Screening of adolescents exposed to diethylstilbestrol in utero.
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OBJECTIVES: To determine whether a low dose of cyproterone acetate (CPA) (50 mg twice a day) with minidose diethylstilbesterol (DES) is efficacious in rapidly reducing and maintaining serum testosterone at less than 10% of pretreatment level and whether the effect is reversible upon cessation of therapy. METHODS: Data were collected prospectively on 62 subjects, aged 50 to 90 years (mean 69) with histologically confirmed prostate cancer and normal serum testosterone levels. Treatment was initiated with CPA 50 mg twice a day plus DES 0.11 mg once a day, both administered orally, and continued or 6 months unless discontinued for reasons unrelated to the study. Subsequent management was at the discretion of the investigator/managing physician. Treatment was discontinued with determination of at least one follow-up testosterone level in 28 patients. RESULTS: Mean pretreatment testosterone level was 13.8 nmol/L (range 4.5 to 46.6, median 14.0, 95% confidence interval [CI] 12.0 to 15.0). Testosterone dropped to a mean of 0.6 nmol/L (range 0.1 to 2.2, median 0.5, 95% CI 0.4 to 0.6) by first follow-up (usually 1 month) in all patients (P <0.001) and remained at this level as long as treatment continued. Testosterone normalized in all subjects whose treatment was discontinued. Side effects were minimal. CONCLUSIONS: An oral dosage of CPA of 50 mg twice a day in combination with a mini-dose of DES results in rapid and reversible reduction in serum testosterone to castrate levels. This regimen minimizes morbidity and monetary costs of therapy and allows the implementation of novel treatment approaches such as intermittent or neoadjuvant withdrawal therapy.
Exposure to estrogenic chemicals during critical periods in fetal life can alter the development of reproductive organs, the neuroendocrine system, and subsequent behavior. We examined the effects of prenatal exposure to the estrogenic chemicals, o,p'-DDT (the estrogenic contaminant in commercial DDT) and the drug diethystilbestrol (DES), as a positive control, on different forms of aggressive behavior in both male and female house mice. We also examined effects of these chemicals on male reproductive organs. From gestation days 11-17 female mice were fed an average concentration (dissolved in oil) 0.018 and 0.18 ng/g body weight of DES. Doses of o,p'-DDT were 18 and 180 ng/g body weight, based on the prediction that the in vivo potency of o,p'-DDT would be approximately 1000-times lower than DES. We found that prenatal exposure to DES increased the frequency of both males and females that responded aggressively to a same-sex conspecific. Preputial glands in males exposed to the 0.018 ng/g dose of DES were significantly enlarged relative to controls. Males exposed to the 18 ng/g dose of DDT had smaller testes than controls. The possible implications of perturbing the development of social behaviors, such as aggression, on individuals reproductive success and social structure of the population are discussed.
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The question was asked whether the feminization of the chick embryo testis by diethylstilboestrol involves oestrogen secretion. The left gonads of male embryos treated with diethylstilboestrol at the stage of 5 days of incubation were removed at the stage of 17 days and cultured in vitro in the presence of radiolabelled androstenedione, dehydroepiandrosterone, progesterone or sodium acetate. Radiochromatography and repeated crystallizations to constant specific activity were used to demonstrate the formation of oestrone and oestradiol. The results show that oestrogen synthesis takes place from any of the 4 precursors. The normal testis does not produce oestrogens or produces them only in small amounts. Thus, it can be concluded that diethylstilboestrol induces oestrogen synthesis in the chick embryo testis. In a second part of the work, it is shown that tamoxifen antagonizes the feminizing action of diethylstilboestrol on the testes, both at the morphological and biochemical levels.
High amounts of estrogens are known to suppress immune functions in both human and animal models. Our supportive data is that the immune functions were activated by gonadectomy in young adults mice. However, recent reports indicate that estrogen is required for the normal development of thymus. These findings lead us to an assumption that sex hormone status induces much more complex effects on immune functions depending on the host age/sex and dose ranges. Here, low doses of DES (diet containing 0.4 or 4.0 microg/kg diet) were given for 2 months to young adult and aged C57BL/6 mice, and thymic and splenic parameters including flow-cytometric subpopulation analyses, mitogenic responses and NK activity were monitored. This study revealed that the low dose effects of exogenous estrogen are strongly dependent on the age and sex of the recipients and many parameters show non-monotonous dose response effect. In conclusion, effect of exogenous estrogens on immune functions should be assessed for all age and sex, and in expectation of non-monotonous dose-response relationship.
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