Serum Hormones and Risk of Subsequent Prostate Cancer1

Vu!. 2,27-32, January/February 1993 Cancer Epidemiology, Biomarkers & Prevention 27

Serological Precursors of Cancer: Serum Hormones and Risk of Subsequent Prostate Cancer1

Ann W. Hsing and George W. Comstock2 of testosterone (18-23); absence of prostate cancer in National Cancer Institute, Division of Cancer Etiology, Bethesda 20892 persons whose testes were removed before puberty (16); [A. W. H.], and The lohns Hopkins University, Baltimore 21205 the low incidence of prostate cancer found in persons [C. W. C.], Maryland with elevated levels of estrogens (hyperestrogenism) (24, 25); the high levels of circulating androgens, as well as receptors for androgens, found in neoplastic prostatic Abstract tissues (26-28); and the regression of prostate cancer A population-based nested case-control study was following ablative or antiandrogen therapy (29-31). conducted to determine the relation of prediagnostic These observations provided the rationale for case-con- serum levels of testosterone, dihydrotestosterone, trol studies that compared the levels of serum/plasma prolactin, follicle-stimulating hormone, luteinizing hormones in prostate cancer patients and men without hormone, estrone, and estradiol to the risk of known prostate cancer. Results from these case-control subsequent prostate cancer. Serum specimens of study studies are equivocal, providing little or no evidence for subjects were available from a blood collection a direct role of hormones in prostatic cancinogenesis. campaign in Washington County, Maryland, in 1974. Some reported elevated levels of testosterone (32-36), Serum hormone levels of 98 histologically confirmed dihydrotestosterone (34, 35), estrogen (33, 37, 38), on prostate cancer cases diagnosed in the subsequent 13 pituitary hormones (39-41) in cases; some reported years were compared to those of 98 controls who were lower levels of these hormones in cases (33, 35, 39, 40); individually matched to cases on the basis of age while others reported similar levels of hormones in cases (within weeks), sex, and race. There were no significant and controls (42-48). Many of these studies did not differences in levels of these hormones between cases control for factors such as age, stage or treatment of and controls, although elevated levels of luteinizing cancer, or selection of controls that could affect case- hormone and of testosterone:dihydrotestosterone ratios control comparisons. Furthermore, all but two of them were associated with mild increased risks of prostate compared hormone levels between diagnosed cases and cancer. controls. It is not clear to what extent the presence of symptomatic prostate cancer may affect the serum levels Introduction of hormones. Prediagnostic serum levels of hormones, such as those reported by Nomura et al. (49) and Barrett- Prostate cancer, having surpassed lung cancer, has be- Connor et al. (50), are clearly more desirable for case- come the most common cancer and the second leading control comparisons. In these reports, lower levels of cause of cancer death among U.S. males (1). In 1992, it dihydrotestosterone and higher levels of the testoster- was estimated that approximately 132,000 new cases one:d i hyd rotestostenone ratio and and rostened ione would be diagnosed and that 34,000 men would die of were related to an increased risk of prostate cancer. this cancer in the United States (2). Despite these num- To further clarify the role of hormones in the etiology bers, the etiology of prostate cancer remains unknown. of prostate cancer, we undertook a population-based Although socioeconomic, dietary, viral, sexual, chemical, nested case-control study, using serum samples collected genetic, smoking, and hormonal factors have all been and frozen in 1974, to determine the association of considered (3-15), only age, race, and increased intake prediagnostic serum hormones with subsequent prostate of dietary fat have consistently been found to be risk cancer. factors for prostate cancer. Endogenous hormones, especially androgens, are believed to play a role in the etiology of prostate cancer Materials and Methods because they are necessary for the growth and mainte- Serum specimens used in the study came from the Wash- nance of the prostate gland (16, 17). Evidence that sup- ington County serum bank. The serum bank has been ports a hormonal hypothesis includes induction of pros- described in detail elsewhere (51-58). Briefly, in 1974 tatic carcinoma in rats following prolonged administration 25,620 Washington County residents (98% whites) gave blood for the study of serological precursors of cancer. Serum specimens from these participants were stored at -70#{176}C. At the time of blood collection, information was Received 5/22/92. 1 Supported in part by research Grant CA36390 and Cance’r Training obtained on demographic characteristics, smoking his- Grant T32CA09314-07 from the National Cancer Institute, and Cance’r tory, and medications. Research Award HL21670 from the Health, Lung, and Blood Institute. Prostate cancer cases diagnosed after 1974 were 2 To whom requests for reprints should be addressed, at the’ Training identified through the Washington County Cancer Regis- Center for Public Health Research, Box 2067, Hagerstown, ME) 2 1742- 2067. try. Since only one black male from this cohort was

