RESUMO
In thyrotoxicosis there is an impaired GH response to GHRH, normal GH responsiveness to GHRP-6 and lack of synergistic GH response after simultaneous administration of both peptides. We have previously shown that the GHRH-induced GH release in these patients increases after an acute reduction of circulating T3 values with administration of iopanoic acid, a compound that inhibits peripheral conversion of T4 to T3. We have now studied the effect of a decrease in serum T3 levels on the GH response to GHRP-6 (1 microg/kg) plus GHRH (100 microg) in 9 hyperthyroid patients before and after 15 days of treatment with iopanoic acid (3 g every 3 days) and propylthiouracil (600 mg/day). Nine normal subjects were also studied. In all hyperthyroid patients iopanoic acid induced a rapid decrease and normalisation of serum T3 levels. In these subjects peak GH (microg/l; mean +/- SE) and AUC (microg/l x 120 min) values after GHRP-6 plus GHRH were significantly higher on day 15 compared to pretreatment values (peak, 18.3 +/- 3.0 vs 13.4 +/- 1.9; AUC, 1227.9 +/- 212.9 vs 968.5 +/- 160.4; p<0.05). Despite the significant enhancement of the GH responsiveness to GHRP-6 plus GHRH after treatment with iopanoic acid, this response remained significantly blunted when compared to controls both in terms of peak GH (18.3 +/- 3.0 vs 83.7 +/- 15.2; p<0.05) and AUC values (1227.9 +/- 212.9 vs 4956.5 +/- 889.3; p<0.05). In conclusion, our results show that an acute decrease of circulating T3 levels enhances, but does not normalise, the GH response to GHRP-6 plus GHRH in thyrotoxicosis. This could suggest that circulating T3 does not have a major role in the mechanisms involved in the synergistic effect of these peptides.
Assuntos
Antitireóideos/uso terapêutico , Hormônio Liberador de Hormônio do Crescimento/farmacologia , Hormônio do Crescimento Humano/sangue , Oligopeptídeos/farmacologia , Tireotoxicose/sangue , Tireotoxicose/tratamento farmacológico , Tri-Iodotironina/sangue , Adolescente , Adulto , Área Sob a Curva , Feminino , Imunofluorescência , Humanos , Hipertireoidismo/complicações , Hipertireoidismo/tratamento farmacológico , Ácido Iopanoico/uso terapêutico , Masculino , Propiltiouracila/uso terapêuticoRESUMO
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.
Assuntos
Doença de Graves/tratamento farmacológico , Hormônio Liberador de Hormônio do Crescimento , Hormônio do Crescimento/metabolismo , Ácido Iopanoico/uso terapêutico , Tri-Iodotironina/sangue , Adulto , Antitireóideos/uso terapêutico , Estudos de Casos e Controles , Feminino , Doença de Graves/sangue , Hormônio do Crescimento/sangue , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Propiltiouracila/uso terapêutico , Estatísticas não Paramétricas , Tireotropina/sangue , Tiroxina/sangueRESUMO
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.
Assuntos
Diabetes Mellitus Tipo 1/sangue , Hormônio Liberador de Hormônio do Crescimento/farmacologia , Hormônios/farmacologia , Hormônio do Crescimento Humano/metabolismo , Oligopeptídeos/farmacologia , Adulto , Análise de Variância , Diabetes Mellitus Tipo 1/fisiopatologia , Feminino , Hormônio do Crescimento Humano/sangue , Humanos , Cinética , Masculino , Valores de ReferênciaRESUMO
OBJECTIVE: Both spontaneous and stimulated GH secretion are reduced in patients with hypothyroidism. The mechanisms involved in these alterations are not yet fully understood. GHRP-6 is a synthetic hexapeptide that releases GH both in vivo and in vitro. Its mechanism of action is unknown, but there is evidence that this peptide acts as a functional somatostatin antagonist at pituitary level. The aim of this study was to evaluate the GH response to GHRP-6 in patients with primary hypothyroidism and in normal controls. DESIGN: Patients with hypothyroidism and normal controls were randomly submitted to 3 tests with GHRH (100 micrograms i.v.), GHRP-6 (1 microgram/kg i.v.) and GHRH + GHRP-6, on separate days. PATIENTS: Eleven patients with primary hypothyroidism were compared with 10 control subjects. MEASUREMENTS: GH, TSH and free T4 were measured by immunofluorometric assay and IGF-1 by radioimmunoassay. RESULTS: Hypothyroid patients had markedly lower peak GH values (mean +/- SE micrograms/l) after GHRH administration (4.1 +/- 0.9) compared to control subjects (24.9 +/- 5.1). After GHRP-6 injection hypothyroid patients had a significantly higher GH release (12.6 +/- 1.9) than that obtained with GHRH, while in control subjects GH values were similar (22.1 +/- 3.6). No significant differences in peak GH responses were observed following the administration of either GHRP-6 alone (controls 22.1 +/- 3.6; patients 12.6 +/- 1.9) or in combination with GHRH (controls 77.4 +/- 15.0; patients 52.8 +/- 10.9), despite the trend to smaller responses in hypothyroid patients. CONCLUSION: We have shown that patients with primary hypothyroidism have higher GH responses to GHRP-6 than to GHRH, which are markedly blunted. When GHRP-6 was associated with GHRH, a significant increase in the GH response was observed in these patients, which could suggest a role for somatostatin in this process. Our data suggest that thyroid hormones modulate GH release induced by GHRH and GHRP-6 through different mechanisms. However, additional studies are necessary to further elucidate this hypothesis.
