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The anemia of end-stage renal failure has multiple contributory factors, including EPO deficiency, toxic inhibitors of EPO action, androgen deficiency, micronutrient deficiency (iron, folate, and pyridoxine), blood loss, and hemolysis (81). Although the balance between these remains conjectural, EPO deficiency is a major factor (82), and androgen therapy has consistent effects on EPO secretion and hemoglobin concentrations (83). Endogenous testosterone is an important physiological determinant of red cell mass in men, because blockade of androgen action lowers hemoglobin levels (84,85). Androgen therapy has no effect on hemoglobin after bilateral nephrectomy

(86), when the major source of endogenous EPO is removed and circulating EPO is not consistently increased by androgens nor related to resultant increases in hemoglobin

(87). Furthermore, posttransplant erythrocytosis may depend on EPO and possibly also endogenous testosterone (88). These findings suggest that androgens may act predominately by enhancing EPOs effect.

Although the effect of androgens on EPO has been long recognized, it has recently become clear that EPO can directly stimulate human Leydig cell testosterone secretion (in men with normal renal function). In a study of infertile, oligozoospermic men undergoing internal spermatic vein cannulation for radiological imaging of varicocele (89), five men received EPO (60 U/kg), another five GnRH (50 ^g) and three saline vehicle control as an i.v. bolus into the cubital vein. Simultaneous internal spermatic and peripheral vein sampling demonstrated that EPO increased spermatic vein testosterone secretion approx 12-fold, without concurrent change in peripheral LH, FSH, or testosterone or spermatic vein LH and FSH concentrations. In men with impaired renal function, EPO increases circulating testosterone concentrations in men on dialysis (65,69) as well as those not yet requiring dialysis (65). The clinical significance of such increases in circulating testosterone is conjectural, given the inconsistent effects of exogenous testosterone on sexual function, growth, and puberty as discussed. However, improved spermatogenesis is possible if intratesticular testosterone concentrations are sufficiently increased to promote spermatogenesis.

Two randomized controlled studies have shown that pharmacological androgen therapy increases hemoglobin in patients with end-stage renal failure. One study randomized 21 men to nandrolone (100 mg/wk) or placebo vehicle injections for 5 mo in a cross-over design (90), whereas another randomized 18 patients to nandrolone decanoate (200 mg/wk) for 3 mo (91). Mean hemoglobin was significantly increased in both (15 g/L and 10 g/L, respectively), with one also reporting a clinically significant reduction in transfusion requirement (90). Subsequent studies have confirmed the beneficial effects of nandrolone decanoate (200 mg/wk), compared with placebo vehicle injections for 4 mo (92), whereas three smaller, less well-conducted (34,93,94) studies using lower dose oral androgen (34,93) have failed to show an increase in hemoglobin. These discrepancies may be explained partly by another randomized, controlled clinical study that compared four androgen regimens in patients on dialysis (95). Intramuscular testosterone enanthate (4 mg/kg/wk) and nandrolone decanoate (3 mg/kg/wk) were more effective in increasing hematocrit than oral oxymetholone (1 mg/kg/d) and fluoxymesterone (0.4 mg/kg/d). However, the relatively arbitrary doses used cause uncertainty whether these differences reflected different effective androgen doses, androgen class (17-a alkylated or not), or administration route (including pharmacokinetics). The use of the obsolete class of hepatotoxic 17-a alkylated androgens in this setting is hard to justify when equally effective, safer androgens are available.

Androgen therapy increases hemoglobin primarily by increasing circulating EPO concentration (92), but also partly by augmenting EPO action (96). However, a prospective but uncontrolled study of 25 men undergoing hemodialysis reported that treatment with nandrolone decanoate (200 mg/wk) for 6 mo resulted in consistent increases in hemoglobin but highly variable changes in circulating EPO. Only 60% of men on dialysis exhibited an increase in EPO and the hemoglobin increase persisted long after circulating EPO fell and androgen therapy ceased (87). The same investigators have subsequently confirmed the lack of association between EPO and hemoglobin using the same study design, but examining nine men undergoing peritoneal dialysis (8). These two studies suggest that the augmentation of endogenous EPO action by androgen therapy may be more important than previously accepted in men undergoing hemodialysis or peritoneal dialysis.

