Prostate‐specific Antigen Testing in Hypogonadism: Implications for the Safety of Testosterone‐replacement Therapy

Abstract

Hypogonadal men have lower prostate volumes and serum prostate-specific antigen (PSA) levels than age-matched controls. When present, prostate cancer in hypogonadal men is more aggressive than in eugonadal men, and given the lack of specificity of PSA for diagnosing prostate cancer, a more accurate test would be desirable in hypogonadal men. Once testosterone-replacement therapy is started in hypogonadal men, PSA levels should be measured regularly; however, there is often an initial rise 3-6 months after starting treatment. A rise of > 0.5 ng/mL within this time requires further investigation. KEYWORDStestosterone, hypogonadism, PSA, prostate cancer, uPM3 INTRODUCTIONThe presence of prostate cancer is an absolute contraindication to testosterone therapy, as was recognised long before the era of PSA testing. Serum PSA levels relate to prostate cancer risk, but PSA expression is itself androgen-dependent; therefore, in hypogonadal men an altered relationship between PSA and prostate cancer might have significant implications for early cancer detection.While the prevalence of prostate cancer increases with age, particularly for men aged > 50 years, testicular function and serum testosterone levels decline. Total and free testosterone levels begin to fall during the third and fourth decade and thereafter decline by ≈ 1% and ≈ 2% per year, respectively. Conversely, sex-hormonebinding globulin levels increase with age, and this reduces the proportion of bioavailable testosterone.Prostate cancer and late-onset hypogonadism (LOH) often coexist, although both are often unrecognized and undiagnosed in advancing age. It is far from clear that this association is safe for the individual. Post-mortem studies indicate that most small low-grade foci are not pathologically significant, however pathologically significant tumours may co-exist. The concept of pathological insignificance indicates that some lesions do not correlate with the natural history of clinical disease. Regardless of their significance, small malignant lesions are likely to express features indicating testosterone sensitivity retained from the characteristics of the normal prostatic epithelium from which they are derived. In clinical disease, due to tumours that are by definition pathologically significant, the epithelium has undergone a pattern of molecular aberration that establishes the capacity for malignant, particularly metastatic, behaviour. This process of true malignant transformation is likely to be quite different, in molecular initiation and molecular progression, from processes giving rise to lesions that are characterised by quiescence despite androgen sensitivity. Thus, testosterone alone appears to be insufficient for inducing a more aggressive phenotype. Consistent with this, testosterone therapy does not appear to increase the cancer rate in men with highgrade prostatic intraepithelial neoplasia (PIN) [1], a lesion that is considered premalignant. Conversely, observational data in men with clinically significant tumours links hypogonadis...

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