In this prospective study, we found several significant associations between serum steroid concentrations and incident BPH. The most consistent findings were linear dose-response associations between higher 17β-diol-glucuronide levels controlled for testosterone and higher testosterone:17β-diol-glucuronide ratio and reduced BPH risk. High serum testosterone and estradiol levels were also associated with lower BPH risk; however, there was no dose-response. In analyses based on quartiles (quartiles 1–4) of testosterone, BPH risk was lower only in quartile 4 (vs. quartiles 1–3); in analyses based on quartiles of estradiol, BPH risk was lower in quartiles 2–4 (vs. quartile 1). Associations of testosterone, estradiol, and testosterone:17β-diol-glucuronide ratio with BPH risk did not differ by age, body mass index, definition of BPH endpoint, or time between baseline and BPH endpoint.
The hypothesis that serum steroids, particularly high levels of testosterone and/or estradiol, are associated with BPH risk has been studied for over 30 years. The study designs have included cross-sectional studies contrasting men undergoing surgery for BPH with hospital controls (11–24); cross-sectional studies contrasting men with and without clinically defined BPH (25
); cross-sectional studies correlating lower urinary tract symptom severity or prostate size with steroid concentrations (27
); and a single prospective study on the risk for BPH surgery (35
). The majority of these studies were only marginally informative about whether or not steroid concentrations affect BPH risk, either because the sample sizes were very small (e.g., <75 BPH cases) (11
) or because analyses were not adequately controlled for age (13
). We therefore focus the discussion below on studies that we believe contribute reliable information on steroids and BPH risk.
In our study, both high serum testosterone levels and the ratio of testosterone to 17β-diol-glucuronide were associated with reduced BPH risk, which is consistent with much of the published literature. Two studies have found that high testosterone is associated with reduced lower urinary tract symptoms (27
), and none have found high testosterone to be associated with increased risk. All studies that have examined the ratio of testosterone to 17β-diol-glucuronide (or dihydrotestosterone) have found that high levels of testosterone relative to 17β-diol-glucuronide are significantly associated with reduced risks of clinical BPH (25
), lower urinary tract symptoms (29
), or surgical BPH treatment (21
) or with smaller prostate size (34
). While confirmation in additional larger studies is warranted, the consistency of these findings makes it reasonable to assume that high levels of testosterone relative to 17β-diol-glucuronide are predictive of reduced BPH risk.
We propose 2 alternative interpretations of our findings on testosterone and the testosterone:17β-diol-glucuronide ratio: 1) these steroids are mediating factors that explain associations of genetic or environmental characteristics with BPH risk or 2) these steroids are serving as nonspecific measures of aging. A strong argument can be made for the mediating factor hypothesis, specifically that the effects of reduced 5-α-reductase activity are mediated through decreased tissue dihydrotestosterone and reflected by an increase in the serum testosterone:17β-diol-glucuronide ratio. This is supported by the well-established effects of 5-α-reductase inhibitors, which include reduced prostate tissue dihydrotestosterone (36
), serum dihydrotestosterone (37
), and 17β-diol-glucuronide (38
) levels and prostate size (4
) and increased levels of serum testosterone (37
) and estradiol (unpublished observation from the Prostate Cancer Prevention Trial). Thus, factors that reduce the activity of 5-α-reductase could be important determinants of BPH risk. There are known polymorphisms in the steroid 5-α-reductase type 2 (SRD5A2
) gene, the gene that codes for the predominant 5-α-reductase in prostate, which affect enzyme activity (39
). Few investigators have examined variants in SRD5A2
and BPH risk; in 2 studies, researchers found no associations (40
), in 1 they reported that the LL genotype of the V89L
variant was associated with increased BPH risk in Hispanic men (42
), and in 1 they reported an association of the same genotype with increased prostate volume (43
). Whether behavioral or environmental factors affect 5-α-reductase is unknown; however, the prospect is reasonable (44
). An equally strong argument can be made for an alternative interpretation that lower testosterone is simply a nonspecific indicator of aging. In our study sample of men without BPH at baseline, testosterone levels did not differ by age, which is in contrast both to what we have observed in the Prostate Cancer Prevention Trial population overall and to what we would expect based on the well-established decline in serum testosterone associated with aging (45
). There is some evidence that declines in serum testosterone are greater in men who develop clinical conditions associated with aging, such as diabetes and obesity (46
). Thus, older men without BPH may be men who are less affected by aging generally, which is reflected by a sustained serum testosterone level. Further research to identify genetic and environmental factors that affect both BPH and 5-α-reductase activity would be helpful in determining whether testosterone and the testosterone:17β-diol-glucuronide ratio are mediators or noncausal consequences of factors that affect BPH pathogenesis.
