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 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.     

Increased growth hormone responses to growth hormone releasing hormone and thyrotropin releasing hormone in patients with metastatic testicular cancer

In 16 patients with metastatic testicular cancer and 10 age matched male control subjects growth hormone (GH) responses to growth hormone releasing hormone (GHRH; 1 microgram/kg body weight iv.) and thyrotropin releasing hormone (TRH; 200 micrograms iv.) were measured. Basal GH levels and GH levels following stimulation with GHRH or TRH were significantly increased in cancer patients compared to control subjects. 9 patients with testicular cancer were studied both in the stage of metastatic disease and after they had reached a complete remission. In complete remission GH responses to GHRH tended to decrease but the differences did not reach statistical significance. Our data suggest an alteration of hypothalamic and/or pituitary regulation of GH secretion in patients with metastatic testicular cancer.     

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.     

Interaction of human pancreatic growth hormone-releasing factor, thyrotropin-releasing hormone, and somatostatin on growth hormone release in chickens

The effects of synthetic somatostatin (SRIF) on serum growth hormone (GH) concentrations stimulated by exogenous administration of synthetic thyrotropin-releasing hormone (TRH) and/or human pancreatic GH-releasing factor (hpGRF) were investigated in 4-week-old cockerels. In addition, the additive effects of TRH and hpGRF on serum GH were examined. TRH and hpGRF, when given in combination intravenously, produced an additive effect on serum GH concentration that peaked 10 min after the injection. The somatostatin did not significantly affect basal GH concentrations when given alone, but did significantly decrease the magnitude of the GH response to hpGRF. In contrast, SRIF did not significantly decrease the stimulatory effects of TRH on GH release. These results suggest that TRH and hpGRF are potent GH releasers in vivo and that their stimulating effects on GH release are additive, suggesting different mechanisms for their stimulation. The results obtained from the combination studies suggest that the main site of the stimulatory action of hpGRF is at the pituitary, and that SRIF significantly inhibited the rise in serum GH induced by a synthetic hpGRF, but not that induced by TRH.     

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.     

Lipolytic activity of purified pituitary and bacterially derived growth hormone on chicken adipose tissue in vitro

The ability of growth hormone (GH) to stimulate lipolysis was examined using chicken abdominal adipose tissue explants incubated in vitro and purified pituitary and bacterially derived chicken and bovine GH. Consistently in the fourth hour of incubation, lipolysis (as determined by glycerol release) was increased by the presence of GH (1 micrograms/ml), irrespective of pituitary or bacterial derivation or of chicken or bovine origins. This effect of GH was observed with adipose tissue originating from young (6-8 weeks old) intact and hypophysectomized chicks and adult (6-9 months old) male chickens. Glycerol release was also enhanced by lower doses of GH (10 ng/ml with tissue from young and 100 ng/ml with tissue from adult chickens).     

Plasma growth hormone responses to repetitive administrations of growth hormone releasing factor in patients with pituitary dwarfism

Plasma growth hormone (GH) responses to the repetitive administrations of synthetic human pancreatic growth hormone releasing factor (hpGRF-44) were studied in 15 patients with GH deficiency (11 diagnosed as idiopathic and 4 diagnosed as secondary to hypothalamo-pituitary tumor). hpGRF-44 was administered by single iv bolus (2 micrograms/kg), repetitive im (100 micrograms, twice a day), and/or repetitive iv infusion (2.5 micrograms/min for 90 min, once a day) for three to six consecutive days. Three of the eleven idiopathic GH deficient patients had plasma GH responses to both single iv bolus injection and repetitive administrations by im, or iv infusion of hpGRF. In four of the remaining eight, who had not had peak plasma GH levels above 5 ng/ml to a single iv bolus of the peptide, repetitive administrations of hpGRF-44 by im injection and/or iv infusion induced GH responses to the peptide. In the four patients with secondary GH deficiency, three had plasma GH response to hpGRF administration but one patient, who had indications of pituitary disorder, did not show any plasma GH response to either single iv injection or repetitive administrations of hpGRF-44. These data show that repetitive administrations of hpGRF-44 can induce plasma GH responses in some GH deficient patients who do not respond to a single iv bolus of the peptide.     

