Effect of simultaneous administration of GHRH (1-40) and TRH on GH, PRL and TSH secretion in normal man

The GHRH test represents a new tool in the study of secretion in man. Nine normal fasting males received on separate occasions in random order 1) GHRH 1-40 (1 microgram/Kg bw) iv at time 0; 2) TRH (6 micrograms/min) infusion between -30 and +120 min; 3) GHRH 1-40 (1 microgram/Kg bw) iv at time 0 plus TRH (6 micrograms/min) infusion between -30 and +120 min. Blood samples were drawn for GH, PRL and TSH at -90, -60, -30, 0 min and then every 15 min for 2 h. GHRH significantly increased GH in all subjects. The same GH response was found during GHRH plus TRH test. No effect was found either on PRL and TSH secretion after GHRH administration, or on GH pattern after TRH administration. A significant decrease of TSH, but not of PRL response was observed after GHRH plus TRH administration in comparison to TRH alone. These results underline that the inhibitory effect exerted by TRH on GH secretion during some experimental conditions is not linked to a pituitary interference between GHRH and TRH. The difference in TSH secretion, following GHRH plus TRH in comparison with TRH alone, could be due to a GHRH-induced central inhibitory mechanism, probably GHRH-related.     

In-vitro control of growth hormone secretion by synthetic releasing factors in young and adult ducks (Anas platyrhynchos)

Release of GH from perifused duckling hemipituitaries was stimulated, in a biphasic manner, by synthetic TRH and human pancreatic GH-releasing factor (GRF). At all effective concentrations, the level of GH release was increased within 5 min of TRH or GRF perifusion and was maximal after 10 min of TRH perifusion and after 20 min of GRF perifusion. Although TRH was perifused for 20 min the level of GH release declined during the last 10 min. The most effective dose of TRH (1.0 micrograms/ml; 2.7 mumol/l) and GRF (0.5 micrograms/ml; 110 nmol/l) provoked similar (250-300%) increases in the level of GH release. However, since the effect of TRH was only of short duration, the total release of GH induced by GRF was higher than that elicited by TRH, especially with the low dose. The increase in release of GH induced by TRH or GRF was blunted when pituitaries from adult ducks were used. As in young ducks, the GH response to GRF was higher, whereas the response to TRH was very low. The GH response of perifused adult pituitaries to GRF was, however, potentiated when TRH was perifused simultaneously. The basal release of GH from both young and adult pituitary glands was unaffected by perifusion with somatostatin-14 (SRIF-14) at doses of 1 and 2 micrograms/ml. The perifusion of hemipituitary glands with similar doses of SRIF-14 was also unable to suppress the stimulation of GH release induced by prior perifusion with GRF, although when SRIF-14 and TRH were simultaneously perifused TRH-induced GH release was markedly suppressed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Arginine stimulates growth hormone secretion by suppressing endogenous somatostatin secretion

To determine how arginine (Arg) stimulates GH secretion, we investigated its interaction with GHRH in vivo and in vitro. Six normal men were studied on four occasions: 1) Arg-TRH, 30 g arginine were administered in 500 mL saline in 30 min, followed by an injection of 200 micrograms TRH; 2) GHRH-Arg-TRH, 100 micrograms GHRH-(1-44) were given iv as a bolus immediately before the Arg infusion, followed by 200 micrograms TRH, iv; 3) GHRH test, 100 micrograms GHRH were given as an iv bolus; and 4) TRH test, 200 micrograms TRH were given iv as a bolus dose. Blood samples were collected at 15-min intervals for 30 min before and 120 min after the start of each infusion. Anterior pituitary cells from rats were coincubated with Arg (3, 6, 15, 30, and 60 mg/mL) and GHRH (0.05, 1, 5, and 10 nmol/L) for a period of 3 h. Rat GH was measured in the medium. After Arg-TRH the mean serum GH concentration increased significantly from 0.6 to 23.3 +/- 7.3 (+/- SE) micrograms/L at 60 min. TRH increased serum TSH and PRL significantly (maximum TSH, 11.1 +/- 1.8 mU/L; maximum PRL, 74.6 +/- 8.4 micrograms/L). After GHRH-Arg-TRH, the maximal serum GH level was significantly higher (72.7 +/- 13.4 micrograms/L) than that after Arg-TRH alone, whereas serum TSH and PRL increased to comparable levels (TSH, 10.2 +/- 3.0 mU/L; PRL, 64.4 +/- 13.6 micrograms/L). GHRH alone increased serum GH to 44.9 +/- 9.8 micrograms/L, significantly less than when GHRH, Arg, and TRH were given. TRH alone increased serum TSH to 6.6 +/- 0.6 mU/L, significantly less than the TSH response to Arg-TRH. The PRL increase after TRH only also was lower (47.2 +/- 6.8 micrograms/L) than the PRL response after Arg-TRH. In vitro Arg had no effect on basal and GHRH-stimulated GH secretion. Our results indicate that Arg administered with GHRH led to higher serum GH levels than did a maximally stimulatory dose of GHRH or Arg alone. The serum TSH response to Arg-TRH also was greater than that to TRH alone. We conclude that the stimulatory effects of Arg are mediated by suppression of endogenous somatostatin secretion.     

