Novel mechanisms of growth hormone regulation: growth hormone-releasing peptides and ghrelin.

Growth hormone secretion is classically modulated by two hypothalamic hormones, growth hormone-releasing hormone and somatostatin. A third pathway was proposed in the last decade, which involves the growth hormone secretagogues. Ghrelin is a novel acylated peptide which is produced mainly by the stomach. It is also synthesized in the hypothalamus and is present in several other tissues. This endogenous growth hormone secretagogue was discovered by reverse pharmacology when a group of synthetic growth hormone-releasing compounds was initially produced, leading to the isolation of an orphan receptor and, finally, to its endogenous ligand. Ghrelin binds to an active receptor to increase growth hormone release and food intake. It is still not known how hypothalamic and circulating ghrelin is involved in the control of growth hormone release. Endogenous ghrelin might act to amplify the basic pattern of growth hormone secretion, optimizing somatotroph responsiveness to growth hormone-releasing hormone. It may activate multiple interdependent intracellular pathways at the somatotroph, involving protein kinase C, protein kinase A and extracellular calcium systems. However, since ghrelin has a greater ability to release growth hormone in vivo, its main site of action is the hypothalamus. In the current review we summarize the available data on the: a) discovery of this peptide, b) mechanisms of action of growth hormone secretagogues and ghrelin and possible physiological role on growth hormone modulation, and c) regulation of growth hormone release in man after intravenous administration of these peptides.

Mechanisms of calcitonin-induced growth hormone (GH) suppression: roles of somatostatin and GH-releasing factor.

Calcitonin (CT) binds to specific receptors in the hypothalamus and has been localized in the pituitary, suggesting a potential neuroendocrine role for this peptide. We and others have previously shown that CT given centrally markedly suppresses pulsatile GH secretion. However, the mechanism mediating this response remains to be elucidated. In the present study, we assessed the involvement of the two hypothalamic GH-regulatory peptides, somatostatin (SRIF) and GH-releasing factor (GRF), using a combination of in vivo and in vitro techniques. Six-hour GH secretory profiles were obtained from eight groups of freely moving rats bearing chronic intracerebroventricular (icv) and intraatrial cannulae. In four groups, salmon (s) CT (250 ng/10 microliters) was administered icv, whereas the remaining four groups received either normal saline (NS) icv or sCT iv. Central injection of sCT caused a severe suppression in amplitude of spontaneous GH pulses compared to NS icv-treated control rats, whereas the same dose of sCT iv had no significant effect. Passive immunization of sCT icv-injected rats with a specific antiserum to SRIF failed to restore the amplitude of GH pulses to normal values. In addition, in vitro basal and 50 mM K+-stimulated SRIF release from incubated hypothalamic fragments was not altered by sCT in doses ranging from 10(-10) to 10(-6) M. The iv administration of a bolus of rat GRF (1-29)NH2 (1 microgram) 1 h after sCT icv injection also failed to augment plasma GH levels compared to sCT iv-treated rats (16.6 +/- 10.0 vs. 326.6 +/- 63.6 ng/ml; P less than 0.001) and NS icv controls (407.2 +/- 145.4 ng/ml; P less than 0.01). Blood calcium levels decreased similarly 1 h after iv and icv sCT administration. These results demonstrate that: sCT inhibits pulsatile GH secretion via a central nervous system site of action, GH suppression induced by sCT is apparently not due solely to increased hypothalamic SRIF release, and centrally administered sCT produces an acute loss of responsiveness of somatotrophs to GRF, which can be dissociated from peripheral blood calcium levels.

Paradoxical enhancement of pituitary growth hormone (GH) responsiveness to GH-releasing factor in the face of high somatostatin tone.

