International Urology and Nephrology 32: 549557, 2001. 2002 Kluwer Academic Publishers. Printed in the Netherlands.

549

Androgen therapy for anemia in elderly uremic patients

Juan F. Navarro & Carmen Mora
Nephrology Service and Research Unit, Hospital Nuestra Seora de Candelaria, Santa Cruz de Tenerife. Tenerife, Spain

Abstract. Androgens were the mainstay of treatment of renal anemia prior to the introduction of recombinant human erythropoietin. With the introduction of this recombinant hormone, the protocols of treatment of anemia were completely modied, and the use of androgens was relegated to the background. However, several authors have continued showing interest in the use of androgenic steroids for the treatment of anemia. This review examines several aspects of aging on androgenic hormones and hematopoiesis, the effects of androgen administration on hematological parameters, the side effects of these compounds and the future of this treatment for anemia in renal patients. Key words: Androgens, Anemia, Elderly, Erythropoietin, Hemodialysis, Peritoneal dialysis

Introduction The myth of Tithonus is an excellent compilation of many of the physiologic aspect of aging [1]. Tithonus was Auroras lover. She requested to her father, Zeus, eternal life for Tithonus, but she forgot to ask him to grant Tithonus eternal youth. By the age of 100 years he was impotent, he had lost his muscle strength, he had kyphosis and he had developed cognitive dysfunction, which was shown in the myth by the fact that he babbled continuously. At this stage, love had wilted and Aurora just wanted to be rid of him. However, since Tithonus was immortal and she could not make him disappear, Aurora changed him into a cicada instead. Therefore, the chirping of a cicada represents the incessant babbling of a senile old man. Many of these changes experienced by Tithonus are related with declining sexual masculine hormone production, and including abnormalities in memory [2], reduction of muscle strength and mass [3], loss of libido [4], osteopenia [5], etc. Disturbances of bone marrow function are also associated to declines in testosterone levels. Androgens and age Androgens are the male steroid hormones. In men, Leydig cells produce approximately 7 mg of testo-

sterone daily [6], which is required for normal sexual differentiation, growth and development, and the maintenance of secondary sexual characteristics [7]. In premenopausal women the ovaries secrete on average 150 g of testosterone daily, but its physiological role remains unclear [8]. In the adult male, plasma testosterone is 3001000 ng/dL, while its concentration in females ranges from 1565 ng/dL. Several studies have shown that testosterone production in men decline with advancing age. Koremann et al. [9] compared testosterone levels in healthy men aged 20 to 45 years with those in subjects aged 50 to 70 years. In the rst group all individuals had no levels lower than 70 ng/dL, whereas approximately half of the group aged 50 to 70 years had levels below those of the younger subjects. In a recent study by Wishart et al. [10], these investigators found a decline in testosterone after age 31 years that continued each decade. Results in agreement with this age-related decline in testicular function has been also reported in various meta-analysis [11]. Testosterone circulates in the plasma largely bound to plasma proteins, mainly albumin and sex hormonebinding globulin, which is not available to tissues [12], whereas only about 12 percent is free [13]. In many target tissues, testosterone is reduced by 5-reductase to dihydrotestosterone, which acts as intracellular mediator for most androgen actions. Both testosterone

550 and dihydrotestosterone work on the target cells by binding to an intracellular protein receptor, and the hormone-receptor complex acts in the nucleus to increase RNA polymerase activity [6]. The main biologic actions of androgens are related to reproductive and sexual physiology in men [7]: stimulate prenatal differentiation, pubertal development and spermatogenesis [14, 15], and play a critical role in stimulating and maintaining sexual function [16]. Besides their androgenic properties, these substances have important anabolic effects, such as increased nitrogen retention, muscle mass and body weight [7, 14, 17]. Although androgens preparations have been available for many years, the benets and risks of androgenic therapy have received less attention than hormonal sex treatment in females. The most common indication for androgen therapy is hypogonadism in men [7], but diverse clinical trials have strengthened the rationale for anabolic applications of androgens and their use in clinical states such as aging, wasting syndromes and cancer [8, 18, 19], and other potential uses of androgens are being explored. Androgens have also been used in the eld of Nephrology. In this article we review the use of androgens as therapy for anemia in elderly patients with end-stage renal failure. number as a consequence of advancing age [25, 26]. However, although involution of marrow in the elderly might limit maximum reactive capacity without compromising hematopoiesis in terms of basal function, older individuals have a decreased ability to respond to increased stimulation and exhibit an increased susceptibility to minor stress [27].

