Biomedical subjects

C Dieguez

Publications and source records attributed to C Dieguez.

At least 127 records · Page 7Linked to original sources

PubMed1996

Evaluation of pituitary GH reserve with GHRP-6.

GH releasing peptides (GHRPs) were developed before the isolation and identification of GH releasing hormone (GHRH) in 1982 yet the clinical era of the GHRPs began in 1988. Since then clinical studies have been greatly extended. We studied the effects of GHRPs on GH release as a function of age, metabolic status and in different neuroendocrine pathologies. The different mechanism of action of GHRPs versus GHRH and the site of action have been addressed. There is a large variability in the stimulatory action of GHRH contrasted with the reproducibility of action of GHRPs. In different metabolic states GH response after GHRH is more impaired than after GHRP-6. On the other hand in different neuroendocrine pathologies GH response after GHRP-6 is more impaired than after GHRH. Each secretagogue provides separate information on GH secretion, necessary not only for linear growth but for general metabolism.

Endocrine System Diseases↗

PubMed1996

Growth hormone releasing hexapeptide-6 (GHRP-6) test in the diagnosis of GH-deficiency.

Pituitary GH reserve can be assessed by substances that act directly at the somatotroph, such as GHRH, or by a variety of metabolic and neuropharmacological tests acting at the hypothalamic level, such as hypoglycemia, clonidine or L-Dopa. In order to evaluate GHRP-6 as a test of pituitary GH reserve, we studied GH responses of i.v. administered GHRP-6 in a group of short-statured children, as well as in a group of adults diagnosed with growth hormone deficiency (GHD) by conventional GH testing. Although we found that the GH response to GHRP-6 was lower in patients with GHD than in normal children, on an individual basis a considerable degree of overlap was observed between the two groups. In contrast, we found an almost complete blockade of GH response to either GHRP-6 or GHRH plus GHRP-6 in patients with pituitary stalk transection, suggesting that this could be a cost-effective test for the diagnosis of this condition. A similar finding was also obtained in GH response to the combined administration of GHRH plus GHRP-6 in patients with GHD of adult onset; this test may well prove valuable in the diagnosis of this clinical entity.

Child↗

PubMed1995

Effect of combined administration of growth hormone (GH)-releasing hormone, GH-releasing peptide-6, and pyridostigmine in normal and obese subjects.

Growth hormone (GH) secretion in response to all provocative stimuli is decreased in patients with obesity. Recently, we found that the combined administration of GH-releasing hormone (GHRH) and the hexapeptide GH-releasing peptide-6 (GHRP-6) induced a large increase in plasma GH levels. To gain further insight into the disrupted mechanism of GH regulation in obesity, we investigated whether the inhibition of somatostatinergic tone with pyridostigmine could further increase the GH response to combined administration of GHRH and GHRP-6. In normal subjects, administration of GHRH plus GHRP-6 induced a marked increase in plasma GH with a peak at 30 minutes (mean +/- SEM, 76.7 +/- 9.7 micrograms/L), which was similar to that obtained after pretreatment with pyridostigmine (74.7 +/- 9.4 micrograms/L). In obese patients, combined administration of GHRH plus GHRP-6 induced a clear increase in GH secretion with a peak at 15 minutes of 42.2 +/- 10.0 micrograms/L, which was also unaffected after pretreatment with pyridostigmine (38.4 +/- 5.8 micrograms/L). The GH response was lower in obese patients than in controls as assessed by the area under the curve after administration of both GHRH plus GHRP-6 (1,846 +/- 396 v 4,773 +/- 653, P < .01) and pyridostigmine plus GHRH plus GHRP-6 (1,989 +/- 372 v 5,098 +/- 679, P < .005). In conclusion, these data suggest that GHRP-6 can behave as a functional somatostatin antagonist, and that somatotrope responsiveness to the combined administration of GHRH plus GHRP-6 is largely independent of somatostatinergic tone.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1995

Regulation of thymosin beta 4 mRNA levels during cell proliferation.