Pituitary GH secretion is regulated by a delicate interplay between stimulatory (GRF) and inhibitory [somatostatin (SRIF)] hypothalamic hormones, although the nature of the GRF/SRIF interaction remains to be elucidated. In the present study, we documented a significant elevation of plasma SRIF-like immunoreactivity in 72-h fasted rats compared to that in fed controls (129.0 +/- 17.9 vs. 38.2 +/- 5.8 pg/ml; P less than 0.01) and used this model of high SRIF tone to further delineate the interrelation between GRF and SRIF in physiological regulation of pulsatile GH secretion. We examined pituitary GH responsiveness to GRF, both in vivo and in vitro, after 72-h exposure to nutritional deprivation and high SRIF secretion. In vivo, GRF-induced GH release was markedly enhanced in the face of high circulating SRIF; freely moving, starved rats released 4- to 8-fold more GH than fed controls in response to rat GRF iv. In vitro, both basal and human GRF-induced GH release were augmented 2- to 4-fold in perifused dispersed anterior pituitary cells of starved rats compared to those in fed controls, and this enhanced responsiveness persisted in the presence of 10(-9) M SRIF. These results demonstrate that SRIF not only inhibits GH secretion stimulated by GRF, but that under different temporal conditions SRIF may act in a paradoxically positive manner to sensitize pituitary GH responsiveness to GRF. Such a cooperative interaction of the two peptides may be necessary to optimize pulsatile GH release. Our findings provide support for the hypothesis that the temporal patterning of hypothalamic GRF/SRIF signals to pituitary somatotrophs may be the major determinant for pulsatile GH secretion and, ultimately, body growth.

Effects of short-term glucocorticoid deprivation on growth hormone (GH) response to GH-releasing peptide-6: studies in normal men and in patients with adrenal insufficiency.

There are no data in the literature about the effects of glucocorticoid deprivation on GH-releasing peptide-6 (GHRP-6)-induced GH release. The aims of this study were to evaluate GH responsiveness to GHRP-6 1) after metyrapone administration in normal men, and 2) in patients with chronic hypocortisolism after glucocorticoid withdrawal for 72 h. In normal subjects, metyrapone ingestion did not alter significantly GH responsiveness to GHRP-6 [n = 8; peak, 39.3 +/-7.1 microg/L; area under the curve (AUC), 1958.8 +/- 445.7 microg/min x L; mean +/- SE] compared to placebo (n = 8; peak, 21.9 +/- 4.5; AUC, 1131.0 +/- 229.6). In patients with chronic hypocortisolism (n = 8), GH responses to GHRP-6 were similar both during replacement therapy (peak, 11.8 +/- 3.9; AUC, 563.2 +/- 208.7) and after withdrawal of prednisone (peak, 14.4 +/- 4.5; AUC, 695.6 +/- 272.9) and did not differ from those in controls. Interestingly, after glucocorticoid withdrawal, GH responsiveness to GHRP-6 in patients with chronic hypocortisolism was significantly lower than that in normal subjects pretreated with metyrapone. Our data suggest that short term glucocorticoid deprivation does not have a major impact on GHRP-6-dependent GH-releasing mechanisms. However, in long standing hypocortisolism, subtle changes in GHRP-6 secretory pathways may be present.

Different growth hormone (GH) response to GH-releasing peptide and GH-releasing hormone in hyperthyroidism.

Altered GH responses to several pharmacological stimuli, including GHRH, have been found in hyperthyroidism. The mechanisms underlying these disturbances have not been fully elucidated. GH-releasing peptide-6 (GHRP-6) is a synthetic hexapeptide that specifically stimulates GH release both in vitro and in vivo. The mechanism of action of GHRP-6 is unknown, but it probably acts by inhibiting the effects of somatostatin on GH release. The aim of this study was to evaluate the effects of GHRP-6 on GH secretion in patients with hyperthyroidism (n = 9) and in control subjects (n = 9). Each subject received GHRP-6 (1 microg/kg, iv), GHRH (100 microg, iv), and GHRP-6 plus GHRH on 3 separate days. GH peak values (mean +/- SE; micrograms per L) were significantly lower in hyperthyroid patients compared to those in control subjects after GHRH alone (9.0 +/- 1.3 vs. 27.0 +/- 5.2) and GHRP-6 plus GHRH (22.5 +/- 3.5 vs. 83.7 +/- 15.2); a lack of the normal synergistic effect of the association of both peptides was observed in thyrotoxicosis. However, a similar GH response was seen in both groups after isolated GHRP-6 injection (31.9 +/- 5.7 vs. 23.2 +/- 3.9). In summary, we have shown that hyperthyroid patients have a normal GH response to GHRP-6 together with a blunted GH responsiveness to GHRH. Our data suggest that thyroid hormones modulate GH release induced by these two peptides in a differential way.

