Withdrawal Of Somatostatin Infusion Research Articles

Somatostatin infusion withdrawal: a study of patients with migraine, cluster headache and healthy volunteers

Migraine and cluster headache are the most common disabling primary headache syndromes and are typically episodic. A reliable method of triggering such headache attacks facilitates the study and treatment of these disorders. There is sufficient clinical and laboratory evidence to suggest that somatostatin withdrawal may be a useful way of triggering headache. We studied 15 subjects, eight migraineurs, four cluster headache sufferers and three healthy controls. Each subject had a standard somatostatin infusion, 250 μg/h for 3.5 h. Subjects were followed for 24 h post-infusion. Growth hormone was suppressed in each subject demonstrating a biologically active infusion of somatostatin. None of the non-headache sufferers had pain. Seven of eight migraine sufferers had no immediate headache and no delayed headache. One migraineur experienced short lasting headache with no migrainous features. Three of four patients with cluster headache had no significant pain with the infusion, while one had pain after 1 h. The results suggest that somatostatin infusion is not a reliable way to produce headache in experimental settings in either migraine or cluster headache. The data do not exclude a role for somatostatinergic mechanisms in primary headache.

Somatostatin infusion withdrawal: studies in the acute and recovery phase of anorexia nervosa, and in obesity.

Changes in GH/IGF-I axis activity occur in both anorexia nervosa (AN) and obesity (OB). A GH hypersecretory state with very low plasma IGF-I levels is present in AN, whereas in morbid OB, GH secretion is dull and plasma IGF-I levels are generally preserved. Endogenous GHRH activity in AN and OB has never been directly studied, although indirect evidence would indicate that GHRH function is altered in either condition, possibly enhanced and reduced respectively. Somatostatin (SS) infusion withdrawal (SSIW) is followed by a rebound rise of plasma GH in animals and humans, an event which, allegedly, is mediated by endogenous GHRH release. In the present study, 28 young women, eight with active AN (A-AN), six with AN in the recovery phase (R-AN), eight with morbid OB, and six healthy age-matched normal weight subjects (NW), were studied. All subjects underwent, on different occasions, the following two tests: (i) acute GHRH injection (1 microg/kg, i.v.); (ii) infusion of SS (9 microg/kg per h i.v. over 60 min), with blood samples drawn prior to and at different intervals after drug injections. Plasma GH levels were measured at each time interval in all sessions, and, in addition, baseline plasma estradiol, free triiodothyronine, TSH, IGF-I and insulin were measured at -30 min. Baseline plasma GH concentrations were significantly higher in A-AN than in NW (4.7+/-0.7 vs 2.1+/-0.6 microg/l, P<0.01). Baseline GH levels in R-AN were also higher than in NW, but the difference did not reach statistical significance (5.6+/-1.7 microg/l, not significant (NS)). Baseline plasma GH concentrations were significantly lower in OB than in NW (0.3+/-0.1 microg/l, P<0.01). GHRH-stimulated GH release was significantly higher in A-AN than in NW (mean change in area under the curve (DeltaAUC) 1904.9+/-626.1 vs 613.9+/-75.9 microg/l per min, P<0.01), whereas no statistically significant difference was present between R-AN and NW (mean DeltaAUC 638.2+/-293.0 microg/l per min, NS); in OB, GHRH failed to evoke a plasma GH rise (mean DeltaAUC 239.8+/-89.9 microg/l per min vs A-AN, R-AN, and NW, P<0.01). SS infusion markedly reduced plasma GH concentrations in both A-AN and R-AN and, to a lesser extent, in NW, but failed to do so in OB. In A-AN, SSIW was followed by a plasma GH rise markedly higher than that present in NW (mean DeltaAUC 193.0+/-42.3 vs 60.1+/-11.4 microg/l per min, P<0.01), whereas in R-AN the GH response after SSIW was nearly superimposable on that registered in NW (mean DeltaAUC 72.9+/-22.8 microg/l per min, NS). There were no changes in plasma GH levels after SSIW in OB (mean DeltaAUC 22.8+/-9.7 microg/l per min). In all groups, DeltaAUCs of the GH response to GHRH and after SSIW were highly positively correlated (r=0.7, P<0.01). These data support the view that a high endogenous GHRH tone, which subsides in the recovery phase of the disease, is present in AN, whereas GHRH hypofunction, possibly associated with pituitary impairment, might indicate OB.

