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Unlabelled: Growth is a fundamental process of mammalian development. Several observations regarding regulation of erythropoiesis during growth are not easily explained by the hypoxia-erythropoietin (Epo) concept. This review focuses primarily on this aspect of the physiology of Epo. The question is raised of whether this regulation during growth is based on the hypoxia-Epo mechanism alone, or whether Epo acts in concert with general growth-promoting factors, particularly growth hormone (GH) and the insulin-like growth factors (IGF-I and -II). Supporting the latter hypothesis is the observation that the Epo and GH/IGF systems are activated by hypoxia and share similar receptors and pathways. Recent studies indicate that human fetal and infant growth is stimulated by GH, IGF-I and IGF-II. Epo, GH and IGFs are expressed early in fetal life. Although the rate of erythropoiesis in the fetus is high, serum Epo levels are low. The Epo response to hypoxia in the fetus and neonate is reduced compared with adults. Following delivery the Epo levels vary between species, probably related to the oxygen transport capacity of the hemoglobin (Hb) mass. IGF-I levels are low in the fetus and increase slowly following birth, except in preterm infants in whom the levels decline. In all mammals Hb declines following birth, giving rise to "early anemia". Except in the human, Epo levels increase proportionally with the fall in Hb, but there is a discrepancy between the curves for serum immunoreactive Epo (siEpo) and for erythropoiesis stimulating factors (ESF): the latter include other stimulatory factors in addition to Epo. Hypertransfusion of mice in the period of "early anemia" suppresses siEpo, but not ESF and erythropoiesis, as it does in adult mice. GH and IGF-I have direct effects on erythropoiesis in vitro and act particularly at the later stages of red cell differentiation. IGF-I acts synergistically with Epo, and its effects are most marked when Epo levels are low. Human recombinant (rhu) IGF-I stimulates erythropoiesis in neonatal rats, but not in newborn mice and lambs. In adult mice, in hypophysectomized rats and in mice with end-stage renal failure, however, a stimulatory effect of this growth factor was found on red cell production. RhuGH stimulates erythropoiesis in GH-deficient short children., Conclusion: Fetal and early postnatal erythropoiesis are dependent on factors in addition to Epo. The likely candidates are GH and IGF-I. The in vitro stimulating effects of these factors on erythropoiesis are convincing, but more data are needed on the in vivo effects.

The in vivo effect of recombinant human insulin-like growth factor (rh-IGF-1) upon erythropoiesis was studied in inbred BALB/C mice. Unweaned, rapidly growing 20 days old mice and adult female mice received subcutaneous rh-IGF-1 or control injections every 6 h for 48 h. The mice were killed either 12 or 48 h after the last injection, i.e. a study time of 60 and 96 h, respectively. Bone marrow erythroid colony forming units (CFU-E), reticulocytes, haematocrit, serum immunoreactive erythropoietin (siEPO) and body and organ weight were measured. An additional group of young mice were given iron prior to the rh-IGF-1 injections to ensure sufficient available iron. No differences in overall body or organ weights were observed. In the young mice erythropoiesis as measured by bone marrow CFU-E, reticulocytes and haematocrit did not differ between rh-IGF-1 group and controls. When iron alone was given, reticulocytes (P < 0.05) and haematocrit (P < 0.0001) increased significantly, but no further stimulation was seen when rh-IGF-1 injections were given in addition to iron. The adult female mice responded with significantly increased erythropoiesis as judged by increased reticulocyte counts following rh-IGF-1 injections (P < 0.001). No significant effect upon CFU-E and haematocrit was detected. The reticulocyte response was more pronounced at 96 than at 60 h after the first rh-IGF-1 injection. SiEPO was significantly (P < 0.01) lower in the adult 96 h rh-IGF-1 group than in the appropriate control group. In conclusion parenteral iron significantly increased haematocrit in unweaned mice. Short time rh-IGF-1 treatment did not stimulate erythropoiesis in these rapidly growing mice, whether or not iron supplementation had been given.(ABSTRACT TRUNCATED AT 250 WORDS)