Androgens and renal anemia Anemia is one of the most consistent ndings in chronic renal failure (CRF). The pathogenesis of this complication is multifactorial, including uremic inhibitors of bone marrow, shortened red cell survival and bleeding disorders [28], although the relative erythropoietin (EPO) deciency is the single most important cause of the anemia [29]. Early investigations rmly established the stimulatory effect of androgens on erythropoiesis [30 32]. In animal models, administration of androgens resulted in an increase in bone-marrow erythropoietic activity, in the reticulocyte count and serum hemoglobin concentration [33]. On the contrary, castration of the adult male animal produced a reduction in the red-cell count and hemoglobin levels [34]. Importantly, androgen administration was associated with a restoration of hematological parameters to normal [35]. Several studies in the 70s were designed to determinate the effect of androgens on the anemia of CRF [3539]. These studies demonstrated that in stable patients on maintenance hemodialysis (HD) androgen administration was associated with a signicant improvement of anemia. However, the results of the different works varied greatly due to the heterogenity of patients and to the diversity of androgens used [40, 41]. Overall, before the advent of recombinant human EPO (rHuEPO), androgens were the mainstay of nontransfusional treatment for nonferropenic anemic patients on dialysis therapy. In 1983 occurred a major breakthrough in the therapy for renal anemia. At that moment, Lin and colleagues isolated and cloned the human EPO gene [42], and subsequently rHuEPO was available. In 1985, rHuEPO was rst given to HD patients as part of a phase I-II clinical trial [43]. Since that time, multiple investigations have demonstrated the efcacy of this recombinant hormone [44, 45], and therefore, the availavility of rHuEPO has completely revolutionized the treatment of anemia of CRF. As a

Age and hematopoiesis There is a recurrent question whether elderly people have an age-related decline in hemoglobin levels. Early epidemiologic studies reported that the prevalence of anemia in men above age 59 was increased [20, 21], with the incidence increasing signicantly with each successive decade in both males and females [22]. Elderly males and females with unexplained anemia had signicantly lower neuthrophil and leukocyte counts than nonanemic individuals, suggesting mild bone marrow failure [23]. However, many of the studies performed to address this question have been limited by the patients general health. Lipschitz et al. [24] studied in detail the effect of age on hematopoiesis in healthy man. The authors compared older individuals (aged more than 70 years) with matched younger persons (aged 2025). A quantication of the hematopoietic cell number did not show an age-related decrease in erythroid cell mass. In agreement with these ndings, other longitudinal studies have showed that there is no decline in hematocrit or alterations in erythroid cell

