| Research Abstract |
Genomic DNA was extracted from peripheral leukocytes, and PCR-based RFLP assays were performed to determine estrogen receptor-α ; PvuII and XbaI, and estrogen metabolizing enzymes, CYP17 ; estrogen biosynthesis (high activity, A2/A2), CYP1A1 ; hydroxylation (high inducibility, vt/vt) and COMT ; inactivation (low activity, L/L) genotypes in 317 postmenopausal Japanese women aged 46 yr and over under (Yokohama Cohort) informed consent. There were no significant differences in ages at menarche and natural menopause, and years of menstruation among each PvuII or XbaI genotype and seven combinations of PvuII and XbaI genotypes. We could find ages at menarche in women with A1/A2 (higher activity of CYP17) (13.6+/-1.2 yr) were significantly earlier than in those with A1/A1 (lower activity of CYP17) (14.1+/-1.3 yr). There were no significant differences in ages at natural menopause and years of menstruation among each CYP17, CYP1A1 or COMT genotypes. The small sample size of each combination o
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f estrogen-metabolizing genotypes made it impractical to evaluate the effects of the interdependency of each genotype including extreme genotype categories such as A2/A2L/Lvt/vt vs. A1/A1H/Hwt/wt genotypes on ages at menarche and/or natural menopause. The results suggest that estrogen metabolizing CYP17 genotype influences on ages at menarche in healthy postmenopausal Japanese women. Further, we aimed to assess whether circulating sex steroids would influence bone density and bone loss, whether part of this influence could be explained by genetic variation measured as polymorphisms in candidate genes affecting circulating hormone levels, or whether gene polymorphisms would have direct effects on bone in 229 postmenopausal Japanese women aged 46 years and over who had been followed for eight years (Yokohama Cohort). Bone mineral density (BMD) in the lumbar spine (L), femoral neck (FN), total hip (T) and distal radius (R) was measured every year, and endogenous sex steroid levels were determined at the start of the study. Dehydroepiandrosterone (DHEA) and androstenedione (AND) levels significantly correlated with bone density in both the axial (L) and the appendicular skeleton (FN, T and R) (r=0.194-0.229 ; P<0.05) whereas estradiol (E2) and AND showed significant correlations with bone change only at the axial skeleton (r=0.205 and r=-0.139, respectively ; P<0.05) on the total cohort. These correlations remained significant in thin/normal-weight women [body mass index (BMI) <25 Kg/m^2)] even after adjustment for years since menopause (YSM) and BMI or age and BMI, suggesting an interaction of BMI and sex steroid/BMD association. On the total cohort, a difference in endogenous DHEA levels between CYP17 homozygote A2 and non-homozygote A2 ; an increasing trend in AND levels from COMT L/L, L/H, to H/H ; and a difference in TS level between COMT homozygote L and non-homozygote L were separately observed. All observations were significant for unadjusted and adjusted analysis, except for COMT and TS. In thin/normal-weight women (BMI, <25 Kg/m^2), the same effects of CYP17 genotypes on DHEA were observed as on the total cohort. GYP17 and COMT genes showed some direct influence on bone density. Mean percent change in T-BMD was negative for CYP17 non-homozygote A2 in contrast to a positive value for homozygote A2. Mean percent change in R-BMD showed the difference between COMT homozygote L and non-homozygote L with a larger decrease for the homozygote L. Together, CYP17 and COMT genotypes might have some effect on bone both directly and indirectly through their effects on endogenous sex steroids in postmenopausal Japanese women. Less
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