Effect of estrogen on the growth hormone (GH) secretory response to GH-releasing factor in the castrate adult female rat in vivo

Five groups (n = 11) of 250-g female rats were oophorectomized and immediately thereafter received daily sc injections of estradiol benzoate (EB; 0.05, 0.5, 5.0, and 50.0 micrograms) or vehicle for 28 days. A sixth group underwent sham operation and received injections of vehicle. Somatomedin-C (SmC) concentrations were determined before EB administration. After 4 weeks of EB treatment, the GH response to human GH-releasing factor (1-44) (GRF; 5 micrograms/kg, iv) was determined under pentobarbital anesthesia in seven animals from each group. Serum PRL, LH, and estradiol and plasma SmC concentrations were also measured. The GH secretory response to GRF (delta GH) was greatest in castrated animals receiving vehicle (P less than 0.05) and was significantly blunted in animals receiving 5.0 and 50.0 micrograms EB (P less than 0.05) compared to that in sham-operated animals. A significant negative correlation was observed between delta GH and serum PRL concentrations (r = -0.53; P less than 0.0001). SmC concentrations after treatment were significantly lower in animals receiving 5.0 and 50.0 micrograms EB (P less than 0.01), than in sham-operated animals and were elevated compared to those in sham-operated controls in the group receiving the lowest dose of EB (0.05 microgram; P less than 0.01). Posttreatment SmC levels correlated positively with delta GH (r = 0.58; P less than 0.001) and negatively with serum estradiol concentrations (r = -0.47; P less than 0.01). Pituitary glands from the remaining animals in each group (n = 4) were weighed and assayed for GH, PRL, and LH content. Pituitary PRL content increased with increasing doses of EB replacement and correlated strongly (r = 0.82; P less than 0.0001) with pituitary weight. In the castrated adult female rat, high doses of estrogen inhibited the GH secretory response to GRF in vivo and decreased SmC concentrations. Low dose estrogen increased SmC concentrations, although the GH secretary response to GRF in this group was similar to that in sham-operated rats. The latter observation suggests that the rise in SmC levels associated with low dose estrogen may not be mediated through a change in GH secretion.     

Human pancreatic tumor growth hormone-releasing factor: dose-response relationships in normal man

Human pancreatic GRF (hpGRF-40; 1 microgram/kg, iv) selectively stimulates GH release in normal men (9). We now report the effects of graded doses of hpGRF-40 on GH release in 12 normal men. Mean peak increments in serum GH after vehicle and the various doses of hpGRF-40 were 1.13, 11.40, 14.60, 17.01, 14.45, and 15.60 ng/ml after vehicle and 0.1, 0.33, 1.0, 3.3, and 10 micrograms/kg hpGRF-40 (iv bolus), respectively. Peak values were observed 30-60 min after hpGRF-40 treatment. There was considerable variability of responsiveness among individual subjects, and no dose-response relationship between the doses and maximal GH values was found. However, the higher doses of 3.3 and 10.0 micrograms/kg resulted in a more prolonged and biphasic pattern of GH release. A side effect of facial flushing of less than 5-min duration occurred in 4 or 6 subjects who received 3.3 micrograms/kg and in all 5 who received 10 micrograms/kg of hpGRF-40. No changes in serum glucose, LH, TSH, PRL, plasma cortisol, or 8 enteropancreatic hormones occurred after hpGRF-40 treatment. There were small increases in serum somatomedin C levels 24 h after the administration of various doses of hpGRF-40 in 11 of 13 studies. Plasma immunoreactive GRF levels measured 5 min after injection were 0.09, 2.0, 4.9, 23.9, and 66.6 ng/ml after 0.1, 0.33, 1.0, 3.3, and 10 micrograms/kg hpGRF-40, respectively. Serum GH responses after insulin-induced hypoglycemia were compared to GH responses after hpGRF-40. Comparable peak GH stimulation occurred with both provocative tests. Mean +/- SEM peak GH was 20.2 +/- 1.0 ng/ml after insulin and 20.9 +/- 3.2 after hpGRF-40 treatment. hpGRF-40 selectively stimulates GH release in normal men over a dose range of 0.1-10 micrograms/kg and is an effective probe to investigate the dynamics of GH release.     

