• prostate;
  • hormones;
  • testosterone;
  • 3α-diolG;
  • sex hormone- binding globulin;
  • androstenedione


  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Sex steroid hormones influence prostate development and maintenance through their roles in prostate cellular proliferation, differentiation and apoptosis. Although suspected to be involved in prostate carcinogenesis, an association between circulating androgens and prostate cancer has not been clearly established in epidemiologic studies. We conducted a nested case-control study with prospectively collected samples in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, to examine associations of prostate cancer with androstenedione (Δ4-A), testosterone (T), sex hormone-binding globulin (SHBG) and 3α-androstanediol glucuronide (3α-diolG). A total of 727 incident Caucasian prostate cancer cases (age ≥ 65 years, N = 396) and 889 matched controls were selected for this analysis. Overall, prostate cancer risks were unrelated to serum T, estimated free and bioavailable T, and SHBG; however, risks increased with increasing T:SHBG ratio (ptrend = 0.01), mostly related to risk in older men (≥65 years, ptrend = 0.001), particularly for aggressive disease [highest versus lowest quartile: odds ratio (OR) 2.76, 95% confidence interval (CI) 1.50–5.09]. No clear patterns were noted for Δ4-A and 3α-diolG. In summary, our large prospective study did not show convincing evidence of a relationship between serum sex hormones and prostate cancer. T:SHBG ratio was related to risk in this older population of men, but the significance of this ratio in steroidal biology is unclear. © 2008 Wiley-Liss, Inc.

Prostate cancer is the most commonly diagnosed nonskin cancer and the second leading cause of cancer mortality among men in the United States.1 Age, race and family history of prostate cancer are the only well-established risk factors for this disease (reviewed in Refs.2,3). Androgens are important in prostate cancer; prolonged administration of testosterone induces prostate cancer in animal models4, 5 and androgens are important modifiers of disease progression and metastases.6, 7

Testosterone (T) is derived in the testes from androstenedione (Δ4-A) and is converted in the prostate to its more active form, dihydrotestosterone (DHT).8 DHT binds in a complex to the androgen receptor (AR), influencing cellular proliferation through control of numerous gene-regulating AR response elements. DHT is further metabolized to 3α-androstanediol (3α-diol) and 3α-androstanediol glucuronide (3α-diolG). In circulation, sex hormone-binding globulin (SHBG) is the major high-affinity carrier of T, while serum albumin serves as an androgen carrier of low binding affinity.8 SHBG may also play a role directly in steroid signaling, through binding to a receptor (RSHBG), inducing cAMP synthesis (reviewed in Ref.9).

Although androgens are important in prostate carcinogenesis,10 epidemiologic studies relating serum hormone levels to prostate cancer risk have been inconclusive, with most prospective studies in the United States and Europe reporting weak or null associations.11–27 We conducted a large nested case-control study including 727 cases and 889 controls, using prediagnostic serum samples, in the prospective Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, to examine associations between Δ4-A, T, SHBG, and 3α-diolG and risk of prostate cancer. Because of the large sample size, we were able to evaluate androgen-associated risks in relation to disease aggressiveness and to consider risks in population subgroups.

Material and methods

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

The PLCO cancer screening trial

This nested case-control study was conducted within the screening arm of the PLCO screening trial, which is a two-armed, randomized controlled trial designed to evaluate the effectiveness of prostate, lung, colorectal and ovarian cancer screening and to investigate etiologic factors and early markers of cancer.28, 29 Approximately 150,000 U.S. men and women, aged 55–74 at enrollment, were randomly assigned to the screening or nonscreening arm of the study. PLCO participants were recruited from 10 screening centers in the United States (Birmingham, AL; Denver, CO; Detroit, MI; Honolulu, HI; Marshfield, WI; Minneapolis, MN; Pittsburgh, PA; Salt Lake City, UT; St. Louis, MO; and Washington, DC) between September 1993 and June 2001.