diagnosed with prostate cancer, study cases were limited Tab!e 1 Percentile values of hormones and hormone ratios used to to whites. Five cases who had developed other primary define quartiles among controls

cancers prior to the diagnosis of prostate cancer were Percentile excluded. A total of 98 cases were selected for the study. Hormones 25th 50th 75th Each case was matched with one control on the basis of age (within weeks), sex, and race. The control subjects Testosterone (ng/dI) 284.8 390.0 536.0 were alive and without a cancer diagnosis (other than a Dihydrotestosterone’ (ng/dl) 36.9 48.6 64.5 Prolactin (ng/mI( 4.2 6.2 8.7 nonnielanonia skin cancer) at the time of the diagnosis Follicle-stimulating hormone (mIU/mI) 7.9 1 1.2 16.6 of the matched case. Luteinizing hormone (mIU/mI) 10.3 14.6 20.9 Serum specimens were grouped into case-control Estrone (pg/mI) 23.6 30.4 46.8 pairs, packed in dry ice, and shipped frozen to the Estradiol (pg/mI) 47.5 60.7 80.8 Testosterone:dihydrotestosterone ratio 6.6 8.5 10.1 laboratory by overnight express mail. On arrival, all spec- Estrone:testosterone ratio 0.05 0.08 0.12 imens were still frozen. Because the specimens were Estradiol:testosterone ratio 0.12 0.15 0.19 identified only by study number, the laboratory person- nel were unaware of the case-control status. In addition, case-control pairs were always analyzed on the same day to minimize any effects of day-to-day laboratory variation. Tab!e 2 Comparison of selected characteristics of prostate cancer Serum levels of androgens and pituitary hormones cases and controls at blood drawing in 1974, . Washington County, Maryland were measured by the Hazleton Laboratory in Vienna, Virginia, using methods described by Abraham (59), Au- Characteristic in 1974 Cases Controls bert (60), and Odell (61). Coefficients of variation for Total 98 98 these assays were as follows: testosterone, 8%; dihydno- testosterone, 20%; prolactin, 5%; follicle-stimulating hor- Age <60 30 29 mone, 5% and luteinizing hormone, 3%. Levels of es- 60-69 43 44 trone and estradiol were measured at the University of 70 25 25 Texas in San Antonio. The coefficients of variation for Marital status these assays were 22% and 26% for estrone and estradiol, Never married 3 4 respectively. Married 90 81 Little is known about the stability of hormones in Divorced, separated 0 6 stored serum/plasma over time. It is generally agreed that Widowed 5 6 little degradation occurs when the blood is stored at Education (years) -70#{176}C(62), although Phillips reported a 20% loss in 0-11 55 50 levels of estradiol in every 2-year period following storage 12 25 24 at -20#{176}C(63). In the present study, there is little evi- 13 18 24

