RESUMEN
The neuroendocrine mechanisms underlying the decline of GH with aging (somatopause) are uncertain. We recently found that the age-dependent diminution of the hypothalamic GH-releasing hormone (GHRH) output contributes to the somatopause in men. As the regulatory mechanisms of GH secretion are sexually dimorphic, we assessed the suppressibility of spontaneous and GHRH-stimulated GH secretion by graded doses of a specific competitive GHRH receptor antagonist in nine young (20-27 yr old) and eight elderly (65-77 yr old) healthy nonobese women to semiquantify hypothalamic GHRH output. Nocturnal mean GH was lower in elderly women (2.2 +/- 0.4 vs. 0.9 +/- 0.2 microg/liter; P = 0.01). Graded boluses of GHRH-44 resulted in similar GH responses in both populations (P = 0.28). Graded infusions of GHRH antagonist inhibited in a dose-dependent manner the GH responses to GHRH in both groups (P = 0.0001-0.04). The dose-inhibition curve for the lowest GHRH bolus dose was shifted to the left compared with the highest one (P = 0.04). However, the dose-inhibition curves for spontaneous GH secretion were not different in young and elderly women (P = 0.50). Thus, the female somatopause is not associated with a measurable decrease in hypothalamic GHRH output. When the dose-inhibition curves for young men and young women were compared, the latter was shifted to the left (P = 0.009), suggesting that the somatotropic system in women operates with less GHRH. We conclude that the contribution of endogenous GHRH to the maintenance of GH secretion and the neuroendocrine mechanisms of somatopause in humans are sexually dimorphic.
Asunto(s)
Hormona Liberadora de Hormona del Crecimiento/metabolismo , Hormona de Crecimiento Humana/sangre , Hipotálamo/metabolismo , Adulto , Anciano , Envejecimiento/metabolismo , Composición Corporal/fisiología , Ritmo Circadiano/fisiología , Relación Dosis-Respuesta a Droga , Femenino , Hormona Liberadora de Hormona del Crecimiento/antagonistas & inhibidores , Hormona Liberadora de Hormona del Crecimiento/farmacología , Humanos , Infusiones Intravenosas , Caracteres SexualesRESUMEN
GH hypersecretion is a hallmark of acromegaly. It is unknown whether the secretory activity of somatotroph adenoma is autonomous or is still governed by central or peripheral mechanisms. In this study we investigated whether GH secretion in acromegaly 1) has a reproducible circadian pattern and 2) is inhibited by exogenous IGF-I. Eleven patients with newly diagnosed acromegaly were studied in 2 protocols. In protocol 1, peripheral blood was sampled every 10 min for 48 h in 6 patients for the determination of concordance between 24-h GH profiles. There was no significant day to day variability in mean 24-h output. There was, however, a significant time effect, and the 24-h GH secretion pattern was maintained between days. In protocol 2, 5 patients were sampled for GH every 10 min twice, once during infusion of normal saline and once during iv infusion of recombinant human IGF-I (10 microg/kg x h). The recombinant human IGF-I infusion increased plasma IGF-I to approximately 230% of the baseline concentration. This resulted in GH suppression (4220 +/- 1950 vs. 3223 +/- 1472 microg/liter.min; P = 0.001), but did not alter GH secretion pattern. There were highly significant cross-correlations for 10 of the 11 of the subjects in the two protocols when the lag was 0 min. By harmonic analysis, nocturnal augmentation of GH was maintained, and maximum daily GH occurred at approximately 2300 h. These data demonstrate that the pattern of GH secretion in acromegaly is not random, but is highly preserved with 24-h periodicity. In addition, negative feedback regulation by IGF-I is preserved, although the degree of negative feedback is grossly attenuated. Thus, secretory activity of somatotroph adenomas is not autonomous or haphazard, but is still subject to both feedback and feedforward regulatory mechanisms.
Asunto(s)
Acromegalia/metabolismo , Hormona de Crecimiento Humana/metabolismo , Factor I del Crecimiento Similar a la Insulina/farmacología , Adulto , Retroalimentación/fisiología , Femenino , Hormona de Crecimiento Humana/sangre , Humanos , Masculino , Persona de Mediana Edad , Proteínas Recombinantes/farmacología , Reproducibilidad de los Resultados , Tirotropina/sangre , Hormona Liberadora de Tirotropina/sangreRESUMEN
To test whether endogenous hypothalamic somatostatin (SRIH) fluctuations are playing a role in the generation of growth hormone (GH) pulses, continuous subcutaneous octreotide infusion (16 microg/h) was used to create constant supraphysiological somatostatinergic tone. Six healthy postmenopausal women (age 67 +/- 3 yr, body mass index 24.7 +/- 1.2 kg/m(2)) were studied during normal saline and octreotide infusion providing stable plasma octreotide levels of 2,567 +/- 37 pg/ml. Blood samples were obtained every 10 min for 24 h, and plasma GH was measured with a sensitive chemiluminometric assay. Octreotide infusion suppressed 24-h mean GH by 84 +/- 3% (P = 0.00026), GH pulse amplitude by 90 +/- 3% (P = 0.00031), and trough GH by 54 +/- 5% (P = 0.0012), whereas GH pulse frequency remained unchanged. The response of GH to GH-releasing hormone (GHRH) was not suppressed, and the GH response to GH-releasing peptide-6 (GHRP-6) was unaffected. We conclude that, in women, periodic declines in hypothalamic SRIH secretion are not the driving force of endogenous GH pulses, which are most likely due to episodic release of GHRH and/or the endogenous GHRP-like ligand.
