Significant associations between the lengths of a highly polymorphic dinucleotide (CA) repeat located within the human estrogen receptor beta (ESR2) gene on chromosome 14, bone mineral density (BMD) and androgen levels have been reported previously in premenopausal women. We measured the size of this microsatellite repeat in 226 healthy women (60-98 years). After adjustment for age, body mass index, hormone replacement status, and other variables known to influence BMD, women with < 25 CA repeats had significantly higher BMD measured in the total skeleton, lumbar spine, and femoral neck when compared with women having longer alleles. Women with shorter alleles also had higher circulating estrone and estradiol levels that approached statistical significance as compared with women harboring longer alleles after appropriate adjustments were performed in linear regression models. Women having both short and long CA repeats had BMD values in all regions of the skeleton that were midway between those found in women homozygous for longer or shorter repeat sizes. Because the ESR2 CA repeat size was neither associated with change in BMD nor serum levels of biochemical markers of bone turnover, it is likely that ESR2 CA repeat genotype is significantly linked to the attainment of peak bone mass in women.

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Tocopherylquinone (TQ), the oxidation product of alpha-tocopherol (AT), is a bioactive molecule with distinct properties from AT. In this study, AT and TQ are investigated for their comparative effects on growth and androgenic activity in prostate cancer cells. TQ potently inhibited the growth of androgen-responsive prostate cancer cell lines (e.g., LAPC4 and LNCaP cells), whereas the growth of androgen-independent prostate cancer cells (e.g., DU145 cells) was not affected by TQ. Due to the growth inhibitory effects induced by TQ on androgen-responsive cells, the anti-androgenic properties of TQ were examined. TQ inhibited the androgen-induced activation of an androgen-responsive reporter and inhibited the release of prostate specific antigen from LNCaP cells. TQ pretreatment was also found to inhibit AR activation as measured using the Multifunctional Androgen Receptor Screening assay. Furthermore, TQ decreased androgen-responsive gene expression, including TM4SF1, KLK2, and PSA over 5-fold, whereas AT did not affect the expression of androgen-responsive genes. Of importance, the antiandrogenic effects of TQ on prostate cancer cells were found to result from androgen receptor protein down-regulation produced by TQ that was not observed with AT treatment. Moreover, none of the androgenic endpoints assessed were affected by AT. The down-regulation of androgen receptor protein by TQ was abrogated by co-treatment with antioxidants. Overall, the biological actions of TQ were found to be distinct from AT, where TQ was found to be a potent inhibitor of cell growth and androgenic activity in androgen-responsive prostate cancer cells.

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