Role of Insulin-Like Growth Factor l in Regulating Growth Hormone Release and Feedback in the Male Rat

Abstract

In vivo and in vitro (static incubation and perifusion) procedures were used to examine the role of insulin-like growth factors (IGFs) in growth hormone (GH) feedback. An α₂-adrenergic agonist, clonidine (CLON; 2 × 10^-8M in vitro or 30 µg/ml/kg body weight i.v. in vivo), which mimics the hypothalamic mechanism triggering GH release, was injected to induce a GH surge. Feedback was initiated by human GH (hGH; 2 × 10-⁶M) in vitro or ovine GH (oGH) (20 µg/2 µl intraventricularly) in vivo. GH-releasing factor (GRF; 1 × 10^–8M) was added at the end of in vitro experiments to test pituitary responsiveness. The involvement of somatostatin (SRIF), GRF and IGFs in mediating GH feedback was evaluated in hypothalamic-pituitary coperifusion. CLON-induced GH release in this system was associated with increased GRF and decreased SRIF release, and the pattern was reversed by hGH. The influence of hGH was mimicked by IGF-I (1.5 × 10^–8 M), except that the GH release was depressed below baseline levels, suggesting a direct effect of IGF-I on the pituitary. Furthermore, the inhibitory effect of hGH on the CLON-induced GH surge and hypothalamic releasing factors (increased SRIF and decreased GRF) was reversed by antisera to IGF-I (1:100), IGF-II (1:100), or both. To determine whether IGF-I is released from hypothalamus or pituitary in response to GH, tissues were tested separately in static incubation. As compared with basal levels, incubation of hypothalami with hGH increased IGF-I and SRIF and decreased GRF release. Because GH and IGF-I release remained unchanged when pituitaries were incubated alone with hGH, the site of IGF-I release and GH feedback is most likely at the hypothalamic level. To evaluate the role of IGFs on GH feedback in vivo, male rats were prepared with permanently implanted 3rd-ventricular and jugular cannulae. CLON was administered intravenously, and oGH, IGF-I (0.5 µg/2 µl), and IGF-I and -II antisera (1:100) were injected intraventricularly. In this as in in vitro studies, IGF-I mimicked the inhibitory feedback effect of GH on the CLON-induced GH surge, and IGF antisera blocked GH feedback. We propose that these studies suggest that endogenous hypothalamic IGF-I mediates the influence of GH in the feedback mechanism by increasing SRIF and depressing GRF release.

Regulatory mechanisms of growth hormone secretion are sexually dimorphic.

“…The simplest explanation for this difference might be a more prominent suppressive effect of rhIGF-I on GHRH neurons in women. IGF-I negative feedback on GHRH has been described in vitro (38) and was recently suggested by in vivo data in rats (39). This feedback could be sexually dimorphic and our results are similar to studies in rats in which exogenous GH suppressed both spontaneous and GHRH-stimulated GH secretion in males but only GHRH-induced GH release in females (35,40).…”

Hypothalamic Regulation of Anterior Pituitary Function

“…IGF-1 also reaches the hypothalamus from the periphery, as the median eminence and parts of the arcuate nucleus are outside the bloodebrain barrier. Up-regulation of endogenous hypothalamic IGF-1 may also block pituitary GH secretion by inhibiting GHRH and stimulating somatostatin release [106].…”

Estradiol and progesterone regulate the expression of insulin-like growth factor-I receptor and insulin-like growth factor binding protein-2 in the hypothalamus of adult female rats

“…IGF-I is produced in the liver and other tissues and may enter the brain (Reinhardt and Bondy, 1994;Fernández-Galaz et al, 1997;Carro et al, 2000), where it could affect hypothalamic neuroendocrine regulation (Berelowitz et al, 1981;Tannenbaum et al, 1983;Wood et al, 1991;Bourguignon et al, 1993;Uchiyama et al, 1994;Becker et al, 1995;Hiney et al, 1996Hiney et al, , 1998. IGF-I from peripheral origins reaches the mediobasal hypothalamus where it appears to be a signal involved with the initiation of puberty in rodents (Hiney et al, 1996).…”