Asunto(s)
Hormona de Crecimiento Humana/metabolismo , Periodicidad , Somatostatina/metabolismo , Anciano , Índice de Masa Corporal , Femenino , Hormona Liberadora de Hormona del Crecimiento/farmacología , Hormonas/administración & dosificación , Hormonas/sangre , Humanos , Hipotálamo/metabolismo , Mediciones Luminiscentes , Persona de Mediana Edad , Octreótido/administración & dosificación , Octreótido/sangre , Oligopéptidos/farmacología , Posmenopausia , Tirotropina/sangre , Hormona Liberadora de Tirotropina/farmacologíaRESUMEN
BACKGROUND: Aging is accompanied by declining growth hormone (GH) and insulin-like growth factor-I (IGF-I) levels. The neuroendocrine mechanisms of this decline have been studied previously, but the interpretation of the data was confounded by the imprecision in GH measurements and by the intervening variables of altered body composition and decreased gonadal steroid milieu in the elderly subjects of both sexes. METHODS: To study the contribution of aging per se, we evaluated discrete parameters of GH pulsatility in young (n = 8 women, n = 8 men) and elderly (n = 11 women, in 10 men) subjects closely matched for body mass index. Blood samples for GH were obtained every 10 minutes for 24 hours. Plasma GH was measured by a sensitive chemiluminescent assay. GH pulsatility was assessed using cluster analysis. RESULTS: The elderly subjects had plasma IGF-I levels and integrated GH concentrations that were 32% to -56% of their sex-matched younger counterparts. The age-associated attenuation in GH was due to a decrease in GH pulse amplitude, whereas pulse frequency and nadir levels were unchanged. The majority of the young subjects (81%) reached their peak GH during the "lights off" period, whereas the majority of the elderly subjects (62%) peaked during the "lights on" period (p = .01). CONCLUSIONS: We conclude that aging in both sexes is accompanied by profound decreases in GH output and in plasma IGF-I concentrations. This effect is separate from the alterations in body mass index that accompany the normal aging process. Attenuation of GH output associated with aging is related solely to the lower GH and, by inference, GH-releasing hormone (GHRH) pulse amplitude.
Asunto(s)
Envejecimiento/sangre , Hormona Liberadora de Hormona del Crecimiento/metabolismo , Hormona de Crecimiento Humana/sangre , Hipotálamo/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Ritmo Circadiano , Femenino , Humanos , Factor I del Crecimiento Similar a la Insulina/análisis , Masculino , Persona de Mediana Edad , Concentración OsmolarRESUMEN
Growth hormone-releasing hormone (GHRH) is a main inducer of growth hormone (GH) pulses in most species studied to date. There is no information regarding the pattern of GHRH secretion as a regulator of GH gene expression. We investigated the roles of the parameters of exogenous GHRH administration (frequency, amplitude, and total amount) upon induction of pituitary GH mRNA, GH content, and somatic growth in the female rat. Continuous GHRH infusions were ineffective in altering GH mRNA levels, GH stores, or weight gain. Changing GHRH pulse amplitude between 4, 8, and 16 microg/kg at a constant frequency (Q3.0 h) was only moderately effective in augmenting GH mRNA levels, whereas the 8 microg/kg and 16 microg/kg dosages stimulated weight gain by as much as 60%. When given at a 1.5-h frequency, GHRH doubled the amount of GH mRNA, elevated pituitary GH stores, and stimulated body weight gain. In the rat model, pulsatile but not continuous GHRH administration is effective in inducing pituitary GH mRNA and GH content as well as somatic growth. These studies suggest that the greater growth rate, pituitary mRNA levels, and GH stores seen in male compared with female rats are likely mediated, in part, by the endogenous episodic GHRH secretory pattern present in males.
