Sex steroids, GHRH, somatostatin, IGF-I, and IGFBP-1 modulate ghrelin's dose-dependent drive of pulsatile GH secretion in healthy older men.

CONTEXT: Ghrelin is a potent endogenous stimulator of GH secretion. However, clinical factors that regulate ghrelin dose-responsiveness are incompletely defined. OBJECTIVE: The aim of the study was to test the multipathway hypothesis that testosterone (T) and estradiol, GHRH, and somatostatin (SS) jointly modulate ghrelin's action. DESIGN/PARTICIPANTS/SETTING: Healthy older men (n = 21) participated in a double-blind, prospectively randomized, placebo (Pl)-controlled study in a Clinical Translational Research Center. INTERVENTIONS: To create a range of sex-steroid milieus, men received leuprolide + Pl (n = 10) or leuprolide + T addback (n = 11). Sixteen to 21 d later, subjects received three separate randomly ordered overnight constant i.v. infusions of saline, GHRH, and SS. Interactions between the peptide clamp and ghrelin were tested by superimposed injections of four randomly ordered bolus i.v. doses of ghrelin (0.03, 0.135, 0.60, and 2.7 µg/kg). GH was measured every 10 min, and GH responses were assessed by nonlinear dose-response analysis. Linear associations were assessed by stepwise regression. OUTCOME MEASURES/RESULTS: The descending numerical order of ghrelin efficacy (maximal GH secretory-burst mass; micrograms/liter) was 107 (GHRH + Pl), 104 (GHRH + T), 73 (saline + T), 73 (SS + T), 60 (saline + Pl), and 52 (SS + Pl) [means], wherein SS + T exceeded SS + Pl. GHRH and IGF binding protein-1 augmented, whereas IGF-I attenuated ghrelin potency. Age and IGF-I decreased ghrelin/GHRH synergy. Ghrelin sensitivity was independent of interventions. CONCLUSIONS: These studies introduce composite regulatory effects of sex hormones, GHRH, SS, IGF binding protein-1, and IGF-I on ghrelin dose-responsiveness, suggesting multipathway modulation of GH-secretagogue action.

Insulin-like growth factor-1 gene delivery may enhance the proliferation of human corpus cavernosal smooth muscle cells.

OBJECTIVES: To investigate the effects of IGF-1 gene transfer in human corpus cavernosal smooth muscle cells (HCCSMCs) ex vivo. Insulin-like growth factor-1 (IGF-1) promotes the proliferation of penile cavernous smooth muscle cells in the rats. METHODS: A plasmid expressing human IGF-1 was constructed by subcloning hIGF-1 into pcDNA3.1 vector. HCCSMCs were harvested from 3 impotent patients and cultured in vitro. The cultured smooth muscle cells were identified by immunofluorescent staining. RNA was extracted from HCCSMCs, and the gene expression of IGF-1 was determined by reverse transcription-polymerase chain reaction. Cell growth was examined by use of a novel cell proliferation assay based on the bioreduction of the fluorescent dye Alamar blue. The subcloned product was transfected into HCCSMCs. Western blotting and immunoassay were performed 2 days after transfection to evaluate the transfection efficiency. RESULTS: Endogenous IGF-1 mRNA expression was detected by reverse transcription-polymerase chain reaction analysis of total RNA extracted from cultured HCCSMCs. Increased proliferation of HCCSMCs in vitro was observed with exogenous treatment with IGF-1 (100 ng/mL) in a dose-dependent manner. Exogenous IGF-1 gene transfer to cultured HCCSMCs enhanced IGF-1 protein expression compared with the control, and the expression level peaked at 4 days after transfection and decreased slowly thereafter. Secretion of IGF-1 from transfected HCCSMCs induced cellular proliferation. CONCLUSIONS: IGF-1 gene transfer into HCCSMCs enhanced cellular proliferation, which was mediated by secretion of IGF-1. Our results suggest that IGF-1 gene therapy may be applied to corpus cavernosum regeneration.

Insulin-like growth factor 1-coated sutures improve anastomotic healing in an experimental model of colitis.