Dynamic evaluation of prolactin secretion in essential hypertension: evidence against hypothalamic-pituitary dopaminergic dysfunction.

Hyperprolactinemia has previously been noted in patients with essential hypertension and it has been suggested that the increased PRL levels in this condition may reflect reduced central dopaminergic activity. In the present study, PRL secretion was evaluated in 17 patients with essential hypertension and in 9 normal controls as an indirect index of hypothalamic-pituitary dopaminergic activity. PRL levels were measured basally, at night, and after TRH (200 micrograms, iv), metoclopramide (10 mg, orally), and L-dopa (500 mg, orally). Basal PRL levels were similar in both groups [essential hypertension, 301.2 +/- 176.2 microunits/ml; controls, 334.2 +/- 98.8 microunits/ml (mean +/- SD)]. No differences in PRL levels were found after TRH, L-dopa, and metoclopramide or during sleep between the 2 groups. When the patients were classified according to their PRA, no differences were noticed in either basal levels or the patterns of PRL response. It is concluded that PRL secretion is normal in patients with essential hypertension, which could be indirect evidence against reduced hypothalamic-pituitary dopaminergic activity in this disease. However, minor abnormalities not detected by PRL measurements could be involved in the pathogenesis of essential hypertension.

Effects of dopamine and morphine on immunoreactive somatostatin and LH-releasing hormone secretion from hypothalamic fragments in vitro.

Dopamine and morphine modulate GH and LH release, probably at a hypothalamic locus. To investigate this in more detail, we studied the influence of these substances on somatostatin and LH-releasing hormone (LHRH) release from rat hypothalamic fragments in vitro. Hypothalamic fragments were incubated in Earle's medium. After 60 min of preincubation, medium from two 20-min incubations was collected and somatostatin and LHRH levels measured by radioimmunoassay. Dopamine (10 nmol/1-0.1 mmol/l) induced a progressive increase (r = 0.41; P less than 0.01) in basal somatostatin levels. K+ (30 mmol/l)-induced somatostatin release was also increased (r = 0.54; P less than 0.01) by increasing doses of dopamine. Metoclopramide (10 mumol/l) blocked the dopamine (1 mumol/l)-induced increase in somatostatin release. No significant relationship between dopamine and LHRH was found either basally or after K+ (30 mmol/l) stimulation. Basal somatostatin was negatively correlated (r = -0.63; P less than 0.01) with morphine concentrations. No significant correlation was found after K+ (30 mmol/l) depolarization. Basal LHRH release was not influenced by morphine, while K+ (30 mmol/l)-induced release was significantly lower than controls only at a concentration of 10 nmol/l. These results suggest that dopamine and morphine act at a hypothalamic level to modulate GH release through alterations in somatostatin secretion. Dopamine and morphine have no consistent effect on hypothalamic LHRH release.

H-Y antigen in 46,XY pure testicular dysgenesis.

Clinical, cytogenetic, pathologic, and histocompatibility-Y (H-Y) antigen studies were performed on a phenotype female with primary amenorrhea and streak gonads. Pathological examination of tissues removed at total hysterectomy and bilateral salpinog-gonadectomy showed gonadoblastoma and dysgerminoma of left streak. A single F-body (Y chromosome) was found in buccal smears. Analysis of blood cells and tumor fibroblasts showed a 46,XY chromosome constitution (Q-banding). The data were consistent with a diagnosis of 46,XY pure testicular dysgenesis. Positive results for H-Y antigen were found in this case.

Growth hormone (GH) response to GH-releasing peptide-6 in patients with insulin-dependent diabetes mellitus.

