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560 Part VI: The Erythrocyte Chapter 38: Erythropoietic Effects of Endocrine Disorders 561

this disease. In a series of patients with Addison disease, some patients GONADAL HORMONES
38
with normal hemoglobin levels developed transient anemia after ini-
tiation of hormone replacement therapy, presumably secondary to an ANDROGENS
increased plasma volume. 38
In experimental animals, adrenalectomy causes a mild anemia that Sexually mature males have higher hemoglobin levels than prepubertal
54
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responds to glucocorticoids. However, the pathophysiologic basis of males, older males, and females. This difference is attributed to andro-
the anemia and any influence of adrenal cortical hormones on erythro- gen production. Testosterone levels directly correlated with hemoglo-
55
poiesis are not well defined. bin levels in a community population of males 30 to 94 years of age.
Pernicious anemia occurs in patients with autoimmune adrenal Another study of males 70 to 81 years of age also found a correlation
insufficiency, but is seen primarily in patients with type I polyglandular between hemoglobin and testosterone levels, but when individuals
autoimmune syndrome, whose other manifestations include mucocu- with hemoglobin less than 13 g/dL and/or a testosterone level less than
56
40
taneous candidiasis and hypoparathyroidism. Anemia as a result of 8 nmol/L were excluded, the association was no longer significant.
primary erythropoietin deficiency was reported in one patient with this Orchiectomy results in a median decrease in hemoglobin concentra-
57
syndrome. 41 tion of 1.2 g/dL. “Medical” castration with combined androgen
blockade by gonadotropin-releasing agonists and antiandrogens also
causes anemia. 58
CUSHING DISEASE AND ALDOSTERONISM The erythropoietic effects of androgens have been widely exploited
Glucocorticoids interact with erythropoietin in vitro to enhance ery- for the treatment of various anemias, especially before the development
throid colony proliferation. Glucocorticoid receptors, activated by of recombinant erythropoietin. Testosterone therapy in hypogonadal
42
their cognate ligand, initiate Janus kinase 2 phosphorylation-mediated men increased the mean hematocrit from 38.0 percent to 43.1 percent within
59
cytoplasmic signal transduction, which may stimulate erythropoiesis by 3 months. Two meta-analyses found that erythrocytosis (defined as a
a mechanism shared with erythropoietin (Chaps. 32 and 57). Erythro- hematocrit greater than 50 or 52 percent) was greater than three times
cytosis has been reported in Cushing syndrome, primary aldostero- more likely to occur in a testosterone-treated group compared to pla-
43
nism, and Bartter syndrome. 45 cebo. 60,61 Erythrocytosis was reported in a woman treated for breast
44
However, a study of 63 women and 17 men with Cushing disease cancer with an aromatase inhibitor, which prevents the conversion of
found that although the hemoglobin levels in the females were evenly androstenedione and testosterone to estrogen. 62
distributed over the normal range, the hemoglobin levels were in the The mechanism of androgen action appears to be complex, with
63
lowest quartile in 14 of the 17 men, and 3 of these 14 were anemic. evidence for stimulation of erythropoietin secretion and a direct effect
46
64
The reduced hemoglobin levels in the male patients correlated with a on the marrow. Androgen receptors have been identified in the mar-
low testosterone level and slowly improved after treatment of Cushing row cells of human males and females. However, the cells expressing
disease. the receptors included stromal cells, endothelial cells, macrophages, and
myeloid precursors, but not erythroid cells, thus the pathophysiologic
65
significance of this association is unclear. Testosterone administration
CONGENITAL ADRENAL HYPERPLASIA is associated with an increase in erythropoietin levels and a decrease
63
The most common cause of congenital adrenal hyperplasia is in hepcidin levels. Although erythropoietin levels declined with con-
tinued testosterone administration, they remained inappropriately high
21-hydroxylase deficiency, which impairs conversion of despite improved hemoglobin levels, suggesting a new setpoint. 63
17-hydroxyprogesterone to 11-deoxycortisol. Patients with the “classic
47
form” present during the neonatal period with adrenal insufficiency, but
others have a late onset presentation with findings of androgen excess. ESTROGENS
Erythrocytosis, likely a consequence of increased androgen levels, has Data regarding the role of estrogens is conflicting. Administration of
been reported in patients with congenital adrenal hyperplasia result- large doses of estrogen led to a moderately severe anemia in rats. 66,67
48
ing from 21-hydroxylase deficiency, and erythrocytosis has also been However, hematopoietic stem cells express estrogen receptor-α and
described as the presenting manifestation of this disease. 49 estrogen signaling via this receptor promotes hematopoietic stem cell
self-renewal and stimulates erythropoiesis. 68
PHEOCHROMOCYTOMA
Pheochromocytomas and the closely related tumor, paraganglioma, are PITUITARY GLAND DISORDERS
rarely associated with erythrocytosis. This finding is believed to be a
result of autonomous erythropoietin production by the tumor, often PITUITARY INSUFFICIENCY
50
mediated by von Hippel-Lindau mutations that cause or contribute to The most common cause of pituitary insufficiency is pituitary tumors
pheochromocytoma development (Chaps. 32 and 57). or consequences of their therapy. Other etiologies include hypotha-
69
However, several individuals with congenital polycythemia have lamic tumors or dysfunction, sarcoidosis or other infiltrative diseases,
developed recurrent pheochromocytomas, paragangliomas, and some- pituitary hemorrhage or infarct, genetic causes, and idiopathic pituitary
times somatostatinomas. 51,52 Their tumors are heterozygous for a het- failure. Regardless of the cause, hypopituitarism results in a moderately
erogeneous gain-of-function mutation of hypoxia-inducible factor-2α severe normochromic normocytic anemia, with an average hemoglobin
gene and erythropoietin transcript is present in tumor tissues (Chaps. level of 10 g/dL. 12,70 Anemia and erythroid hypoplasia have also been
32 and 57). However, these mutations are generally not found in non- described in hypophysectomized animals. 71,72
tumor tissues, so the etiology of the association of these tumors with In rats, removal of the posterior lobe of the pituitary, which secretes
polycythemia is unknown. 51,52 vasopressin and oxytocin, does not result in anemia. Thus, the anemia
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A syndrome of congenital polycythemia associated with a muta- of hypopituitarism presumably results from the absence of the ante-
tion in the proline hydroxylase type 2 gene and recurrent paraganglio- rior lobe hormones, adrenocorticotropic hormone, thyroid-stimulating
mas has also been described in a single family. 53 hormone, follicle-stimulating hormone, luteinizing hormone, growth

Kaushansky_chapter 38_p0559-0562.indd 560 9/17/15 6:19 PM