Effects of repetitive administration of thyrotropin-releasing hormone at short intervals in acromegaly

We investigated the pattern of GH secretion in response to repetitive TRH administration in patients with active acromegaly and in normal subjects. Nine acromegalic patients and 10 normal subjects received three doses of 200 micrograms of TRH iv at 90-min intervals. There was a marked serum GH rise in acromegalic patients after each TRH dose (net incremental area under the curve [nAUC]: first dose = 4448 +/- 1635 micrograms.min.l-1; second dose = 3647 +/- 1645 micrograms.min.l-1; third dose = 4497 +/- 2416 micrograms.min.l-1; NS), though individual GH responses were very variable. In normal subjects TRH did not elicit GH secretion even after repeated stimulation. Each TRH administration stimulated PRL release in acromegalic patients, though the nAUC of PRL was significantly higher after the first (1260 +/- 249 micrograms.min.l-1) than after the second and the third TRH administration (478 +/- 195 and 615 +/- 117 micrograms.min.l-1, respectively; P less than 0.01). In normal subjects too, PRL secretion was lower after repeated stimulation (first dose = 1712 +/- 438 micrograms.min.l-1; second dose = 797 +/- 177 micrograms.min.l-1; third dose = 903 +/- 229 micrograms.min.l-1 P less than 0.01), though different kinetics of PRL secretion were evident, when compared with acromegalic patients. TSH secretion, assessed in only 4 patients, was stimulated after each TRH dose, though a minimal but significant reduction of nAUC of TSH after repeated TRH challenge occurred. Both T3 and T4 increased steadily in the 4 patients. The same pattern of TSH, T3, and T4 secretion occurred in normal subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Altered growth hormone response after growth hormone releasing hormone administration in chronic renal failure

Eleven chronic renal failure patients and 11 matched controls, received growth hormone GHRH (1 microgram/kg iv) or TRH (400 microgram iv) on separate occasions, immediately before undergoing hemodialysis. GHRH-induced GH peak in uremics (22.7 +/- 5.2 micrograms/l) was not different from that obtained in control subjects (16.0 +/- 4.3 micrograms/l). However, the uremic patients did not show the habitual post-peak fall, remaining GH levels over 10 micrograms/l till the end of the test. Differences between the two groups were significant (p less than 0.05). Uremic patients showed PRL values higher than in controls, however their TRH-induced PRL peak (20.6 +/- 6.6 micrograms/l) was not different from that of controls (26.5 +/- 3.0 micrograms/l). Again chronic renal failure patients showed PRL plasma values abnormally elevated till the end of the test. Differences between the two groups were significant (p less than 0.05). Administration of placebo to a different group of seven uremic patients did not alter GH and PRL plasma levels. This sustained secretion of both GH and PRL in uremia could be attributed to reduced kidney clearance. However, when subjects were examined individually both the GHRH- and the TRH-induced hormonal peaks and the subsequent fall were not different in both groups. Unlike with controls, in uremic patients GHRH-stimulated GH and TRH-stimulated PRL/GH peaks were dispersed throughout the 120 min period. In controls GH and PRL peaks clustered around 15-30 min. The peak dispersion created a false impression of flattened curves or sustained hypersecretion in uremia.(ABSTRACT TRUNCATED AT 250 WORDS)     

In vivo and in vitro stimulation of growth hormone release in chickens by synthetic human pancreatic growth hormone releasing factor (hpGRFs)

