Effect of fetal ethanol exposure on the in vitro release of growth hormone, somatostatin and growth hormone-releasing factor induced by clonidine and growth hormone feedback in male and female rats.

This study was designed to examine the effect of fetal ethanol (ETOH) exposure on the sensitivity of the hypothalamic-growth hormone (GH) axis to clonidine (an alpha 2-adrenoreceptor agonist) stimulation and GH feedback. During gestation, dams were fed either a liquid diet in which 36% of the calories were derived from ETOH, or pair-fed an isocaloric control liquid diet without ETOH. A second set of controls were fed lab chow ad libitum. After birth, offspring of ETOH-fed dams were cross-fostered to a separate group of ad libitum control dams. The hypothalami and pituitaries of 10-, 20-, 30-, and 50-day-old offspring were separated by age, diet, and sex; pooled 6 to 8 per chamber; and tested in a hypothalamic-pituitary coperifusion system. Chambers were perifused with either clonidine (2 x 10(-8) M) alone, which mimics the endogenous trigger for GH release, or clonidine in combination with human GH (2 x 10(-9) M) to determine sensitivity of tissue to feedback regulation. Both stimuli act at the hypothalamic level and indirectly modulate GH release via effects on hypothalamic factors. Results of this study indicate that tissue from control male rats is responsive to the clonidine-induced GH surge by 10 days of age and to feedback depression of GH release by 20 days of age. This sensitivity persists after puberty and is associated with corresponding changes in somatotropin-release inhibiting factor (SRIF) and GH-releasing factor (GRF) release (i.e., clonidine inhibits SRIF and stimulates GRF release, and human GH reverses this pattern). Fetal ETOH exposure depresses GH sensitivity to both stimuli in male pups (age x diet x drug: p 0.05 (NS) at 50 days of age for ETOH pups]. The depressed response of GH to clonidine after puberty may be attributable to a combination of the trends toward decreased sensitivity of both SRIF and GRF at this age. The female GH axis was both less sensitive to stimuli and less effected by ETOH than corresponding tissue from male rats (sex x age x drug x diet: p < 0.011). GH release from control female pituitaries was sensitive to clonidine before, but not after, puberty and insensitive to GH feedback at both developmental stages. On the other hand, there was a specific effect of ETOH on SRIF release at 10 days of age (diet x drug: p < 0.014), and SRIF release remained sensitive to clonidine in pups from all diet groups after puberty. Because GH release was not influenced by these changes in SRIF, these findings suggest that GH release is less sensitive to SRIF in females. In conclusion, this study suggests that fetal ETOH exposure interferes with the development of the sensitivity of the GH axis to alpha 2-adrenergic stimulation and feedback in males. Thus, the male GH axis is both more sensitive to the stimuli tested in this study and more effected by ETOH than the female axis. Furthermore, the effects of ETOH on these mechanisms do not alter GH release in males until the peripubertal period. It is likely, therefore, that the GH regulatory mechanism examined in this study does not contribute to growth retardation before puberty. If the effects of ETOH on GH release contributes to growth retardation in prepubertal males and in females, it most likely involves other regulatory mechanisms. On the other hand, because the adult pattern of GH release is programmed during development, the influence of ETOH on these developmental events may influence the male pattern of GH release and GH activity in adulthood.