Low-dose growth hormone-releasing hormone tests: a dose-response study

We have evaluated parameters of the serum growth hormone (GH) concentration response to saline and 1-, 10- and 100-micrograms intravenous bolus doses of amide analogue of GH-releasing hormone (GHRH (1-29)NH2) given in random order to 10 adult male volunteers of median body weight 68 (60-90)kg. Compared with saline, both 10- and 100-micrograms GHRH(1-29)NH2 doses (but not 1 microgram) resulted in significant peak GH responses (means and 95% confidence intervals: 24.03 (11.22-51.29) vs 26.09 (16.40-41.50) mU/l, respectively). Although the average rate of serum GH rise was similar after both 10 micrograms (2.05 (1.13-2.97) mU.l-1.min-1) and 100 micrograms of GHRH(1-29)NH2 (1.52 (0.69-2.35) mU.l-1.min-1; ANOVA F = 0.93, p = 0.35), the average rate of serum GH decline after peak GH was slower after the higher dose (10 micrograms vs 100 micrograms: 0.65 (0.40-0.90) vs 0.37 (0.23-0.50) mU.l-1.min-1; ANOVA F = 5.14, p = 0.04), suggesting continued GH secretion. Increasing GHRH(1-29)NH2 doses delayed the time to peak GH (1 microgram: 7.00 (3.50-10.52) min; 10 micrograms: 15.80 (13.62-17.98) min; 100 micrograms: 24.80 (18.40-31.12) min) and serum GH levels were still elevated significantly 2 h after injection of 100 micrograms GHRH(1-29)NH2 compared with other doses (saline: 0.98 (0.48-2.04) mU/l; 1 microgram: 0.68 (0.48-0.93) mU/l; 10 micrograms: 1.07 (0.56-2.04) mU/l; 100 micrograms: 5.01 (2.34-10.86) mU/l; ANOVA F = 11.10, p < 0.001). In a second study we tested five adult male volunteers with lower doses (0.5-10 micrograms) of GHRH(1-29)NH2.(ABSTRACT TRUNCATED AT 250 WORDS)     

The growth hormone response to hexarelin in patients with Prader-Willi syndrome

Hexarelin (Hex) is a synthetic hexapeptide with potent GH-releasing activity in both animals and men. Aim of this study was to evaluate the GH response to a maximal dose of Hex and GH-releasing hormone (GHRH) in a group of patients with Prader-Willi syndrome (PWS). Seven patients (4 boys and 3 girls, age 2.4-14.2 yr) with PWS, 10 prepubertal obese children (7 boys and 3 girls, age 7.5-12.0 yr), and 24 prepubertal short normal children (11 boys and 13 girls, age 5.9-13 yr) with body weight within +/- 10% of their ideal weight were studied. All subjects were tested on two occasions with GHRH 1-29 at the dose of 1 microgram/Kg i.v., and with Hex at the dose of 2 micrograms/Kg i.v. In the PWS patients the GH response to GHRH (peak = 6.4 +/- 2.0 micrograms/l, p < 0.0001; AUC = 248 +/- 70 micrograms min/l, p < 0.0001) was significantly lower than that observed in the short normal children and similar to that observed in the obese children. In the PWS children the GH response to Hex (peak = 7.5 +/- 1.6 micrograms/l; AUC = 309 +/- 53) was similar to that observed after GHRH and significantly lower than that observed in the obese children (p < 0.05). The results of this study show that PWS patients have a blunted GH response to the administration of a maximal dose of Hex. Whether these findings reflect a more severe pituitary GH deficiency in PWS than in obese children or a deranged hypothalamic regulation of GH secretion need further investigation.     

Evidence for an inhibitory effect of physiological levels of insulin on the growth hormone (GH) response to GH-releasing hormone in healthy subjects

It has been previously reported that in healthy subjects, the acute reduction of free fatty acids (FFA) levels by acipimox enhances the GH response to GHRH. In the present study, the GH response to GHRH was evaluated during acute blockade of lipolysis obtained either by acipimox or by insulin at different infusion rates. Six healthy subjects (four men and two women, 25.8 +/- 1.9 yrs old, mean +/- SE) underwent three GHRH tests (50 micrograms iv, at 1300 h) during: 1) iv 0.9% NaCl infusion (1200-1500 h) after oral acipimox administration (250 mg) at 0700 h and at 1100 h; 2) 0.1 mU.kg-1.min-1 euglycemic insulin clamp (1200-1500 h) after oral acipimox administration (250 mg at 0700 h and at 1100 h); 3) 0.4 mU.kg-1.min-1 euglycemic insulin clamp (1200-1500 h) after oral placebo administration (at 0700 and 1100 h). Serum insulin (immunoreactive insulin) levels were significantly different in the three tests (12 +/- 2, 100 +/- 10, 194 +/- 19 pmol/L, P < 0.06), plasma FFA were low and similar (0.04 +/- 0.003, 0.02 +/- 0.005, 0.02 +/- 0.003, not significant), and the GH response to GHRH was progressively lower (4871 +/- 1286, 2414 +/- 626, 1076 +/- 207 micrograms/L 120 min), although only test 3 was significantly different from test 1 (P < 0.05). Pooling the three tests together, a significant negative regression was observed between mean serum immunoreactive insulin levels and the GH response to GHRH (r = -0.629, P < 0.01). Our results indicate that in healthy subjects, acipimox and hyperinsulinemia produce a similar decrease in FFA levels and that at similar low FFA, the GH response to GHRH is lower during insulin infusion than after acipimox. These data suggest that insulin exerts a negative effect on GH release. Because the insulin levels able to reduce the GH response to GHRH are commonly observed during the day, for instance during the postprandial period, we conclude that the insulin negative effect on GH release may have physiological relevance.     

