Relationship between self-reported periodontal status and skeletal bone mineral density in Japanese postmenopausal women.

OBJECTIVE: Several investigators have linked periodontal disease progression and low skeletal bone mineral density in postmenopausal women. However, little is known about whether self-reported periodontal status is the reflection of skeletal bone mineral density. We investigated whether self-reported poor periodontal status is associated with low skeletal bone mineral density in postmenopausal women. DESIGN: Relationships among self-reported periodontal status, number of teeth remaining, and bone mineral density of the lumbar spine and the femoral neck were evaluated in 253 Japanese postmenopausal women (mean +/- SD, 56.6 +/- 7.7) recruited from the patients who visited our clinic for bone mineral assessment between 1997 and 2003. Self-reported periodontal symptoms included gingival swelling, gingival bleeding, purulent discharge, and tooth mobility at the time of bone mineral assessment. RESULTS: Analysis of covariance adjusted for age, height, weight, years since menopause, duration of estrogen use, and regular oral care revealed that subjects without periodontal symptoms had significantly higher BMD of the lumbar spine than did those with periodontal symptoms (mean +/- SEM, 0.962 +/- 0.014 vs 0.921 +/- 0.013; P = 0.038); however, there were no significant differences in the number of remaining teeth and bone mineral density of the femoral neck between them. The odds of low spine bone mineral density in subjects with periodontal symptoms was 2.01 (95% CI = 1.15 to 3.50). CONCLUSION: Our results suggest that self-reported poor periodontal status may be associated with low bone mineral density of the lumbar spine in postmenopausal women.

Relative expression levels of Th1 and Th2 cytokine mRNA are independent prognostic factors in patients with ovarian cancer.

The aim of the present study was to examine mRNA expression levels of Th1 (TNF-alpha , IFN-gamma, and IL-12p40) and Th2 (IL-6 and IL-10) cytokines for any association with clinicopathological characteristics of epithelial ovarian cancer. mRNA was isolated, and cDNA prepared from 40 samples of epithelial ovarian cancers. Expression level of each cytokine mRNA was examined by the real-time PCR technique (GAPDH gene, internal control). Expression ratio (target gene/GAPDH) was used to evaluate gene expression. Results were analyzed against clinical stage, histological grade, and histological type. Prognostic significance of expression levels of each combination of Th1/Th2 values was assessed. Tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) expression levels were significantly higher in serous adenocarcinoma than in non-serous adenocarcinoma (p<0.05), but with no difference between individual cytokine mRNA expression levels and clinical stage or histological grade. Log-rank testing showed that high TNF-alpha mRNA expression (p=0.033) and the diameter of largest residual lesion at initial surgery (p=0.012) significantly correlate with longer survival in advanced stage (II/III/IV) ovarian carcinomas. In examining all combinations of Th1/Th2 expression values, the most significant association was between high IFN-gamma.IL-12p40/IL-6 expression levels and better prognosis in advanced stage (II/III/IV) ovarian carcinomas (p=0.004). In multivariate analysis, high IFN-gamma.IL-12p40/IL-6 expression (p=0.009) and the diameter of residual lesion (p=0.011) remained significantly associated with survival, whereas high TNF-alpha expression lost significance. In conclusion, Th1 and Th2 cytokines might play an important role in regulating the immune reaction in epithelial ovarian cancer cells. IFN-gamma.IL-12p40/IL-6 expression may be a useful prognostic molecular marker for patients with advanced ovarian cancer.

Skp2 overexpression is a prognostic factor in patients with ovarian adenocarcinoma.

