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Effects of Recombinant Human Insulin-Like Growth Factor I Administration on Growth Hormone (GH) Secretion, Both Spontaneous and Stimulated by GH-Releasing Hormone or Hexarelin, a Peptidyl GH Secretagogue, in Humans¹

Division of Endocrinology (E.G., L.G., E.A., J.R., M.R.V., F.B.), Department of Internal Medicine, University of Turin; Unit of Adolescentology (M.R.), University of Pisa; Division of Endocrinology (F.C.), San Luca Hospital; and Department of Pharmacology (E.E.M.), University of Milan, 20129 Milano, Italy

Address all correspondence and requests for reprints to: Prof. E. E. Müller, Department of Pharmacology, University of Milan, Via Vanvitelli 32, 20129, Milano, Italy.

The negative feedback exerted by insulin-like growth factor I (IGF-I) on GH secretion occurs at the pituitary, as well as the hypothalamic level, via stimulation of SS and/or inhibition of GHRH release. In fact, recombinant human IGF-I (rhIGF-I) administration inhibits basal GH secretion, at least in fasted humans, though its effect on the GH response to GHRH is still controversial. GH secretagogues (GHS) are peptidyl and nonpeptidyl molecules that act on specific receptors at the pituitary and/or the hypothalamic level. Contrary to GHRH, the GH-releasing activity of GHS is strong, reproducible, and even partially refractory to inhibitory influences such as exogenous somatostatin. We studied the effects of rhIGF-I administration (20 µg/kg sc at 0 min) on GH secretion, either spontaneous or stimulated by GHRH (2 µg/kg iv at +180 min) or Hexarelin (HEX, 2.0 µg/kg iv at +180 min), a GHS, in eight normal young women (age, mean ± SEM, 28.3 ± 1.2 yr; body mass index, 20.1 ± 0.5 kg/m2). rhIGF-I administration increased IGF-I levels (peak vs. baseline: 420.3 ± 30.5 vs. 274.4 ± 25.3 µg/L, P < 0.05) within the physiological range from +120 to +300 min. No variation in glucose or insulin levels was recorded. rhIGF-I did not reduce spontaneous GH secretion [areas under curves (AUC)_{0–300 min} 140.6 ± 66.3 vs. 114.6 ± 32.1 µg/L·h], whereas it inhibited the GH response to both GHRH (AUC_{180–300 min} 447.7 ± 159.4 vs. 715.9 ± 104.3 µg/L·h, P < 0.05) and HEX (620.3 ± 110.4 vs. 1705.9 ± 328.9 µg/L·h, P < 0.03). The percent inhibitory effect of rhIGF-I on the GH response to GHRH (41.7 ± 12.8%) was lower than that on the response to HEX (57.7 ± 11.0%). In fact, the GH response to GHRH alone was clearly lower than that to HEX alone (P < 0.05), whereas the GH responses to GHRH and HEX were similar after rhIGF-I. Our findings show that the sc administration of low rhIGF-I doses inhibits the GH response to GHRH and, even more, that to HEX; whereas, at least in this experimental design in fed conditions, it does not modify the spontaneous GH secretion. Because GHS generally show partial refractoriness to inhibitory inputs, including exogenous somatostatin, the present results point toward a peculiar sensitivity of GHS to the negative feedback action of IGF-I.

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