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OBJECTIVE Levels of IGFI have been shown to be low in transfusion-dependent thalassaemia and there is preliminary evidence to suggest that this may be reversed by GH treatment. In this further study we have evaluated serum growth hormone (GH) binding protein (GHBP), IGF-I and IGFBP-3 in patients with β-thalassaemia major and the effects of GH treatment on these various parameters. PATIENTS Fifty-six transfusion dependent patients with β-thalassaemia major without GH deficiency between 2 and 20 years of age were studied. Thirteen non-GH deficient patients with heights of −1.5 SD or more were treated with GH at a dose of 0.14 IU/kg/day subcutaneously for 1 year. MEASUREMENTS Serum GHBP, IGF-I and IGFBP-3 were measured in all the patients. In the 13 patients treated with GH, these serum parameters were measured before and after 3, 6 and 12 months of treatment. RESULTS The mean serum GHBP concentrations were normal in both prepubertal and pubertal children but the serum IGF-I and IGFBP-3 concentrations were low throughout childhood and adolescence. There was a significant correlation between serum IGF-I and IGFBP-3 concentrations (r = 0.79; P = 0.0001) but there was no correlation between the height SDS of the patients with serum GHBP, IGF-I or IGFBP-3 levels. GH treatment in the 13 patients resulted in significant growth acceleration associated with a significant rise in the serum IGF-I and IGFBP-3 and a significant fall in serum GHBP concentrations. CONCLUSIONS The low serum concentrations of IGF-I and IGFBP-3 in the presence of normal GH reserve and serum GHBP concentrations in patients with β-thalassaemia suggest a state of partial GH insensitivity at the post-receptor level. This partial GH insensitivity state can be overcome by supraphysiological doses of exogenous GH. The lack of correlation of IGF-I, IGFBP-3 and GHBP with height SDS of the patients imply that the growth failure commonly observed in patients with β-thalassaemia major may not be specifically related to dysregulation of the GH–IGF-I axis. GH therapy resulted in significant increase in serum IGF-I and IGFBP-3 but a significant fall in GHBP.

OBJECTIVE: To investigate if pegvisomant treatment in acromegaly induces gradual elevations in endogenous serum growth hormone (GH) levels and if serum pegvisomant levels predict the therapeutic outcome. PATIENTS AND METHODS: Seventeen patients (6 females), mean age 46.3 years (range: 23.2-76.2), were studied. For each patient, four hospital visits were identified including "active disease" (no treatment) and last follow up. At each visit, 12 blood samples were drawn during 3 hours including an oral glucose tolerance test (OGTT). Eight patients received a somatostatin analogue in addition to pegvisomant on the last visit. RESULTS: Median (range) pegvisomant doses (mg/d) were 10 (10-10), 15 (10-15), and 15 (10-15) at visit 2, 3, and 4, respectively, and the mean duration of pegvisomant treatment was 17.5±3.2 (sem) months. Serum IGF-I changed significantly during the treatment period with the highest level at baseline and lowest levels at visit 3 and 4. GH levels increased in a dose dependent manner during pegvisomant treatment and decreased at visit 4. Changes in IGF-I levels correlated negatively with changes in serum pegvisomant levels between visits. Serum pegvisomant at each visit correlated with baseline growth hormone levels, whereas no associations between serum pegvisomant and either dose, gender, age, or body weight were found. CONCLUSIONS: 1) Serum GH levels increased initially, but remained stable during prolonged pegvisomant treatment in acromegalic patients, 2) Serum pegvisomant levels predicted the reduction in serum IGF-I during treatment, 3) The inter-individual variation in serum pegvisomant levels seems not predicted by either age, gender or body composition. This article is protected by copyright. All rights reserved.