PURPOSE: The purpose of this study was to examine Skp2 expression in epithelial ovarian tumors and to identify the association of Skp2 expression levels with patient survival. EXPERIMENTAL DESIGN: Skp2 protein expression was examined by immunohistochemistry in 134 epithelial ovarian tumors [20 adenomas, 23 low malignant potential (LMP) tumors, and 91 adenocarcinomas]. Results of immunostaining were correlated with clinicopathological variables and overall survival. Skp2 mRNA expression was examined by semiquantitative PCR in 32 ovarian adenocarcinomas and in 3 ovarian cancer cell lines. RESULTS: Skp2 expression was detected in neither ovarian adenomas nor LMP tumors. In contrast, Skp2 expression was detected in 47.3% (43 of 91) of adenocarcinomas. Positive Skp2 expression was detected significantly more often in adenocarcinomas than in LMP tumors (P < 0.0001) or in adenomas (P < 0.0001). A significantly higher detection rate of Skp2 expression was observed in advanced-stage diseases compared with early-stage diseases (P = 0.010). Log-rank testing showed that Skp2 overexpression was significantly correlated with poor patient survival (P = 0.0035). Older age (P = 0.0026), advanced clinical stage (P < 0.0001), and high histological grades of the tumors (P = 0.0018) were also significantly associated with poor prognoses. In multivariate analysis, Skp2 overexpression (P = 0.0069) and clinical stage (P < 0.0001) remained significantly associated with overall survival, whereas age and histological grade lost their significance. Considerable levels of Skp2 mRNA expression were detected in all ovarian adenocarcinomas examined by semiquantitative PCR. CONCLUSIONS: Skp2 expression might play an important role in the development and progression of ovarian adenocarcinomas, and Skp2 overexpression is an independent prognostic marker of ovarian adenocarcinoma patients.

Human kallikrein gene 11 (KLK11) mRNA overexpression is associated with poor prognosis in patients with epithelial ovarian cancer.

PURPOSE: The purpose of this study was to examine expression levels of the human tissue kallikrein 11 gene (KLK11) in epithelial ovarian tumors and to identify the relationship between KLK11 expression and patient survival. EXPERIMENTAL DESIGN: KLK11 mRNA expression was examined by semiquantitative PCR in 64 epithelial ovarian tumors (7 adenomas, 6 low malignant potential tumors, and 51 adenocarcinomas) and in 10 normal ovaries. Semiquantitative PCR results were correlated with clinicopathologic variables and overall survival. cDNA from human normal tissues and tumor tissues was also analyzed. RESULTS: KLK11 mRNA expression was detected in various human cancer tissues including breast, lung, colon, prostate, pancreas, and ovarian carcinoma. The mean value of relative KLK11 expression ratio was significantly higher in ovarian tumor samples than in normal ovary samples (compared with normal samples: adenoma, P = 0.0006; low malignant potential tumor, P = 0.0049; and carcinoma, P < 0.0001). No statistically significant associations between KLK11 mRNA expression level and clinical stage, histological type, or histological grade were observed. The log-rank test showed that high KLK11 mRNA expression and advanced clinical stage significantly correlated with poor patient survival (P = 0.0185 and P = 0.0043, respectively). High KLK11 mRNA expression and clinical stage remained significantly associated with overall survival (P = 0.0225 and P = 0.0202, respectively) after multivariate analysis. CONCLUSIONS: KLK11 expression may play an important role in ovarian cancer development and act as an independent prognostic marker in ovarian cancer patients.

Pregnancy rate, multiple pregnancy rate, and embryo quality: Clues for single blastocyst transfer from double blastocyst transfer in an unselected population.

Objective: Minimizing multiple pregnancy is a priority in assisted reproduction. As implantation rates are critical to success and reduce multiple pregnancy, we investigated whether blastocyst grade determined implantation rate following double blastocyst transfer in unselected cases. Materials and Methods: We studied 69 three-cleavage stage embryo transfers and 64 two-blastocyst transfers. Two blastocysts, or one when two blastocysts were not available, were transfered after evaluating the grade of blastocysts. The difference in pregnancy and implantation rates to patient age, the number of retrieved oocytes and grade of blastocysts were analyzed. Results: Blastocyst and grade 3AA rates per fertilized egg were 50.3% and 26.0%, respectively. Following two-blastocyst transfer, pregnancy rate per transfer, implantation rate per embryo, and multiple pregnancy rate per pregnancy were 39.1%, 26.5%, and 24.0%, respectively. Two-blastocyst transfer achieved implantation more often than three-cleavage-stage embryo transfer, but did not reduce multiple pregnancy. Pregnancy, implantation, and multiple pregnancy rates did not reflect maternal age. Higher pregnancy and implantation rates per transfer were attained for with six or more oocytes retrieved or transfer of two-blastocyst graded 3AA or higher especially when two or more blastocysts graded 3AA or higher are available, but the latter showed a high multiple pregnancy rate (38.5%). Conclusions: Single embryo transfer could be carried out when two or more blastocysts of grade 3AA or higher have been developed. (Reprod Med Biol 2005; 4: 153-160).

