Testosterone and Ageing: What Have We Learned Since the Institute of Medicine Report and What Lies Ahead?

M. M. Miner; A. D. Seftel


Int J Clin Pract. 2007;61(4):622-632. 

In This Article

Prostate Health

The IOM report concluded that there was no clear evidence of a link between testosterone levels and benign prostatic hypertrophy (BPH).[1] However, a major safety concern raised by the IOM report was the potential risk of prostate cancer during testosterone replacement therapy. Based on available evidence at that time, the panel concluded that 'the influence of testosterone on prostate carcinogenesis and other prostate outcomes remains poorly defined, but could greatly influence the risk-benefit ratio for supplementation in both young and elderly populations'.[1] The primary source of concern about prostate cancer arose from animal studies and anecdotal case reports, which cannot be extrapolated to determine whether testosterone replacement therapy increases risk relative to the high background incidence of prostate cancer in ageing men. For example, a recent review of the files of six urologists revealed 20 cases of clinically significant prostate cancer during testosterone therapy,[9] but the total number of patients receiving testosterone replacement therapy and the incidence of prostate cancer in the absence of testosterone replacement therapy were not provided for comparison.

The IOM panel also reported that higher endogenous testosterone concentrations may be associated with less aggressive forms of prostate cancer,[1] and recent clinical studies have supported this conclusion. Examination of total testosterone concentrations in men with localised prostate cancer showed that pretreatment concentrations were lower among men with non-organ confined cancer than among those with organ-confined cancer.[10] Similarly, evaluation of total testosterone before radical prostatectomy for clinically localised cancer revealed that lower preoperative testosterone concentrations were associated with advanced pathological stage.[11] Finally, a retrospective study determined that poorly differentiated prostate cancer was associated with significantly lower testosterone concentrations.[12] Thus, it seems that low serum testosterone may portend a more aggressive degree of prostate cancer.

Comparative trials have revealed no consistent effect on prostate outcomes. A recent meta-analysis of 19 randomised, double-blinded, controlled clinical studies evaluated the safety of > 3 months of testosterone therapy in 651 men ≥ 45 years of age.[13] Testosterone-treated men were 1.78-fold more likely than men in the placebo groups to have any prostate event. However, the 'prostate event' was largely attributable to the increase in prostate biopsy rates during testosterone replacement therapy (odds ratio, 1.87) caused by a rise in serum prostate-specific antigen (PSA) (odds ratio, 1.19). In this meta-analysis, the risks of individual events and the risk of prostate cancer (odds ratio, 1.09) did not increase significantly during testosterone replacement therapy.

Because of concerns about prostate health, randomised trials of testosterone replacement therapy have not been performed in men with a history of prostate cancer. A retrospective analysis of hypogonadal men who underwent prostate biopsy prior to testosterone replacement therapy revealed no increase in the risk of prostate cancer in men with vs. those without prostatic intraepithelial neoplasia at baseline.[14] Two recent reports in a limited number of hypogonadal men with a history of organ-confined or locally advanced prostate cancer provided no evidence of cancer recurrence with long-term testosterone replacement therapy.[15,16]

Nor have recent clinical studies demonstrated an abnormal effect of testosterone replacement therapy on PSA levels.[17,18,19,20] A non-comparative analysis of hypogonadal men who received open-label testosterone replacement therapy for 36 months, after initially participating in a 6-month controlled trial, found no effect of long-term testosterone replacement therapy on PSA levels.[17] Similarly, a study of 187 men with erectile dysfunction reported that testosterone replacement therapy for 1 year did not increase PSA.[18] A retrospective study of men receiving testosterone replacement therapy reported that changes in PSA were not influenced by the mode of testosterone replacement therapy, patient age, or baseline levels of PSA or testosterone.[19] In a recent randomised clinical trial, use of a testosterone gel or a testosterone patch for 24 weeks in 162 hypogonadal men did not result in significant changes from baseline in either PSA or prostate volume.[20] Increases in PSA of < 0.5 ng/ml/year are expected in hypogonadal men during testosterone replacement therapy, particularly elderly men receiving testosterone replacement therapy.[21] Hypogonadal men have depressed PSA levels compared with eugonadal age-matched men – androgen suppression with finasteride has been shown to reduce serum PSA 2.2-fold[22] – so regression to the mean is expected for PSA levels during testosterone replacement therapy. Prostate health should be monitored closely before and during testosterone replacement therapy, including assessment of PSA level, documentation of voiding history and digital rectal examination (DRE) to rule out nodules, asymmetry or areas of increased firmness.[23] The value of performing both DRE and PSA testing during testosterone replacement therapy was supported by 20 case reports of prostate cancer; 25% of patients presented with elevated PSA alone, 35% with abnormal DRE alone and 40% with both abnormalities.[9]

The rate of change in total PSA, or PSA velocity, is more predictive of prostate outcomes than is a single PSA measurement; indeed, prostate cancer can develop in men with PSA values < 4 ng/ml.[23] Although specific recommendations vary, most experts agree that clinicians should perform baseline DRE and PSA before starting a patient on testosterone replacement therapy, and PSA should be checked again within 3-6 months, regardless of the route of administration of testosterone.[21,23,24,25] PSA should then be monitored semi-annually as long as the patient remains on testosterone replacement therapy, in addition to annual or semi-annual DRE.[23,26] Typically, a PSA velocity > 0.75 ng/ml/year (regardless of the baseline PSA) or a nodule on DRE during testosterone replacement therapy should prompt further evaluation by a urologist and possible prostate biopsy.[23] However, the optimal frequency of monitoring and cutoff points, both for referral to urology and prostate biopsy, remain somewhat controversial. This ambiguity is reflected in the various PSA cutoff points that have been suggested, ranging from > 0.4 to > 1.5 ng/ml/year, depending on how many years of observation are considered ( Table 4 ).[21,23]

In summary, evidence for an association between testosterone replacement therapy and prostate cancer is still inconclusive. That said, no new prostate safety issues have been reported in studies published since the IOM report, including studies of men at highest risk for prostate cancer. These data continue to provide reassurance that at present, there is no conclusive evidence to link hypogonadism and testosterone replacement to worsening of BPH symptoms or to the development of prostate cancer.


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