Effect of withdrawal of somatostatin plus growth hormone (GH)-releasing hormone as a stimulus of GH secretion in Cushing's syndrome.

Somatostatin (SS) may not merely be inhibitory to GH secretion but, under appropriate temporal conditions, may act in a paradoxically positive manner to sensitize somatotroph responsiveness to GHRH. SS infusion withdrawal (SSIW) produces a rebound GH rise in humans and increases GHRH-induced GH release. Theoretically SSIW leaves the somatotroph cell in a situation of low endogenous SS. In Cushing's syndrome, GH secretion appears blunted to all stimuli. The mechanisms by which glucocorticoids impair GH secretion in Cushing's syndrome are unknown. There are no data evaluating GH responsiveness to SSIW plus GHRH in Cushing's syndrome patients. The aim of the present study was to evaluate the GH response to SSIW plus GHRH in a group of Cushing's syndrome patients, in order to further understand the deranged GH secretory mechanisms in Cushing's syndrome. Eight female patients with Cushing's syndrome were studied. As a control group, eight normal subjects of similar age and sex were studied. Three tests were done. On one day, SS intravenous (i.v.) infusion (500 micro g for 0-90 min) was performed followed by placebo i.v. bolus at min 90 after SS withdrawal (SSIW). On another day, SS i.v. infusion (500 micro g for 0-90 min) was performed followed by GHRH (100 micro g) i.v. bolus at min 90 after SS withdrawal. On a third day, slow infusion of 150 mmol/l NaCl administration was performed followed by GHRH (100 micro g) i.v. bolus at min 90 after the start of the infusion. Blood samples were taken at appropriate intervals for determination of GH. GHRH-induced GH secretion in normal subjects showed a mean peak of 15.4 +/- 2.1 micro g/l (conversion factor: 1 micro g/l = 1.2 mUI/l). Normal control subjects had a mean peak of 3.3 +/- 1.6 micro g/l after SSIW-induced GH secretion. When GHRH was administered after SSIW there was increased GH secretion with a mean peak of 23.7 +/- 4.2 micro g/l significantly greater than the response after SSIW alone (P < 0.05) and GHRH alone (P < 0.05). The patients with Cushing's syndrome had a blunted GH response after GHRH administration with a mean peak of 1.4 +/- 0.4. After SSIW, Cushing's syndrome patients had a mean peak of 1.0 +/- 0.5 micro g/l. When GHRH was administered after SSIW there was a similar GH response with a mean peak of 1.7 +/- 0.6 micro g/l, not statistically different than the response after SSIW alone (P = ns) and GHRH alone (P = ns). When we compare the response of normal subjects and Cushing's syndrome patients, after SSIW plus GHRH, it was decreased in Cushing's syndrome patients (P < 0.05), with a mean GH peak of 23.7 +/- 4.2 micro g/l and 1.7 +/- 0.6 micro g/l for normal subjects and Cushing's syndrome patients, respectively. This study has demonstrated a significantly blunted peak GH response to somatostatin infusion withdrawal plus GHRH in Cushing's syndrome patients. In this theoretical situation of decreased somatostatinergic tone there is persistence of GH hyposecretion in Cushing's syndrome, suggesting the existence of a pituitary defect responsible for the decreased GH secretion in Cushing's syndrome.

Effect of withdrawal of somatostatin plus GH-releasing hormone as a stimulus of GH secretion in obesity.