Men randomized to the screening arm of the trial (N = 38,350) were offered prostate cancer screening by serum prostate-specific antigen (PSA) and digital rectal exam (DRE) at study entry and then annually for 5 and 3 years, respectively. If a PSA test result was >4 ng/ml or DRE was suspicious for prostate cancer, men were referred to their healthcare providers for prostate cancer diagnostic evaluation. In addition, suspected prostate cancer diagnosis was obtained through annual mailed questionnaires, periodic search of the National Death Index and cancer registries, if available, or from physician/relative reports. All medical and pathologic records related to diagnosis were obtained for participants suspected of having prostate cancer through screening or annual questionnaire. Furthermore, death certificates and supporting medical/pathologic records were collected. Data related to cancer diagnoses and deaths were abstracted by trained medical record specialists. Participants of the trial are followed for the incidence of cancer and all causes of mortality for at least 13 years from their randomization date. Screening arm participants were asked to provide a blood sample at each of the screening visits. All participants provided written informed consent. The trial was approved by the institutional review boards of the U.S. National Cancer Institute and the 10 study centers.

Study population

Of the 38,350 men randomized to the screening arm, we excluded men who did not have at least 1 valid screening for prostate cancer (PSA and/or DRE) before October 1, 2001 (the censor date for this analysis), men with a prior history of prostate cancer, men who did not complete the baseline risk factor questionnaire, men who refused to provide a blood sample, men with an ethnic/racial background other then non-Hispanic white or non-Hispanic black and men who did not sign the informed consent for etiologic studies on cancer. After exclusion, the analytic cohort included 28,243 men. All men were followed from their initial valid prostate cancer screen (PSA and/or DRE) to first occurrence of prostate cancer, loss to follow-up, death or October 1, 2001, whichever came first.

Cases were defined as men diagnosed with adenocarcinoma of the prostate. Clinical stage grouping was assigned on the basis of clinical and pathological assessment of the extent of tumor involvement by using the TNM system.30 Tumor (T) stage was categorized according to the 4th or 5th edition of the American Joint Committee on Cancer Cancer Staging Manual,31, 32 depending on the date of diagnosis. Clinical information for nodal (N) and metastatic (M) staging was recorded when available. In order to minimize the potential effects of undetected pre-existing disease on serum hormone levels, we excluded cases diagnosed within the first year of follow-up.

Among the 28,243 eligible men, 803 non-Hispanic white prostate cancer cases were identified. Controls (n = 947) were selected by incidence-density sampling,33 with a case-control ratio of 1:1.2, by age at entry (5-year intervals), time since initial screen (1-year time windows) and year of blood draw (study entry). Laboratory results could not be obtained for 8% of the 1,750 eligible men due to lack of sufficient sample volume (n = 134), resulting in a study population of 727 cases and 889 controls.

Laboratory measurement of androstenedione, 3α-diolG, testosterone and SHBG

Nonfasting blood samples were collected at baseline, aliquoted to 1.8 ml storage vials within 2 hr of collection and stored at −70°C. Serum samples for our study were aliquoted at NCI and shipped for analysis to the International Association for Research on Cancer, with cases and their matched controls analyzed in the same batch. Androstenedione and 3α-diolG were measured by direct double-antibody radioimmunoassay (Diagnostic Systems Laboratories, Webster, TX), testosterone by direct radioimmunoassay (Immunotech, Marseille, France) and SHBG by a sandwich immunoradiometric assay (CIS-Bio, Gif-sur-Yvette, France).

For the case and control sample analysis, we included blinded quality control samples (2 duplicates from each of 2 subjects in each analytic batch, showing overall CVs of 14, 11, 14 and 18% for Δ4-A, 3α-diolG, T and SHBG, respectively. We also determined temporal intrasubject variability for these analytes (r = 0.41, 0.91, 0.58 and 0.81 for Δ4-A, 3α-diolG, T and SHBG, respectively), by correlating results for study (baseline) sera with serum samples collected 1 year later from the same control subjects (n = 49). The corresponding intraclass correlation coefficients (ICCs) for Δ4-A, 3α-diolG, T and SHBG were 0.34, 0.82, 0.41 and 0.80.

Assessment of questionnaire-based covariates

Participants completed self-administered questionnaires at enrollment, including information on age, ethnicity, height, weight, education, current and past smoking behavior, history of cancer and other diseases, use of selected drugs, recent history of screening exams and prostate-related health factors.

Statistical analyses

T:SHBG ratio was calculated by conversion of testosterone from ng/ml to nmol/L (conversion factor = 3.467) and then division by SHBG (nmol/L). Free and bioavailable T were calculated from the total concentration and the concentration of SHBG using the equations provided by Ly and Handelsman34 and Morris et al.35; these algorithms have been validated in male populations against a reference method. Free T indicates the concentration of T that is not bound to either SHBG or albumin, while bioavailable T includes the free and albumin-bound fractions.