The levels of thymosin beta 4 mRNA were studied throughout the cell cycle of NIH 3T3 cells. In serum deprived, quiescent cells, the levels of thymosin beta 4 were undetectable; after serum restoration, the cells were induced to proliferate and we found a pronounced increase in thymosin beta 4 mRNA levels at the G1/S transition. Thymosin beta 4 mRNA was induced even in the presence of cycloheximide. On the other hand, cycling cells that were synchronized at different stages of the cycle by means of mitotic shake-off after nocodazole arrest or a double thymidine block did not show any variation in the levels of thymosin beta 4 mRNA when they progressed synchronously through the cycle. In conclusion, the present data indicate that the thymosin beta 4 gene is regulated by cell proliferation but it is not a cell cycle-regulated gene. Finally, we studied thymosin beta 4 mRNA stability by inhibiting thymosin beta 4 gene transcription with actinomycin D. Our results suggest that thymosin beta 4 mRNA has a pronounced stability, a fact that might be relevant to account for the presence of thymosin beta 4 in enucleated cells like platelets.

Animals↗

PubMed1995

Growth hormone secretion after the administration of GHRP-6 or GHRH combined with GHRP-6 does not decline in late adulthood.

OBJECTIVE: Growth hormone (GH) secretion in middle and late adulthood declines with age. However, the precise mechanisms causing this impairment in GH release are unknown. His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GHRP-6) is a synthetic compound that releases GH in a dose related and specific manner in several species, including man. In order to gain a further insight into disrupted GH secretion in late adulthood, we evaluated GH responses to GHRP-6 or GHRH, administered either alone or in combination, in healthy young and late adulthood groups of subjects. DESIGN: All subjects underwent three different tests carried out in random order and separated by at least one week. Tests were performed at 0900 h after an overnight fast. GHRH (100 micrograms), GHRP-6 (90 micrograms) either alone or in combination were administered as an i.v. bolus. SUBJECTS: Groups of healthy young (mean +/- SEM 22 +/- 1.1 years, n = 9) and older adult subjects (59.5 +/- 1.7 years, n = 9) were studied. MEASUREMENTS: Serum GH levels were measured by radioimmunoassay. RESULTS: In the group of young adult subjects the combined administration of GHRH and GHRP-6 elicited a greater GH increase than GHRH alone (F = 21.9, P < 0.001) or GHRP-6 alone (F = 6.2, P = 0.01). Similarly, the response to the combined stimuli was also greater than with GHRH alone (F = 21.8, P < 0.001) or GHRP-6 alone (F = 23.9, P < 0.001) in the late adulthood group of subjects. GH responses to GHRH were greater in younger than in older subjects (F = 3.45, P = 0.03). In contrast, GH responses to either GHRP-6 (F = 0.71, P = NS) or combined GHRH plus GHRP-6 administration (F = 0.68, P = NS) were not significantly different between the two groups. CONCLUSIONS: These data show that GH responses to GHRP-6 are much greater than to GHRH in late adulthood. The marked increase of plasma GH levels observed after administration of GHRP-6 alone or in combination with GHRH indicates that impaired GH secretion in late adulthood is a functional and potentially reversible state.

Adult↗

PubMed1995

Plasma growth hormone response to growth hormone-releasing hexapeptide (GH-RP-6) in children with short stature.

Eighteen children with short stature were evaluated for growth hormone (GH) reserve after pharmacological tests and a single iv injection of GH-RP-6. These children were divided into two groups: 10 were diagnosed as having idiopathic GH deficiency by classical stimulation tests (group A) and the remaining 8 (group B) were considered growth-retarded children with normal GH secretion, following conventional stimulation, but reduced endogenous GH secretion. The results were compared with a group of 12 normal children. As a group, patients in group A showed a lower GH response to GH-RP-6, while patients in group B had a similar response as normal controls. However, on an individual basis, a considerable degree of overlapping in responses among the three groups was evident. These data indicate that, on an individual basis, GH-RP-6 testing is not of diagnostic value in children suspected of having idiopathic GH deficiency.

