The somatostatin analog octreotide inhibits the secretion of growth hormone (GH)-releasing hormone, thyrotropin, and GH in man

The effects of the somatostatin analog octreotide on plasma GH, TSH, and immunoreactive GH-releasing hormone (IR-GHRH) were studied in 10 normal men. After morning sc administration of 50 or 100 micrograms octreotide or placebo, plasma GH, TSH and GHRH were measured frequently for 6 h. Plasma GH or IR-GHRH concentrations did not change after placebo injection, but plasma TSH levels gradually decreased, in conformity with a circadian rhythm during the morning. The mean plasma GH levels after sc injection of 50 or 100 micrograms octreotide declined, and no spontaneous GH pulses occurred for 5 h. Plasma TSH decreased rapidly after both doses of octreotide and was significantly lower than the level after placebo treatment from 90-315 min (P less than 0.05) and 60-360 min (P less than 0.05 or P less than 0.01), respectively. Plasma IR-GHRH levels also were significantly lower from 30-360 min (P less than 0.05) in the group given 100 micrograms octreotide compared with the value in the placebo group. We conclude that octreotide inhibits not only GH and TSH secretion from the pituitary, but also GHRH release from the hypothalamus and/or peripheral tissues. These findings suggest that somatostatin controls GH secretion not only by suppressing pituitary secretion of GH but also by suppressing GHRH release from the hypothalamus.     

Long term pulsatile growth hormone (GH)-releasing hormone therapy in children with GH deficiency

We treated seven GH-deficient children with 3-hourly 1 microgram/kg sc pulses of GHRH-(1-44) for 6 months and 2 micrograms/kg.pulse for another 6 months. Four patients had a serum GH response to iv GHRH before treatment, and an additional patient responded to iv GHRH after 1 month of pulsatile sc GHRH administration. The mean cumulative growth velocity increased from a pretreatment mean of 2.7 +/- 0.2 (+/- SE) to 8.4 +/- 2.5 and 5.4 +/- 0.7 cm/yr after 2 months and 1 yr of treatment, respectively. Low dose pulsatile GHRH therapy was effective in promoting growth in five of seven children, with height gain ranging from 4.4-7.5 cm at the end of 1 yr's therapy. Only one of the two patients who did not respond to GHRH had an improvement in linear growth when they were subsequently treated with synthetic GH. The other patient, a 16.5-yr-old pubertal girl who had both satisfactory GH and somatomedin-C responses during GHRH therapy, did not respond to either GHRH or, later, synthetic GH. The pretreatment serum GH response to iv GHRH, the serum somatomedin-C concentrations, and the peak serum GH response during sc GHRH therapy were not reliable predictors of clinical response.     

Evidence for a limited growth hormone (GH)-releasing hormone (GHRH)-releasable quantity of GH: effects of 6-hour infusions of GHRH on GH secretion in normal man

Human GH-releasing hormone [hGHRH-40 (GHRH)] stimulates GH release in a dose-dependent fashion when administered as single iv bolus doses or as continuous 90-min infusions. However, there has been variability in the GH responses, and it appears that there are waxing and waning effects of GHRH. To address whether these are a result of the dose of GHRH, time, or intermittent changes in sensitivity of the somatotrophs, we administered 6-h infusions of vehicle and different doses of GHRH to six normal men. In addition, an iv bolus injection of GHRH was given after 5.5 h of infusion to evaluate residual GH secretory capacity. The subjects were given infusions of either vehicle or GHRH (1, 3.3, and 10 ng/kg X min), followed by an iv bolus injection of 3.3 micrograms/kg on four separate occasions. GHRH infusions stimulated GH secretion compared to basal secretion. The changes from basal GH secretion (mean +/- SEM) were 2.0 +/- 1.6, 4.6 +/- 1.5, 12.7 +/- 5.1, and 8.2 +/- 1.8 ng/ml X h during the vehicle and GHRH (1, 3.3, and 10 ng/kg X min) infusions, respectively. The changes from basal GH secretion for 2 h after the iv bolus dose (after 5.5 h of infusion) were 33.3 +/- 8.7, 22.4 +/- 3.8, 14.0 +/- 3.6, and 10.5 +/- 2.0 ng/ml X h on the vehicle and GHRH (1, 3.3, and 10 ng/kg X min) infusion days, respectively. The magnitude of the GH response was inversely related to the GHRH infusion dose. The total amount of GH released during the 7.5-h study periods was not different among the vehicle and 3 GHRH infusion days. Thus, it appears that a finite amount of GH is released by GHRH. There was variability in the degree of responsiveness to the continuous infusions of GHRH. Surges of GH release occurred during the GHRH infusions, which may be attributed to intermittent secretion of a GH inhibitor, such a somatostatin.     

