Growth hormone and prolactin response to thyrotropin releasing hormone and growth hormone releasing factor in the immature turkey

Synthetic thyrotropin releasing hormone (TRH) and human pancreatic growth hormone releasing factor (hpGRF) stimulated growth hormone (GH) secretion in 6- to 9-week-old turkeys in a dose-related manner. TRH and hpGRF (1 and 10 micrograms/kg, respectively) each produced a sixfold increase in circulating GH levels 10 min after iv injection. Neither TRH nor hpGRF caused a substantial change in prolactin (PRL) secretion in unrestrained turkeys sampled through intraatrial cannulas. However, some significant increases in PRL levels, possibly related to stress, were noted.     

In vitro pituitary hormone releasing activity of 40 residue human pancreatic tumor growth hormone releasing factor

The hypophysiotropic activities of a synthetic human pancreatic growth hormone releasing factor (hpGRF) with 40 residues was examined in vitro using rat pituitary halves. At concentrations from 10(-10) M to 10(-7) M the peptide stimulated GH release in a dose-dependent manner with the ED50 being 1.2 x 10(-9) M. The concentration of 10(-10) M hpGRF is comparable to the basal hypophyseal portal blood levels of other known hypothalamic hypophysiotropic hormones. However, GH release was enhanced three-fold by concentration as low as 10(-12) M, though no dose-response relationship was observed up to 10(-10) M. Thus, this peptide not only stimulates the release of GH in a dose-dependent manner, but at lower concentrations also maintains elevated GH levels. The release of ACTH, beta-endorphin, LH, and FSH was not affected by hpGRF at any of the concentrations tested. At hpGRF concentrations less than 10(-7) M, the release of TSH and PRL were unaffected. However, at 10(-6) M, TSH release was enhanced about 2.5 fold and prolactin release was elevated slightly.     

Growth hormone response to growth hormone releasing hormone 1-40 in Turner's syndrome

The response of growth hormone (GH) to acute administration of GH-releasing hormone 1-40 (GHRH) was evaluated in 12 patients with Turner's syndrome and in 12 prepubertal or early pubertal girls. In 7 of 12 patients GHRH induced a definite increase (greater than 10 ng/ml) of plasma GH levels. In 5 patients there was a poor GH rise after GHRH administration (less than 10 ng/ml). Overall, the mean GH response of patients was significantly lower than that of normal girls. Five out of 7 patients with a 45 X,O karyotype had a reduced GH rise after GHRH, while all patients with non X,O karyotype (mosaicism and/or 46 X,iX) had a normal GH response to GHRH. Although the cause of short stature in patients with Turner's syndrome is most likely multifactorial, a reduced pituitary GH reserve, as documented by the reduced GH response to GHRH in some of our patients, may contribute to the growth impairment in this disorder.     

Effects of corticotropin releasing factor and growth hormone releasing factor on pituitary hormone secretion in patients with congenital thyrotropin deficiency. Abnormal response of growth hormone to corticotropin releasing factor

Blood concentrations of anterior pituitary hormones, ACTH, GH, TSH, PRL, LH, and FSH were determined in corticotropin releasing factor (CRF) test (synthetic ovine CRF 1.0 microgram per kg body weight) and growth hormone releasing factor (GRF) test (synthetic human pancreatic GRF-44 100 micrograms) in 2 female sibling patients with congenital isolated TSH deficiency, in their mother, in 2 patients with congenital primary hypothyroidism and in 8 normal controls. The patients with isolated TSH deficiency showed normally increased plasma ACTH and serum GH after CRF and GRF, respectively, and also showed an abnormal GH response to CRF. The serum GH showed a rapid increase to maximum levels (12.9 ng/ml) within 30 to 60 min followed by decrease. The possibility of secretion of abnormal GH could be excluded by the fact that on serum dilution, GH value gave a linear plot passing through zero. In addition, serum PRL, LH and FSH levels after CRF administration in case 1 and PRL after GRF in case 2 were also slightly increased but these responses were marginal. The mother of the patients, patients with congenital primary hypothyroidism, and normal healthy controls showed normal responses of pituitary hormones throughout the experiment. Data from the present study and a previous report show that abnormal GH response to the hypothalamic hormones (CRF, TRH and LHRH) may be observed in patients with congenital isolated TSH deficiency.     

Abnormalities of growth hormone release in response to human pancreatic growth hormone releasing factor (GRF (1-44) ) in acromegaly and hypopituitarism.