Asunto(s)
Hormona Liberadora de Hormona del Crecimiento/administración & dosificación , Hormona del Crecimiento/genética , Periodicidad , ARN Mensajero/biosíntesis , Animales , Relación Dosis-Respuesta a Droga , Femenino , Expresión Génica/efectos de los fármacos , Hormona del Crecimiento/sangre , Hormona del Crecimiento/metabolismo , Masculino , Hipófisis/efectos de los fármacos , Hipófisis/metabolismo , Ratas , Ratas Sprague-Dawley , Aumento de Peso/efectos de los fármacosRESUMEN
Whether GH secretion in women varies over the menstrual cycle is uncertain. Previous investigations have led to conflicting conclusions; some studies suggested that there is an estrogen mediated rise in GH during the periovulatory (PO) and luteal (L) phases whereas others indicated no change in GH axis over the cycle. Differences in conclusions could relate to heterogeneity of the study populations, GH sampling paradigms or sensitivity of the GH assays used. In order to investigate whether GH secretion varied over the cycle, 24-h GH profiles using every 10-min sampling were obtained in 6 ovulatory women during the early follicular (EF), PO and L phases of the cycle. The TSH response to TRH, GH response to GRH and fasting plasma IGF-I were measured on each occasion. There was a trend toward higher integrated GH concentration (IGHC) during the PO phase, although this difference was not statistically significant (3284+/-721 vs 4542+/-872 vs 4071+/-699 microg/min/L; EF vs PO vs L; p=0.09). Similarly, deconvolution estimated GH secretion did not vary over the cycle (p=0.56). There were no differences in GH pulse amplitude or frequency. There were no correlations between IGHC and sex steroids. Serum IGF-I was constant over the cycle (272+/-38 vs 277+/-31 vs 265+/-38 microg/L; p=0.89). The TSH response to TRH and GH response to GRH did not vary over the cycle. We concluded that the effect of changes in the ovarian steroid milieu on the GH axis during spontaneous menstrual cycles is minimal.
Asunto(s)
Hormona de Crecimiento Humana/metabolismo , Ciclo Menstrual , Adulto , Recolección de Muestras de Sangre , Índice de Masa Corporal , Femenino , Hormona Liberadora de Hormona del Crecimiento , Hormona de Crecimiento Humana/sangre , Humanos , Factor I del Crecimiento Similar a la Insulina/análisis , Esteroides/sangre , Hormonas Tiroideas/sangre , Tirotropina/sangre , Hormona Liberadora de TirotropinaRESUMEN
We studied the effects of cortisol withdrawal and patterned replacement upon spontaneous GH secretion and circadian rhythmicity in 7 patients with Addison's disease. Hydrocortisone was administered in physiological daily total dosages, and all resulting plasma cortisol values were 2-15 micrograms/dl. It was given in 3 pulsatile modes: simulating "physiological" rhythm, "reverse" diurnal rhythmicity and "continuous" pulsatility. All modes of cortisol administration increased mean 24 h, GH pulse amplitude and interpulse GH levels. During saline infusions circadian GH rhythmicity was preserved, with GH being at its highest between 2400-0400 h. Administration of hydrocortisone in any mode did not modify circadian GH rhythmicity. We conclude: Cortisol replacement in physiological daily doses increases GH output in patients with Addison's disease by augmenting GH pulse amplitude and interpulse levels. This is likely due to the attenuation of hypothalamic somatostatin (SRIF) secretion by physiologic levels of cortisol. By inference, it implies that cortisol deficiency leads to diminution of GH output with low GH pulse amplitude, likely as a result of an augmented hypothalamic somatostatin secretion. However, circadian rhythmicity of GH secretion is glucocorticoid-independent.
Asunto(s)
Enfermedad de Addison/metabolismo , Ritmo Circadiano/efectos de los fármacos , Hormona de Crecimiento Humana/metabolismo , Hidrocortisona/administración & dosificación , Hidrocortisona/deficiencia , Enfermedad de Addison/tratamiento farmacológico , Adulto , Anciano , Femenino , Hormona de Crecimiento Humana/sangre , Humanos , Hidrocortisona/sangre , Hidrocortisona/uso terapéutico , Masculino , Persona de Mediana Edad , Flujo PulsátilRESUMEN
GH secretion declines with aging. The neuroendocrine mechanisms of somatopause are uncertain. To semiquantify endogenous hypothalamic GHRH output, we measured the suppressibility of spontaneous and GHRH-stimulated GH secretion by graded doses of a specific competitive GHRH receptor antagonist (N-Ac-Tyr1,D-Arg2)GHRH-(1-29) in healthy young and elderly men. Nocturnal GH was about 30% lower in the elderly than in the young. Graded boluses of GHRH elicited dose-dependent GH responses, with no difference between the two age groups. Graded infusions of GHRH antagonist suppressed GH responses to GHRH in a dose-dependent manner, but with similar potency in both groups. The degree of inhibition depended on the magnitude of GHRH bolus: the dose-inhibition curves for the low GHRH boluses were shifted to the left compared to those with the high GHRH bolus (P = 0.01). Similarly, the dose-inhibition curve for spontaneous GH secretion was shifted to the left for the elderly compared to the young men (P = 0.01). Thus, the model of graded infusions of GHRH antagonist differentiates between different amounts of GHRH presented to the pituitary, permitting semiquantification of the endogenous hypothalamic GHRH output in vivo. Our data suggest that there is an age-dependent decrease in the endogenous hypothalamic GHRH output contributing to the age-associated GH decline.
