The Role of the Multiple Hormonal Dysregulation in the Onset of “Anemia of Aging”: Focus on Testosterone, IGF-1, and Thyroid Hormones

Figure 1

Potential molecular mechanisms underlying the hormonal regulation of erythropoiesis. The figure depicts the potential molecular mechanisms underlying the hormonal regulation of erythropoiesis (IGF-1, T, and thyroid hormones) hypothesized in both in vitro and animal studies. Testosterone. By binding with a nuclear androgen receptor (AR), testosterone may exert a direct role on bone marrow erythroblast and red cell precursor survival leading to an increase in erythroid mass and erythroid and myeloid colony formation. The erythropoietic activities of T may also be related to the stimulation of EPO synthesis and secretion at kidney level (by modulating the hypoxia or hypoxic sensing). Testosterone also enhances the sensitivity of erythroid progenitor cells to EPO, determining an increase in red cell production. An alternative hypothesis considers the suppression of hepcidin, the iron-regulating hormone, as a contributory factor in the T-related erythrocytosis. Testosterone might reduce hepcidin levels by modulating inflammatory cytokines, especially interleukin-6 (IL-6), known modulator of the liver production of hepcidin. IGF-1. IGF-1 directly stimulates the proliferation and differentiation of the late stage of primitive erythroid progenitor cells and/or early erythroid progenitor cells. IGF-1 might also increase the expression of cell-surface transferrin-receptors by determining a redistribution from the intracellular compartment to the cell surface. Alternatively, IGF-1 can act together with EPO in a synergistic way suggesting for IGF-1 a role of EPO substitute. TSH and Thyroid Hormones. Thyroid-stimulating hormone (TSH), L-triiodothyronine (T3), and L-thyroxine (T4) might play a direct role in ensuring normal erythropoiesis. Thyroid-stimulating hormone could affect hematopoiesis by binding to a functional thyrotropin receptor (TSHR), which is found in both erythrocytes and some extrathyroidal tissues. T3 is involved in the control of growth and apoptosis of hematopoietic cells and bone marrow tissue by potentiating the erythroid burst-forming unit (BFU-E) proliferation. T4 has been shown to exert a direct, β2-adrenergic receptor-mediated stimulation of red cell precursors. The effects of thyroid hormones on erythropoiesis seem to be mediated at the molecular level by the T3 binding to specific nuclear receptors (the endogenous receptor alpha, c-erbA/TRα) and the closely related retinoic acid receptor α (RARα) involved in the regulation of normal erythroid differentiation. In hypothyroid conditions, reduced EPO levels might also account for anemia.