551 nal consequence, the use of androgens was almost completly abandoned in the rHuEPO era. Androgens for anemia in the erythropoietin era The generalized use of rHuEPO has limitations mainly derived from aspects: the side effects and the high cost. The main adverse effect of rHuEPO therapy, and that of most concern, is the development or aggravation of arterial hypertension, which has an incidence ranging between 2030% [4348]. Respect to the economical evaluation, Powe et al. [49] performed in 1993 an analysis of the net cost effect to Medicare of the increasing use of rHuEPO instead of red blood cell transfusions or androgens in the management of anemia for the approximately 100,000 HD patients in the U.S. End-Stage Renal Disease program. The authors developed a computerized decision model that took into account the effectiveness and possible side effects of rHuEPO, androgens and transfusions. They concluded that at ve years, for every 10,000 HD patients treated with rHuEPO, net Medicare expenditures will be much greater than if androgens are used by $118,370,000. Furthermore, a recent study by Teruel et al. [50] showed that the cost of a whole cycle of nandrolone decanoate (6 months) was $350, whereas the cost of rHuEPO therapy for the same time amounted to between $1750 and $5750. In spite of the success of rHuEPO and the parallel decline of androgens, interest has persisted in the use of androgenic steroids for the treatment of anemia, both alone or combined with rHuEPO. Several studies have analyzed the potential role of androgens in enhancing response and reducing dose requirements of rHuEPO in HD patients, suggesting a potential role as adjuvant therapy in these subjects. After 16 weeks of follow-up, Berns et al. [51] did not nd any benet of weekly intramuscular nandrolone decanoate (2 mg/kg) plus intravenous rHuEPO (120 IU/kg/week) compared with rHuEPO alone. However, Ballal et al. [52] observed that the mean hematocrit level experienced a slight increase from 25.3% to 27.4% (not signicant) in seven patients treated for 12 weeks with rHuEPO alone at a dose of 6000 IU/week, whereas in a group of 8 subjects who received 100 mg of nandrolone decanoate intramuscularly each week plus rHuEPO, the hematocrit increased signicantly, from 24.4% to 32.9% (p < 0.001). Finally, a recent 6month prospective randomized trial by Gaughan et al. [53] demonstrated that the combination of low-dose rHuEPO and nandrolone decanoate was associated with a higher increment in hematocrit than the use of rHuEPO alone. In this work, 19 anemic HD patients were randomized into two groups. The rst group received 1500 IU of rHuEPO intravenously three times a week (n = 10), while the second group received the same dose of rHuEPO plus 100 mg of nandrolone decanoate intramuscularly weekly (n = 9). At the end of the study, both groups showed a signicant increase in mean hematocrit compared with basal values, but the rise in patients treated with androgens was statistically greater than in the group receiving rHuEPO alone (8.2% vs 3.5%, p = 0.012). Apart from these works based on the combination of rHuEPO and androgens, other studies have showed that nowadays androgens alone may also have a role in the treatment of anemia in HD patients [3739]. In 1995, Teruel et al. [54] reported the evolution of hemoglobin and hematocrit levels in 25 HD patients treated with nandrolone decanoate (3.2 0.5 mg/kg/week) for 6 months. These parameters signicantly increased from 8 0.9 g/dL and 24 2.7% at baseline, to 10.7 1.8 g/dL and 32.9 4.2% at the end of the study, respectively (p < 0.001). In a retrospective study published in 1996 [55], these authors reviewed their experience during 16 years with the use of androgens as therapy for anemia. In that period 84 stable HD patients (67 males and 17 females) completed a cycle of six months with nandrolone decanoate (200 mg/week intramuscularly). In the total group, hemoglobin and hematocrit rose from 6.9 1.3 g/dL and 22 4% to 8.7 2 g/dL and 27 6%, respectively (p < 0.01). This increase of hematologic parameters was not related to primary renal disease, basal hematologic values, sex or dose of nandrolone decanoate (corrected by body weight). However, a relationship between favorable therapeutic response and patients age was observed. Therefore, hemoglobin concentration increased by 0.8 g/dL in patients younger than 46 years, by 1.8 g/dL in patients aged between 46 and 55 years, and by 2.7 g/dL in patients older than 55 years (p < 0.01 between groups). Moreover, whereas in 62% of patients younger than 46 years the increase in hemoglobin level was minimal, in patients older than 55 years 70% showed an increase greater than 2 g/dL. Finally, in a study comparing androgens versus rHuEPO, the same group [50] found that after 6 months of treatment the increase of hemoglobin concentration (from 7 0.6 to 10.4 1 g/dL, p < 0.001) in 22 patients (aged 47 15 years) treated with rHuEPO (initial dose 123 IU/kg/week) was similar to that observed

552 in 18 subjects (aged 62 12 years) treated with 200 mg/week of nandrolone decanoate (from 7.3 0.8 to 10.8 1.7 g/dL, p < 0.001). Similar results have been recently reported by Gascn et al. [56] in a prospective randomized trial. In this study, 33 patients older than 65 years receiving rHuEPO at maintenance doses were randomized to continue this therapy (n = 19) or to stop rHuEPO 2 weeks before the start of nandrolone decanoate 200 mg/week (n = 14). After 6 months of follow-up, hematological parameters did not change in the rst group. However, after an initial decrease in hemoglobin and hematocrit, these parameters progressively increased in patients receiving androgens, without signicant differences respect to rHuEPO treated patients at the end of the work. Most studies on the use of androgens in dialysis patients have been performed in HD, whereas the data are scarce in PD. This fact is a reect of the patterns of treatment of anemia. In 1997, Gagnon et al. [57] presented at the 30th annual meeting of the American Society of Nephrology a survey which characterized the patterns of treatment of anemia within a large dialysis center. In this center, of the 117 HD patients, 13% received rHuEPO in combination with androgens and 21% were treated with androgens alone, whereas none of the subjects under PD treatment received androgens. In a recent study, we prospectively analyzed the evolution of hematologic parameters after androgen administration in patients on maintenance PD [58]. Nine elderly male patients completed a cycle of nandrolone decanoate, 200 mg/week intramuscularly for 6 months. Hemoglobin and hematocrit values improved throughout the study, rising from a mean of 9.2 g/dL and 27.7% to 11.9 g/dL and 35.3%, respectively. effects of androgens were completely blocked by antiEPO antibodies [5964]. Therefore, the erythropoietic response to androgens was considered as greatly due to an increased production of EPO [65]. However, in a recent prospective study in HD patients treated with nandrolone decanoate we found that this treatment did not produce an increase of serum EPO in all patients [54]. Fifteen out of the 25 patients included in the study showed an EPO rose higher than 5 mIU/mL, and were considered as responders, whereas serum EPO did not change in the remaining 40% of subjects. Interestingly, the increase in hemoglobin concentration during androgen therapy was similar both in responders and non-responders, and moreover, there was no signicant correlation between the serum EPO levels and the response of the anemia. Finally, after stopping androgen administration, the hemoglobin values remained elevated in spite of a rapid decline in the serum EPO concentration. Different studies have showed that the inuence of androgen steroids on erythropoiesis is not related to an effect on the EPO levels. Thus, the possibility that androgens might act synergistically with rHuEPO have been also suggested. It has been reported that androgens may produce an increase in the sensitivity of erythroid progenitors to EPO, including colonyforming units-erythroid (CFU-E) and burst-forming units (BFU-E) [52, 6668]. It has been postulated that the intimal mechanism of this action may be mediated by triggering the pluripotential stem cells from G0 phase or prolonged G1 phase into a G1 interval responsive to EPO [69]. The works by Solomon and Hendler based on ferrokinetic data and red cell enzyme determinations [70, 71] showed that the increase in the red blood cell (RBC) mass after administration of nandrolone decanoate to HD patients resulted from two different mechanisms: an increase of erythropoiesis, shown by a simultaneous increment in RBC mass and erythron iron turnover and also a rise of RBC survival, suggested by an increment in RBC mass without a concomitant increase in erythron iron turnover. The existence of a direct effect of androgens on erythropoietic precursors at various stages of maturity, ranging from the multipotential hematopoietic stem cell (CFU-S) to the late erythroid progenitors which actively synthesize hemoglobin [7274], is supported by other investigations. Androgens cause an enhancement of the BFU-E and CFU-E population, as well as increase the total number of marrow CFU-S and the fraction of CFU-S that are in S phase of the cell cycle