Assuntos
Hormônio Liberador de Hormônio do Crescimento/farmacologia , Hormônio do Crescimento/metabolismo , Hipotireoidismo/sangue , Oligopeptídeos/farmacologia , Adulto , Feminino , Hormônio do Crescimento/sangue , Hormônios/farmacologia , Humanos , Hipotireoidismo/fisiopatologia , Masculino , Pessoa de Meia-Idade , Tireotropina/sangue , Tiroxina/sangueRESUMO
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.
Assuntos
Doença de Graves/fisiopatologia , Hormônio Liberador de Hormônio do Crescimento , Hormônio do Crescimento/metabolismo , Oligopeptídeos , Adulto , Análise de Variância , Interações Medicamentosas , Feminino , Doença de Graves/sangue , Hormônio do Crescimento/sangue , Hormônio Liberador de Hormônio do Crescimento/administração & dosagem , Humanos , Injeções Intravenosas , Cinética , Oligopeptídeos/administração & dosagem , Valores de Referência , Fatores de TempoRESUMO
OBJECTIVE: Several abnormalities in the GH response to pharmacological stimuli have been described in hyperthyroidism. Both normal and high serum IGF-I levels have been reported, as well as a decrease in IGF-I bioactivity. We have evaluated the GH response to GH-releasing hormone (GHRH) in hyperthyroid patients and the effects of hyperthyroidism on serum IGF-I levels. The possible relations between nutritional status, thyroid hormones and IGF-I levels were also investigated. We also studied the influence of long-term beta-adrenoceptor blockade on the GH response to GHRH in these patients. DESIGN: In 18 hyperthyroid patients and in 12 control subjects, GHRH (100 micrograms) was administered as an i.v. bolus injection. Eight hyperthyroid patients and 8 control subjects received 50 micrograms GHRH i.v. Seven hyperthyroid patients were reevaluated after beta-adrenoceptor blockade. IGF-I and albumin levels were measured initially in all hyperthyroid patients and control subjects. Body composition was determined in 11 hyperthyroid patients and in a group of 33 matched normal controls. PATIENTS: Hyperthyroid patients were compared to control subjects. MEASUREMENTS: GH, TSH and free T4 were measured by immunofluorometric assay. IGF-I, total T3 and total T4 were measured by radioimmunoassay. Body composition was determined using a dual-energy X-ray absorptiometer. RESULTS: The GH response to 100 micrograms GHRH in hyperthyroid patients was blunted compared to control subjects. The mean peak GH levels and the area under the curve were significantly lower in hyperthyroid patients compared to control subjects (11 +/- 1 vs 27 +/- 5 micrograms/l and 820 +/- 113 vs 1879 +/- 355 micrograms/l 120 min, respectively; P < 0.01). IGF-I levels were significantly reduced in hyperthyroid patients compared to controls (131 +/- 10 vs 201 +/- 16 micrograms/l, respectively; P < 0.01). Ideal body weight, serum albumin levels and the lean body mass were also reduced in hyperthyroid patients. After beta-adrenoceptor blockade there were no changes in the blunted GH response to GHRH in hyperthyroid patients. CONCLUSION: Our data suggest that the blunted GH response to GHRH in hyperthyroidism is apparently not related to circulating IGF-I levels. It is possible that nutritional factors could play a role in the reduced circulating IGF-I levels found in these patients.