ummary. objectives To establish a normal range for urinary growth hormone in adults and to investigate the urinary growth hormone levels in patients with acromegaly, comparing these with the serum growth hormone results of a glucose tolerance test. We also studied the molecular Identity of the growth hormone recognized by our assay method. design Overnight urine samples and, in some cases, timed urine samples taken during the day were obtained from healthy volunteers and acromegalic patients. A standard glucose tolerance test with serum growth hormone measurements was performed on the acromegalic patients. patients One hundred and thirty-five normal adults and 33 acromegalic patients were studied. measurements Urinary growth hormone was measured using a sensitive and precise assay developed previously. RESULTS in healthy volunteers overnight urinary growth hormone values fell gradually with increasing age, but there was no significant difference between men and women in any decade or between smokers and non-smokers. Sexual intercourse had no detectable effect on the values, but there was a large increase following strenuous exercise. Studies of the diurnal patterns in normal and abnormal adults suggested that it might be possible to diagnose acromegaly on a random urine sample. Gel filtration studies on a urine sample from an acromegalic patient showed a single peak of molecular weight 22000. Using overnight collections there was clear discrimination between the values given by the normal adults and the acromegalic patients and an excellent correlation between urinary growth hormone levels in acromegatlc patients and the mean serum growth hormone in a glucose tolerance test. conclusions in contrast to some other groups we conclude that urinary growth hormone provides a useful, non-invasive screening test for acromegaly, but this conclusion depends crucially on the assay being sensitive and precise at low values.

OBJECTIVES We compared a sensitive assay for GH (ELISA) with a conventional immunoradiometric (IRMA) assay with particular reference to the oscillatory activity detected by Fourier transformation and the estimation of trough concentrations using occupancy analysis. DESIGN Eight healthy adult male volunteers underwent 24-hour profiles during which samples were drawn at 20-minute intervals. Samples were analysed by an ELISA and an IRMA system. MEASUREMENTS The 24-hour serum GH concentration profiles were subjected to Fourier transformation and to occupancy analysis. RESULTS No additional GH periodicities could be determined in the ELISA data other than the well documented 180–200-minute periodicity. Median observed concentrations (OC) at 5% occupancy were 0.035 mU/l (range 0.004–0.22) for the ELISA and 0.035 mU/l (range 0.001–0.50) for the IRMA. For all OC parameters, 5,50 and 95%, there was a good correlation between the ELISA and IRMA systems. The mean difference (bias) between the ELISA and IRMA were - 0.05, - 0.28 and -1.40 mU/l at OC values of 5, 50 and 95% respectively and the standard deviations of the difference at the same OC values were 0.10, 0.50 and 1.61 mU/l. CONCLUSION Although there is a qualitative improvement on visual inspection of individual 24-hour serum GH profiles obtained using the ELISA system, there is little additional information gained in terms of pulse periodicity or occupancy analysis.

Summary. objective The effects of sex and age on serum growth hormone binding protein (GHBP) levels during adulthood were investigated. design The levels of GHBP, insulin-like growth factor-I (IGF-1), and growth hormone (GH) were determined and analysed as a function of sex and age. patients We studied 101 normal adults (45 men, aged 20–77 years; 56 women, aged 20–80 years). measurements GHBP levels were determined using an Ultrogel AcA 44 minicoiumn. results During the second and third decade, GHBP levels were not different between men (22.8±1.1%) (mean ± SE) and women (23.2±0.8%). After the age of 40 years, however, GHBP levels in men were significantly decreased (19.1 ± 0.7%), and were lower than those in women (22.7±0.9%). IGF-I levels correlated positively with GHBP levels in men (r= 0.51, P < 0.01) but not in women (r= 0.16, NS). conclusions These results indicate that both sex and age may have some effects on the GH-GH receptor-IGF-I axis.

We have studied the serum growth hormone (GH) response to two consecutive doses of growth hormone releasing hormone (GHRH) (50, 100, 200 micrograms) given 1, 2 or 3 h apart in seven adult males. The serum GH profile was analysed by deconvulution incorporating a variable half-life for GH. All three doses of GHRH stimulated maximal GH secretion: 50 micrograms, 146.0 mU/min (SEM 24.0); 100 micrograms, 128.1 mU/min (SEM 14.3); 200 micrograms, 134.1 mU/min (SEM 20.5) (one-way ANOVA, P = NS). The magnitude of the second secretory burst after the second dose of GHRH was less than that induced by the first injection of GHRH, particularly when doses of 200 micrograms were used. Factors influencing the response to the second dose were the GH secretory status at the point that the stimulus was applied and the time interval between administration of the first and second doses. These studies demonstrate that the pituitary gland is capable of responding to two consecutive doses of GHRH although the second response is always less than the first. The data demonstrate the importance of using methods of assessing GH secretion and not relying simply on measured serum GH concentration values.

