European Urology European Urology 46 (2004) 285–295 Review PreventionofProstateCancerbyAndrogens: ExperimentalParadoxorClinicalReality Miche `le Algarte ´-Ge ´nin a , Olivier Cussenot a,b,* , Pierre Costa c a CeRePP/EA3104, UFR Biome ´dicale, Universite ´ Paris 5/Paris 7, France b De ´partement d’Urologie, Ho ˆpital Tenon (AP-HP), 4 rue de la Chine, 75020 Paris, France c Urologie, Ho ˆpital G. Doumergue, Nı ˆmes, France Accepted 1 April 2004 Available online 10 May 2004 Abstract Androgen replacement therapy in the aging male with partial androgen deficiency improved quality of life. However, such treatment is prohibited for men with a preexisting prostate cancer. The possibility of an increased risk of prostate cancer for healthy men has also been suggested on theoretical basis but recent experimental data showed that androgens may act in prevention of prostate cancer. In this review, we try to evaluate benefits and risks associated to a hormonal replacement therapy in regard to recent data. Several studies analyzing the role of testosterone for prostatic epithelial cells evidenced that testosterone acts in prostatic cell differentiation but does not have a direct role for induction of cell proliferation. Moreover, clinical studies have shown that low free testosterone levels in serum is associated with aggressive prostate cancer, like that has been observed in men with prostate cancer under prostate cancer chemo- prevention by finasteride. These data suggest that an androgen pathway disruption in prostate is responsible of cell deregulations that may be associated not only with apoptosis of differentiated prostatic cells but also with potential cell transformation. The effects of androgens withdrawal for prostate cancer therapy induced in a short time the tumor arrest growth. However with time, cells adapt to low levels of androgens leading to the evolution of an androgen-independent tumor, which is more aggressive and most often fatal. The molecular mechanisms of this evolution begin to merge. A hypothesis is that such mechanisms could be initiated in elderly men with an androgen deficiency. The question is raised of whether hormonal replacement therapy could prevent prostate cancer. An encouraging recent study performed on rats demonstrated a protective effect of DHEA for prostate cancer. However, the putative role of the normalization of DHEA or other androgen levels in prevention of prostate cancer should be evaluated in clinical trials. # 2004 Elsevier B.V. All rights reserved. Keywords: Androgens; Hormonal replacement therapy; Prostate cancer; Prevention; Androgen receptor; Androgen antagonists; 5a-reductase inhibitors 1. Introduction Testosterone levels decrease with age and elderly men present a partial androgen deficiency. The evolution of androgen deficiency has been estimated to be 16.2% (40–49 years), 20% (50–59 years), 22.6% (60–69 years) and 26% (80 years and more). Testosterone deficiency is associated with multiple deregulations that can lead to symptoms as decreased libido, loss of muscle mass, osteoporosis, decreased cognitive ability and depres- sion. Multiple studies have demonstrated that the rees- tablishment of normal hormonal levels improves quality of life and decreases symptoms associated with the loss of androgens. However, it has been reported that andro- gen replacement therapy increased the growth of already existing prostate carcinoma, meaning that before prescription, patients should be carefully screened to detect the presence of a preexisting tumor. However, for healthy patients, the question is raised of whether androgen replacement therapy could induce * Corresponding author. Tel. þ33-1-56-01-64-95; Fax: þ33-1-56-01-73-06. E-mail address: olivier.cussenot@tnn.ap-hop-paris.fr (O. Cussenot). 0302-2838/$ – see front matter # 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2004.04.012