What The Published Literature Says About Testosterone and Prostate Cancer

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Excerpts from 23 studies indicating that testosterone does not cause prostate cancer

This paper presents a quantitative review of the data from eight prospective epidemiological studies, comparing mean serum concentrations of sex hormones (free and bound testosterone, estrogen, DHT SHGB, DHEA) in men who subsequently developed prostate cancer with those in men who remained cancer free. No differences in the average concentrations of the hormones were found between prostate cancer cases and controls. These data suggest that there are no large differences in circulating hormones between men who subsequently go on to develop prostate cancer and those who remain free of the disease.

British Journal of Cancer (1999 Jun;80(7):930-4)

Study conducted: Imperial Cancer Research Fund, Cancer Epidemiology Unit, Radcliffe Infirmary, Oxford, UK.

We evaluated androgen levels in 3 age-matched groups of men who were part of the Baltimore Longitudinal Study of Aging: luteinizing hormone, total testosterone, and free testosterone were measured on stored sera. The median number of repeated sex steroid measurements ranged from 6-9 over a period from 7-25 years prior to the diagnosis of prostate disease. There were no significant differences in age-adjusted luteinizing hormone, total testosterone, SHBG, or calculated free testosterone levels among the groups at 0-5, 5-10, and 10-15 years before diagnosis. These data suggest that there are no measurable differences in serum testosterone levels among men who are destined to develop prostate cancer and those without the disease.

Prostate 1995 Jul;27(1):25-31

Study conducted: Department of Urology, Johns Hopkins University School of Medicine, James Buchanan Brady Urological Institute, Johns Hopkins Hospital, Baltimore, MD 21287-2101, USA.

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 testosterone: 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.

Cancer Epidemiology Biomarkers Prev (1997 Nov;6(11):967-9)

Study conducted: Department of Community Medicine and General Practice, University Medical Center, Trondheim, Norway. lars.vatten@medisin.ntnu.no

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.

Cancer Epidemiol Biomarkers Prev (1996 Aug;5(8):621-5)

Study conducted: Japan-Hawaii Cancer Study, Kuakini Medical Center, Honolulu 96817, USA.

Prostate cancer was identified in 14% (11/77) of the entire group and in 10 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 testosterone levels, and (2) PSA levels may be altered by naturally occurring reductions in serum androgen levels.

Journal of the American Medical Association (JAMA) 1996 Dec 18;276(23):1904-6

Study conducted: Division of Urology, Beth Israel Hospital, Harvard Medical School, Boston, Mass. 01215, USA.

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.

Cancer Epidemiology and Biomarkers Prev (1998 Dec;7(12):1069-74)

Study conducted: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892-7374, USA. jd7g@nih.gov

We report a nested case-control study of serum biomarkers 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.

Cancer Epidemiology Biomarkers Preventics (1997 Jan;6(1):21-4)

Study conducted: Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill 27509-7400, USA.

Serum samples were obtained from 6860 men during their study examination from 1971 to 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.

Cancer Research (1988 Jun 15;48(12):3515-7)

Study conducted: Japan-Hawaii Cancer Study, Kuakini Medical Center, Honolulu 96817.

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 behaviour 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 oestradiol (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).

European Journal of Cancer Prevention (1992 Apr;1(3):239-45)

Study conducted: Department of Urology, Erasmus University Rotterdam, The Netherlands.

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.

Cancer Epidemiology Biomarkers Prev (1993 Jan-Feb;2(1):27-32)

Study conducted: National Cancer Institute, Division of Cancer Etiology, Bethesda, Maryland 20892.

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.

Cancer Research (1991 Jul 1;51(13):3445-50)

Study conducted: Department of Endocrinology and Reproduction, Erasmus University Rotterdam, The Netherlands.

Frozen serum samples were analyzed for PSA, DHT, testosterone and SHBG, and compared to the diagnosis and tumour 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 tumours. 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, tumour stage and ploidy. The testosterone/DHT ratio tended to be higher in patients with more advanced tumours. SHBG levels were lower in patients with cancer than in controls but the differences were not statistically significant. There were no systematic variations of tumour stage, grade and ploidy. Within a group, DHT levels tended to be lower among cases and in those with more advanced tumours. No systematic variation were found in the levels of testosterone or SHBG.

British Journal of Urology (1996 Mar;77(3):433-40)

Study conducted: Department of Urology, Karolinska Institute at Stockholm Soder Hospital, Sweden.

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 brothers with or without prostatic cancer than among nonbrothers.

Prostate (1985;6(2):121-8)

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.

Cancer Research (1990 Jan 1;50(1):169-73)

Study conducted: Department of Community and Family Medicine, University of California San Diego, La Jolla 92093.

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 non-significantly lower among cases.

British Journal of Cancer 1993 Jul;68(1):97-102

Study conducted: Department of Urology, Orebro Medical Center Hospital, Sweden.

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.

Prostate 1987;11(2):171-82

Study conducted: Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill 27514.

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 testosterone 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.

Prostate 1983;4(3):223-9

A 4-fold higher relative risk for the development of static cancer was observed for brothers of prostatic cancer cases compared to their brothers-in-law and males in the general population of the state Utah. Probands and their brothers, and sons of the patients with the disease had significantly lower plasma testosterone 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 the cancer than among the families without cancer.

Journal of Clinical Endocrinology and Metabolism (1982 Jun;54(6):1104-8)

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 yr 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.