SUMMARY. Serum growth hormone (GH) behaviour after levodopa administration was measured in twelve healthy subjects both in basal conditions and after a 4 day course of pimozide (4 mg daily), a specific blocker of dopamine (DA) receptors. In addition, fasting plasma GH was measured on the first, second and third day of treatment. No significant difference was found between GH response to levodopa in basal conditions and after pimozide; moreover, fasting GH was uninfluenced by pimozide.

In normal women, intravenous injection of the H2-antihistamine, cimetidine, provoked a 3-4 fold rise in serum prolactin, without changes in serum growth hormone, thyrotrophin, or gonadotrophins. Hyperprolactinaemic patients with pituitary tumours, idiopathic hyperprolactinaemia or hypothalamic lesions demonstrated little or no rise in serum prolactin (expressed as a percentage increment) in response to cimetidine; these responses were significantly more blunted than the prolactin responses to intravenous TRH in the same subjects. Post-partum women also demonstrated blunted percentage prolactin responses to cimetidine, although responses to TRH were, in most patients, normal. Dynamic testing of prolactin secretion with cimetidine is no more useful than TRH in distinguishing tumourous from non-tumourous hyperprolactinaemia.

SUMMARY Nine acromegalic patients were treated by the somatostatin analogue SMS 201–995 octreotide (Sandostatin (octreotide), Sandoz, Basle, Switzerland)) 250 μg/ day in 4 divided s.c. injections (50 + 50 + 50 +100 μg) for 1 month, 250 μg/24 h as continuous s.c. infusions for another month and thereafter 200 μg three times daily as s.c. injections. Echocardiography was performed before the treatment, following 1 month of octreotide s.c. infusion/injection and after 6 and after 12 months of octreotide treatment. No differences in serum growth hormone, heart rate, blood pressure, cardiac contractility or left ventricular wall mass or wall thickness were found between the infusion and the injection periods. As compared to the pretreatment levels serum growth hormone decreased by 62 and 66%, respectively following 6 and 12 months octreotide treatment. The heart rate per minute (± SD) decreased from the pretreatment level of 75 ± 12 to 63·13 (P> 0.007) at month 12. The systolic and the diastolic blood pressure decreased from the pretreatment level of 121 ± 8 and 79 ± 5 mmHg respectively to 108 ± 7 (P> 0.0007) and 71 ± 7 mmHg (P> 0.0001) respectively at month 12. The left ventricular wall thickness was reduced from 26 ± 3 mm before treatment to 24 ± 3 mm (P> 0.05) at month 6 and to 24 ± 4 mm (P> 0.04) at month 12. The left ventricular wall mass was 168 ± 48 g/m2 before octreotide treatment, 156 ± 46 g/m2 (NS) after 6 months and 157 ± 52 g/m2 after 12 months (P> 0.08) of octreotide treatment. In age and sex-matched normal control subjects the left ventricular wall thickness was 20 ± 2 mm, and the left ventricular wall mass was 122 ± 26 g/m2. The wall thickness and the wall mass were increased in the acromegalic patients as compared to the controls before and following the octreotide treatment periods. We suggest that reduction of serum growth hormone levels by octreotide in acromegalic patients is associated with a decrease of the left ventricular wall thickness, but the wall thickness is not reduced to levels of normal control subjects.

SUMMARY A continuous blood sampling technique has been used to monitor human growth hormone (GH) during sleep in fourteen normal short children (age range 6.5-15.0 years), twelve hypopituitary children (2.8-17.3 years), three children with psychosocial GH deficiency (4.0-13.0 years), and three children with intrauterine growth retardation (9.5-11.3 years). The mean GH level of a 5 h sleep period (22.30-03.30 hours) was used to represent the GH response to sleep. The GH response to insulin induced hypoglycaemia (IST) was also determined. In normal short children there was a significant relationship between 5 h mean GH levels and chronological age. The curve defining this relationship was similar to the third centile linear growth velocity curve. The 5 h mean GH levels of the hypopituitary and psycho-social GH deficiency children were more than 2 SD below the age related mean established for normal short children. The children with intrauterine growth retardation demonstrated values which were more than 2 SD above the age related mean. The evaluation of serum growth hormone (GH) during sleep, has recently been used as a test of pituitary function in growth retarded children (Eastman & Lazarus, 1973; Wise et al., 1975). Interpretation of the response is difficult because normal GH values during sleep have not been established. We have used a continuous blood sampling technique to define the range of nocturnal GH levels for normal short children. The sleep GH response of children with hypopituitarism, psychosocial GH deficiency and intrauterine growth retardation (IUGR) has been similarly investigated and is reported with reference to the range established for normal short children.

