Prostate CancerDihydrotestosterone Levels and Survival in Screening-Detected Prostate Cancer: A 15-yr Follow-up Study
Introduction
With a growing number of patients diagnosed with prostate cancer, more men are receiving surgery or radiation therapy with curative intent. Both methods are considered effective but have side effects that may negatively affect the quality of life [1], [2]. Studies have demonstrated that many cases of prostate cancer have a low risk of progression, even when left untreated [3], [4], [5]. To prevent unnecessary side effects of treatment as well as to increase cost-effectiveness, there is a need for markers with higher predictive value to distinguish those who would benefit from treatment from those who would not. An increased knowledge of the etiology of prostate cancer is also important to develop effective primary and secondary prevention measures.
Androgens are instrumental in the differentiation and maturation of the male reproductive organs and the development of male secondary sex characteristics [6]. There is established evidence that androgens promote the development of prostate cancer [7], [8]. This relationship is not explained by a simple dose-response pattern, but instead a saturation model is more adequate. In such a model, a certain amount of androgen is needed for cancer growth, but higher levels do not contribute to cancer development and can even have the opposite effect [9]. In vitro androgens have been shown to increase the production of insulin-like growth factor-I (IGF-I), having a potential paracrine effect on prostate epithelial cells [10]. Several studies have assessed the potential association between serum levels of androgens and the risk of developing prostate cancer, but no simple mechanistic relationship has yet been found [11]. Other studies have tried to establish a correlation between the androgen level and the pathological stage of the cancer [12].
Testosterone is the principal androgen in the circulation, and the main intracellular androgen in the prostate is dihydrotestosterone (DHT) [13]. DHT arises primarily from intraprostatic conversion of testosterone by 5α-reductase and binds to the intracellular androgen receptor with an affinity several-fold higher than testosterone. The DHT androgen-receptor complex seems to be the main regulator of fundamental prostatic function [14], [15]. In one theoretical model, DHT was suggested to protect the cell from apoptosis by binding to the intracellular androgen receptor [16].
Weihua et al. [17] hypothesized that DHT protects the prostate from development of high-grade cancer. The mechanism behind this somewhat paradoxical idea is that oestrogen receptor β (ERβ), which inhibits epithelial growth in prostatic tissue, is activated by 3-β-androstanediol (3βAdiol), a metabolite of DHT. Low levels of DHT would thus lead to low levels of 3βAdiol and less binding to ERβ, which in turn leads to loss of growth inhibition and tumour progression. To assess these hypotheses, we evaluated serum-DHT levels at the time of prostate-cancer diagnosis in relation to survival in a cohort of screening-detected patients with 15 yr of follow-up.
Section snippets
Methods
The study was approved by the local ethical committee at Karolinska Institutet. A population-based screening study of 1782 men aged 55–70 yr was undertaken from 1988 through 1989 [18]. Participants were examined with digital rectal examination (DRE), transrectal ultrasonography (TRUS), and prostate-specific antigen (PSA). If they had abnormal findings on DRE and/or TRUS, they underwent TRUS-guided biopsies. If PSA level was over 7 ng/ml, a new TRUS was performed. If the PSA level was over 10
Results
The median age at diagnosis was 65 yr (range: 55–71 yr). Median follow-up time of subjects was 12.8 yr (range: 1.1 to 15.3 yr). Among the 65 men with prostate cancer, 41 had died by the end of follow-up. Seventeen of the 41 deaths were attributed to prostate cancer. Table 1 presents univariate characteristics of the cohort.
Patients with DHT above the median had a significantly better survival rate than those with DHT below the median (log rank p = 0.0075; Fig. 1). No such association was found
Discussion
To our knowledge, there is no previous study on the outcome for screening-detected prostate cancer patients related to hormone levels. The results indicate that a low DHT level may be a promoting factor in the progression of prostate cancer. Our data also suggest that serum DHT may be a prognostic factor in prostate cancer, although it remains to be elucidated whether DHT has any prognostic value beyond that of PSA.
Although statistical power was low in this study due to small numbers of
Conclusions
This study provides evidence of an association between low DHT and decreased survival in prostate cancer patients. It remains unclear whether DHT at diagnosis has any prognostic value beyond that of PSA and PSA velocity. PSA levels merely reflect tumour stage and grade, whereas DHT may play an etiological role in the progression of the tumour.
Conflicts of interest
The authors have no conflict of interest in connection to this paper.
Acknowledgements
The authors thank Drs Michael Häggman, Hans Wijkström, and Lennart Öst for their contribution in evaluating causes of death. The study was supported by the Stockholm County Council, the Thure and Brita Grafström Foundation, and a grant from Odd Fellows 164 Södertälje.
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