Clifford W. Gurney

THE ERYTHROPOIETIC-STIMULATING EFFECTS OF ANDROGENS

Several authors have reported that testosterone is capable of stimulating erythropoiesis in some patients with various types of anemias.13 More knowledge of the mechanism by which testosterone affects erythropoiesis might improve our understanding of the pathogenesis of these anemias and thereby lead to a more rational basis for their therapy with androgens. Blacher first suggested that the sex hormones influence erythropoiesis after he described differences in the red blood counts of male and female fowl.4 Shortly thereafter Juhn and Domm showed that these differences were dependent on the presence of intact gonads in the male.5 Vollmer et al.6,7 showed that testosterone propionate stimulated erythropoiesis in female rats, in castrated male rats and in hypophysectomized rats. In this paper we shall report the results of studies on the mechanism by which androgens and other anabolic steroids stimulate erythropoiesis in mice. We will also discuss the effect of testosterone on mice with anemia resulting from mutation at the W locus. Finally we shall speculate on the relationship between these findings and the way that testosterone stimulates erythropoiesis in anemic patients.

Erythropoietic effect of plasma from mice receiving testosterone.

THE clinical effectiveness of testosterone in some previously refractory anaemias1–3 has aroused interest in its mechanism of action.

A comparison of erythropoietin bioassays.

Summary The transfused plethoric mouse is sensitive to quantities of erythropoietin as small as 0.05 unit as measured by radioiron administered 2 1/2 days after challenge with the hormone. A sigmoidal curve describes the relationship between incremental log-doses of purified erythropoietin and incorporation of radioiron into circulating red blood cells.

Studies of erythropoietin: the hormone regulating red cell production.

There is mounting evidence that erythropoiesis is controlled by a humoral factor or factors. Since Carnot and DCflandrel first published this thesis in 1906, many investigators have attempted to substantiate their work, but it has been largely in the last twenty years that such investigators as Reissmann,Z Erslevj3 Gordon and his co-~orkers ,~ Borsook et u Z . , ~ and Stohlman et aL6 have succeeded in bringing the problem to the point of serious study and acceptance. In 1952 Grant and Root7 wrote a comprehensive review of the literature on the subject. The first convincing support of Carnot’s hypothesis is found in the work of Reissmann,2 and Stohlman et uL6 Reissmann demonstrated that increased erythropoiesis occurred in both parabionts even though only one of the pair was maintained in low O2 tension. Stohlman and Rath found that erythroblastic hyperplasia was not confined to the areas of regional hypoxia in a human being with regional hypoxia secondary to a patent ductus arteriosus. Hyperplasia was also observed in the bone marrow that was supplied by blood with a normal 0 2 saturation. Of necessity, the relationship of the humoral factor that is present in anemic plasma to the maintenance of a normal amount of red blood cells and hemoglobin has been one of conjecture until recently, when Gurney and his associates demonstrated its presence in normal plasma.* The exact relationship of arterial oxygen saturation to the production of circulatory erythropoietint and, thus, to erythropoiesis has likewise not been established. During the past several years we have been concerned with: (1) applying the technique of Fe69 incorporation as a measure of red cell production; (2) finding more sensitive assay preparations for erythropoietin; (3) elucidating the role of erythropoietin in maintaining the dynamic equilibrium of erythropoiesis; (4) determining the basic conditions that control erythropoietin blood levels and, thus, the rate of erythropoiesis; (5) studying the effect of cobaltous ion on erythropoietin production; (6) searching for the site of erythropoietin production; and, of course, (7) using the information obtained to solve certain clinical problems. A brief discussion of our research and some interpretations of the data are the subjects of this paper.

THE PHYSIOLOGIC AND CLINICAL SIGNIFICANCE OF ERYTHROPOIETIN

Excerpt Until recently it was generally agreed that low oxygen tension in the bone marrow constituted a direct stimulus for red cell production. This view was challenged by many investigators whose...

Erythropoietic Effect of Testosterone in the Polycythemic Mouse

Summary Testosterone has been demonstrated to stimulate erythropoiesis in the polycythemic mouse. A response can be observed following a single injection of 0.5 mg of testosterone. One mg is as effective as larger single doses. A greater erythropoietic response was observed with 10 daily injections. Possible mechanisms of action of testosterone on erythropoiesis are discussed.

Use of Mild Plethora to Demonstrate an Erythropoietic Effect from Small Amounts of Androgens

Summary Two daily injections of as little as 0.1 mg testosterone are capable of stimulating erythropoiesis in mildly plethoric mice. Twenty-five hundredths of a milligram of testosterone is sufficient to elevate the erythropoietin titers of hypoxic mice.

Combined Effect of Cobalt and Testosterone on Erythropoiesis

Summary It has been demonstrated that a combination of cobalt and testosterone serves to potentiate erythropoiesis in the polycythemic mouse, and acts synergistically to increase erythropoietin levels in the plasma of the normal mouse. When these 2 substances are used together, the erythropoietic response in plethoric animals and the amount of erythropoietin elaborated in normal animals are substantially greater than the sum of the responses produced by each agent separately.

Studies on Erythropoiesis IX. Mechanism of Decreased Erythropoiesis In Experimental Polycythemia

Summary 1) Reduction of erythropoiesis in rats rendered polycythemic by intraperitoneal infusion of packed red cells bears a relation to the degree of plethora produced. Plasma from anemic rats, a heat-denatured plasma extract from a patient with aplastic anemia, and subcutaneous cobaltous chloride all stimulate erythropoiesis in the polycythemic rat. These observations are consistent with the theory that decreased erythropoiesis in the polycythemic rat is the immediate consequence of a decreased titer of erythropoietin in these animals, and constitute further support for the theory of the humoral regulation of erythropoiesis. 2) In these experiments it was not possible to suppress erythropoiesis completely, as measured by the reticulocyte count, in normal rat by transfusion, although complete suppression was readily accomplished in transfused hypophysectomized rat.

Assessment of Actinomycin and Radiation Damage of Stem Cells by the Erythropoietin Tolerance Test

A technique for the measurement of the combined effect of x irradiation and actinomycin D on the responsiveness of stem cells to erythropoietin is reported. Findings indicate that, when irradiation was administered to mice immediately after actinomycin injection, deleterious effects on the stem cell, as measured by the erythropoietin tolerance test, were additive. Approximately 87 mu g of actinomycin per kg produced the same impairment of response to a standard dose of erythropoietin as does 150 r of total-body irradiation. Although the response to a standard dose of erythropoietin in the hypertransfused animal was normal 4 and 5 days after administration of the 87 mu g of actinomycin D per kg, residual damage in such animals could be detected when the challenging dose of erythropoietin was delayed until the sixth day.