Asunto(s)
Envejecimiento/metabolismo , Hormona Liberadora de Hormona del Crecimiento/deficiencia , Hormona Liberadora de Hormona del Crecimiento/metabolismo , Hipotálamo/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Composición Corporal , Ritmo Circadiano , Hormona Liberadora de Hormona del Crecimiento/antagonistas & inhibidores , Hormona Liberadora de Hormona del Crecimiento/sangre , Hormona Liberadora de Hormona del Crecimiento/farmacología , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Although insulin-induced hypoglycemia is a potent stimulus for growth hormone (GH) secretion in humans, hypoglycemia was reported to suppress GH in sheep. We investigated whether GH suppression in sheep during insulin hypoglycemia resulted from the dose of insulin administered or the fed state of the animal. Saline or insulin (0.05, 0.2, 1.0, or 5.0 U/kg) intravenous boluses were administered to eight fasted ewes in a crossover experiment. In another experiment, four sheep were fed 2 h before intravenous administrations of either 0.2 or 5 U/kg of insulin. All doses of insulin resulted in comparable hypoglycemia, although the duration of hypoglycemia increased directly with insulin dose. Hypoglycemia in fasted animals stimulated GH secretion. The GH rise above baseline was inversely related to the insulin dose, and the insulin doses of 1 and 5 U/kg resulted in late suppression of GH below baseline concentrations. Insulin administration to fed animals caused an identical degree of hypoglycemia but no increase in GH. Insulin-hypoglycemia stimulates GH secretion in sheep in a manner similar to humans, and the response is dependent on both fed state and insulin dose.
Asunto(s)
Hormona del Crecimiento/metabolismo , Hipoglucemia/inducido químicamente , Hipoglucemia/metabolismo , Hipoglucemiantes , Insulina , Animales , Relación Dosis-Respuesta a Droga , Ingestión de Alimentos/fisiología , Ayuno/fisiología , Femenino , Hipoglucemiantes/administración & dosificación , Inyecciones Intravenosas , Insulina/administración & dosificación , Ovinos , Factores de TiempoRESUMEN
Sprague-Dawley rats, which become obese (obesity prone) when fed a moderately high-fat (MHF; 32.5% of kcal as fat) diet, have decreased growth hormone (GH) concentrations compared with obesity-resistant rats fed the same diet. To determine whether plasma GH concentrations are different in obesity-prone rats compared with obesity-resistant rats before diet-induced obesity occurs, total integrated GH concentrations were determined in male Sprague-Dawley rats before exposure to the MHF diet. After initial blood sampling, rats were fed an MHF diet for 15 wk, over which time the animals were separated into two discrete populations based on body weight gain. Analysis of GH in episodic blood samples showed that the obesity-prone group had a GH secretion deficit before the onset of obesity (115.2 +/- 12.9 ng . ml-1 . 200 min-1) compared with obesity-resistant rats (237.2 +/- 47.1 ng . ml-1 . 200 min-1). The GH concentration difference was due to a decrease in mean GH peak height in rats that later became obese (34.8 ng/ml) compared with rats that remained lean (74.2 ng/ml). The results suggest that GH secretion impairment exists before dietary challenge or onset of obesity and may contribute to the susceptibility to obesity observed in these animals.
Asunto(s)
Grasas de la Dieta , Hormona del Crecimiento/sangre , Obesidad/fisiopatología , Animales , Peso Corporal , Susceptibilidad a Enfermedades , Ingestión de Energía , Metabolismo Energético , Hormona del Crecimiento/metabolismo , Masculino , Obesidad/etiología , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
Sexually dimorphic growth hormone (GH) secretory pattern is important in the determination of gender-specific patterns of growth and metabolism in rats. Whether GH secretion in humans is also sexually dimorphic and the neuroendocrine mechanisms governing this potential difference are not fully established. We have compared pulsatile GH secretion profiles in young men and women in the baseline state and during a continuous intravenous infusion of recombinant human insulin-like growth factor I (rhIGF-I). During the baseline study, men had large nocturnal GH pulses and relatively small pulses during the rest of the day. In contrast, women had more continuous GH secretion and more frequent GH pulses that were of more uniform size. The infusion of rhIGF-I (10 microg/kg/h) potently suppressed both spontaneous and growth hormone-releasing hormone (GHRH)-induced GH secretion in men. In women, however, rhIGF-I had less effect on pulsatile GH secretion and did not suppress the GH response to GHRH. These data demonstrate the existence of sexual dimorphism in the regulatory mechanisms involved in GH secretion in humans. The persistence of GH responses to GHRH in women suggests that negative feedback by IGF-I might be expressed, in part, through suppression of hypothalamic GHRH.
