Cuttler L, Collins B J, Marone P A, Szabo M
Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio 44106.
Endocr Res. 1993 Mar;19(1):33-46. doi: 10.3109/07435809309035406.
The factors that regulate growth hormone (GH) release during the perinatal period are not well understood. Circulating GH levels are markedly elevated in mammalian fetuses and newborns compared with mature animals, and the immature pituitary is highly responsive to the GH-stimulatory effect of GH-releasing factor (GHRF). The etiology of these developmental changes in GH secretion is not known. In order to investigate the mechanisms underlying GH release from immature pituitaries, we tested the effects of agents that increase intracellular cyclic adenosine 3',5' monophosphate (cAMP) production independent of the GHRF receptor on GH release from pituitaries of developing and mature rats. Pituitary cell cultures from fetal (day 20 of gestation), newborn (postnatal day 2), juvenile (postnatal day 12-15), adult male (3-4 months), and adult female (3-4 months) rats were tested with isobutylmethylxanthine (IBMX; 0.001-1.0 mM), forskolin (0.01-10 microM), and cholera toxin (0.025-25 ng/ml). IBMX, forskolin, and cholera toxin stimulated GH release in a dose-dependent manner from pituitary cultures of all age groups. However, the magnitude of the GH responses to these agents was highly age-dependent. Perinatal pituitaries exhibited markedly greater GH responses to IBMX, forskolin, and cholera toxin than did those of mature animals (P < 0.001 for age effect with each agent). GH release in response to the highest dose of IBMX (1 mM) was 301 +/- 8, 389 +/- 37, 296 +/- 33, 198 +/- 14, and 187 +/- 19% of control values from pituitary cell cultures of fetal, newborn, juvenile, adult male, and adult female rats, respectively (P < 0.001). In response to the highest dose of forskolin (10 microM) GH release was 537 +/- 46, 601 +/- 75, 274 +/- 22, 270 +/- 37, and 248 +/- 35% of control values in the same respective age groups (P < 0.001). Similarly, the highest dose of cholera toxin (25 ng/ml) stimulated GH release to 407 +/- 55, 365 +/- 43, 249 +/- 26, 186 +/- 11, and 186 +/- 1% of controls in these respective age groups (P < 0.003). The marked stimulation of GH release from perinatal pituitaries by IBMX, forskolin, and cholera toxin is consistent with the concept that cAMP is a potent mediator of GH release from immature as well as mature somatotrophs. The developmental changes in the GH secretory response to these agents further suggest that signal transduction pathways mediating GH release may undergo maturation, at least in part, at intrasomatotroph loci distal to the GHRF receptor.
围产期调节生长激素（GH）释放的因素尚未完全明确。与成熟动物相比，哺乳动物胎儿和新生儿的循环GH水平显著升高，且未成熟的垂体对生长激素释放因子（GHRF）的GH刺激作用高度敏感。GH分泌这些发育变化的病因尚不清楚。为了研究未成熟垂体释放GH的潜在机制，我们测试了独立于GHRF受体增加细胞内3',5'-环磷酸腺苷（cAMP）生成的药物对发育中和成熟大鼠垂体GH释放的影响。用异丁基甲基黄嘌呤（IBMX；0.001 - 1.0 mM）、福司可林（0.01 - 10 μM）和霍乱毒素（0.025 - 25 ng/ml）对来自妊娠第20天的胎儿、出生后第2天的新生儿、出生后第12 - 15天的幼年、3 - 4个月大的成年雄性和3 - 4个月大的成年雌性大鼠的垂体细胞培养物进行测试。IBMX、福司可林和霍乱毒素以剂量依赖的方式刺激所有年龄组垂体培养物中的GH释放。然而，GH对这些药物反应的程度高度依赖于年龄。围产期垂体对IBMX、福司可林和霍乱毒素的GH反应明显大于成熟动物（每种药物的年龄效应P < 0.001）。来自胎儿、新生儿、幼年、成年雄性和成年雌性大鼠垂体细胞培养物对最高剂量IBMX（1 mM）的GH释放分别为对照值的301±8、389±37、296±33、198±14和187±19%（P < 0.001）。对最高剂量福司可林（10 μM）的GH释放，在相同各年龄组中分别为对照值的537±46、601±75、274±22、270±37和248±35%（P < 0.001）。同样，最高剂量的霍乱毒素（25 ng/ml）在这些各年龄组中将GH释放刺激至对照值的407±55%、365±43%、249±26%、186±11%和186±1%（P < 0.003）。IBMX、福司可林和霍乱毒素对围产期垂体GH释放的显著刺激与cAMP是未成熟和成熟生长激素分泌细胞释放GH的有效介质这一概念一致。GH对这些药物分泌反应的发育变化进一步表明，介导GH释放的信号转导途径可能至少部分在GHRF受体远端的生长激素分泌细胞内位点发生成熟。
