Gormley GJ
Merck Research Laboratories, Rahway, NJ 07065, USA.
Semin Urol Oncol; 14(3):139-44 1996

Finasteride, an orally active type II 5 alpha-reductase (5 alpha R) inhibitor, blocks conversion of testosterone (T) to dihydrotestosterone (DHT). The utility of finasteride in effectively managing benign prostatic hyperplasia has been documented. Use of the drug results in reduced prostate volume and serum levels. Patients receiving finasteride should be monitored with periodic digital-rectal examination (DRE) and serum PSA measurement. Patients with a sustained increase in serum PSA or an abnormal DRE require additional evaluation. There is no evidence that use of finasteride has an adverse effect on prostate cancer detection, if the drug's effect on serum PSA is recognized and accounted for.

Gormley GJ; Stoner E; Bruskewitz RC; Imperato-McGinley J; Walsh PC; McConnell JD; Andriole GL; Geller J; Bracken BR; Tenover JS; et al
Merck Research Laboratories, Rahway, NJ 07065.
N Engl J Med; 327(17):1185-91 1992

BACKGROUND. Benign prostatic hyperplasia is a progressive, androgen-dependent disease resulting in enlargement of the prostate gland and urinary obstruction. Preventing the conversion of testosterone to its tissue-active form, dihydrotestosterone, by inhibiting the enzyme 5 alpha-reductase could decrease the action of androgens in their target tissues; in the prostate the result might be a decrease in prostatic hyperplasia and therefore in symptoms of urinary obstruction.

METHODS. In a double-blind study, we evaluated the effect of two doses of finasteride (1 mg and 5 mg) and placebo, each given once daily for 12 months, in 895 men with prostatic hyperplasia. Urinary symptoms, urinary flow, prostatic volume, and serum concentrations of dihydrotestosterone and prostate-specific antigen were determined periodically during the treatment period.

RESULTS. As compared with the men in the placebo group, the men treated with 5 mg of finasteride per day had a significant decrease in total urinary-symptom scores (P less than 0.001), an increase of 1.6 ml per second (22 percent, P less than 0.001) in the maximal urinary-flow rate, and a 19 percent decrease in prostatic volume (P less than 0.001). The men treated with 1 mg of finasteride per day did not have a significant decrease in total urinary-symptom scores, but had an increase of 1.4 ml per second (23 percent) in the maximal urinary-flow rate, and an 18 percent decrease in prostatic volume. The men given placebo had no changes in total urinary-symptom scores, an increase of 0.2 ml per second (8 percent) in the maximal urinary-flow rate, and a 3 percent decrease in prostatic volume. The frequency of adverse effects in the three groups was similar, except for a higher incidence of decreased libido, impotence, and ejaculatory disorders in the finasteride-treated groups.

CONCLUSIONS. The treatment of benign prostatic hyperplasia with 5 mg of finasteride per day results in a significant decrease in symptoms of obstruction, an increase in urinary flow, and a decrease in prostatic volume, but at a slightly increased risk of sexual dysfunction.

Boehm S, Nirnberger G, Ferrari P
Department of Neuropharmacology, University of Vienna, Austria.
Stefan.Boehm@univie.ac.at
Wien Klin Wochenschr 1998 Dec 11;110(23):817-23

Estrogen suppression has been introduced as a pharmacotherapeutic strategy in the medical treatment of benign prostatic hyperplasia. Recent negative results obtained in placebo-controlled trials with the aromatase inhibitor atamestane raised doubts about the efficacy of estrogen reduction. However, inhibition of aromatase not only reduces estrogens but also increases androgens which promote prostatic growth. In order to reevaluate the therapeutic efficacy of estrogen suppression, we summarize clinical trials investigating the therapeutic effects of mepartricin in the treatment of uncomplicated benign prostatic hyperplasia. Mepartricin has been reported to lower the levels of circulating estrogens without causing changes in other hormones such as androgens. By applying stringent inclusion criteria, 23 studies (including 7 placebo-controlled trials, 3 post-marketing surveillance studies, and 13 open trials) published between 1982 and 1996 were selected to be included in this report. In 79.9% of 4635 patients treated with mepartricin, its therapeutic effect was rated "good" or "excellent". In 6 out of 7 placebo-controlled trials, the therapeutic efficacy of mepartricin was significantly superior to that of placebo. Comparison of these data with results obtained with alpha 1-adrenoceptor antagonists or with the 5 alpha-reductase inhibitor finasteride indicates that mepartricin is as efficient as these widely accepted medical treatments for benign prostatic hyperplasia. Since mepartricin acts selectively upon estrogens, the present results show that estrogen suppression may be considered an efficient pharmacotherapeutic strategy in the medical treatment of uncomplicated benign prostatic hyperplasia.