Adolescent↗

PubMed1995

Regulation of the pituitary-specific transcription factor GHF-1/Pit-1 messenger ribonucleic acid levels by growth hormone-secretagogues in rat anterior pituitary cells in monolayer culture.

Pituitary-specific expression of the GH gene is dependent on a pituitary-specific transcription factor GH factor-1 (GHF-1), a homeodomain protein also known as pituitary-specific transcription factor-1 (Pit-1). The aim of this study was to investigate the regulation of GHF-1 messenger RNA (mRNA) levels in primary monolayer cultures of rat anterior pituitary cells. Specifically, in addition to direct activators of second messenger signaling systems, we studied the effects of different hormones, all of which are known to be involved in the regulation of somatotroph cell function. We found that GH-releasing hormone (GHRH) increased GHF-1 mRNA levels in a time- and dose-dependent fashion. GHF-1 mRNA levels were increased 2.5-fold (P < 0.01) after incubation for 2 h with 10(-8) M GHRH. Longer incubations (6, 12, or 24 h) with GHRH failed to show a similar stimulatory effect. A significant increase in GHF-1 mRNA concentration (1.7-fold, P < 0.01) was observed after a 2-h treatment with physiological concentrations (10(-11) M) of GHRH. The action of GHRH seems to occur at the transcriptional level without the need of protein synthesis. Thus, treatment of cells with actinomycin D (5 micrograms/ml) completely abolished GHRH-induced increase in GHF-1 mRNA levels. Cycloheximide (23 micrograms/ml) alone increased GHF-1 mRNA levels (6-fold increase after treatment for 12 h, P < 0.01), as well as potentiating GHRH-induced increase in GHF-1 mRNA concentration (9-fold increase after treatment with GHRH plus cycloheximide for 12 h, P < 0.01). The effect of GHRH on GHF-1 mRNA levels could be mimicked by direct activators of second messenger signaling systems such as forskolin (10(-5) M) or the phorbol ester tumor promoter tetradecanoyl phorbol acetate (TPA) (10(-6) M). Other peptides such as pituitary adenylate cyclase activating polypeptide-38 (10(-7) M) but not GHRP-6 (10(-10) to 10(-5) M), were also able to increase GHF-1 mRNA levels. Treatment of the cells with somatostatin (10(-6) M) for either 2 or 48 h failed to modify basal or GHRH-induced GHF-1 mRNA levels. In contrast, pretreatment of the cells with insulin-like growth factor-1 (5 nM) inhibited basal GHF-1 mRNA concentration as well as completely blunting the subsequent response to cells exposed to GHRH for 2 h. These data demonstrate that GHRH, acting at the transcriptional level and through a mechanism not dependent on protein synthesis, plays a stimulatory role on GHF-1 mRNA levels.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenylyl Cyclases↗

PubMed1995

Absence of growth hormone (GH) secretion after the administration of either GH-releasing hormone (GHRH), GH-releasing peptide (GHRP-6), or GHRH plus GHRP-6 in children with neonatal pituitary stalk transection.