Somatostatin (SS) may not merely be inhibitory to GH secretion but, under appropriate temporal conditions, may act in a paradoxically positive manner to sensitize somatotroph responsiveness to GH-releasing hormone (GHRH). SS infusion withdrawal (SSIW) produces a rebound GH rise in humans and increases GHRH-induced GH release. Theoretically, SSIW leaves the somatotroph cell in a situation of low endogenous SS. In obesity, there is markedly decreased GH secretion. In both children and adults, the greater the body mass index (BMI), the lower the GH response to provocative stimuli. It has been postulated that increased hypothalamic somatostatin secretion is the main mechanism responsible for the blunted GH secretion of obesity. There are no data evaluating GH responsiveness to SSIW plus GHRH in obese adults. The aim of the present study was to evaluate the GH response to SSIW plus GHRH in a group of control subjects and a group of obese patients. Seven obese patients (six female, one male) with a BMI of 36.1 +/- 7.7 kg/m2 were studied. As a control group, seven normal subjects (six female, one male) with a BMI of 20.3 +/- 0.9 kg/m2 were also studied. Two tests were performed. On one day, somatostatin (SS) i.v. infusion (500 microg from 0-90 min) was performed followed by a placebo i.v. bolus 90 min after SS withdrawal (SSIW). On another day, SS i.v. infusion (500 microg from 0-90 min) was performed followed by a GHRH (100 microg) i.v. bolus 90 min after SS withdrawal. A second group of seven obese patients (six female, one male) with a BMI of 32.2 +/- 2.3 kg/m2 were studied. As a second control group, seven normal healthy subjects (six female, one male) with a BMI of 20.1 +/- 0.6 kg/m2 were also studied. On one day, saline infusion was performed followed by a placebo i.v. bolus at 90 min. On another day, saline infusion was performed followed by a GHRH (100 microg) i.v. bolus at 90 min. Blood samples were taken at appropriate intervals for determination of GH. Serum GH was measured by chemiluminescent immunometric assay. Statistical analysis was performed by Wilcoxon and Mann-Whitney tests. GHRH-induced GH secretion in normal subjects showed a mean peak of 15.8 +/- 2.1 microg/l. Normal control subjects had a mean peak of 3.1 +/- 1.5 microg/l after SSIW-induced GH secretion. When GHRH was administered after SSIW there was an increased GH secretion with a mean peak of 23.3 +/- 4.4 microg/l, significantly greater than the response after SSIW alone (P < 0.05) and GHRH alone (P < 0.05). GHRH-induced GH secretion in obese patients was decreased with a mean peak of 3.9 +/- 1.5 microg/l. In obese patients, GH secretion after SSIW was markedly decreased with a mean peak of 1.0 +/- 0.4 microg/l. When GHRH was administered after SSIW, an increase in GH secretion was observed with a mean peak of 4.3 +/- 0.9 microg/l, significantly greater than SSIW alone (P < 0.05) but not GHRH alone (P = NS), and significantly less than in normal subjects (P < 0.05). This study demonstrates a significantly blunted peak GH response to somatostatin infusion withdrawal plus GHRH in obese patients compared to normal subjects. In this theoretical situation of decreased somatostatinergic tone, there is persistence of GH hyposecretion in obesity, suggesting the existence of multiple defects responsible for decreased GH secretion in obesity. We also found that in obese patients, in contrast to normal subjects, SSIW did not increase GHRH-induced GH secretion.

Growth hormone (GH) rebound rise following somatostatin infusion withdrawal: studies in dogs with the use of GH-releasing hormone and a GH-releasing peptide.