Human pancreatic growth hormone releasing factor (GRF (1-44)) is the parent molecule of several peptides recently extracted from pancreatic tumours associated with acromegaly. A study was conducted to examine its effects on the release of growth hormone in normal volunteers and in patients with hypopituitarism and acromegaly. GRF (1-44) dose dependently stimulated the release of growth hormone in normal people and produced no appreciable side effect. This response was grossly impaired in patients with hypopituitarism and, although similar to the growth hormone response to hypoglycaemia, was of quicker onset and a more sensitive test of residual growth hormone function. Patients with acromegaly appeared to fall into (a) those with a normal response to GRF, whose growth hormone suppressed significantly with oral glucose, and (b) those who had an exaggerated response to GRF (1-44), whose growth hormone had not suppressed previously after oral glucose. Present methods for testing growth hormone deficiency entail using the insulin stress test, which is time consuming, unpleasant, and sometimes dangerous. A single intravenous injection of GRF now offers the possibility of an easier, safer, and more reliable routine test for growth hormone deficiency. It has the further advantage of being free of side effects and readily performed in outpatients. Hence it seems likely to become the standard test and take the place of the insulin stress test.     

The growth hormone secretory response to growth hormone releasing factor in the developing rhesus monkey.

We studied the development of the GH response to growth hormone releasing hormone (GHRH) using two doses of GHRH. The newborns demonstrated higher baseline GH and responses to GHRH than animals of any older age. There was no difference noted between the rise in GH in male and female subjects with 10 mcg/kg vs 1 mcg/kg. Serum cortisol concentrations did not correlate with serum GH concentrations. These developmental patterns of serum GH are similar to those known in the human being.     

Investigation of human growth hormone releasing factor in adults

A dose-effect relationship between human growth hormone (GH) releasing factor (hGRF) and GH response was demonstrated for doses ranging from 5 micrograms per subject (minimal active dose) to 40-80 micrograms per subject (minimal dose for maximal effect). Bioactivity of GH released under hGRF was proven in the Nb2 lymphoma cell multiplication assay. Unwanted effects were observed for doses equal to or larger than 150 micrograms. Pharmacokinetic parameters were calculated from the immunoreactive GRF plasma concentrations obtained after intravenous injections of various doses. The half-lives were 6.8 +/- 0.4 min and 43.2 +/- 3 min for distribution and elimination phases, respectively. Subcutaneous administration of hGRF was shown to be effective for promoting GH release, with doses higher than those required by intravenous administration. Intermittent intravenous injection of hGRF, at 3-hour intervals, resulted in a decrease in the magnitude of GH response in normal subjects.     

Growth hormone response to thyrotropin releasing hormone in a pellagrin

An abnormal hyperresponse of GH to intravenous injection of TRH in a 66-year-old female pellagra patient with typical 3'D's was reported. Diagnosis of pellagra was mainly based on her clinical course and manifestations, although serum levels of nicotinic acid and serotonin were within the normal range. Serum vitamin A and B2 levels were low. However, these findings did not exclude the diagnosis. The abnormal GH response to TRH observed in this patient was decreased at 2 months and thoroughly disappeared at 10 months after admission. GH response to arginine showed an exaggerated and sustained response on admission, decreased at 2 months and showed an almost normal pattern at 10 months after admission. TSH and prolactin response to TRH were normal throughout the clinical course. LH and FSH response to LH-RH were exaggerated, suggesting post-menopausal hypogonadism. Cortisol response to ACTH showed slightly sustained reactions at both times of the provocation. Oral glucose tolerance test revealed a slight impairment in this patient. These results suggest that pellagra is one of the disorders which exhibit an abnormal hyperresponse of GH to intravenous administration of TRH.     

The influence of age on human pancreatic growth hormone releasing hormone stimulated growth hormone secretion

63 non-obese healthy subjects aged 18 to 95 years were investigated for age-dependence of GHRH-stimulated GH-secretion. In addition, priming of GH-secretion with three oral doses of propranolol (3 x 80 mg, the last dose 2 hours prior to the second GHRH-bolus) was carried out in 15 subjects below 40 years and 13 subjects older than 70 years. We found that mean maximal incremental GH-levels were inversely correlated with chronological age (r = -0.44, P = 0.001) of the probands. Propranolol premedication caused a significant rise of both basal and peak GHRH-induced relative increases in all subjects tested, whereas GHRH-induced relative increases of GH remained unchanged. In a well selected group of non-obese healthy subjects stimulated GH-secretion is found to undergo an aging process that is supposed to be of pituitary and suprapituitary origin. Priming GH-secretion with a beta-Blocker is possible both in young and very old healthy subjects and is likely to affect the basal GH secretory tone and not GHRH-stimulated GH-secretion.     

