PUBLISHED STUDIES

Studies Indicating That Testosterone Does
Not Cause Prostate Cancer

Study 1
"This nested case-control study was based on the cohort of men who donated blood to the Janus serum bank at Oslo University Hospital between 1973 and 1994. Cancer incidence was ascertained through linkage with the Norwegian Cancer Registry. The study included sera from 59 men who developed prostate cancer subsequent to blood donation and 180 men who were free of any diagnosed cancer in 1994 and were of similar age and had similar blood storage time. Neither testosterone, DHT, nor the ratio of testosterone to DHT was associated with risk of developing prostate cancer. These results showed no association, positive or negative, between androgens measured in serum and the subsequent risk of developing prostate cancer" (Vatten et al. Cancer Epidemiology Biomarkers Prev. 1997 Nov; 6(11): 967-9 (212). Study conducted at Department of Community Medicine and General Practice, University Medical Center, Trondheim, Norway [lars.vatten@medisin.ntnu.no]).

Study 2
"We conducted a nested case-control study in a cohort of 6860 Japanese-American men examined from 1971 to 1975. At the time of examination, a single blood specimen was obtained, and the serum was frozen. After a surveillance period of more than 20 years, 141 tissue-confirmed incident cases of prostate cancer were identified, and their stored sera and those of 141 matched controls were assayed for total testosterone, free testosterone, dihydrotestosterone, 3-alpha-androstanediol glucuronide, androsterone glucuronide, and androstenedione. The findings of this study indicate that none of these androgens is strongly associated with prostate cancer risk" (213) (Nomura et al. Cancer Epidemiol. Biomarkers Prev. 1996 Aug; 5(8): 621-5. Study conducted at Japan-Hawaii Cancer Study, Kuakini Medical Center, Honolulu, HI 96817).

Study 3
"Prostate cancer was identified in 14% (11/77) of the entire group and in ten men (29%) aged 60 years or older. The median age for men with cancer was 64 years. No significant differences were noted between the cancer and benign groups with regard to PSA level, PSA density, prostate volume, total testosterone level, or free testosterone level. A high prevalence of biopsy-detectable prostate cancer was identified in men with low total or free testosterone levels despite normal PSA levels and results of digital rectal examination. These data suggest that (1) digital rectal examination and PSA levels are insensitive indicators of prostate cancer in men with low total or free tes-tosterone levels, and (2) PSA levels may be altered by naturally occurring reductions in serum androgen levels" (213) (Morgentaler et al. J. Am. Med. Assoc. 1996 Dec 18; 276(23): 1904-6. Study conducted at Division of Urology, Beth Israel Hospital, Harvard Medical School, Boston, MA 02215).

Study 4
"We conducted a prospective nested case-control study to evaluate the relationships of serum androgens and estrogens to prostate cancer using serum collected at baseline for the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. None of the individual androgens or estrogens was significantly related to prostate cancer. These results do not support a strong relationship of serum androgens and estrogens with prostate cancer in smokers" (189) (Dorgan et al. Cancer Epidemiol. Biomarkers Prev. 1998 Dec; 7(12): 1069-74. Study conducted at Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892-7374 [jd7g@nih.gov]).

Study 5
"We report a nested case-control study of serum bio-markers of 5-alpha-reductase activity and the incidence of prostate cancer. From a cohort of more than 125,000 members of the Kaiser Permanente Medical Care Program who underwent multiphasic health examinations during 1964-1971, we selected 106 incident prostate cancer cases. A control was pair matched to each case on age, date of serum sampling, and clinic location. The adjusted odds ratios and 95% confidence intervals for a one quartile score increase were 1.00 for total testosterone (1.00 = no increased risk), 1.14 for free testosterone, 1.13 for androsterone glucuronide, and 1.16 for 3-alpha-diol G" (190) (Guess et al. Cancer Epidemiology Biomarkers Prev. 1997 Jan; 6(1): 21-4. Study conducted at Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC 27599-7400).

