The objective of this study was to characterize the effect of inhalable growth hormone (GH) delivered by an insufflator to the lungs of hypophysectomized Sprague Dawley rats. In the first cohort, the safety and efficacy of the insufflated GH were evaluated. Three experimental groups (n ϭ 7 per group) were treated with GH for 15 d: One group received sc injection of GH daily at 200 g/kg (SC200). Two other groups received GH by insufflation daily: 200 g/kg (INS 200) and 600 g/kg (INS 600). In the

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... second set of experiments, GH was administered in three routes [SC200, INS200, intravenous (IV200)] (nϭ10) for 5 d, and escape latency and N-methyl D-aspartate (NMDA) receptor expression were evaluated. In the first cohort, INS200 showedsimilarbioactivityasSC200ingrowthpromotion,tibialgrowth,aswellasescapelatencyonthe12th day of treatment. Insufflated GH was well tolerated without significant inflammatory responses. In the second cohort, expression of the NMDA receptor 1 and 2B in hippocampus measured after 3 or 6 d of dailytreatmentsweresignificantlyhigherinINS200ascomparedtoIV200,consistentwiththeimprovement of the escape latency. In summary, the inhalable form of GH delivered by intratracheal insufflation was safe, and its bioactivity was comparable to sc injection both in promotion of growth and acquisition of learning ability. If applied properly to human, inhalable GH would be effective for growth promotion and possibly for several disorders caused by underexpression of NMDA receptors. (Endocrinology 151: 4418-4427, 2010)