ISSN:0300-0664    

DOI:10.1046/j.1365-2265.1996.716535.x

出版商:Blackwell Science Ltd    

年代:1996

数据来源: WILEY

摘要:

OBJECTIVE The aim of this investigation was to characterize the GH–IGF axis of patients with AIDS associated wasting. A special emphasis was placed on determining whether IGF binding proteins (IGFBPs) of patients who have lost more than 10% of their ideal body mass are structurally different from the IGFBPs of patients with no weight loss.DESIGN AND PATIENTS A cross‐sectional study of 11 AIDS patients was performed to determine whether the IGF system is abnormal in AIDS patients with wasting. Seven additional AIDS patients were followed longitudinally to determine whether AIDS patients experience long‐term changes to their IGF system.MEASUREMENTS Serum levels of GH and IGF‐I were measured by radioimmunoassay, IGF‐II was measured by radioreceptor assay, and IGFBP‐1 was measured by an enzyme linked immunoassay. IGFBP‐3 and IGFBP‐3 protease activity were measured by ligand blotting and a BP‐3 protease assay, respectively. IGFBP‐3 ternary complex formation and IGFBP‐1 phosphovariants were analysed by non‐denaturing PAGE.RESULTS AIDS patients who had lost more than 10% of their ideal body mass demonstrated a 55% reduction in serum IGF‐I (81vs179 μg/l) and a 70% reduction in IGF‐II (226vs776 μg/l), compared to healthy HIV negative subjects. IGF‐I levels were depressed, in some patients, despite high serum levels of GH. AIDS patients who had lost more than 10% of their ideal body mass had low levels of IGFBP‐3 and a reduced ability to form the IGFBP‐3 ternary complex. The IGFBP‐3 ternary complex could be restored only upon addition of pure IGFBP‐3 and acid labile subunit to serum. Serum IGFBP‐1 was increased more than threefold compared to control subjects (90vs24 μg/l). IGFBP‐1 was present as a free phosphoprotein in AIDS patients with low levels of IGF‐I and in a bound form when serum IGF‐I levels were normal. Changes in the GH–IGF axis were sustained for up to 25 months in AIDS patients with wasting.CONCLUSIONS AIDS wasting is associated with a GH resistant state that results in low levels of serum IGF‐I, IGF‐II and IGFBP‐3, elevated levels of phosphory

ISSN:0300-0664    

DOI:10.1046/j.1365-2265.1996.705526.x

出版商:Blackwell Science Ltd    

年代:1996

数据来源: WILEY

摘要:

OBJECTIVE Circulating IGF‐I and IGF binding protein‐3 (IGFBP‐3) levels both increase in puberty where growth velocity is high. The amount of free IGF‐I is dependent on the IGF‐I level and on the concentrations of the specific IGFBPs. Furthermore, IGFBP‐3 proteolysis regulates the bioavailability of IGF‐I. However, the concentration of free IGF‐I and possible IGFBP‐3 proteolytic activity in puberty has not previously been studied.SUBJECTS AND MEASUREMENTS We investigated serum levels of easily dissociable IGF‐I concentrations and ultrafiltrated free IGF‐I levels by specific assays in 60 healthy boys and in 5 boys with precocious puberty before and during GnRH agonist treatment. In addition, total serum IGF‐I, IGFBP‐1 and IGFBP‐3 levels as well as IGFBP‐3 protease activity were determined.RESULTS Free (dissociable and ultrafiltrated) IGF‐I concentrations were significantly higher in pubertal boys than in prepubertal children and correlated significantly with the molar ratio between IGF‐I and IGFBP‐3 (r=0.69,P<0.0001 andr=0.54,P=0.0008, respectively) and inversely with IGFBP‐1 (r=−0.47,P<0.0001 andr=−0.43,P=0.0003, respectively). Multiple regression analysis suggested that IGFBP‐3 level, and not IGFBP‐1, was the major determinant of the free IGF‐I serum level in normal boys. Free IGF‐I levels were elevated in boys with precocious puberty and decreased during GnRH treatment. IGFBP‐3 proteolysis was constant throughout puberty (mean 20%).CONCLUSIONS We conclude that easily dissociable and ultrafiltrated free IGF‐I serum levels are increased in boys with normal and precocious puberty and suggest that the increased free IGF‐I serum concentration in puberty primarily reflects changes in total concentrations of IGF‐I and IGFBPs secondary to increased GH secretion