Stimulation of growth hormone release in dwarf and normal chickens by thyrotrophin releasing hormone (TRH) or human pancreatic growth hormone releasing factor (hpGRF)

The effect of thyrotrophin releasing hormone (TRH) or human pancreatic growth hormone releasing factor (hpGRF) on growth hormone (GH) release was studied in both dwarf and normal Rhode Island Red chickens with a similar genotype except for a sex-linked dw gene. Both TRH (10 micrograms/kg) and hpGRF (20 micrograms/kg) injections stimulated plasma GH release within 15 min in young and adult chickens. The increase in GH release was higher in young cockerels than that in adult chickens. The age-related decline in the response to TRH stimulation was observed in both strains, while hpGRF was a still potent GH-releaser in adult chickens. The maximal and long acting response was observed in young dwarf chickens, suggesting differences in GH pools releasable by TRH and GRF in the anterior pituitary gland. The pituitary gland was stimulated directly by perifusion with hpGRF (1 microgram/ml and 10 micrograms/ml) or TRH (1 microgram/ml). Repeated perifusion of GRF at 40 min intervals blunted further increase in GH release, but successive perifusion with TRH stimulated GH release. The results suggest the possibility that desensitization to the effects of hpGRF occurs in vitro and that the extent of response depends on the number of receptors for hpGRF or TRH and/or the amount of GH stored in the pituitary gland.     

Growth hormone releasing hormone-sensitive adenylate cyclase activity in growth hormone-producing pituitary adenoma: correlation to the response of plasma growth hormone to growth hormone releasing hormone in patients with acromegaly

The correlation between response of plasma GH to GHRH and the GHRH-induced stimulation of the intracellular adenylate cyclase (AC) activity in pituitary adenoma cell membranes in acromegalic patients was investigated. Each peak plasma GH level after iv administration of GHRH ranged from 1.1 to 13.8 times the basal level in 13 acromegalic patients. On the other hand, the maximal stimulation of intracellular AC activity (cAMP production) induced by GHRH varied from 1.4 to 6.4 times the control level in each GH-producing pituitary adenoma cell membrane. A significant positive correlation (r = 0.89, P less than 0.005) between plasma GH response to GHRH and intracellular cAMP production stimulated by GHRH was observed in nine of the acromegalic patients. In contrast, the response of plasma GH to GHRH was significantly blunted, despite a fairly large production of intracellular cAMP stimulated by GHRH, in the other four acromegalic patients. These results suggest that GHRH-induced GH release from GH-producing pituitary adenomas of patients with acromegaly may be regulated not only by GHRH receptor-adenylate cyclase system but also modified by several other factors including somatostatin and Sm-C.     

Synthetic human pancreatic growth hormone releasing factor (GRF) stimulates growth hormone secretion in the domestic fowl (Gallus domesticus)

Synthetic human pancreatic Growth Hormone-Releasing Factor (hpGRF) elevated the plasma concentration of growth hormone (GH) in young and adult domestic fowl. This in vivo effect of hpGRF appeared to be largely similar for both the 32 amino-acid (hpGRF 1-32) or 40 amino-acid (hpGRF 1-40) polypeptide, although the effect of hpGRF 1-32 was more prolonged than that of hpGRF 1-40 in adult domestic fowl. The increase in plasma GH concentrations following hpGRF administration (10 micrograms/kg) was somewhat greater in young than adult chickens (the increase in plasma concentration of GH being 230 ng/ml at 1 week old, 282 ng/ml at 6 week old, 241 ng/ml at 10 weeks and 150 ng/ml in adults). In the adult domestic fowl hpGRF stimulated a greater increase in the plasma concentration of GH than did thyrotropin-releasing hormone (TRH). However in the young chicks TRH was more active. The in vitro release of GH from dispersed chicken pituitary cells was elevated by hpGRF (1-32) and hpGRF (1-40).     