GH-releasing peptide (GHRP-6; His-D-Trp-Ala-Trp-D-Phe-Lys-NH2) is a synthetic compound that releases GH in a specific and dose-related manner through mechanisms and a point of action that are mostly unknown, but different from those of GHRH. In man, GHRP-6 is more efficacious than GHRH, and a striking synergistic action occurs when both compounds are administered together. To explain such a synergistic effect, it has been postulated, but not proven, that GHRP-6 acts through a double mechanism, with actions exerted at the pituitary and the hypothalamic level. On the other hand, patients with the syndrome of GH deficiency due to perinatal pituitary stalk transection have any hypothalamic factor nonoperandi. The aim of the present study was 3-fold: 1) to further understand how relevant, if at all, the hypothalamic action of GHRP-6 is for GH regulation; 2) to evaluate whether GHRP-6 plus GHRH could be a suitable diagnostic tool in children with pituitary stalk transection; and 3) to compare these results with similar published studies performed in patients with hypothalamo-pituitary disconnection, who developed the disease as adults. Seven patients with GH deficiency and different degrees of panhypopituitarism due to perinatal pituitary stalk transection and 7 age- and sex-matched normal controls were studied. The subjects underwent 3 different tests on separate occasions, being challenged with GHRH (1 microgram/kg, iv), GHRP-6 (1 microgram/kg, iv), or GHRH plus GHRP-6. GH was analyzed as the area under the curve (mean +/- SE; micrograms per L/90 min). In normal subjects, GH secretion was 1029 +/- 202 after GHRH treatment, 1221 +/- 345 after GHRP-6, and 3542 +/- 650 after GHRH plus GHRP-6; the latter value was significantly (P < 0.05) higher than the secretion elicited by GHRH or GHRP-6 alone. In the group of patients with perinatal pituitary stalk transection, the level of GH after GHRH treatment was 116 +/- 22 and was even more reduced (P < 0.05) after GHRP-6 treatment (37 +/- 8). After GHRH plus GHRP-6, GH secretion in those patients was 177 +/- 27, significantly higher (P < 0.05) than the secretion induced by either GHRH or GHRP-6 alone. Individually examined, none of the patients tested with the most potent stimulus known to date (GHRH plus GHRP-6) exhibited GH secretion greater than 5 micrograms/L.(ABSTRACT TRUNCATED AT 400 WORDS)

Child↗

PubMed1995

Blocked growth hormone-releasing peptide (GHRP-6)-induced GH secretion and absence of the synergic action of GHRP-6 plus GH-releasing hormone in patients with hypothalamopituitary disconnection: evidence that GHRP-6 main action is exerted at the hypothalamic level.

GH-releasing peptide (GHRP-6; His-D Trp-Ala-Trp-D Phe-Lys-NH2) is a synthetic compound that releases GH in a specific and dose-related manner through mechanisms and a point of action that are mostly unknown but different from those of GHRH. In man, GHRP-6 is more efficacious than GHRH, and a striking synergistic action on GH release is observed when GHRP-6 and GHRH are administered simultaneously. Based on such a synergistic action, it has been hypothesized that GHRP-6 acts through a double mechanism by actions exerted both at the pituitary and hypothalamic levels. The aim of the present study was 2-fold: 1) to further characterize the mechanism of action and synergistic effects of GHRP-6; and 2) to study its action in patients with hypothalamopituitary disconnection. Twelve patients with different neuroendocrine pathologies leading to a state of hypothalamopituitary disconnection (functional stalk section) and 11 age- and sex-matched normal controls were studied. Each subject underwent 3 tests on separate occasions, being challenged with GHRH (100 micrograms, i.v.), GHRP-6 (90 micrograms, i.v.), or GHRH plus GHRP-6. GH was analyzed as the area under the curve (mean +/- SE, micrograms per L/120 min). In normal subjects GH secretion was 483.7 +/- 99.2 after GHRH, 1434.8 +/- 393.0 after GHRP-6, and 3771.5 +/- 399.6 after GHRH plus GHRP-6; the level of GH secreted after GHRH plus GHRP-6 treatment was significantly (P < 0.05) higher than after the arithmetic sum of GH levels after both compounds administered separately. In the group of patients with hypothalamopituitary disconnection, the level of GH secreted after GHRH was similar to that in controls (423.4 +/- 62.8); however, a complete blockade was observed after GHRP-6 (97.3 +/- 7.9), significantly (P < 0.05) lower than after GHRH as well as lower than the GHRP-6-induced GH release in control subjects (P < 0.01). After GHRH plus GHRP-6, the patients with hypothalamopituitary disconnection showed severely reduced secretion (745.3 +/- 67.6; P < 0.01 vs. controls), a value that was not significantly different from the arithmetic addition of levels produced by both compounds administered separately.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

PubMed1995

Role of the serotonin receptor subtype 5-HT1D on basal and stimulated growth hormone secretion.