Using conditional logistic regression analysis, odds ratios (ORs) were calculated for the relationship of study analytes to incident adenocarcinoma of the prostate. The analytes were modeled as categorical variables defined by the quartile distributions among controls. Other factors [body mass index (BMI), height, diabetes, family history of prostate cancer, physical activity, cigarette smoking, intake of various nutrients and study center] were evaluated as potential confounders by assessing whether their inclusion altered risk estimates by at least 10%; none of these factors remained in the final models. Missing values (1–2%) for continuous and categorical confounding variables were replaced by the median and mode values, respectively, of these variables in the study population.36 Final models included mutual adjustment for androgens and SHBG.21, 37, 38

To determine if the relationship between the measured analytes and prostate cancer risk differed by these factors, stratification was performed by age (<65 vs. 65+ years), BMI (<25, 25–30 and ≥30 kg/m2) and time between blood draw and diagnosis (1–2 vs. 3–7 years). Likelihood ratio tests were performed to test for multiplicative interactions. Polytomous logistic regression was used to assess the relationship between the androgens and SHBG and nonaggressive versus aggressive disease. Aggressive disease was classified by Gleason grade ≥ 7 or stage III–IV. To test for linear trends in ORs across groups, we created score variables representing the median of each quartile, including these into the logistic regression models as continuous variables. To test for the homogeneity of ORs across categories of tumor aggressiveness by levels of exposure, we compared polytomous regression models within each quartile of serum analyte using the likelihood ratio test. To assess the homogeneity of linear trends between aggressive and nonaggressive disease, we compared polytomous regression models using the Wald test. All analyses were performed using the STATA statistical package, Version 9 (STATA Corporation, College Station, TX).


  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Aggressive and nonaggressive prostate cancer cases and controls were similar with respect to age (Table I); median age at diagnosis for cases was 68 years (range 57–81 years). Sixty-eight percent of the combined cases were diagnosed 3 or more years after study entry (mean, 3.5 years). Cases had higher levels of PSA than controls (median, 3.5 vs. 1.2 ng/ml; p < 0.001). Case diagnoses often followed an elevated PSA (57%), an abnormal DRE (14%) or both (17%); only 11% were diagnosed due to other reasons. Hormone levels tended to be strongly correlated among controls (p < 0.001; results not shown). Most serum hormone levels were not correlated with PSA in cases or controls, however, T:SHBG was correlated with PSA in controls (p < 0.05). With the exception of SHBG, serum hormone levels were inversely associated with age.

Table I. Demographics of the Study Population in Controls and Cases, by Diseases Aggressiveness1
Demographics, N (%)Prostate cancer casesControls (N = 889)
Aggressive cases (N = 277)Nonaggressive cases (N = 450)
  • 1

    BMI = body mass index, PSA = prostate-specific antigen.

Age (years)
 55–5934 (12.3)57 (12.7)118 (13.3)
 60–6488 (31.8)152 (33.8)293 (33.0)
 65–69106 (38.3)151 (33.6)313 (35.2)
 70–7449 (17.7)90 (20.0)165 (18.6)
BMI (kg/m2)
 <25.082 (29.6)116 (25.8)243 (27.3)
 25.0–29.9150 (54.2)249 (55.3)461 (51.9)
 ≥3045 (16.2)85 (18.9)185 (20.8)
 No266 (96.0)420 (93.3)820 (92.2)
 Yes11 (4.2)30 (6.7)69 (7.8)
Ever smoker
 No126 (45.7)198 (44.0)355 (39.9)
 Yes150 (54.3)252 (56.0)534 (60.1)
Study year
 1–2163 (58.8)271 (60.2)542 (61.0)
 3–473 (26.4)141 (31.3)254 (28.6)
 ≥541 (14.8)38 (8.4)93 (10.5)
PSA (ng/ml), median (IQR)3.4 (2.4–4.9)3.6 (2.4–5.0)1.2 (0.7–2.1)

Risks tended to increase with greater total, free and bioavailable T, and to decrease with greater SHBG, but these findings were not statistically significant (Table II). T:SHBG ratio, however, was associated with increased risk for prostate cancer [highest quartile OR 1.54, 95% confidence interval (CI) 1.13–2.10; ptrend = 0.01]. Δ4-A and 3α-dG were not associated with overall prostate cancer risk.