Growth hormone-releasing factor on growth hormone secretion in prepubertal calves

The effects of iv administration of growth hormone-releasing factor (GRF) on growth hormone (GH) release and on nitrogen metabolism were measured in prepubertal calves. Crossbred beef heifers (111 kg) were used in a Latin square design to test the effects of 0, 0.01, 0.033, 0.067, and 0.1 microgram human pancreatic (hp) GRF [hpGRF (1,40)OH]/kg body wt on plasma GH concentrations. When they were given doses of 0.067 and 0.1 microgram hpGRF/kg body wt, plasma GH increased (P less than 0.05) within 5-15 min, compared with injections of control buffer, and then returned to preinjection concentrations. The response to 0.067 microgram hpGRF/kg body wt every 3 hr for 42 hr was studied in five heifers (137 kg body wt). The animals responded to 50% of the GRF injections with an increase in plasma GH during every 6-hr period measured. Nitrogen retention, hormone concentrations, and weight gain were measured in five bull calves (90 kg body wt) administered 0 or 0.067 microgram Nle rat hypothalamic GRF (1,29)NH2/kg body wt every 4 hr for 10 days. Metabolic parameters were interpreted to indicate an anabolic response to GRF even though increases of 16% in nitrogen retention, 23% in plasma somatomedin C concentrations, and 36% in weight gain with pulsatile GRF treatment were variable and statistically similar to those of controls. These results indicate that GRF induces peak GH secretion within 15 min in prepubertal calves and that calves can respond to multiple injections of GRF with an increase in plasma GH.     

Thyroid hormone response to thyrotrophin releasing hormone (TRH) in the sex-linked dwarf chicken

The effect of an injection of thyrotrophin releasing hormone (TRH) on plasma levels of thyroid hormones was studied in dwarf and normal Rhode Island Red chickens with similar genotypes other than for the sex-linked dwarf gene dw. The sex-linked dwarf chickens had different plasma iodothyronine levels from control normal chickens: high thyroxine (T4), low triiodothyronine (T3) and similar reverse T3 (rT3) levels. The injection of TRH (10 micrograms/kg) in 5-day- and 5-week-old normal chickens increased the plasma T4 within 30 min without a significant increase in T3, whereas the injection of TRH in 11-and 26-week-old normal chickens increased plasma T3 60 min later. In dwarfs the response of T4 to TRH was the same as that in normals but no increased T3 response was observed. The plasma level of rT3 was not influenced by the TRH injection in either strain. These results suggest that although in the sex-linked dwarfs thyroidal response to exogenous TRH is similar to that of normals, the dwarf gene dw inhibits the conversion of T4 to T3 in peripheral tissues without any inhibitory effect on rT3 production.     

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.     

Pharmacokinetics of growth hormone secretion in humans induced by growth hormone releasing hormone

This investigation compares the age- and sex-related changes in growth hormone (GH) response to growth hormone releasing hormone (GHRH) in normal subjects using an appropriate pharmacokinetic model. Twenty-five subjects (14 males and 11 females) aged 23-89 yr received a single intravenous bolus dose (1 microgram/kg) of GHRH-40 solution. Plasma GH concentration-time profiles are best characterized by a biexponential equation (or one-compartment model) with first-order release and disappearance rates and an equilibration lag time. The harmonic mean release rate half-life is similar for both sexes (males: 12.6 min vs. females; 11.4 min) but significantly different across age groups (23-35 yr: 7.2 min vs. 50-89 yr: 16.8 min). The mean disappearance rate half-life and GHRH-equilibration time lag for females (33.6 and 20.4 min, respectively) and the higher age group subjects (32.4 and 21.6 min, respectively) are significantly longer than those of males (22.8 and 9 min, respectively) and the lower age-group subjects (21.6 and 8.4 min, respectively). The mean metabolic clearance rate of GH is significantly lower (p less than 0.02) for females than for males (3.1 vs. 4.83 ml/hr.m2). However, the production rate and the amount of GH released by the pituitary for our subjects appear to be very similar for both males (8.7 micrograms/hr.m2 and 4.65 micrograms/m2) and females (9.33 micrograms/hr.m2 and 5.11 micrograms/m2).     