Growth hormone response of bull calves to growth hormone-releasing factor

Three experiments were conducted to determine serum growth hormone (GH) response of bull calves (N = 4; 83 kg body wt) to iv injections and infusions of human pancreatic GH-releasing factor 1-40-OH (hpGRF). Peak GH responses to 0, 2.5, 10, and 40 micrograms hpGRF/100 kg body wt were 7 +/- 3, 8 +/- 3, 18 +/- 7, and 107 +/- 55 (mean peak height +/- SEM) ng/ml serum, respectively. Only the response to the 40-microgram dose was greater (P less than 0.05) than the 0-microgram dose. Concentrations of prolactin in serum were not affected by hpGRF treatment. In calves injected with hpGRF (20 micrograms/100 kg body wt) at 6-hr intervals for 48 hr, GH increased from a mean preinjection value of 3.1 ng/ml serum to a mean peak response value of 70 ng/ml serum. Differences in peak GH response between times of injection existed within individual calves (e.g., 10.5 ng/ml vs 184.5 ng/ml serum). Concentrations of GH in calves infused continuously with either 0 or 200 micrograms hpGRF/hr for 6 hr averaged 7.4 +/- 3 and 36.5 +/- 11 ng/ml serum, respectively (P less than 0.05). Concentrations of GH oscillated markedly in hpGRF-infused calves, but oscillations were asynchronous among calves. We conclude that GH response of bull calves to hpGRF is dose dependent and that repeated injections or continuous infusions of hpGRF elicit GH release, although magnitude of response varies considerably. We hypothesize that differences in GH response to hpGRF within and among calves, and pulsatile secretion in the face of hpGRF infusion may be related to the degree of synchrony among exogenous hpGRF and endogenous GRF and somatostatin.     

Growth hormone, thyrotropin and prolactin responses to simultaneous administration of human growth hormone-releasing factor and thyrotropin releasing hormone in the bovine

The effects of intravenous injection of synthetic human pancreatic growth hormone-releasing factor-44-NH2 (hpGRF-44) and synthetic thyrotropin releasing hormone (TRH), or hpGRF-44 in combination with TRH on growth hormone (GH), thyrotropin (TSH), and prolactin (PRL) release in dairy female calves (6- and 12-month-old) were studied. When 0.25 microgram of hpGRF-44 per kg of body weight (bw) was injected in combination with TRH (1.0 microgram per kg of bw), the mean plasma GH concentration of the 12-month-old calves rose to a maximum level of 191.5 ng/ml (P less than 0.001) at 15 min from the value of 6.8 ng/ml before injection at 0 min. The maximum level was 3.1 and 6.1 times as high as the peak values obtained after injection of hpGRF-44 (0.25 microgram per kg of bw) and TRH (1.0 microgram per kg of bw), respectively (P less than 0.001). The area under the GH response curve for the 12-month-old calves for 3 hr after injection of hpGRF-44 in combination with TRH was 2.5 times as large as the sum of the areas obtained by hpGRF-44 and TRH injections. In contrast, the mean plasma GH level was unchanged in saline injected calves. The magnitudes of the first and the second plasma GH responses in the 6-month-old calves to two consecutive injections of hpGRF-44 in combination with TRH at a 3-hr interval were very similar. The peak values of plasma GH in the calves after hpGRF-44 injection were 2-4 times as high as those after TRH injection.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of growth hormone releasing factor on pancreatic secretion in vivo and in vitro

Growth hormone releasing factor (GRF), a 44-residue peptide originally isolated from human pancreatic tumors, shows structural similarities to the members of the secretin-vasoactive intestinal peptide (VIP) peptides. This study was designed to determine the effects of human GRF (hGRF-(1-44] on pancreatic secretion in vivo in conscious dogs and in vitro in dispersed rat pancreatic acini. GRF given i.v. in graded doses in dogs caused a small but significant stimulation of pancreatic HCO3- and protein outputs and potentiated secretin- and cholecystokinin (CCK)-induced pancreatic HCO3- but not protein secretion. When given together with somatostatin, GRF failed to reverse the inhibitory action of this peptide on HCO3- and protein responses to secretin plus CCK in dogs. Studies in vitro dispersed rat pancreatic acini showed that GRF added to the incubation medium of these acini caused an increase in basal amylase release and shifted to the left the amylase dose-response curve to caerulein and urecholine but failed to affect the amylase response to VIP. This study indicates that GRF in vivo stimulates basal and augments secretin- or CCK-induced pancreatic HCO3- secretion and that this is probably due to direct stimulatory action of the peptide on pancreatic secretory cells.     

Specific binding of synthetic human pancreatic growth hormone releasing factor (1-40-OH) to bovine anterior pituitaries

We have studied the specific binding of a synthetic 40 amino acid, free carboxy terminus analog of human pancreatic growth hormone releasing factor (hp GRF-40-OH) to partially purified homogenates of bovine anterior pituitaries. The binding of hpGRF-40-OH to pituitary receptors at 4 degrees C reached maximal level in 4 hours and remained steady for the next 18 hours. Specific binding increased linearly with the amount of protein present in the assay. 125I-hpGRF-40-OH binding to pituitary homogenates was competitively inhibited by hpGRF-40-OH but not by unrelated hormones. The competition curve and Scatchard analysis suggest the presence of single class of receptors with a Kd congruent to 3nM and binding capacity of approximately 200 fmoles/mg protein. This is the first demonstration of specific receptors for GRF on anterior pituitary cells.