Estrogen replacement suppresses function of thrombin stimulated platelets by inhibiting Ca(2+) influx and raising cyclic adenosine monophosphate.

OBJECTIVE: Estrogen replacement therapy (ERT) in postmenopausal women reduces the risk of cardiovascular diseases. Beneficial changes in lipid profiles account for only one part, thereby raising the question of other estrogen induced benefit that may be lost at menopause. The purpose of this study was to determine the effects of estrogen replacement therapy (ERT) on platelet function of postmenopausal women. METHODS: The effect of 4 weeks ERT (conjugated estrogens 0.625 mg/day) on platelet function was evaluated ex vivo in 18 postmenopausal women (mean age 53 +/- 5 years, after menopause 3.8 +/- 1.9 years). RESULTS: After ERT, (1) plasma concentrations of estrone and estradiol significantly increased (estrone: 16 +/- 7-211+/- 80 pg/ml, estradiol: 14+/- 3-125 +/- 49 pg/ml, P<0.05) and LDL-cholesterol decreased (129 +/- 23-94 +/- 25 mg/dl, P<0.05). Plasma 6-keto-PG F(1) alpha significantly increased (7.2 +/- 3.4-13.3 +/- 6.7 pg/dl, P<0.05). (2) platelet aggregation and positive staining for P-selectin in thrombin- (0.1 and 1.0 U/ml) stimulated platelets were inhibited (Th 0.1 U/ml: 4.0 +/- 0.9-2.4 +/- 1.0/control, P<0.05), but positive staining for GP IIb-IIIa complex did not alter significantly. (3) Ca(2+) influx induced by thrombin decreased (Th 0.3 U/ml: 345 +/- 29-298 +/- 24 nmol/l, P<0.05). The baseline [Ca(2+)](i), the release of Ca(2+) from internal stores induced by thrombin and the size of internal Ca(2+) stores did not alter. (4) platelet c-AMP increased (Th 0.3 U/ml: 66.4 +/- 9.4-82.6 +/- 13.0 fmol/l, P<0.05), but platelet nitrite/nitrate (NO(x)) or c-GMP did not alter significantly. CONCLUSIONS: These results suggest that modulation of platelet function by decreasing Ca influx and increased production of c-AMP may account in part for the cardiovascular benefit of ERT.

Estrogen regulates the production of VEGF for osteoclast formation and activity in op/op mice.

UNLABELLED: Op/op mice have a severe deficiency of osteoclasts because of lacking functional M-CSF that is an essential factor of osteoclast differentiation and function. We now report that OVX induces osteoclast formation and cures osteopetrosis by increasing the VEGF that regulates osteoclast formation in these mice. INTRODUCTION: We have found that estrogen deficiency induced by ovariectomy (OVX) upregulated osteoclast formation in op/op mice. We have recently demonstrated that vascular endothelial growth factor (VEGF) could substitute for macrophage colony-stimulating factor (M-CSF) in the support of osteoclastic bone resorption in these mice. Therefore, in this study, we wished to assess the effects of VEGF on bone loss induced by OVX in these mice. MATERIALS AND METHODS: Eight-week-old op/op mice were bilateral OVX or sham-operated. Mice were killed at 8, 10, and 12 weeks of age, and femurs were removed for preparations. Some OVX mice were treated with three consecutive injections of 120 microl/body of VEGF-neutralizing antibody at 12-h intervals starting from 36 h before death at 4 weeks after OVX. VEGFR-1/Fc chimeric protein (600 microg/kg/day) or 17beta-estradiol (0.16 microg/day) was administered in a dorsal subcutaneous pocket of the mice at the time of OVX. These mice were killed 2 weeks after surgery. Changes of serum levels of VEGF were measured by ELISA. Changes of mRNA levels of VEGF, Flt-1, interleukin-6, and osteoclast differentiation factor (ODF/TRANCE/RANKL) in bone tissue were measured by reverse transcriptase-polymerase chain reaction. RESULTS: In OVX op/op mice, trabecular bone volume of the femur was decreased, and the number of osteoclasts was significantly increased. Serum levels of VEGF were demonstrated to be higher in OVX mice than in sham-operated mice. VEGF mRNA, Flt-1 mRNA, interleukin-6 mRNA, and RANKL mRNA levels in bone tissue were elevated in OVX mice over that in sham-operated mice. The increase in osteoclast number was inhibited by VEGF antagonist treatment in OVX mice. CONCLUSIONS: In this study, we have demonstrated that the production of VEGF and RANKL stimulated by OVX results in increased osteoclast formation in op/op mice.