Somatostatin inhibition of growth hormone secretion in an adult bird: the domestic fowl

1. The intravenous (i.v.) infusion of somatostatin (SRIF, 1.0 microgram/kg per min) promptly (within 5 min) reduced the growth hormone (GH) concentration in the plasma of conscious adult chickens. 2. The GH concentration progressively declined throughout a 60-min period of SRIF infusion, but was dramatically increased above pre-infusion levels within 5 min of SRIF withdrawal and maintained at an elevated level for at least 30 min afterwards. 3. Sodium pentobarbitone-anaesthesia lowered the basal GH concentration to levels comparable with those in conscious birds infused with SRIF. When administered to anaesthetized birds, exogenous SRIF was unable to further reduce the GH concentration and unable to induce 'rebound' GH release. 4. While thyrotropin releasing hormone (TRH, 10 micrograms/kg) increased the GH concentration in both conscious and anaesthetized birds, only the GH response in the anaesthetized birds was diminished by SRIF infusion. 5. Rebound GH secretion following the termination of SRIF infusion was observed in both conscious and anaesthetized birds injected with TRH. 6. These results demonstrate that SRIF can inhibit basal and TRH-stimulated GH secretion in adult domestic fowl and indicate that anaesthesia disrupts the normal control of GH releases.     

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)     

Effect of 3-hydroxy-4-1(H)pyridone on the basal and thyrotropin-releasing hormone-stimulated release of thyroid-stimulating hormone from perifused anterior pituitary fragments

This study investigated the direct effect of 3-hydroxy-4-1(H)-pyridone (DHP), the breakdown product of mimosine in the rumen, on thyroid-stimulating hormone (TSH) secretion by perifusion of rat anterior pituitary fragments. During a 2-h perifusion with thyrotropin-releasing hormone (TRH), the total release of TSH increased linearly (P less than 0.05, r = 0.966) with increasing concentration of TRH from 1 to 100 ng/ml. The release was maximal at 100 ng/ml. There were no differences in total basal TSH release among control and DHP-treated pituitary fragments. DHP at concentrations of 1, 10, and 100 micrograms/ml had no significant effect on the TSH response to TRH. However, DHP at the concentration of 1 mg/ml significantly suppressed the TSH response to TRH administered continuously or as a 10-min pulse. These results suggest that DHP modulates the pituitary thyrotroph's response to TRH.     

Gastric erosions induced by intracisternal thyrotropin-releasing hormone (TRH) in rats

Intracisternal injection of TRH (1 microgram) under light ether anesthesia induced within 4 hr gastric lesions in 24-hr fasted rats maintained unrestrained at room temperature. Saline, ovine corticotropin-releasing factor (oCRF, 10 micrograms), or human pancreatic growth hormone-releasing factor [hpGRF(1-40), 10 micrograms] tested under the same conditions did not modify the integrity of the gastric mucosa. TRH injected intravenously (100 micrograms/kg) proved to be ineffective. The production of gastric erosions elicited by intracisternal TRH (0.1-1 microgram) or by a stabilized TRH analog, RX 77368 [pGlu-His-(3,3'-dimethyl)-ProNH2, (0.01-0.1 microgram)] was dose-dependent. RX 77368 shows an enhanced potency over TRH. TRH action on gastric mucosa was reversed by atropine, omeprazole and cimetidine. These results demonstrate that TRH, unlike the other hypothalamic releasing factors CRF or GRF, is able to act within the brain to cause the formation of gastric erosions probably through mechanisms involving changes in gastric acid secretion. Intracisternal injection of TRH or its potent analog RX 77368 appears also as a new, simple method to produce centrally mediated experimental gastric erosions in 24 hr-fasted rats.     

Central somatostatinergic regulation of growth hormone secretion in dwarf chickens.

1. Basal circulating growth hormone (GH) concentrations in sex-linked-dwarf (SLD) chickens were unaffected by the intracerebroventricular (icv) injection of 10, 50 or 100 micrograms somatostatin (SRIF). 2. The GH response to systemic thyrotropin-releasing hormone (TRH; 10 micrograms/kg, iv) was, however, 'paradoxically' enhanced 20 min after icv SRIF administration. 3. A lower dose (1.0 micrograms) of SRIF had no effect on basal or TRH-induced GH release. 4. High-titre SRIF antisera (4 microliters) also had no acute effect on basal plasma GH concentrations, but augmented the GH response to TRH challenge. 5. SRIF would appear to act at central sites to modulate stimulated GH secretion in SLD chickens.     