ISSN:0300-0664    

DOI:10.1046/j.1365-2265.1996.711531.x

出版商:Blackwell Science Ltd    

年代:1996

数据来源: WILEY

摘要:

OBJECTIVE Little information is available regarding the regulation of serum acid‐labile subunit (ALS) in human disease. We have studied alterations in serum ALS of the insulin‐like growth factor (IGF) ternary complex in children with untreated insulin‐dependent diabetes mellitus (IDDM) and subjects with severe burns before and after insulin therapy. In addition, we have investigated the effect of insulin plus GH on serum ALS in burn patients.DESIGN Serum samples were obtained from children with newly diagnosed and untreated IDDM before the initiation of insulin therapy and 1 month thereafter. Serum samples were also obtained from adult patients with severe burns who were on a continuous infusion of a carbohydrate‐rich enteral diet via nasogastric and duodenal catheters under basal conditions, after a 1‐week period of continuous insulin infusion, and after an additional week of insulin plus recombinant GH.PATIENTS Twenty children and adolescents with untreated IDDM, aged 1.2–16 years, and 6 young adult patients with severe burns aged 17–28 years were studied longitudinally. Control sera were obtained from age, sex and pubertal status matched subjects (for children with IDDM) and from fed healthy adults.MEASUREMENTS Serum insulin, GH, cortisol and IGF‐I were measured by radioimmunoassay, and serum ALS levels were assessed by Western immunoblot before and after treatment periods.RESULTS  Serum ALS levels were lower in untreated children with IDDM (69 ± 6% of control children). Insulin therapy significantly increased serum ALS (79 ± 5%,P<0.05) in these children. Patients with severe burns also had lower serum ALS levels (79 ± 10% of control adults). After one week of insulin therapy serum ALS levels increased to 90 ± 15% of control values (P<0.05). Addition of GH to insulin therapy for another week did not significantly further increase serum ALS levels (95 ±  27%). Serum IGF‐I concentrations increased nearly 2.5‐fold in diabetic subjects and fourfold in burn subjects at the end of the study periods. There were no proteolytic fragments of ALS in the sera studied. The deglycosylation pattern of ALS did not differ between diabetic and control sera.CONCLUSION Serum ALS levels were diminished in children with untreated IDDM and were partially restored after the initiation of insulin therapy. Serum ALS levels were also diminished in patients with severe burn injury and restored by insulin treatment. Addition of GH to insulin therapy did not significantly increase serum ALS levels over levels obtained during insulin therapy alone. These decreases in serum ALS were smaller than the decrease in serum IGF‐I concentrations in both conditions, suggesting that IGF‐I is the limiting factor for the ternary complex formation in the catabolic states. Insulin may regulate circulating ALS

ISSN:0300-0664    

DOI:10.1046/j.1365-2265.1996.726547.x

出版商:Blackwell Science Ltd    

年代:1996

数据来源: WILEY

摘要:

OBJECTIVE Growth hormone release in response to all known stimuli of GH secretion is blunted in obese subjects. Several studies, usingdl‐fenfluramine (dl‐FF) as a serotoninergic tool, suggest that brain serotonin plays a role in the pathogenesis of this phenomenon. However, the effect ofdl‐FF appears to be dependent on the stimulus used to induce GH release. Furthermore,dl‐FF has catecholamingergic properties apart from its capacity to stimulate serotonin release and to block its re‐uptake. In this study, we investigated whether subchronic treatment with the highly selective serotoninergic drug dexfenfluramine (d‐FF) affects the GH response to galanin or GHRH in obese subjects.DESIGN The study had a randomized, cross‐over, placebo controlled design.d‐FF was administered in a dose of 15 mg twice daily during 6 days. On days 5 and 6 of treatment (with eitherd‐FF or placebo) an i.v. bolus injection of 100 μg hGHRH(1‐44) or a continuous infusion of p‐galanin (40 pmol/kg/min over 40 minutes) were administered in randomized order. All tests were performed in the follicular phase of two consecutive menstrual cycles.PATIENTS Eight obese women (body mass index (BMI) 34.5 ± 3.6 kg/m2); 7 normal weight (BMI 21.9 ± 1.9 kg/m2) age‐matched control women. All women had a regular menstrual cycle. None used oral contraceptive drugs.MEASUREMENTS GH response to either stimulus was measured both during treatment withd‐FF and during treatment with placebo.RESULTS The GH response to galanin and the response to GHRH were significantly smaller in obese subjects.d‐FF significantly reduced the galanin induced GH secretion in obese subjects, but not in normal weight controls. It did not significantly affect GH release in response to GHRH in either group.CONCLUSION This study confirms that GH secretion in response to stimuli with varying mechanisms of action is blunted in obese subjects. A decrease of central serotonin mediated neurotransmission does not

ISSN:0300-0664    

DOI:10.1046/j.1365-2265.1996.727548.x

出版商:Blackwell Science Ltd    

年代:1996

数据来源: WILEY

摘要:

OBJECTIVE Increased plasma concentrations of GH and increased GH responses to provocative stimuli are reported in patients with poorly controlled type I diabetes and are suggested to be related to complications. Our aim was to investigate GH concentrations in moderately controlled patients.PATIENTS AND MEASUREMENTS We have investigated IGF‐I concentrations and fasting GH concentrations and the response to 1 μg/kg body weight GH‐releasing hormone (GHRH) intravenously and/or to 150 μg clonidine intravenously in 77 moderately controlled patients with type I diabetes and in 46 healthy controls.RESULTS Median HbA1c in the patients was 8.5% (upper level of normal 6.3%). Fasting GH and GH concentrations after the administration of GHRH were not significantly different in patients with type I diabetes compared with normal controls. Fasting and stimulated GH concentrations after the administration of clonidine were significantly higher in the patients, but this could be explained by their lower age and body mass index compared with controls. In controls but not in patients there was a negative correlation between GH and glucose concentrations. IGF‐I was significantly lower in patients with diabetes than in controls, even after correction for age, body mass index and sex.CONCLUSIONS Patients with moderately controlled type I diabetes mellitus have normal baseline and stimulated GH concentrations after the administration of GHRH or clonidine compared with healthy controls, when corrected for age, body mass index and sex. However, these ‘normal’ GH concentrations must be considered inappropriately high in view of the hyperglycaemia in these patients. The low plasma IGF‐I concentrations might be responsible f

ISSN:0300-0664    

DOI:10.1046/j.1365-2265.1996.713534.x

出版商:Blackwell Science Ltd    

年代:1996

数据来源: WILEY

摘要:

