Mean Peak Plasma Growth Hormone Research Articles

Acipimox potentiates growth hormone response to growth hormone-releasing hormone by decreasing serum free fatty acid levels in hyperthyroidism

Hyperthyroidism is associated with an impairment of growth hormone (GH) responses to secretagogues. The aim of this study was to evaluate the effect of acipimox, an antilipolytic agent able to decrease free fatty acids (FFA), on GH response to GH-releasing hormone (GHRH) in hyperthyroid and normal control subjects. We studied six men with hyperthyroidism; seven normal men served as control subjects. Each subject underwent treatment with (1) 2 tablets of placebo orally or (2) 500 mg acipimox orally, 120 minutes before intravenous (IV) injection of 1 μg/kg GHRH-(1–29)NH 2. GH response to GHRH in hyperthyroid patients was markedly reduced; the mean peak GH response (9.6 ± 1.0 μg/L) and the area under the GH response curve (12.9 ± 1.3 μg/L × 2 h) were lower than those of control subjects (25.7 ± 1.8 μg/L, P < .05; 28.7 ± 2.1 μg/L × 2 h, P < .05). Hyperthyroid patients had higher baseline levels of plasma FFA than control subjects (998.0 ± 38.9 v 498.0 ± 36.0 μEq/L, P < .01). Acipimox decreased FFA levels in both hyperthyroid and control subjects; the lowest FFA levels of hyperthyroid subjects induced by acipimox were similar to those of control subjects. After acipimox pretreatment, GH responses to GHRH increased significantly ( P < .05); the mean peak plasma GH level (25.9 ± 4.6 μg/L) was similar to the peak GH levels of control subjects during the GHRH test, and the area under the GH response curve (41.1 ± 6.7 μg/L × 2 h) was even higher than that of control subjects with the GHRH test. However, the enhanced GH responses of hyperthyroid patients were still lower that those of control subjects during the acipimox plus GHRH test. We demonstrated that the decreased FFA levels induced by acipimox potentiate somatotrope responsiveness, likely acting at the pituitary level. Our results indicate that high FFA levels are responsible for impaired GH responses to GHRH in hyperthyroidism.

GH secretion status in myotonic dystrophy

Frequent endocrine alterations and abnormal growth hormone (GH) secretion have been reported in myotonic dystrophy (MD). To evaluate GH secretion status in MD, GH response to 100 μg of growth hormone releasing hormone (GHRH) with or without pyridostigmine pretreatment and its relation with insulin-induced hypoglycemia was investigated in MD patients and compared with normal controls. The mean peak plasma GH response to GHRH was 27.8 ± 19.2 μg/l normal subjects and 11.4 ± 8.7 μg/l in MD patients. In five of seven patients GH reached a mean peak of 12.6 ± 4.2 μg/l after insulin-induced hypoglycemia, compared with 5 ± 2.8 μg/l after GHRH. Conversely, in two patients GH reached a peak of 16.1 and 32 μg/l after GHRH, and only 2.5 and 5.3, respectively, after hypoglycemia. Pretreatment with pyridostigmine in nine patients tested potentiated GHRH-induced GH release with a peak of 17.6 ± 12.5 μg/l, compared with 10.05 ± 6.7 μg/l after GHRH alone; IGF-I levels were normal in all patients.

Cholinergic Receptor Activation by Pyridostigmine Restores Growth Hormone (GH) Responsiveness to GH Releasing Hormone Administration in Obese Subjects: Evidence for Hypothalamic Somatostatinergic Participation in the Blunted GH Release of Obesity*