Growth hormone responses to growth hormone-releasing hormone and clonidine before and after erythropoietin therapy in CAPD patients

Correction of anemia with recombinant human erythropoietin (rhEPO) in patients with end-stage renal disease has been associated with improvement of several abnormalities in hypothalamo-hypophyseal functions. The aim of the present work was to evaluate the growth hormone (GH) responses to GH-releasing hormone (GHRH) and clonidine stimulation, as well as the baseline concentrations of insulin-like growth factor I(IGF-I), before and after the correction of anemia with rhEPO in a group of uremic patients undergoing continuous ambulatory peritoneal dialysis (CAPD). Nine clinically stable patients (1 male, 8 female; mean age 55.4 years; mean duration of CAPD 14.1 months) were studied. Twelve normal volunteers were studied as controls. GHRH and clonidine stimulation tests were performed prior to starting rhEPO and again after partial correction of anemia with rhEPO therapy (60-130 U/kg/week, s.c., for 12 weeks). Blood samples for GH were collected during 2 h after GHRH (100 micrograms i.v. in bolus) or clonidine (0.15 mg/m2, p.o.) administration. In basal plasma samples IGF-I concentrations were also measured. Mean (+/- SEM) blood hemoglobin concentration rose from 5.32 +/- 0.25 to 7.22 +/- 0.25 mmol/l (p < 0.001) after rhEPO treatment. GH responses to GHRH were characterized by marked differences in single patients when compared with the control group. However, the GH peak and the area under the secretory curves (AUC) of GH responses in CAPD patients (9.89 +/- 4.01 micrograms/l and 15.06 +/- 6.02 micrograms.h/l, respectively) did not differ from those obtained in control subjects (14.58 +/- 3.25 microgram/l and 16.94 +/- 4.31 microgram.h/l, respectively). The study after correction of anemia showed an evident potentiation of GH values that reached statistically significant values at 60 and 90 min. GH AUC after rhEPO therapy rose to 25.61 +/- 9.25 micrograms.h/l (p = 0.01). In control subjects, clonidine administration was followed by a GH release that reached a maximum at 90 min (7.67 +/- 2.24 micrograms/l). However, CAPD patients exhibited a blunted response to clonidine both before (2.00 +/- 0.78 microgram/l) and after (2.78 +/- 0.76 microgram/l, NS) correction of the anemia with rhEPO. On the other hand, IGF-I concentrations after rhEPO therapy (32.05 +/- 5.52 nmol/l) were not significantly different from those found prior to starting therapy (38.13 +/- 8.44 nmol/l). In conclusion, these results suggest that correction of the anemia with rhEPO therapy potentiates GH responses to direct pituitary stimulation with GHRH although it is unable to restore the blunted response of GH to clonidine that is found in CAPD patients.     

Impairment of growth hormone responsiveness to growth hormone releasing hormone and pyridostigmine in patients affected by Prader-Labhardt-Willi syndrome

In order to evaluate the impairment of GH response in patients affected by Prader-Labhardt-Willi (PLW) syndrome, in 18 patients we studied GH response to clonidine and to GHRH + pyridostigmine, a cholinergic drug which enhances GHRH induced GH responsiveness in obese patients. After clonidine GH response was abnormal in 14/18 subjects (mean GH peak: 4.1 +/- 1.3 micrograms/l; area under curve: 208.1 +/- 74.2 micrograms/l.h) while all but 5 patients showed an inadequate GH response to GHRH + pyridostigmine (mean GH peak: 13.4 +/- 2.5 micrograms/l; area under curve: 903.4 +/- 171.0 micrograms/l.h). However, in the three patients with low adiposity index, GH response to GHRH + pyridostigmine was significantly higher than that observed in fatter subjects. In addition, GH response to GHRH + pyridostigmine was negatively correlated to age and adiposity index. In conclusion, our data are consistent with the hypothesis of the existence of a complex derangement of GH neuroendocrine regulation in these subjects.     