In insulin-dependent diabetes mellitus (IDDM), inappropriate growth hormone (GH) responses to several stimuli, including GH-releasing hormone (GHRH), have been described. A decreased hypothalamic somatostatinergic tone is one of the most likely explanations for these findings. His-DTrp-Ala-Trp-DPhe-Lys-NH2 [GH-releasing peptide-6 [GHRP-6]] is a synthetic hexapeptide that stimulates GH release in vitro and in vivo. The mechanism of action of GHRP-6 is unknown, but it probably does not inhibit hypothalamic somatostatin secretion. Also, GHRH and GHRP-6 apparently activate different intracellular pathways to release GH. The aim of this study was to evaluate whether there is a differential effect of IDDM on GHRP-6- and GHRH-induced GH secretion. Six patients with IDDM and seven control subjects were studied. Each subject received GHRP-6 (1 microgram/kg intravenously [IV]), GHRH (100 micrograms IV), and GHRP-6 + GHRH on 3 separate days. GH peak values (mean +/- SE in micrograms per liter) were similar in controls and diabetics after GHRH (22.5 +/- 7.8 v 24.0 +/- 9.7) and after GHRP-5 (20.5 +/- 5.3 v 24.4 +/- 6.3). The association of GHRP-6 and GHRH induced a significantly higher GH release than administration of the isolated peptides in both groups. The synergistic GH response to combined administration of GHRP-6 and GHRH was not different in controls (70.5 +/- 20.0) and diabetics (119.0 +/- 22.2). In summary, the effectiveness of GHRP-6 in IDDM could reinforce the evidence that this peptide probably does not release GH through a decrease in hypothalamic somatostatin secretion. Moreover, our data suggest that both GHRH and GHRP-6 releasing mechanisms are unaltered in IDDM.

Long-acting injectable bromocriptine (Parlodel LAR) in the chronic treatment of prolactin-secreting macroadenomas.

OBJECTIVE: To evaluate the efficacy and tolerability of Parlodel LAR (Sandoz, Basel, Switzerland), a long-acting injectable bromocriptine, in PRL-secreting macroadenomas. DESIGN: Eleven patients with macroprolactinomas were studied in an academic environment in an open and prospective protocol. Ten patients were followed for 6 months and 8 for 1 year. Fifty to 200 mg IM of Parlodel LAR were administered every 28 days. RESULTS: At the end of the 1st month, 64% of the patients had PRL suppression of > 75% of baseline values. After 1 year, 88% of the cases had PRL suppression of > 90%. Persistent PRL normalization was seen in three cases. Tumor shrinkage was seen in 64% of the patients on day 5, in 73% on day 28, and in 90% after 6 months of treatment. Early visual field improvement was seen in 83% of the cases. All patients had improvement of clinical symptoms. CONCLUSION: Parlodel LAR is well tolerated and very effective in the long-term treatment of patients with PRL-secreting macroadenomas.

Long-acting oral bromocriptine (Parlodel SRO) in the treatment of hyperprolactinemia.

OBJECTIVES: To compare the effect of Parlodel SRO (Sandoz, Basel, Switzerland), a long-acting oral bromocriptine, to Parlodel (Sandoz) and to study the chronic effects of Parlodel SRO. DESIGN: The study was twofold: (1) random, double-blind and (2) open. SETTING: Patients were studied in an academic environment. PATIENTS: Hyperprolactinemic patients were selected. Sixteen patients were treated during 1 month. Ten patients completed the 1-year follow-up. INTERVENTIONS: Parlodel SRO or Parlodel was administered during 1 month (first 15 days: 5 mg/d; afterwards: 10 mg/d). Parlodel SRO was given during 1 year in variable doses (maximal 20 mg/d). MAIN OUTCOME MEASURES: Prolactin (PRL) levels, clinical improvement, and side effects were evaluated. RESULTS: After 1 month, 63% of the patients in both groups had normal PRL and 43% had menses. Side effects were similar. After 1 year all patients except one had normal PRL levels, and 89% were ovulating. CONCLUSIONS: The efficacy, tolerability, and long duration of action of Parlodel SRO make it an excellent alternative for the treatment of hyperprolactinemic patients.