Table II. Odds Ratios and 95% CI for Prostate Cancer in Relation to Serum Levels of Hormones
  • 1

    Conditional OR, matched on age at randomization, fiscal year of first screen, and study year of diagnosis/reference; mutual adjustment for Δ4-A, T, SHBG and 3α-diolG.

  • 2

    Conditional OR, matched on age at randomization, fiscal year of first screen, and study year of diagnosis/reference; adjustment for Δ4-A and 3α-diolG.

Δ4-A (ng/ml)
 Median, IQR0.77, 0.66–0.871.07, 1.00–1.121.34, 1.26–1.411.77, 1.62–2.02 
 OR (95% CI)1Reference0.86 (0.64, 1.14)1.00 (0.75, 1.35)0.96 (0.70, 1.32)0.76
T (ng/ml)
 Median, IQR2.68, 2.29–3.074.02, 3.72–4.355.31, 4.99–5.767.78, 6.91–9.34 
 OR (95% CI)1Reference1.32 (0.97, 1.73)1.29 (0.97, 1.73)1.39 (0.92, 2.08)0.22
SHBG (nmol/l)
 Median, IQR25.62, 20.85–30.0837.78, 35.07–40.9850.60, 47.23–54.1673.67, 64.86–91.09 
 OR (95% CI)1Reference0.84 (0.63, 1.14)0.86 (0.62, 1.20)0.76 (0.52, 1.10)0.22
 Median, IQR0.07, 0.06–0.080.09, 0.09–0.100.12, 0.11–0.120.16, 0.14–0.18 
 OR (95% CI)2Reference1.24 (0.92, 1.66)1.21 (0.90, 1.63)1.54 (1.13, 2.10)0.01
Free T (nmol/l)
 Median, IQR0.23, 0.20–0.250.30, 0.29–0.320.37, 0.35–0.390.47, 0.44–0.54 
 OR (95% CI)2Reference1.15 (0.86, 1.52)1.08 (0.80, 1.45)1.20 (0.87, 1.65)0.36
Bioavailable T (nmol/l)
 Median, IQR3.24, 2.84–3.614.53, 4.26–4.875.79, 5.48–6.157.91, 7.15–9.12 
 OR (95% CI)2Reference1.23 (0.92, 1.64)1.24 (0.92, 1.67)1.20 (0.87, 1.66)0.37
3α-diolG (ng/ml)
 Median, IQR3.22, 2.45–3.655.38, 4.76–6.098.31, 7.58–9.3914.10, 12.19–17.35 
 OR (95% CI)1Reference1.10 (0.83, 1.46)1.29 (0.97, 1.73)0.87 (0.60, 1.18)0.31

Risks were elevated in older men in relation to serum T greater than the lowest quartile, but risks did not increase in a dose–response fashion over the total range of this analyte. (Table III). Similar patterns were also noted for free T and bioavailable T. The overall association of greater T:SHBG with increased prostate cancer risk was due to risks in men 65 years of age or older (Table III; ptrend = 0.001), with risks rising to greater than 2-fold in the highest T:SHBG quartile (OR 2.07, 95% CI: 1.33–3.21). Increased risks for Δ4-A and 3α-diolG were suggested only in younger men (pint = 0.04 and pint = 0.004, respectively).

Table III. Association Between Sex Steroid Hormones and Risk of Prostate Cancer, by Age at Study Entry1
  • 1

    Case/control number provided for each stratum.

  • 2

    Conditional OR, matched on age at randomization, fiscal year of first screen, and study year of diagnosis/reference; mutual adjustment for Δ4-A, T, SHBG, and 3α-diolG.

  • 3

    Conditional OR, matched on age at randomization, fiscal year of first screen, and study year of diagnosis/reference; adjustment for Δ4-A and 3α-diolG.