BACKGROUND: : Exogenously applied insulin-like growth factor (rhIGF-1) may improve normal intestinal healing. This study examined the effect of rhIGF-1-coated sutures on anastomotic healing in experimental colitis. METHODS: : Acute colitis was induced in rats by dextran sodium sulphate (DSS). Inflammation was assessed by clinical Disease Activity Index (DAI), myeloperoxidase (MPO) measurement and histological examination. A distal colonic anastomosis was performed using sutures coated with rhIGF-1 dissolved in poly(D,L-lactide) (PDLLA) under general anaesthetic. Anastomotic healing was evaluated histologically, and by hydroxyproline measurement and bursting parameters after 1, 3 and 7 days, and compared with healthy, DSS and DSS + PDLLA controls. RESULTS: : DAI, MPO and histological inflammation scores were significantly increased in all animals treated with DSS. Bursting occurred less often within the anastomotic line on day 3 in the IGF group than in DSS controls (three versus eight of ten). On day 7, the IGF group had significantly increased histological healing scores (mean(s.e.m.) 12.5(0.7) versus 9.2(0.8) (P < 0.050)) and hydroxyproline content (4.6(0.3) versus 3.6(0.1) mg/g tissue; P < 0.050) compared with DSS controls. CONCLUSION: : IGF-1-coated sutures improve important aspects of anastomotic healing in rats with experimental colitis.

Kidney growth in normal and diabetic mice is not affected by human insulin-like growth factor binding protein-1 administration.

Insulin-like growth factor I (IGF-I) accumulates in the kidney following the onset of diabetes, initiating diabetic renal hypertrophy. Increased renal IGF-I protein content, which is not reflected in messenger RNA (mRNA) levels, suggests that renal IGF-I accumulation is due to sequestration of circulating IGF-I rather than to local synthesis. It has been suggested that IGF-I is trapped in the kidney by IGF binding protein 1 (IGFBP-1). We administered purified human IGFBP-1 (hIGFBP-1) to nondiabetic and diabetic mice as three daily sc injections for 14 days, starting 6 days after induction of streptozotocin diabetes when the animals were overtly diabetic. Markers of early diabetic renal changes (i.e., increased kidney weight, glomerular volume, and albuminuria) coincided with accumulation of renal cortical IGF-I despite decreased mRNA levels in 20-day diabetic mice. Human IGFBP-1 administration had no effect on increased kidney weight or albuminuria in early diabetes, although it abolished renal cortical IGF-I accumulation and glomerular hypertrophy in diabetic mice. Increased IGF-I levels in kidneys of normal mice receiving hIGFBP-1 were not reflected on kidney parameters. IGFBP-1 administration in diabetic mice had only minor effects on diabetic renal changes. Accordingly, these results did not support the hypothesis that IGFBP-1 plays a major role in early renal changes in diabetes.

Deficiencia de la hormona de crecimiento en el adulto: efectos del tratamiento sustitutivo sobre la composición corporal y la calidad de vida relacionada con la salud / Growth hormone deficiency in adults: effects of replacement therapy on body composition and health-related quality of life

FUNDAMENTO Y OBJETIVO: La deficiencia de hormona de crecimiento (GH) en el adulto se acompaña de alteraciones en la composición corporal y de una disminución de la calidad de vida relacionada con la salud (CVRS) que pueden ser revertidas mediante la administración de GH. El objetivo de este estudio fue valorar la respuesta bioquímica y sobre la composición corporal, así como la CVRS y la seguridad del tratamiento sustitutivo con GH. PACIENTES Y MÉTODO: Se estudió a 165 pacientes con hipopituitarismo y deficiencia de GH. El diseño fue de doble ciego, aleatorio, placebo-control durante un período de 6 meses, seguido de otros 6 en el que todos los pacientes recibieron GH. La dosis inicial fue de 0,125 UI/kg/semana, seguida de 0,25 UI/kg/semana. La composición corporal se determinó mediante impedanciometría bioeléctrica, y la CVRS se evaluó con los cuestionarios Perfil de Salud de Nottingham (PSN) y QoL-AGHDA. RESULTADOS: Las concentraciones de IGF-1 se incrementaron a los 6 meses en el grupo GH/GH pero no en el placebo/GH, y fueron normales para un grupo control de su mismo sexo y edad. Se observó un incremento significativo de la masa libre de grasa durante el tratamiento con GH y simultáneamente una disminución de la masa grasa. El agua corporal total presentó un aumento durante el tratamiento. A los 6 meses se produjeron cambios en las dimensiones de energía y reacción emocional en ambos grupos, valoradas con el PSN, sin apreciarse modificaciones en el resto de las dimensiones. Con el QoL-AGHDA se apreció una mejoría progresiva en la CVRS en el grupo tratado y no en el grupo placebo. Los efectos adversos se debieron fundamentalmente a retención hídrica y se resolvieron al disminuir las dosis. CONCLUSIONES: El tratamiento con GH en adultos con déficit de esta hormona fue generalmente bien tolerado y produjo efectos beneficiosos sobre la composición corporal y la CVRS (AU)