Acromegaly due to ectopic growth hormone (GH)-releasing hormone (GHRH) production: dynamic studies of GH and ectopic GHRH secretion

Dynamic studies of GH and GH-releasing hormone (GHRH) secretion were performed in a man with a GHRH-producing carcinoid tumor and acromegaly. Insulin hypoglycemia stimulated and metoclopramide inhibited both GH and GHRH acutely. Bromocriptine suppressed GH both acutely and chronically without altering circulating GHRH levels and also blunted the GH response to exogenous GHRH. TRH acutely stimulated GH, but not GHRH, secretion, and iv bolus doses of synthetic GHRH-(1-40) stimulated GH release acutely. Somatostatin infusion decreased both GH and GHRH concentrations and blunted the GH responses to TRH and GHRH-(1-40). We conclude that prolonged exposure of the pituitary gland to high concentrations of GHRH is associated with chronic GH hypersecretion and may be accompanied by a preserved acute GH response to exogenous GHRH; a paradoxical response of GH to TRH may be mediated at the pituitary level, consequent to prolonged pituitary exposure to GHRH; bromocriptine suppression of GH in acromegaly is due to a direct pituitary effect of the drug; and somatostatin inhibits both ectopic GHRH secretion as well as GH responsiveness to GHRH in vivo. Since GH secretory responses in patients with somatotroph adenomas are similar to those in this patient, augmented GHRH secretion may play a role in development of the "classic" form of acromegaly.     

Medical management of acromegaly due to ectopic production of growth hormone-releasing hormone by a carcinoid tumor

A 59-yr-old woman with a disseminated carcinoid tumor was evaluated for acromegaly. She had previously undergone a hypophysectomy for acromegaly and an enlarged pituitary, with a reduction in her serum GH levels from 100 to 4 micrograms/L. Recurrence of acromegalic symptoms 2 yr later was accompanied by elevated serum GH (16 micrograms/L) and insulin-like growth factor I (IGF-I; 528 micrograms/L) and plasma GHRH levels (12 micrograms/L; normal, less than 30 ng/L). Computed tomographic scan did not reveal pituitary enlargement. Metastatic carcinoid tissue in bone removed at biopsy contained GHRH (100 pg/mg tissue). High performance liquid chromatography of plasma GHRH revealed predominantly GHRH-(3-40)-OH, a biologically inactive GHRH metabolite, along with mature GHRH forms, while carcinoid tissue contained both GHRH-(1-40)-OH and GHRH-(1-44)-NH2. Treatment with pergolide initially resulted in reduction in serum GH and IGF-I levels and amelioration of symptoms of acromegaly. However, after 14 months of pergolide therapy, serum GH levels increased despite administration of up to 1000 micrograms pergolide/day. Plasma GHRH levels remained elevated throughout the treatment period. Subsequent treatment with SMS 201-995, a long-acting somatostatin analog, for over 1 yr resulted in sustained reductions of ectopic GHRH secretion, GH hypersecretion, and IGF-I levels. Plasma GHRH levels correlated with simultaneously measured serum GH levels in response to acute SMS 201-995 administration. SMS 201-995 was an effective medical treatment for acromegaly caused by ectopic GHRH production in this patient.     