Evidence has been presented that in both animals and humans the rebound secretion of growth hormone (GH) following withdrawal of an infusion of somatostatin (SS) is due to the functional activation of the hypothalamic GH-releasing hormone (GHRH) neurons of the recipient organism. Based on this premise, this study has sought to assess the existence of functional interactions between endogenous GHRH released by a SS infusion withdrawal (SSIW) and growth hormone-releasing peptides (GHRPs), a class of compounds allegedly acting via GHRH. Five young dogs (3 to 4 years old, 2 male and 3 female) were administered, on different occasions, three consecutive intravenous boli of physiological saline (0.1 ml/kg), or GHRH (2 microg/kg), or EP92632 (125 microg/kg), a GHRP compound, or GHRH plus EP92632 at the end of three cycles of 1-h SS infusions (8 microg/(kg x h)) or during a 6-h infusion of saline. Under saline infusion (SALI), plasma GH levels were unaltered, whereas each SSIW cycle was followed by similar GH secretory episodes. Administration of the first GHRH bolus under SALI induced a rise in plasma GH concentrations slightly higher than that induced by the first cycle of SSIW, but the GH response to the second and third GHRH boli was similar to that after SSIW. Following SSIW, the response to the first bolus of GHRH was higher than that during SALI, but the second and third cycles of SSIW induced GH responses similar to those evoked by the GHRH bolus. During SALI, administration of the first bolus of EP92632 induced a rise in plasma GH which was higher than that induced by the first GHRH bolus, the second bolus elicited a GH peak of lesser amplitude and there was a partial restoration of the GH response to the third peptide bolus. SSIW strikingly enhanced the GH release to the first EP92632 bolus, a pattern also present, although to a lesser extent, with the second and third cycles of SSIW. Under SALI, combined administration of GHRH and EP92632 had a synergistic effect on GH release, but a progressive reduction was present in the GH response to the second and third GHRH plus EP92632 boli. SSIW increased only weakly the GH response to the first co-administration of the peptides over that present after administration of EP92632 alone, and did not induce a GH response higher than that present during SALI when the second bolus of the peptides was administered; after the third SSIW a GH rise higher than that present during SALI was elicited by the combined administration of the peptides. (i) the uniformity of the GH rebound responses to multiple cycles of SSIW may indicate that the latter activate a physiological mechanism which mimics that normally controlling GH pulse generation; (ii) EP92632 elicits, under our experimental conditions, a plasma GH rise higher than that induced by GHRH; (iii) SSIW enhances the GH response to EP92639 alone, to an extent reminiscent of that following combined administration of GHRH and EP92632. This pattern reinforces the view that SSIW elicits release of endogenous GHRH, and infers that the GHRP challenge after SSIW may be exploited in humans to distinguish between healthy and GH-deficient adults.

Somatostatin Infusion Withdrawal: Studies in Normal Children and in Children with Growth Hormone Deficiency

Somatostatin Infusion Withdrawal: Studies in Normal Children and in Children with Growth Hormone Deficiency

Somatostatin infusion withdrawal: studies in normal children and in children with growth hormone deficiency.

Withdrawal of a somatostatin infusion (SSIW) is followed by a rebound rise of GH in both animals and normal adult men, a phenomenon likely mediated by endogenous GHRH function. In the present study, we have evaluated the GH response to SSIW in a group of 28 prepubertal children (18 boys and 10 girls; aged 3.7-11.1 yr). Six children had GH deficiency [GHD; GH responses to pyridostigmine (PD)+GHRH and to clonidine <20 and <7 microg/L, respectively], 4 children had GH neurosecretory dysfunction (GHND; GH responses to PD+GHRH and to clonidine > or =20 and >7 microg/L, respectively; mean integrated nighttime GH concentrations <3 microg/L), and 18 children were short normal children [normal controls (NC)]. All children received a constant infusion of SS at the dose of 3 microg/Kg x h for 90 min. SSIW elicited a clear-cut GH rise in NC children (13.7+/-1.0 microg/L), but not in GH-deficient children, regardless of the underlying etiology (GHD, 1.6+/-0.4 microg/L; GHND, 2.4+/-0.3 microg/L). The GH response to SSIW was similar between GHD and GHND children. There was no overlapping of the maximum SSIW-stimulated GH peaks between NC and GHD or GHND children. In conclusion, we have demonstrated that SSIW elicits a significant GH rise in NC children, but not in GH-deficient children, regardless of the underlying etiology (GHD or GHND). This resulted in complete discrimination of NC from GHD or GHND children. Were these present findings confirmed on a larger number of children, SSIW, because of its testing efficaciousness and safety, procedural simplicity, and economy holds promise of being a useful diagnostic tool for GH-dependent growth disorders.