Growth hormone secretion during pregnancy: altered effects of growth hormone releasing factor and insulin-like growth factor-I in vitro

Growth hormone (GH) secretion is controlled by growth hormone releasing factor (GRF) but changes in the circulating level of this hormone are difficult to measure. Insulin-like growth factor (IGF-I) is a GH-dependent growth factor which significantly but slightly inhibits stimulated GH release in vitro. We have tested the effects of GRF and IGF-I on GH release in pregnancy, a state in which serum concentrations of GH are elevated and levels of IGF-I are lowered. We have found, in a system of acutely dispersed adenohypophysial cells prepared from pregnant (day 21-23) or control cycling female rats, that adenohypophysial cells from pregnant rats have an increased GH release with GRF. In contrast, IGF-I inhibition is similar but slightly smaller. These altered responses may result in elevated serum GH levels during pregnancy.     

Growth hormone releasing effect of hpGRF-40 in rats at different time intervals following ablation of the mediobasal hypothalamus

We have investigated the effect of hypothalamo-pituitary disconnection in the rat on the growth hormone (GH) responsiveness to human pancreatic GH-releasing factor (hpGRF). Adult female rats, sham-operated (sham-op) or bearing a complete mechanical ablation of the mediobasal hypothalamus (MBH-A) were challenged, while under urethane anesthesia, with hpGRF-40 (20,100,500 ng/rat i.v.) at different time intervals after surgery. In sham-op rats only 500 ng/rat of hpGRF-40 stimulated GH release, while in 1-and 7-day MBH-A rats the stimulation also occurred with the lower hpGRF doses and the rise in plasma GH was greater than in sham-op controls. Twenty-one and 42 days after the placing of the lesions the GH response to hpGRF-40 was still present at the 500 ng/rat dose, though it was smaller than in sham-op controls. Evaluation of pituitary GH content demonstrated a progressive and rapid decline starting the first day after the placing of the lesions. These data indicate that GH responsiveness to hpGRF is: 1) enhanced in the anterior pituitary shortly after hypothalamo-pituitary disconnection and, 2) despite a striking reduction of the pituitary GH stores, it is maintained after these lesions.The physiologic growth hormone (GH) releaser in the rat is GH-releasing factor and, recently, a group of peptides has been characterized from human pancreatic tumors (hpGRFs) (1,2) which are potent and specific GH-releasers in both animals (3) and man (4). The availability of these peptides, which show a high degree of homology with the physiologic rat hypothalamic GRF (5), offers the unique opportunity to assess somatotrope responsiveness to GRF molecules in rats with hypothalamo-pituitary disconnection.In this study we have first evaluated the GH pituitary responsiveness to increasing doses of hpGRF-40 in rats following mechanical ablation of the mediobasal hypothalamus (6). These rats, by definition, lack the effect of both central nervous system (CNS) inhibitory (e.g. somatostatin) and stimulatory (e.g. GRF) influences to GH release. With the aim to ascertain how the lack of these two opposing inputs reflects on the secretory capacity of the somatotropes, we also investigated the GH response to hpGRF-40 at different time intervals after the lesioning. In a study in rats with electrolytic lesions of the ventromedial-arcuate region of the hypothalamus Tannenbaum et al (7) had shown persistence of the GH response to huge doses of a hpGRF analog.     

Stimulation of growth hormone release by thyrotropin-releasing hormone in elderly subjects

The effect of thyrotropin-releasing hormone (TRH) on the release of growth hormone (GH) was investigated in 16 elderly male subjects aged 74-88 years. Intravenous injection of 200 micrograms TRH induced a clear-cut GH rise (greater than or equal to 10 ng/ml) in 7 of 16 subjects. TRH administration did not raise plasma GH in 10 adult subjects aged 36-58 years. The results suggest disorders in neurobiochemical mechanisms regulating hypothalamopituitary function in elderly men.