Calcitonin suppresses growth hormone (GH) response to growth hormone-releasing hormone (GHRH) in man

Calcitonin (CT) receptors have been found in the hypothalamus, suggesting a neuroendocrine role for this peptide. We have recently shown that, in the rat, central administration of salmon calcitonin (sCT) suppresses basal and GHRH-stimulated GH secretion. To further investigate how sCT alters GH secretion, we studied the effects of sCT (100U MRC, im) or placebo on basal and GHRH (50 micrograms, iv)-stimulated GH secretion in 6 normal men. GHRH was administered 1 h after sCT injection. Basal GH levels were not altered by sCT administration. However, GH response to GHRH was markedly suppressed by sCT (area under the curve - sCT: 574.6 +/- 69.7 vs placebo: 1057.2 +/- 284.8 micrograms. min/L; p less than 0.02). Cortisol levels were higher in sCT-treated subjects compared to controls, from 45 to 105 min after sCT injection (p less than 0.05). However, no correlation was found between GH response to GHRH and cortisol levels. No changes in glucose, calcium and PTH levels were seen. These results demonstrate that sCT inhibits GHRH-induced GH secretion in man by a mechanism apparently independent of changes in peripheral cortisol, glucose, calcium and PTH levels.     

Short term continuous intravenous infusion of growth hormone (GH) inhibits GH-releasing hormone-induced GH secretion: a time-dependent effect

We previously reported that GH secretion evoked by GHRH is inhibited after 5 days of treatment with im GH. This impaired pituitary response was associated with a significant increase in the serum concentration of insulin-like growth factor I (IGF-I). To dissociate the possible effects of circulating IGF-I from other effects of GH on the pituitary response to GHRH, we carried out the following study in eight normal men. A bolus injection of GHRH (1 microgram/kg, iv) was administered 2 h after the start of a 4-h continuous iv infusion of GH (180-micrograms bolus dose, then 3 micrograms/min in 150 mmol/L NaCl) or placebo (150 mmol/L NaCl). In addition, a similar injection of GHRH was given 4 h after the start of a 6-h continuous iv GH infusion (180-micrograms bolus dose, then 3 micrograms/min). During the GH infusions, plasma GH levels reached steady state concentrations in the 9-13 micrograms/L range. The mean GHRH-induced GH response was not significantly blunted during the 4-h infusions of GH [724 +/- 163 (+/- SE) vs. 1184 +/- 373 micrograms.min/L during placebo; P = 0.29], but was significantly inhibited during the 6-h GH infusions (226 +/- 105 micrograms.min/L; P = 0.04 vs. control). Serum IGF-I or plasma glucose did not change significantly throughout the GH infusions. During the 6-h GH infusions, plasma FFA increased to levels significantly above basal values during the last 3 h of the 6-h infusion. These results indicate that short term GH infusion inhibits the plasma GH response to GHRH in a time-dependent manner. The inhibition is not due to changes in circulating IGF-I and glucose concentrations. Fluctuations in hypothalamic somatostatin secretion, changes in lipid or other GH-dependent metabolites, paracrine effects of IGF-I, or a direct effect of GH itself may cause the impaired pituitary responsiveness during short term iv GH infusion.     

A persistent pattern of varying pituitary responsivity to exogenous growth hormone (GH)-releasing hormone in GH-deficient children: evidence supporting periodic somatostatin secretion

The pattern and degree of variation in pituitary responsivity to GHRH was examined in four GH-deficient children (two boys and two girls, aged 4 3/12 to 10 4/12 yr). All children were studied before and on multiple (three to six per child) occasions during long term GHRH therapy (1 or 2 micrograms/kg, sc, every 3 h) in an identical fashion. Each study comprised withdrawal of blood for serum GH measurements every 20 min between 2000 and 0800 h. All subjects received GHRH at 2000, 2300, 0200, and 0500 h as well as at 0800, 1100, 1400, and 1700 h throughout the long term treatment period (6-18 months). Although all children had low level (less than 7.0 micrograms/L) pulsatile GH secretion during baseline studies, the maximal peak values occurred at times other than 0500 h. Before GHRH treatment, serum GH levels rose significantly in response to 91% (62 of 68) of the GHRH doses administered. GH pulse amplitudes varied throughout the studies in all children, and this variability persisted despite 1300-3600 consecutive doses in each child. In all 17 study periods the highest serum GH concentration occurred shortly after the 0500 h GHRH dose. The mean peak GH concentration after the 0500 h GHRH dose [18.4 +/- 3.5 (+/- SE) micrograms/L] was significantly higher than those after the 2000 h (5.3 +/- 1.0 micrograms/L; P = 0.0001), 2300 h (7.4 +/- 2.1 micrograms/L; P = 0.0003), and 0200 h (10.9 +/- 2.5 micrograms/L; P = 0.011) doses. These results demonstrate that the responsivity of the pituitary to GHRH varies throughout the night in some GH-deficient children. There appears to be a direct relationship between the time of night and the degree of pituitary responsivity to GHRH. We suggest that this variable responsivity may be due to intermittent hypothalamic somatostatin secretion.     

