Estrogen receptor b in the urogenital tract of both male and female

• The central finding of this thesis is that estrogen receptors regulate androgen receptor expression: ERalpha unpregulates AR and ERbeta down-regulates AR. With this theme, we explored the physiological role of an ER-AR pathway, especially ERbeta-AR, in some urogenital tissues, uterus, ovary and prostate, using ERbeta knockout mice. In paper I, we presented the following evidence to support the hypothesis that ER and AR pathways are not separate but sequential steps in stimulating uterine luminal epithelial cellular proliferation. (1) ERalpha but not ERbeta is the ER that induces AR; (2) The estrogen induction of IGF-1 (the major growth factor mediating ER's mitogenic effects), could be blocked by both antiestrogen and antiandrogen; (3) Estrogen induced CRISP (cysteine-rich secretory protein) and this induction was inhibited by both antiestrogen and antiandrogen; and (4) The estrogen induced increase in proliferation rate in the uterus (measured by BrdU labelling), was blocked by both antiestrogen and antiandrogen. In this paper, we also demonstrated, with two different ERbeta antibodies, that there is ERbeta protein expression in the rat uterus and that, upon estradiol treatment, the ERbeta expressing cells are not the ones in which AR is induced. Because ERbeta is not expressed in the myometrium where AR is induced by estradiol, and estradiol down-regulates ERbeta in this compartment, it was speculated that ERbeta might have an inhibitory role of AR expression. In paper II, vie found that the uterus of BERKO mouse is hypersensitive to estradiol treatment in terms of uterine fluid secretion, IGF-1 induction, interleukin 10 induction and epithelial cellular proliferation. Moreover, in the untreated uterus of BERKO mouse there were many cells expressing the proliferation marker, Ki67, indicating that they were not in GO but were in some other phase of the cell cycle. In addition there was over-expression of IGF-1 and AR. In paper III, we described another tissue where ERbeta represses AR expression and showed that AR over expression is one of the causes of the ovarian phenotype of BERKO mouse. In BERKO mice there is abnormal follicular development and very reduced fertility. At 3 weeks of age, no significant morphological differences were discernible between wild type (WT) and BERKO mouse ovaries but by 5-months of age, atretic follicles were abundant and there were very few healthy late antral follicles or corpora lutea in BERKO mice. At two years of age, unlike their WT littermates, BERKO mouse ovaries were devoid of healthy follicles but had numerous, large, foamy lipid-filled stromal cells. The late antral and atretic follicles in BERKO mice were characterized by a high level of expression of the androgen and IGF-1 receptors (AR and IGF-1 R). These proteins were abundantly expressed in granulosa cells of preantral and early antral follicles in both genotypes but their expression was extinguished in late antral follicles of WT mice. Healthy late antral follicles and corpora lutea were restored in BERKO mouse ovaries after 15 days of treatment of mice with the antiandrogen, flutamide. In paper IV, We found that the loss of ERbeta results in over-expression of AR in the BERKO mouse ventral prostate, and that this is accompanied by epithelial hyperplasia, which becomes more severe with age. Moreover, we found that it is not estradiol, but 3betaAdiol, which is the most estrogenic steroid in the ventral prostate. In normal mice but not in BERKO mice, 3betaAdiol down-regulates AR in the ventral prostate. In paper V, we tested the roles of the major estrogen in the prostate, 3betaAdiol, CYP7B1, ERbeta and AR in the regulation of prostatic epithelial cellular growth. In this study we show that ERbeta 3betaAdiol, a metabolite of DHT, and 3betaAdiol hydroxylase (CYP7B1) are components of a pathway that regulates growth of the rodent ventral prostate. In this pathway, ERbeta is an antiproliferative receptor; 3betaAdiol is an ERbeta ligand and CYP7B1 is the enzyme that regulates ERbeta function by regulating the level of 3betaAdiol CYP7B1 is also expressed in human prostate epithelium and high levels were found in prostate cancer. We suggest that high levels of CYP7B1 in prostate cancer is associated with high proliferative potential and that the beneficial effect of treatment with P-450 inhibitors (like ketoconazol), used as adjuvant therapy in prostate cancer, could be due to inhibition of CYP7B1. The study further suggests that treatment with ERbeta ligands or their precursors (like DHEA) is one approach for regulation of prostate growth and preventing development of androgen-independent growth after androgen ablation in ERbeta positive prostate cancers. In summary, from data shown in this thesis, we have found that ERbeta is important for the normal functions of both male and female urogenital organs, the uterus, the ovary and the prostates, and repressing AR expression is one of mechanisms by which ERbeta functions.

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