Hiramatsu M, Maehara I, Ozaki M, Harada N, Orikasa S, Sasano H
Department of Pathology, Tohoku University School of Medicine, Sendai, Japan.
Prostate 1997 May 1;31(2):118-24

The expression and activity of aromatase was evaluated in 19 individuals with benign prostatic hyperplasia (BPH) and 26 prostatic carcinoma (PC) patients to elucidate the possible biological significance of in situ estrogen production in the development of human prostatic disorders. Marked aromatase immunoreactivity was observed in proliferative stromal cells, especially those around hyperplastic glands in 18 (95%) BPH patients and in stromal cells surrounding carcinomatous glands in 18 (69%) PC patient specimens. The percentage of aromatase-positive stromal cells did not differ between BPH and PC. No significant correlation was apparent between the percentage of aromatase-positive cells and either the extent of carcinoma differentiation or surgical stage in the PC patients. Quantitation of aromatase activity by the [3H] water assay yielded values of 27.23 +/- 6.87 and 26.52 +/- 9.12 fmol/hr/mg of protein for BPH (nine patients) and PC (nine patients), respectively. Reverse transcriptase and polymerase chain reaction analysis revealed that the mean aromatase mRNA content was 1.671 +/- 0.82 and 1.11 +/- 0.51 attomole/ng of total RNA (tRNA) for BPH (seven patients) and PC (four patients), respectively. There were no significant differences in aromatase activity or aromatase mRNA concentration between PC and BPH. The alternative use of multiple exons 1 of the aromatase gene was also examined. Predominant aromatase gene transcripts contained exon 1b in three of four of PC specimens and two of three BPH specimens examined, in contrast to the use of exon 1d previously described in normal prostate. Unlike breast and endometrium, therefore, aromatase expression in human prostate was not associated with malignancy. However, overexpression of aromatase, possibly attributable to abnormal gene regulation, may result in estrogen production in situ and play a role in the induction or development of human prostatic disorders.

Tsugaya M, Harada N, Tozawa K, Yamada Y, Hayashi Y, Tanaka S, Maruyama K, Kohri K
Department of Urology, Nagoya City University, Medical School, Japan.
Int J Urol 1996 Jul;3(4):292-6

BACKGROUND: Estrogens are suspected to play a role in the pathogenesis of benign prostatic hyperplasia (BPH) and prostate cancer. In this study, the expression of aromatase messenger ribonucleic acid (mRNA) was determined, and these levels were quantitated, in human prostatic tissues to evaluate the role of estrogens in the pathogenesis of BPH and prostate cancer.

METHODS: Prostatic tissues were obtained either by retropubic prostatectomy, radical prostatectomy, or radical cystectomy from patients with BPH, prostate cancer, and bladder cancer. The expression of aromatase mRNA in the prostatic tissues was studied by Southern blot analysis of the reverse transcription and polymerase chain reaction technique (RT-PCR) products. Aromatase mRNA levels were measured in human prostatic tissues by the RT-PCR using a fluorescent primer.

RESULTS: Aromatase mRNA was identified in all specimens by Southern blot analysis of the RT-PCR products. The concentrations of aromatase mRNA (mean +/- SD) which were measured by fluorometric quantitation in 16 of 19 patients with BPH and in 3 of 4 patients with prostate cancer, were 1.81 +/- 3.02, and 0.84 +/- 0.27, x 10(-3) attomoles/micrograms of total RNA, respectively.

CONCLUSIONS: These results demonstrate local formation of estrogen in the prostates of patients with BPH and prostate cancer. Controlled studies will be necessary to determine whether this may be a factor in the development of BPH and prostate cancer.

Douglas TH, Connelly RR, McLeod DG, Erickson SJ, Barren R 3rd, Murphy GP
Department of Surgery, Walter Reed Army Medical Center, Washington, D.C. 20307-5001, USA.
J Surg Oncol 1995 Aug;59(4):246-50

Previous studies have suggested that serum prostate-specific antigen (PSA) levels are under androgenic influence, especially in patients with adenocarcinoma of the prostate. PSMA (prostate-specific membrane antigen) is thought to reflect hormonal or clonal resistance or an independence with respect to testosterone regulation. The influence of testosterone on serum PSA expression in normal men is not clear. We studied the effect of exogenous testosterone administration on the serum levels of PSA and PSMA in hypogonadal men. Serial serum PSA, serum PSMA by Western blot, 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. Linear and quadratic orthogonal polynomial scores were calculated for PSMA, PSA, and testosterone. A 2-tailed, paired t-test failed to demonstrate a significant correlation between serum PSA (linear P = 0.432, quadratic P = 0.290) or PSMA (linear P = 0.162, quadratic P = 0.973) and serum testosterone levels. This study suggests that in hypogonadal men, neither PSMA nor PSA expression is testosterone-dependent.