Glucose-induced changes in somatostatin-14 and somatostatin-28 released from rat hypothalamic fragments 'in vitro'.

Previous data suggest that somatostatin is present and released from the hypothalamus in several molecular forms, basally and after K+ or electrical stimulation. In order to evaluate the proportions of somatostatin-14 (S14) and somatostatin-28 (S28) released during a stimulus which may be more closely related to the control of growth hormone secretion 'in vivo', we studied the molecular forms of somatostatin released from hypothalamic fragments ' in vitro', during incubations with different glucose concentrations (1.35 and 22mM), which we have previously shown to be inversely related to somatostatin release. Sephadex G-50 chromatography demonstrated that both forms are released in the same proportions (S14: 70%; S28: 30%) during incubation with different glucose concentrations; there is a parallel increase in both forms when low glucose is used. Although on a molar basis less S28 is released than S14, the higher potency, longer duration of action and higher affinity for pituitary receptors of S28 suggests that it may be of major physiological importance.

Dose-dependent effects of vasoactive intestinal polypeptide on somatostatin release from hypothalamic fragments in vitro.

1. Vasoactive intestinal polypeptide (VIP) is present in high concentrations in the hypothalamus and appears to be involved in the modulation of growth hormone (GH) secretion. The effects of VIP on hypothalamic somatostatin (SMS) release are, however, controversial. 2. To further elucidate the mechanism of action of this peptide on GH secretion we studied the effects of VIP on SMS secretion from incubated rat hypothalamic fragments in vitro. 3. At 10(-6) M, VIP induced a significant increase in basal SMS release (P less than 0.01), whereas at 10(-10) M it had an inhibitory effect. 4. We suggest that the increase in GH after in vivo administration of VIP may be modulated, at least in part, by a direct effect of this peptide on SMS neurons, while the stimulatory effect of high doses of VIP on SMS release may represent a pharmacological interaction of this peptide with growth hormone releasing hormone, peptide histidine isoleucine, or glucagon receptors.

Prevalence and magnitude of osteopenia in patients with prolactinoma.

1. The association between hypogonadism and osteoporosis has been reported. We conducted a study to establish the prevalence and magnitude of osteopenia in patients with prolactinoma and the relationship of bone loss with the duration of hypogonadism. 2. We measured the bone mineral density (BMD) of spine and femur (a site that has not been analyzed earlier) in 35 patients with prolactinoma using a dual-energy X-ray absorptiometer. The patients were classified as normal BMD and low BMD (osteopenics). 3. Seventeen patients (48%) showed osteopenia. The mean bone loss in the different regions was: spine, 13%; femoral neck, 15%; trochanter, 11%; Ward's, 22%. This difference was only significant when the spine and Ward's region were compared. The duration of hypogonadism was significantly greater in the low-BMD group (11.3 vs 4.9 years) when compared to the normal BMD group. There was a positive relationship between the duration of hypogonadism and magnitude of bone loss in both spine and femur (P = 0.04; r = 0.6). 4. A high prevalence of osteopenia in both spine and femur was found in patients with prolactinoma, and was highly associated with the duration of hypogonadism. Early treatment of this condition seems important to prevent bone loss.

Inhibitory effect of calcitonin on growth hormone response to growth hormone releasing hormone in acromegaly.

