Erythropoietic Activity of Steroid Metabolites in Mice

Abstract

Abstract. The per cent Fe59 incorporation into circulating erythrocytes as an indicator for new hemoglobin production was used in the polycythemic exhypoxic mouse system to study the effects of certain steroid hormone metabolites on erythropoiesis. Enhanced Fe59 incorporation was observed after the administration of several metabolites with a 5,3-H configuration, while those with a 5a-H configuration had no stimulatory effect. The stimulatory effect in avian systems has been shown by others to be due to an increased activity of 6-aminolevulinic acid synthetase, the limiting enzyme in heme biosynthesis. These in vivo studies thus indicate that in this mouse system, as in previously reported studies with avian and human bone marrow cells, some steroid metabolites stimulate hemoglobin synthesis. The observation that the same structure-junction relationship exists in the currently described system as in the avian suggests that these steroids probably induce 6-aminolevulinic acid synthetase in the mouse. The erythropoietic action of these nonandrogenic steroid metabolites may prove to be clinically useful.Recent studies by Granick and Kappas'-1 and Levere et al.4 have indicated a possible role for steroid metabolites with a 5fl-H configuration, in regulating porphyrin-heme biosynthesis via their ability to induce the de novo formation of 6-aminolevulinic acid synthetase, the rate-limiting enzyme in this pathway. The tissues in which 5-aminolevulinic acid synthetase was shown to be inducible by these steroids included the avian embryo liver and the erythroid cell precursors of the chick blastoderm. Unlike certain porphyria-inducing drugs, such as allylisopropylacetamide, which could induce 5-aminolevulinic acid synthetase in liver cell cultures but failed to do so in the chick blastoderm, the steroid metabolites were active in both tissues. A working hypothesis was presented which suggested that these metabolites may act as derepressor agents for the structural gene coding for 5-aminolevulinic acid synthetase, permitting it to transcribe more actively, leading to enhanced formation of this enzyme and thus to increased production of heme. If this formulation were correct, one could predict that these steroid metabolites might be able to regulate heme synthesis in other types of cells where 5-aminolevulinic acid synthetase was inducible such as the hepatic or erythroid tissues of other species.It was the purpose of this study to test this question by examining the effects 564

Aplastic Anemia: Some Clinical and Laboratory Aspects and an Evaluation of the Androgen-Glucocorticoid Treatment

“…The side effects of this therapy, liver toxicity and virilization in females, justify temporary withdrawal of treatment, followed by a trial with another androgen, only in case of icterus. Concerning viriliza tion, experiments are now being carried out on new 5/9-H-steroid metab olites, devoided of virilizing effects, which will probably be used cur rently in clinical practice in a near future [10,11], Also, a small dose of glucocorticoids is generally associated to andro gen therapy [1,23,25]. The clinical results obtained in our patients do not seem to justify this treatment.…”

“…In conclusion, the prolonged use of androgens, particularly of the new metabolites devoided of virilizing effects [10,11] and eventually bone marrow homotransplantation, made possible by the striking im provement in tissue typing techniques, appear to be the most promising therapeutic mean in this disease.…”

Hematologic Disorders in Renal Failure

“…Moreover, it has been recently shown that androgens increased 2,3-diphosphogIycerate in red cells of hemodialyzed patients, increasing the unloading of oxygen to the tissues [82]. Certain 5(3-H steroids are more active than other compounds [45,46]. Mirand et al [66] and Eschbach and Adamson [29] have found a minute increase in erythropoietin plasma level in some anephric patients after andro gen therapy.…”

Effect of Hyperoxia and Androgen on Red Cell 2,3-Diphosphoglycerate and Oxygen Affinity

“…Plasma for ESF determination was also obtained from hyperoxic mice 1, 2, 3, and 4 days after two daily administrations each of 2.5 mg 19-ND dis solved in 0.1 ml of propylene glycol. Plasma ESF levels were measured in the post hypoxic polycythemic mouse system by injecting plasma samples of 0.5 or 1.0 ml each to mice on the 3rd and 5th hypoxic days, and 72 h radioiron incorporation was begun on the 6th posthypoxic day as previously described [19,23].…”