GH secretion in response to provocative stimuli is decreased in obese individuals. However, the precise mechanism causing this decrease is unknown. In an attempt to determine if reduced cholinergic stimulation accounts for the decreased GH secretion, we studied the effect of enhanced cholinergic tone induced by pyridostigmine on GHRH-stimulated GH secretion in a group of seven obese and seven normal subjects. When GHRH (100 micrograms, iv) was administered after placebo in the obese group, mean plasma GH rose from 0.5 +/- (0.1 (+/- SE) to 3.6 +/- 1.5 micrograms/L at 30 min. When the same obese subjects were given GHRH 60 min after pyridostigmine administration (120 mg, orally), the mean plasma GH level rose from 1.8 +/- 0.6 to 21.0 +/- 7.5 micrograms/L at 30 min. The responses to placebo and pyridostigmine were significantly different at 15, 30, 45, 60, and 90 min. In the normal subjects, a similar dose of GHRH induced a GH peak of 24.3 +/- 7.1 micrograms/L, and the GHRH-stimulated peak was significantly higher (56.2 +/- 16.8 micrograms/L) after pyridostigmine administration. To study the effect of pyridostigmine alone six other obese and six other normal subjects were tested with pyridostigmine or placebo on different days. In the normal subjects the mean peak plasma GH level after pyridostigmine was 12.5 +/- 3.1 micrograms/L, and in the obese subjects it was 4.6 +/- 1.3 micrograms/L. Thus, pyridostigmine potentiated the action of GHRH, rather than merely being additive. We conclude that pyridostigmine stimulates GH secretion in obese as well as normal subjects, although the response was less in the former group. Pyridostigmine potentiates the response to GHRH in both groups, but again, the response was less in the obese subjects. These results suggest that the impaired somatotroph responsiveness in obese subjects may be due to chronically decreased hypothalamic cholinergic tone, resulting in enhanced somatostatinergic tone.

Naloxone Inhibition of Postprandial Growth Hormone Releasing Hormone-Induced Growth Hormone Release in Obesity

The effects of opiate receptor antagonist naloxone on growth hormone (GH) release after growth hormone-releasing hormone (GHRH) administration were investigated, before or after feeding, at 13.00 h, in 20 obese women and in 10 normal women. When GHRH was administered to obese women before a meal at lunch time, the mean peak plasma GH levels were very low, while plasma GH responses significantly increased after feeding. Naloxone, infused at a rate of 1.6 mg/h starting 1 h before GHRH administration (50 micrograms i.v. as a bolus), was capable of inhibiting GH release induced by administration of GHRH after feeding. On the contrary, naloxone did not induce significant variations on the fasting GHRH-induced GH release. In normal women, naloxone did not significantly modify the GH response to GHRH, both before and after lunch. The inhibitory effect of naloxone indicates that in obese women there is an increased opioid activity, which could represent an abnormal response of the gastrointestinal tract to food ingestion.

Discordance between growth hormone (GH) responses after GH-releasing hormone and insulin hypoglycemia in myotonic dystrophy.

Plasma GH responses to human GHRH, arginine, L-dopa, and insulin-induced hypoglycemia were determined in seven myotonic dystrophy (MD) patients. An iv bolus injection of GHRH-(1-44)-NH2 (1 microgram/kg BW) only slightly increased plasma GH concentrations in MD patients. The mean peak plasma GH level after GHRH injection [4.2 +/- 0.8 (+/- SE) micrograms/L] was significantly lower than that in 10 age-matched normal subjects (26.7 +/- 4.3 micrograms/L) or that in 6 patients with progressive muscular dystrophy (22.8 +/- 6.6 micrograms/L) whose nutritional status was similar to that of the MD patients. Even with a larger dose of GHRH (3 micrograms/kg BW), the plasma GH rises were minimal in the MD patients (mean peak, 5.9 +/- 1.8 micrograms/L). The plasma GH responses to a 30-min iv infusion of arginine (0.5 g/kg BW) and oral ingestion of L-dopa (0.5 g) were attenuated to a similar extent, whereas insulin-induced hypoglycemia caused a significant increase in plasma GH in all seven MD patients [mean peak, 17.4 +/- 4.1 (+/- SE) microgram/L]. The plasma TSH responses to TRH and plasma insulin-like growth factor I levels were similar in the MD patients and normal subjects. These findings suggest that 1) the impaired GH release after GHRH, arginine, and L-dopa administration in MD patients is not due to somatotroph deficiency, since the GH response to hypoglycemia is well preserved; and 2) insulin-induced hypoglycemia may stimulate GH release at least in part via inhibition of somatostatin release.

Differential effects of feeding on the ultradian variation of the growth hormone (GH) response to GH-releasing hormone in normal subjects and patients with obesity and anorexia nervosa.