1. A neuroendocrine role for calcitonin (CT) has been suggested by the finding of CT receptors in the hypothalamus. We have recently shown that salmon calcitonin (sCT) inhibits growth hormone releasing hormone (GHRH)-induced GH secretion in man by a mechanism apparently independent of changes in peripheral cortisol, glucose, calcium or parathyroid hormone levels. 2. We have further investigated the inhibitory action of sCT on GH secretion by studying the effects of sCT (100 MRC units, im) or placebo on basal and GHRH (1-29) NH2 (50 micrograms, iv) stimulated GH secretion in 6 acromegalic patients with active disease. 3. Basal GH levels were not altered by sCT administration (placebo: 136 +/- 99 micrograms/l vs sCT: 99 +/- 53 micrograms/l). However, the GH response to GHRH was decreased by sCT. The area under the curve was significantly smaller when patients were treated with sCT compared to placebo controls (placebo: 77202 +/- 57036 vs sCT: 64828 +/- 51909 micrograms min-1 l-1; P less than 0.02). No changes in glucose or calcium levels were observed. 4. These results demonstrate that sCT decreases GHRH-induced GH secretion in acromegalic patients. Although the mechanism of action of sCT on GH secretion is unknown, our results indicate that the inhibitory effect of this peptide on GH secretion is also observed in patients harboring pituitary adenomas.

Different effects of pyridostigmine on growth hormone (GH) response to GH-releasing hormone in endogenous and exogenous hypercortisolemic patients.

1. Somatostatin may play a role in the inhibition of growth hormone (GH) response to GH-releasing hormone (GHRH) in hypercortisolism. To examine this hypothesis we studied the effect of pyridostigmine, a cholinergic agonist that decreases hypothalamic somatostatin, on the GH response to GHRH in 8 controls, in 6 patients with endogenous hypercortisolism (3 with Cushing's disease and 3 with adrenal adenomas) and in 8 patients with exogenous hypercortisolism (lupus erythematosus chronically treated with 20-60 mg/day of prednisone). Each subject received GHRH(1-29)NH2,100 micrograms iv twice, preceded by pyridostigmine (120 mg) or placebo, orally. 2. The GH response to GHRH was significantly blunted in all hypercortisolemic patients compared to controls both after placebo (GH peak, 5.8 +/- 1.6 vs 46.2 +/- 15.9 micrograms/l, mean +/- SEM) and after pyridostigmine (15.7 +/- 5.6 vs 77.2 +/- 19.8 micrograms/l). 3. The GH response was absent in endogenous hypercortisolemic patients compared to the exogenous group, both after placebo (2.2 +/- 0.3 vs 8.5 +/- 2.4 micrograms/l) and after pyridostigmine (4.9 +/- 2.5 vs 23.8 +/- 8.7 micrograms/l). The GH release after GHRH/pyridostigmine for the exogenous group was similar to the response of controls treated with GHRH/placebo. 4. These results confirm that the GH response to GHRH is blunted in hypercortisolism, although more pronounced in the endogenous group. Pyridostigmine partially reversed this inhibition in the exogenous group. Therefore, somatostatin may play a role in the inhibition of GHRH-induced GH release in exogenous hypercortisolemic states.

Dexamethasone does not increase IGF-I and IGFBP-3 levels in man in the absence of endogenous GH.

It has been previously shown that short-term glucocorticoid administration increases circulating IGF-I and IGFBP-3 levels both in men and rats. An increase in endogenous GH secretion or a direct hepatic effect have been suggested as possible mechanisms. The aim of this study was to investigate the effect of short-term dexamethasone administration (3 mg orally during 7 days) in 8 patients with Sheehan's syndrome in replacement therapy. All patients had GH values <2.5 pg/l after clonidine administration. Before treatment IGF-I values were 9.3 3.6 microg/l (mean +/- SE) and IGFBP-3 levels were 1,195 +/- 208 microg/l. After dexamethasone administration there were no significant changes either in IGF-I or IGFBP-3 values (10.7 +/- 4.1 and 1,110 +/- 214 microg/l, respectively). A significant increase in insulin values was observed after dexamethasone administration (before: 120 +/- 10 micromol/l; after: 175 +/- 27 pmol/l; p<0.05), while glucose levels did not reach statistical significance (before: 4.6 +/- 0.3 mmol/l; after: 5.9 +/- 1.0 mmol/l). Our data suggest that dexamethasone is unable to increase circulating IGF-I and IGFBP-3 levels in man in the absence of endogenous GH.

Acute dexamethasone administration enhances GH responsiveness to GH releasing peptide-6 (GHRP-6) in man.