At present, four main types of serotonin (5-HT) receptors have been identified in the brain (5-HT1, 5-HT2, 5-HT3, and 5-HT4). In addition, the 5-HT1 have been further subclassified. We have taken advantage of a new selective 5-HT1D receptor agonist 3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulfonamide succinate, Sumatriptan, to evaluate the role of 5-HT1D receptors on GH secretion. To this end, several tests with or without sumatriptan were undertaken in normal prepubertal children. Furthermore, we assessed the effect of Sumatriptan on basal GH secretion and the GH response to GHRH in obese children. In normal children, Sumatriptan administration (3 mg, sc) resulted in an increase in basal GH levels at 30 min (7.7 +/- 1.5 micrograms/L; P < 0.05) and increased GH responses to GHRH (47.3 +/- 6.4 vs. 29.6 +/- 9.7 micrograms/L; P < 0.05). The Sumatriptan-induced increase in GH responses to GHRH was dependent on the stimulus tested. Pretreatment with Sumatriptan did not modify the GH response to clonidine or pyridostigmine, as assessed by the peak GH response and the area under the curve. In contrast, it increased the GH response to arginine. In the obese subjects, the GH response to GHRH was reduced (7.3 +/- 1.0 vs. 29.6 +/- 9.7 micrograms/L at 30 min) compared to that in control children (P < 0.05). Sumatriptan administration did not alter the basal GH value (peak GH, 1.7 +/- 0.3 micrograms/L at 30 min). However, Sumatriptan administration clearly increased the effect of GHRH, resulting in a GH peak of 14.6 +/- 3.1 micrograms/L at 30 min (P < 0.01). To assess the specificity of Sumatriptan on anterior pituitary hormone secretion, we studied its effect on TSH and PRL responses to TRH as well as LH-releasing hormone-induced LH and FSH secretion. Administration of Sumatriptan did not alter the response of any of these hormones. Our results indicate that 5-HT1D receptors have a stimulatory effect on GH secretion, possibly by inhibiting hypothalamic somatostatin release.

Arginine↗

PubMed1995

Growth hormone (GH) responses to the combined administration of GH-releasing hormone plus GH-releasing peptide 6 in adults with GH deficiency.

In recent years the health problems of adults with growth hormone deficiency (GHD) and the benefits of GH replacement therapy have received considerable attention. However, the reliability of conventional GH tests in the assessment of pituitary GH reserve in this group of patients is still controversial. In this study, we assessed GH secretion after the combined administration of GH-releasing hormone (GHRH) (1 microgram/kg iv) and GH-releasing peptide 6 (GHRP-6, 1 microgram/kg iv) in adult patients diagnosed with GHD by conventional GH testing, and correlate this response with insulin-like growth factor I levels. Twenty-one subjects (13 male, 8 female) with long-standing diagnosis of GHD aged 21-54 years were studied. In 13 subjects GH responses to GHRH plus GHRP-6 were markedly reduced (peak GH response < 10 mU/l), whereas in the remaining eight the response was greater (range 11-100 mU/l). In conclusion, our data show that combined administration of GHRH plus GHRP-6 elicited a significant increase in plasma GH levels in about 40% of patients diagnosed with GHD by conventional GH testing.

Adult↗

PubMed1994

Inhibition of growth hormone release after the combined administration of GHRH and GHRP-6 in patients with Cushing's syndrome.