Hot water swallows improve symptoms and accelerate esophageal clearance in esophageal motility disorders

The mechanism of action of the synthetic growth hormone (GH)releasing peptide hexarelin is not yet fully understood. Although a direct effect on pituitary cells has been demonstrated, the peptide is also active at hypothalamic level, where specific binding sites have been found. The observation that hexarelin acts synergistically with GH-releasing hormone (GHRH) in releasing GH has suggested that it might suppress endogenous somatostatin secretion. As somatostatin is also inhibitory on TSH secretion, to verify the occurrence of modifications of the somatostatinergic tone induced by hexarelin, we studied its effects on TRH-induced TSH secretion. Seven normal subjects (4 women and 3 men aged 24-29 years) underwent the following tests on 3 different days: a) TRH (200 micrograms/l i.v.) + placebo; b) hexarelin (1 microgram/Kg bw i.v.) + placebo c) combined TRH + hexarelin administration. Hexarelin induced significant and similar increases in serum GH levels when given in combination either with placebo or with TRH (1217 +/- 470 vs 986 +/- 208 micrograms/min/l p:NS), while no modifications of GH levels were seen after TRH + placebo. Serum TSH levels were unmodified by hexarelin + placebo injection. The TSH increase elicited by hexarelin + TRH was superimposable to that elicited by TRH + placebo (1124 +/- 530 and 1273 +/- 380 mU/min/l respectively). Circulating PRL levels slightly increased after hexarelin + placebo too (897 micrograms/min/l), and the PRL response to hexarelin + TRH was slightly, although not significantly, greater than that observed after TRH + placebo (2680 +/- 1517 and 2243 +/- 1108 micrograms/min/l, respectively). In conclusion, our data show that hexarelin does not alter basal and TRH-stimulated TSH secretion, thus suggesting that it does not inhibit somatostatin release. Furthermore a modest PRL-releasing effect of this peptide has been confirmed.     

UK study of intrapartum care for low risk primigravidas: a survey of interventions

GH-releasing peptides (GHRPs) and their non-peptidly mimetics are synthetic molecules which possess marked, dose-related and reproducible GH-releasing effect even after oral administration. Their potent stimulatory effect on GH secretion suggested that GHRP could be useful as provocative test on the diagnosis of GH deficiency. We compared the GH response to the maximal effective dose of Hexarelin (2 micrograms/kg i.v.), an hexapeptide belonging to GHRP family, with that of GHRH (1 microgram/kg i.v.) alone and combined with arginine (ARG, 0.5 g/kg i.v.), which likely acts via inhibition of hypothalamic somatostatin release. We studied 6 prepubertal (4 boys and 2 girls, age 2.6-12.2 yr) and 6 pubertal children with normal short stature (3 boys and 3 girls, age 10.3-14.4 yr) as well as 12 normal young adults (6 males and 6 females, age 22-30 yr) and 12 normal elderly subjects (6 males and 6 females, age 53-79 yr). In prepubertal children, the GH response to HEX (19.0 +/- 4.6 micrograms/l; 611.5 +/- 121.4 micrograms/l/h) was lower than that to GHRH (27.4 +/- 12.7 micrograms/l; 1209.0 +/- 590.9 micrograms/l/h) but this difference did not attain statistical significance. Both these responses were, in turn, lower (p < 0.05) than that to ARG + GHRH (57.9 +/- 15.1 micrograms/l; 2483.6 +/- 696.6 micrograms/l/h). In pubertal children, the GH response to HEX (67.6 +/- 12.7 micrograms/l; 2755.3 +/- 547.3 micrograms/l/h) was higher than that to ARG + GHRH (49.1 +/- 8.9 micrograms/l; 2554.1 +/- 356.6 micrograms/l/h) but this difference did not attain statistical significance; both these responses were, in turn, clearly higher (p < 0.05) than that to GHRH alone (23.1 +/- 7.9 micrograms/l; 1004.8 +/- 214.3 micrograms/l/h). In young adults, the GH response to HEX 60.9 +/- 8.0 micrograms/l; 2401.0 +/- 376.2 micrograms/l/h) was similar to that to ARG + GHRH (68.9 +/- 11.7 micrograms/l; 3035.7 +/- 466.6 micrograms/l/h) and both were clearly higher (p < 0.001) than that to GHRH alone (21.6 +/- 3.6 micrograms/l; 790.0 +/- 137.0 micrograms/l/h). In elderly subjects, the GH response to HEX (22.4 +/- 4.9; 855.0 +/- 199.0 micrograms/l/h) was higher (p < 0.01) than that to GHRH (3.6 +/- 0.8 micrograms/l; 151.8 +/- 24.6 micrograms/l/h) but lower (p < 0.05) than that to ARG + GHRH (48.1 +/- 4.6 micrograms/l; 1758.2 +/- 149.1 micrograms/l/h). In conclusion, GHRPs are a powerful stimulus of GH secretion in pubertal children and young adults only. On the other hand, the age-related variations in the GH response to GHRPs probably limit their reliability for the evaluation of GH releasable pool in prepubertal children and elderly subjects.     

