Androgens in Health and Disease.pdf - E Library

234 Basaria and Dobs
losses in women, because young women who have undergone hysterectomy still have
lower hemoglobin levels compared to age-matched men (5). Similar to animal studies,
anemia develops in castrated and eunuchoid men (1,2). This is reversed with androgen
administration. The prevalence of anemia in both genders increases after age 60 and
worsens with every decade thereafter (6). This was further evaluated by Lipschitz et al.,
who found that elderly men with unexplained anemia had lower levels of erythroid
precursors compared with nonanemic young men and elderly controls (7).
MECHANISM OF ACTION OF ANDROGENS
Androgens stimulate erythropoiesis through a variety of direct and indirect ways. In
this section we attempt to elucidate these mechanisms.
Stimulation of Erythropoietin Secretion
Animal studies have shown that androgen administration increases the synthesis and
secretion of erythropoietin (Epo). Administration of androgens to female rats results in
hypertrophy of renal tissue and an increase in Epo secretion (8). Testosterone acts by
binding to cytoplasmic receptors in the renal parenchymal cells. This hormone-receptor
complex is transported to the nucleus where it results in transcription of certain proteins
that increase cellular mass (9), resulting in an increase in Epo synthesis and secretion.
This observation is confirmed by animal studies showing that various doses of nandrolone
decanoate when given to a mouse with renal failure results in an increase in Epo synthesis
and hemoglobin concentration (10). This increase in Epo secretion is blocked by injection
of antierythropoietin antibody (11), further proving that androgens act by increasing
Epo levels.
Androgens also stimulate Epo synthesis in humans. Alexanian administered
fluoxymesterone at a dose of 40 mg/m2 to anemic men and control men and 10 mg/m2 of fluoxymesterone to hypogonadal men and anemic women (12). Two-thirds of the
hypogonadal and/or anemic patients showed an elevation of red cell volume by at least
15%. All of the groups also showed an increase in the urinary levels of Epo. Humans
(both genders) also have an extrarenal source of Epo and, therefore, even nephrectomized
men respond to androgens (13). The site of this extrarenal Epo synthesis remains
unclear. Another study showed that the main mechanism by which androgens stimulate
erythropoiesis is by stimulating secretion of Epo (14). In this study, simultaneous administration
to mice of cyproterone acetate (an antiandrogen) with testosterone propionate
significantly decreased erythropoiesis. However, administration of synthetic Epo in the
presence of cyproterone acetate did not inhibit erythropoiesis.
Action on Bone Marrow
Androgens stimulate erythroid colony-forming units in the bone marrow. Incubation
of human bone marrow culture supplemented with variable testosterone concentrations
results in stimulation of erythroid colony formation (15). Androgens also convert the
uncommitted bone marrow cells from Epo-nonreponsive to Epo-responsive cells. After
these initial steps, Epo is mandatory for the maturation of these cells into the erythroid
cell line. The combination of testosterone and Epo has a synergistic effect on erythropoiesis
(15). Testosterone makes the marrow cells Epo responsive and then Epo differentiates
these uncommitted marrow cells into the erythroid cell line.