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.