Vasoactive intestinal peptide-induced prolactin release in hypothyroid patients

VIP is an established prolactin-releasing factor. VIP gene expression at the anterior pituitary level and the central nervous system is regulated by thyroid hormones. On the other hand, primary hypothyroidism leads in many cases to amenorrhea, galactorrhea and hyperprolactinemia. In this study we assessed prolactin responses to VIP (75 micrograms iv infusion over 12 min) in a group of six hypothyroid women (mean age +/- SE, 38.8 +/- 3.3 yr; serum TSH levels, mU/L, 116.3 +/- 23.9), before treatment and after normalization of thyroid hormone levels during thyroxine (T4) replacement therapy (100-150 micrograms/day over 12-16 weeks). Furthermore, we assessed if VIP infusion had any effects on serum GH levels in these patients. In hypothyroid women, VIP infusion increased serum prolactin concentrations with peak levels being attained at 15 min (28.8 +/- 3.4 micrograms/L). The Area Under the Curve (AUC) was 1921 +/- 103 micrograms/L/2h. PRL responses to VIP were unchanged after T4 therapy, both in terms of peak levels (28.7 +/- 2.2 micrograms/L, NS) and of AUC (2079 +/- 261 micrograms/L/2h, NS). Serum GH levels were unaffected by VIP administration. In conclusion our study shows that, in hypothyroid patients, restoration of normal thyroid hormone levels by thyroxine replacement therapy does not affect lactotroph responsiveness to VIP. Therefore, our data do not support the hypothesis that VIP might contribute to the hypothyroid-induced hyperprolactinemia seen in man.     

Favourable effect of olive oil in patients with non-insulin-dependent diabetes. The effect on blood pressure, blood glucose and lipid levels of a high-fat diet rich in monounsaturated fat compared with a carbohydrate-rich diet

The aim of the study was to elucidate the role of the neuropeptide galanin in the regulation of somatotropic and gonadotropic function in normal women. Thirteen normally ovulating (aged 28 to 40 years), non-obese (body mass index, 18.4 to 27.1 kg/m2) women with infertility due to a tubal or male factor were studied. Each woman underwent three tests: (1) bolus intravenous (IV) injection of growth hormone (GH)-releasing hormone (GHRH) (1-29)NH2 1 microgram/kg plus gonadotropin-releasing hormone (GnRH) 100 micrograms at time 0; (2) IV infusion of porcine galanin 500 micrograms in 100 mL saline from -10 minutes; and (3) bolus IV injection of GHRH(1-29)NH2 1 microgram/kg plus GnRH 100 micrograms at time 0 plus IV infusion of porcine galanin 500 micrograms in 100 mL saline from -10 to +30 minutes. All results are expressed as the mean +/- SEM. GH peak after GHRH was 14 +/- 5 micrograms/L; porcine galanin significantly increased serum GH (GH peak, 7.3 +/- 1.2) with respect to baseline levels. No significant differences were observed between either GH peak or GH absolute values after galanin as compared with GHRH alone. Porcine galanin significantly enhanced GH response to GHRH (peak, 31.4 +/- 4.4 micrograms/L) with respect to either GHRH or galanin alone. Luteinizing hormone (LH)/follicle-stimulating hormone (FSH) peaks after GnRH were 16.5 +/- 5.3 and 17.4 +/- 4 IU/L, respectively. Porcine galanin did not cause significant increases in serum LH and FSH levels with respect to baseline.(ABSTRACT TRUNCATED AT 250 WORDS)     

Factors determining the long-term outcome of surgery for acromegaly

Seventy-nine patients with acromegaly were investigated before and after transsphenoidal adenomectomy, to determine the immediate and late outcome, the pre-operative features associated with a good result, and the accuracy of post-operative testing in predicting outcome. Pre-operative evaluation included basal growth hormone (GH), GH response to oral glucose tolerance test (OGTT), GH response to thyrotrophin-releasing hormone (TRH), tests of pituitary reserve, and pituitary scanning to assess tumour size. A few weeks after surgery, these tests were repeated. The patients were recalled for late assessment 1-13 years (median 86 months) after the operation. At the immediate postoperative testing, minimum GH after oral glucose was < or = 2 mU/l in 48.7%, < 5 mU/l in 76.3% and < 10 mU/l in 84.2%. Only 12 patients had GH > 10 mU/l. Basal GH was < or = 2 mU/l in 21%, < 5 in 59.2%, < 10 in 73.6% and < 20 in 90.8%. A minimum GH of < or = 2 mU/l during an OGTT was achieved in 67.4% of patients with intrasellar tumours, compared with 27.3% with extrasellar tumours. Basal GH and post-glucose GH correlated with the late outcome. GH response to TRH showed no correlation with outcome. IGF-1, which could not be assessed in detail, correlated with GH but was not a reliable indicator of outcome. Transsphenoidal adenomectomy is thus a very satisfactory treatment for acromegaly. Postoperative levels of basal growth hormone < 5 mU/l and post-glucose GH < or = 2 mU/l can be regarded as a biochemical cure. Postoperative radiotherapy is not required in patients who achieve a good result. The preoperative factors which significantly influenced the final outcome were basal GH, post-glucose minimum GH, tumour size and impaired pituitary reserve.     