The effect of the synthetic human pancreatic GH releasing factors (hpGRFs, hpGRF44 and hpGRF40) on GH release was studied both in vivo and in vitro. Four-week-old cockerels were injected iv with hpGRFs at 0.1 microgram, 1.0 microgram, and 10.0 micrograms/bird. The 0.1 microgram dose of hpGRFs had no effect on plasma GH levels, but the 1.0 microgram and 10.0 micrograms doses of hpGRFs caused a dose-dependent elevation of plasma GH. Plasma GH levels returned to basal 60 min after injection. HpGRFs, thyrotropin releasing hormone (TRH) and somatostatin (SRIF) were examined in a chicken in vitro pituitary cell culture system. In vitro hpGRFs and TRH caused a significant dose-dependent release of chicken GH, and the ability to stimulate GH was additive when hpGRF44 and TRH were added together in the culture medium. SRIF showed no consistent effect on the release of chicken GH, but it inhibited the stimulatory effect of hpGRF44 on chicken GH release. We conclude that hpGRF is a potent releaser of chicken GH in vivo and in vitro.     

On the mechanism of growth hormone autofeedback regulation: possible role of somatostatin and growth hormone-releasing factor

To determine the role of somatostatin (SRIF) and GH-releasing factor (GRF) in GH autofeedback, 20 micrograms rat GH in 2 microliter were injected into the third ventricle (IVT) 1 or 3 h before injection of the alpha 2-receptor stimulator clonidine (50 micrograms/kg, iv), which elevates plasma GH and TSH levels in normal rats. GH preinjected 1 or 3 h before clonidine significantly suppressed the clonidine-induced GH surge, whereas TSH release was not affected by GH. Preinjection of ovine LH IVT following the same protocol did not inhibit the clonidine-induced GH surge, suggesting a specific effect of IVT GH. Passive immunization with 400 microliters sheep antisomatostatin serum did not reverse the inhibition of the clonidine-induced GH surge by exogenous GH administered IVT either 1 or 3 h before clonidine. The TSH response was augmented by this procedure. Furthermore, IVT GH did not reduce the surges of GH and TSH elicited by GRF (250 ng/kg, iv) and TRH (150 ng/kg, iv) administered 1 or 3 h after IVT rat GH. These results suggest that GH autofeedback is mediated by reduced GRF secretion, rather than enhanced SRIF release.     

Effect of thyrotropin-releasing hormone on growth hormone release in normal subjects pretreated with human pancreatic growth hormone-releasing factor 1-44 pulsatile administration

Growth hormone (GH) increase after thyrotropin-releasing hormone (TRH) has been documented in many pathological conditions. In order to evaluate whether exposure to growth hormone-releasing factor (GRF) might contribute to this effect in normal subjects, we studied GH responses to placebo, TRH, GRF and GRF plus TRH either in basal condition or after GRF administration. Ten subjects received placebo, TRH, GRF and GRF plus TRH on four separate occasions. GRF induced a clear rise in plasma GH, statistically different from those obtained after placebo or TRH (p less than 0.01). TRH was completely ineffective in both stimulating GH release and amplifying the secretory GH response to GRF. Twenty subjects, subdivided in four groups, received 3 consecutive intravenous GRF boli at two-hour intervals. Two hours later they were given a fourth stimulus: 5 had another 25 micrograms GRF i.v., 5 had 200 micrograms TRH i.v., 5 were tested with simultaneous 25 micrograms GRF and 200 micrograms TRH i.v. injection, and 5 with 1 ml saline. GH secretory responses were quantitated by determining the net incremental area under the curve (nAUC) over 60 min after the administration of each stimulus. The pattern of GH secretion after 1-3 GRF boli was not statistically different among the four groups. Plasma GH nAUC was higher after the first GRF injection than after the following ones (p less than 0.01). The administration of a fourth GRF bolus also caused a GH increase which was significantly smaller than that after the first one (p less than 0.01), but greater than that after placebo (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of acute infusion of erythropoietin on paradoxical responses of growth hormone to thyrotropin-releasing hormone in acromegalic patients

