Mechanism of Thyroxine Action on Erythropoiesis

T4, at 5 and 25 jug daily dose levels, effectively stimulated red blood cell (RBC)radioiron incorporation in mice. This increase in erythropoiesis occurred approximately 1 day after the appearance of significantly elevated levels of erythropoietin (ESF) in the plasma, suggesting that the enhancement of erythropoiesis induced by T4 was attributable to the ESF. A 25 jug dose level of T< also potentiated the effects of hypoxia on both erythropoiesis and the production of the ESF. The inability of some previous investigators to evoke ESF production in response to thyroid hormone treatment may have resulted from ineffective dosage, an insufficient period over which the hormone was administered, or a relatively low sensitivity of the ESF assay system. (Endocrinology 89: 609, 1971) I IS well established that thyroidectomy in rats results in a significant decrease in erythropoiesis (1-3). The ensuing anemia is completely reversed by administration of thyroid hormone (4, 5). Anemia is also observed in untreated hypothyroid patients (6). In addition, it has been reported that T3 and T4 exert a stimulatory influence on erythropoiesis in normal animals (7-10). The lowered requirement for oxygen in conditions of thyroid deficiency and the increased need for oxygen in hyperthyroidism may relate to the mechanisms underlying the decrease and increase in erythropoiesis noted, respectively, in these 2 states. Moreover, since the elevated rate of erythropoiesis induced by T3 or T4 in mice can be inhibited by anti-erythropoietin, it has been suggested that the response evoked by thyroid hormones may be mediated through Received February 5, 1971. Supported by a grant (5 RO1-HE03357-14) from the National Heart Institute of the NIH, USPHS. 1 Present address: Department of Medicine (Hematology), Mount Sinai School of Medicine, New York, N. Y. 2 Predoctoral Trainees of the National Heart Institute of the NIH, USPHS (Training Grant 5 TO1-HE05645-06). an increased production of erythropoietin (ESF) (3,11,12). On the other hand, it has been reported that no ESF activity is detectable in the plasmas of T4and T3-treated animals (13, 14). In some studies, however, bilateral nephrectomy abolished that erythropoietic action of thyroid hormone (9, 10), thus once again suggesting that this principle may stimulate erythropoiesis through increased production of the ESF. The present experiments were undertaken to investigate further the mechanism underlying the influence of T4 on erythropoiesis. A phase of this study involved determinations of the ESF content of the plasma and the erythrogenin levels of the kidney in the T4-treated animals. Erythrogenin is a renal factor which interacts with a plasma component to generate the ESF (15, 16). Materials and Methods In all experiments, female mice of the CF-1 strain weighing 20-25 g or female rats of the LongEvans strain weighing 200-250 g were employed. The animals were maintained on a diet of Purina Lab Chow and tap water ad lib. In direct assays, 5 or 25 jug/day of T4 was injected in mice sc, in a volume of 0.2 ml vehicle, for periods ranging from 1 to 7 days. In the hypoxia 610 NOTES AND COMMENTS Volume 89 TABLE 1. Effects of T4 on RBC-radioiron incorporation and ESF plasma activity in normal mice Days of treatment Mean % RBC-'Fe incorporation ± SEM