OBJECTIVE: Acute administration of glucocorticoids stimulates GH secretion probably by a decrease in hypothalamic somatostatin release. GHRP-6 is a synthetic hexapeptide that increases GH secretion by a mechanism of action not yet fully known, but apparently not by inhibition of hypothalamic somatostatin release. The aim of this study was to evaluate the effect of acute dexamethasone administration on GH responsiveness to GHRP-6 in man. DESIGN: One group of subjects received iv GHRP-6 (1 microg/kg), GH-releasing hormone (GHRH; 100 microg), GHRH plus GHRP-6 or saline 3.5 h after oral acute dexamethasone administration (4 mg; at 0600 h). A second study group was treated with GHRP-6, GHRH or GHRP-6 plus GHRH after placebo ingestion, following the same protocol. PATIENTS: Sixteen normal subjects (mean age: 29 +/- 3.3 years), with normal BMI (22.4 +/- 2.0 kg/m2), were studied. Eight subjects received dexamethasone and the other eight were treated with placebo. MEASUREMENTS: Serum GH was measured by a two site monoclonal antibody immunofluorometric assay. RESULTS: In the placebo-treated subjects, mean peak GH (mU/l; mean +/- SE) and AUC (mU.min/l) values after GHRP-6 administration (peak: 43.8 +/- 9.0; AUC: 2262.0 +/- 459. 2) did not differ from those observed after GHRH injection (peak: 49. 8 +/- 12.0; AUC: 2903.4 +/- 872.6). The association of the two peptides markedly increased GH levels (peak: 172.4 +/- 34.2; AUC: 10393.0 +/- 1894.8) compared with the isolated administration of GHRP-6 or GHRH. In the subjects who received dexamethasone 3.5 h before saline injection, GH baseline values were significantly higher than those observed after 90 min of sampling (12.4 +/- 9.4 vs. 4.6 +/- 2.0). Mean GH peak and AUC values after GHRP-6 (peak: 78.8 +/- 11.0; AUC: 4114.6 +/- 588.2) and after GHRH administration (peak: 46.8 +/- 16.0; AUC: 3006.8 +/- 1010.0) did not differ significantly in the dexamethasone-treated subjects. In this study group, the administration of the two peptides together caused a significant increase in both peak (119.2 +/- 16.0) and AUC values (7377.0 +/- 937.2) compared with the response obtained after each peptide alone. When the two groups were compared, a significant increase in GH responsiveness to GHRP-6 was observed after dexamethasone administration compared with placebo. No differences in GH response to GHRH, or to the administration of the two peptides together, were seen between the two groups. CONCLUSIONS: Oral dexamethasone, at a dose of 4 mg, enhances GH releasing peptide-6-induced GH release when administered 3.5 h earlier. These results suggest that dexamethasone and GHRP-6 could act at different sites of GH releasing mechanisms. Further studies are necessary to elucidate these findings.

Iopanoic acid-induced decrease of circulating T3 causes a significant increase in GH responsiveness to GH releasing hormone in thyrotoxic patients.

