GH-DEPENDENT VS -INDEPENDENT EFFECTS OF IGF-I ON PUBERTY

生长激素（GH）及其作用的主要介质， 胰岛素样生长因子-I（IGF-I）可影响生殖发育， 功能然而，GH-IGF-I轴和胰岛素抵抗之间的多重相互作用， 下丘脑-垂体-性腺（H-P-G）轴了解甚少。在 特别是，GH和IGF-I的直接作用的具体作用存在于 体循环与局部IGF-I产生在控制中的作用 青春期和成年生殖功能的变化仍有待描述。小鼠 由于GH受体的靶向破坏（“敲除，KO "）导致的GH抗性 GH-R-KO小鼠的青春期延迟，成年后出现数量缺陷。 生殖功能，虽然大多数男性和一些女性可以繁殖。在 相反，IGF-I完全缺乏的IGF-I-KO小鼠发育不全， 生殖系统和不育。这两种效果之间的主要区别 IGF-I基因和GH-R基因的破坏意味着不同的作用 生长激素依赖性与生长激素非依赖性IGF-I产生的差异。我们建议利用 GH-R-KO小鼠作为鉴定GH依赖性IGF-I作用的模型系统 生产在控制性成熟，并为更清楚地界定 GH依赖性的作用（可能是脑和性腺而不是肝） IGF-I在这个过程中。我们已经决定， 重组人IGF-I可使GH-R-KO小鼠阴道开口年龄提前 小鼠在拟议的研究中，我们将确定外源性IGF-I是否会 提前这些GH抗性小鼠的首次排卵年龄， 表征GH抗性对IGF-I和IGF-I表达的影响 在青春期前GH-R-KO中，脑、卵巢和睾丸中的IGF-IR 小鼠此外，我们将确定GH抗性对时间的影响 IGF-I和IGF-IR表达的变化过程以及 自发性青春期和青春期加速期H-P-G轴 通过IGF-I治疗的发展。这些研究的结果将表明 系统性IGF-I是否会影响局部的发育和功能， 性成熟过程中下丘脑和性腺中的IGF-I系统。

Both growth hormone (GH) and the main mediator of its actions, insulin-like growth factor-I (IGF-I) can affect reproductive development and function. However, the multiple interactions between the GH-IGF-I axis and the hypothalamic-pituitary-gonadal (H-P-G) axis are poorly understood. In particular, the specific roles of direct actions of GH and IGF-I present in the systemic circulation versus the role of local IGF-I production in the control of puberty and adult reproductive functions remain to be delineated. Mice with GH resistance due to targeted disruption ("knock-out, KO) of the GH receptor gene (GH-R-KO mice) have delayed puberty and quantitative deficits in adult reproductive function, although most males and some females can reproduce. In contrast, IGF-I-KO mice with complete IGF-I deficiency have underdeveloped reproductive system and are sterile. This major difference between the effects of the disruption of the IGF-I gene and the GH-R gene implies differential role of GH dependent vs. GH-independent IGF-I production. We propose to utilize the GH-R-KO mice as a model system for identifying the role of GH-dependent IGF-I production in the control of sexual maturation, and for more clearly defining the role of GH-dependent (presumably brain and gonadal rather than hepatic) IGF-I in this process. We have already determined that administration of recombinant human IGF-I will advance the age of vaginal opening in GH-R-KO mice. In the proposed studies, we will determine whether exogenous IGF-I will advance the age of first ovulation in these GH-resistant mice, and will characterize the impact of GH resistance on the expression of IGF-I and IGF-I receptor (IGF-IR) in the brain, ovaries, and testes in pre-pubertal GH-R-KO mice. In addition, we will determine the impact of GH resistance on the time course of changes in the expression of IGF-I and IGF-IR and in the function of the H-P-G axis during spontaneous puberty and during acceleration of pubertal development by treatment with IGF-I. Results of these studies will indicate whether systemic IGF-I can influence development and function of the local IGF-I systems in the hypothalamus and in the gonads during sexual maturation.