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Growth hormone (GH) and IGF-I bind to specific membrane-bound receptors located in widely distributed target tissues. Although initial post-receptor signal transduction pathways differ - GH: associated tyrosine kinase (Jak) that activates signal transducers and activators of transcription (Stat) transcription factors; IGF-I: intrinsic tyrosine kinase that activates insulin receptor substrate (IRS) docking proteins, involved in several down stream effector pathways - many of the pathways are overlapping for GH and IGF-I, which makes it sometimes difficult to determine which hormone is responsible for the action being evaluated.

GH and IGF-I are best known for their stimulatory effects on the growth of bone and soft tissues. Most, but not all, of the known GH actions are mediated by circulating or endocrine IGF-I, produced essentially by the liver. However, many other tissues also synthesize GH and IGF-I locally, and thus each could also function as an autocrine/paracrine growth regulator. Recent in vivo studies using transgenic and classical or tissue-specific knockout models have helped shed light on how the two hormone/growth factors function. GH and IGF-I have independent as well as overlapping functions, and both are needed for maximal effect. However, increasing the circulating levels of IGF-I is frequently sufficient to induce a maximal response.

We examined bone development and remodeling in GH receptor (GHR) knockout (KO) and Stat5ab KO mice (kindly provided by J Kopchick and J Ihle). Markers of bone formation and resorption were reduced in GHR KO mice after two weeks of age. IGF-I treatment almost completely rescued all defects of bone growth and remodeling observed in GHR KO mice. Although bone length is slightly reduced in Stat5ab KO mice, the lack of any effect on trabecular bone remodeling or growth-plate width strongly suggests that the effects of GH in bone may not involve Stat5 activation.

The role of GH and IGF-I on reproductive functions was studied in female GHR KO mice. Litter size was markedly decreased in these animals due to a reduction in the rate of ovulation. IGF-I treatment was ineffective in rescuing this defect, suggesting that the effects of GH on follicular growth are independent of circulating IGF-I. In the same model, the actions of GH and IGF-I on muscle cell growth and differentiation were studied in vivo and in vitro. The absence of GH signaling resulted in a significant reduction in muscle mass without affecting the fiber number.

Almost all tissues except the liver express IGF-I transcripts in the absence of a functional GHR. Hepatic IGF-I production is dependent on GH, and this IGF-I, working together with GH, is primarily responsible for most of the growth signaling pathways, although this model may not be valid for all GH/IGF-I responsive tissues.

Recombinant growth hormone has been used for approximately two decades and is now widely used worldwide in a variety of situations. Post-marketing data collected by growth hormone manufacturers have provided an enormous amount of information on the safety and efficacy of these treatments. In addition to this approach, national registries have provided data on a population basis. In France, the France-Hypophyse Association has collected data up to 1997 and has produced several analyses, which are summarized here.