Potential Adverse Effects of Androgen Therapy
By by Dana Ohl, M.D. Associate Professor of Surgery University of Michigan
Hepatotoxidty
As mentioned above, the oral, alkylated forms of testosterone can create a situation of liver toxicity (Semin Liver Dis 7:230, 1987; Liver 42:73, 1992). Since I believe that these oral agents should never be given, this problem can in general be circumvented. There is little evidence that other methods of administration cause liver dysfunction, but I think it is prudent that in men on testosterone therapy, liver function tests be performed at approximately six month intervals.
Water retention
Androgen therapy can cause water retention, with the fear of exacerbation of hypertension or inducing or worsening congestive heart failure in older men undergoing such therapy. Weight gain thought to be due to water retention has been demonstrated ( J Clin Endocrinol Metab 75:1092, 1992; JAm Geratr Soc 41:149, 1993), but no study has shown clinically significant pathology due to this retention.
Erythropoiesis
Androgens cause an increase in hematocrit. Two~studies showed a rise in hematocrit between 3.6 and 7.0% in older men receiving T supplementation (J Clin Endocrinol Metab 75:1092, 1992; J Am Ceratr Soc 41:149, 1993). Typically this rise in hematocrit, although measurable, is not clinically significant. Since many older men are also anemic prior to testosterone therapy due to their hypogonadism and/or aging/nutritional changes, the rise in hematocrit may be beneficial.
Sleep apnea
Sleep apnea may be worsened in men on testosterone therapy (Clin Endocrinol (Oxf) 22:713, 1985). This may be due to changes in tissue surrounding the posterior pharynx. Therefore, if there is a clinical history of sleep apnea in a man considered for T therapy, this should be investigated and treated prior to institution of therapy.
Changes in plasma lipoproteins
This area is perhaps one of the more controversial areas in testosterone replacement therapy. The differences in incidence of atherosclerotic vessel disease between men and women has been ascribed to hormonal differences. Since HDL levels begin to drop in males coincident with the rise of testosterone seen at puberty, the evidence has been compelling. However, a large review of studies that attempted to compare HDL levels with circulating T levels failed to reach. the conclusion that T level is correlated with lower HDL (Diabetes Metab 21:156, 1995). In fact, most of the evidence shows that higher endogenous T levels are associated with a higher HDL, and presumably a lower cardiovascular risk.
This data has been interpreted by some clinicians to indicate that testosterone replacement therapy will cause beneficial changes in HDL. However, when one looks at multiple studies regarding replacing testosterone- in- men who are hypogonadal, a mix of results are seen. Administration of alkylated testosterone derivatives causes a substantial reduction in HDL-C (JAMA 261:1165, 1989). This further adds to the recommendation that these drugs should not be given. When parenteral T esters are administered in weekly 100 mg injections, no change is generally seen, but there is a significant decline in HDL when 200 mg injections are given every 2 weeks (Metabolism 42:446, 1993; Ann Intern Med 116:967, 1992; JAMA 261:1165, 1989). Data on patch therapy is still being generated.
I think it is safe to say that one should view this issue with caution. It would be prudent to get a fasting cholesterol/HDL profile on all hypogonadal men in whom androgen replacement therapy is being suggested and then another profile at three months to look for these potentially unfavorable changes.
Prostatic changes
It is clear that without androgens present, prostatic pathology does not develop. Prostatic cancer and benign prostatic hyperplasia never develops in eunuchs. Prostatic diseases represent very clinically significant problems in the elderly and the effect of androgen replacement therapy on the prostate needs to be very carefully considered.
The prostate increases in size during androgen replacement therapy in older men (J Clin Endocrinol Metab 75:1092, 1992). Therefore, symptomatic prostatism may potentially become worse with androgen therapy. Because of this one needs to take a careful voiding history prior to initiation of therapy to uncover such problems.
Prostate cancer has never been proven to be associated with androgen replacement therapy. While there are scattered case reports of development of prostate cancer while on such therapy it is commonly accepted that prostatic cancer which is present (and may be occult when considering androgen replacement therapy) will probably be accelerated by elevation of the serum androgens. In this way an occult prostatic cancer may become apparent during therapy. Surveillance for prostate cancer development and growth is essential during therapy.
Infertility
Via suppression of the hypothalamic-pituitary-gonadal axis, administration of exogenous androgens results in suppression of spermatogenesis. In many cases, this will lead to complete azoospermia. Indeed, administration of testosterone as a contraceptive agent has been proven to be effective in recent multi-center studies (Lancet 336:955, 1993). Therefore, in all men who are considering treatment of hypogonadism, and in whom fertility is a concern, exogenous androgens must not be given.