Age < 65 years (n = 742)
Δ4-A (ng/ml)60/8873/7884/114114/131  
 OR (95% CI)2Reference1.38 (0.85, 2.25)1.06 (0.66, 1.72)1.24 (0.76, 2.03)0.39 
T (ng/ml)78/9975/9682/10396/113  
 OR (95% CI)2Reference0.94 (0.59, 1.49)0.95 (0.57, 1.59)1.00 (0.54, 1.82)0.85 
SHBG (nmol/l)91/10975/10284/10281/98  
 OR (95% CI)2Reference0.91 (0.58, 1.41)0.98 (0.60, 1.60)0.99 (0.57, 1.73)0.96 
 OR (95% CI)3Reference1.35 (0.86, 2.11)1.11 (0.70, 1.77)1.17 (0.73, 1.84)0.71 
Free T (nmol/l)76/9573/10284/10098/114  
 OR (95% CI)3Reference0.85 (0.55, 1.32)0.95 (0.60, 1.48)1.02 (0.63, 1.64)0.64 
Bioavailable T (nmol/l)73/9376/10385/10297/113  
 OR (95% CI)3Reference0.90 (0.58, 1.41)0.98 (0.63, 1.55)1.04 (0.64, 1.68)0.65 
3α-diolG (ng/ml)52/9989/93117/10373/116  
 OR (95% CI)2Reference1.89 (1.20, 2.99)2.25 (1.43, 3.55)1.22 (0.76, 1.98)0.73 
Age ≥ 65 years (n = 874)
Δ4-A (ng/ml)127/13493/145106/10870/91  
 OR (95% CI)2Reference0.67 (0.46, 0.96)1.04 (0.71, 1.52)0.78 (0.50, 1.22)0.100.04
T (ng/ml)85/123127/127100/11984/107  
 OR (95% CI)2Reference1.74 (1.15, 2.63)1.63 (1.03, 2.59)1.86 (1.05, 3.29)0.140.61
SHBG (nmol/l)101/113102/121104/12088/124  
 OR (95% CI)2Reference0.75 (0.49, 1.13)0.77 (0.49, 1.21)0.57 (0.34, 0.98)0.100.79
 OR (95% CI)3Reference1.11 (0.75, 1.65)1.27 (0.86, 1.89)2.07 (1.33, 3.21)<0.010.12
Free T (nmol/l)92/127116/11997/12290/108  
 OR (95% CI)3Reference1.46 (1.00, 2.14)1.24 (0.82, 1.86)1.37 (0.88, 2.14)0.210.49
Bioavailable T (nmol/l)87/129118/119107/11983/109  
 OR (95% CI)3Reference1.57 (1.07, 2.31)1.52 (1.01, 2.29)1.33 (0.85, 2.09)0.420.44
3α-diolG (ng/ml)116/12396/129105/12079/106  
 OR (95% CI)2Reference0.76 (0.52, 1.10)0.86 (0.58, 1.26)0.71 (0.47, 1.09)0.26<0.01

More pronounced risks associated with elevated total T (Q4 vs. Q1: OR 1.84, 95% CI 1.06–3.17; ptrend = 0.12) and T:SHBG (Q4 vs. Q1: OR 1.73, 95% CI 1.12–2.66; ptrend = 0.06) were observed for aggressive than nonaggressive disease, although tests of heterogeneity between groups were not significant (results not shown). Similar risks of aggressive disease were observed for free T and bioavailable T, while no notable differences by disease aggressiveness were observed for Δ4-A and 3α-dG.

When age differentials in risk were further examined by disease aggressiveness, the excess risks noted in older men were found to be largely due to risks for aggressive disease (Table IV), with excess risks noted at the higher levels of T (ptrend = 0.05) and T:SHBG (ptrend = 0.005); trends were not significant for free T (ptrend = 0.14) and bioavailable T (ptrend = 0.23). Decreased risks were noted at the higher levels of SHBG (Q4 vs. Q1: OR 0.45, 95% CI 0.23–0.89), however, trends were not significant (ptrend = 0.06). A trend of decreasing risks was noted at the higher levels of 3α-diolG (p = 0.05) in older men. Although nonaggressive prostate cancer showed weaker associations with most hormone-related analytes in older men, risk of nonaggressive disease was significantly elevated at the higher range of T:SHBG (ptrend = 0.02).

Table IV. The Influence of Age and Disease Aggressiveness on the Association Between Sex Steroid Hormones and Risk of Prostate Cancer1
  • 1

    Aggressive disease defined as Gleason ≥ 7 or Stage III/IV.–

  • 2

    Polytomous logistic regression, adjusted for matching variables (age at randomization, fiscal year of first screen, study year of diagnosis/reference); mutual adjustment for Δ4-A, T, SHBG and 3α-diolG.–

  • 3

    Polytomous logistic regression, adjusted for matching variables, Δ4-A and 3α-diolG.