OBJECTIVE Hexarelin is a synthetic six‐amino‐acid compound capable of releasing GH in animals and in man. Its mechanism of action is not understood and little is known about the GH response after repeated administration. The aim of this study was to determine the GH response to the administration of two intravenous boluses of hexarelin, growth hormone releasing hormone (GHRH) or hexarelin with GHRH.DESIGN Single boluses of hexarelin (1 μg/kg), GHRH‐(1–29)‐NH2(1 μg/kg) or hexarelin with GHRH‐(1–29)‐NH2were administered intravenously. Each study was performed on two further occasions, with a second bolus being administered 60 or 120 minutes after the first. A control study was performed giving saline intravenously. Studies were performed in a random order.SUBJECTS Six healthy adult males (25.4–34.1 years) were studied.MEASUREMENTS Serum GH was measured by radioimmunoassay. GH secretion rates were derived from the measured serum GH concentrations using the technique of deconvolution analysis.RESULTS The peak GH secretion rate following the first intravenous bolus of hexarelin was greater than that following the first bolus of GHRH‐(1–29)‐NH2(P < 0.001), and was greatest following the administration of hexarelin with GHRH‐(1–29)‐NH2(P < 0.001). The coadministration of the two secretagogues resulted in peak GH secretion rates significantly greater than the arithmetic sum of those following their isolated administration (P = 0.001), demonstrating synergism. Compared to saline, the administration of a second bolus of hexarelin, GHRH‐(1–29)‐NH2or both resulted in significant further GH secretion (P = 0.02,P = 0.002,P = 0.03, respectively).The administration of a second bolus of hexarelin or hexarelin with GHRH‐(1–29)‐NH2120 minutes after the first bolus resulted in lower peak GH secretion rates (P = 0.03). The reductions in peak GH secretion rates following the 60‐minute boluses were not statistically significant. The peak GH secretion rates following the first GHRH‐(1–29)‐NH2boluses were similar to those following the 60 and 120‐minute GHRH‐(1–29)‐NH2boluses (P = NS). Irrespective of the interval between the boluses of hexarelin with GHRH‐(1–29)‐NH2, the peak GH secretion rates following the second boluses were not significantly different from the arithmetic sum of those following the administration of the second boluses of hexarelin or GHRH‐(1–29)‐NH2, indicating loss of synergism on repeated administration.CONCLUSIONS This study shows that hexarelin is a potent GH secretagogue active after two successive doses; the magnitude of the GH response to the second dose was influenced by the dosing interval. Hexarelin and GHRH‐(1–29)‐NH2are synergistic, a property which is lost after repeated administration. These findings may help

ISSN:0300-0664    

DOI:10.1046/j.1365-2265.1996.722543.x

出版商:Blackwell Science Ltd    

年代:1996

数据来源: WILEY

摘要:

OBJECTIVE Changes in calcium homeostasis and bone mass around the climacteric are poorly understood. We examined relations between endocrine factors and indices of bone mass and metabolism in healthy women approaching the menopause.DESIGN Cross‐section study.PATIENTS Sixty‐eight spontaneously menstruating women aged 45–55.MEASUREMENTS Bone density measured at lumbar spine (LS) and femoral neck (FN) using dual energy X‐ray absorptiometry and distal non‐dominant forearm using peripheral quantitative computed tomography. We recorded menstrual history, physical activity and dietary calcium, and measured serum calcium, phosphate, alkaline phosphatase, osteocalcin, vitamin D, fT3, T4, TSH, PTH, FSH and oestradiol (E2), and urinary pyridinoline (PYD) and deoxypyridinoline (DPD) excretion.RESULTS Using serum FSH level as a marker of ovarian function, 63 subjects could be classified into one of three groups: group A (serum FSH35 U/l,n = 7). Bone density fell with declining ovarian function at the LS, FN and forearm trabecular (but not cortical) sites. Serum PTH was lower in group AvsB (mean (SD) 2.68 (0.97)vs3.52 (1.17) pmol/l,P < 0.05), but similar to group C (2.90 (1.09) pmol/l,P = NS). Serum phosphate was elevated in group C compared to groups A and B (1.17 (0.15)vs1.04 (0.11) and 1.05 (0.13) mmol/l,P < 0.05), and urinary PYD (61.1 (8.0)vs50.4 (11.6) and 43.9 (8.1) μmol/mol creatinine) and DPD (15.9 (3.9)vs12.0 (3.6) and 11.4 (3.6) μmol/mol creatinine) excretion were also increased. There were no significant differences in vitamin D metabolites or osteocalcin. Multivariate analysis suggested serum osteocalcin was positively related to physical activity and serum 1,25‐dihydroxycholecalciferol levels. Serum free T3 was positively correlated with urinary DPD excretion, and inversely related to serum PTH. In all subjects, serum PTH was related to body weight (r = 0.38,P = 0.002).CONCLUSIONS Declining ovarian function before menopause is accompanied by reductions in bone mass and altered calcium metabolism. Free T3

