Laroque P, Molon-Noblot S, Prahalada S, Stabinski L G, Hoe C M, Peter C P, Duprat P, van Zwieten M J
Merck Sharp & Dohme-Chibret Laboratories, Department of Safety Assessment, Riom, France.
Toxicol Pathol. 1998 Mar-Apr;26(2):201-6. doi: 10.1177/019262339802600202.
Growth hormone (GH) synthesis and release from the pituitary is regulated by hypothalamic releasing hormone, insulin-like growth factor-1 (IGF-1), and somatostatin. However, the potential effects of pharmacological doses of exogenous GH on the pituitary are not well studied. To determine the potential chronic effects of exogenous GH on pituitary morphology in dogs, porcine GH (pGH) was administered subcutaneously to 3 groups of dogs (4 animals/sex/group) at doses of 0.025, 0.1, and 1.0 IU/kg/day for 14 wk. A group (4/sex) of dogs served as the vehicle control. The pituitaries from all dogs were weighed and fixed in appropriate fixatives for light and electron microscopic examination; in addition, cells of the pars distalis were quantitated by a point counting method following immunostaining to identify cells containing GH, prolactin (PRL), and adrenocorticotrophic (ACTH) hormones. Administration of pGH resulted in a statistically significant (p < or = 0.05) increased pituitary weight through the high dose. By light microscopy (LM), hypertrophy of pars distalis cells was evident in mid- and high-dose female dogs. The pituitaries of dogs given the lowest dose (0.025 IU/kg/day) of pGH were not remarkable based on weight and LM findings. In addition, transmission electron microscopic (TEM) examination of the pituitary gland of high-dose demonstrated, in both sexes, pituitary cells with variably dilated rough endoplasmic reticulum and decreased numbers of secretory granules; some of these cells reacted positively to GH immunostaining. Quantitative analysis of the pituitary gland of high-dose males and females showed an increase in the absolute volume of all cell populations studied: GH-, PRL-, and ACTH-positive cells. Based on the LM and TEM findings, the increased volume of the cell populations studied is likely related to cellular hypertrophy. The expected elevation in serum GH levels following repeated administration of pGH and an associated elevation in serum IGF-1 levels resulted in morphologic changes in the pituitary gland of dogs given high doses (> or = 0.1 IU/kg/day) of pGH; these observations differed from the reported findings in pituitaries of transgenic mice secreting large quantities of bovine GH.
生长激素（GH）从垂体的合成与释放受下丘脑释放激素、胰岛素样生长因子-1（IGF-1）和生长抑素调节。然而，药理剂量的外源性GH对垂体的潜在影响尚未得到充分研究。为了确定外源性GH对犬垂体形态的潜在慢性影响，将猪生长激素（pGH）以0.025、0.1和1.0 IU/kg/天的剂量皮下注射给3组犬（每组4只动物/性别），持续14周。一组（每组4只/性别）犬作为溶剂对照组。对所有犬的垂体进行称重，并固定在适当的固定剂中用于光镜和电镜检查；此外，在免疫染色后通过点计数法对远侧部细胞进行定量，以识别含有GH、催乳素（PRL）和促肾上腺皮质激素（ACTH）的细胞。给予pGH导致高剂量组垂体重量有统计学意义的增加（p≤0.05）。通过光镜（LM）观察，中、高剂量雌性犬的远侧部细胞肥大明显。根据重量和光镜检查结果，给予最低剂量（0.025 IU/kg/天）pGH的犬垂体无明显异常。此外，高剂量组垂体的透射电镜（TEM）检查显示，两性均有粗面内质网不同程度扩张且分泌颗粒数量减少的垂体细胞；其中一些细胞对GH免疫染色呈阳性反应。高剂量雄性和雌性犬垂体的定量分析显示，所研究的所有细胞群体的绝对体积均增加：GH、PRL和ACTH阳性细胞。根据光镜和电镜检查结果，所研究细胞群体体积的增加可能与细胞肥大有关。重复给予pGH后血清GH水平的预期升高以及血清IGF-1水平的相关升高导致给予高剂量（≥0.1 IU/kg/天）pGH的犬垂体出现形态学变化；这些观察结果与分泌大量牛GH的转基因小鼠垂体的报道结果不同。
