in man, we administered to nine healthy subjects a daily s.c. injection of 100 microg GHRP-2 over 5 days. Every day blood samples were taken to determine GH, IGF-I, IGF-binding protein (IGFBP)-3 and osteocalcin levels. On days 1,3 and 5, GH was measured at -20,0,20,40,60,90,120 and 180 min using an immunometric and an immunofunctional assay. Mean-/+S.D). peak GH concentrations were 83+/-31, 59+/-22 and 51+/-13 microg/l on days 1, 3 and 5 respectively. Mean+/-S.D. areas under the curve for days 1, 3 and 5 were 6366+/-2514, 3987 +/- 1418 and 3392+/-1215 mU/l per min. Despite the maintained GH release, analysis of variance revealed that significant response attenuation occurred (P < 0.01). Mean serum IGF-I concentration did not increase after a 5 day treatment with GHRP-2. Mean basal levels were 22, 25,23,25,23,24 nmol/l measured on days 1 to 6. However, osteocalcin, another serum marker of GH activity in tissue, increased significantly from 3.2+/-1.0 to 4.2+/-0.4 microg/l (mean+S.D.) (P< 0.01).

Adult↗
PubMed1998

Spontaneous and cationic lipid-mediated uptake of antisense oligonucleotides in human monocytes and lymphocytes.

Monocytes are important target cells for anti-inflammatory antisense strategies. However, monocytes are characterized by strong phagocytic and catalytic activity which may limit the effect of antisense oligonucleotides. Intracellular distribution of oligonucleotides in monocytes and the effect of cationic lipids on oligonucleotide uptake in monocytes and other leukocytes have not been evaluated. We investigated cationic lipid-mediated uptake of oligonucleotides in human monocytes and lymphocyte subpopulations. Incorporation of oligonucleotides was quantified by flow cytometry and by confocal microscopy. In the absence of cationic lipids, nearly 100% of monocytes and of B lymphocytes incorporated oligonucleotides compared with only 12% of natural killer cells and 1% of T lymphocytes. The amount of oligonucleotide uptake per cell, as determined by mean fluoresence intensity of positive cells, was four times higher in monocytes than in B lymphocytes. Cationic lipids, which form complexes with oligonucleotides, markedly enhanced the amount of oligonucleotide uptake in all cell types and were most effective at a ratio of 1.1 of positive-to-negative molar charges. In monocytes, oligonucleotides incorporated spontaneously (without a lipid carrier) were trapped in cytoplasmic vesicles. In contrast, cationic lipid-mediated uptake of fluorescence-labeled oligonucleotides resulted in cytoplasmic and nuclear staining. We conclude that 1) monocyte and lymphocyte subpopulations differ in the degree of spontaneous oligonucleotide uptake, and 2) lipofectin both quantitatively and qualitatively affects this uptake. Our results may explain the necessary role of cationic lipids in most antisense models with leukocytes as target cells.

Flow Cytometry↗
PubMed1997

Insulin-like growth factor-I (IGF-I) plasma concentrations are increased in depressed patients.

There is some evidence that the somatotrophic system in depression, as assessed by basal growth hormone (GH) concentrations and by GH releasing hormone (GHRH) challenge, might be dysfunctional. However, the rather limited data have been inconclusive so far and plasma concentrations of both insulin-like growth factor-1 (IGF-I) and binding proteins (IGFBP 1 to IGFBP-6) have not been measured simultaneously in depressed patients. We studied 24 severely depressed patients and 33 healthy controls and estimated 24-hour mean plasma cortisol, six-hour evening mean plasma growth hormone (GH), morning plasma IGF-I, IGFBP 2 and 3 and GH-binding protein (GH-BP). Twenty-four-hour mean cortisol (306 +/- 69 vs. 196 +/- 30 nmol/l, p < .001) and IGF-I (157 +/- 40 vs. 120 +/- 33 micrograms/l, p < .01) plasma concentrations were found to be significantly increased in depressed patients, while there was no difference in GH or binding proteins between both groups. MANOVA analysis revealed age and diagnosis to have main effects upon plasma IGF-I. Especially young age and a diagnosis of major depression are associated with higher plasma IGF-I. After treatment only patients in remission had attenuated IGF-I plasma concentrations. We conclude that plasma IGF-I is increased in acutely depressed patients similar to other states of hypercortisolemia.

Adult↗
PubMed1997

New growth hormone assays: potential benefits.

Three recently published new assays are described for the measurement of growth hormone (GH). Two of these--the eluted stain assay (ESTA) and the immunofunctional assay (IFA)--have been developed to measure the bioactivity of GH, rather than the immunoactivity as measured by conventional radioimmunoassays (RIAs). The third assay--the 22 kDa exclusion assay (22 k GHEA)--is designed to measure the concentrations of the different isoforms of GH present in the circulation. The ESTA is a variant of the Nb2 bioassay for lactogenic hormones, but has been adapted for specific GH measurement in serum samples. It has a lower detection limit than previous bioassays and permits the quantification of GH in large series of samples. The IFA uses a binding-site-specific antibody in combination with GH-binding protein (GHBP) in order to quantify only those GH molecules that are able to dimerize the extracellular domain of the GH receptor (GHBP), which is a prerequisite for GH signal transduction in target cells. The IFA is as convenient to use as immunoassays and can be employed routinely for GH determinations. The clinical usefulness of the 22 k GHEA has not been established, but it should provide a means of augmenting our understanding of the regulation of GH and its various isoforms. Once the ESTA bioassay or the IFA become commercially and widely available, either could replace the RIA as the standard reference method for measuring GH, as both more closely reflect the biologically active proportion of GH in serum samples than that measured by RIA.