OBJECTIVE: In patients with Cushing's syndrome there is a blunted GH response to all types of stimuli. Although inferential data point towards a direct perturbation in the pituitary exerted by glucocorticoids, the basic mechanism is unknown. His-D-TRP-ALA-TRP-D-Phe-Lys-NH2 (GHRP-6) is a synthetic hexapeptide which releases GH by a direct pituitary effect through receptors other than GHRH receptors. Furthermore, the combined administration of GHRH and GHRP-6 is able to induce a large GH discharge even in some pathological states such as obesity, associated with GH blockade. To gain further insight into the disrupted mechanisms of GH secretion, Cushing's syndrome patients were challenged with either GHRH, GHRP-6 or GHRH together with GHRP-6. A group of normal subjects was included for control purposes. DESIGN: Three different tests were undertaken: (a) GHRH 100 micrograms i.v.; (b) GHRP-6 100 micrograms i.v. and (c) GHRH plus GHRP-6 100 micrograms i.v. of each; administered to each subject on different days, at least 4 days apart. PATIENTS: Ten patients (8 women, 2 men) with untreated Cushing's syndrome, 9 Cushing's disease and 1 adrenal adenoma. Five healthy volunteers (3 women, 2 men) of similar ages served as a control group. MEASUREMENTS: Plasma GH levels were measured by immunoradiometric assay. RESULTS: The areas under the curve (AUC) of GH secretion (mean +/- SEM in mU/I/120 min) in the control subjects after each test were: GHRH, 1420 +/- 330; GHRP-6, 2278 +/- 290 and GHRH plus GHRP-6, 7332 +/- 592 (P < 0.05 vs each compound alone). The AUCs for Cushing's syndrome patients were: GHRH, 248 +/- 165; GHRP-6 530 +/- 170 and for GHRH plus GHRP-6, 870 +/- 258 (P < 0.05 vs GHRH alone). After the combined stimulus only one out of the ten patients with hypercortisolism showed a GH peak over 20 mU/I, while all the controls had a peak over 84 mU/I. CONCLUSIONS: GHRP-6 induced GH secretion as well as the GH discharge elicited by GHRH and GHRP-6 are considerably reduced in Cushing's syndrome patients. This suggests that the main impairment of GH secretion in that pathological state resides at pituitary level.

Adult↗

PubMed1994

Growth hormone releasing hormone 1-44 NH2 and 1-40 OH levels in normal subjects during growth hormone stimulation tests.

OBJECTIVE: Little is known about the relative circulating concentrations of growth hormone releasing hormone (GHRH) 1-44 NH2 and 1-40 OH in response to dynamic GH stimulation. We therefore studied the concentrations of growth hormone-releasing hormone (GHRH) 1-44 NH2 and 1-40 OH in the peripheral plasma of normal male subjects during GH stimulation tests. DESIGN: Tests were performed at 0900 h after an overnight fast. Stimulation tests, commenced at 0 minutes, included alpha-adrenergic activation with adrenaline (10 micrograms/min from 0 to 30 minutes) following beta-blockade with propranolol (1.5 mg/min from -10 to 0 minutes), alpha 2-adrenergic activation with clonidine 150 micrograms i.v., insulin hypoglycaemia (0.15 U/kg soluble insulin), L-arginine infusion (30 g from 0 to 30 minutes), L-dopa (500 mg orally) and oral glucose (100 g). SUBJECTS: Groups of healthy male volunteers aged 20-42 years, all within 10% of ideal body weight. MEASUREMENTS: Serum GH and plasma GHRH 1-44 NH2 and 1-40 OH were measured at intervals for between 60 and 390 minutes, depending on the stimulation test. RESULTS: There were no significant changes in either GHRH 1-44 or 1-40 following alpha-adrenergic activation with propranolol/adrenaline infusion, alpha 2-adrenergic activation with i.v. clonidine, insulin-induced hypoglycaemia or arginine infusion despite the expected rise in GH levels. After oral glucose, GH was initially suppressed with a late rise. There were no changes in GHRH 1-44 or 1-40 levels during either phase of this response. After L-dopa GH levels peaked at 90 minutes, 24.5 +/- 11.0 mU/l (mean +/- SEM). At 0 minutes GHRH 1-44 and 1-40 levels were 3.25 +/- 0.89 and 4.93 +/- 1.28 pmol/l respectively and rose in both cases, peaking at 60 minutes at 4.23 +/- 1.01 and 7.55 +/- 1.80 pmol/l (P < 0.05). At no time was there any evidence of differential secretion of GHRH 1-44 or 1-40. CONCLUSIONS: We have confirmed previous studies demonstrating a small rise in GHRH before the GH response to L-dopa. However, in all other situations of pharmacological stimulation of GH release we were unable to detect any significant changes in GHRH 1-44 or 1-40 levels. It seems most likely that peripheral GHRH does not reflect hypothalamic secretion. As yet there is no evidence for differential release of GHRH 1-44 and 1-40.