OBJECTIVE: Our aim has been to evaluate the effects of i.v. infusion of recombinant human erythropoietin (rhEPO) on the responses of growth hormone (GH), prolactin (PRL) and thyrotropin (TSH) to thyrotropin-releasing hormone (TRH) stimulation in acromegalic patients. METHODS: We studied 16 patients (8 females, aged 29-68 years) with active acromegaly and 12 control subjects (7 females, 24-65 years). All participants were tested with TRH (400 microg i.v. as bolus) and with TRH plus rhEPO (40 U/kg at a constant infusion rate for 30 min, starting 15 min before TRH injection) on different days. Blood samples were obtained between -30 and 120 min for GH and PRL determinations, and between -30 and 90 min for TSH determinations. Hormone responses were studied by a time-averaged (area under the secretory curve (AUC)) and time-independent (peak values) analysis. RESULTS: Twelve patients exhibited a paradoxical GH reaction after TRH administration with great interindividual variability in GH levels. When patients were stimulated with rhEPO plus TRH there were no changes in the variability of GH responses or in the peak and AUC for GH secretion. Infusion with rhEPO did not induce any significant change in GH secretion in normal subjects. Baseline and TRH-stimulated PRL concentrations in patients did not differ from those values found in controls. When TRH was injected during the rhEPO infusion, a significant (P<0.05) increase in PRL concentrations at 15-120 min was found in acromegalic patients. Accordingly, the PRL peak and the AUC for PRL secretion were significantly increased in patients. Infusion with rhEPO had no effect on TRH-induced PRL release in control subjects. Baseline TSH concentrations, as well as the TSH peak and the AUC after TRH, were significantly lower in patients than in controls. Infusion with rhEPO modified neither the peak TSH reached nor the AUC for TSH secretion after TRH injection in acromegalic patients and in healthy volunteers. CONCLUSION: Results in patients with acromegaly suggest that (i) the paradoxical GH response to TRH is not modified by rhEPO infusion, (ii) rhEPO has no effect on TRH-induced TSH release, and (iii) acute rhEPO administration increases the TRH-induced PRL release in acromegalic patients.     

Comparative stimulation of growth hormone secretion in anaesthetized chickens by human pancreatic growth hormone-releasing factor (hpGRF) and thyrotrophin-releasing hormone (TRH)

Plasma concentrations of growth hormone (GH) were elevated in anaesthetized male domestic fowl following the intravenous administration of either synthetic human pancreatic GH-releasing factor 1-44 (NH2) (hpGRF) or synthetic thyrotrophin-releasing hormone (TRH). In 6-week-old chicks the plasma GH level was elevated between 5 and 10 min after the injection of hpGRF at doses between 1 and 80 micrograms/kg. The magnitude of the response increased with doses of hpGRF between 1 and 10 micrograms/kg but declined with higher doses. The GH concentration rapidly declined between 10 and 20 min and between 20 and 40 min after injection. The administration of TRH had similar effects on GH secretion, although the responses were greater than with comparable doses of hpGRF, and the most effective dose (1-1.4 micrograms/kg) was less than with hpGRF. In anaesthetized adult cockerels GH secretion was also increased by the administration of hpGRF (1-20 micrograms/kg) or TRH (0.1-80 micrograms/kg) and in both cases the dose-response relationship was biphasic. The maximal response to TRH in adult birds was again greater than that produced by hpGRF although the response was less than that elicited in immature birds and required a higher dose (20 micrograms/kg) of TRH. The optimal dose of hpGRF and the magnitude of the GH response induced in adult birds was comparable with that in immature chicks. These results demonstrate provocative effects of TRH and hpGRF on GH secretion in the domestic fowl. The sensitivity of the GH response to TRH suggests that it may have a physiological role in the hypothalamic control of GH secretion.     

Decreased growth hormone (GH) response to oral clonidine in endemic cretinism: effect of L-T3 therapy