Carter HB, Pearson JD, Metter EJ, Chan DW, Andres R, Fozard JL, Rosner W, Walsh PC
Department of Urology, Johns Hopkins University School of Medicine, James Buchanan Brady Urological Institute, Johns Hopkins Hospital, Baltimore, MD 21287-2101, USA.
Prostate 1995 Jul;27(1):25-31

Androgens are thought to play a role in the pathogenesis of prostate cancer. We evaluated androgen levels in 3 age-matched groups of men who were part of the Baltimore Longitudinal Study of Aging: 1) 16 men with no prostatic disease by urologic history and exam (control group); 2) 20 men with a histologic diagnosis of benign prostatic hyperplasia (BPH) who had undergone simple prostatectomy; and 3) 20 men with a histologic diagnosis of prostate cancer (16 with local/regional cancer, and 4 with metastatic cancer). Luteinizing hormone (LH), total testosterone (T), and free T were measured on stored AM sera by radioimmunoassay (RIA). Free T was also calculated from the measured concentrations of total T and sex hormone binding globulin (SHBG). 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 LH, total T, SHBG, or calculated free T 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.

Levine AC, Kirschenbaum A, Gabrilove JL
Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
J Androl 1989 May-Jun;10(3):240-7

BACKGROUND: It has long been suspected that sex steroids play a key role in the pathogenesis of benign prostatic hyperplasia (BPH). Prostatic diseases do not occur in males castrated before puberty or in males with heritable disorders of androgen production or action. Both estrogens and androgens have been shown to induce BPH in experimental animals.

METHODS: Clinical studies utilizing hormonal therapies to treat BPH were reviewed. Studies that used total medical castration therapy via the use of a long-acting gonadotropin-releasing hormone (GnRH agonist), partial androgen blockade via the use of the 5 alpha-reductase inhibitor finasteride, and estrogen blockade (via the use of aromatase inhibitors) were analyzed.

RESULTS AND CONCLUSIONS: Both the GnRH agonists and finasteride result in prostatic size reduction and alleviate symptoms in some patients. Both therapies are more effective in men with larger prostates (> 40 cc). Finasteride is less efficacious in terms of size reduction than the GnRH agonists but also has fewer side effects. To date, clinical trials with aromatase inhibitors have not yielded dramatic positive results in the treatment of BPH.

Eaton NE, Reeves GK, Appleby PN, Key TJ
Imperial Cancer Research Fund, Cancer Epidemiology Unit, Radcliffe Infirmary, Oxford, UK.
Br J Cancer 1999 Jun;80(7):930-4

This paper presents a quantitative review of the data from eight prospective epidemiological studies, comparing mean serum concentrations of sex hormones in men who subsequently developed prostate cancer with those in men who remained cancer free. The hormones reviewed have been postulated to be involved in the aetiology of prostate cancer: androgens and their metabolites testosterone (T), non-SHBG-bound testosterone (non-SHBG-bound T), di-hydrotestosterone (DHT), androstanediol glucuronide (A-diol-g), androstenedione (A-dione), dehydroepiandrosterone sulphate (DHEAS), sex hormone binding globulin (SHBG), the oestrogens, oestrone and oestradiol, luteinizing hormone (LH) and prolactin. The ratio of the mean hormone concentration in prostate cancer cases to that of controls (and its 95% confidence interval (CI)) was calculated for each study, and the results summarized by calculating the weighted average of the log ratios. No differences in the average concentrations of the hormones were found between prostate cancer cases and controls, with the possible exception of A-diol-g which exhibited a 5% higher mean serum concentration among cases relative to controls (ratio 1.05, 95% CI 1.00-1.11), based on 644 cases and 1048 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. Further research is needed to substantiate the small difference found in A-diol-g concentrations between prostate cancer cases and controls.

