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B Hanstein, S Djahansouzi, P Dall, MW Beckmann and HG Bender

Evidence for a role of ovarian factors in the growth of metastatic breast cancer was first recognized over 100 years ago. Today, anti-estrogens are central to the treatment of breast cancer of all stages. We now understand that the action of estrogen is mediated by the estrogen receptors (ER) which are members of the nuclear receptor family of ligand-regulated transcription factors. In this article we review the molecular mechanisms through which ER activates transcription of target genes and through which available anti-estrogens mediate their therapeutic effects. We discuss possible mechanisms of failure of treatment with current anti-estrogens and how newer anti-estrogens under development attempt to address these problems. In addition an expanded view of the molecular mechanisms of estrogen action is leading to the development of novel selective ER modulators or SERMs.

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MW Beckmann, P Wieacker, MM Dereser, U Flecken and M Breckwoldt

The physiological regulation of 5α-reductase (5αR) as well as the complex pathogenesis of male and female androgenic disorders are still incompletely understood. Therefore, we examined the influence of various steroid hormones on the 5αR activity in female and male genital skin fibroblasts in primary culture to test whether the 5αR activity is identically regulated in genital skin samples of both sexes. Nine foreskin samples of male patients and 11 specimens of female genital skin were prepared and cultured as primary tissue cultures. After pre-incubation with various unlabeled steroids, [3H]-testosterone was added to the cultures and the 5αR activity (conversion of testosterone to dihydrotestosterone) measured. (a) The pre-incubation of male foreskin fibroblasts with unlabeled androstenedione and androstandione both resulted in stimulation of 5αR activity. Other unlabeled steroid hormones, including progesterone, testosterone, dihydrotestosterone, and estradiol had no significant effect on 5αR activity. (b) In female genital skin fibroblasts, pre-incubation with testosterone also led to an increase in 5αR activity, whereas pre-incubation with estradiol decreased 5αR activity. None of the other unlabeled steroid hormones applied had significant effects. These data on male foreskin in culture suggest a physiologic regulatory mechanism of 5αR activity independent of the concentration of the enzymatic substrate or product, whereas the results for the female genital skin suggest a cellular regulation of the androgen levels by the enzymatic substrate testosterone and a possible negative feedback mechanism of estrogens. Furthermore, the data suggest that the 5αR activity regulation of genital skin fibroblasts is different in female and male.