In vitro and in vivo responses to short-term recombinant human insulin-like growth factor-1 (IGF-I) in a severely growth-retarded girl with ring chromosome 15 and deletion of a single allele for the type 1 IGF receptor gene.

OBJECTIVES: Patients with single allele defects in the gene encoding the type 1 IGF receptor have been reported to have growth failure, but fibroblasts from affected patients have not exhibited insensitivity to the effects of IGF-I in vitro. The in vitro and in vivo responses to short-term recombinant human IGF-I (rhIGF-I) in a severely growth-retarded girl with ring chromosome 15 and deletion of a single allele for the type 1 IGF receptor gene have been investigated. DESIGN AND PATIENT: The child exhibited prenatal and severe post-natal growth failure, and delayed psychomotor development. Southern blotting revealed a 50% reduction in IGF-I receptor DNA, and in an RNase protection assay (RPA), a quantitatively similar reduction in steady-state mRNA for type 1 IGF receptor. rhIGF-I was administered in graded doses of 40, 60 and 80 microg/kg twice daily by subcutaneous injection for periods of 2-2.5 days each. RESULTS: During rhIGF-I treatment, mean urinary nitrogen excretion was unchanged and urinary calcium rose to 60% greater than in the pre-treatment period. rhIGF-I injections produced only a modest decrease in indices of GH secretion, assessed by frequent (every 20 min) sampling over periods of 12 h. There was no significant difference between the mean GH concentrations during rhIGF-I treatment (5.32 +/- 6.2 mU/l) compared with that before rhIGF-I treatment (8.46 +/- 10.2 mU/l). Mean IGFBP-3-values were increased (4.5 mg/l before vs. 5.4 mg/l during rhIGF-I). TSH values after injection of TRH were not significantly reduced by IGF-I (mean of all values, 18.6 mU/l vs. 15.5 mU/l during rhIGF-I treatment). In vitro binding of radiolabelled IGF-I to the patient's fibroblasts was less than that bound by control fibroblasts (patient, 0.69% binding by 248 000 cells, vs. 1.41% binding by 260 000 fibroblasts from an age-matched control). However, the patient's fibroblasts exhibited a growth response in vitro to the addition of IGF-I in a fashion similar to that of control fibroblasts. CONCLUSIONS: These studies show evidence in each of the indices examined of in vivo resistance to IGF-I and suggest that the growth retardation observed in such patients may be the direct result of the absence of one of the alleles encoding the type 1 IGF receptor.

Retinal changes mimicking diabetic retinopathy in two nondiabetic, growth hormone-treated patients.

A role for GH in the pathogenesis of diabetic retinopathy has long been postulated. Previous clinical studies, however, have been confounded by hyperglycemia. We have identified 2 cases of retinopathy associated with exogenous GH therapy in nondiabetic patients. Cases were identified through the MedWatch drug surveillance system of the U.S. Food and Drug Administration. Causality by concomitant medications was excluded by a search of the literature and the FDA data base. The first patient, an obese, 31-yr-old male with traumatic hypothalamic injury, presented with nonproliferative retinopathy and macular edema, resulting in decreased visual acuity (OD 20/40-1; OS count fingers), which required laser surgery. Human GH had been initiated at 0.009 mg/ kg.day, 14 months earlier, and titrated to 0.017 mg/kg.day. The second patient, a nonobese, 11-yr-old girl receiving GH for the management of short stature in Turner's Syndrome, presented with neovascularization. GH doses were 0.033 mg/kg.day for the first 17 months and 0.043 mg/ kg.day for the following 5 months. Cumulative laboratory and clinical observations suggest that GH and related peptides have a role in retinal pathology independent of the degree of glucose tolerance.

Papilledema in 15 renally compromised patients treated with growth hormone.

Intracranial hypertension with papilledema has been reported in renal patients, but a survey of the literature suggests that the incidence rate is low. We present reports of 15 of approximately 1,670 patients with renal disorders, who were treated with growth hormone for impaired growth and subsequently developed symptoms and/or signs of intracranial hypertension. The male:female ratio was 6.5:1, and the median age was 12 years. The median duration of growth hormone treatment before onset of symptoms or signs was 13 weeks. All but 2 patients were symptomatic. In the patients in whom growth hormone therapy is known to have been discontinued, the symptoms and signs of intracranial hypertension abated. At least 4 of these patients experienced a recurrence when re-exposed to growth hormone. Many of the affected patients presented with predisposing conditions, but growth hormone appears to have been the precipitating factor. Prospective funduscopic evaluation may be warranted in patients with renal disorders who are receiving growth hormone.

Endocrine profile of catch-up growth in the cynomolgus monkey.

We studied catch-up growth following withdrawal of glucocorticoid administration in seven intact prepubertal cynomolgus monkeys. To reduce stress during blood sampling, a vascular access port was implanted subcutaneously in each animal for the duration of the study. After a baseline observation period of 50 weeks, the monkeys received injections of dexamethasone at a dose of 100 micrograms.kg-1.day-1 for 15 weeks. Growth velocity was monitored every 3 weeks by measuring lower leg length and body weight. Spontaneous serum growth hormone (GH) concentrations and GH levels after insulin and L-dopa stimulation, as well as serum insulin-like growth factor I (IGF-I) and plasma thyrotropin, triiodothyronine and thyroxine, were measured during the study. Differences between animals were analyzed by repeated measures analysis of variance and Student's paired t-test. Mean +/- SEM growth velocity (mm/3 weeks) decreased from 0.90 +/- 0.08 during the baseline period to 0.29 +/- 0.07 (p < 0.001) during the period of growth retardation, and increased to 1.23 +/- 0.2 (p < 0.001) during the period of catch-up growth. Spontaneous GH and peak GH levels following insulin did not show any significant variation during the study. Peak GH during the L-dopa test decreased from 15.4 +/- 3.2 micrograms/l during the baseline period to 6.2 +/- 2.4 micrograms/l during the period of growth retardation (p < 0.05), and increased to 23.0 +/- 5.9 micrograms/l during the period of catch-up growth (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Steroid secretion by a virilizing lipoid cell ovarian tumor: origins of dehydroepiandrosterone sulfate.

A 78-year-old woman had a 3-year history of severe virilization caused by a lipoid cell ovarian tumor localized by pelvic ultrasound examination and NP-59 scan. Steroid secretion was evaluated by the following: 1) peripheral plasma levels before and after hormonal stimulation with ACTH or hCG, 2) venous catheterization and measurement of steroid levels in the left and right ovarian veins during surgery, 3) measurements of enzymatic activities in the tumor tissue compared with those in normal ovarian tissue, and 4) steroid secretion studies in vitro of the tumor tissue, surrounding tissue, and contralateral ovarian tissue. The tumor tissue secreted both delta 5 and delta 4 androgens, including dehydroepiandrosterone sulfate. Dehydroepiandrosterone sulfate was also secreted by the surrounding and contralateral ovarian tissue.