Administration of IGF-I affects the GH axis and adolescent growth in normal monkeys.

Abstract

The present study examined the effects of IGF-I on serum concentrations of IGF binding protein-3 (IGFBP-3) and GH and assessed how treatment with estradiol and IGF-I would stimulate adolescent growth in monkeys with normal pituitary function. In study I, ovariectomized, juvenile female rhesus monkeys (21 months of age; n = 6) received a bolus injection of IGF-I (1 mg/kg s.c.) and serum samples were collected periodically through 48 h. The consequential elevation in serum IGF-I resulted in a parallel increase in serum IGFBP-3 at 1 and 3 h after treatment with values returning to baseline by 7 h. In contrast, the elevation in serum IGF-I resulted in a significant decline in serum GH within 3 h of treatment. These data confirm that an elevation in IGF-I increases IGFBP-3 while simultaneously acting in a negative feedback capacity to inhibit GH. In study II, ovariectomized, juvenile female rhesus monkeys served either as controls (Con, n = 6) or received a constant s.c. infusion of IGF-I (300 micrograms/day; Igf, n = 6) from 13 through 32 months of age. At approximately 26 months, females entered an estradiol-treatment protocol in which they received alternating blocks of 3 weeks of estradiol followed by 3 weeks of no estradiol. As found in study I, the elevation in serum IGF-I resulted in a significant increase in serum IGFBP-3 throughout the study in Igf compared with Con females. Estradiol administration significantly increased serum IGF-I and IGFBP-3 levels in both groups. Although the nano-molar ratio of IGF-I to IGFBP-3 was consistently higher in Igf females, the magnitude of the change in IGF-I:IGFBP-3 following estradiol treatment was similar between groups. Finally, the age-dependent increase in serum GH was dampened in Igf compared with Con females and the increase in response to estradiol was less in Igf females. Although total growth in crown-rump length was similar in both groups, Igf females grew more prior to estradiol replacement while Con females grew more once estradiol treatment was initiated. In addition, skeletal maturity was advanced more quickly in Igf females once estradiol treatment had been initiated. These data suggest that, in female monkeys with normal pituitary function, IGF-I administration inhibits endogenous GH secretion but is capable of stimulating crown-rump growth. Although IGF-I increased serum levels of IGFBP-3, the increase was not proportional to the increase in serum IGF-I achieved by the treatment. These data would suggest that IGF-I may regulate the release of this binding protein but that GH may be required to maintain equi-molar proportions of IGF-I to IGFBP-3. In addition, the observation that serum concentrations of IGF-I were increased further in IGF-I-treated females by the administration of estradiol without a change in serum GH, suggests that estradiol has a direct effect on IGF-I synthesis and release independent of GH.