Study 6
"Serum samples were obtained from 6860 men during their study examination from 1971-1975. After a surveillance period of about 14 years, 98 incident cases of prostate cancer were identified. Their stored sera and that of 98 matched controls from the study population were tested for the following: testosterone, dihydrotestosterone, estrone, estradiol, and sex hormone globulin. There was a suggestion that serum dihydrotestosterone levels were lower and the testosterone/dihydrotestosterone ratios were higher in the prostate cancer cases compared with their controls. However, none of these associations or that of the other hormones was strongly significant" (191) (Nomura et al. Cancer Res. 1988 Jun 15; 48(12): 3515-7. Study conducted at Japan-Hawaii Cancer Study, Kuakini Medical Center, Honolulu, HI 96817).

Study 7
"A case-control study of prostatic cancer was carried out to examine the association between selected physical characteristics and factors related to sexual development and behavior and the risk for this disease. The levels of testosterone (T), dihydrotestosterone, salivary testosterone and T/SHBG (sex hormone binding globulin) did not vary with age. Older men had higher estradiol (estrogen) levels. Further, little association between hormone levels and risk factors was found, except for married subjects having increased serum androgens and heavy subjects having decreased serum androgens (not significant)" (192) (Hayes et al. Eur. J. Cancer Prev. 1992 Apr; 1(3): 239-45. Study conducted at Department of Urology, Erasmus University, Rotterdam, the Netherlands).

Study 8
"A population-based nested case-control study was conducted to determine the relation of prediagnostic serum levels of testosterone, dihydrotestosterone, prolactin, follicle-stimulating hormone, luteinizing hormone, estrone, and estradiol to the risk of subsequent prostate cancer. Serum specimens of study subjects were available from a blood collection campaign in Washington County, Maryland, in 1974. There were no significant differences in levels of these hormones between cases and controls, although elevated levels of luteinizing hormone and of testosterone/dihydrotestosterone ratios were associated with mild increased risks of prostate cancer" (194) (Hsing et al. Cancer Epidemiol. Biomarkers Prev. 1993 Jan-Feb; 2(1): 27-32. Study conducted at National Cancer Institute, Division of Cancer Etiology, Bethesda, MD 20892).

Study 9
"The possible relationship between changes in peripheral hormone levels and the occurrence of prostatic pathology was studied in a case-control study involving estimation of various plasma hormones in 368 Dutch and 258 Japanese men, who were grouped as controls and patients with benign prostatic hyperplasia, focal prostatic carcinoma, or clinically evident prostatic carcinoma. There were no significant differences in plasma androgen levels between Japanese or Dutch prostate cancer cases and their respective control subgroups. These findings do not support a correlation between the lower plasma testosterone levels and a lower incidence of prostate cancer in the Japanese men. Furthermore, no significant differences were found between salivary levels of testosterone or the ratio between testosterone and SHBG in the various Dutch subgroups. In Japanese benign prostatic hyperplasia patients, the testosterone to SHBG ratio was significantly increased. In conclusion, the results of this retrospective, cross-sectional study do not indicate that hormonal levels play a primary role in the origin or promotion of prostatic abnormalities" (195) (de Jong et al. Cancer Res. 1991 Jul 1; 51(13): 3445-50. Study conducted at Department of Endocrinology and Reproduction, Erasmus University, Rotterdam, the Netherlands).

Study 10
"Frozen serum samples were analysed for PSA, DHT, testosterone and SHBG, and compared to the diagnosis and tumor stage, grade, and ploidy. DHT levels were slightly lower in patients with prostate cancer but the difference was not statistically significant. There was a trend towards lower DHT values in more advanced tumors. Testosterone levels were lower in patients with cancer than in the control group, but the differences were not significant. There was no correlation between testosterone levels, tumor stage, and ploidy. The testosterone/DHT ratio tended to be higher in patients with more advanced tumors. SHBG levels were lower in patients with cancer than in controls, but the differences were not statistically significant. There were no systematic variations of tumor stage, grade, and ploidy. Within a group, DHT levels tended to be lower among cases and in those with more advanced tumors. No systematic variation was found in the levels of testosterone or SHBG" (197) (Gustafsson et al. Br. J. Urol. 1996 Mar; 77(3): 433-40. Study conducted at Department of Urology, Karolinska Institute at Stockholm Soder Hospital, Sweden).