Asunto(s)
Hormona de Crecimiento Humana/metabolismo , Adulto , Estradiol/sangre , Femenino , Hormona Liberadora de Hormona del Crecimiento/farmacología , Humanos , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/análisis , Factor I del Crecimiento Similar a la Insulina/farmacología , Masculino , Proteínas Recombinantes/farmacología , Factores Sexuales , Testosterona/sangre , Tirotropina/sangreRESUMEN
GH-releasing peptide-6 (GHRP-6) is a potent GH secretagogue that releases GH by uncertain mechanisms. To assess whether GHRH is required for GH release by GHRP-6 in humans, we used the specific antagonist to GHRH (N-Ac-Tyr1,D-Arg2)GHRH(1-29)NH2 (GHRH Ant). We have previously shown that GHRH-Ant (400 microg/kg) blocked the GH response to 0.33 and 3.3 microg/kg boluses of GHRH by 95% and 81%, respectively. Nine healthy men between the ages of 20 and 30 yr were studied on two occasions. They received either saline or GHRH-Ant (400 microg/kg, i.v.) at 0840 h, followed by GHRP-6 (1 microg/kg, i.v. bolus) at 0900 h. Blood was sampled every 10 min from 0800-1100 h. GH responses were measured as the maximal increase over the baseline GH concentration and as the area under the curve. GHRH-Ant eliminated most of the GH response to GHRP-6 [maximal increase over the baseline GH concentration, 33.8 +/- 4.8 vs. 6.2 +/- 1.8 microg/L (mean +/- SEM; P < 0.0001); area under the curve, 1701 +/- 278 vs. 376 +/- 113 microg/min x L (P < 0.001)]. These data show that endogenous GHRH is necessary for most of the GH response to GHRP-6 in humans.
Asunto(s)
Hormona Liberadora de Gonadotropina/fisiología , Hormona Liberadora de Hormona del Crecimiento/fisiología , Hormonas/farmacología , Hormona de Crecimiento Humana/metabolismo , Hipotálamo/efectos de los fármacos , Oligopéptidos/farmacología , Adulto , Humanos , Hipotálamo/metabolismo , Masculino , Tasa de Secreción/efectos de los fármacos , Sermorelina/análogos & derivados , Sermorelina/farmacología , Estimulación QuímicaRESUMEN
We have recently demonstrated that a competitive antagonist of GHRH, (N-Ac-Tyr1,D-Arg2)GHRH-(1-29)NH2 (GHRH-Ant), eliminates nearly all nocturnal GH pulsatility in normal subjects, supporting the hypothesis that GH pulsatility is driven by GHRH. In this study, we compared the effects of every 12 h i.v. boluses of either GHRH-Ant or saline on 24-h GH profiles in a patient with acromegaly due to a metastatic GHRH-secreting carcinoid tumor. Bolus doses of GHRH-Ant (400 micrograms/kg, i.v.) acutely suppressed GH concentration to 30-40% of the pretreatment baseline, and this effect lasted 3-4 h. Administration of GHRH (0.33 microgram/kg, i.v.) bolus resulted in a small rise in GH, and this effect was blocked by GHRH-Ant (400 micrograms/kg). During saline treatment, the secretory patterns of both GH and ectopic GHRH were pulsatile; however, there was no correlation between changes in plasma GHRH and GH concentrations. This lack of correlation was probably due to the majority of circulating GHRH immunoreactivity consisting of nonbiologically active GHRH fragments. These data support the hypothesis that GH hypersecretion in the ectopic GHRH syndrome requires GHRH receptor occupancy and validates the use of GHRH-Ant to probe the potential involvement of endogenous GHRH in patients with acromegaly due to pituitary somatotropinoma.
