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LE Magazine November 1999


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Featured:

  • DHEA
  • Prostate Cancer

Later stage protection
Chemoprevention of rat prostate carcinogenesis by early and delayed administration of dehydroepiandrosterone
Cancer Res. 1999 Jul 1;59(13):3084-9

Two in vivo bioassays were conducted to evaluate the efficacy of dehydroepiandrosterone (DHEA) as an inhibitor of prostate carcinogenesis in rats. Prostate adenocarcinomas were induced in male Wistar-Unilever rats by a sequential regimen of cyproterone acetate and testosterone propionate, followed by a single i.v. injection of N-methyl-N-nitrosourea (MNU) and chronic androgen stimulation. In the first experiment, DHEA (1000 or 2000 mg/kg diet) was administered continuously to rats beginning 1 week before MNU exposure. In the second experiment, continuous administration of DHEA (2000 mg/kg diet) was begun either 1 week before, 20 weeks after, or 40 weeks after MNU exposure. Controls received basal diet without added DHEA. Studies were terminated at 13 months after MNU administration, and prostate cancer incidence was determined by histopathological evaluation of step sections of accessory sex glands. In the first study, continuous dietary administration of DHEA beginning 1 week before MNU resulted in a dose-related inhibition of prostate cancer induction. In the second experiment, comparable reductions in prostate cancer incidence were observed in groups exposed to DHEA beginning 1 week before, 20 weeks after, and 40 weeks after carcinogen exposure. These data demonstrate that nontoxic doses of DHEA confer significant protection against prostate carcinogenesis in rats. The efficacy of delayed administration of DHEA suggests that the compound confers protection against later stages of prostate cancer induction and can suppress the progression of existing preneoplastic lesions to invasive disease.


Hormone concentrations and prostate cancer
Endogenous sex hormones and prostate cancer: a quantitative review of prospective studies.
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), dehydroepi- androsterone 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.


DHEA inhibits prostate cancer
Chemoprevention of hormone-dependent prostate cancer in the Wistar-Unilever rat
Eur Urol 1999;35(5-6):464-7

The high incidence and long latent period of prostate cancer make it an ideal target for chemoprevention. We have evaluated a series of agents for chemopreventive efficacy using a model in which hormone-dependent prostate cancers are induced in the Wistar-Unilever (WU) rat by sequential treatment with antiandrogen (cyproterone acetate), androgen (testosterone propionate), and direct-acting chemical carcinogen (N-methyl-N-nitrosourea), followed by chronic androgen stimulation (testosterone). This regimen reproducibly induces prostate cancers in high incidence, with no gross toxicity and a low incidence of neoplasia in the seminal vesicle and other non-target tissues. Dehydroepiandrosterone (DHEA) and 9-cis-retinoic acid (9-cis-RA) are the most active agents identified to date. DHEA inhibits prostate cancer induction both when chronic administration is begun prior to carcinogen exposure, and when administration is delayed until preneoplastic prostate lesions are present. 9-cis-RA is the most potent inhibitor of prostate carcinogenesis identified; a study to determine the efficacy of delayed administration of 9-cis-RA is in progress. Liarozole fumarate confers modest protection against prostate carcinogenesis, while N-(4-hydroxyphenyl)retinamide (fenretinide), alpha-difluoromethylornithine, oltipraz, DL-alpha-tocopherol acetate (vitamin E), and L-selenomethionine are inactive. Chemoprevention efficacy evaluations in the WU rat will support the identification of agents that merit study for prostate cancer chemoprevention in humans.


Unlikely risk factors
The relationship of serum dehydroepiandrosterone and its sulfate to subsequent cancer of the prostate
Cancer Epidemiol Biomarkers Prev 1993 May-Jun;2(3):219-21

Levels of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S) in sera collected and frozen in 1974 were studied among 81 prostate cancer cases diagnosed in the following 12 years and 81 age- and race-matched controls. Although mean levels of DHEA were 11% lower among cases than controls and DHEA-S levels were 12% lower than among controls, no dose-response association was noted for either DHEA or DHEA-S. It seems unlikely that serum levels of DHEA or DHEA-S are important risk factors for prostate cancer.


Oral DHEA and ED
Dehydroepiandrosterone in the treatment of erectile dysfunction: a prospective, double-blind, randomized, placebo-controlled study
Urology 1999 Mar;53(3):590-4; discussion 594-5

OBJECTIVES: In 1994, the Massachusetts Male Aging Study presented an inverse correlation of the serum levels of dehydroepiandrosterone (DHEA) and the incidence of erectile dysfunction (ED). We evaluated the efficacy of DHEA replacement in the treatment of ED in a prospective, double-blind, randomized, placebo-controlled study. METHODS: The inclusion criteria included ED, normal physical and neurologic examinations, serum levels of testosterone, dihydrotestosterone, prolactin, and prostate-specific antigen (PSA) within the normal range, and a serum DHEA sulfate level below 1.5 micromol/L. Also all patients had a full erection after a pharmacologic erection test with 10O microg prostaglandin E1; pharmacocavernosography showed no visualization in corporeal venous structures. Forty patients from our impotence clinic were recruited and randomly divided into two groups of 20 patients each. Group 1 was treated with an oral dose of 50 mg DHEA and group 2 with a placebo one time a day for 6 months. The International Index of Erectile Function (IIEF), a 15-item questionnaire, was used to rate the success of this therapy. RESULTS: Therapy response was defined as the ability to achieve or maintain an erection sufficient for satisfactory sexual performance according to the National Institutes of Health Consensus Development Panel on Impotence. DHEA treatment was associated with higher mean scores for all five domains of the IIEF. There was no impact of DHEA treatment on the mean serum levels of PSA, prolactin, testosterone, the mean prostate volume, and the mean postvoid residual urine volume. CONCLUSIONS: Our results suggest that oral DHEA treatment may be of benefit in the treatment of ED. Although our patient data base is too small to do relevant statistical analysis, we believe that our data show a biologically obvious trend that justifies further extended studies.


DHEA and BPH
Androgens in patients with benign prostatic hyperplasia before and after prostatectomy
J Clin Endocrinol Metab 1976 Dec;43(6):1250-4

Plasma androgens [testosterone (T), 17beta-hydroxy-5alpha-androstan-3-one (DHT), androst-4-en-3,17 dione(A), and dehydroepiandrosterone (DHEA)] as well as 17 hydroxyprogesterone were measured in a group of patients (age 60-80 yrs.) with benign prostatic hyperplasia (BPH) just before prostatectomy and compared to values obtained in subjects of similar age without signs of BPH. The most important difference was observed in the mean DHT level which was significantly (P less than 0.025) higher than in the control group; mean T and free testosterone levels in BPH patients were slightly higher (P less than 0.05) in the age group 70-80 yrs; whereas in age group 60-70 mean values were similar to those observed in normal controls. Mean A, DHEA and 17 OHP and E2 levels were not significantly different in BPH patients when compared to age matched controls. 2-5 months after prostatectomy, T and DHT levels were significantly higher than immediately preoperatively. The preoperative stress may have influenced the preprostatectomy values.