Recombinant human erythropoietin (rhEPO) treatment potentiates growth hormone (GH) response to growth hormone releasing hormone (GHRH) stimulation in hemodialysis patients

On the basis of previously described effects of recombinant human erythropoietin (rhEPO) treatment on endocrine abnormalities present in uremia, we assessed the possible effect of treatment with rhEPO on growth hormone (GH) response to growth hormone releasing hormone (GHRH) in a group of uremic patients. Eight patients on maintenance hemodialysis for 12 to 228 months, not previously treated with rhEPO, were tested with 100 micrograms of GHRH i.v. in bolus before and after three months of rhEPO treatment (40 U/kg i.v. three times a week). Before treatment, the GH response to GHRH was characterized, in uremic patients, by remarkable differences in plasma GH values and in the pattern of response curve in single patients. The variability of GH response was not modified after rhEPO treatment; however, an overall potentiation of GH response with a significant increase of plasma GH (p = 0.017 at 15 min, p = 0.035 at 30 min after GHRH injection) was observed in the tests performed after treatment. rhEPO administration induced an evident improvement of anemia, blood hemoglobin concentration being 5.3-7.6 g/dl before and 9.1-11.3 g/dl after treatment; however a demonstrable correlation between the potentiation of GH response to GHRH and the increase of hemoglobin concentration was not observed.     

Heat loss in humans covered with cotton hospital blankets

We have studied the pharmacokinetics and the effects of BIM 23,014 (BIM), a new, long-acting octapeptide somatostatin analogue, on basal and stimulated GH secretion in normal men. BIM 250 micrograms sc significantly reduced a GHRH-induced increase in plasma GH. The continuous sc administration of BIM for 24 h dramatically blunted spontaneous GH secretion; 2000 and 3000 micrograms daily reduced GH secretion to a greater extent than 1000 micrograms daily. During these experiments a significant negative correlation (r - 0.66) was found between plasma GH and BIM levels. Acute sc administration of 1000 micrograms BIM significantly reduced the rise in plasma GH observed in the second part of the oral glucose tolerance test. Plasma BIM levels peaked around 30 min, and the elimination half life was 90 min. Plasma BIM levels were below 1 ng/ml 6 h after the injection of 1000 micrograms BIM, and at that time GH started to rise again. We conclude that BIM 23,014 250 to 1000 micrograms sc is able to reduce the plasma GH response to GHRH or to the fall in glucose following an oral glucose tolerance test; a constant infusion of BIM, in doses 1000 micrograms daily, dramatically suppresses spontaneous GH secretion; 2000 micrograms/day by chronic subcutaneous infusion was the most effective dose of BIM in the suppression of GH secretion, and was associated only with minor adverse effects.     

Treatment of vancomycin-resistant Enterococcus faecium infections with an investigational streptogramin antibiotic (quinupristin/dalfopristin): a report of fifteen cases

OBJECTIVE: Previous studies of surgical treatment for acromegaly have used varied criteria for 'cure', but elevated GH levels are considered to be associated with continuing disease activity. We wished to analyse the results of transsphenoidal pituitary surgery for acromegaly and assess the longer-term outcome for patients not offered further treatment when post-operative levels of GH < 5 mU/l were achieved. DESIGN: We studied a retrospective group of patients who underwent transsphenoidal surgery for acromegaly at St Bartholomew's Hospital between 1985 and 1993. PATIENTS: One hundred consecutive patients (53 male, mean age 46 years, range 18-68 years) undergoing transsphenoidal surgery for acromegaly were assessed. The patients were followed for a mean of 3.8 years (range 0.5-8 years) after operation. MEASUREMENTS: GH levels are represented as a mean value from a four-point day curve taken at 0830, 1300, 1700 and 1900 h. ACTH reserve was assessed basally and, if this was normal, with the insulin tolerance or glucagon tests. TSH, T4, PRL, LH, FSH, testosterone or oestradiol and plasma and urine osmolality were also measured. RESULTS: Post-operatively, 42% of patients achieved a mean GH level of < 5 mU/l. The success of surgery was related to the preoperative GH level; 65% of the patients with preoperative GH levels < 20 mU/l but only 18% of the patients with GH levels > 100 mU/l achieved post-operative GH values < 5 mU/l. In addition, tumour size influenced the outcome of surgery with 61% of patients with a microadenoma but only 23% of patients with a macroadenoma achieving post-operative GH levels of < 5 mU/l. Of the 42 patients considered in remission post-operatively (mean GH < 5 mU/l), 32 were available for long-term follow-up and were not offered any further treatment: only one of these has shown evidence of mild biochemical recurrence after a mean follow-up of 3.8 years (range 0.5-8). There were no peri-operative deaths. Two patients required surgical repair for CSF leaks and there were eight documented cases of meningitis. Permanent diabetes insipidus was noted in eight patients post-operatively. New anterior pituitary deficiency occurred in 21% of patients following surgery; 73% had unaltered pituitary function and in 6% recovery of partial hypopituitarism was noted. CONCLUSIONS: The stated outcome of surgery depends on the criteria adopted. Safe GH levels (mean levels < 5 mU/l) can be achieved in 42% of an unselected series of patients with acromegaly and if the tumour is a microadenoma this figure rises to 61%. Based on the current evidence it is safe not to offer further treatment to those patients in whom post-operative GH < 5 mU/l are achieved.     