Serum growth hormone binding protein (GHBP) activity was estimated in healthy neonates (n = 6), children and adolescents (n = 97) and young adults (n = 19). GHBP activity was measured by incubating 125I-hGH (human growth hormone) (approximately 25,000 c.p.m.) with serum (100 microliters) in the presence and in the absence of excess unlabelled hGH, followed by separation of specifically bound 125I-hGHBP complexes from free 125I-hGH by gel filtration on Ultrogel AcA44 minicolumns. The results are expressed as the percentage specific binding relative to an adult reference serum (%RSB), after correction for endogenous hGH of the unknown serum. The between-assay coefficients of variation for two sera of %RSB activity of 51.2 and 115.4% were 6.0 and 7.0% respectively. In neonates, low values of serum GHBP were found (%RSB = 27.1 +/- 5.0 SEM) followed by a major rise during the first 6 years of life to a mean value (%RSB = 68.3 +/- 4.1 SEM) which more than doubled that of neonates. Thereafter, values rose progressively throughout childhood and puberty to reach maximum values in young adults (%RSB = 95.0 +/- 3.1 SEM). A novel observation was that serum GHBP activity correlated significantly with height standard deviation score (SDS) (males: r = 0.77, P less than 0.001; females: r = 0.56, P = 0.01) and weight SDS (P less than 0.001) for both sexes before puberty. During puberty GHBP correlated only with weight SDS in males (r = 0.60, P less than 0.01). In all age groups studied, no correlation could be found between serum GHBP and height velocity.

Apomorphine hydrochloride (0.75 mg s.c.) has been compared with L-dopa (500 mg p.o.) in their effects on growth hormone secretion in a double blind cross-over study involving nine healthy men. Apomorphine increased serum GH levels above 10 ng/ml in all nine subjects 30-60 min after injection. In contrast, only six of these subjects showed a similar elevation with L-DOPA and in only three had the level increased above 6 ng/ml by 60 min. One subject failed to respond to L-dopa and in two others the peak was less than 6 ng/ml. GH levels were significantly higher at 30, 45 and 60 min following apomorphine than following L-dopa. Apomorphine-induced GH release was not related to changes in serum cortisol or blood sugar. Benztropine mesylate (1 mg i.m.) had no effect on apomorphine-induced GH release. These results suggest: (a) apomorphine may have advantages over L-dopa as a provocative agent to assess GH secretory capacity; (b) a dopaminergic mechanism subserves GH secretion; (c) cholinergic mechanisms do not antagonize dopaminergic-related GH release.

Cabergoline, the new long-acting dopaminergic ergoline derivative, was given orally in single doses of 0.3 and 0.6 mg to eight dopamine-responsive acromegalic patients. Serum GH and PRL levels were determined before treatment, 3, 4, and 6 h and 1, 3, 5, 7 and 14 days after treatment. A control test with a single oral dose of 2.5 mg of bromocriptine was also performed. Cabergoline induced a marked fall in serum PRL level, starting within 3 h and continuing for 7 days after administering 0.3 mg, and for 14 days after 0.6 mg. The mean maximal decrease was 49% after 0.3 mg and 63% after 0.6 mg and occurred after 24 h in both cases. The latter was of similar magnitude to that induced by bromocriptine (67% at 4 h). Serum GH levels did not change after 0.3 mg of cabergoline, but decreased significantly from 3 h to 3 days after 0.6 mg of the compound with a mean maximal decrease of 42% after 24 h, and from 3 to 6 h after giving bromocriptine (mean maximal decrease 63% at 4 h). Once a week repeated administration of 0.3-0.6 mg of cabergoline was carried out in six patients, five of whom had completed the acute study; a normalization of serum GH and insulin-like growth factor I (IGF-I) levels occurred in three patients, one of whom had very high pretreatment values. In three poorly or nonresponsive patients, a better response, as assessed by both GH and IGF-I levels, was induced by increasing the dose up to 0.6 mg twice or 0.4 mg three times a week; in one case this was associated with marked tumour shrinkage. Sustained normalization of PRL levels was achieved in all cases. These data indicate that a single dose of 0.6 mg of cabergoline inhibits GH as well as PRL secretion in dopamine-responsive acromegalic patients and suggests that doses of 0.3-0.6 mg once to three times a week may prove suitable for treatment of this condition.