Somatostatin withdrawal as generator of pulsatile GH release in the dog: a possible tool to evaluate the endogenous GHRH tone?

Reportedly, somatostatin (SS) withdrawal is an effective generator of pulsatile GH release in mammals and it has been proposed that the amplitude of the GH bursts is related to the functional activity of GHRH-producing neurons. Our study was designed to test this hypothesis in the unanesthetized dog, under different conditions of endogenous GHRH function. First, we evaluated the ability of withdrawal of SS infusion to induce a GH secretory burst under basal conditions when GHRH function is thought to be enhanced, i.e. in young (2- to 3-year-old) dogs under sustained (30 days) caloric restriction (CR) or a 2-day fast. Secondly, we performed experiments in aged (11- to 17-year-old) dogs, in which hypothalamic GHRH secretion is thought to be reduced. Old dogs were evaluated under basal conditions, after a 2-day fast and after a 10-day administration of GHRH alone or followed by fasting. Both before and 14 h after the end of each experimental period, young and old dogs underwent a 3-hour (from 10.00 to 13.00 h) intravenous SS infusion (4 micrograms.kg-1.h-1). The secretory profile of GH was generated by 15-min sampling from 09.00 to 15.00 h. Under baseline conditions, SS withdrawal induced a significant burst of GH in young but not in old dogs. After CR, termination of SS infusion was followed in young dogs by a robust GH burst, significantly higher than that observed when dogs were fed ad libitum. In this instance, reduction of plasma IGF-I concentrations was unlikely to be responsible for the higher GH burst; the same pattern was present in the young dogs after a 2-day fast, when circulating IGF-I was unaltered. In old dogs, SS withdrawal did not modify baseline GH levels even after fasting, but induced a significant GH increase after GHRH priming. When GHRH priming was followed by fasting, SS withdrawal resulted in a GH burst higher than that occurring after fasting or GHRH alone. Altogether, these data support the view that the rebound rise in GH induced by withdrawal of SS is related to the endogenous GHRH tone. It is suggested that extrapolation of these findings to humans might permit probing, albeit inferentially, the endogenous GHRH tone under different physiologic or pathologic conditions.

Somatostatin reduces transcription of the growth hormone gene in rats.

To examine whether somatostatin (SS) exerts influences on the steady state levels of GH-releasing factor (GRF), the effect of SS on GH gene transcription was examined in rats. This approach was used because it has been shown that GRF stimulates GH gene transcription independent of GH release, and SS does not inhibit basal or GRF-stimulated GH gene transcription. Therefore, it is assumed that an effect of SS on GH gene transcription would be mediated by a change in GRF levels. Adult female Sprague-Dawley rats were provided with right atrial cannulae. Studies were performed using unanesthetized rats. Pituitary GH gene transcription was measured by transcription assay. An iv administration of antiserum to rat GRF 150 min previously significantly decreased GH gene transcription compared with that in control rats given normal goat serum. A continuous infusion of SS (300 micrograms/kg.h) via the cannula for 150 min significantly decreased GH gene transcription compared with that in control rats receiving 0.9% NaCl. When GRF (3 micrograms/kg.h) was given simultaneously with SS (300 micrograms/kg.h), GH gene transcription increased significantly compared with that in rats receiving SS infusion alone. After the withdrawal of SS infusion, GH gene transcription rapidly and significantly increased. The data suggest that SS reduces the steady state levels of GRF.