As GH secretion is dependent upon thyroid hormone availability, the GH responses to clonidine (150 micrograms/m2) and the TSH and PRL response to TRH were studied in eight endemic (EC) cretins (3 hypothyroid, 5 with a low thyroid reserve) before and after 4 days of 100 micrograms of L-T3. Five normal controls (N) were also treated in similar conditions. Both groups presented a marked increase in serum T3 after therapy (N = 515 +/- 89 ng/dl; EC = 647 +/- 149 ng/dl) followed by a decrease in basal and peak TSH response to TRH. However, in the EC patients an increase in serum T4 levels and in basal PRL and peak PRL response to TRH after L-T3 therapy was observed. One hypothyroid EC had a markedly elevated PRL peak response to TRH (330 ng/dl). There were no significant changes in basal or peak GH values to treatment with L-T3 in normal subjects. In the EC group the mean basal plasma GH (2.3 +/- 1.9 ng/ml) significantly rose to 8.8 +/- 3.2 ng/ml and the mean peak response to clonidine (12.7 +/- 7.7 ng/ml) increased to 36.9 +/- 3.1 ng/ml after L-T3. Plasma SM-C levels significantly increased in N from 1.79 +/- 0.50 U/ml to 2.42 +/- 0.40 U/ml after L-T3 (p less than 0.01) and this latter value was significantly higher (p less than 0.05) than mean Sm-C levels attained after L-T3 in the EC group (respectively: 1.14 +/- 0.59 and 1.78 +/- 0.68 U/ml). These data indicate that in EC the impaired GH response to a central nervous system mediated stimulus, the relatively low plasma Sm-C concentrations, and the presence of clinical or subclinical hypothyroidism may contribute to the severity of growth retardation present in this syndrome.     

Sexual differentiation of growth hormone feedback effects on hypothalamic growth hormone-releasing hormone and somatostatin

To investigate possible sex differences in the feedback regulation of growth hormone (GH) secretion, concentrations of immunoreactive GH-releasing hormone (GRF) and somatostatin (SS) were measured in the median eminence (ME) and the hypothalamus of male and female rats bearing the MtTW15 tumor, which secretes high amounts of GH and prolactin (PRL). Four weeks after tumor implantation in male rats, the GRF concentration in the whole hypothalamus, including the ME, was decreased by 37% (0.29 +/- 0.02 vs. 0.46 +/- 0.02 ng/mg protein in intact male controls; p less than 0.001) and the concentration of SS was increased by 40% (11.5 +/- 0.7 vs. 8.1 +/- 0.3 ng/mg protein in male controls; p less than 0.01). In female rats, the presence of tumor for 4 weeks caused a smaller (18%) reduction in GRF concentrations (0.27 +/- 0.02 vs. 0.33 +/- 0.03 ng/mg protein in intact female controls; p less than 0.05) and no significant change in SS concentrations (10.2 +/- 0.08 vs. 9.7 +/- 0.8 ng/mg protein in female controls). Tumor-related changes in GRF and SS concentrations were also more pronounced in male rats than in females, when determined separately in the microdissected ME and in the remaining hypothalamus. These differences occurred despite similar increases in serum GH, PRL and insulin-like growth factor I concentrations in male and female tumor-bearing rats. To assess which hormone (GH or PRL) was responsible for these changes, intact male rats were treated for 10 days with 2 daily s.c. injections of rat GH (rGH; 100 and 250 micrograms/day), rat PRL (100 and 250 micrograms/day) or vehicle.(ABSTRACT TRUNCATED AT 250 WORDS)     

Combined pituitary stimulation test: interactions of hypothalamic releasing hormones in man

The use of hypothalamic releasing hormones for the clinical assessment of anterior pituitary function is both simple and free of severe side effects. Tests with the recently discovered substances GRF and CRF as well as with combinations of several releasing hormones are therefore used in many clinics. A reliable interpretation of such combined tests, however, is only possible when positive or negative interactions between these releasing hormones are known. After a rest of 2 h to reach basal cortisol levels, 7 groups of 5 male volunteers each received an iv bolus injection consisting of either: A): GRF (100 micrograms) + CRF (50 micrograms) + TRH (200 micrograms) + LHRH (100 micrograms), B): CRF + TRH, C): GRF + TRH, D): LHRH + TRH, E): TRH, F): GRF, G): CRF. During the following 2 h, GH, TSH, cortisol, LH, FSH and prolactin were measured every 15 min. The TSH response after the injection of all 4 releasing hormones was significantly higher (delta TSH = 16.5 +/- 2.0 microU/ml, x +/- SE) compared to the injection of TRH alone (delta TSH = 9.3 +/- 1.4 microU/ml; p less than 0.025). This increment in TSH secretion was confirmed when 2 groups of 5 female volunteers were studied with the TRH-test (delta TSH = 9.9 +/- 1.8 microU/ml) or the combination of all four releasing hormones (delta TSH = 16.8 +/- 2.9 microU/ml; p less than 0.05). This exaggerated TSH-response to TRH was demonstrated to be entirely due to simultaneous administration of GRF, whereas CRF and LHRH in combination with TRH had no additional effect on TSH release.(ABSTRACT TRUNCATED AT 250 WORDS)     

