RESUMEN
OBJECTIVE: Patients with Laron syndrome (LS) can now be treated with recombinant IGF-I. We describe the development of androgenization during IGF-I treatment of female LS patients. PATIENTS: Six female patients with LS--two clinically prepubertal (11.6 and 13.8 years of age) and four young adults (30 to 39 years old)--underwent long-term replacement treatment with recombinant IGF-I. The daily doses were 150 micrograms/kg/day by subcutaneous (s.c.) injection in the girls and 120 micrograms/kg/day in the adult women. METHODS: Testosterone, delta 4-androstenedione, LH, FSH, insulin and IGF-I were determined by radioimmunoassay. Blood samples were obtained after an overnight fast before the IGF-I injection. Serum IGF-I was also determined 4 hours after the s.c. injections. RESULTS: During IGF-I treatment, four out of the six patients (two girls and two adults) developed progressive clinical symptoms and signs of hyperandrogenism (oligo/amenorrhoea and acne). Laboratory determinations showed a significant elevation in serum testosterone, delta 4-androstenedione and LH/FSH ratio. The hyperandrogenism occurred concomitantly with an increase in IGF-I serum and a decrease in serum insulin concentrations. Reduction in IGF-I dose or interruption in IGF-I treatment restored androgen levels to normal values. At the same time, the acne and oligomenorrhoea resolved. CONCLUSIONS: Overdosage of IGF-I can lead to androgenization, a previously undescribed undesirable effect of IGF-I. Long-term IGF-I treatment necessitates progressive adjustment of the IGF-I dose to avoid overtreatment.
Asunto(s)
Trastornos del Crecimiento/sangre , Hiperandrogenismo/etiología , Factor I del Crecimiento Similar a la Insulina/efectos adversos , Factor I del Crecimiento Similar a la Insulina/deficiencia , Adolescente , Adulto , Androstenodiona/sangre , Niño , Esquema de Medicación , Femenino , Hormona Folículo Estimulante/sangre , Trastornos del Crecimiento/tratamiento farmacológico , Humanos , Insulina/sangre , Hormona Luteinizante/sangre , Síndrome del Ovario Poliquístico/sangre , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/uso terapéutico , Testosterona/sangreRESUMEN
Forty-six prepubertal children with idiopathic short stature (ISS), 39 boys and 7 girls, with a mean age of 7.4 +/- 1.8 (SD) years, and mean bone age of 4.5 +/- 1.5 years were treated by human growth hormone (GH) 0.1 U/kg/day s.c. for 30.5 +/- 16.2 months (M +/- SD) (2-5 years range) and were followed for 1-2 years after stopping GH. The mean net gain in height at the end of treatment was 1.03 +/- 0.6 SDS and the bone age SDS was accelerated by 0.95 +/- 1.05. Despite a transitory "catch-down" in growth velocity after stopping GH administration, there was a mean height gain at the end of 2 years follow-up of 0.87 SDS. Children who started treatment before age 6.5 benefited more than older ones. In conclusion, the gain in height observed in children with ISS by GH treatment was maintained during 2 years of follow-up after interruption of treatment. Even if this benefit is transitory and not permanent, it may help short children to achieve self-confidence and raise their physical performance at the critical period of school entry.
Asunto(s)
Estatura , Crecimiento , Hormona de Crecimiento Humana/uso terapéutico , Determinación de la Edad por el Esqueleto , Niño , Femenino , Hormona de Crecimiento Humana/administración & dosificación , Humanos , Masculino , PubertadRESUMEN
OBJECTIVE: Hexarelin is a recently synthesized small growth hormone releasing peptide (GHRP) (His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys- NH2). It is active by intravenous, oral and intranasal administration in animals and man. The aim of this study was to find out whether long-term administration of this peptide would promote growth in short children. DESIGN AND PATIENTS: Intranasal hexarelin was administered in a dose of 60 micrograms/kg thrice daily to 8 prepubertal short children aged 4-11.6 years for periods of up to 8 months. RESULTS: Hexarelin treatment stimulated insulin-like growth factor-I (IGF-I) secretion raising the level from 10.4 +/- 3.9 (SD) to 14.1 +/- 4.6 nmol/l (P < 0.004). The rise in IGF-I led to a significant increase in the mean (+/- SD) linear growth velocity from 5.3 +/- 0.8 to 8.3 +/- 1.7 cm/year (P < 0.0001). There was also a significant decrease in skinfold thickness despite increase in body weight and an increase in head circumference. Additional findings were a rise in serum phosphate from 1.5 +/- 0.1 to 1.8 +/- 0.1 mmol/l (P < 0.004) and of alkaline phosphatase from 219 +/- 74 to 261 +/- 75 U/l (P < 0.05). CONCLUSIONS: The long-term GH/IGF-I stimulating, anabolic and growth promoting effects achieved by intranasal administration of this hexapeptide, seemingly without undesirable side-effects, suggests clinical potential for this new class of drugs.