Study 11
"Index cases and their brothers and sons had a significantly lower mean plasma testosterone content than controls of comparable age. Preliminary data suggest that the metabolic clearance rate of testosterone and the conversion ratio of testosterone to estradiol are relatively high in probands. The observations indicate that familial factors are potent risk factors for the development of prostatic cancer. They also suggest that plasma androgen values in families with prostatic cancer cluster in the lower range of normal and that plasma sex-steroid content is more similar in each brother with or without prostatic cancer than among non-brothers" (198) (Meikle et al. Prostate 1985; 6(2): 121-8).

Study 12
"Baseline sex hormone levels were measured in 1008 men ages 40-79 years who had been followed for 14 years. There were 31 incident cases of prostatic cancer and 26 identified from death certificates with unknown dates of diagnosis. In this study, total testosterone, estrone, estradiol, and sex hormone-binding globulin were not related to prostate cancer, but plasma androstenedione showed a positive dose-response gradient" (199) (Barrett-Connor et al. Cancer Res. 1990 Jan 1; 50(1): 169-73. Study conducted at Department of Community and Family Medicine, University of California, San Diego, La Jolla, CA 92093).

Study 13
"The hypothesis that serum concentrations of pituitary hormones, sex steroid hormones, or sex hormone-binding globulin (SHBG) affect the occurrence of prostatic cancer was tested in a consecutive sample of 93 patients with newly diagnosed, untreated cancer and in 98 population controls of similar ages without the disease. Remarkably close agreement was found for mean values of total testosterone (15.8 in cases and 16.0 in controls), and free testosterone (0.295 and 0.293, respectively), with corresponding odds ratios for the highest vs. lowest tertile of 1.0 (1.00 = no increased risk) for testosterone and 1.2 for free testosterone. Similar close agreement between cases and controls was found for serum concentrations of estradiol, androstenedione, and SHBG, although the mean estradiol level was nonsignificantly lower among cases" (200) (Andersson et al. Br. J. Cancer 1993 Jul; 68(1): 97-102. Study conducted at Department of Urology, Orebro Medical Center Hospital, Sweden).

Study 14
"Modest depression of serum testosterone and estradiol was noted for prostate cancer patients compared to clinic controls, although the differences were not statistically significant. This depression was interpreted to be a likely result of the malignant process rather than a cause of it" (202) (Hulka et al. Prostate 1987; 11(2): 171-82. Study conducted at Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, NC 27514).

Study 15
"The prostate cancer patients had a slightly lower mean free testosterone and mean estradiol/free T ratio than the BPH patients. The mean estradiol/free tes-tosterone ratio was significantly higher in the BPH patients and in the PC patients than in the young controls. It seems possible that the observed age-dependent significant increase in plasma estrogen concentration in the BPH patients may act as a protective factor against prostatic cancer" (203) (Rannik-ko et al. Prostate 1983; 4(3): 223-29).

Study 16
"A fourfold higher relative risk for the development of prostatic cancer was observed for brothers of prostatic cancer cases compared to their brothers-in-law and males in the general population of the state of Utah. Probands and their brothers, and sons of the patients with the disease, had significantly lower plasma tes-tosterone levels than controls of comparable age. This is the first documentation indicating that familial (possibly genetic) factors are potent risk factors for predisposing men to the development of prostatic cancer and in regulating the plasma content of androgens. Our results indicate that plasma androgen levels in families with prostatic cancer are clustered in the lower range of the normal population. They also suggest that plasma androgen content is more similar within each family with cancer than among families without cancer" (204) (Meikle et al. J. Clin. Endocrinol. Metabol. 1982 Jun; 54(6): 1104-1108).

