Controls of corticotrophin-releasing factor output by hypothalamic tissue from fetal sheep in vitro

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Abstract
Corticotrophin-releasing factor (CRF) is thought to be an important physiological regulator of the pituitary-adrenal axis in fetal sheep and, as such, plays a fundamental role in the initiation of parturition in this species. However, little is known of the controls of CRF secretion from the fetal hypothalamus. We looked for the presence of CRF in fetal hypothalami, and examined whether the hypothalamic CRF concentration or molecular species changed in relation to gestational age. We established an in-vitro perifusion system to examine the release of CRF from perifused hypothalami taken from fetuses at day 100 and day 140 of pregnancy, under basal conditions and in response to potassium depolarization and/or dexamethasone administration. Immunoreactive CRF was present in fetal hypothalami as early as day 100 (2·42 ± 0·99 (s.e.m.) μg/g protein, n = 9) and in similar concentrations at day 140 (2·31 ± 0·69 μg/g protein, n = 9). There was a significant (P < 0·05) increase in hypothalamic CRF content to 14·79 ± 4·09 μg/g protein (n = 16) between day 122 and day 135 of gestation. Using Sephadex G-75 chromatography, hypothalamic extracts at day 100, days 122–135 and day 140 eluted with a single peak of immunoreactivity which corresponded to synthetic ovine CRF(1–41). The basal release of CRF from perifused hypothalami at day 140 (76·6 ± 10·4 pg/fraction, n = 8) was significantly (P < 0·05) greater than at day 100 (50·1 ± 10·2 pg/fraction, n = 11). Dexamethasone significantly inhibited basal CRF release at day 140 of gestation but not at day 100. Potassium depolarization caused a rapid release of CRF in all cases, a response which was independent of gestational age or treatment with dexamethasone. We conclude that the fetal hypothalamus contains immunoreactive CRF as early as day 100 of gestation and that this material may be released when perifused in vitro under basal conditions and in response to a depolarizing agent. The basal release of CRF from perifused hypothalami of day-140 fetuses was greater than at day 100 and was inhibited by dexamethasone, suggesting maturation of negative feedback control of CRF output between days 100 and 140. Since dexamethasone had no effect on potassium-stimulated release of CRF, we suggest that its effects are at sites other than the hypothalamic CRF nerve terminals. Journal of Endocrinology (1989) 122, 15–22

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