Androgen treatment in hypogonadism and effects on erythropoiesis

As mentioned above, early studies in artificially hypogonadal rats demonstrated the positive effects of testosterone on erythropoiesis by withdrawal and substitution trials; androgen administration to healthy men can cause a marked increment in erythropoiesis (Kamischke et al. 2002; Palacios et al. 1983; Wu et al. 1996). Correspondingly, hypogonadal men very often present with markedly lowered concentrations of erythrocytes and/or hemoglobin, hence anemia. Indeed, anemia can be used as a diagnostic tool to evaluate whether a patient with borderline hypogonadism should receive androgen substitution therapy (e.g. Behre etal. 2000).

Various forms of androgen substitution can be used for treatment of male hypogonadism (see Chapter 10), ranging from oral testosterone undecanoate, to transdermal preparations, to long acting injected esters and testosterone implants. A parameter that assures the quality of androgen substitution is restoration of normal hemoglobin and erythrocyte concentrations. In addition, frequent assessment of red blood cell mass, hemoglobin content and also hematocrit is crucial in androgen therapy surveillance in order to detect overstimulation of the erythropoietic system resulting in polycythemia, which might cause adverse side effects (see below).

Therapy of hypogonadism with oral testosterone undecanoate (TU) (see Chapter 14) is effective in terms of restoring the red blood cell pool. This has been demonstrated in a mixed sample of men with primary or secondary hypogonadism receiving various treatment options (oral mesterolone, oral TU, injections with testosterone enanthate and implants with crystalline testosterone). Mesterolone, a non-aromatizable weak androgen did not have significant effects but such were demonstrated in those patients receiving oral TU: hemoglobin concentrations increased significantly (Jockenhovel etal. 1997). These effects were also seen for the other "full androgens" (see below). In agreement, the efficacy of oral TU to treat hypogonadism-related anemia was also demonstrated by a placebo-controlled trial in men with androgen deficiency and diabetes mellitus type 2 (Boyanov et al. 2003).

Concerning transdermal testosterone preparations and erythropoiesis, the effects of a non-scrotal transdermal patch system and intramuscular testosterone enan-thate for the treatment of male hypogonadism were compared in a randomized study involving sixty-six adult hypogonadal men who were randomly assigned to receive either transdermal patches (two 2.5-mg systems applied nightly) or testosterone enanthate (200 mg injected every 2 weeks). Both treatment modalities stimulated erythropoiesis significantly. In patients receiving treatment with testosterone enanthate causing markedly higher serum concentrations of testosterone, abnormal hematocrit elevations (43.8% of patients) were seen more frequently compared with patch-treated men (15.4% of patients) (Dobs et al. 1999). Corresponding effects were also seen in 227 hypogonadal men receiving androgen substitution via the transdermal testosterone gel system in two different doses. Marked elevations in red blood cell mass were observed in a dose-dependent manner: those patients receiving the higher gel dose of 100 mg per day vs. those receiving 50 mg per day exhibited a significantly stronger increase in hemoglobin concentrations. Nevertheless, effects reached a plateau after several weeks of treatment (Wang et al. 2000). The significant positive effects of the intramuscularaly injected testosterone enanthate on erythropoiesis in hypogonadal men, a substance used for 50 years, have been mentioned above (Dobs et al. 1999; Jockenhovel et al. 1997). A trial in 60 artificially hypogonadal men receiving androgen ablation by administration of a long-acting GnRH agonist and following treatment with various doses of intramuscularly injected testosterone enanthate demonstrated a non-linear dose-dependent effect on erythropoiesis (Bhasin et al. 2001). Nevertheless, a recent non-human primate study comparing the effects of various intramuscularly injected testosterone esters (testosterone undecanoate, enanthate or buciclate) demonstrated that pharmacokinetics of these different preparations also have a differential influence on androgen target tissues. Despite the higher total dose of testosterone enanthate, effects on erythropoiesis were not different from those observed in the long-acting esters which provided a much more stable environment of elevated androgen concentrations (Weinbauer et al. 2003).

As mentioned above, testosterone undecanoate is also available as an injectable ester with quite favorable kinetics allowing injection intervals of up to 12 weeks (also see Chapter 14). This long-acting depot preparation has been investigated in several trials for androgen replacement therapy in hypogonadal men. The effects on erythropoiesis were significant but exhibited a moderate pattern, thus avoiding polycythemia (Nieschlag et al. 1999; von Eckardstein and Nieschlag 2002). This is confirmed by Chinese investigations using the same substance in a different vehicle (see Chapter 14): a marked increment in hemoglobin levels was demonstrated and was accompanied by a corresponding elevation of EPO levels (Cui etal. 2003).

The modality with the most prolonged kinetics used for androgen substitution therapy is the subdermal implantation of crystalline testosterone pellets (Handelsman et al. 1997) (see chapter 14). Stimulation of erythropoiesis is effective and is, due to rather high androgen concentrations during the first months after implantation, comparable to effects achieved by intramuscular testosterone enanthate (Jockenhovel etal. 1997).

The synthetic androgen 7a-methyl-nortestosterone (MENT, see Chapters 13 and 14) has been recently tested for its efficacy in substitution therapy of hypogonadal men. The substance, which exhibits a markedly decreased 5a-reduction rate in comparison to testosterone, was able to maintain erythropoietic effects achieved by testosterone enanthate during a run-in phase, albeit in a dose-dependent manner (Anderson etal. 2003).

As demonstrated by all studies on androgen substitution and erythropoiesis, there is a certain amount of variation among patients despite similar regimens. This may be attributable to genetically determined modulations of androgen effects, facilitated by androgen receptor polymorphisms, such as the CAG repeat polymorphism

(see Chapter 3). Whether this polymorphism exerts a similar influence on the efficacy of testosterone therapy on erythropoiesis as has been demonstrated for prostate tissue (Zitzmann etal. 2003), remains speculative.

A mechanism by which androgen effects on erythropoiesis may be counter-regulated is the negative feedback by the red cell mass on EPO production, which is facilitated via the renal oxygen sensor (Lacombe etal. 1991). One could speculate that this oxygen sensor has different thresholds in various patients, which could explain the differences in dose-response-relationships of erythropoiesis to androgen exposure in men. In addition, due to cardiac insuffiency or chronic pulmonary diseases resulting in lower oxygen supply in target tissues, the development of polycythemia under androgen therapy might be promoted. Especially these patients would be put at risk due to increased blood viscosity (see next section). Finally, androgen therapy may also be useful in treatment of anemia of non-gonadal origin. See Section 15.3 for a review of publications.

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