Dihydrotestosterone Levels and Survival in Screening-Detected Prostate Cancer: A 15-yr Follow-up Study

Abstract

Objectives

It has been hypothesized that dihydrotestosterone (DHT), the main intracellular androgen in the prostate, affects prostatic tumour progression. In this study, we evaluated serum DHT levels at the time of prostate-cancer diagnosis in relation to survival.

Methods

Sixty-five screening-detected patients diagnosed in 1988–1989 were followed for 15 yr. DHT levels at the time of diagnosis were determined through radio-immuno assay. Subjects were followed up through the nationwide tax register. Medical records of all dead subjects were reviewed, and cause of death was established by an endpoint committee. Data were analyzed through Kaplan-Meier estimation and Cox proportional-hazards regression.

Results

Seventeen of 41 deaths in the cohort during follow-up were attributed to prostate cancer. Patients with DHT above the median had a significant better prostate-cancer-specific survival than those with DHT below the median (log rank p = 0.0075). In the univariate analyses, one unit increase in DHT was associated with a hazard ratio (HR) of 0.14 (95% CI = 0.02–0.93). In the multivariate model, including prostate-specific antigen level, the association between DHT and prostate-cancer-specific survival was not significant (HR = 0.18; 95% CI = 0.02–1.6). DHT level below the median remained significantly associated with decreased survival in the multivariate model (HR = 0.23; 95% CI = 0.06–0.90). No association was found between DHT level and hazard of dying from causes other than prostate cancer.

Conclusions

Although the prognostic value of DHT levels at diagnosis remains unclear, these results provides evidence of an association between low DHT and decreased survival in prostate cancer patients.

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.