Relationship between dental panoramic radiographic findings and biochemical markers of bone turnover.

UNLABELLED: We investigated whether mandibular cortical measures on dental panoramic radiographs are associated with biochemical markers of bone turnover in 82 postmenopausal women. Mandibular cortical shape was significantly associated with biochemical markers and spinal BMD. Our results suggest that dentists may be able to identify postmenopausal women with low BMD by using dental panoramic radiographs. INTRODUCTION: Recent studies suggest that mandibular inferior cortical shape and width on dental panoramic radiographs may be useful screening tools for low skeletal bone mineral density (BMD) or increased risk of osteoporotic fracture. However, little is known as to whether these measures are associated with bone turnover. We investigated relationships among dental panoramic radiographic findings, spine BMD, and biochemical markers of bone turnover in postmenopausal women. MATERIALS AND METHODS: Of 609 women who visited our clinic for BMD assessment between 1996 and 2002, 82 Japanese postmenopausal women, 46-68 years of age (54.1 +/- 4.9 years), were recruited for this study. Mandibular inferior cortical shape (normal, mild/moderate erosion, severe erosion) and width were evaluated on dental panoramic radiographs. BMD at the lumbar spine (L2-L4) was measured by DXA and categorized as normal (T-score > -1.0), osteopenia (T-score, -1.0 to -2.5), or osteoporosis (T-score < -2.5). Bone turnover was estimated by serum total alkaline phosphatase (ALP) and urinary N-telopeptide cross-links of type I collagen (NTx), corrected for creatinine. RESULTS: The odds of low spine BMD in subjects with any cortical erosion were 3.8 (95% CI, 1.2-12.5). Mandibular cortical erosion was significantly associated with increased NTx (p < 0.001) and ALP (p < 0.05) levels. The associations of spine BMD with NTx and ALP were similar. Mandibular cortical width was significantly associated with spine BMD but not with NTx and ALP levels. CONCLUSIONS: Our results suggest that mandibular inferior cortical shape on dental panoramic radiographs may be an indicator of bone turnover and spine BMD in postmenopausal women. Dentists may be able to identify postmenopausal women with increased risk of osteopenia and osteoporosis on routine dental panoramic radiographs.

Hormone replacement effects on endothelial function measured in the forearm resistance artery in normocholesterolemic and hypercholesterolemic postmenopausal women.

We investigated whether forearm resistance artery endothelial function differed between hypercholesterolemic postmenopausal women (n = 41) and normocholesterolemic postmenopausal women (n = 37), both generally and in terms of effects of long-term hormone replacement therapy (HRT) on endothelial function. Both menopause and hypercholesterolemia are associated with endothelial dysfunction and increased coronary risk. Forearm blood flow (FBF) during reactive hyperemia and after sublingual nitroglycerin (NTG) administration was measured by strain-gauge plethysmography. Treated women received conjugated equine estrogen (0.625 mg) plus medroxyprogesterone acetate (2.5 mg) daily for 6 months. Nitrite/nitrate, angiotensin-converting enzyme, and lipids were measured in serum. FBF during reactive hyperemia as well as serum nitrite/nitrate concentrations were significantly lower in hypercholesterolemic than normocholesterolemic subjects. Increases in the FBF induced by NTG were similar in the two groups. HRT significantly increased estradiol, high-density lipoprotein cholesterol, and serum nitrite/nitrate, while decreasing circulating angiotensin-converting enzyme activity in both groups. Reduction in total and low-density lipoprotein cholesterol was seen only in hypercholesterolemic subjects. After 6 months of HRT, maximal FBF response during reactive hyperemia increased in both groups. Augmentation of this response was greater in hypercholesterolemic than in normocholesterolemic subjects (maximal FBF, 55.4 +/- 11.2 vs. 25.9 +/- 11.5%; P < 0.05). Changes in the FBF with NTG were not altered by HRT in either group. Long-term HRT augments endothelial function in forearm resistance artery. This beneficial effect is greater in patients with hypercholesterolemia.