dence of degradation of serum hormones, since levels of Cigarette smoking hormones among 98 controls were similar to reported Nonsmokers 29 28 levels of controls with similar age distributions in previous Exsmokers 43 49 studies using fresh blood (33-36, 47, 48). In addition, Current smokers 26 20 because cases and controls were always treated similarly, Medication use for hypertension differential losses should not have occurred, so case- Yes 20 20 control comparisons on a relative scale should not be No 78 74 affected. Hours since last meal Distributions of serum hormones in cases and con- 0-2 58 56 trols were examined, and means, medians, and SDs were 3-5 29 36 used to evaluate the location and the spread of the 6 11 6 distribution. Differences of means between cases and

controls were evaluated by Student’s t test for paired samples. Because the distributions of hormones were skewed, a log transformation was used when levels of Results hormones were treated as continuous variables. In categorical analyses, quartiles were determined There were no significant differences between cases and according to the distributions among controls, and odds controls at the time of blood collection with respect to ratios were computed for each quartile compared with age, marital status, years of education, cigarette smoking, the lowest quartile. The values for the 25th, 50th, and medication use for hypertension, or hours since last meal 75th percentiles (upper values for the three lowest quar- (Table 2). Age at diagnosis of cancer cases ranged from 47 to 93 years, with a median of 71 years. tiles) are shown in Table 1 . Conditional logistic regression models were used for the risk estimates, with simulta- Comparisons of mean levels of serum testosterone, neous adjustment for several covaniates. Linear trends of DHT,3 prolactin, follicle-stimulating hormone, LH, es- the odds ratios were tested by a x2 method (64). Unless trone, estradiol, and ratios of hormones (testoster- otherwise specified, 95% confidence limits and two- one: D HT, estrone:testosterone, and estrad iol:testos- sided P values are presented in this report. Whenever appropriate, covaniates, including marital status, years of

education, cigarette smoking, and medication use for 3 The abbreviations used are: DHT, dihydrotestosterone; LH, luteinizing hypertension, were included for adjustment. hormone.

Tab!e 3 Means and SD of serum h ormone levels in prostate can cer cases and controls, Washi ngton County, Maryland . 1974-1986

Cases (n = 98) Controls (n = 98) Percentage Serum hormones . P difference’ Mean (SD) Mean (SD)

Testosterone (ng/dI) 449.7 (187.1) 440.8 (237.5) 2.0 0.26 Dihydrotestosterone (ng/dI) 52.6 (20.8) 52.8 (23.8) -0.4 0.75 Prolactin (ng/nil) 6.8 (3.3) 6.8 (3.2) 0.0 0.94 Follicle-stimulating hormone (mIU/mI) 14.8 (9.4) 14.2 (12.4) 4.2 0.36 Luteinizing hormone (mIU/mI) 19.2 (12.1) 18.6 (15.5) 3.2 0.29 Estrone (pg/mI) 35.2 (13.7) 35.5 (17.9) -0.8 0.69 Estradiol pg/mI) 67.3 (24.9) 63.9 (22.2) 5.3 0.46 Testosterone:DHT ratio 8.9 (2.6) 8.4 (2.6) 5.9 0.09 Estrone:Iestosterone ratio 0.09 (0.04) 0.11 (0.11) -18.2 0.69 Estradiol:Iestosterone ratio 0.17 (0.08) 0.19 (0.18) -10.5 0.80

‘ Percentage difference = 100 (Mean of cases - mean of controls(/mean of controls. b Paired t test based on log-transformed values.