Age <65 years (N = 742)
Nonaggressive disease (N = 209 cases)
 Δ4-A (ng/ml)2Reference1.04 (0.59, 1.82)0.97 (0.58, 1.64)1.01 (0.60, 1.72)0.71
 T (ng/ml)1,2Reference0.91 (0.54, 1.55)0.89 (0.50, 1.59)1.06 (0.55, 2.06)0.72
 SHBG (nmol/l)1,2Reference0.98 (0.60, 1.61)0.88 (0.50, 1.54)0.90 (0.48, 1.69)0.70
 T:SHBG3Reference1.19 (0.71, 2.00)0.99 (0.58, 1.68)1.18 (0.72, 1.95)0.54
 Free T (nmol/l)3Reference0.70 (0.42, 1.17)0.78 (0.47, 1.30)1.00 (0.60, 1.69)0.57
 Bioavailable T (nmol/l)1,3Reference0.78 (0.47, 1.29)0.85 (0.51, 1.41)0.93 (0.55, 1.57)0.87
 3α-diolG (ng/ml)2Reference2.35 (1.36, 4.05)2.79 (1.63, 4.79)1.36 (0.76, 2.43)0.79
Aggressive disease (N = 122 cases)
 Δ4-A (ng/ml)2Reference2.05 (1.05, 4.02)1.16 (0.58, 2.29)1.61 (0.83, 3.14)0.36
 T (ng/ml)1,2Reference0.99 (0.51, 1.92)1.06 (0.52, 2.15)0.94 (0.42, 2.12)0.95
 SHBG (nmol/l)1,2Reference0.65 (0.34, 1.23)1.05 (0.54, 2.02)0.97 (0.46, 2.06)0.91
 T:SHBG3Reference1.61 (0.86, 3.04)1.31 (0.68, 2.52)1.10 (0.58, 2.09)0.94
 Free T (nmol/l)3Reference1.13 (0.61, 2.12)1.27 (0.68, 2.35)0.97 (0.50, 1.88)0.95
 Bioavailable T (nmol/l)1,3Reference1.10 (0.58, 2.07)1.20 (0.64, 2.27)1.16 (0.60, 2.24)0.55
 3α-diolG (ng/ml)2Reference1.34 (0.72, 2.52)1.57 (0.85, 2.90)1.04 (0.54, 2.00)0.79
Age ≥ 65 years (N = 874)
Nonaggressive disease (N = 241 cases)
 Δ4-A (ng/ml)2Reference0.75 (0.49, 1.14)1.02 (0.66, 1.57)0.70 (0.42, 1.19)0.36
 T (ng/ml)1,2Reference1.34 (0.83, 2.17)1.46 (0.86, 2.47)1.33 (0.70, 2.53)0.64
 SHBG (nmol/l)1,2Reference0.83 (0.51, 1.33)1.01 (0.61, 1.67)0.66 (0.37, 1.19)0.37
 T:SHBG3Reference0.82 (0.52, 1.29)0.99 (0.63, 1.55)1.72 (1.08, 2.76)0.02
 Free T (nmol/l)3Reference1.25 (0.80, 1.95)1.14 (0.72, 1.81)1.08 (0.65, 1.80)0.96
 Bioavailable T (nmol/l)1,3Reference1.30 (0.83, 2.03)1.35 (0.85, 2.15)1.09 (0.65, 1.83)0.89
 3α-diolG (ng/ml)2Reference0.70 (0.45, 1.10)0.85 (0.54, 1.33)0.89 (0.55, 1.44)0.99
Aggressive disease (N = 155 cases)
 Δ4-A (ng/ml)2Reference0.53 (0.31, 0.90)1.02 (0.61, 1.69)0.91 (0.51, 1.63)0.60
 T (ng/ml)1,2Reference2.74 (1.51, 4.92)1.98 (1.00, 3.91)3.29 (1.51, 7.18)0.05
 SHBG (nmol/l)1,2Reference0.64 (0.37, 1.11)0.48 (0.26, 0.88)0.45 (0.23, 0.89)0.06
 T:SHBG3Reference1.84 (1.05, 3.23)2.02 (1.14, 3.56)2.76 (1.50, 5.09)<0.01
 Free T (nmol/l)3Reference1.87 (1.09, 3.21)1.43 (0.80, 2.56)1.97 (1.07, 3.61)0.14
 Bioavailable T (nmol/l)1,3Reference2.18 (1.26, 3.77)1.85 (1.03, 3.32)1.84 (0.98, 3.45)0.23
 3α-diolG (ng/ml)2Reference0.84 (0.50, 1.40)0.85 (0.50, 1.43)0.52 (0.28, 0.97)0.05

Risks of prostate cancer for the measured hormones did not differ by BMI, family history or year on study (data not shown).