Blur and contrast as pictorial depth cues

OBJECTIVE: Infusion of GH secretagogues appears to be a novel endocrine approach to reverse the catabolic state of critical illness, through amplification of the endogenously blunted GH secretion associated with a substantial IGF-I rise. Here we report the dynamic characteristics of spontaneous nightly TSH and PRL secretion during prolonged critical illness, together with the concomitant effects exerted by the administration of GH-secretagogues, GH-releasing hormone (GHRH) and GH-releasing peptide-2 (GHRP-2) in particular, on night-time TSH and PRL secretion. PATIENTS AND DESIGN: Twenty-six critically ill adults (mean +/- SEM age: 63 +/- 2 years) were studied during two consecutive nights (2100-0600 h). According to a weighed randomization, they received 1 of 4 combinations of infusions, within a randomized, cross-over design for each combination: placebo (one night) and GHRH (the next night) (n = 4); placebo and GHRP-2 (n = 10); GHRH and GHRP-2 (n = 6); GHRP-2 and GHRH + GHRP-2 (n = 6). Peptide infusions (duration 21 hours) were started after a bolus of 1 microgram/kg at 0900 h and infused (1 microgram/kg/h) until 0600 h. MEASUREMENTS: Serum concentrations of TSH and PRL were determined by IRMA every 20 minutes and T4, T3 and rT3 by RIA at 2100 h and 0600 h in each study night. Hormone secretion was quantified using deconvolution analysis. RESULTS: During prolonged critical illness, mean night-time serum concentrations of TSH (1.25 +/- 0.42 mlU/l) and PRL (9.4 +/- 0.9 micrograms/l) were low-normal. However, the proportion of TSH and PRL that was released in a pulsatile fashion was low (32 +/- 6% and 16 +/- 2.6%) and no nocturnal TSH or PRL surges were observed. The serum levels of T3 (0.64 +/- 0.06 nmol/l) were low and were positively related to the number of TSH bursts (R2 = 0.32; P = 0.03) and to the log of pulsatile TSH production (R2 = 0.34; P = 0.03). GHRP-2 infusion further reduced the proportion of TSH released in a pulsatile fashion to half that during placebo infusion (P = 0.02), without altering mean TSH levels. GHRH infusion increased mean TSH levels and pulsatile TSH production, 2-fold compared to placebo (P = 0.03) and 3-fold compared to GHRP-2 (P = 0.008). The addition of GHRP-2 to GHRH infusion abolished the stimulatory effect of GHRH on pulsatile TSH secretion. GHRP-2 infusion induced a small increase in mean PRL levels (21%; P = 0.02) and basal PRL secretion rate (49%; P = 0.02) compared to placebo, as did GHRH and GHRH + GHRP-2. CONCLUSIONS: The characterization of the specific pattern of anterior pituitary function during prolonged critical illness is herewith extended to the dynamics of TSH and PRL secretion: mean serum levels are low-normal, no noctumal surge is observed and the pulsatile fractions of TSH and PRL release are reduced, as was shown previously for GH. Low circulating thyroid hormone levels appear positively correlated with the reduced pulsatile TSH secretion, suggesting that they have, at least in part, a neuroendocrine origin. Finally, the opposite effects of different GH-secretagogues on TSH secretion further delineate particular linkages between the somatotrophic and thyrotrophic axes during critical illness.     

Effect of 14 days'' subcutaneous administration of the human amylin analogue, pramlintide (AC137), on an intravenous insulin challenge and response to a standard liquid meal in patients with IDDM

Individuals with insulin-dependent diabetes mellitus (IDDM or type 1 diabetes) are deficient in both insulin and amylin, peptides secreted by the beta cell. We have investigated the effects of amylin replacement therapy employing the human amylin analogue, pramlintide (25, 28, 29-pro-human amylin, previously referred to as AC137), upon the responses to a standardized insulin infusion (40 mU. kg-1. h-1) for 100 min and a liquid Sustacal meal (360 kcal) in 84 healthy IDDM patients. Following baseline evaluations, patients were randomly assigned to receive subcutaneous injections of placebo, 30, 100 or 300 micrograms pramlintide 30 min before meals for 14 days. There was no meaningful difference between adverse events reported by the 30-micrograms pramlintide and the placebo groups, but ten subjects withdrew due to nausea, eight of these in the 300-micrograms dose group. Peak plasma pramlintide concentrations for the 30-micrograms group were 21 +/- 3 and 29 +/- 5 pmol/l on Days 1 and 14, respectively. These values are similar to postprandial plasma amylin concentrations in normal volunteers. The plasma glucose, free insulin, glucagon, epinephrine and norepinephrine concentrations during the insulin infusion test before and after therapy were identical in each of the group. Prior to pramlintide therapy, Sustacal ingestion produced a 4.0-4.8 mmol/l rise in plasma glucose concentrations in each of the groups. Pramlintide therapy reduced postprandial hyperglycaemia as reflected by the 3-h incremental AUCglucose (AUCglucose above or below fasting glucose concentration) Day 1 vs Day 14: 30 micrograms, 322 +/- 92 vs -38 +/- 161 mmol/l.min, p = 0.010; 100 micrograms, 317 +/- 92 vs -39 +/- 76 mmol/l.min, p = 0.001; and 300 micrograms, 268 +/- 96 vs -245 +/- 189 mmol/l.min, p = 0.077. Thus, pramlintide therapy with these regimens did not appear to impair either in vivo insulin action or the counter-regulatory response to hypoglycaemia but did show a clear effect of blunting postprandial hyperglycaemia following a standardized meal.     