Dorgan JF, Albanes D, Virtamo J, Heinonen OP, Chandler DW, Galmarini M, McShane LM, Barrett MJ, Tangrea J, Taylor PR
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892-7374, USA. jd7g@nih.gov
Cancer Epidemiol Biomarkers Prev 1998 Dec;7(12):1069-74

Several lines of evidence suggest that sex hormones may be involved in the etiology of prostate cancer. 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. The 29,133 male smokers who participated in the trial were 50-69 years old at baseline. During 5-8 years of follow-up, 246 men were diagnosed with prostate cancer, and 116 of these were randomly selected for inclusion in the current study. For each case, two controls matched on age, date of blood collection, intervention group, and study center were selected. Hormones were measured in serum by RIA using standard procedures. None of the individual androgens or estrogens was significantly related to prostate cancer. These findings were unaltered by simultaneous evaluation of serum androgen and estrogen concentrations in multivariate models. These results do not support a strong relationship of serum androgens and estrogens with prostate cancer in smokers. Within-person variation in concentrations of some hormones may have contributed to the lack of significant associations.

Guess HA, Friedman GD, Sadler MC, Stanczyk FZ, Vogelman JH, Imperato-McGinley J, Lobo RA, Orentreich N
Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill 27599-7400, USA.
Cancer Epidemiol Biomarkers Prev 1997 Jan;6(1):21-4

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. Serum levels of total testosterone, free testosterone, androsterone glucuronide, and 5 alpha-androstane-3 alpha,17 beta androstanediol glucuronide (3 alpha-diol G) were measured on the stored samples and scored as quartiles. Potential confounders included alcohol, smoking, and body mass index. The adjusted odds ratios and 95% confidence intervals for a one quartile score increase were 1.00 (0.75-1.34) for total testosterone, 1.14 (0.86-1.50) for free testosterone, 1.13 (0.84-1.53) for androsterone glucuronide, and 1.16 (0.86-1.56) for 3 alpha-diol G. A limitation of this study is that there are two different 5 alpha-reductase isoenzymes, only one of which is expressed in high levels within the prostate, yet both of which may affect serum biomarkers. Since the two isoenzymes are encoded on different chromosomes, variation in one would act as an independent source of measurement error in any analysis of serum biomarker effects of the other. Consequently, the odds ratios may be underestimated and the study, although negative, cannot exclude the previously hypothesized possibility that a positive relationship between intraprostatic 5 alpha-reductase activity and prostate cancer may exist. A clinical trial to test this hypothesis is under way.

Nomura A, Heilbrun LK, Stemmermann GN, Judd HL
Japan-Hawaii Cancer Study, Kuakini Medical Center, Honolulu 96817.
Cancer Res 1988 Jun 15;48(12):3515-7

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. Further work is needed to clarify the relationship between sex hormones and prostate cancer risk.

Hayes RB, de Jong FH, Raatgever J, Bogdanovicz J, Schroeder FH, van der Maas P, Oishi K, Yoshida O
Department of Urology, Erasmus University Rotterdam, The Netherlands.
Eur J Cancer Prev 1992 Apr;1(3):239-45

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. In consideration of an endocrinologic mechanism for these putative risk factors, the association between selected factors and serum hormone level in a comparison group, free of prostate cancer, was also examined. One-hundred cases and 113 controls were included for study. An elevated risk for prostatic cancer was found for those currently married (odds ratio (OR) = 4.0), those who had been married once (OR = 2.8), and those who were currently practising a religion (OR = 2.0). Compared to subjects with one child, those with more than one child and those with no children were more common among cases than controls. Prostatic cancer risk was associated with large body size and, in particular, with greater weight (p < 0.01). Early age at attainment of adult height was also associated with prostatic cancer risk (p < 0.01). Only moderate associations were found between increased frequency of sexual intercourse and prostatic cancer risk. 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 levels. Further, little association between hormone levels and risk factors was found, except for married subjects having increased serum androgens (p < 0.05) and heavy subjects having decreased serum androgens (not significant).

Signorello LB, Tzonou A, Mantzoros CS, Lipworth L, Lagiou P, Hsieh C, Stampfer M, Trichopoulos D
Department of Epidemiology and Harvard Center for Cancer Prevention, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
Cancer Causes Control 1997 Jul;8(4):632-6

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. Samples were analyzed blindly in Boston, Massachusetts (USA) for testosterone (T), estradiol (E2), sex hormone-binding globulin (SHBG), and dihydrotestosterone (DHT). The data were modeled using multiple logistic regression with adjustment for age, height, body mass index (wt/ht2), years of schooling, and mutually among hormones. DHT was associated inversely, significantly, and strongly with the risk of prostate cancer, whereas T was associated marginally positively, and E2 was associated nonsignificantly inversely with the disease. No association was observed in this study with respect to SHBG.