Study 17
"Pretreatment hormone levels were determined in 222 patients with prostatic cancer and their prognostic value assessed. The patients were grouped into yearly survival categories and only those whose cause of death was due to the disease were included in the study. Low concentrations of testosterone in plasma at the time of diagnosis related to a poor prognosis. Patients who died within 1 year of diagnosis had the lowest mean plasma levels of this steroid. The pretreatment mean plasma testosterone concentrations were found to be higher as the survival period of the various groups lengthened. The indications from this study are that poor testicular function is associated with early death from prostatic carcinoma and that the measurement of blood levels of testosterone at diagnosis could provide a prognosis of subsequent life span" (205) (Harper et al. Eur. J. Cancer Clin. Oncol. 1984 Apr; 20(4): 477-82).

Study 18
"Pretreatment plasma concentrations of total tes-tosterone, prolactin, and total estradiol were measured in 123 prostatic cancer patients who were categorized into groups according to the UICC classification. The mean follow-up time was 48 months. Higher pretreatment estradiol and testosterone levels were associated with better survival" (207) (Haapiainen et al. Scand. J. Urol. Nephrol. Suppl. 1988; 110: 137-43. Study conducted at Second Department of Surgery, Helsinki University Central Hospital, Finland).

Study 19
"This cross-sectional study was undertaken to determine whether serum hormones (free testosterone, androstenedione, luteinizing hormone, or prolactin) have any influence on serum prostate specific antigen (PSA) levels in patients with stage A-C prostate cancer. None of the hormones in any of the analyses showed any association to serum PSA values. Serum free testosterone, androstenedione, and luteinizing hormone appeared to have no influence on serum PSA values in nonmetastatic cancer patients" (208) (Vijayakumar et al. J. Natl. Med. Assoc. 1995 Nov; 87(11): 813-19. Study conducted at Department of Radiation Oncology, Michael Reese Hospital, Center for Radiation Therapy, University of Chicago).

Study 20
"Serum levels of testosterone, DHT, androsterone, 5 alpha-androstane-3 alpha, 17-beta-diol (5 alpha-diol), and estradiol were measured by radioimmunoassay in the sera of 9 patients with untreated prostatic cancer and in 11 with benign prostatic hypertrophy (BPH). Although no specific changes in steroid hormone levels in either disease group were found, response patterns of serum T, DHT, and E2 were shown to be those characteristic of male senescence, suggesting a relative predominance of estrogens over androgens" (211) (Isurugi et al. Prostate Suppl. 1981; 1: 19-26).

Study 21
"We studied the effect of exogenous testosterone administration on the serum levels of PSA (prostate-specific antigen) and PSMA (prostate-specific membrane antigen) in hypogonadal men. Serial serum PSA, serum PSMA, and serum total testosterone levels were obtained at intervals of every 2-4 weeks in ten hypogonadal men undergoing treatment with exogenous testosterone, delivered as testosterone enanthate injection or by testosterone patch. A two-tailed, paired t-test failed to demonstrate a significant correlation between serum PSA or PSMA and serum testosterone levels. This study suggests that in hypo-gonadal men, neither PSMA nor PSA expression is testosterone-dependent" (185) (Douglas et al. J. Surg. Oncol. 1995 Aug; 59(4): 246-50. Study conducted at Department of Surgery, Walter Reed Army Medical Center, Washington, D.C. 20307-5001).

Study 22
"Blood samples were collected from 52 incident cases of histologically confirmed prostate cancer and 52 age- and town of residence-matched healthy controls in Athens, Greece. DHT was associated inversely, significantly, and strongly with the risk of prostate cancer, whereas testosterone was associated marginally positively, and E2 was associated non-significantly inversely with the disease" (Signorello et al. Cancer Causes Control 1997 Jul; 8(4): 632-36. Study conducted at Department of Epidemiology and Harvard Center for Cancer Prevention, Harvard School of Public Health, Boston, MA 02115).