The role of androgen therapy relative to EPO therapy in patients with chronic renal disease remains unresolved, because direct comparisons in well-controlled studies are lacking. A retrospective analysis of 84 patients receiving androgen therapy (nandrolone decanoate 200 mg/wk) for 6 mo reported that men older than 55 yr of age had the best hemoglobin responses and that this response was comparable with those treated with EPO (97). This was subsequently confirmed in two controlled prospective studies using nandrolone decanoate 200 mg/wk or EPO (6000 U/wk) for 6 mo. The first study (98) reported similar hemoglobin responses and safety profiles in 18 men aged older than 50 yr treated with androgen therapy (nandrolone decanoate 200 mg/wk) compared with 6 men under 50 yrs and 16 women receiving EPO (6000 U/wk), but the lack of randomization and noncomparability of groups by age and gender limit the interpretation of these findings. In the second study (9), 33 patients over the age of 65 yr who were receiving maintenance EPO treatment three times weekly were assigned to receive intramuscular nandrolone decanoate (200 mg/wk, n =14 men) without EPO or to continue the same EPO treatment (n = 12 men, 7 women) for 6 mo. Nandrolone alone was at least as effective as continued EPO treatment in maintenance of all hematological and nutritional variables, suggesting that androgen therapy may be more cost-effective than EPO, particularly in older men on dialysis. These findings were corroborated in a small, uncontrolled study of nine older (>50 yr) men undergoing peritoneal dialysis who received nandrolone decanoate (200 mg/wk) for 6 mo (8). These studies highlight that intramuscular nandrolone decanoate (200 mg/wk) in older men on dialysis (>50 yr old) is as effective as EPO in maintaining hemoglobin at a much lower cost. The comparative safety of these treatments requires more detailed evaluation.

Androgen therapy may also have a role in sparing EPO dose and cost. The addition of androgen therapy to intravenous EPO administered with hemodialysis has been examined in two randomized studies (99,100) and one nonrandomized (96) study. In the largest study with the longest treatment duration (99), 19 patients on dialysis were randomized to receive nandrolone (100 mg wk) plus EPO (4500 U/wk) or EPO alone for 26 wk. The addition of nandrolone to low-dose EPO (approximately equal to 60 U/kg/wk) resulted in a significantly greater rise in hematocrit. Similar significant additional increases in hemoglobin were reported in a small nonrandomized study of eight men choosing to receive nandrolone decanoate (100 mg/wk) plus intermediate-dose EPO (6000 U/wk) compared with EPO alone (96) for 12 wk. However, another small but randomized study employing a higher dose of EPO (120 U/kg/wk) did not detect any benefit of nandrolone decanoate (2 mg/kg/wk) for 16 wk plus EPO compared with the same dose of EPO alone in 12 on dialysis patients (100). Whether these discrepancies result from study design, age, or EPO dose remains to be clarified. It is possible that androgens have greatest synergism with submaximal EPO dosage and that the higher EPO dose obviates any additional androgen effect on hemoglobin. No study has examined the effect of subcutaneous EPO, and randomized prospective studies to examine the use of low-dose subcutaneous EPO with adjunctive androgen therapy are needed (101), particularly in older men.

A caveat on androgen therapy is the risk of polycythemia, which may occur in men with normal renal function who are receiving exogenous testosterone (102). Testosterone-induced polycythemia may be more common in older men receiving im testosterone injections (103) but has been observed with all forms of exogenous androgen (104) (see Chapter 18).

In summary, although androgen therapy is considerably cheaper than EPO (105), its wider use is limited by modest efficacy when used alone and by adverse effects, notably virilization of women and children, and the hepatotoxicity of 17a-alkylated androgens. Restricting use to non-17a-alkylated androgens, particularly in older men

(9,97), may avoid most of the hazards. Present practice limits the role of androgen therapy in chronic renal failure to patients in whom EPO is contraindicated or unavailable, although evidence for its use as an EPO-sparing agent is accumulating. Whether it is more effective according to the degree of androgen deficiency induced by renal failure or according to the EPO dose remains to be clarified.

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