Prospective Study of Sex Hormone Levels and Risk of Prostate Cancer

Background: Sex steroids, particularly androgens, have been implicated in the pathogenesis of prostate cancer. Data from previous studies comparing circulating hormone levels in men with and without prostate cancer are difficult to interpret, since the studies were limited in size, hormone levels were analyzed in blood drawn after the diagnosis of cancer, nonrepresentative control subjects were used, and hormone and hormone-binding protein levels were not simultaneously adjusted. Purpose: We conducted a prospective, nested casecontrol study to investigate whether plasma hormone and sex hormone-binding globulin (SHBG) levels in healthy men were related to the subsequent development of prostate cancer. Methods: Among participants in the Physicians' Health Study who provided plasma samples in 1982, we identified 222 men who developed prostate cancer by March 1992. Three hundred ninety control subjects, matched to the case patients on the bases of age, smoking status, and length of follow-up, were also identified. Immunoassays were used to measure the levels of total testosterone, dihydrotestosterone (DHT), 3a-androstanediol glucuronide (AAG), estradiol, SHBG, and prolactin in the stored (at -82 °C) plasma samples. Correlations between individual hormone levels and between hormone levels and SHBG in the plasma of control subjects were assessed by use of Spearman correlation coefficients (r). Odds ratios (ORs) and 95% confidence intervals (CIs) specifying the prostate cancer risk associated with quartile levels of individual hormones, before and after adjustment for other hormones and SHBG, were calculated by use of conditional logistic regression modeling. Reported P values are two-sided. Results: No clear associations were found between the unadjusted levels of individual hormones or SHBG and the risk of prostate cancer. However, a strong correlation was observed between the levels of testosterone and SHBG (r = .55), and weaker correlations were detected between the levels of testosterone and the levels of both estradiol (r = .28) and DHT (r = .32) (all /> 2.5 ng/mL) were excluded from the analyses. Conclusions: High levels of circulating testosterone and low levels of SHBG—both within normal endogenous ranges—are associated with increased risks of prostate cancer. Low levels of circulating estradiol may represent an additional risk factor. Circulating levels of DHT and AAG do not appear to be strongly related to prostate cancer risk. [J Natl Cancer Inst 1996;88:1118-26] A longstanding and diverse body of evidence suggests that sex steroids, particularly androgens, play a role in the etiology of prostate cancer. Androgens are essential for normal growth and maintenance of the prostate, stimulate the proliferation of human prostate cancer cells in vitro, and, when given in large amounts, can produce prostate cancer in rodents {12)- In addition, eunuchs rarely develop prostate cancer, and androgen ablation frequently causes prostate tumors to regress (3). In contrast, a reduced risk of prostate cancer has been associated with certain hyperestrogenic states (4), and estrogen therapy has a palliative effect in advanced cases (J). These observations on extreme variations in sex-steroid exposure add credibility to the hypothesis that prostate cancer risk is also related to the smaller contrasts in levels of androgens and estrogens that are found within the normal endogenous range (7). However, studies com