Impaired inhibitory effects of somatostatin on growth hormone (GH)-releasing hormone stimulation of GH secretion after short term infusion

We examined the effect of prior exposure to somatostatin (SRIH) on its inhibition of GH and TSH responses to GHRH and TRH stimulation to determine whether SRIH desensitization has physiological significance in man. Six men received GHRH (1 microgram/kg, iv) and TRH (0.3 microgram/kg, iv) 20 min after starting a saline or SRIH (5.5 ng/kg/min, iv) infusion and again 6 h later. Hormone responses were quantified by measuring the area under the curve, corrected for GH concentration at injection time. Similar results were obtained when GH responses were quantified by measuring the hormone secretory rate using the program Detect. Plasma GH and TSH responses to the two GHRH and TRH injections during saline were similar. However, the effects of prior exposure to SRIH were hormone specific. SRIH blunted GH responses to GHRH at 20 min (1609 +/- 286 micrograms/L.min vs. 451 +/- 224), but did not significantly inhibit the responses 6 h later (1422 +/- 410 micrograms/L.min vs. 1000 +/- 302). In contrast, SRIH inhibition of TSH responses to the two TRH injections was similar (first, 946 +/- 201 micrograms/L.min vs. 700 +/- 148; second, 813 +/- 175 micrograms/L.min vs. 562 +/- 66). We next used these results to study whether the previously reported attenuation of GH responses to repeated GHRH stimulation at 2-h intervals is mediated by SRIH. Eight men received GHRH (1 microgram/kg, iv) 380 min after starting a saline or SRIH (5.5 ng/kg/min, iv) infusion or 90 min after starting a primed (5 mg, iv) infusion of propranolol (80 micrograms/min, iv) and again 2 h later. As in the first protocol, GH responses to GHRH were not inhibited when preceded by a 6-h SRIH infusion. However, the 6-h SRIH infusion resulted in a partial restoration of plasma GH responses to the second GHRH injection (saline infusion: first, 1429 +/- 342 micrograms/L.min; second, 254 +/- 75; SRIH infusion: first, 1042 +/- 247 micrograms/L.min; second, 468 +/- 105). beta-Blockade by propranolol resulted in enhanced GH responses to GHRH, but did not prevent the attenuation of GH responses to the second GHRH injection (first, 1937 +/- 366 micrograms/L.min; second, 614 +/- 99). The desensitization to SRIH inhibition of GH responses to GHRH after a 6-h SRIH infusion provides evidence of physiological consequences of SRIH receptor down-regulation. The impaired GH responses to repeated GHRH stimulation are mediated at least in part by enhanced SRIH secretion, which appears independent of a beta-adrenergic mechanism.     

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.     

Growth hormone-releasing peptide-2 infusion synchronizes growth hormone, thyrotrophin and prolactin release in prolonged critical illness

OBJECTIVE: During prolonged critical illness, nocturnal pulsatile secretion of GH, TSH and prolactin (PRL) is uniformly reduced but remains responsive to the continuous infusion of GH secretagogues and TRH. Whether such (pertinent) secretagogues would synchronize pituitary secretion of GH, TSH and/or PRL is not known. DESIGN AND METHODS: We explored temporal coupling among GH, TSH and PRL release by calculating cross-correlation among GH, TSH and PRL serum concentration profiles in 86 time series obtained from prolonged critically ill patients by nocturnal blood sampling every 20 min for 9 h during 21-h infusions of either placebo (n=22), GHRH (1 microg/kg/h; n=10), GH-releasing peptide-2 (GHRP-2; 1 microg/kg/h; n=28), TRH (1 microg/kg/h; n=8) or combinations of these agonists (n=8). RESULTS: The normal synchrony among GH, TSH and PRL was absent during placebo delivery. Infusion of GHRP-2, but not GHRH or TRH, markedly synchronized serum profiles of GH, TSH and PRL (all P< or =0.007). After addition of GHRH and TRH to the infusion of GHRP-2, only the synchrony between GH and PRL was maintained (P=0.003 for GHRH + GHRP-2 and P=0.006 for TRH + GHRH + GHRP-2), and was more marked than with GHRP-2 infusion alone (P=0.0006 by ANOVA). CONCLUSIONS: The nocturnal GH, TSH and PRL secretory patterns during prolonged critical illness are herewith further characterized to include loss of synchrony among GH, TSH and PRL release. The synchronizing effect of an exogenous GHRP-2 drive, but not of GHRH or TRH, suggests that the presumed endogenous GHRP-like ligand may participate in the orchestration of coordinated anterior pituitary hormone release.     

