EFFECTS OF GROWTH-HORMONE SECRETAGOGUES IN THE TRANSGENIC GROWTH-RETARDED (TGR) RAT

Exogenous GH inhibits endogenous GH release by hypothalamic feedback. We have recently exploited this to generate transgenic growth-retarded (Tgr) rats, in which human GH is expressed in the hypothalamus, under the control of the rat GRF gene promoter. These rats show reduced pit uitary size, GH deficiency, and dominant dwarfism, but are large enoug h for serial blood sampling studies to examine their spontaneous GH se cretion and responses to GRF, somatostatin, and GH-releasing peptide-6 (GHRP-6). Like their normal wild-type littermates, Tgr rats show a se xually dimorphic pattern of GH secretion; males secrete GH in 3-h epis odes, whereas females exhibit a more continuous irregular output, with higher baseline GH levels. In anesthetized male Tgr rats, the GH resp onses to GRF or GHRP-6 were markedly reduced compared with those of th eir nontransgenic litter-mates, but the differences were smaller in fe males. Despite the reduction in pituitary GH, peak plasma GH responses to serial GRF injections in conscious Tgr males or intermittent somat ostatin infusions in conscious Tgr females were indistinguishable from the responses in their wild-type littermates. Furthermore, 7-day iv i nfusions of GRF (12.5-100 mu g/day), given either continuously or as a pulsatile infusion stimulated growth in Tgr rats, as did pulsatile in fusions of GHRP-6. Thus, despite their pituitary GH deficiency and dwa rfism, Tgr rats maintain a sexually dimorphic pattern of GH release an d can produce large GH secretory responses to exogenous secretagogues. They represent the first genetic model of GH deficiency in the rat in which dwarfism can he corrected by treatment with exogenous GK secret agogues.