Asunto(s)
Hormona Liberadora de Hormona del Crecimiento/antagonistas & inhibidores , Hormona Liberadora de Hormona del Crecimiento/fisiología , Hormona de Crecimiento Humana/metabolismo , Acromegalia/etiología , Acromegalia/metabolismo , Adulto , Tumor Carcinoide/etiología , Tumor Carcinoide/metabolismo , Hormona Liberadora de Hormona del Crecimiento/metabolismo , Hormona de Crecimiento Humana/sangre , Humanos , Masculino , Concentración Osmolar , Flujo Pulsátil , Factores de TiempoRESUMEN
The neuroendocrine mechanisms underlying the generation of pulsatile GH secretion in humans are poorly understood. GH secretory pulses are likely to result from acute GHRH secretory episodes, acute decreases in hypothalamic somatostatin secretion, or a combination of these mechanisms. In earlier studies we demonstrated that a single i.v. bolus of a competitive GHRH antagonist [N-Ac-Tyr1,D-Arg2)GHRH-(1-29); GHRH-Ant] blocked 40% of the nocturnal GH release. Failure to more completely eliminate nocturnal GH secretion could be due to either incomplete antagonism of endogenous GHRH action by GHRH-Ant or a non-GHRH component of GH release. We subsequently investigated whether a continuous infusion of GHRH-Ant would more completely eliminate nocturnal GH secretion. Eight men were given a 400 micrograms/kg i.v. bolus of GHRH-Ant at 2300 h, followed by a 50 micrograms/kg.h i.v. infusion of GHRH-Ant between 2300-0700 h or a saline bolus followed by a saline infusion. An i.v. bolus of GHRH (1 microgram/kg) was given at 0500 h on both occasions. Blood was sampled every 10 min between 2300-0700 h. As measured by the area under the curve (AUC) from 2400-0500 h, GHRH-Ant suppressed GH secretion by an average of 89% (1795 +/- 412 vs. 164 +/- 46 micrograms/min.L; P = 0.004). The response to GHRH was suppressed by 79% (484 +/- 140 vs. 64 +/- 19 micrograms/min.L; P = 0.02). These data demonstrate that the previously observed nonsuppressible GH secretion was probably due to incomplete blockade of pituitary GHRH receptors and that all or nearly all of nocturnal GH pulsatility can be attributed to the effect of hypothalamic GHRH.
Asunto(s)
Hormona Liberadora de Hormona del Crecimiento/antagonistas & inhibidores , Hormona del Crecimiento/metabolismo , Adolescente , Adulto , Hormona Liberadora de Hormona del Crecimiento/fisiología , Humanos , Infusiones Intravenosas , Masculino , Factores de TiempoRESUMEN
The site-specific regulation of somatic growth by sex steroids is poorly understood. The aim of the present study was to assess the influence of 17 beta-estradiol (E2) and 5 alpha-dihydrotestosterone (DHT) on somatic growth and pituitary GH and hepatic insulin-like growth factor I (IGF-I) secretion and synthesis in the adult female rat. Animals (200-250 g) underwent sham surgery or bilateral ovariectomy. Some ovariectomized (OVX) rats were given sc implants that provided almost physiological female E2 (OVX/E2) and male DHT (OVX/DHT) levels. Animals were killed 3, 7, 14, and 26 days later. Body weight gain was calculated, and pituitary GH content, pituitary GH messenger RNA (mRNA) levels, plasma GH, and circulating IGF-I concentrations were measured. Levels of hepatic IGF-I mRNA were measured at 26 days. Ovariectomy increased body weight gain (P < 0.001) in parallel with a significant elevation in plasma IGF-I (P < 0.001). Replacement of E2 markedly suppressed somatic growth (P < 0.001), plasma IGF-I concentrations (P < 0.001), and liver IGF-I gene expression (P < 0.002). However, circulating GH concentrations were high in OVX/E2 animals (P < 0.001), whereas pituitary GH stores were significantly attenuated (P < 0.05). In contrast, DHT exposure increased body weight gain (P < 0.001), circulating IGF-I concentrations (P < 0.05), and steady state hepatic IGF-I mRNA levels (P < 0.05). Pituitary GH stores were markedly elevated (P < 0.001) in DHT-treated animals, but circulating GH levels remained very low. Pituitary GH mRNA rose transiently at 7 days in OVX and OVX/E2 rats, but no consistent changes between the groups were observed thereafter. We conclude that 1) gonadal steroids have disparate effects on somatic growth in female rats, with E2 suppressing and DHT stimulating body weight gain; 2) these effects are likely to be primarily mediated at the level of IGF-I synthesis and secretion; and 3) changes in pituitary GH content and secretion probably reflect normal adjustment to changes in the intensity of IGF-I negative feedback.
