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 μg·kg−1 iv or 120– 150 μg· 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. As the clinical use of recombinant IGF-I extends for longer periods than those described, it is recommended that thyroid function is followed.
Beatrice Klinger, Anna Ionesco, Sarah Anin and Zvi Laron
Hannah Kanety, Avraham Karasik, Beatrice Klinger, Aviva Silbergeld and Zvi Laron
Insulin-like growth factor binding protein-3 (IGFBP-3) is the major carrier of insulin-like growth factor I (IGF-1) in serum, and its production is growth hormone (GH) dependent. It is unclear whether in humans IGFBP-3 production is directly regulated by GH or mediated via IGF-I. We addressed this question in six patients with Laron-type dwarfism, a syndrome characterized by the absence of GH receptor activity (LTD), who were chronically treated with recombinant IGF-I. Analysis of the electrophoretic profiles of serum IGFBPs in these patients by Western ligand blotting revealed an extremely low IGFBP-3 level. A striking progressive increase in serum IGFBP-3 was observed with continuous treatment, despite the absence of GH action. In LTD children, serum IGFBP-3 increased up to 19-fold after six months of therapy and equalled levels observed in controls, whereas in adult LTD patients the increase was smaller. A rise in serum levels of 34, 30 and 24 kDa BPs (presumably IGFBP-2, -1 and -4, respectively was also noted with chronic IGF-I therapy. This proof of GH-independent induction of IGFBP-3 by IGF-1 may be a major advantage in the therapeutic use of biosynthetic IGF-I in several types of short stature children.
Beatrice Klinger, Aviva Silbergeld, Romano Deghenghi, Jenny Frenkel and Zvi Laron
Klinger B, Silbergeld A, Deghenghi R, Frenkel J, Laron Z. Desensitization from long-term intranasal treatment with hexarelin does not interfere with the biological effects of this growth hormonereleasing peptide in short children. Eur J Endocrinol 1996;134:716–9. ISSN 0804–4643
A clinical, prospective experiment was carried out to determine whether long-term intranasal administration of the growth hormone-releasing peptide hexarelin (His-d-2-methyl-Trp-Ala-Trp-d-Phe-Lys-NH2) affects pituitary growth hormone secretion. Hexarelin (60 μg/kg t.i.d.) was administered to seven prepubertal constitutionally short children (mean age ±sd = 7.6 ± 2.4 years). Serum human growth hormone (hGH) response to an intranasal (20 μg/kg) and intravenous (1 μg/kg) bolus of hexarelin before, during and after 6–10 months of treatment was measured. The mean (±sd) peak rise of hGH to the intranasal bolus before treatment was 70.6 ± mU/I. After 7 days of hexarelin treatment, mean peak values dropped to 34.1 ±15.7 mU/l (p < 0.002) and thereafter remained constant for 6 months of treatment at 37.5 10.3 ±mU/l (p < 0.03). The pretreatment peak to the iv hexarelin bolus was 84.8 52.5 ±mU/l, and at the end of the treatment period it was 19.8 10.9 ±mU/l (p < 0.05). Three months after stopping treatment the mean (±sd) hGH response rose to 42.1 ±4.7 mU/l (p < 0.005). Growth velocity increased from 5.3±0.9 cm/year (before treatment) to 7.4 1.6 cm/year at ±6–10 months of treatment (p < 0.005). In conclusion, the partial suppression of pituitary hGH responsiveness to long-term intranasal hexarelin treatment, probably due to desensitization, does not affect the observed increase in growth velocity.
Z Laron, Pediatric Endocrinology, 11 El Al Street, Ramat Efal, 52960, Israel
Zvi Laron, Anne-Maria Suikkari, Beatrice Klinger, Aviva Silbergeld, Athalia Pertzelan, Markku Seppälä and Veikko A Koivisto
Insulin-like growth factors (IGFs) mediate the effects of growth hormone (GH), and the insulin-like growth factor-binding proteins (IGFBPs) modulate the actions of IGFs in tissues. We studied the circulating levels of IGFBP-1 in 6 children and 9 adults with Laron type dwarfism (LTD), in 11 children and 21 adults with growth hormone deficiency (GHD), and in 8 children with constitutional short stature. Compared with the situation in healthy children, the basal serum IGFBP-1 concentration was 5.4-fold higher in LTD children, 4.1-fold higher in GHD children, and 3.8-fold higher in children with short stature (p<0.02 vs controls in all groups). In adult patients with multiple pituitary hormone deficiency (MPHD), the IGFBP-1 concentration was 2-fold elevated, but it was normal in adult LTD patients. Intravenous (N= 10) or subcutaneous (N=9) administration ofIGF-I (75 μg·kg−1 and 150 μg·kg−1, respectively) in LTD children resulted in a rapid 50–60% fall in serum insulin (p<0.02), a decline in blood glucose and a concomitant 40–60% rise of IGFBP-1 levels (p<0.05). Treatment for seven days with IGF-I (150 μg·kg−1·d−1) resulted in a decrease by 34% and 44% of serum IGFBP-1 level in two out of three children with LTD. After prolonged GH therapy, the IGFBP-1 level fell in GHD children by 29% (p<0.05), in GHD adults by 52% (p<0.02) and in children with constitutional short stature by 17% (p<0.02). IGFBP-1 and insulin concentrations were inversely related in patients with GHD (r= −0.66, p<0.001) or with LTD (r= −0.57, p<0.05). Our data suggest that: (a) increased IGFBP-1 concentration in LTD, GHD and constitutional short children may, at least in part, be accounted for by an IGF-I deficiency; (b) both the rise in IGF-I and a fall in insulin contributed to the rise in IGFBP-1 after acute IGF-I administration; (c) prolonged IGF-I or GH treatment causes a persistent decline in IGFBP-1 concentration. In conclusion, IGF-I and GH may regulate IGFBP-1 secretion either directly or via insulin.