Mediation by the central nervous system is critical to the in vivo activity of the GH secretagogue L-692,585

To investigate the effect of hypophyseal transection (HST) on GH secretagogue activity of the non-peptidyl GH secretagogue L-692,585 in the conscious pig, male castrated swine were randomly assigned to either a hypophyseal stalk transection group (HST; n = 3) or to a sham-operated control group (SOC; n = 3). Treatments administered were L-692,585 (100 micrograms/kg), human GH-releasing factor(1-29)NH2 (GRF; 20 micrograms/kg) or L-692,585 (100 micrograms/kg) + GRF (20 micrograms/kg) on days -7 to -3 before surgery and days +3 to +8 after surgery. To evaluate the integrity of the pituitary gland, the animals were challenged with corticotropin-releasing hormone (CRH; 150 micrograms) or GnRH (150 ng/kg) both before and after surgery. Blood was collected from -60 to +180 min post treatment and assayed for GH, cortisol and LH. Before surgery, no significant difference (P > 0.05) in peak GH response (ng/ml) was present between the two groups (SOC vs HST) in response to L-692,585 (101 +/- 12 vs 71 +/- 9) or L-692,585 + GRF (171 +/- 21 vs 174 +/- 21). Only two out of three SOC vs three out of three HST pigs responded to GRF (13 +/- 2 vs 25 +/- 3) resulting in a significant difference between groups. Following surgery, significant differences were present in peak GH response (ng/ml) between SOC and HST groups following L-692,585 (79 +/- 6 vs 13.8 +/- 1.0); however, the response to L-692,585 + GRF was similar (115 +/- 8 vs 94 +/- 7). All animals responded to GRF; however, a significant difference was present between groups due to the magnitude of the responses. Whereas the cortisol responses (ng/ml) to L-692,585 in the SOC and HST groups were similar before surgery, a significant difference was present after surgery (44.4 +/- 6.4 vs 14.6 +/- 2.1). No significant difference was noted between the HST and SOC groups in response to CRH or GnRH either before or after surgery. These results indicated that L-692,585 induced an immediate GH response in the intact animal in contrast to GRF where the GH release was variable. L-692,585 also stimulated an immediate increase in cortisol levels. Transection of the hypophyseal stalk dramatically decreased but did not ablate the GH or cortisol response to L-692,585. Co-administration of L-692,585 + GRF induced an immediate GH response of similar magnitude in the intact and HST animal. We conclude that L-692,585 has a direct but limited action at the level of the pituitary and that an intact hypophyseal stalk is required for a maximal GH and cortisol response. L-692,585 acts with GRF at the level of the pituitary to induce a maximal GH response. These findings suggest that L-692,585 stimulates GH secretion by acting in combination with GRF and interrupting the inhibitory tone of somatostatin on the somatotroph.     

The diagnosis of malignant pleural mesothelioma]

OBJECTIVE: To investigate the existence of an opioid stimulatory tone on growth hormone (GH) secretion in the human male. DESIGN: Seven healthy male volunteers, aged 19-30, were studied in the Endocrine Unit of the University of Sassari. GH-releasing hormone (GHRH), 100 micrograms as an intravenous (IV) bolus, as administered with and without preadministration of IV naloxone, 2 mg as a bolus followed by a constant infusion of 2 mg/h. Blood samples were taken for 120 minutes after GHRH administration. RESULTS: Naloxone significantly blunted the GH response to GHRH, measured either as mean peak value (at times 30 to 90) or as integrated concentrations. CONCLUSIONS: Naloxone is able to decrease the effect of a maximal dose of GHRH, thus suggesting the existence of an opioid stimulatory tone on GH secretion.     

Developmental pattern of fetal growth hormone, insulin-like growth factor I, growth hormone binding protein and insulin-like growth factor binding protein-3

AIMS: To evaluate the developmental pattern of fetal growth hormone (GH), insulin-like growth factor I (IGF-I), GH binding protein (GHBP) and IGF binding protein-3 (IGF-3); to determine the implications for fetal growth. METHODS: Serum GH, IGF-I, GHBP and IGFBP-3 were measured in 53 fetuses, 41 aged 20-26 weeks (group A) and 12 aged 31-38 weeks (group B). Fetal blood samples were obtained by direct puncture of the umbilical vein in utero. Fetal blood samples were taken to rule out beta thalassaemia, chromosome alterations, mother to fetus transmissible infections, and for maternal rhesus factor. GHBP was determined by gel filtration chromatography of serum incubated overnight with 125I-GH. GH, IGF-I and IGFBP-3 were determined by radioimmunoassay. RESULTS: Fetal serum GH concentrations in group A (median 29 micrograms/l, range 11-92) were significantly higher (P < 0.01) than those of group B (median 16.7 micrograms/l, range 4.5-29). IGF-I in group A (median 20 micrograms/l, range 4.1-53.3) was significantly lower (P < 0.01) than in group B (median 75.2 micrograms/l, range 27.8-122.3). Similarly, IGFBP-3 concentrations in group A (median 950 micrograms/l, range 580-1260) were significantly lower than those of group B (median 1920 micrograms/l, range 1070-1770). There was no significant difference between GHBP values in group A (median 8.6%, range 6.6-12.6) and group B (median 8.3%, range 6-14.3). Gestational age correlated positively with IGF-I concentrations (P < 0.0001) and IGFBP-3 (P < 0.0001) and negatively with GH (P < 0.0001). GHBP values did not correlate with gestational age. Multiple regression analysis showed a negative correlation between GH:IGF-I ratio and fetal growth indices CONCLUSIONS: The simultaneous evaluation of fetal GH, IGF-I, IGFBP-3 and GHBP suggests that the GH-IGF-I axis might already be functional in utero. The progressive improvement in the efficiency of this axis in the last part of gestation does not seem to be due to an increase in GH receptors.     