A comparison of low-dose and standard-dose oral estrogen on forearm endothelial function in early postmenopausal women.

We investigated the effects of low-dose estrogen plus progestin on endothelial function. Postmenopausal women received daily doses of conjugated equine estrogen (CEE, 0.625 mg) plus medroxyprogesterone acetate (MPA, 2.5 mg) (standard-dose group, n = 18), CEE (0.3 mg) plus MPA (2.5 mg) (low-dose group, n = 18), or no treatment (control group, n = 15) for 3 months. Serum concentrations of lipids and malondialdehyde (MDA)-modified low-density lipoprotein (LDL) were measured. Forearm blood flow (FBF) during reactive hyperemia and after sublingual nitroglycerin administration was measured by strain-gauge plethysmography. Decreases in serum concentrations of LDL cholesterol and MDA-modified LDL and increases in high-density lipoprotein cholesterol and nitrite/nitrate were observed in both treatment groups. After 3 months of treatment, similar increases in the maximal FBF response during reactive hyperemia were observed in both treatment groups (standard-dose group, from 35.8 +/- 3.0 to 47.5 +/- 2.8 ml/min per 100 ml tissue; and low-dose group, from 35.2 +/- 2.2 to 46.8 +/- 3.4 ml/min per 100 ml tissue, P < 0.01). FBF levels in the control group were unchanged. Treatment did not affect nitroglycerin-induced dilation. The incidences of vaginal bleeding and breast tenderness were lower with the low-dose group than with the standard-dose group. Low-dose CEE plus MPA augments endothelial function in forearm resistance arteries and decreased MDA-modified LDL levels similarly to standard doses of CEE plus MPA, with fewer side effects.

Identification and characterization of extracellular matrix metalloproteinase inducer in human endometrium during the menstrual cycle in vivo and in vitro.

Extracellular matrix metalloproteinase inducer (EMMPRIN) participates in the breakdown of the extracellular matrix (ECM) by augmenting matrix metalloproteinase (MMP) expression. In the present study, we identified and characterized the menstrual cycle-dependent expression of EMMPRIN in human endometrium in vivo. At the proliferative phase of the menstrual cycle, EMMPRIN was detected in glandular epithelium of the basal layer in endometrium. In addition, at the superficial region of the functional layer, EMMPRIN was expressed in stroma but not glandular epithelium. At the secretory phase, EMMPRIN was found in both stroma and glandular epithelium of the functional layer and glandular epithelium of the basal layer. Furthermore, EMMPRIN colocalized with MMP-1/collagenase-1 in the glandular epithelium in vivo. Western blot analysis of tissue from the functional layer showed that EMMPRIN species with molecular weights of approximately 35 and 47 kDa were detected at the proliferative phase, whereas approximately 35- and 51-kDa EMMPRIN species were predominantly expressed at the secretory phase. In addition, the variant EMMPRIN molecules were found to differ in glycosylation. On the other hand, EMMPRIN was constitutively produced in primary cultured endometrial stromal and glandular epithelial cells. The production and glycosylation of EMMPRIN in the stromal cells were augmented by progesterone at the posttranscriptional and posttranslational stages, respectively. These results suggest for the first time that EMMPRIN is expressed in human endometrium during the menstrual cycle and that its expression and glycosylation are augmented by progesterone. Moreover, EMMPRIN may be involved in ECM breakdown at the interface between endometrial cells and ECM by using EMMPRIN-bound MMP-1.

Forearm endothelial function and bone mineral loss in postmenopausal women.

It is widely believed that the vasculature plays an important role in bone remodeling. We investigated the relationship between forearm endothelial function and bone mass in the lumbar spine in early postmenopausal women without a history of smoking or diabetes mellitus. We studied the forearm resistance artery endothelial function in 110 Japanese women-52 postmenopausal women with normal spinal bone mineral density (BMD), 36 postmenopausal women with osteopenia, and 22 osteoporotic postmenopausal women. Forearm blood flow (FBF) during reactive hyperemia and after sublingual nitroglycerin (NTG) administration was measured by strain-gauge plethysmography. BMD of the lumbar spine (L2-L4) was measured by dual-energy X-ray absorptiometry. After adjustment for age, body mass index, years since the start of menopause, and basal FBF, women with osteoporosis had a lower maximal FBF response to reactive hyperemia (28.4 +/- 3.8 mL/min per 100 mL tissue) than those with normal BMD (39.8 +/- 2.8 mL/min per 100mL tissue) or osteopenia (35.6 +/- 2.5 mL/min per 100mL tissue) (P = 0.029). A significant increase in serum angiotensin-converting enzyme (ACE) activity (P = 0.042) and a significant decrease in the serum concentrations of nitrite/nitrate (P = 0.041) were noted in osteoporotic women compared to women with normal BMD or osteopenia. The present findings suggest that postmenopausal women with low BMD, especially those with osteoporosis, have impaired endothelial function in the forearm resistance arteries.