Failure to respond to growth hormone releasing hormone (GHRH) in acromegaly due to a GHRH secreting pancreatic tumor: dynamics of multiple endocrine testing

Growth hormone releasing hormone (GHRH) has recently been isolated and sequenced from pancreatic tumors secreting GHRH. Patients with untreated acromegaly due to a pituitary tumor respond to exogenous administration of GHRH with a further rise of their elevated basal growth hormone (GH) levels. For the first time, we report the effects of exogenously administered synthetic GHRH in a patient with acromegaly due to a GHRH secreting pancreatic tumor. The diagnosis was established by high peripheral IR-GHRH levels (1100 pg/ml) and an arterio- venous tumor gradient of IR-GHRH. In this patient GH failed to respond to 1 microgram/kg of exogenous GHRH with the pancreatic tumor in situ; however, further increase of serum GH levels occurred after TRH administration, hypoglycemia and oral glucose administration. After removal of the tumor, serum GH levels decreased and a normal response to GHRH and TRH were demonstrated. The extract of the tumor contained 1.7 micrograms IR-GHRH per g wet tissue. Thus, lack of response to exogenous GHRH in untreated acromegaly may indicate the presence of an ectopic GHRH producing tumor.     

Effects of intravenous, subcutaneous, and intranasal administration of growth hormone (GH)-releasing hormone-40 on serum GH concentrations in normal men

In addition to stimulating GH release in normal subjects, GH-releasing hormone-40 (GHRH-40) stimulates GH secretion in some adults and children with GH deficiency. Recognizing that GHRH-40 may have potential as a therapeutic agent for the treatment of GH deficiency, we examined the effects of iv, sc, and intranasal (in) GHRH-40 administration on GH secretion and measured the plasma levels of immunoreactive GHRH achieved after the administration of the peptide via these different routes. Normal men were given vehicle or GHRH-40 iv (0.003, 0.01, 0.03, and 0.1 micrograms/kg; n = 10), sc (1, 3.3, and 10 micrograms/kg; n = 8), or in (3, 10, 30, and 100 micrograms/kg; n = 5). No subject had any symptoms after administration of vehicle or GHRH-40. During the 2-h period after iv administration of GHRH-40, the maximal increment in serum GH levels above basal (nanograms per ml; mean +/- SD) after the 0.1 micrograms/kg dose was 15.5 +/- 10.4 compared to 2.4 +/- 4.1 after vehicle (P = 0.0017). During the 3-h period after sc administration, when compared to the maximal increment in serum GH above basal after vehicle alone (10.2 +/- 12.9), the maximal increments above basal in serum GH were increased after both the 3.3 micrograms/kg (26.2 +/- 23.1; P = 0.022) and 10 micrograms/kg (63.6 +/- 53.5; P = 0.0003) doses. During the 3-h period after in administration, when compared to the maximal increment in serum GH above basal after vehicle alone (2.8 +/- 6.4), the maximal increments above basal in GH were higher after both the 30 micrograms/kg (18.5 +/- 10.4; P = 0.0053) and 100 micrograms/kg (21.7 +/- 8.1; P = 0.0028) doses. In addition, significant dose-response relationships were documented between the maximal increments above basal in serum GH and GHRH-40 administered by all routes. The mean (+/- SEM) peak plasma level of IR-GHRH (nanograms per ml) achieved after administration of 10 micrograms/kg GHRH-40, iv, as reported previously (66.6 +/- 17.6), was approximately 60- and 500-fold higher than the mean levels in the current study after administration of the same dose sc (1.11 +/- 0.39) or in (0.14 +/- 0.02), respectively. In summary, although GHRH-40 stimulates GH release when administered iv, sc, or in, significantly higher doses were required using the sc and in routes to achieve responses comparable to those obtained with iv administration.     