Asunto(s)
Trastornos del Crecimiento/tratamiento farmacológico , Sustancias de Crecimiento/administración & dosificación , Oligopéptidos/administración & dosificación , Administración Intranasal , Fosfatasa Alcalina/sangre , Peso Corporal/efectos de los fármacos , Cefalometría , Niño , Preescolar , Esquema de Medicación , Femenino , Trastornos del Crecimiento/sangre , Sustancias de Crecimiento/uso terapéutico , Hormonas/administración & dosificación , Hormonas/uso terapéutico , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Oligopéptidos/uso terapéutico , Fosfatos/sangre , Grosor de los Pliegues Cutáneos , Estimulación QuímicaRESUMEN
We have evaluated the effect of exogenous administration of IGF-I on the thyroid axis in four separate studies: (1) iv bolus injection; (2) single sc injection; (3) seven days' sc treatment, and (4) four months' treatment. Thirteen patients with Laron-type dwarfism (LTD) participated in the investigations. In studies 1 and 2, 10 healthy subjects were also included. Before and during long-term treatment (study 4) six LTD patients underwent a TRH test. IGF-I was administered in a dose of 75 micrograms.kg-1 iv or 120-150 micrograms.kg-1 sc. Single injections of IGF-I caused significant decreases of serum TSH in LTD patients (iv: 1.7 +/- 0.2 to 1.1 +/- 0.1 mU/l; sc: from 2.1 +/- 0.4 to 1.1 +/- 0.2; p < 0.0005). In controls the decrease was for iv from 1.2 +/- 0.2 to 0.8 +/- 0.2 mU/l (p < 0.02) and for sc from 2.0 +/- 0.5 to 0.8 +/- 0.2 mU/l (p < 0.05). Long-term administration of IGF-I induces a transitory decrease of both serum TSH and fT4, followed by a spontaneous rise to pretreatment or even higher values. No changes in T3 were observed. TSH stimulation by TRH was significantly augmented after four months of IGF-I treatment (p < 0.005). The effects of IGF-I can be explained by an early stimulation of somatostatin release causing a decrease in TSH and followed by the development of compensatory mechanisms. All changes were within the normal ranges, not causing abnormal thyroid function.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Enanismo/fisiopatología , Factor I del Crecimiento Similar a la Insulina/farmacología , Glándula Tiroides/fisiología , Adolescente , Adulto , Niño , Enanismo/sangre , Femenino , Humanos , Inyecciones Intravenosas , Inyecciones Subcutáneas , Factor I del Crecimiento Similar a la Insulina/administración & dosificación , Masculino , Proteínas Recombinantes/farmacología , Somatostatina/metabolismo , Somatostatina/fisiología , Glándula Tiroides/metabolismo , Tirotropina/sangre , Tiroxina/sangre , Factores de Tiempo , Triyodotironina/sangreRESUMEN
Patients with Laron-type dwarfism are clinically indistinguishable from those with isolated growth hormone (GH) deficiency, yet have high circulating GH concentrations associated with an inability to generate endogenous insulin-like growth factor I (IGF-I). Biosynthetic IGF-I was administered subcutaneously once daily for 3 to 10 months to 5 children with Laron-type dwarfism aged 3.3 to 14.5 years. There was a rapid stimulation of linear growth in body limbs, with a striking increase in head circumference, increased body weight, and a reduction in subcutaneous fat. Administration of IGF-I to patients with Laron-type dwarfism seems to have a beneficial effect on growth similar to that observed with long-term administration of GH in children with GH deficiency.
Asunto(s)
Enanismo Hipofisario/tratamiento farmacológico , Crecimiento , Factor I del Crecimiento Similar a la Insulina/uso terapéutico , Tejido Adiposo , Adolescente , Antropometría , Cefalometría , Niño , Preescolar , Enanismo Hipofisario/sangre , Enanismo Hipofisario/fisiopatología , Femenino , Crecimiento/efectos de los fármacos , Hormona del Crecimiento/sangre , Humanos , Masculino , Proteínas Recombinantes/uso terapéuticoRESUMEN
Biosynthetic insulin-type growth factor I (IGF-I) was given as an intravenous bolus of 75 micrograms/kg to 9 patients with Laron-type dwarfism. Rapid onset of hypoglycaemia (-45% of basal level) was associated with a reduction in plasma insulin (-55% of basal level); thus, the lack of growth hormone receptors in this condition does not apply to IGF-I receptors and post-receptor pathways. Long-term treatment may therefore be beneficial in Laron-type dwarfism.