Mechanism of action of androgens on erythropoiesis EPO is the primary regulator of erythropoiesis. However, a variety of hormones modulate this function. Androgenic steroids exert a signicant stimulatory effect on the rate of erythropoiesis, although the mechanism by which androgens may improve anemia is not entirely understood. In early studies, the administration of androgens to animals and humans resulted in a signicant increase in the level of EPO. Furthermore, the erythropoietic

553 [69, 75]. In addition, in vitro studies have showed that androgens may also stimulate hemoglobin synthesis [76, 77], an effect which is probably mediated by an increase in the activity of -aminolevulinic synthetase, the rate-limiting enzyme for the heme synthesis [78, 79]. Finally, the intimate mechanisms by which elderly patients might have a greater response to androgens are unknown. However, a potential role for androgen receptors may be suggested. Techniques for culturing erythroid precursors clearly established that androgens had a direct effect on these cells, and strongly suggested that these actions were mediated by a nuclear androgen receptor [80]. Several studies have investigated the relationship between the androgen receptor content of human foreskin and agedependent physiological changes [81]. In these works, the androgen receptor was predominantly localized to the nuclear compartment at those development stages characterized by higher levels of circulating blood androgens, i.e. pubertal males and adults. By contrast, the androgen receptor was conned almost exclusively to the cytosolic compartment at stages of low plasma androgen levels. Therefore, it is possible to hypothesize that androgen administration produce changes in the intracellular distribution of androgen receptors that might explain the better response in elderly subjects. On the other hand, incubation of skin broblasts with androgens (dihydrotestosterone, mibolerone) produces a rise in the ratio of augmented to basal specic androgen binding [82]. Thus, it may be suggested that androgen administration might induce an increase in the androgen receptor binding activity. tion [83], ranging from a mild increase in sulfobromophthalein retention to a picture of cholestasis that may ocasionally result in hepatic failure [84]. Hepatic and splenic peliosis, not related to the dose or the lenght of treatment, can also occur during therapy with alkylated compounds [8486]. Finally, hepatocellular adenoma and carcinoma have been also described following long-term administration of 17-alkylated anabolic steroids [87, 88]. In contrast to the common hepatic complications after treatment with alkylated agents, the accumulated data show that non-alkylated androgens rarely cause liver disorders [7]. Adverse changes on serum lipid prole have been considered a classic side effect of androgen administration, which are in part conditioned by the type of compound. Thus, 17-alkylated agents induce hepatic triglyceride lipase activity resulting in highdensity lipoprotein (HDL) cholesterol subfraction2 (HDL2) reduction [89], whereas non-alkylated androgens have little effects on this enzyme with no signicant consequences on HDL cholesterol or apolipoprotein A-I [8992]. Nandrolone decanoate, a 19nortestosterone derivate, has been showed that does not produce signicant alterations of lipids in healthy individuals [93]. The effects of ND on the lipid prole in chronic HD patients have been recently evaluated by Teruel et al. [94]. The authors observed that ND produced an increase of apolipoprotein B levels and a decrease of both HDL cholesterol, due exclusively to a decline of the HDL2 , and lipoprotein(a) [Lp(a)]. A reduction of apolipoprotein A-I and an increment of triglycerides were also detected, but these changes were not statistically signicant. The most interesting nding in the study by Teruel et al. was the reduction of Lp(a), an independent cardiovascular risk factor in dialysis patients [95, 96]. Respect to basal values, median Lp(a) levels decreased by 64%, without correlation with the changes in the other lipidic parameters. Similar results have been recently reported by Gascn et al. [56], and furthermore, in this study Lp(a) decreased in patients receiving ND, but not in subjects treated with rHuEPO. In PD patients we have also and (Personal communication) that after ND therapy the serum levels of total cholesterol, LDL cholesterol and apolipoprotein A-I did not experience signicant variations. However, triglycerides increased whereas apolipoprotein B and Lp(a) decreased. The mean reduction of Lp(a) in our study was 41% respect to baseline.