Adult↗

PubMed1994

Decreased growth hormone response to dexamethasone stimulation test in obese children.

Acute administration of glucocorticoids is a recently described stimulus for growth hormone secretion. The aim of the present study was the assessment of dexamethasone-induced growth hormone secretion in obese children. Dexamethasone iv tests were carried out in 14 normal control and 8 obese children. Growth hormone was measured by radioimmunoassay up to 5 h after dexamethasone administration. Dexamethasone elicited clear growth hormone secretion in normal children (mean peak 12.3 +/- 1.6; area under the curve 682.3 +/- 74.3). In the obese children, dexamethasone induced a slight but significant (p < 0.01) increase in growth hormone over basal values. However, the growth hormone response in this group was significantly lower than in the normal controls, when comparing both mean peak (5.5 +/- 2.3, mean +/- SEM) (p < 0.01) and area under the curve (306.8 +/- 44.5) (p < 0.001).

Adolescent↗

PubMed1994

Growth hormone (GH) secretion in active acromegaly after the combined administration of GH-releasing hormone and GH-releasing peptide-6.

His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (called GHRP-6) is a synthetic compound that releases GH in a dose-related, specific, and nonspecies-specific manner, through mechanisms different from those of GHRH. Being, normally, more potent than GHRH, GHRP-6 shows a striking synergistic action when administered simultaneously with GHRH, although the mechanisms and point of action of such a potentiating effect are unknown. The aim of the present study was 2-fold: 1) to further characterize the actions and mechanisms of GHRP-6 as well as its synergistic effects, and 2) to study its actions in acromegalic patients. Eleven acromegalic patients and 12 normal subjects, age and sex matched as controls, underwent 3 tests each on separate occasions, being challenged with GHRH (100 micrograms, iv), GHRP-6 (90 micrograms, iv), or GHRH plus GHRP-6. GH was analyzed as the area under the curve (mean +/- SE; micrograms per L/120 min). In normal subjects, GH secretion was 686 +/- 227 after GHRH, 1787 +/- 510 after GHRP-6, and 4111 +/- 671 after GHRH plus GHRP-6; the level of GH secreted after GHRH plus GHRP-6 treatment was significantly (P < 0.05) higher than the arithmetic sum of GH levels after both compounds administered separately. In acromegalic patients, the level of GH secreted after GHRH was 1468 +/- 499, that after GHRP-6 was 2595 +/- 762, and that after GHRH plus GHRP-6 was 4949 +/- 1043; this last value was not significantly different from the arithmetical addition of levels produced by both compounds administered separately. These results indicate that GH-secreting pituitary adenomas respond surprisingly well to either GHRH or GHRP-6 despite being deprived for long periods (even years) of the physiological regulation exerted by the hypothalamus. In addition, the synergistic action of GHRH plus GHRP-6 was observed in normal subjects, but not in acromegalic patients. These results suggest that GHRP-6 does not need to operate through hypothalamic factors to exert its GH-releasing action, even for eliciting a greater response than GHRH. On the other hand, the synergistic effect of GHRH plus GHRP-6 appears to need the cooperation of the hypothalamus, but how this occurs is still undetermined.