tenone) for cases and controls are shown in Table 3. the age of 70 years as reported previously (39), we Although no significant differences were observed for examined the risk of prostate cancer separately for 44 any of these hormones, cases in general had higher mean case-control pairs whose ages (age at diagnosis of the levels of serum hormones than those of controls, except cases) were below the age of 70 and 54 case-control for DHT, estrone, and the ratios of estrogens to testos- pairs older than 70 years. Because ofthe smaller numbers terone. The percentage differences between cases and in each age group, tertiles were used in the analysis. As controls ranged from -18.2 to 5.9, with the es- shown in Table 5, although the dose-response trends trone:testosterone ratio showing the greatest difference, were neither linear nor statistically significant, elevated although differences for the testosterone:DHT ratio most levels of LH and ratios of testosterone:DHT were asso- nearly attained statistical significance. ciated with increased risks of prostate cancer in persons Risks of prostate cancer were also assessed using below the age of 70, while elevated levels of testosterone quartiles of serum hormone levels among controls. As or estrone were associated with increased risks in persons shown in Table 4, nonsignificant dose-response associa- above the age of 70. tions were seen for testosterone, follicle-stimulating hor- To address whether the observed effects of testos- mone, LH, and the testosterone:DHT ratio; persons in terone, LH, and testosterone:DHT ratios were biological the upper three quartiles had elevated risk compared to markers for undiagnosed prostate cancer that was pres- men in the lowest quartile. Adjustment for marital status, ent at the time of blood collection in 1974, we examined years of education, cigarette smoking, and medication stratified case-control differences and odds ratios, group- use for hypertension did not materially change the risk ing them into 3- or 4-year subgroups based on time from esti mates. 1974 to cancer diagnosis. There were no trends in case- Of the 98 cancer cases, 18 had latent prostate cancer control differences or odds ratios by time between blood (stage A) diagnosed through transurethral resection of the collection and diagnosis. prostate for benign prostatic hyperplasia. Mean serum levels of testosterone, LH, and testosterone:DHT ratio of these 1 8 latent cases were lower than those of clinically Discussion overt cases. The exclusion of the 18 case-control pairs Our findings suggest that elevated levels of serum testos- from the analysis increased the magnitude of the risk terone, LH, or testosterone:DHT ratios may be associated estimates for testosterone, LH, and testosterone:DHT with increased risks of prostate cancer. However, we ratio but did not alter the results for any other hormone. found no evidence to support the hypothesis that dihy- To address the possibility that the risk patterns of drotestosterone, estrogen, or prolactin was related to prostate cancer may differ in persons below and above prostate cancer risk. The suggestive findings regarding testosterone, LH, and testosterone:DHT ratios are intriguing. The testosten- one finding is in accord with the results of animal studies Tab!e 4 Odds ratios for prostate cancer by quartiles of serum (18-23) and of studies using postdiagnostic blood (33- hormones among controls from 98 case-control pairs, 37), although Nomura et al. (49), using prediagnostic Washington County, Maryland, 1974-1986 blood from Japanese-Americans for case-control corn- Quartiles p for panisons, reported lower levels of serum testosterone in Serum hormones trend 1 (low) 2 3 4 (high) cases (means, 4205.5 versus 4308.8 pg/mI). The testosterone findings in both studies were weak, and chance Testosterone 1.0 1.7 2.0 1.5 0.3 Dihydrotestosterone 1.0 0.7 0.8 1.0 0.9 differences cannot be ruled out. Prolactin 1.0 1.2 0.9 1.1 1.0 Although testosterone is the primary plasma andro- FoIIicIe-stimulatinghormone 1.0 1.3 1.7 1.6 0.2 gen, the active hormone within the prostate gland is Luteinizinghormone 1.0 1.7 2.1 1.8 0.2 DHT, which is metabolized from testosterone by 5-ce- Estrone 1.0 0.8 2.1 0.8 0.6 Estradiol 1.0 0.9 1.1 1.0 0.9 reductase enzyme. However, consistent with the findings Testosterone:DHT ratio 1 .0 1 .4 1 .4 1 .7 0.3 of Nornura et al. (49), we found that cases had lower Estrone:testosterone ratio 1.0 0.6 1.4 0.8 0.8 serum levels of DHT than their controls. It is possible Estradiol:testosterone ratio 1.0 0.8 0.7 1.1 0.9 that hormone levels in the blood, especially DHT, may

