THE ONTOGENY OF GROWTH-HORMONE, INSULIN-LIKE GROWTH-FACTORS AND SEX STEROIDS - MOLECULAR ASPECTS

Insulin-like growth factors (IGF-1 and IGF-2) are synthesized by many tissues in response to GH treatment and regulate cellular growth and d ifferentiation. Fetal serum contains abundant GH, and many fetal tissu es express GH receptors, but the clinical significance of GH in fetal development in humans is uncertain because hypopituitary newborns have normal birth size. The biological actions of IGFs are modulated by a family of binding proteins (IGFBPs). The demonstration of IGF and IGFB P transcripts in preimplantation embryos indicates that the influence of IGFs and IGFBPs in fetal development begins even prior to implantat ion. IGF and IGFBP mRNAs, except IGFBP-1 mRNA, are expressed at variab le levels in many fetal tissues throughout gestation. Although the IGF mRNAs are widely expressed, IGFBP mRNAs manifest in specific cell typ es in a spatially and temporally specific manner, suggesting that they indicate sites of IGF action. Conditions of undernutrition and chroni c hypoxemia, known to cause intrauterine growth retardation in fetuses , alter IGFBP and IGF-1 but not IGF-2 gene expression, thus indicating the role for IGF-1 and IGFBPs as mediators of altered growth. IGF and IGFBP genes are also expressed in many fetal endocrine tissues includ ing those secreting sex steroids. Null mutation of the IGF-1 gene lead s to retarded development of the primary sex organs. In the fetal adre nal gland, IGF-2 mRNA is localized to 3 beta-hydroxysteroid hydrogenas e (3 beta-HSD) immunoreactive cells, suggesting a close relationship t o steroid hormone biosynthesis. IGFBPs are important paracrine modulat ors of IGF action during development, and are crucial regulators of ce llular growth and differentiation by modulating IGF-dependent or -inde pendent actions in all tissues including developing endocrine glands.