Acromegaly↗

PubMed1994

Oral dexamethasone administration: new pharmacological test for the assessment of growth hormone secretion.

Acute intravenous (i.v.) dexamethasone administration has been described recently as a new test for the diagnosis of growth hormone (GH) deficiency. In the present study, a new protocol of dexamethasone administration was evaluated. Twelve normal adults and 18 normal prepubertal children were studied. The dexamethasone i.v. test was performed in six adults at a dose of 4 mg and 12 children at a dose of 2 mg/m2. Blood samples were collected 15 min before, at time zero and every 15 or 30 min during 5 h, resulting in a total of 16 samples. In the remaining six adults and six children, 8 and 4 mg, respectively, of dexamethasone were administered orally at the subject's home, and blood sampling started 90 min later when they arrived at the hospital. Plasma GH was measured by radioimmunoassay. The dexamethasone-induced GH response (mean +/- SEM, micrograms/l) to the i.v. or oral protocol did not differ in either the adults (i.v. 8.2 +/- 2.1; oral 8.0 +/- 1.6) or the children (i.v. 14.9 +/- 1.3; oral 13.6 +/- 1.8). It is concluded that the simpler protocol of acute oral dexamethasone administration hereby presented can be a safe and suitable test of GH secretion.

Administration, Oral↗

PubMed1993

Vasoactive intestinal peptide-induced prolactin release in hypothyroid patients.

VIP is an established prolactin-releasing factor. VIP gene expression at the anterior pituitary level and the central nervous system is regulated by thyroid hormones. On the other hand, primary hypothyroidism leads in many cases to amenorrhea, galactorrhea and hyperprolactinemia. In this study we assessed prolactin responses to VIP (75 micrograms iv infusion over 12 min) in a group of six hypothyroid women (mean age +/- SE, 38.8 +/- 3.3 yr; serum TSH levels, mU/L, 116.3 +/- 23.9), before treatment and after normalization of thyroid hormone levels during thyroxine (T4) replacement therapy (100-150 micrograms/day over 12-16 weeks). Furthermore, we assessed if VIP infusion had any effects on serum GH levels in these patients. In hypothyroid women, VIP infusion increased serum prolactin concentrations with peak levels being attained at 15 min (28.8 +/- 3.4 micrograms/L). The Area Under the Curve (AUC) was 1921 +/- 103 micrograms/L/2h. PRL responses to VIP were unchanged after T4 therapy, both in terms of peak levels (28.7 +/- 2.2 micrograms/L, NS) and of AUC (2079 +/- 261 micrograms/L/2h, NS). Serum GH levels were unaffected by VIP administration. In conclusion our study shows that, in hypothyroid patients, restoration of normal thyroid hormone levels by thyroxine replacement therapy does not affect lactotroph responsiveness to VIP. Therefore, our data do not support the hypothesis that VIP might contribute to the hypothyroid-induced hyperprolactinemia seen in man.

Adult↗

PubMed1993

Effect of neurotensin on growth hormone release in vivo.

In order to investigate the mechanisms involved in the in vivo Growth Hormone (GH) response to Neurotensin (NT) we assessed the influence of estrogen status as well as the effect of passive immunization with antisomatostatin and anti-Growth Hormone-Releasing Hormone (GHRH) on NT-induced GH secretion in pentobarbital anesthetized rats. We found that, contrary to GH responses to GHRH, estrogen-treated rats (one single injection of 200 micrograms s.c. of estradiol valerate, 3 days before the experiment), exhibited markedly increased GH responses to different doses of NT (7.5, 15 and 30 micrograms/kg, i.v.). The stimulatory effect of NT (30 micrograms/kg) on estrogen-treated rats was similar in rats that received normal rabbit serum or passively immunized with antisomatostatin or anti-GHRH serum. In conclusion, estrogens play a facilitatory role on NT-induced GH release in the rat, which is exerted through a mechanism independent of hypothalamic GHRH or somatostatin release.

Animals↗