Animals↗
PubMed1997

Effects of growth hormone and insulin-like growth factor I binding to natural killer cells.

Human growth hormone (GH) and insulin-like growth factor I (IGF-I) are known to bind to, and exert modulatory effects on, different immunocompetent cells, including CD16+/CD3- natural killer (NK) cells. NK cells are involved in various non-major-histocompatibility-complex-restricted actions of the immune system. Although no clinically significant defect in tumour or virus defence has been reported in GH-deficient patients, the data available indicate decreased NK cell activity in these patients. In most studies, the absolute number and percentage of NK cells have been found to be normal. Substitution with GH has been reported to normalize the decreased NK cell activity in GH-deficient patients. In a cross-sectional study in GH-deficient adults, decreased basal and interferon-beta (IFN-beta)-stimulated NK cell activity in vitro. Preliminary data on GH binding to NK cells indicate enhanced binding in GH-deficient patients when compared with normal controls.

Adult↗
PubMed1997

Measurement of serum exon 3-retaining growth hormone-binding protein in children and adolescents by radioimmunoassay.

Recently described assays for the determination of growth hormone-binding protein (GHBP) show a wide variety of normal ranges. Their results depend on the assay design and in the case of ligand-immunofunctional assay (LIFA), probably also on the binding characteristics, i.e. epitope specificity and affinity of the employed antibody. These facts underline the necessity to look for more accurate and specific assays. In this report we describe an accurate and simple radioimmunoassay (RIA) which allows the specific quantitation of the exon 3-retaining GHBP isoform (E3-GHBP). Data of the E3-GHBP RIA were compared to those of a LIFA measuring undifferentiated functional forms of GHBP. Our results demonstrate significant relationships between GHBP and age, BMI and IGF-I as determined by RIA and by LIFA in normal children and adolescents (n = 115, p < 0.001). Moreover, BMI is the only regulating factor of GHBP for both methods as shown by multiple regression analysis (p < 0.001). All our data suggest a qualitatively paralleled regulation of E3-GHBP and undifferentiated functional GHBP forms. This finding was confirmed by a good correlation between RIA and LIFA data (r = 0.74, p < 0.001). Children with idiopathic short stature (ISS, n = 47) had significantly lower GHBP levels than normal controls (n = 58) measured by the E3-GHBP RIA (p < 0.0001) and by LIFA (p < 0.01). We conclude that (1) ISS children may have a structural or quantitative defect at the level of the GHR, and (2) the highly specific assay for E3-GHBP immunoreactivity provides a sensitive diagnostic tool in conditions with partial GH insensitivity.

Adolescent↗
PubMed1997

Adult growth hormone (GH)-deficient patients demonstrate heterogeneity between childhood onset and adult onset before and during human GH treatment. Adult Growth Hormone Deficiency Study Group.

The onset of adult GH deficiency may be during either adulthood (AO) or childhood (CO), but potential differences have not previously been examined. In this study the baseline and GH therapy (12.5 micrograms/kg per day) data from CO (n = 74; mean age 29 yr) and AO (n = 99; mean age 44 yr) GH-deficient adult patients have been compared. The first 6 months comprised randomized, double-blind treatment with GH or placebo, then all patients were GH-treated for a further 12 months. At baseline the height, body weight, body mass index, lean body mass, and waist/hip ratio of AO patients were significantly (P < 0.001) greater than in CO patients. Serum insulin-like growth factor-I (IGF-I) levels were below normal but were lower in CO than AO patients (P < 0.001), and the correlation with IGF binding protein-3 was stronger in CO than in AO patients. Osteocalcin concentration in CO patients was above the normal range and significantly greater than in AO patients. Both groups had significant psychosocial distress, but the deviation from normality was greater in AO patients. Throughout GH therapy there was a significant increase in lean body mass and significant decrease in percent body fat and sum of skinfolds in each group. Wais/hip ratio was decreased by long-term therapy in AO but not CO patients. Total and low density lipoprotein cholesterol levels were decreased from baseline at 6 months in AO but not CO patients and high density lipoprotein cholesterol was increased in both groups throughout therapy. IGF-I and IGF binding protein-3 were increased into the normal range by GH therapy in both groups. Mean osteocalcin level in AO patients was increased at 6 months with no further change with GH therapy, whereas in CO patients there was a steep increase up to 12 months but then a sharp decrease. Nottingham Health Profile scores showed significant improvements in physical mobility and energy at 18 months of therapy in AO patients but no consistent effects in CO patients. GH-induced side effects were mainly reported by AO patients; very few CO patients reported treatment-emergent adverse events. These results demonstrate significant differences in clinical and biochemical presentation and responses to therapy of the adult GH deficiency syndrome. This is consistent with the existence of two entities, developmental (CO) and metabolic (AO), and the different functions of GH at different periods of life.

Adult↗