Hsing AW, Comstock GW
National Cancer Institute, Division of Cancer Etiology, Bethesda, Maryland 20892.
Cancer Epidemiol Biomarkers Prev 1993 Jan-Feb;2(1):27-32

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. Serum hormone levels of 98 histologically confirmed prostate cancer cases diagnosed in the subsequent 13 years were compared to those of 98 controls who were individually matched to cases on the basis of age (within weeks), sex, and race. 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.

de Jong FH, Oishi K, Hayes RB, Bogdanowicz JF, Raatgever JW, van der Maas PJ, Yoshida O, Schroeder FH
Department of Endocrinology and Reproduction, Erasmus University Rotterdam, The Netherlands.
Cancer Res 1991 Jul 1;51(13):3445-50

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. Results of a number of previous, smaller studies concerning interrelationships between hormone levels in elderly men were confirmed within the Dutch and Japanese groups. Plasma levels of testosterone and estradiol were significantly lower in the Japanese men, when compared with those in Dutch men. Probably as a result of this difference in testosterone levels, the ratio between serum levels of testosterone and sex hormone-binding globulin (SHBG) was decreased in the Japanese men, while the ratio between the concentrations of dihydrotestosterone and testosterone was increased. These differences were also found when results from Japanese subgroups (controls and patients with prostate pathology) were compared with those from the Dutch subgroups. 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. The finding of a lower plasma testosterone in the Japanese men, however, remains suggestive, warranting a more extensive prospective study.

Carlstrom K, Stege R
Department of Obstetrics and Gynaecology, Karolinska Institutet, Huddinge University Hospital, Sweden.
Br J Urol 1997 Mar;79(3):427-31

OBJECTIVE: To compare the endocrine status of patients with prostate cancer with that of age-matched healthy controls.

PATIENTS, SUBJECTS AND METHODS: 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.

RESULTS: 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.

CONCLUSIONS: 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.

Gustafsson O, Norming U, Gustafsson S, Eneroth P, Astrom G, Nyman CR
Department of Urology, Karolinska Institute at Stockholm Soder Hospital, Sweden.
Br J Urol 1996 Mar;77(3):433-40

OBJECTIVE: To investigate the possible relationship between serum levels of prostate specific antigen (PSA), dihydrotestosterone (DHT), testosterone, sexual-hormone binding globulin (SHBG) and tumour stage, grade and ploidy in 65 cases of prostate cancer diagnosed in a screening study compared to 130 controls from the same population.

PATIENTS, SUBJECTS AND METHODS: From a population of 26,602 men between the ages of 55 and 70 years, 2400 were selected randomly and invited to undergo screening for prostate cancer using a digital rectal examination, transrectal ultrasonography and PSA analysis. Among the 1782 attendees, 65 cases of prostate cancer were diagnosed. Each case was matched with two control subjects of similar age and prostate volume from the screening population. Frozen serum samples were analysed for PSA, DHT, testosterone and SHBG, and compared to the diagnosis and tumour stage, grade and ploidy. Comparisons between these variables, and multivariate and regression analyses were performed.

RESULTS: There were significant differences in PSA level with all variables except tumour 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 and the difference for T-stages was close to statistical significance (P = 0.059). 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, but the differences in testosterone level in tumours of a low grade of differentiation compared to those with intermediate and high grade was nearly significant (P = 0.058). 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. Multivariate analysis showed that if the PSA level was known, then DHT, testosterone or SHBG added no further information concerning diagnosis, stage, grade or ploidy. Regression analysis on T-stage, PSA level and DHT showed an inverse linear relationship between PSA and DHT for stage T-3 (P = 0.035), but there was no relationship between PSA and testosterone.

CONCLUSION: PSA was of value in discriminating between cases and controls and between various tumour stages and grades, but no statistically significant correlation was found for ploidy. If PSA level was known, no other variable added information in individual cases. Within a group, DHT levels tended to be lower among cases and in those with more advanced tumours. There was an inverse relationship between tumour volume, as defined by PSA level, and 5 alpha-reductase activity, as defined by DHT level, and the testosterone/DHT ratio. This trend was most obvious with T-stage. No systematic variation were found in the levels of testosterone or SHBG.

Meikle AW, Smith JA, West DW
Prostate 1985;6(2):121-8

Whether familial factors affect the frequency of prostatic cancer and the plasma content of sex-steroids was investigated. Brothers (n = 257) of probands (n = 150) diagnosed with prostatic cancer before age 62 years had a fourfold higher risk for developing the disease than men in the general population in the State of Utah and their brothers-in-law (n = 202). Familial factors markedly affected the plasma content of sex steroids (testosterone, dihydrotestosterone, the ratio of testosterone to DHT, sex-hormone binding globulin, and the free fraction of testosterone) in nonendocrinologically treated probands and their brothers and sons and in normal men in the general populations. 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.

