Effects of growth hormone resistance on female reproduction: Lessons learned from the 'Laron' mouse.

摘要

A wide body of evidence suggests that components of the somatotropic-hepatic axis (SHA), including growth hormone (GH) and insulin-like growth factor-I (IGF-I) mediate several facets of sexual maturation and reproductive function. The 'Laron' mouse provides a unique mammalian model for investigating the influence of SHA constituents in reproductive processes. Developed by Zhou et al. (1997b) through targeted disruption, or 'knockout' of the GH receptor/GH binding protein gene, 'Laron' mice (aka, GHR-KO mice) express high levels of circulating GH and significantly reduced levels of circulating, presumably GH-independent IGF-I. They are, therefore, especially well suited for establishing the individual influence of GH and IGF-I in reproductive function. I have investigated several aspects of sexual maturation and adult reproductive function in female GHR-KO mice to further characterize the reproductive phenotype in these animals and more fully assess the impact of GH resistance on female reproductive processes.; The main findings in my work demonstrate that, in addition to delaying puberty onset in both males and females, GH resistance also affects the tempo of sexual maturation. Full sexual maturity is delayed in both sexes in GHR-KO mice, but significantly more so in males than in females. In females, housing conditions and pheromonal influences during the juvenile-to-adult transition significantly influence sexual maturation and adult estrous cyclicity, but these effects are more pronounced in GHR-KO than in normal females. Moreover, hypoinsulinemia, secondary to GH resistance, and/or nutritional stress during puberty may contribute to the delay in sexual maturation in GHR-KO mice. Administration of insulin to immature females was associated with increased relative ovarian and uterine weights, and promoted folliculogenesis, as evidenced by significant increases in the percentage of medium and large antral follicles in the GHR-KO ovary. Moreover, dietary sucrose supplementation during the juvenile-to-adult transition period significantly advanced first conceptions in GHR-KO mice, but had no similar beneficial effects in normal females. In adult females, I have established that reduced ovulation rate, is the primary maternal variable associated with reduced litter size in GHR-KO mice, and that the ability of virgin females to form functional corpora lutea of pregnancy in response to mating is impaired.