Whether or not there is a relation of estrogens with BPH risk remains uncertain. Gann et al. (35
) reported a positive association between estradiol and incident BPH surgery but only among men with low testosterone and only after controlling for estrone, which suggests that the strong collinearity of estrone and estradiol may have yielded an unstable statistical model. Rohrmann et al. (29
) reported a positive association of estradiol with lower urinary tract symptoms. In contrast, both we and others (26
) found that estradiol was significantly and negatively associated with BPH. The prostate expresses both estrogen receptor β (in epithelium, where it inhibits growth) and estrogen receptor α (in stroma, where it promotes growth). There is little evidence that estrogen receptor α has a role in BPH (47
), and thus a growth-inhibitory effect of estradiol could be consistent with reduced BPH risk. It is also possible that a high estradiol level simply reflects a high testosterone level, because estradiol in older men is almost exclusively formed by aromatization of testosterone. This picture is further complicated by observations in the Prostate Cancer Prevention Trial (48
) and other studies (49
) that abdominal obesity is a risk factor for BPH, because abdominal obesity also increases estradiol levels. Additional studies of the effects of estradiol on BPH pathogenesis are needed.
We examined whether insulin-like growth factors were mediators or confounders of the associations between steroids and BPH risk. This is because insulin-like growth factor binding protein 3 has been found to be associated with reduced BPH risk (52
) and because there are complex, although not entirely consistent, associations among insulin-like growth factors, insulin, testosterone, and androgen receptor activation (53
). Nevertheless, the associations of insulin-like growth factor binding protein 3, insulin-like growth factor 1, and steroids with BPH risk were unchanged when all of them were included in statistical models. We also examined whether associations of dietary patterns and obesity with BPH risk were mediated by serum steroids. This is because the diet-related measures associated with increased risk of BPH, including total fat, red meat, and obesity (10
), are also associated with increased levels of estradiol and decreased levels of testosterone (57
). For reasons that are not clear, associations of steroids were somewhat stronger in the subset of men with dietary data; however, associations of dietary factors and steroids with BPH risk were unchanged when all of them were included in statistical models. On the basis of these results, our observed associations of steroids with BPH risk are independent of diet, obesity, insulin-like growth factor 1, and insulin-like growth factor binding protein 3.
The unique strength of this analysis is that it was prospective. Men with a history of BPH were excluded and, at the time of the baseline blood drawing, men were free of BPH symptoms. Cross-sectional or case-control studies of BPH and steroid hormones are problematic, because it is plausible that differences in serum steroids, especially higher levels of 17β-diol-glucuronide, are due to and not the cause of prostate enlargement. In addition, this study reflects both lower urinary tract symptoms and all current BPH treatments; many previous studies used BPH surgery alone as an endpoint, which may have biased the results, because this definition cannot separate factors associated with surgical treatment (e.g., health insurance, age, comorbidity) from those that predict severe BPH.
This study had several important limitations. The definition of BPH by severe lower urinary tract symptoms is not specific, as symptoms such as urgency can be related to bladder conditions and not prostate enlargement (59
). There is little agreement about the best definition of BPH for large epidemiologic studies, and we chose a definition based on treatment or symptoms collected by standardized and validated questionnaire. Our definition did not include clinical measures of BPH—for example, prostate size or urinary flow. We did have measures of prostate size based on ultrasonography, but only in the subset of 260 cases and 214 controls who completed end-of-study biopsies. In these men, mean prostate size in cases was significantly larger than that in controls (37.5 cm3
vs. 33.6 cm3
0.0001). We limited our study to men with no significant lower urinary tract symptoms at baseline, and we considered as controls only men who were free of significant lower urinary tract symptoms through the 7-year trial, because we judged that this would yield the clearest contrast between BPH cases and noncases. We could have included as an additional study group men who developed intermediate lower urinary tract symptoms that were not sufficiently severe to meet the BPH definition; however, we felt this was not justified considering the fact that the Prostate Cancer Prevention Trial biorepository is a limited resource with many competing demands for baseline blood samples and the cost of serum steroid assays was high. Our study sample was not a representative sample of older men; they were all participants in a clinical trial, mostly Caucasian, and free of significant lower urinary tract symptoms at baseline. Finally, blood samples were nonfasting and were drawn at all times during the day, which would have introduced variability in steroid concentrations. However, this is unlikely to have introduced bias, because we have no reason to believe that the distribution of times of blood drawing differed markedly between cases and controls.
In summary, we found no evidence that higher levels of testosterone or estradiol increase the risk of symptomatic BPH. To the contrary, we found that higher concentrations of testosterone relative to 17β-diol-glucuronide (measuring indirectly the conversion of testosterone to dihydrotestosterone in the prostate), as well as testosterone and estradiol, were associated with reduced risk. The consistency of findings on both 17β-diol-glucuronide controlled for testosterone and testosterone:17β-diol-glucuronide ratio with the published literature and the known effects of 5-α-reductase inhibitors suggests that either genetic or environmental factors that reduce the conversion of testosterone to dihydrotestosterone may reduce the risk of symptomatic BPH.