Barrett-Connor E, Garland C, McPhillips JB, Khaw KT, Wingard DL
Department of Community and Family Medicine, University of California San Diego, La Jolla 92093.
Cancer Res 1990 Jan 1;50(1):169-73

Endogenous androgens have been suggested as determinants of risk of prostatic cancer. To examine this possibility, 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. Age-adjusted relative risks of prostatic cancer for low (0-2.2 nM), middle (2.3-3.1 nM), and high (3.2+ nM) tertiles of androstenedione were 1.00, 1.34, and 1.98, respectively (P trend less than 0.05). The linear gradient of risk persisted after adjustment for age and body mass index. If confirmed, these data suggest that androstenedione might increase the occurrence of clinically manifest prostatic cancer.

Andersson SO, Adami HO, Bergstrom R, Wide L
Department of Urology, Orebro Medical Center Hospital, Sweden.
Br J Cancer 1993 Jul;68(1):97-102

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. Cases did not differ significantly from controls regarding serum levels of luteinising hormone (LH) or follicle stimulating hormone (FSH). Remarkably close agreement was found for mean values of total testosterone (15.8 nmol l-1 in cases and 16.0 in controls), and free testosterone (0.295 and 0.293 nmol l-1, respectively), with corresponding odds ratios for the highest vs lowest tertile of 1.0 (95% confidence interval 0.5-1.9) for testosterone and 1.2 (95% confidence interval 0.6-2.4) 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 (P = 0.30) lower among cases. Changes secondary to the disease were unlikely to have affected the results materially, since only LH and FSH were associated with stage of disease and this relationship was weak. Our findings suggest that further analyses of serum hormone levels at the time of diagnosis are unlikely to improve our understanding of the etiology of prostatic cancer.

Haapiainen R, Rannikko S, Alfthan O, Adlercreutz H
Second Department of Surgery, Helsinki University Central Hospital, Finland.
Prostate 1988;12(4):325-32

Pretreatment plasma concentrations of total testosterone (T), sex hormone binding globulin binding capacity (SHBG). T/SHBG ratio, and free testosterone (fT) were measured in 123 patients with prostatic cancer categorized into groups according to the UICC classification. The patients were randomized to orchiectomy or estrogen therapy and the mean follow-up time was 48 months. The mean plasma levels of T were higher in patients without metastases and with intracapsular cancer, but the differences were not statistically significant. The calculated ratio of T/SHBG was noticed to be significantly higher (p less than 0.05) in the M0 category. The prognostic significance of pretreatment T and, more impressively, T/SHBG ratio and fT was confirmed. Low pretreatment values indicated poorer prognosis. This study supports the view that there are differences in the pretreatment T and fT levels in prostatic cancer patients in relation to the stage of tumor and that these hormone assays could be used as prognostic factors.

Hulka BS, Hammond JE, DiFerdinando G, Mickey DD, Fried FA, Checkoway H, Stumpf WE, Beckman WC Jr, Clark TD
Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill 27514.
Prostate 1987;11(2):171-82

This study sought to identify differences in serum hormone levels between prostatic cancer (CaP) patients, benign prostatic hyperplasia (BPH) patients, and clinic controls (CC). Serum testosterone, estradiol, and prolactin values were obtained from 35 CaP, 42 BPH, and 161 CC patients attending a single medical center between January 1984 and April 1985. Relative risk estimates adjusted for age and race were calculated to compare hormone values between each case group and the CC. The distributions of hormone values and the testosterone to estradiol (T/E) ratios were grouped into thirds with the lowest third forming the reference category. The relative risk estimates for BPH in the middle and high thirds of testosterone were greater than unity (1.26 and 2.10, respectively), whereas the relative risk estimates in the middle and high thirds of estradiol were less than unity (0.63 and 0.35, respectively). For the middle and high thirds of the T/E ratio, the relative risk estimates for BPH showed statistically significant three- to fourfold increases. Modest depression of serum testosterone and estradiol was noted for CaP patients compared to CC, 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, whereas the development of clinically evident BPH was felt to be a biologically plausible response to an elevated T/E ratio.

