Bartke A, Chandrashekar V, Turyn D, Steger R W, Debeljuk L, Winters T A, Mattison J A, Danilovich N A, Croson W, Wernsing D R, Kopchick J J
Department of Physiology, School of Medicine, Southern Illinois University, Carbondale 62901-6512, USA.
Proc Soc Exp Biol Med. 1999 Nov;222(2):113-23. doi: 10.1046/j.1525-1373.1999.d01-121.x.
Transgenic mice overexpressing growth hormone (GH) exhibit alterations in the function of the hypothalamic-pituitary-gonadal (HPG) axis and the H-P-adrenal axis. Alterations in the turnover of hypothalamic neurotransmitters, in plasma hormone levels, and in regulation of their release are associated with reproductive deficits, particularly in females. Results reported after publication of our minireview on this subject provided evidence that GH-transgenic mice have increased binding of GH to GH binding proteins in plasma, are hyperinsulinemic and insulin resistant, and have major alterations in energy budgets with increased allocation to growth. Reduced life span and fertility of these animals may be related to insufficient allocation of energy to reproduction and maintenance. Growth hormone resistance induced by transgenic expression of an antagonistic bGH analog or by targeted disruption (knock-out, KO) of the GH receptor (GH-R) gene leads to dramatic suppression of plasma levels of insulin-like growth factor-1 (IGF-1), and dwarf phenotype due to reduced growth and increased adiposity. In both models of GH resistance, there are marked reproductive deficits in females, decline of breeding performance of males, and alterations in the function of the HPG axis. In GH-R-KO females, puberty is delayed, and litter size is reduced. Fetal weights are reduced whereas placental weights are increased, and the weight of newborn pups is reduced despite an increase in the length of gestation. In GH-R-KO males, copulatory behavior and fertility are reduced, plasma PRL is elevated, and responses to luteinizing hormone releasing hormone (LHRH) in vivo and to LH in vitro are suppressed. However, reproductive deficits in GH-R-KO mice are very mild when compared to those described previously in IGF-KO animals. Apparently, the amounts of IGF-1 that may be produced locally in the absence of GH stimulation are sufficient for sexual maturation and fertility in both sexes, whereas quantitative deficits in reproductive function reflect absence of GH-dependent IGF-1 production and other consequences of eliminating GH signaling. The reproduction phenotype of the GH-R-KO mice is also mild when compared to dwarf mice that lack GH, prolactin (PRL), and thyroid stimulating hormone (TSH). This is presumably related to the presence of redundant mechanisms in the stimulatory control of the gonads by the pituitary and the ability of animals capable of producing PRL and TSH to compensate partially for the absence of GH signaling.
过度表达生长激素（GH）的转基因小鼠，其下丘脑 - 垂体 - 性腺（HPG）轴和下丘脑 - 垂体 - 肾上腺（H - P - 肾上腺）轴的功能会发生改变。下丘脑神经递质周转、血浆激素水平及其释放调节的改变与生殖功能缺陷有关，尤其是在雌性小鼠中。在我们关于该主题的小综述发表后报道的结果表明，GH转基因小鼠血浆中GH与GH结合蛋白的结合增加，存在高胰岛素血症和胰岛素抵抗，并且能量分配发生重大改变，更多能量用于生长。这些动物寿命缩短和生育力降低可能与能量分配不足有关，无法满足生殖和维持身体机能的需求。通过转基因表达拮抗型bGH类似物或靶向破坏（敲除，KO）GH受体（GH - R）基因诱导的生长激素抵抗，会导致血浆胰岛素样生长因子 - 1（IGF - 1）水平显著降低，以及由于生长减缓、肥胖增加而呈现侏儒表型。在这两种生长激素抵抗模型中，雌性小鼠存在明显的生殖功能缺陷，雄性小鼠繁殖性能下降，HPG轴功能改变。在GH - R - KO雌性小鼠中，青春期延迟，窝仔数减少。胎儿体重降低，而胎盘重量增加，尽管妊娠期延长，但新生幼崽体重仍降低。在GH - R - KO雄性小鼠中，交配行为和生育力降低，血浆催乳素（PRL）升高，体内对促黄体生成素释放激素（LHRH）和体外对促黄体生成素（LH）的反应受到抑制。然而，与之前在IGF - KO动物中描述的情况相比，GH - R - KO小鼠的生殖功能缺陷非常轻微。显然，在没有GH刺激的情况下，局部产生的IGF - 1量足以使两性性成熟和具备生育能力，而生殖功能的定量缺陷反映了缺乏GH依赖性IGF - 1的产生以及消除GH信号的其他后果。与缺乏GH、催乳素（PRL）和促甲状腺激素（TSH）的侏儒小鼠相比，GH - R - KO小鼠的生殖表型也较为轻微。这可能与垂体对性腺刺激控制中存在冗余机制，以及能够产生PRL和TSH的动物能够部分补偿缺乏GH信号的能力有关。