Effects of the somatostatin analog BIM 23014 on the secretion of growth hormone, thyrotropin, and digestive peptides in normal men

BIM 23014 (BIM) is a long-acting octapeptide somatostatin analog. We studied the effects of this analog on the secretion of GH, TSH, and gastroenteropancreatic hormones [secretin, motilin, and pancreatic polypeptide (PP)] in normal men. In the first protocol three BIM doses (125, 250, and 500 micrograms) and vehicle were administered sc in random order at 2000 h to eight normal young men. Plasma GH concentrations decreased during the first part of the night only after the highest dose (P less than 0.05). Plasma secretin levels did not change, while plasma motilin decreased after the 250- and 500-micrograms doses (P = 0.05 and P = 0.02, respectively), and plasma PP decreased after all three doses (P less than 0.05, P less than 0.01, and P less than 0.01, respectively) during the first part of the night. In the second protocol, eight men received BIM, administered by constant sc infusion during the night in a dose of 2 mg/12 h, or vehicle, either alone or in association with a 10 ng/kg.min iv GHRH or vehicle infusion. Nocturnal GH secretion was suppressed by the BIM infusion (P less than 0.001). GH secretion, stimulated by GHRH infusion (P less than 0.001), was reduced by concomitant BIM infusion (P less than 0.001) and was pulsatile during the combined infusions. BIM infusion suppressed the physiological nighttime rise in plasma TSH levels. Plasma motilin and PP levels were reduced by BIM, when administered either alone or in combination with GHRH. We conclude that: 1) BIM is capable of reducing GH secretion when administered sc in a dose of 500 micrograms and of abolishing nocturnal GH secretion when constantly infused at a dose of 2 mg/12 h; 2) BIM, constantly infused, reduces the nocturnal rise in TSH secretion; and 3) motilin and PP secretion are more sensitive than that of GH to BIM, as they are reduced by a lower dose.     

Effects of insulin-like growth factor I (IGF-I) on growth hormone-releasing factor (GRF) and thyrotropin-releasing hormone (TRH) stimulation of growth hormone (GH) secretion in the domestic fowl (Gallus domesticus)

Recent studies in mammalian species indicate that IGF-I may act as a negative feedback inhibitor of GH release through alteration of pituitary secretion or sensitivity to hypothalamic regulatory factors. Although avian GH secretion appears to be regulated by the differential release of hypothalamic inhibitory (somatostatin) and stimulatory (GRF and TRH) factors, feedback effects of IGF-I on in vivo GH release in birds have not been investigated. To study the effects of elevated IGF-I concentration on GRF- and TRH-stimulated GH secretion, 4-week-old chickens received an intravenous injection of recombinant human IGF-I either 15 min prior to (6 micrograms, study 1), or simultaneous with (10 micrograms, study 2). GRF (hGRF44NH2, 5 micrograms/kg) or TRH (0.5 microgram/kg) administration. Radioimmunoassay analysis of plasma collected prior to and following peptide treatment indicated that circulating IGF-I concentrations were elevated 83.9, 60.6, 77.9, and 88.8% at the time of TRH and GRF administration in studies 1 and 2, respectively. Peak GH concentrations (mean of +5- and +15-min samples) subsequent to TRH injection were significantly (P less than 0.01) depressed 45.1 and 48.2% in IGF-I-treated as compared with control chicks in the first and second studies, respectively. GRF-stimulated GH secretion was significantly (P less than 0.01) decreased by IGF-I administration in study 2 (41.3%) but not in study 1. An estimated half-life for IGF-I in the chicken is less than 15 min based on the disappearance rate of the elevation produced by exogenous IGF-I injections. Thus, IGF-I exerts a negative feedback effect on pituitary hormone secretion in avian as well as mammalian species.