madman
Super Moderator
INTRODUCTION
The regulatory effects of androgens on haematopoiesis have been recognized since the early twentieth century. Castration of male rats causes anemia (1) which is reversible after treatment with androgens (2). A classical clinical study by Vahlquist provided indirect evidence that men had intrinsically higher haematocrit (Hct) levels when compared with women; it was observed that pre-menopausal women did not have higher Hct levels when compared with post-menopausal women, and did have an increased Hct in response to iron supplementation (3). Anecdotal data from competitive athletes suggest that androgen misuse can improve performance, partly through increasing the VO2max (Hb-mediated blood oxygen carrying capacity), albeit at the expense of an increased risk of arterial and venous thrombosis (4). Equally, women suffering from hyperandrogenic endocrinopathies such as congenital adrenal hyperplasia and Cushing’s syndrome, may exhibit relative erythrocytosis (5, 6). The above historic findings underpin the androgens on stimulating bone morrow erythropoiesis.
ANDROGENS AND ERYTHROPOIESIS
Animal and human studies suggested a direct and indirect stimulatory effect of androgens on erythropoiesis, though the exact mechanism of such relation remains vaguely understood. Androgens administration results in an increase in the erythroid cell mass, the colony forming units for erythrocytes (CFU-E), and the production and secretion of Erythropoietin (EPO) (6) while androgen deprivation causes a reduction in red blood cell indices due to reduced proliferation of marrow erythroid precursors (18). Androgens are converted to 17-keto-steroids capable of increasing the synthesis of mRNA in the nucleus causing differentiation of bone marrow cells from EPO-non-responsive to EPO responsive (6). Moreover, androgens enhances the glucose uptake resulting in glycolysis and gene transcription and mRNA synthesis in erythroid (19–21).
T may increase Hct by inhibiting secretion of hepcidin, the principal iron regulatory peptide, thereby leading to an increase in bioavailable iron (22) but may also enhance the incorporation of iron into the red blood cells (23) and improve red blood cells survival (24). Finally, the finding of raised insulin like growth factor 1 (IGF-1) levels in those receiving androgens suggested a potential link between androgens and an IGF-1 driven erythroid progenitor cells proliferation and differentiation (25, 26).
The effect of T on erythropoiesis is most pronounced during puberty, with prepubertal Hb being similar in boys and girls, but increases in boys after age 13 years in tandem with increasing T concentrations (6, 27). Boys with delayed puberty have Hb levels similar to those of prepubertal boys and girls, and treatment with T normalizes hemoglobin levels to those observed in the late male puberty (28, 29).
FUTURE CONSIDERATIONS
As life-expectancy increases, aging and frailty have become increasing health priorities worldwide. For instance, the number of people over 65 years of age is projected to reach 15–20% of the entire population by 2030 (61, 62). Unexplained anemia is common in older men, hypogonadism accounts for a proportion of these cases. Hypogonadism may negatively impact men’s health and aggravate frailty, morbidity and mortality. Androgen therapy also has potential to treat anemia of CKD in hypogonadal men as an adjunct to EPO. Given the long-standing risks associated with T therapy, further studies are required to determine which men would most benefit functionally from T therapy without exposing them to unnecessary adverse effects or long-term complications.
The regulatory effects of androgens on haematopoiesis have been recognized since the early twentieth century. Castration of male rats causes anemia (1) which is reversible after treatment with androgens (2). A classical clinical study by Vahlquist provided indirect evidence that men had intrinsically higher haematocrit (Hct) levels when compared with women; it was observed that pre-menopausal women did not have higher Hct levels when compared with post-menopausal women, and did have an increased Hct in response to iron supplementation (3). Anecdotal data from competitive athletes suggest that androgen misuse can improve performance, partly through increasing the VO2max (Hb-mediated blood oxygen carrying capacity), albeit at the expense of an increased risk of arterial and venous thrombosis (4). Equally, women suffering from hyperandrogenic endocrinopathies such as congenital adrenal hyperplasia and Cushing’s syndrome, may exhibit relative erythrocytosis (5, 6). The above historic findings underpin the androgens on stimulating bone morrow erythropoiesis.
ANDROGENS AND ERYTHROPOIESIS
Animal and human studies suggested a direct and indirect stimulatory effect of androgens on erythropoiesis, though the exact mechanism of such relation remains vaguely understood. Androgens administration results in an increase in the erythroid cell mass, the colony forming units for erythrocytes (CFU-E), and the production and secretion of Erythropoietin (EPO) (6) while androgen deprivation causes a reduction in red blood cell indices due to reduced proliferation of marrow erythroid precursors (18). Androgens are converted to 17-keto-steroids capable of increasing the synthesis of mRNA in the nucleus causing differentiation of bone marrow cells from EPO-non-responsive to EPO responsive (6). Moreover, androgens enhances the glucose uptake resulting in glycolysis and gene transcription and mRNA synthesis in erythroid (19–21).
T may increase Hct by inhibiting secretion of hepcidin, the principal iron regulatory peptide, thereby leading to an increase in bioavailable iron (22) but may also enhance the incorporation of iron into the red blood cells (23) and improve red blood cells survival (24). Finally, the finding of raised insulin like growth factor 1 (IGF-1) levels in those receiving androgens suggested a potential link between androgens and an IGF-1 driven erythroid progenitor cells proliferation and differentiation (25, 26).
The effect of T on erythropoiesis is most pronounced during puberty, with prepubertal Hb being similar in boys and girls, but increases in boys after age 13 years in tandem with increasing T concentrations (6, 27). Boys with delayed puberty have Hb levels similar to those of prepubertal boys and girls, and treatment with T normalizes hemoglobin levels to those observed in the late male puberty (28, 29).
FUTURE CONSIDERATIONS
As life-expectancy increases, aging and frailty have become increasing health priorities worldwide. For instance, the number of people over 65 years of age is projected to reach 15–20% of the entire population by 2030 (61, 62). Unexplained anemia is common in older men, hypogonadism accounts for a proportion of these cases. Hypogonadism may negatively impact men’s health and aggravate frailty, morbidity and mortality. Androgen therapy also has potential to treat anemia of CKD in hypogonadal men as an adjunct to EPO. Given the long-standing risks associated with T therapy, further studies are required to determine which men would most benefit functionally from T therapy without exposing them to unnecessary adverse effects or long-term complications.