ISSN:0300-0664    

DOI:10.1046/j.1365-2265.1996.717539.x

出版商:Blackwell Science Ltd    

年代:1996

数据来源: WILEY

摘要:

OBJECTIVE The polycystic ovarian syndrome is frequently associated with human infertility and is a partially characterized syndrome of unknown aetiology. The aim of this study was to describe the functional integrity of granulosa cells from polycystic ovaries.PATIENTS Follicular aspirates were collected from polycystic ovaries of ovulatory (n = 24) and anovulatory (n = 7) patients. Follicular aspirates were also collected from normal ovaries of untreated (n = 24) and superovulated (n = 10) subjects. All patients were enrolled for the recovery of their oocytes forin vitromaturation and fertilization.MEASUREMENTS FSH receptors and apoptosis were measured in the granulosa cells of the different patients. FSH‐stimulated oestradiol and LH‐stimulated progesterone production by granulosa cells of the different patients were also measured.RESULTS The binding of125I‐labelled human recombinant FSH to granulosa cells from anovulatory subjects with polycystic ovaries was significantly higher than that found in granulosa cells from normal (180%) and superovulated (163%) ovaries. However, the ligand binding to granulosa cells from ovulatory subjects with polycystic ovaries was not significantly higher than that found in normal granulosa cells. Also, granulosa cells obtained from anovulatory subjects with polycystic ovaries cultured with FSH produced more oestradiol than normal granulosa cells but oestradiol production was similar to that of granulosa cells from superovulated ovaries (mean ± SEM, 244.94 ± 22.02, 24.23 ± 2.92, 211.87 ± 50.39 nmol/l/24 h, respectively). Flow cytometric analysis showed that the proportions of viable and apoptotic granulosa cells (mean ± SDM, 70 ± 5 and 7 ± 1%, respectively) were similar in normal subjects and in those with polycystic ovaries.CONCLUSION We conclude that most of the granulosa cells of polycystic ovaries are healthy and non‐apoptotic, expressing high levels of FSH receptors and highly responsive to this hormone in culture. These data provide direct e

ISSN:0300-0664    

DOI:10.1046/j.1365-2265.1996.724545.x

出版商:Blackwell Science Ltd    

年代:1996

数据来源: WILEY

摘要:

OBJECTIVE The use of GnRH agonists for desensitization of the pituitary is widespread in gynaecological practice. For indications such as contraception and treatment of uterine leiomyomata partial desensitization may suffice. With respect to partial desensitization of the pituitary we have addressed three basic questions: (1) Is the degree of pituitary desensitization dependent on the dose of agonist used? (2) What is the optimal way to measure the degree of pituitary desensitization? (3) Is it possible to create a standard to express the degree of pituitary desensitization?DESIGN AND PATIENTS Twenty‐four women were randomized into 4 groups of 6 women. To achieve pituitary desensitization, the groups received 0.1, 0.25, 0.5 and 1.0 μg/min GnRH respectively, for 6 weeks.MEASUREMENTS Pituitary desensitization was measured by gonadotrophin levels and responses to a 100‐μg bolus of GnRH and an oestradiol benzoate challenge‐test.RESULTS The level of LH and the responses of LH and FSH to the GnRH challenge showed significant dose‐dependent suppression. Multiple regression indicated the LH response to the GnRH challenge was the best way to measure pituitary desensitization. From the LH responses to the GnRH‐challenge a ‘standard curve’ was established for the assessment of the degree of pituitary desensitization.CONCLUSION The LH response to the GnRH challenge test is the best available measure of pituitary desensitization du

ISSN:0300-0664    

DOI:10.1046/j.1365-2265.1996.730551.x

出版商:Blackwell Science Ltd    

年代:1996

数据来源: WILEY