Nutritional status and metabolic fuels are factors involved in the regulation of GH secretion and GH responses to GHRH. The effects of feeding on GHRH-induced GH release were studied in 13 normal women, 14 obese women, and 9 women with anorexia nervosa. GHRH-(1-44) (50 micrograms, iv) was administered at 0900 h after an overnight fast or at 1300 h after a normal meal at 0800 h, and at the same times 45 min after a 800-Cal meal on different days. The mean peak plasma GH responses to GHRH administered before a meal at 0900 h were 52.8 +/- 5.6 (+/- SE) micrograms/L in normal women, 8.2 +/- 1.3 micrograms/L in obese women, and 53.2 +/- 7.7 micrograms/L in anorexic women. When GHRH was administered before a meal at 1300 h, the mean peak plasma GH levels were lower than those at 0900 h; this reduction was -64.2% in normal women, -64.9% in obese women, and -55.8% in women with anorexia nervosa. After feeding, the plasma GH responses to GHRH were blunted in normal women at 0900 h (-60.9%) and 1300 h (-34.6%) compared with the fasting peak responses. In obese women the plasma GH response to GHRH after feeding was increased compared with that when these women had fasted (+60% at 0900 h and +406.9% at 1300 h). Finally, differential effects of feeding were present in anorexic women; the response was lower at 0900 h (-46.4%) and greater at 1300 h (+50.8%). We conclude that there is an ultradian variation in GHRH-stimulated GH secretion and that the responses differ according to nutritional status and body weight.

Enhancement of cholinergic tone by pyridostigmine promotes both basal and growth hormone (GH)-releasing hormone-induced GH secretion in children of short stature.

Increased cholinergic tone induced by pyridostigmine (PD) increases basal plasma GH levels and potentiates the GH response to GHRH in normal adults. In this study the effects of PD (60 mg, orally) on both basal and GHRH (1 microgram/kg)-induced GH secretion in seven children with familial short stature (FSS), six with GH deficiency (GHD) and 10 with constitutional growth delay (CGD) were studied and compared with results obtained by stimulation with insulin-induced hypoglycemia (IH) and GHRH alone. The mean peak plasma GH levels were variable, but individual values were frequently low in all groups after both IH [FSS, 9.7 +/- 1.3 (+/- SEM) ng/mL; GHD, 1.6 +/- 0.4 ng/mL; CGD, 7.0 +/- 0.8 ng/mL] and GHRH (FSS, 23.8 +/- 6.6 ng/mL; GHD, 11.1 +/- 5.8 ng/mL; CGD, 15.1 +/- 4.5 ng/mL) administration. PD induced GH responses (FSS, 14.5 +/- 1.6 ng/mL; GHD, 3.8 +/- 0.8 ng/mL; CGD, 18.3 +/- 3.2 ng/mL) that in many children in the FSS and CGD groups were higher than those after IH and GHRH treatment. PD clearly increased the GH response to GHRH in all children [FSS, 69.5 +/- 9.4 ng/mL (P less than 0.01 vs. other stimuli); GHD, 18.0 +/- 7.5 ng/mL; CGD, 50.0 +/- 8.5 ng/mL (P less than 0.01 vs. other stimuli)]. We conclude that in children with short stature, as in adults, enhancement of cholinergic tone increases both basal and GHRH-induced GH secretion, and that PD plus GHRH is the best provocative stimulus for evaluating the somatotroph response.

Growth Hormone (GH) Response to GH-Releasing Hormone in Children with Subnormal Integrated Concentrations of GH*

We determined the GH responses to human GH-releasing hormone-40 (GHRH) in poorly growing children who had either normal or deficient GH secretion, as measured by pharmacological stimulation and integrated concentration of GH (IC-GH). Ten patients had both normal pharmacologically stimulated GH and IC-GH (GH-normal), 15 patients had normal pharmacologically stimulated GH but deficient IC-GH [GH neurosecretory dysfunction (GHND)], and the remaining 7 patients had both subnormal stimulated GH and IC-GH [GH deficiency (GHD)]. The mean peak plasma GH response to GHRH was 11.7 +/- 8.5 (+/- SD) ng/ml in GHD patients, significantly lower than the responses of both the GHND (49.2 +/- 39.2 ng/ml; P less than 0.0001) and GH-normal (51.8 +/- 44 ng/ml; P less than 0.0001) groups. The range of peak GH responses to GHRH in GHD patients overlapped the lower end of the range of responses in the GHND and GH-normal patients. Three GH-normal and eight GHND patients had greatly enhanced GH responses to GHRH (greater than 50 ng/ml); no GHD patients had a response over 24.2 ng/ml. There was no difference between the GH responses of male and female patients within groups to GHRH. There was a significant correlation between the log of the peak GH response to GHRH and the log of the maximal GH response to standard pharmacological stimuli (r = 0.51; P less than 0.005). Because of the variability of GH responses to GHRH encountered among the patients, the response to GHRH cannot be used as a test for identifying patients with inadequate spontaneous GH secretion. The IC-GH is the only method that can identify children with GHND.