Increased expression of IGF II mRNA-binding protein 1 mRNA is associated with an advanced clinical stage and poor prognosis in patients with ovarian cancer.

The purpose of this study was to examine the expression of IGF II mRNA-binding protein (IMP-1, -2, and -3) mRNA in epithelial ovarian tumors, and to identify the association of IMP-1, -2, and -3 expression levels with patient survival. IMP mRNA expression levels were examined by semi-quantitative PCR in 59 epithelial ovarian tumors (8 adenomas, 5 LMP tumors, and 46 adenocarcinomas) and in 7 normal ovaries. Results of semiquantitative PCR were correlated with clinicopathological variables and overall survival. Human normal and tumor tissue cDNAs were included in all of the analyses. The IMP family mRNA expression was detected in almost all cancer tissues examined, including breast, lung, colon, prostatic, and ovarian carcinoma with the exception of pancreatic carcinoma. The mean value of the relative IMP-1 mRNA expression ratio was significantly higher in both ovarian cancer and adenoma samples compared to normal ovarian samples (p<0.05). IMP-2 and IMP-3 expression levels were significantly higher in both ovarian cancer and ovarian LMP tumor samples compared to either ovarian adenomas or to normal ovary samples (p<0.05). A significantly higher IMP-1 mRNA expression level was observed in patients with an advanced clinical stage (p=0.015) and high histological grade (p=0.023). Log-rank testing showed that IMP-1 overexpression (p=0.0398) and an advanced clinical stage (p=0.0050) were significantly correlated with poor patient survival, whereas neither IMP-2 nor IMP-3 overexpression were associated with poor prognoses. In multivariate analysis, IMP-1 overexpression lost its significance, whereas the clinical stage (p=0.0432) remained significantly associated with overall survival. IMP mRNA expression levels might play an important role in ovarian cancer development and progression, and IMP-1 overexpression is a prognostic marker for patients with ovarian cancer.

Expression of cyclooxygenase-2 and its relationship to p53 accumulation in ovarian adenocarcinomas.

To investigate cyclooxygenase-2 (COX-2) expression and its relationship to p53 accumulation in ovarian adenocarcinomas, COX-2 and p53 protein expressions were examined by immunohistochemistry in 86 ovarian adenocarcinomas and six normal ovaries. In addition, COX-2 mRNA expression level was examined by semi-quantitative PCR in 36 ovarian adenocarcinomas. Neither COX-2 expression nor p53 accumulation were detected in normal ovarian surface epithelium or germinal inclusion cyst epithelial cells. In contrast, COX-2 protein expression was detected in 31.4% of adenocarcinomas, and p53 protein accumulation was found in 30.2% of adenocarcinomas. A significantly higher COX-2 expression rate was observed in endometrioid adenocarcinomas than in either mucinous (p=0.019) or clear cell (p=0.021) adenocarcinomas, and a significantly higher p53 accumulation rate was observed in serous adenocarcinomas compared to clear cell adenocarcinomas (p=0.015). p53 accumulation correlated with advanced clinical stage (stage I vs. stage II/III/IV: p=0.007), whereas no correlation was found between COX-2 expression and clinical stage. There was a significant positive correlation between COX-2 expression and p53 accumulation status (p=0.003). Log-rank testing showed that p53 accumulation was significantly correlated with poor patient survival (p=0.004), whereas no correlation was found between COX-2 expression and survival. COX-2 mRNA expression was detected in 72.2% of ovarian adenocarcinomas, and a significant correlation between COX-2 mRNA expression status and immunoreactivity (p=0.023) was observed. These results suggest that COX-2 expression might play an important role in ovarian cancer development and that COX-2 expression in ovarian adenocarcinomas is frequently associated with p53 protein accumulation. COX-2 overexpression in ovarian cancer cells might partly be caused by dysfunctional p53.

