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JOHN B. WELSH, LEONA CUTTLER, MARTA SZABO, Ontogeny of the in Vitro Growth Hormone Stimulatory Effect of Thyrotropin-Releasing Hormone in the Rat, Endocrinology, Volume 119, Issue 5, 1 November 1986, Pages 2368–2375, https://doi.org/10.1210/endo-119-5-2368
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Abstract
The ontogenic changes in the somatotroph’s responsiveness to TRH were examined in enzymatically dissociated rat pituitary cells in primary monolayer culture. Exposure to TRH (10-8m) caused a significant increase in GH release in cultured pituitary cells from rats ranging in age from −1 day (20 days of gestational age) to 90 days. The magnitude of the response, expressed as a percent increment above control rat GH (rGH) release, rose progressively until it reached a maximum of 209 ± 5% (mean ± se) on postnatal day 12. Thereafter, the response declined to values ranging from 10–30% above control rGH release. In cultured adenohypophyseal cells of rats on postnatal day 12, the effect of TRH was dose related; the effective concentration range was 10−10−10−7m, with an EC50 of 2.5 ± 0.6 × 10-9m. TRH (10-8m) potentiated the GH stimulatory effect of a submaximally effective concentration of human GHreleasing factor-40 (hGRF-40; 10-9m) in cultured pituitary cells of developing rats, aged x−1 to 30 days, and that of (Bu)2cAMP (5 × 10-4m) in cultured pituitary cells of rats aged −1 to 45 days. The rGH response to the combined addition of TRH with either hGRF-40 or (Bu)2cAMP was up to 2 times greater (P < 0.05) than the sum of the individual responses. When the interaction of TRH (10-8m) with multiple concentrations of hGRF-40 (10-10,10-9, and 10-8m) was tested in cultured pituitary cells of 4- to 36-day-old rats at 4-day intervals, synergism was least at the lowest and greatest at the highest concentration of hGRF-40; synergistic interaction decreased progressively after 20 days of age to undetectable levels by 36 days. In cultured anterior pituitary cells of 12-day-old rats, maximally stimulatory TRH (10-7m) potentiated the GH stimulatory effects of both hGRF-40 and (Bu)2cAMP at concentrations at the EC50 value or greater, with synergism being most pronounced at maximally effective concentrations. Whereas the GH response to the combined addition of maximal hGRF-40 (10-7m) and (Bu)2cAMP (1.5 × 10-3m) was not greater than that to maximal hGRF alone, TRH potentiated the responses to both secretagogues whether added separately or combined. In cultured adenohypophyseal cells of 12-day-old rats, the GH stimulatory effect of TRH was markedly suppressed by three different inhibitors of Ca2+ influx into the cell, verapamil (10-4m), EGTA (2.5 × 10-3m), and CoCl2 (2 × 10-3m), and by the calmodulin inhibitor trifluoperazine (5 × 10-5m), suggesting that the effect of TRH is mediated by a Ca2+/calmodulin-requiring pathway in the rat somatotroph. We conclude that TRH is a potent stimulator of basal as well as GRF- and (Bu)2cAMP-induced GH release in the immature rat and that it may function as a GH secretagogue during early development. (Endocrinology119: 2368–2375, 1986)