Rannikko S, Adlercreutz H
Prostate 1983;4(3):223-9

The nature of hormonal changes with age and the possible role of these changes in the development of benign prostatic hyperplasia (BPH) and prostatic cancer (PC) were studied by assaying the plasma levels of total and free testosterone (T), estradiol (E2), prolactin, and sex hormone binding globulin binding capacity (SHBG) in 20 normal healthy men aged 40-59 years, in 30 patients with BPH aged 63-79 years, and in 30 patients with PC of similar height, weight, and age as the BPH patients. The mean E2 was highly significantly (P less than 0.0005) lower in the PC patients and in the young controls than in the BPH patients. The mean free T was significantly higher in the young controls than in the BPH patients (P less than 0.025) and PC patients (P less than 0.0005). The PC patients had a slightly lower (P less than 0.05) mean free T and mean E2/free T ratio than the BPH patients. The mean E2/free T ratio was significantly higher in the BPH patients (P less than 0.0005) and in the PC patients (P less than 0.0025) 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.

Meikle AW, Stanish WM
J Clin Endocrinol Metab 1982 Jun;54(6):1104-8

We investigated whether familial factors influence 1) the incidence of prostatic cancer and 2) the plasma content of sex steroids. A 4-fold higher relative risk for the development of prostatic cancer was observed for brothers (n = 257) of prostatic cancer cases (n = 150) compared to their brothers-in-law (n = 202) and males in the general population of the state Utah. The intraclass correlation for plasma testosterone content [intraclass correlation coefficient (r1) = 0.51; P less than 0.01] and the apparent free testosterone concentration (r1 = 0.54; P less than 0.01) were highly significant in nonendocrinologically treated cases and their brothers. Further, sons and their fathers had significant intraclass correlations for both plasma dihydrotesterone (r1 = 0.83; P less than 0.01) and the ratio of testosterone to dihydrotestosterone (r1 = 0.46; P less than 0.05). 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.

Harper ME, Pierrepoint CG, Griffiths K
Eur J Cancer Clin Oncol 1984 Apr;20(4):477-82

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. This relationship was observed both when the total data were analysed and also when the patients were subgrouped depending on clinical evidence of spread of the tumour beyond the prostatic capsule (T3) or on the presence of metastases (M1). High pretreatment plasma concentrations of luteinizing hormone were also associated with poor survival. Follicle-stimulating hormone, prolactin and growth hormone concentrations did not correlate with survival time. 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.

Morgentaler A, Bruning CO 3rd, DeWolf WC
Division of Urology, Beth Israel Hospital, Harvard Medical School, Boston, Mass. 02215, USA.
JAMA 1996 Dec 18;276(23):1904-6

OBJECTIVE: To determine the prevalence of occult prostate cancer in men with low serum total testosterone or free testosterone levels.

DESIGN: Retrospective analysis of a consecutive series of men.

SETTING: Academic teaching hospital.

PATIENTS: Seventy-seven men with low total testosterone or free testosterone levels, with normal results of digital rectal examination and prostate-specific antigen (PSA) levels of 4.0 ng/mL or less. The mean age was 58 years.

INTERVENTIONS: Sextant prostate needle biopsies with ultrasound guidance.

MAIN OUTCOME MEASURES: Results of prostate needle biopsies, transrectal ultrasound, prostate volume, PSA level, PSA density, total and free testosterone levels.

RESULTS: 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. Histologic examination showed Gleason scores of 6 or 7 for all cancers. 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.

CONCLUSIONS: 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

Haapiainen R, Rannikko S, Alfthan O, Adlercreutz H
Second Department of Surgery, Helsinki University Central Hospital, Finland.
Scand J Urol Nephrol Suppl 1988;110:137-43

Pretreatment plasma concentrations of total testosterone, prolactin, and total estradiol-17 beta (E2) were measured in 123 prostatic cancer patients who were categorized into groups according to the UICC classification. Patients with intracapsular tumour without metastases had significantly higher (p less than 0.05) pretreatment total estradiol levels than those with more advanced disease. The patients were treated either by orchiectomy or estrogens. The mean follow-up time was 48 months. Higher pretreatment estradiol and testosterone levels were associated with better survival. Prolactin assays seemed to be of no value in this respect.

Vijayakumar S, Quadri SF, Dong L, Ignacio L, Kathuria IN, Sutton H, Halpern H
Department of Radiation Oncology, Michael Reese Hospital, Center for Radiation Therapy, University of Chicago, Illinois, USA.
J Natl Med Assoc 1995 Nov;87(11):813-9