A major strength of the study is the use of predi- Tab!e 5 Odds ratios for prostate cancer by tertiles of serum hormones among controls from 98 case-control pairs and by age at diagnosis, agnostic blood for case-control comparisons. Although Washington County. Maryland, 1974-1986 temporal relationships can thus be more easily estab-

Tertiles p for lished, the observed case-control differences might still Serum hormones be a consequence of the long-standing presence of un- 1 (low) 2 3 (high) tren diagnosed prostate cancer. We used two approaches to <70 years (44 pairs) examine this issue: examination of case-control differ- Testosterone 1.0 1.1 1.1 0.8 ences over time; and exclusion of case-control pairs with Dihydrotestosterone 1.0 0.9 0.7 0.6 early case diagnosis (1974-76) from the analysis. In both Prolactin 1.0 0.8 0.9 0.9 Follicle-stimulating hormone 1 .0 0.7 1 .1 0.8 approaches, the associations with testosterone, LH, and Luteinizing hormone 1.0 2.8 1.9 0.2 testosterone:DHT ratios persisted. Estrone 1.0 0.9 1.5 0.5 While prostate cancer has been considered a hor- Estradiol 1.0 0.8 0.6 0.4 Testosterone:DHT ratio 1.0 1.0 3.0 0.06 mone-related cancer, there are few epiderniological data Estrone:testosterone ratio 1 .0 1 .6 1 .9 0.4 thus far to support such a relationship. Measurement Estradiol:testosterone ratio 1 .0 0.7 1 .8 0.4 errors, resulting from substantial intraindividual variation and intra- and interassay variations in the laboratory, the 70 years (54 pairs) Testosterone 1 .0 2.4 1 .7 0.3 effect of cancer on the hormone levels due to use of Dihydrotestosterone 1.0 1.0 1.6 0.3 postdiagnostic blood, small sample size, and confound- Prolactin 1.0 0.8 0.9 0.8 ing by unknown factors may contribute to the lack of a FoIIicIe-stimulatinghormone 1.0 1.2 1.5 0.4 hormonal association in previous studies. Luteinizing hormone 1 .0 1 .4 1 .0 0.8 Estrone 1.0 2.3 2.2 0.2 Future epidemiological studies of the hormone-pros- Estradiol 1.0 0.8 0.9 0.8 tate relationship could profit from the following steps: Testosterone’:DHT ratio 1 .0 1 .3 0.9 0.8 use of biological materials that more closely reflect tissue Estrone:teslosterone ratio 1 .0 1 . 1 1 .4 0.5 levels of hormones; use of assays with improved accu- Estradiol:testoste’rone ratio 1 .0 0.5 0.7 0.4 racy; use of biological markers to identify preclinical disease (latent prostate cancer) among controls; comparison of hormone levels among latent and among clinically overt prostate cancer cases and controls; and minimizing not reflect the metabolism or carcinogenesis within the the effect of factors that may affect hormone levels (time prostate gland, since they do not correlate well with of biological material collection or smoking). hormone levels in prostatic tissue (42). The testosterone:DHT ratios in the plasma thus pro- Acknowledgments vide an indirect measure of the metabolic activity within the prostate, since direct comparisons in intra- or extra- The authors thank Dr. B. J. Stone for her assistance on data analysis, Sue Ann Sullivan and Kathie Niswander for their support on data collection, glandular hormonal metabolism between cases and nor- and Debbie Eyler for preparation of the manuscript. mal controls are not feasible. Consistent with two other studies, we found that elevated levels of testoster- References one:DHT ratios were associated with increased risks of prostate cancer (33, 49), suggesting that hormonal me- 1. Ries, L. A. C., Hankey, B. F., Miller, B. A., Hartman, A. M., and Edwards, B. K. Cancer Statistics Review 1973-88, NIH Publication no. tabolism within the prostate may play a role in the 91-2789. Bethesda: National Cancer Institute, 1991. development of prostate cancer. Recently, data from two 2. Boring, C. C.. Squires, T. 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A W Hsing and G W Comstock

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