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0 4 8 12 16 Post-natal age (weeks)

Fig. 2. Ontogeny of GH receptor mRNA expression in the rat liver and brain. RNA levels were quantified by solution hybridization and are redrawn from (13) liver, and (22) brain, shown here as percentage change from birth. Note the postnatal decline in GH receptor expression in brain compared to its increase in liver. Y-axis values are shown on a log scale.

adulthood (13,28). Therefore, it is reasonable to assume that GHR signals may be involved in early events in tissue proliferation and development because there is evidence for early expression in embryonic stem cells (29). This raises the question of what the source of ligand might be (embryonic vs extraembryonic). GH may also be produced in very early embryos or reach them later from a maternal or placental source, but one may also have to consider the possibility that other GH-related ligands may signal via the embryonic receptor, or even that some form of basal signaling might be constitutive in the absence of ligand and autonomously controlled by varying the level of GHR expression itself.

The functional role of fetal GHR expression is far from clear. It seems unlikely that GHR signaling has a major effect on intrauterine growth since Laron dwarves that lack functional GHRs have relatively minor growth impairments at birth. Furthermore, the IGF-1 link, so well established in later life, seems less obvious during fetal life with nutritional influences of IGF-1 of more importance. Nevertheless, GH secretion is high during fetal life particularly around term. Experimental studies in sheep have shown this to be regulated by hypothalamic control mechanisms, such as GHRH and SRIF, although some GH feedback mechanisms do not seem to be operative in fetal and neonatal sheep (30). Recent multiple sampling studies in premature infants confirm the marked pulsatility of GH secretion several weeks before full term (31). Although some of the GH secreted in neonates may not be intact, biologically active GH, the role of such high GH secretory activity in the face of high GHR expression if the GHRs are not functionally coupled to growth promotion remains unclear. Although the evidence that GH is necessary for statural growth in fetal life is rather unconvincing this does not rule out the possibility that GHRs are coupled to metabolic processes and could be involved with normal tissue proliferation and development in such tissues as skin, gut, and brain. How CNS effects of GH relate to the inability of most CNS neural cells to proliferate after birth is unclear, but the fetal GH/GHR axis has been implicated in the protective responses of the fetus to maternal under nutrition that may have adverse consequences in later life (32). GHR activation may be poorly coupled to IGF-1 generation in the CNS, but that does not mean that all its effects are direct. By analogy, it may be that some effects of GH in the CNS are exerted indirectly via the regulation of one or more of the newly described tissue-specific growth and survival factors for CNS glial and neuronal cells.

Fig. 3. GH receptor transcripts in the arcuate nucleus of the rat brain in adult age-matched normal and dw/dw GH-deficient dwarf rats. GHR expression receptor was identified by in situ hybridization using full-length riboprobes. Measurements are expressed as a percentage of normal. (A) is a comparison of GH receptor gene expression in normal vs dwarf rats. (B) Infusion of hGH at 200 ^g/d for 6 d in dwarf rat normalized the reduction in GHR. *p < 0.05, **p < 0.01 compared to normal. (Redrawn from ref. 40).

Fig. 3. GH receptor transcripts in the arcuate nucleus of the rat brain in adult age-matched normal and dw/dw GH-deficient dwarf rats. GHR expression receptor was identified by in situ hybridization using full-length riboprobes. Measurements are expressed as a percentage of normal. (A) is a comparison of GH receptor gene expression in normal vs dwarf rats. (B) Infusion of hGH at 200 ^g/d for 6 d in dwarf rat normalized the reduction in GHR. *p < 0.05, **p < 0.01 compared to normal. (Redrawn from ref. 40).

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Pregnancy And Childbirth

Pregnancy And Childbirth

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