Substitution of transdermal estradiol during oral estrogen-progestin therapy in postmenopausal women: effects on hypertriglyceridemia.

OBJECTIVE: We investigated effects of changing from oral estrogen to transdermal estradiol on the lipid and lipoprotein profile of postmenopausal women who developed hypertriglyceridemia (serum concentrations exceeding 150 mg/dL) during estrogen-progestin therapy. DESIGN: Sixty-one postmenopausal Japanese women receiving 0.625 mg of conjugated equine estrogen plus 2.5 mg of medroxyprogesterone acetate daily for 12 months had developed serum triglyceride concentrations exceeding 150 mg/dL after 12 months of treatment. Thirty-six of them, chosen randomly for study, were assigned at random to either a group that continued this oral regimen or another that changed to transdermal estradiol while continuing 2.5 mg of oral medroxyprogesterone acetate for the next 3 months (n = 18 for each). Blood lipids were compared between groups. RESULTS: Serum concentrations of triglyceride and very-low-density lipoprotein triglyceride decreased significantly after changing to transdermal estradiol (triglyceride, from 226.0 +/- 43.9 to 110.5 +/- 44.1 mg/dL, P < 0.01). No changes were seen in concentrations of low-density lipoprotein cholesterol or high-density lipoprotein cholesterol. CONCLUSION: Changing to transdermal estradiol may improve triglyceride metabolism in women who developed hypertriglyceridemia during oral estrogen-progestin therapy, with minimal effect on cholesterol profiles.

Combination therapy of low-dose medroxyprogesterone acetate and oral estrogen does not affect endothelial function in the forearms of postmenopausal women.

OBJECTIVE: We investigated whether low-dose medroxyprogesterone acetate (MPA) combined with oral estrogen had adverse effects on endothelial function compared with oral estrogen alone in postmenopausal women with mild hypercholesterolemia. DESIGN: Subjects were divided into two groups. One group received conjugated equine estrogen (CEE, 0.625 mg daily) orally for the first 3 months, followed by estrogen combined with MPA (2.5 mg daily) orally for an additional 3 months ( = 26). The other group received no treatment (control group, = 12). Forearm blood flow (FBF) during reactive hyperemia and after sublingual nitroglycerin administration was measured by strain-gauge plethysmography. Nitrite/nitrate, angiotensin-converting enzyme, and lipid concentrations were measured in the serum. RESULTS: Both CEE and CEE combined with MPA significantly increased the FBF during reactive hyperemia. This increase was similar in both active treatment phases. No changes were seen in controls. FBF after sublingual nitroglycerin did not change over 6 months in either group. Significant and similar increases in serum concentration of nitrite/nitrate and plasma renin activity as well as decreases in angiotensin-converting enzyme activity were found in both treatment phases. No such changes occurred in the control group. There was no significant increase in high-density lipoprotein cholesterol or decrease in low-density lipoprotein cholesterol between the treatment phases. Likewise, no such changes were observed in the control group. CONCLUSIONS: Our 6-month study suggests that the addition of low-dose MPA with CEE had no adverse effects on forearm resistance artery endothelial function compared with CEE alone.

Effect of estrogen use on tooth retention, oral bone height, and oral bone porosity in Japanese postmenopausal women.

OBJECTIVE: Recent studies in the United States support the protective effect of estrogen use on tooth retention; however, little is known as to how estrogen promotes tooth retention. The aims of this study were to investigate the effects of estrogen use on tooth retention, oral bone height, and oral bone porosity in Japanese postmenopausal women and to clarify how estrogen promotes tooth retention. DESIGN: Relationships among the number of teeth remaining (total, anterior, and posterior teeth), oral bone height, oral bone porosity, bone mineral density of the lumbar spine and the femoral neck, estrogen use status, and the duration of estrogen use were evaluated in 330 Japanese postmenopausal women (mean age +/- SD, 56.8 +/- 7.6 y). RESULTS: Analysis of covariance adjusted for confounding variables revealed that estrogen users (66 women) tended to have more posterior teeth than did nonusers (264 women) (P = 0.065), although there were no significant differences in number of total (P = 0.196) and anterior (P = 0.751) teeth remaining, oral bone height (P = 0.970), oral bone porosity (P = 0.745), and bone mineral density of the lumbar spine (P = 0.459) and the femoral neck (P = 0.749) between estrogen users and nonusers. Multiple regression analysis showed that the duration of estrogen use was significantly associated with number of total (P = 0.019) and posterior (P = 0.007) teeth remaining, independent of age and oral bone height. CONCLUSION: Our results suggest that estrogen may promote tooth retention by strengthening the periodontal attachment surrounding the teeth, but not increasing oral bone height and not decreasing oral bone porosity.