  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Overall, in this large prospective study, we observed no clear relationship between serum androgens and prostate cancer, however, serum T tended to be directly and SHBG indirectly related to aggressive disease in older men. Biologically-based and validated measures of free and bioavailable T34, 35, 39 did not show clear dose–response relationships with prostate cancer; the strongest link observed was with the T:SHBG ratio.

In 1996, Gann et al.37 in a large study reported similar T and SHBG-related risks for prostate cancer, particularly aggressive disease, in older men. Travis et al. in a recent large study24 also reported similar, albeit nonsignificant, results for high grade disease, in relation to total and free testosterone. Others, however, have reported that serum testosterone is either not associated12, 19, 25, 27 or inversely associated with risk of aggressive or high grade tumors.21, 22 A limitation in comparing studies is that age-specific associations were often not reported,12, 16, 20, 24, 25, 27 and age distributions and analytic age strata have differed between investigations. Also, PSA, and associated likelihood of cancer detection, may be correlated with serum androgens,21 however, in our study testosterone and PSA levels were unrelated in either cases or controls.

Much attention in assessing androgens in prostate carcinogenesis has focused on the role of SHBG and albumin in regulating the bioavailability of T to enter target cells in the unbound form (<2% is unbound).38 In our study, estimated values of free and unbound T were not more predictive of prostate cancer risk than simpler measures of T, SHBG and their ratio. The precise role of these compounds in normal physiologic regulation is not completely understood.

Independent of its role as a carrier protein, unliganded SHBG may also play a role in cell signaling by direct binding to a receptor (RSHBG), inducing synthesis of cAMP and initiating downstream signaling and genomic effects40, 41; under this mechanism, steroids bound to SHBG42, 43 may influence RSHBG-mediated signaling40, 44, 45 and cell growth.46

Similar to our findings, Δ4-A was unrelated to prostate cancer in most12, 13, 15, 17, 19 but not all previous studies.11 In our study, higher levels of serum 3α-diolG were associated with decreased risk of aggressive prostate cancer in older men. Most other studies report no overall association,13, 14, 17, 19, 22, 24, 26, 37 while Platz et al.21 and Chen et al.12 showed trends of increasing risks in younger men. Circulating 3α-diolG is a putative marker of peripheral androgen metabolism (prostate, skin) and action,26 thought to reflect 5α-reductase activity and DHT levels in the prostate; however, it is also an end product of androgen metabolism. Therefore, the implication of elevated serum 3α-diolG is not entirely clear.

The current study has a number of design strengths: it is the largest prospective study to examine the relationship between endogenous sex hormones and risk of prostate cancer. Samples were collected prior to diagnosis and our substudy of bloods collected at 2 time points showed that a single measure of these analytes gave a good representation of a given individual's exposure level. The large study size allowed us to evaluate risks in relation to age and tumor aggressiveness. Our study focused on men 55 years of age or older (median, 65 years), with 87% of subjects older than 60 years at entry. Comparison of age-specific results with other studies may be constrained by differences in age distributions, with many studies including younger men,11, 12, 15, 17, 19–27, 37 several with mean/median ages of 55–60 years.13, 15, 17, 20, 26, 27

There are several limitations in epidemiologic studies relating serum hormone levels to prostate cancer risk. Serum measures are only an indirect indicator of steroid hormones at the glandular level. Measures at older ages may not reflect cumulative lifetime exposures or exposures at the etiologically relevant time period. For example, Δ4-A and T did not exhibit strong reproducibility between baseline and 1 year of follow-up (ICCs 0.34 and 0.41, respectively). Therefore, serum measurements at a single time point may not be reflective of those at the etiologically relevant time period. Finally, risks were evaluated shortly after blood draw, however, we noted no differential patterns for men diagnosed 1–2 versus 3–7 years after blood draw.

In summary, our study showed only modest overall associations between endogenous sex hormones and prostate cancer, however, greater serum testosterone and lower SHBG were associated with increased risk for aggressive disease in older men.


  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

The authors thank Ms. J. Bouzac, Ms. P. Amouyal and Mr. D. Achaintre at IARC for their assistance with the laboratory analyses.


  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
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