Adverse effects of androgens The adverse effects of anabolic steroids are essentially due to their androgenic actions, and depend on the class of agent used, the dosage and the route of administration. In general, the dose of androgens used in dialysis patients to enhance erythropoiesis may be associated with undesired effects. Usual side effects have been reported mainly in adolescents, young men and women and consist of ushing of the skin and acne, hirsutism, deepening and hoarseness of the voice, masculinization, amenorrhea and increase in libido [7, 83]. Treatment with 17-alkylated androgens has been consistently associated with disturbances in liver func-

554 Finally, a potential deleterous effect of androgens on the prostate must be considered. Administration of ND to HD patients did not produce changes in the serum concentrations of prostatic acid phosphatase and prostate-specic antigen, suggesting that ND has not signicant effects on the prostate gland in these patients [97]. of primary renal disease or sex. However, a favorable therapeutic response is related to patients age, with the maximal response being observed in elderly subjects. Therefore, patients older than 50 years seem to be the ideal candidates to this therapy, whereas androgens must be avoided in young males and women. In spite of the growing knowledge on the use of androgens in clinical practice, several aspects need to be claried, such as the optimal schedule of administration (i.e, intermittently or as a continous low dose), the safety of the long-term use, the possible role of these drugs in pre-dialysis subjects and the denitive place that androgens may have in the therapeutic protocols for treatment of anemia (i.e., as an adjunctive therapy in combination with or as a sole treatment being an alternative to rHuEPO).

Conclusions Two decades ago, androgens were the main therapeutic option in the treatment of anemia associated to end-stage renal disease. After the introduction of rHuEPO during the late 1980s the use of these compounds has been almost anecdotic. The future respect to the use of these compounds in countries with adequate resources is pessimistic. In the report by the Anemia Work Group of the National Kidney Foundation Dialysis Outcomes Quality Initiative [98], this group stated that the potential risks of primary androgen therapy alone make this form of treatment unacceptable. However, in the recent workshop on the potential role for adjuvant therapy in patients treated with rHuEPO, it was concluded that androgens could be useful in combination with rHuEPO in countries where resources were limited [99]. Furthermore, despite the signicant reduction in the use of androgens and previous negative arguments, nowadays several authors continue using these agents in selected patients, with diverse studies showing their usefulness and safety. Moreover, androgens have been included as an important therapeutic option in the protocols for anemia in dialyzed patients, with similar results to those observed with the use of rHuEPO [50, 55, 56]. Several key issues must be taken into account before the application of these agents, such as the class of androgen and the characteristics of the patients. There are different androgenic compounds with specic properties, which determine their benecial actions and adverse effects. Nandrolone decanoate is the most extensive androgen used in the recent years, and nowadays, available data suggest that ND is likely the androgenic drug of choice to be administered to uremic subjects. Conversely, other compounds such as alkylated agents must be avoided. Characteristics of patients are also important in order to obtain the maximal benet from androgen administration. Results of previous studies suggest that the response of hematologic parameters is independent

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Address for correspondence: Juan F. Navarro, Nephrology Service, Hospital Nuestra Seora de Candelaria, E-38010 Santa Cruz de Tenerife, Tenerife, Spain Phone: +34 922 602-059; Fax: +34 922 602-349 E-mail: jnavarro@hcan.rcanaria.es

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