Association of estrogen and vitamin D receptor gene polymorphisms with tooth loss and oral bone loss in Japanese postmenopausal women.

OBJECTIVE: To investigate the relationship between estrogen receptor (ER) and vitamin D receptor (VDR) gene polymorphisms and tooth loss, oral bone loss, and postcranial bone mineral density (BMD) in Japanese postmenopausal women. DESIGN: Polymorphisms at the ER PvuII and XbaI and VDR BsmI gene sites, number of teeth remaining, oral bone mass, and BMD of the lumbar spine and the hip were evaluated in 149 Japanese postmenopausal women. RESULTS: The distribution of ER PvuII and XbaI and VDR BsmI restriction fragment length polymorphisms was as follows: pp, 30.2%; Pp, 49.7%; PP, 20.1%; xx, 71.8%; Xx, 22.5%; XX, 2.7%; bb, 76.5%; Bb, 22.2%; and BB, 1.3%. Analysis of covariance adjusted for confounding variables revealed that participants with pp allele had fewer teeth remaining than did those with P allele. There were no significant differences in oral bone mass and postcranial BMD among three alleles at the PvuII site. Participants with X and bb allele had less oral bone mass and lower postcranial BMD than did those with xx and B allele, respectively. We could not clarify the positive associations between XbaI and BsmI polymorphism and number of teeth. CONCLUSIONS: PvuII polymorphism was associated with tooth loss, but not with oral bone mass and postcranial BMD. XbaI and BsmI polymorphisms may be associated with bone mass or density; however, PvuII polymorphism might contribute to another unknown pathway related to tooth loss.

Indoleamine 2,3-dioxygenase: distribution and function in the developing human placenta.

Studies in mice have suggested that the placenta is protected from immune rejection by maternal T cells by means of localised indoleamine 2,3-dioxygenase dependent depletion of tryptophan. To determine whether such mechanisms might operate in the human placenta, we have studied the physiological importance of human placental indoleamine 2,3-dioxygenase immunohistochemically and functionally. Indoleamine 2,3-dioxygenase is detectable immunohistochemically from day 6 human blastocysts and thereafter throughout pregnancy in syncytiotrophoblasts, extravillous cytotrophoblasts and macrophages in the villous stroma and in the fetal membranes. Interferon-gamma added to villous explants markedly stimulates indoleamine 2,3-dioxygenase protein expression in macrophages. Indoleamine 2,3-dioxygenase-mediated tryptophan degradation in the first trimester villous and decidual tissue explants is stimulated by interferon-gamma and inhibited by 1-methyl-tryptophan (an inhibitor of indoleamine 2,3-dioxygenase). Peripheral blood mononuclear cell proliferation is controlled by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. These results suggest the cellular basis of a mechanism present at the human maternal-fetal interface involved in regulating the maternal immune response to conceptus.

Endometrial cytodiagnosis using a new softcyte versus a conventional endocyte.

A new endometrial cytologic sampling device, softcyte, was used in cytological screening for endometrial cancer, and was compared with the endocyte with regard to manipulability, adverse effects (including pain and hemorrhage), and cellular findings (including the quantity of cells collected, the success rate, cell freshness, and cellular clumping). A total of 315 women (premenopause 251, postmenopause 64) were randomly assigned to two groups who underwent the endometrial cytological screening with either the softcyte or the endocyte. To assess the value of the softcyte we compared it with the endocyte. Endometrial cytology using a softcyte or an endocyte achieved high correct diagnosis rate for cancer, and both instruments are valuable as endometrial cytologic sample devices. The softcyte causes only mild pain on introduction and during collection, and a large quantity of cells could be harvested. These results suggest that the softcyte is a useful cytologic sampling device in screening for endometrial cancer.