The effect of glucose on growth hormone (GH)-releasing hormone-mediated GH secretion in man.

The effect of glucose on GH-releasing hormone (GHRH)-mediated GH secretion was examined in six normal young men. In two paired experiments, the six men drank a 75-g glucose solution or an equal volume of water 30 min before receiving, iv, 100 micrograms of the 44-amino acid form of human pancreatic GHRH (hGHRH-44). One week later, the same men underwent an identical experimental protocol in a cross-over trial. Basal plasma GH concentrations before hGHRH-44 administration were not statistically different in the two experiments [glucose experiment, 2.1 +/- 0.1 (+/- SE) ng/ml; water experiment, 2.6 +/- 0.6 ng/ml]. The mean peak plasma GH level occurred 30 min after hGHRH-44 administration in both experiments. However, the mean GH response was significantly diminished when the men received glucose (8.12 +/- 1.12 ng/ml) compared to that when they received only water (23.70 +/- 8.46 ng/ml; P less than 0.01). Thus, hyperglycemia may exert an inhibitory effect on the plasma GH response to hGHRH-44.

The inter- and intra-subject variabilities of plasma GH response to human growth hormone-releasing hormone (1-44) NH2 in men.

The effects of intravenously given human growth hormone-releasing hormone (1-44) NH2 (hGRH-44) on growth hormone (GH) secretion were studied in normal men. A wide variability of intersubject GH response to hGRH-44 was observed. The peak plasma GH levels in response to 50, 100 and 200 micrograms hGRH-44 in 7 normal men were 9.1 +/- 3.2 ng/ml (Mean + SEM), 19.3 +/- 3.3 ng/ml and 22.4 +/- 4.0 ng/ml, respectively. Both the mean peak values for plasma GH response to 100 and 200 micrograms were significantly greater than that for 50 micrograms hGRH-44 injection (p less than 0.01), although there was no significant difference of the mean peak plasma GH values and mean concentrations at each time point, except for those at 120 min, when 100 or 200 micrograms hGRH-44 was administered. A significant difference in the mean amount of plasma GH secreted in response to hGRH-44 was observed only between 50 and 200 micrograms hGRH-44 injection (p less than 0.01). Furthermore, a dose-related plasma GH increase in response to hGRH-44 was not always observed in each subject. In contrast to the wide intersubject variability, the difference among responses of plasma GH to 100 micrograms or 200 micrograms of hGRH-44 given at multiple times separated by intervals of at least 1 week in each individual was relatively small.(ABSTRACT TRUNCATED AT 400 WORDS)

RESPONSE OF GROWTH HORMONE DEFICIENT PATIENTS TO SYNTHETIC GROWTH HORMONE-RELEASING FACTOR

We studied the growth hormone (GH) response to synthetic growth hormone-releasing factor (GRF (1-44)-NH2)† in non-GH deficient (NGHD) subjects (4-33 yrs) and GH deficient (GHD) patients (5-24 yrs). The mean (±SE) peak GH response of 6 NGHD children after 5 μg/kg IV of GRF (27.1±5.8 ng/ml) was similar to that of NGHD young men previously reported (JCEM 57:677). Of 20 patients with severe GH deficiency 17 responded to 5 μg/kg IV of GRF, but the mean peak plasma GH concentration was less than that of the NGHD group (5.0±1.2 vs 27.2±3.5 ng/ml; p<0.001). Patients with isolated GH deficiency had responses similar to those with multiple pituitary hormone deficiencies. The GH responses of the GHD children correlated negatively with chronologic age (r= −0.758, p<0.02). Six partially GHD children had a higher GH response to GRF than severely GHD children (13.1±1.8 vs 6.9±1.7 ng/ml; p<0.04) but lower than NGHD children (p<0.05). GRF induced higher plasma GH levels in GHD than did arginine, insulin, or L-dopa. The GRF test is useful for assessing GH reserve. Although a GH response to GRF in GHD patients suggests GRF deficiency, the lack of response does not exclude it. The GH response to synthetic GRF in many GHD children is consistent with a hypothalamic abnormality as the etiology of their GH deficiency and supports the potential therapeutic usefulness of GRF or an analog in these patients.