Bartke A, Cecim M, Tang K, Steger R W, Chandrashekar V, Turyn D
Department of Physiology, School of Medicine, Southern Illinois University, Carbondale 62901-6512.
Proc Soc Exp Biol Med. 1994 Sep;206(4):345-59. doi: 10.3181/00379727-206-43771.
Availability of recombinant growth hormone (GH) and development of long-acting formulations of this material will undoubtedly lead to widespread use of GH in animal industry and in medicine. GH can act, directly or indirectly, on multiple targets, but its influence on the reproductive system and on the hormonal control of reproduction is poorly understood. Overexpression of GH genes in transgenic animals provides a unique opportunity to study the effects of long-term GH excess. Transgenic mice overexpressing bovine, ovine, or rat GH (hormones with actions closely resembling, if not identical to, those of endogenous [mouse] GH), exhibit enhancement of growth, increased adult body size, and reduced life-span as well as a number of endocrine and reproductive abnormalities. Ectopic overexpression of bovine GH (bGH) driven by metallothionein or phosphoenolpyruvate carboxykinase promoters is associated with altered activity of hypothalamic neurons which produce somatostatin, loss of adenohypophyseal GH releasing hormone (GHRH) receptors, and suppression of endogenous (mouse) GH release. Elevation of plasma levels of GH (primarily bGH) and insulin-like growth factor (IGF-I) in these transgenic mice leads to increases in the number of hepatic GH and prolactin (PRL) receptors, in the serum levels of GH-binding protein (GHBP), in the percent of GHBP complexed with GH, and in the circulating insulin levels. In addition, plasma adrenocorticotropic hormone (ACTH) and corticosterone levels are elevated. Plasma levels of luteinizing hormone (LH), as well as its synthesis and release, are not consistently affected, but follicle-stimulating hormone (FSH) levels are suppressed, apparently due to pre- and post-translational effects. Pituitary lactotrophs exhibit characteristics of chronic enhancement of secretory activity, and plasma PRL levels are elevated. Prolactin responses to mating or to pharmacological blockade of dopamine synthesis are abnormal. Reproductive life span and efficiency are reduced in both sexes, with the severity and frequency of reproductive deficits being related to plasma bGH levels. Most transgenic females expressing high levels of bGH are sterile due to luteal failure. Overexpression of human GH which, in the mouse, interacts with both GH and PRL receptors leads to additional endocrine and reproductive abnormalities including stimulation of LH beta mRNA levels and LH secretion, loss of responsiveness to testosterone feedback, overstimulation of mammary glands, enhanced mammary tumorigenesis, and hypertrophy of accessory reproductive glands in males.
重组生长激素（GH）的可得性以及该物质长效制剂的开发无疑将导致GH在动物产业和医学中的广泛应用。GH可直接或间接作用于多个靶点，但其对生殖系统及生殖激素调控的影响却知之甚少。转基因动物中GH基因的过表达为研究长期GH过量的影响提供了独特的机会。过表达牛、羊或大鼠GH（这些激素的作用即使与内源性[小鼠]GH不完全相同，也极为相似）的转基因小鼠，表现出生长增强、成年体型增大、寿命缩短以及一些内分泌和生殖异常。由金属硫蛋白或磷酸烯醇丙酮酸羧激酶启动子驱动的牛GH（bGH）异位过表达与产生生长抑素的下丘脑神经元活性改变、腺垂体GH释放激素（GHRH）受体丧失以及内源性（小鼠）GH释放受抑制有关。这些转基因小鼠血浆中GH（主要是bGH）和胰岛素样生长因子（IGF-I）水平升高，导致肝脏中GH和催乳素（PRL）受体数量增加、血清中GH结合蛋白（GHBP）水平升高、与GH结合的GHBP百分比增加以及循环胰岛素水平升高。此外，血浆促肾上腺皮质激素（ACTH）和皮质酮水平升高。黄体生成素（LH）的血浆水平及其合成和释放并不总是受到影响，但促卵泡激素（FSH）水平受到抑制，这显然是由于翻译前和翻译后的影响。垂体催乳细胞表现出分泌活性慢性增强的特征，血浆PRL水平升高。催乳素对交配或多巴胺合成的药理学阻断的反应异常。两性的生殖寿命和效率均降低，生殖缺陷的严重程度和发生率与血浆bGH水平有关。大多数表达高水平bGH的转基因雌性由于黄体功能不全而不育。人GH在小鼠中与GH和PRL受体均相互作用，其过表达导致额外的内分泌和生殖异常，包括刺激LHβmRNA水平和LH分泌、对睾酮反馈的反应丧失、乳腺过度刺激、乳腺肿瘤发生增强以及雄性附属生殖腺肥大。