Asunto(s)
Dihidrotestosterona/farmacología , Estradiol/farmacología , Hormona del Crecimiento/metabolismo , Hipófisis/metabolismo , Aumento de Peso/efectos de los fármacos , Animales , Femenino , Expresión Génica/efectos de los fármacos , Hormona del Crecimiento/genética , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Hígado/metabolismo , Masculino , Ovariectomía , ARN Mensajero/metabolismo , Ratas/crecimiento & desarrollo , Ratas Sprague-DawleyRESUMEN
The roles of hypothalamic growth hormone-releasing hormone (GHRH) and of somatostatin (SRIF) in pharmacologically stimulated growth hormone (GH) secretion in humans are unclear. GH responses could result either from GHRH release or from acute decline in SRIF secretion. To assess directly the role of endogenous GHRH in human GH secretion, we have used a competitive GHRH antagonist, (N-Ac-Tyr1,D-Arg2)GHRH(1-29)NH2 (GHRH-Ant), which we have previously shown is able to block the GH response to GHRH. We first tested whether an acute decline in SRIF, independent of GHRH action, would release GH. Pretreatment with GHRH-Ant abolished the GH response to exogenous GHRH (0.33 microgram/kg i.v.) but did not modify the GH rise after termination of an SRIF infusion. We then investigated the role of endogenous GHRH in the GH responses to pharmacologic stimuli of GH release. The GH responses to arginine (30 g i.v. over 30 min), L-dopa (0.5 g orally), insulin hypoglycemia (0.1 U/Kg i.v.), clonidine (0.25 mg orally), or pyridostigmine (60 mg orally) were measured in healthy young men after pretreatment with either saline of GHRH-Ant 400 microgram/kg i.v. In every case, GH release was significantly suppressed by GHRH-Ant. We conclude that endogenous GHRH is required for the GH response to each of these pharmacologic stimuli. Acute release of hypothalamic GHRH may be a common mechanism by which these compounds mediate GH secretion.
Asunto(s)
Hormona Liberadora de Hormona del Crecimiento/fisiología , Hormona del Crecimiento/metabolismo , Agonistas alfa-Adrenérgicos/farmacología , Arginina/farmacología , Inhibidores de la Colinesterasa/farmacología , Clonidina/farmacología , Femenino , Hormona Liberadora de Hormona del Crecimiento/antagonistas & inhibidores , Antagonistas de Hormonas/farmacología , Humanos , Hipoglucemia/metabolismo , Levodopa/farmacología , Masculino , Bromuro de Piridostigmina/farmacología , Tasa de Secreción/efectos de los fármacos , Somatostatina/fisiologíaRESUMEN
To investigate the mechanisms of the negative feedback inhibition of growth hormone (GH) secretion by IGF-I, we studied parameters of GH pulsatility in six normal, fed men before and during a 48-h infusion of recombinant human IGF-I (rhIGF-I) (10-15 micrograms/kg per h). Plasma levels of IGF-I increased from the baseline value of 163.5 +/- 9.3 micrograms/liter (mean +/- SE) to a new steady state of 452.0 +/- 20.9 micrograms/liter during the infusion. Plasma GH concentrations were measured every 10 min for 24 h during both saline and rhIGF-I infusions using a sensitive chemiluminescent assay. Overall, GH concentrations were suppressed during the rhIGF-I infusion by 85 +/- 3%, mainly by attenuating spontaneous GH pulse amplitude (77 +/- 4% suppression). The apparent GH pulse frequency was attenuated from 7.8 +/- 0.9 to 4.7 +/- 0.6 pulses/24 h (P = 0.006). Administration of rhIGF suppressed GH responses to exogenous GH-releasing hormone by 82 +/- 3%, and thyroid-stimulating hormone responses to thyrotropin-releasing hormone were also suppressed by 44 +/- 9%. This constellation of hormonal effects is most compatible with the rhIGF-I-induced stimulation of hypothalamic somatostatin secretion.
