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Regulation of Growth Hormone (GH) Secretion by GH-Releasing Factor, Somatostatin, and Insulin-Like Growth Factor I in Ovine Fetal and Neonatal Pituitary Cells in Vitro^*

BERNARD L. SILVERMAN, MARKUS BETTENDORF, SELNA L. KAPLAN, MELVIN M. GRUMBACH and WALTER L. MILLER

Department of Pediatrics, University of California San Francisco, California 94143

Address all correspondence and requests for reprints to: Dr. Walter L. Miller, Room 677-S, Department of Pediatrics, University of California, San Francisco, San Francisco, California 94143.

Abstract

Serum GH concentrations in the ovine fetus are much higher than those in the neonate, and the maximal GH response induced by GRF is 5-fold greater in the fetus than in the neonate. To clarify these in vivo observations further, we studied the effects of GRF, somatostatin (SRIF), and insulinlike growth factor I (IGF-I) on primary cultures of fetal and neonatal ovine pituitary cells. GH secretion from fetal ovine pituitary cells increased from 148 ± 34 to 950 ± 130 ng/105 cells · 3 h in response to 1 nM GRF, whereas GH secretion from neonatal pituitary cells rose from 113 ± 26 to 1221 ± 129 ng/105 cells-3 h, a significantly greater response (P < 0.001). This greater GRF-induced GH response in neonatal than fetal cells differs from the response in vivo and suggests that the increased in vivo response in the fetus is not due to inherently increased sensitivity of pituitary cells to GRF. SRIF (10 nM) decreased maximal GRF-induced GH secretion by 37 ± 3% in fetal cells compared with 59 ± 8% in neonatal cells (P < 0.01). This may explain in part the decreased in vivo sensitivity to SRIF in the ovine fetus compared to that in the neonatal lamb. In fetal pituitary cells, 10 nM GRF increased ovine (o) GH mRNA from 100 ± 14% to 145 ± 40%, SRIF decreased oGH mRNA to 84 ± 3%, and GRF and SRIF in combination increased fetal oGH mRNA to 126 ± 24%. Values in neonatal pituitary cell cultures were similar (control, 100 ± 17%; GRF, 132 ± 6%, SRIF, 85 ± 15%; GRF plus SRIF, 105 ± 26%).

Pretreating fetal cells with 100 nM IGF-I for 3 days reduced GRF-stimulated GH secretion from 1049 ± 38 to 232 ± 8 µg/106 cells-3 h (P < 0.001). Similarly, IGF-I pretreatment of neonatal cells reduced GRF-stimulated GH secretion from 810 ± 18 to 419 ± 16 µg/106 cells-3 h (P < 0.001). The mean secreted IGFI was 0.58 µml (36 nM) in culture medium from neonatal cells and was unchanged by incubation for 3 days with 5 fig/ml hGH. Secreted IGF-I in medium from fetal cells was 0.87 U/ml (54 nM) without GH and 0.81 U/ml (51 nM) after incubation with human GH. IGF-I mRNA was present in neonatal pituitary and brain.

These data indicate that pituitary insensitivity to the suppressant effects of SRIF may explain in part elevated serum GH concentrations in the ovine fetus. Secondly, the capacity of IGFI to inhibit GRF-induced GH secretion in vitro suggests that IGF-I has a direct action on fetal and neonatal somatotropes. Finally, IGF-I secretion by fetal and neonatal pituitary cell cultures suggests an intrapituitary ultrashort loop feedback mechanism affecting the secretion of GH. (Endocrinology 124: 84–89,1989)

Footnotes

^* This work was supported in part by NIH Grants HD-02335 and DK-37922.

Trainee in Pediatric Endocrinology, sponsored by the NIDDK, NIH (Grant T32-DK-07161).

Fellow in Pediatric Endocrinology, sponsored by Deutsche Forschungsgemeinschaft (Grant BE-1040/12).

Received July 1, 1988.

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