The GH-releasing hormone (GHRH) test in acromegaly before and after adenomectomy

The GHRH test may represent a new tool in the study of GH dynamics in acromegaly. GH responsiveness to GHRH 1-40 (50 micrograms iv) has been studied in 21 acromegalic patients. Nineteen out of 21 had active disease. Five patients were also studied 1-12 months after neurosurgery. Two apparently cured acromegalics were studied 1-2 yr after surgery. GH secretion has been evaluated in all patients by means of TRH, bromocriptine and insulin hypoglycemia tests, too. GH response to GHRH has also been performed in 14 normal subjects. In acromegaly, GH responses after GHRH (p less than 0.01 vs placebo) were variable. The GH peak ranged from 8 to 445 ng/ml in patients with active disease. Maximum GH increase after GHRH (calculated as peak/basal value ratio) was significantly reduced in acromegaly (2.9 +/- 0.5 ng/ml; mean +/- SE) in comparison to controls (34.1 +/- 10.9 ng/ml; p less than 0.01). No significant differences in GH pattern after GHRH were found between untreated and previously treated patients with active disease. A significant correlation was found between GH basal levels and GH incremental area (p less than 0.05) and between GH basal and peak levels (p less than 0.01) after GHRH. A significant increase in PRL secretion was observed in acromegalic patients after GHRH (p less than 0.01 vs placebo). No discernable variation was found in the other pituitary hormones pattern after the peptide administration. A positive correlation was observed between GH increase after GHRH and insulin hypoglycemia (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Atenolol enhances nocturnal growth hormone (GH) release in GH-deficient children during long term GH-releasing hormone therapy

The effect of the selective beta 1-adrenergic blocking agent atenolol (50 or 100 mg, orally) on spontaneous and GH-releasing hormone (GHRH)-stimulated GH release was evaluated in six GH-deficient children during long term therapy with GHRH. Nocturnal GH concentrations were determined every 20 min for 12 h under the following four conditions: 1) control, 2) atenolol administration only, 3) sc GHRH administration only, and 4) combined GHRH and atenolol administration. The mean 12-h nocturnal GH concentrations after administration of atenolol alone [2.4 +/- 0.6 microgram/L (mean +/- SEM)] or GHRH alone (2.7 +/- 1.0 micrograms/L) were indistinguishable from baseline values (2.0 +/- 0.5 microgram/L; P greater than 0.05). In contrast, the addition of atenolol to ongoing GHRH therapy caused a clear augmentation of 12-h overnight GH release compared to that during all other study periods (5.0 +/- 1.3 micrograms/L; P less than 0.05). In a subset of three subjects for whom GH pulse characteristics were determined, the primary mode of the enhanced GH release was through an increase in the amplitude of serum GH pulses. These results are consistent with the hypothesis that beta-adrenergic blocking compounds enhance the responsivity of the pituitary gland to agents that permit GH release by inhibiting hypothalamic somatostatin secretion or action. They suggest that atenolol may have potential as an adjunctive therapy in some children with abnormalities of GH secretion when GHRH is the primary therapeutic agent.     

Continuous subcutaneous octreotide infusion markedly suppresses IGF-I levels whilst only partially suppressing GH secretion in diabetics with retinopathy

The response to GH releasing hormone (GHRH 1-29) and 24-h serum GH and IGF-I levels were measured in 9 insulin-dependent diabetics with retinopathy and 6 normal volunteers before and after different treatment regimens with octreotide, a long-acting somatostatin analogue. Octreotide, 50 micrograms by sc injection, completely suppressed GHRH-stimulated GH release in both groups. Thrice daily sc injections for up to 20 weeks were associated with variable plasma octreotide levels and failed completely to suppress GH secretion in either the patients or the normal controls. Three days of continuous sc pump infusion (500 micrograms/24-h) resulted in consistently high plasma octreotide levels and completely suppressed 24-h GH in 4 normal subjects, whilst treatment for up to 16 weeks only partially suppressed GH levels in 6 patients (AUC mU.l-1.h-1; 209 +/- 81 vs 121 +/- 82; P = 0.01). Mean +/- SD IGF-I levels (micrograms/l) in the patients (but not controls) were suppressed into the hypopituitary range by median 6 weeks (range 2-16) pump administration (203 +/- 62 vs 60 +/- 25; P = 0.02). Pump treatment achieved total GH suppression in normal subjects; diabetics with retinopathy seem more resistant to the GH suppressing effects of the drug. However, the reduction of serum IGF-I with prolonged treatment may be of clinical value in arresting the progress of diabetic retinopathy.     