MR findings in growth hormone deficiency: correlation with severity of hypopituitarism

BACKGROUND AND PURPOSE: Growth hormone deficiency may present as an isolated deficit (IGHD) or in association with multiple deficiencies (MPHD). Previous studies have not compared the MR imaging findings with the severity of hypopituitarism. Our purpose was to determine whether MR imaging can distinguish between IGHD and MPHD. METHODS: Forty-four patients with growth hormone deficiency who were examined by MR imaging were included in this retrospective study. On the basis of the endocrinologic findings, 21 were determined to have IGHD and 23 to have MPHD. The presence, size, location, and morphologic characteristics of the stalk, the neurohypophysis, and the adenohypophysis were recorded in each case. Findings in the two groups were compared. Statistical significance was determined by t-test. RESULTS: The stalk was normal in one patient with IGHD and in none of those with MPHD; it was truncated or thin in 19 patients with IGHD (90%) and in only one with MPHD (4%); it was absent in 22 patients with MPHD (96%) and in only one patient with IGHD (5%). These differences between the two groups were highly significant. In 81% of the IGHD patients and in 91% of the MPHD patients the location of the neurohypophysis was ectopic. This difference between the two groups was not significant. Among IGHD patients, the adenohypophysis was of normal size in 13 patients (62%), small in six (29%), and absent in two (9%); the corresponding findings in MPHD patients were seven (30%), six (26%), and 10 (44%). CONCLUSION: The majority of IGHD patients had a truncated or thin stalk and a normal or small adenohypophysis. An absent stalk and adenohypophysis are characteristic of MPHD. MR imaging can contribute to the prediction of the pattern and severity of hypopituitarism in patients with growth hormone deficiency.     

Hypothalamic/pituitary-axis of the spontaneous dwarf rat: autofeedback regulation of growth hormone (GH) includes suppression of GH releasing-hormone receptor messenger ribonucleic acid

In this study, the spontaneous dwarf rat (SDR) has been used to examine GHRH production and action in the selective absence of endogenous GH. This dwarf model is unique in that GH is not produced because of a point mutation in the GH gene. However, other pituitary hormones are not obviously compromised. Examination of the hypothalamic pituitary-axis of SDRs revealed that GHRH messenger RNA (mRNA) levels were increased, whereas somatostatin (SS) and neuropeptide Y (NPY) mRNA levels were decreased, compared with age- and sex-matched normal controls, as determined by Northern blot analysis (n = 5 animals/group; P < 0.05). The elevated levels of GHRH mRNA in the SDR hypothalamus were accompanied by a 56% increase in pituitary GHRH receptor (GHRH-R) mRNA, as determined by RT-PCR (P < 0.05). To investigate whether the up-regulation of GHRH-R mRNA resulted in an increase in GHRH-R function, SDR and control pituitary cell cultures were challenged with GHRH (0.001-10 nM; 15 min), and intracellular cAMP concentrations were measured by RIA. Interestingly, SDR pituitary cells were hyperresponsive to 1 and 10 nM GHRH, which induced a rise in intracellular cAMP concentrations 50% greater than that observed in control cultures (n = 3 separate experiments; P < 0.05 and P < 0.01, respectively). Replacement of GH, by osmotic minipump (10 microg/h for 72 h), resulted in the suppression of GHRH mRNA levels (P < 0.01), whereas SS and NPY mRNA levels were increased (P < 0.05), compared with vehicle-treated controls (n = 5 animals/treatment group). Consonant with the fall in hypothalamic GHRH mRNA was a decrease in pituitary GHRH-R mRNA levels. Although replacement of insulin-like growth factor-I (IGF-I), by osmotic pump (5 microg/h for 72 h), resulted in a rise in circulating IGF-I concentrations comparable with that observed after GH replacement, IGF-I treatment was ineffective in modulating GHRH, SS, or NPY mRNA levels. However, IGF-I treatment did reduce pituitary GHRH-R mRNA levels, compared with vehicle-treated controls (P < 0.05). These results further validate the role of GH as a negative regulator of hypothalamic GHRH expression, and they suggest that SS and NPY act as intermediaries in GH-induced suppression of hypothalamic GHRH synthesis. These data also demonstrate that increases in circulating IGF-I are not responsible for changes in hypothalamic function observed after GH treatment. Finally, this report establishes modulation of GHRH-R synthesis as a component of GH autofeedback regulation.