Asunto(s)
Hormona del Crecimiento/metabolismo , Hipotálamo/fisiología , Factor I del Crecimiento Similar a la Insulina/farmacología , Somatostatina/fisiología , Adolescente , Adulto , Glucemia/análisis , Retroalimentación , Hormona Liberadora de Hormona del Crecimiento/farmacología , Humanos , Factor I del Crecimiento Similar a la Insulina/análisis , Masculino , Proteínas Recombinantes/farmacología , Tirotropina/metabolismoRESUMEN
Bolus injection of the synthetic hexapeptide GH-releasing peptide-6 (GHRP-6) reliably promotes GH secretion. However, desensitization to the GH-releasing effects of GHRP has been shown to occur during short term iv infusion. To determine whether humans would remain responsive to prolonged exposure to GHRP and to study the mechanism of action of GHRP, we compared the effects of a 34-h iv infusion of either GHRP or normal saline on parameters of pulsatile GH concentration in nine healthy young men. Each infusion was administered from 0800 h on day 1 to 1800 h on day 2. GHRP was given as a 1 microgram/kg loading bolus, then at the rate of 1 microgram/kg.h. A 50-microgram iv bolus of TRH was given at 0800 h on day 2, followed by iv boluses of GH-releasing hormone (GHRH; 1 microgram/kg, iv, at 1000, 1200, and 1400 h) and then a bolus of GHRP (1 microgram/kg at 1600 h). The integrated GH concentration (IGHC) and parameters of pulsatile GH concentration were calculated for the period between 1400 h on day 1 to 0800 h on day 2, and IGHC was calculated for 2 h after each bolus of GHRP or GHRH. During GHRP infusion, there was a significant increase in IGHC (2908 +/- 450 vs. 1374 +/- 160 micrograms x min/L), maximum pulse amplitude (15.2 +/- 2.8 vs. 8.4 +/- 1.7 micrograms/L), and mean pulse amplitude (7.0 +/- 1.1 vs. 3.8 +/- 1.5 micrograms/L). Plasma insulin-like growth factor-I increased from 252 +/- 23 to 312 +/- 23 micrograms/L. There was no change in either GH pulse frequency or interpulse GH concentration. During GHRP infusion, the GH responses to the GHRH boluses were augmented; however, baseline TSH was lower, and the GH and TSH/PRL responses to GHRP and TRH, respectively, were smaller. We conclude that the pituitary remains sensitive to GHRP during a prolonged GHRP infusion. The mechanisms of the GHRP effect on GH secretion are uncertain, and the possibility that GHRP acts as a functional somatostatin antagonist is discussed. The contrasting effects of GHRP on GH and TSH/PRL secretion could be due to differential effects of GHRP on the pituitary and hypothalamus.
Asunto(s)
Hormona Liberadora de Hormona del Crecimiento/farmacología , Hormona del Crecimiento/metabolismo , Oligopéptidos/farmacología , Adulto , Secuencia de Aminoácidos , Humanos , Infusiones Intravenosas , Masculino , Datos de Secuencia Molecular , Prolactina/sangre , Somatostatina/fisiología , Tirotropina/sangre , Hormona Liberadora de Tirotropina/farmacologíaRESUMEN
To assess the relative roles of growth hormone-releasing hormone (GHRH) pulse and somatostatin withdrawal as potential generators of pulsatile growth hormone (GH) release in humans, we studied GH responses to iv bolus GHRH (1 microgram/kg) and to termination of a 4 h iv somatostatin infusion (7.2 micrograms.kg-1.h-1) in five normal young men, and in five men with previously diagnosed isolated GH deficiency. The patients were diagnosed 8-15 years previously on the basis of typical auxological and hormonal criteria, were treated with exogenous GH and were off GH therapy for 1.5-8.9 years prior to this study. Growth hormone rises to a bolus GHRH were similar between the controls and the patients (maximum GH 27.3 +/- 15.3 vs 8.0 +/- 4.0 micrograms/l). The controls exhibited only a small GH rise to somatostatin withdrawal (maximum GH 2.9 +/- 1.2 micrograms/l), while the patients did not (maximum GH 0.7 +/- 0.1 micrograms/l; p < 0.05). We conclude that somatostatin withdrawal by itself is an ineffective promoter of GH pulsatility. Periodic quiescence of somatostatinergic neurons must be associated with a concomitant GHRH pulse in order to result in a robust GH pulse.
Asunto(s)
Hormona del Crecimiento/metabolismo , Hipófisis/metabolismo , Somatostatina/fisiología , Adulto , Análisis por Conglomerados , Hormona del Crecimiento/deficiencia , Hormona Liberadora de Hormona del Crecimiento/administración & dosificación , Hormona Liberadora de Hormona del Crecimiento/farmacología , Humanos , Infusiones Intravenosas , Factor I del Crecimiento Similar a la Insulina/biosíntesis , Masculino , Radioinmunoensayo , Somatostatina/administración & dosificación , Somatostatina/sangre , Factores de TiempoRESUMEN
Syngeneic grafts of liver tissue slices are accepted by normal murine recipients except in the case of male to female grafts in strains which carry the H-2b haplotype. In mouse strains which are known models of autoimmune disease, liver tissue slices are sometimes rejected even when donors and recipients are of the same sex. Although New Zealand Black (NZB) male liver tissue grafts survive in NZB males, female liver tissue grafts are rejected by NZB females. NZB females in which the mouse's own liver has been surgically traumatized accept female liver tissue grafts. In PN females, liver tissue grafts from syngeneic females proliferate. Male to male and male to female grafts show high levels of immunological activity although mostly surviving at 70 days after grafting. MRL male to male, BXSB female to female and NZB male to female grafts all proliferate. Mouse models of autoimmune disease show patterns of liver tissue graft survival which are different from those seen in non-autoimmune mice. These patterns vary among autoimmune strains. Males and females have different antigraft response as well as different cellular lesions controlling their autoimmune disease.