Growth hormone (GH) is essential for postnatal growth and regulation of fuel homeostasis. Its role in fetal and neonatal growth is less certain. The time at which GH begins to regulate perinatal growth in developing mammals is not established. Some models of GH deficiency show very early effects on growth. We have shown that the GH-responsive mRNAs, Spi 2.1 and 2.3, increase around birth in rat pups while GHR mRNA is stable at ≈10% of adult levels(A J Physiol 264:E973). To test the hypothesis that GH is active in perinatal life in promoting hepatic GH-responsive gene expression, we assessed GH action by measurement of hepatic Spi 2.1/2.3 gene expression in a model of neonatal GH deficiency. To determine if GH-responsive gene expression in the perinatal period is diminished by induction of GH deficiency and restored by GH administration, maternal/neonatal hypothyroidism (and consequent GH deficiency) was induced by administration of methimazole to timed pregnant female rats beginning at d 14 of gestation. Pups at days 2 and 7 of age were treated with GH 1.5 ug/g sq (GH-deficient pups injected with an equal vol of saline.) GH response was evaluated by measurement of hepatic Spi 2.1/2.3 mRNA, as expression of these genes is significantly increased by GH administration in adult animals. RNA levels were measured using Northern blots hybridized simultaneously to Spi 2.1/2.3 and GAPDH cDNAs. Intensity of hybridization was quantitated by phosphorimaging. Spi 2.1/2.3 values were normalized to GAPDH values. There was no significant difference between GH-deficient (def) and GH-treated (Rx) pups at d 2 (mean d 2 GH-def 0.40 +/- 0.01 (SEM) OD units, mean d 2 GH-Rx 0.44 +/- 0.04 OD units) but at d 7 GH administration resulted in significant (95% by Fisher PLSD) Spi 2.1/2.3 induction (mean d 7 GH-def 0.21 +/- 0.04 (SEM) OD units, mean d 7 GH-Rx 0.82 +/- 0.12 OD units). We conclude that the response to GH administration changes between days 2 and 7 of neonatal rat life, with relative insensitivity to GH administration at d 2 but clear response to GH by d 7. We speculate that this may be due to changes in post receptor responses to GH.