OBJECTIVE: Thyroid hormones participate in GH synthesis and secretion, and an impaired GH response to many pharmacological stimuli, including GH releasing hormone (GHRH), has been found in thyrotoxicosis. Although the mechanisms involved in this process have not been fully elucidated, there is evidence that thyroid hormones could act at both hypothalamic and pituitary levels. There are no data in the literature about the effect of an acute reduction of circulating T3 levels on GH secretion in hyperthyroidism. The GH responsiveness to GHRH was therefore evaluated in a group of hyperthyroid patients during short-term treatment with iopanoic acid. Iopanoic acid is a compound that induces a rapid decrease in serum T3 levels, mainly by inhibition of peripheral conversion of T4 to T3. To the authors' knowledge, there is no evidence of a direct effect of iopanoic acid on GH secretion. DESIGN: Hyperthyroid patients were submitted to a GHRH test (100 microg, i.v.) before (day 0), and on days 4, 7 and 15 after oral treatment with iopanoic acid (3 g every 3 days) and propylthiouracil (200 mg every 8 h). A group of normal control subjects was also submitted to a single GHRH test (100 microg, i.v.). PATIENTS: Nine patients with thyrotoxicosis (eight women, one man), with a mean age of 34 years, were studied. All patients had high serum levels of total T3 and total T4, and suppressed TSH levels. None of them had taken any medication for at least 3 months before the study. The patients were compared with a group of nine control subjects (five women, four men) with a mean age of 31 years. MEASUREMENTS: GH and TSH were measured by immunofluorometric assays. Total T3, total T4 and IGF-I were determined by radioimmunoassay. Albumin levels were measured by a colorimetric method. RESULTS: Iopanoic acid induced a rapid and maintained decrease in serum T3 concentrations, with a significant reduction on days 4, 7 and 15 compared with pre-treatment values. In hyperthyroidism, peak GH levels (mean +/- SE mU/l) after GHRH were significantly higher on day 15 (24.4 +/- 3.8) than those observed on days 0 (14.2 +/- 1.6), 4 (15.2 +/- 3.0) and 7 (19.6 +/- 5.0). There was a 79% increase in this response on day 15 compared with the pre-treatment period. Hyperthyroid patients had a blunted GH response to GHRH on days 0, 4 and 7 in comparison with control subjects. However, on day 15, no differences were observed between the area under the curve (mean +/- SE mU/l.120 min) in thyrotoxic patients (1770 +/- 306) and in the control group (3300 +/- 816). IGF-I and albumin levels did not change during iopanoic acid administration. CONCLUSIONS: The results show that an acute reduction in serum T3 levels elicits an increase in GH responsiveness to GHRH in hyperthyroidism. Although the mechanisms involved in this process are still unknown, it is possible that T3 influences GH responsiveness to GHRH via hypothalamic somatostatin release. Alternatively, T3 could have a direct effect at the pituitary somatotroph, modulating GHRH intracellular pathways.

Different effects of growth hormone releasing peptide (GHRP-6) and GH-releasing hormone on GH release in endogenous and exogenous hypercortisolism.

OBJECTIVE: Chronic hypercortisolism is associated with decreased GH responsiveness to GHRH. GHRP-6 is a synthetic hexapeptide that releases GH in several species, including man. As GHRH and GHRP-6 apparently stimulate GH release by different mechanisms, we evaluated the GH responses to these peptides in patients with endogenous and exogenous glucocorticoid excess and also in control subjects. DESIGN: Six patients with endogenous hypercortisolism, nine with exogenous glucocorticoid excess and 10 normal controls were submitted to three tests, in random order, with GHRH (100 micrograms), GHRP-6 (1 microgram/ kg) or GHRP+GHRP-6, in the same doses, i.v., on separate days. MEASUREMENTS: GH was measured by immunofluorometric assay. IGF-I was determined by radioimmunoassay. Plasma glucose was measured by the glucose-oxidase technique. RESULTS: Peak GH values (mean +/- SE; microgram/l) after GHRH were significantly blunted in endogenous (2.0 +/- 0.7) and exogenous (3.6 +/- 1.2) hypercortisolaemic patients compared to controls (24.9 +/- 6.1). The endogenous group had lower peak GH values after GHRP-6 alone (7.7 +/- 1.9) or together with GHRH (18.8 +/- 5.8) than those observed in controls (GHRP-6: 22.1 +/- 3.6; GHRH+GHRP-6: 77.4 +/- 15.0) and in exogenous hypercortisolism (27.4 +/- 6.2 and 78.1 +/- 19.9). There were no differences in the GH responses to GHRP-6 alone or in combination with GHRH when controls were compared to the exogenous group. No changes in plasma IGF-I and glucose levels were observed. CONCLUSIONS: Our results suggest that hypercortisolism had a different effect on the GH-releasing mechanisms stimulated by GHRH and GHRP-6. Moreover, in endogenous hypercortisolism both GHRH and GHRP-6 pathways are affected, while in the exogenous group GHRP-6 releasing mechanisms are apparently preserved.