Role of dopamine in the regulation of growth hormone secretion: dopamine and bromocriptine augment growth hormone (GH)-releasing hormone-stimulated GH secretion in normal man

The role of the dopaminergic system and its interaction with GH-releasing hormone (GHRH) in the regulation of GH secretion was investigated in normal men in two complementary studies. The men were given continuous iv infusions of 0.15 M saline (5 h), dopamine (4 micrograms/kg X min; 1 h), GHRH (2 ng/kg X min; 2 h), and GHRH (2 ng/kg X min; 2 h) plus dopamine (4 micrograms/kg X min; 1 h) on four separate occasions, and serum GH responses were measured. In a second study, on separate days, placebo or bromocriptine (2.5 mg/dose) was administered, and GH and PRL responses to a single iv GHRH dose were measured. A continuous infusion of dopamine and GHRH on separate days stimulated GH secretion in all subjects. The mean integrated GH secretion was 13.2 +/- 3.1 (+/- SEM) ng/mL X h during the dopamine infusion and 14.7 +/- 4.6 during GHRH, compared with 1.7 +/- 0.4 during the saline infusion. The combination of GHRH and dopamine resulted in the greatest stimulation of GH secretion (29.8 +/- 5.7 ng/ml X h; P less than 0.05 vs. 3 other study days). The oral dopamine agonist bromocriptine also augmented GHRH-stimulated GH secretion. Integrated GH secretion after a single iv injection of GHRH following two doses of bromocriptine was 160 +/- 29.5 ng/ml X h compared with 81.3 +/- 22.2 after placebo (P = 0.04). We suggest that these findings are compatible with the hypothesis that dopamine inhibits hypothalamic somatostatin secretion, which then allows for a greater stimulatory effect of GHRH.     

Interaction of glucose and pyridostigmine on the secretion of growth hormone (GH) induced by GH-releasing hormone (GHRH)

In order to investigate the mechanisms by which hyperglycaemia induces an inhibition of GHRH-induced GH release, we gave the following treatments to seven normal men: a) GHRH 100 micrograms iv; b) pyridostigmine (PD) 120 mg po 60 min before GHRH; c) glucose 250 mg/kg iv as a bolus (10 min before GHRH) plus 10 mg/kg/min until the end of the test; d) glucose pyridostigmine and GHRH as above. Glucose significantly reduced GHRH-stimulated GH levels, whereas PD significantly enhanced them. When PD and glucose were given together, the effect on GHRH-stimulated GH secretion was not different from the algebraic sum of the single effects of the two substances. Thus glucose seems to be able to exert its inhibition, at least partially, also when pyridostigmine is coadministered.     

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 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.     

Results of 1-year growth hormone (GH)-releasing hormone-(1-44) treatment on growth, somatomedin-C, and 24-hour GH secretion in six children with partial GH deficiency

