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e u r o p e a n u r o l o g y 5 5 ( 2 0 0 9 ) 5 4 3 – 5 4 5 a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m j o u r n a l h o m e p a g e : w w w . e u r o p e a n u r o l o g y . c o m Referring to the article published on pp. 533–542 of this issue Oestrogens and Prostate Cancer: Novel Conceptsabout an Old Issue Department of Urology, Vita-Salute University, Milan, Italy In recent years, several studies have focused on cancer than the level of serum-circulating steroid the association between androgens and prostate hormones. This may be one of the reasons explain- ing the reported lack of association between serum needed for prostate growth and differentiation. What it is still unclear is whether patients with higher levels Besides androgens, there is now an increasing of serum androgens are at higher risk for prostate body of evidence suggesting a key role played by cancer. Indeed, although there is evidence in favour oestrogens in the intraprostatic abnormal signalling of an association between androgens and prostate involved in the development of prostate cancer, as carcinogenesis in animal models , some studies extensively addressed in the excellent review by failed to demonstrate a direct association between Bonkhoff and Berges . Intraprostatic presence of serum androgens and prostate cancer risk oestrogens in addition to androgens is key for In a recent meta-analysis including 18 prospec- prostate carcinogenesis. Aromatase-knockout mice, tive studies reporting data on serum concentrations which cannot produce oestrogens locally, are prone of sex hormones, no associations were found to developing benign prostatic hyperplasia (BPH); between serum concentrations of endogenous conversely, they do not develop prostate cancer androgens and the risk of prostate cancer Never- Moreover, prostate cancer developed more rapidly theless, androgen serum level might not correspond when oestrogen was administered in addition to to the same level found within the prostate. Previous testosterone in rats In contrast, prolonged studies showed a weak correlation between serum treatment with DHT only resulted in BPH .
and intraprostatic androgen levels .
In humans, a novel oestrogen receptor-depen- Moreover, although testosterone is the major dent mechanism has been shown to regulate circulating androgen, it is mainly dihydrotestoster- TMPRSS2:ERG expression, which is associated with one (DHT) that is found in tissues. Furthermore, more aggressive prostate cancer variants. Interest- testosterone is also converted within the prostate ingly, expression of TMPRSS2:ERG decreased after into oestrogens by the enzyme aromatase. Interest- oestrogen receptor b (ER-b) agonist treatment (0.43- ingly, when only intraprostatic hormone levels are fold difference) and increased after oestrogen considered, higher androgen concentrations are receptor a (ER-a) agonist treatment (4.63-fold found in the prostates of patients with prostate difference) . Therefore, even in the prostate, the effect of oestrogens is extremely different concentration of androgens within the prostate according to the subtype of oestrogen receptor might be more indicative of the risk of prostate DOI of original article: 10.1016/j.eururo.2008.10.035 0302-2838/$ – see back matter # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved. e u r o p e a n u r o l o g y 5 5 ( 2 0 0 9 ) 5 4 3 – 5 4 5 How can all of these concepts be applied in a Historically, oestrogens have been considered human model of prostate carcinogenesis? Recently, protective against prostate cancer and have been Singh et al speculated that oestrogens might be used as a second-line therapy for the treatment of considered as initiating drivers of prostate cancer advanced cases. Such effect is mainly associated development and progression. They postulated a with negative feedback on the hypothalmo–pitui- model in which several factors such as ageing, tary–gonadal axis, leading to a state of chemical obesity, diet, environment, and use of 5-a reductase castration. In view of the new findings involving inhibitors may significantly modify the oestrogenic oestrogens and ER activity in prostate carcinogen- status of men, resulting in a reduction in the bio- esis, a reasonable approach would be to selectively available testosterone whilst increasing the oestra- interfere with oestrogen activity through selective diol (E2)–testosterone ratio. This imbalance of modulation of ER activation. This strategy may be oestrogens and androgens in favour of oestrogens theoretically applicable to prostate cancer preven- might be responsible for either receptor- or non– receptor-mediated mechanisms involved in pros- In this context, selective ER modulators (SERMs) tate carcinogenesis. According to this model, oes- trogens would represent the initiating factor in the peculiarity of this class of drugs would reside in the development of prostate cancer. Although several ability to selectively modulate the activity of ER aspects of this model need to be elucidated and isoforms, which act in opposite directions and many steps might be more complex than a simpli- promote either prostate proliferation (ER-a) or fied scheme, these concepts have opened new doors differentiation (ER-b). SERMs may act as ER ago- in the field of prostate cancer prevention.
nists or antagonists in a dose- and tissue-depen- We are all aware of the results of the highly cited dent manner. In the prostate, toremifene has been Prostate Cancer Prevention Trial (PCPT). Within the shown to mediate action though a selective PCPT, finasteride reduced prostate cancer prevalence modulation of ER-a, if given at lower doses. In by 25%. Concurrently, a higher rate of high-grade preclinical studies, toremifene was able to prevent prostate cancer (Gleason sum 7–10) was seen in prostate cancer in the transgenic TRAMP mouse finasteride-exposed men (37.0%), relative to the model . Similarly, the use of toremifene was placebo group (22.2%, p < 0.001) . This increase able to prevent prostate cancer in men with high- in high-grade prostate cancer stirred many contro- grade prostatic intraepithelial neoplasia in a versies, and several explanations have been pro- double-blind, placebo-controlled, phase 2b clinical posed. Among these, only two focused on the trial Interestingly, no significant side effects finasteride-induced abnormal intraprostatic hormo- were associated with toremifene treatment. More- nal milieu. The first postulated that the higher rate of over, toremifene had only a modest impact on high-grade prostate cancer found in men exposed to serum androgen levels. A large, multicentre, phase finasteride might be due to increased intraprostatic 3 pivotal clinical study is currently ongoing to levels of testosterone, which may rise 10-fold under further define the profile of the 20-mg dose of finasteride. This might directly or indirectly promote toremifene in decreasing the incidence of prostate (through increased oestrogen levels following testos- cancer. Finally, toremifene has been shown to terone aromatisation) the development of high-grade decrease the side effects of androgen deprivation prostate cancer . The second explanation focused on decreased activity of ER-b, which is key for In conclusion, there is currently increasing prostate differentiation and cellular homeostasis of evidence on the role of oestrogens in prostate cancer the prostatic epithelium. It has been suggested that finasteride, by blocking the conversion of testoster- advances in understanding of the mechanism of one to DHT, inhibits the production of a steroid, 5a- action of oestrogens within the prostate, the com- androstane-3b,17b-diol (3b-androstanediol), a meta- plex intraprostatic interaction between oestrogens bolite of DHT. Interestingly, 3b-androstanediol has all and androgens as well as their (combined) effect at the characteristics of the natural ligand for ER-b, the genomic level remains to be ascertained. The which would translate into decreased ER-b activity, elucidation of the mechanisms of action of oestro- thus suppressing and preventing the differentiation gens in the prostate carcinogenesis will likely spur of epithelium . Although these intriguing biologic novel strategies in the fields of prostate cancer explanations may be speculative, they cannot be completely refuted, despite the results of a recentpathologic review of PCPT high-grade cases .
Conflicts of interest: The author has nothing to disclose.
e u r o p e a n u r o l o g y 5 5 ( 2 0 0 9 ) 5 4 3 – 5 4 5 aggressive prostate cancer. J Natl Cancer Inst 2008;100:815–25.
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