Potential risks

As to the risks of androgen replacement therapy in elderly men, we consider here only effects of "physiological" doses of testosterone and not those of massive "pharmacological" doses, as used by body builders. Traditionally, it has been a matter of concern that prolonged treatment with androgen may increase the risk of cardiovascular disease. The complex relationship between endogenous and exogenous androgens and cardiovascular risk is discussed in Chapter 10. With the evidence currently available, improving cardiovascular risk can certainly not be considered an indication for androgen treatment, but there is also no suggestion that treatment with moderate, close to physiological doses carries an unacceptable risk that should deter initiating otherwise indicated androgen treatment. It should be reminded that no conclusive data is currently available on the effects of androgen treatment on cadiovascular morbidity or mortality in elderly men.

Androgen treatment results in a significant increase of hematocrit and blood hemoglobin level (Gruenewald and Matsumoto 2003). Polycythemia is not uncommon and may necessitate dose reduction, temporary interruption of treatment, or alternative measures such as phlebotomy (see Chapter 13). Whereas a moderate increase in hematocrit in elderly males is probably beneficial, Hajjar et al. (1997) observed that out of 27 elderly hypogonadal males receiving 200 mg of testosterone enanthate or cypionate every two weeks, 11 (24%) developed polycythemia sufficient to require phlebotomy or temporary withholding of testosterone, one third of which occurred less than one year after starting treatment. Sih etal. (1997) reported a similarly frequent development of polycythemia. The occurrence of polycythemia appears to be more likely when subjects are exposed to markedly supraphysiological androgen levels, as is often the case with commonly applied treatment regimens, consisting of intramuscular administration of depot preparations of testosterone esters at intervals of two to three weeks (Dobs et al. 1999). Significant increases of hematocrit and hemoglobin levels are also seen during transdermal administration of either testosterone (Snyder et al. 1999b; Steidle et al. 2003) or DHT (Kunelius et al. 2002; Ly et al. 2001), occasionally leading to erythrocytosis. Monitoring for occurrence of exaggerated elevations of hematocrit or hemoglobin concentrations during androgen treatment in elderly men is advisable, keeping in mind that some patients, in particular some with pulmonary disease, can have a high a priori risk of erythrocytosis.

Androgens may exacerbate obstructive sleep apnea (Matsumoto et al. 1985; Sandblom et al. 1983). Therefore, patients should be specifically questionned for symptoms of sleep apnea, and chronic obstructive pulmonary disease, especially in overweight subjects or heavy smokers, who may be regarded as having a relative contra-indication for androgen therapy.

Gynecomastia, related to the conversion of testosterone to estradiol in peripheral tissues, mainly fat tissue, which is relatively increased in elderly men, is a not uncommon but benign side-effect in elderly men, especially in the obese. This side-effect is probably less frequent when avoiding exposure to largely supraphysiological serum levels of testosterone. Testosterone causes some sodium and water retention (Wilson 1988), this cannot cause a problem, except in patients with congestive heart failure, hypertension or renal insufficiency. Hepatotoxicity is very rare when non-oral routes of administration of testosterone are used.

Of greater concern are the possible effects on the prostate, which is an androgen dependent organ (Bhasin et al. 2003) (see Chapter 12). As far as benign prostatic hyperplasia (BHP) is concerned, studies to date failed to observe an important growth of the prostate (Behre et al. 1994; Wallace et al. 1993) and all studies have failed to find any relationship between plasma and BPH tissue levels of testosterone, DHT or estradiol. It appears that tissue levels are determined by the enzyme activity in the tissue itself, rather than by surrounding plasma androgen levels. Treatment does not seem to result in increased voiding symptoms or postvoid residual volume (Gruenewald and Matsumoto 2003), and only in cases of severe lower urinary tract obstructive symptoms is benign prostate disease considered a contraindication for androgen treatment (Bhasin etal. 2003; Morales 1999).

Clinical prostate carcinoma undoubtedly is an androgen sensitive tumor (Goldenberg et al. 1995): hence presence of a clinical prostate carcinoma is an absolute contraindication to testosterone supplementation. Subclinical carcinoma, only detectable on histology but undetectable by biochemical or clinical procedures, is found in a majority of men over 70 years old. Only a small minority of these subclinical carcinomas will develop further into a clinical carcinoma. It is not known whether testosterone treatment will stimulate the progression of subclini-cal carcinoma and so far no available data indicate that testosterone substitution will activate subclinical carcinoma (Schroder 1996; Jackson et al. 1989, see also Chapter 12). However, all studies so far concern only small numbers of carefully selected elderly males treated for short periods of time. In any case, before starting testosterone supplementation careful exclusion of the presence of a prostate carcinoma by rectal examination and serum PSA, and, when required, supplemented by ultrasonography, is mandatory. For treated patients it is advised to perform controls of rectal examination, PSA and a symptom questionnaire for benign prostatic hyperplasia after three, six and twelve months, thereafter yearly controls (Bhasin etal. 2003; Morales 1999).

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