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. Blood samples were collected prior to any treatment in 36 patients; in 19 (group 1), three blood samples were collected 10 minutes apart between 9:00 AM and 9:30 AM for each patient and pooled together to avoid diurnal and episodic variation in serum testosterone values. In the remaining patients, only one sample could be collected (group 2). Free testosterone, androstenedione, luteinizing hormone, prolactin, and PSA levels were determined with appropriate radioimmunoassay techniques. Statistical analyses were performed separately for groups 1 and 2, and then with pooled data. None of the hormones in any of the analyses showed any association to serum PSA values except for prolactin for the pooled data and for group 2. This statistical significance for prolactin disappeared on multivariate analysis. There were 21 African-American men and 15 whites in the study; no racial differences in hormonal levels were found except for lower luteinizing hormone levels in African Americans in group 2 and pooled data. No differences were found between group 1 and group 2 in the mean serum prolactin and luteinizing hormone values. Serum free testosterone, androstenedione, and luteinizing hormone appeared to have no influence on serum PSA values in nonmetastatic cancer patients. Serum prolactin values were inversely associated with PSA values in univariate analysis for the pooled data; this disappeared in multivariate analysis. Unlike other studies that found higher serum testosterone levels in African-American college students than whites, no such differences were seen in this age group

Meikle AW, Smith JA, Stringham JD
Prostate 1987;10(1):25-31

It was previously unknown whether the production and metabolism of testosterone was altered in men with prostatic cancer. We recently observed a familial influence on the plasma concentration of sex steroids in men with the cancer. We have now determined, by isotope dilution techniques, the blood testosterone production and clearance rates and testosterone metabolism to potent androgen metabolites in men with prostatic cancer, their brothers, and unrelated controls. Nineteen men had a diagnosis of prostatic cancer before age 63 (probands), 23 were brothers of these index cases, and nine controls matched for age were selected randomly from the general population. None had received endocrine therapy. The plasma content of testosterone, dihydrotestosterone, sex hormone binding globulin, apparent free testosterone concentration, follicle-stimulating hormone, and luteinizing hormone were not significantly different between the groups. The metabolic clearance rate of testosterone was significantly (P = .04) higher in probands (458 liters/day/body surface area, median) than in controls (306 liters/day/body surface area). The conversion ratios of both testosterone (1.8%) and dihydrotestosterone (16.9%) to 3 alpha-androstanediol were significantly greater (P = .04 and P = .004, respectively) in probands than in controls (0.95%, 7.8%). These results indicate that men with prostatic cancer have elevated clearance rates of testosterone and an increased conversion ratio of testosterone to its potent 5 alpha-reduced metabolites.

Verhelst J, Denis L, Van Vliet P, Van Poppel H, Braeckman J, Van Cangh P, Mattelaer J, D'Hulster D, Mahler C
Department of Endocrinology, A. Z. Middleheim, Antwerp, Belgium.
Clin Endocrinol (Oxf) 1994 Oct;41(4):525-30

OBJECTIVE: Casodex (Zeneca) is a new potent, long-acting non-steroidal anti-androgen, which produces androgen deprivation by blocking the androgen receptor. We evaluated the endocrine effects of Casodex 150 mg daily given in monotherapy as primary treatment for patients with prostate cancer.

DESIGN: As part of a large, multicentre study comparing the therapeutic effects of surgical castration with 150 mg/day Casodex in monotherapy for patients with prostate cancer, a subgroup of 23 patients on Casodex were studied in detail for changes in endocrine parameters. Serum levels of LH, FSH, testosterone, DHT, oestradiol, prolactin, sex hormone binding globulin and free testosterone were measured at the start of therapy and after 1, 4, 8, 12 and 24 weeks. Effects on libido, sexual activity and the appearance of hot flushes, breast pain and gynaecomastia were recorded.

RESULTS: Administration of Casodex resulted in a rise in LH levels in all patients with a mean increase after 24 weeks of 102% (P < 0.001). Mean FSH levels showed a limited increase (7%) after 24 weeks, which was significant only after 1 week (P < 0.001). As a result of the high LH levels, total testosterone levels increased after 24 weeks by 66% (P < 0.001), free testosterone by 57% (P < 0.001) and dihydrotestosterone by 24% (P = 0.0112). Parallel to testosterone, oestradiol levels rose by a mean of 66% (P < 0.001). Mean sex hormone binding globulin and prolactin levels rose by respectively 8% (P = NS) and 65% (P < 0.01). Despite an increase in testosterone levels, excellent androgen blockade was obtained, as shown by a decrease in prostate specific antigen levels in 22/23 patients. Libido was maintained in 8/11 patients, and sexual activity in 5/6. No patient complained of hot flushes. However, mild gynaecomastia and/or breast tenderness were seen in 48 and 30% of cases respectively.

CONCLUSION: Casodex 150 mg/day monotherapy resembles surgical castration in achieving androgen deprivation, despite an increase in LH and testosterone levels. In contrast to castration, libido and sexual activity are usually maintained and hot flushes are rare. However, mild gynaecomastia and/or breast tenderness were noted in 48 and 30% of patients.

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