European Journal of Cancer Clinical Oncology (1984 Apr;20(4):477-82)

Pretreatment plasma concentrations of total testosterone, 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.

Scandanavian Journal of Urology and Nephrology Supplmental (1988;110:137-43)

Study conducted: Second Department of Surgery, Helsinki University Central Hospital, Finland.

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.

Journal of the National Medical Association 1995 Nov;87(11):813-9

Study conducted: Department of Radiation Oncology, Michael Reese Hospital, Center for Radiation Therapy, University of Chicago, Illinois, USA.

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.

Prostate Supplemental (1981;1:19-26)

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 10 hypogonadal men undergoing treatment with exogenous testosterone, delivered as testosterone enanthate injection or by testosterone patch. A 2-tailed, paired t-test failed to demonstrate a significant correlation between serum PSA or PSMA and serum testosterone levels. This study suggests that in hypogonadal men, neither PSMA nor PSA expression is testosterone-dependent.

Journal of Surgical Oncology (1995 Aug;59(4):246-50)

Study conducted: Department of Surgery, Walter Reed Army Medical Center, Washington, D.C. 20307-5001, USA.

The Neutral Study

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 nonsignificantly inversely with the disease.

Cancer Causes Control 1997 Jul;8(4):632-6

Study conducted: Department of Epidemiology and Harvard Center for Cancer Prevention, Harvard School of Public Health, Boston, Massachusetts 02115, USA.

Five Studies Indicating Testosterone Causes Prostate Cancer

We conducted a prospective, nested case-control 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. 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 P < .001). When hormone and SHBG levels were adjusted simultaneously, a strong trend of increasing prostate cancer risk was observed with increasing levels of plasma testosterone (ORs by quartile = 1.00, 1.41, 1.98, and 2.60 [95% CI = 1.34-5.02]; P for trend = .004), an inverse trend in risk was seen with increasing levels of SHBG (ORs by quartile = 1.00, 0.93, 0.61, and 0.46 [95% CI = 0.24-0.89]; P for trend = .01), and a non-linear inverse association was found with increasing levels of estradiol (ORs by quartile = 1.00, 0.53, 0.41), and 0.56 [95% CI = 0.32-0.98]; P for trend = .03). No associations were detected between the levels of DHT or prolactin and prostate cancer risk. 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.

Journal of the National Cancer Institute (1996 Aug 21;88(16):1118-26)

Study conducted: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Basal serum concentrations of sex steroids, sex hormone-binding globulin (SHBG) and gonadotrophins, and the basal levels and response to adreno-corticotropic hormone (ACTH) of adrenocortical steroids, were measured before treatment in 72 patients with prostate cancer and in 42 age-matched healthy controls. Patients aged < 60 years with prostate cancer had significantly elevated levels of total testosterone and unconjugated (E1) and total (tE1) oestrone while patients aged > or = 60 years had significantly elevated levels of total and non-SHBG-bound testosterone (NST). 17 alpha-hydroxyprogesterone and tE1. Gonadotrophins, SHBG levels and relationships between total testosterone and SHBG were normal in both age groups of patients, as were basal levels and ACTH-induced increments of adrenocortical steroids. The patients had normal age-related variations in SHBG and NST and in basal levels and ACTH-induced increments of adrenocortical steroids. There was a significant age-related increase in serum E1 in the control subjects but not in the patients. Patients with metastatic disease had significantly lower tE1 levels than had patients without metastases. The results suggest an increased sensitivity of the testis to gonadotrophic stimulation, as well as an increased peripheral oestrogen synthesis in patients with prostate cancer, the latter being most pronounced in younger subjects. Men developing prostate cancer may have been exposed to a combination of elevated endogenous oestrogen and androgen levels for a long time. These findings support the theory of a synergism between oestrogens and androgens as an important factor in the aetiology of prostate cancer.

British Journal of Urology (1997 Mar;79(3):427-31)

Study conducted: Department of Obstetrics and Gynaecology, Karolinska Institutet, Huddinge University Hospital, Sweden.

A blinded, case-control study was undertaken to determine if hair patterning is associated with risk of prostate cancer, as well as specific hormonal profiles. The study accrued 315 male subjects who were stratified with regard to age, race, and case-control status (159 prostate cancer cases/156 controls). Free testosterone was greater among cases than in controls (16.4 +/- 6.1 vs. 14.9 +/- 4.8 pg/ml, P = 0.02). Conversely, DHT-related ratios were greater among controls. Data suggest that increased levels of free testosterone may be a risk factor for prostatic carcinoma.

Journal of Andrology (1997 Sep-Oct;18(5):495-500)

Study conducted: Division of Urology, Duke University Medical Center, Durham, North Carolina 27710, USA.

We present the case of a hypogonadal patient in whom a 20-fold increase in prostate-specific antigen and a palpable prostatic nodule developed 6 months into the administration of intramuscular testosterone.

Urology (1999 Feb;53(2):423-4)

Study conducted: Department of Urology, Lahey Clinic Medical Center, Burlington, Massachusetts 01805, USA.

The metabolic clearance and production rates of testosterone were significantly higher in (prostate cancer) patients than in controls. These results indicate that men with prostatic cancer have elevated clearance and production rates of testosterone without an alteration of estradiol production or clearance.

Journal of Steroid Biochemistry (1989 Jul;33(1):19-24 r.)

Study conducted: Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City 84132.

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