Six children with short stature and partial GH deficiency in response to two pharmacological tests received GHRH for 12 months (10 micrograms/kg X day, sc) each evening. Twenty-four-hour GH secretion was studied before and after 3 and 12 months of treatment, and GHRH tests (2 micrograms/kg, iv) were done before and after 6 months of treatment. Plasma somatomedin-C was measured before and after 1.5, 3, 6, 9, and 12 months of treatment. Statural growth was measured at 3-month intervals. Mean growth velocity increased from 4.2 to 8.6 cm/yr, with a good result in five children and no response in the other. The growth response was substantial during the first 3 months. It was maintained during the following 6 months, and then decreased during the last 3 months. The peak plasma GH level in response to GHRH increased from 34.5 +/- 14.2 (+/-SD) ng/mL before treatment to 47.8 +/- 3.4 ng/mL after 6 months of treatment. Twenty-four-hour GH secretion increased in all parameters at 3 months (maximum peak, area under the curve, integrated concentration, and number of peaks) and at 12 months (with the exception of the maximum peak). Nycthemeral secretory profiles became normal, with reappearance of secretory pulses in two children, slight increases in three children, and no change in one child. Plasma somatomedin-C levels rose from 0.8 +/- 0.3 U/mL before treatment to 2.0 +/- 1.0 U/mL at 3 months, then decreased to 1.3 +/- 0.6 U/mL at 12 months. These results indicate that GHRH administered by sc injection for a 1-yr period stimulated growth and GH secretion. However, a decrease in activity was noted during the last 3 months of treatment. Tests for anti-GHRH antibodies were positive in the only child who did not respond to treatment.     

The effects of PGE2, 2-DG and L-arginine on hypothalamic GHRH and SRIF releases in conscious rats, with respect to GH secretion

The effects of prostaglandin E2 (PGE2), 2-deoxy-D-glucose (2-DG) and L-arginine on hypothalamic GHRH and SRIF release with respect to GH secretion were studied in conscious male rats. Intracerebroventricular (icv) injection of 5 micrograms PGE2 and intravenous (iv) infusion of 1 g/kgBW L-arginine caused an increase in plasma GH levels, but icv (36 micrograms) or iv (400 mg/kgBW) injection of 2-DG suppressed spontaneous GH surge in conscious rats. The concentration of hypothalamic GHRH was decreased in all three groups of the animals, but the concentration of hypothalamic SRIF was decreased only in 2-DG-treated animals. In the perifusion system using rat hypothalamus, PGE2 (0.28 microM, 2.8 microM), 2-DG (22 mM) and L-arginine (3 mM) stimulated GHRH release from rat hypothalamus. 2-DG also stimulated SRIF release more predominantly than GHRH release. Passive immunization with anti-GHRH serum inhibited the GH secretion induced by icv injection of 5 micrograms PGE2 and by iv infusion of 1 g/kgBW L-arginine in conscious rats. In contrast, GH secretion induced by iv injection of 50 micrograms/kgBW PGE2 was not affected by the pretreatment with the antiserum. These results suggest that the central effect of PGE2 and peripheral effect of L-arginine to stimulate GH secretion are mediated by hypothalamic GHRH release, and that the inhibitory effect of 2-DG on GH secretion is predominantly mediated by hypothalamic SRIF release rather than GHRH release in rats.     

PLASMA IMMUNOREACTIVE GHRH AND SERUM GH CONCENTRATIONS FOLLOWING PULSATILE GHRH 1-40 ADMINISTRATION IN GH DEFICIENT CHILDREN

We have studied the clearance from plasma of immunoreactive growth hormone releasing hormone 1-40 (IR-GHRH) following intravenous (i.v.) and subcutaneous (s.c.) administration and the relationship between exogenous plasma IR-GHRH concentrations and GH secretion in five GH insufficient children receiving long term nocturnal pulsatile GHRH 1-40. The i.v. studies with GHRH 1-40 1 micrograms/kg demonstrated a distribution half life (t1/2) of 3.9 (SD 0.9) min and an elimination t1/2 of 53.1 (SD 3.2) min. In the s.c. studies the elimination phase was similar to the i.v. results but the transit time to the GHRH peak was slower than the i.v. distribution t1/2 9.9 (SD 3.6) min. These characteristics were maintained during successive pulses of subcutaneous GHRH. The mean IR-GHRH peaks following s.c. GHRH 1-40 administration of 1 microgram/kg and 2 micrograms/kg were 37- and 18-fold lower respectively than the mean IR-GHRH peak observed after the i.v. 1 microgram/kg bolus study. A significant correlation was shown between peak plasma IR-GHRH and serum GH concentrations during the s.c. (r = 0.75) but not the i.v. studies. Pulsatile GHRH administration has been shown to stimulate GH secretion and growth acceleration in GH insufficient children. Knowledge of the relationship between GHRH 1-40 absorption from the subcutaneous site and GH secretion is important for the development of an optimal GHRH treatment regimen in GH insufficient children.