Among men randomized to the placebo group in the PCPT, there were no associations of baseline levels of estrogens with prostate cancer risk. Among those randomized to the finasteride group, high estrogen levels at baseline were associated with a moderately increased risk of low-grade but not high-grade prostate cancer. Serum concentrations of both estrone and estradiol increased modestly following finasteride treatment; however, this increase was not associated with prostate cancer risk.
Previous epidemiologic studies provide inconsistent results on the relationships between circulating levels of estrogens and prostate cancer risk. While most studies found null associations [19
], which may have driven a same conclusion in several meta- and pooled-analysis [3
], three studies showed reduced risk among those with high estrogen levels [13
]. In contrast, a recent case-cohort study with 275 prostate cancer cases reported an increased risk among those in the highest 3 quartiles of estrone levels, but there were no associations with estradiol levels [27
]. This inconsistency may be due to the balance of the opposing effects of estrogens in the prostate, and the lack of assessment of estrogen receptor activity in the prostate gland. It has been hypothesized that estrogens may play dual and opposing roles in prostatic homeostasis and carcinogenesis [28
]. Estrogens can cause abnormal proliferation, inflammation, and prostate malignancy, mediated by estrogen receptor α (ER-α), but they may also confer important beneficial effects, including anti-proliferation, anti-inflammation, and anti-carcinogenesis, mediated by ER-β. The balance between activities of the two ER subtypes may dictate prostatic responses to estrogens [29
]. The exact mechanisms for coordination between these opposing effects of estrogens and disruption during prostate carcinogenesis are unclear.
Among men in the finasteride group, high estrogen levels at baseline were associated with an increased risk of low-grade prostate cancer. It is possible that finasteride could modify the relationships between estrogens and prostate cancer risk, although a mechanism for this is not obvious. Alternatively, estrogen may modify the efficacy of finasteride for prevention of low-grade prostate cancer. Because of the nested case–control design, we could not distinguish these possibilities. This issue needs to be investigated in the entire PCPT cohort and would require measurement of serum estrogen levels from all participants, which is currently available only from cases and controls included in this nested study. We examined the linear correlations of baseline concentrations of estrone and estradiol with the change of 5α-androstane-3α,17β-diol glucuronide (3α-diol G), a metabolite of DHT that reflects concentrations of intra-prostatic DHT and thus indirectly measures the finasteride treatment effect, following finasteride treatment. There were significant inverse associations between baseline estrogens and change in 3a–dG (r
= −0.09 for estrone and r
= −0.11 for estradiol, both P
< 0.001). However, because the strength of these correlations was weak, it does not support a strong or direct effect of estrogens on finasteride treatment efficacy. It is also possible that the observed increased risk was biased by factors potentially related to estrogen. Estrogen concentrations are positively associated with obesity; however, the effects of finasteride on cancer risk did not differ by obesity [30
]. The possibility that whether other factors such as diet or physical activity modify the effects of finasteride treatment have not yet been evaluated.
Baseline estrogens may have been associated with high PSA and therefore bias in cancer detection; but there were no associations of estrogen concentrations with baseline PSA (Spearman correlation coefficient ranges from −0.08 to 0.05 in cases or controls from the placebo or finasteride arm, with or without adjustment for age and BMI). Lastly, we could not rule out the possibility that these findings were due to chance alone. However, the hypotheses were all a priori and the associations were observed consistently for estrone and estradiol with significant trends, which lower the likelihood of chance findings. Overall, we cannot explain the findings of a positive association of baseline estrogens with cancer risk in finasteride-treated men, which warrants further research.
We had hypothesized that the magnitudes of increases in estrogens following finasteride treatment may have increased prostate cancer risk. However, with only a single exception, neither the changes in estrogens nor the posttreatment estrogen concentrations were associated with cancer risk. There was a suggestive trend of increased risk of low-grade cancer with percentage increase in estrone; however, because the odds ratio contrasting extreme quartiles was not statistically significant and there was no association of absolute change with risk, we deem this as a chance finding. Moreover, the magnitude of changes in estrogens in the finasteride arm following treatment were modest (mean change, 4.6 pg/ml for estrone and 2.5 pg/ml for estradiol), compared to the inter-quartile differences in at baseline (for estrone, Q1 ≤ 35.5 pg/ml, Q4 > 53.2 pg/ml; for estradiol, Q1 ≤ 26.7 pg/ml, Q4 > 39.4 pg/ml). Thus, it is unlikely that changes in estrogens of these small magnitudes have physiological or clinical significance.
The study benefits from vigorous annual screening by DRE and PSA test, and an end-of-study biopsy offered to all men who were cancer-free at the exit of the study. These measures greatly reduced the likelihood of undiagnosed prostate cancer in the control group and minimize misclassification. Moreover, the PCPT adapted a centralized and standardized approach for cancer grading, minimizing misclassification. Other strengths include purification steps before RIA for estrogen measurement and a large sample size nested within a completed multi-center trial. However, several limitations should also be considered in this study. First, non-fasting blood samples were collected at different daily times and thus variations in estrogen levels throughout the day could not be controlled for; however, these variations were not likely to be systematically different between cases and controls [17
]. Second, circulating estrogens may not reflect intraprostatic levels [31
]. Local expression of aromatase and production of estrogen in the prostate further complicates the relevance of circulating levels to prostate cancer etiology [32
]. However, this issue is not specific to our study but common to all studies examining circulating biomarkers, and measurement of intra-prostatic hormone levels is currently not feasible for large-scale epidemiologic studies.
In summary, we found no evidence for an association of estrogen levels with prostate cancer risk among men not on finasteride. Among those taking finasteride, there may be a positive association of pretreatment estrogen concentrations and risk of low-grade prostate cancer; however, we know of no mechanisms that could explain such an association. These results add to a body of previous published studies finding no associations of circulating estrogen concentrations with prostate cancer risk. The moderate increase in risk of low-grade prostate cancer associated with high baseline levels of estrogen among men taking finasteride warrants further investigation.