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Beatrice Klinger, Anna Ionesco, Sarah Anin and Zvi Laron

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.

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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

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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.

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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.