These results suggest accumulation of BPA in early fetuses and significant exposure during the prenatal period, which must be considered in evaluating the potential for human exposure to endocrine-disrupting chemicals.

Endothelium-dependent vasodilatation varies during the menstrual cycle. The endogenous estradiol may be involved in this menstrual cycle-related vasodilatation.

The phosphatidylinositol 3V-kinase (PI3K) pathway is activated in many human cancers. In addition to inactivation of the PTEN tumor suppressor gene, mutations or amplifications of the catalytic subunit A of PI3K (PIK3CA) have been reported. However, the coexistence of mutations in these two genes seems exceedingly rare. As PTEN mutations occur at high frequency in endometrial carcinoma, we screened 66 primary endometrial carcinomas for mutations in the helical and catalytic domains of PIK3CA. We identified a total of 24 (36%) mutations in this gene and coexistence of PIK3CA/PTEN mutations at high frequency (26%). PIK3CA mutations were more common in tumors with PTEN mutations (17 of 37, 46%) compared with those without PTEN mutations (7 of 29, 24%). Array comparative genomic hybridization detected 3q24-qter amplification, which covers the PIK3CA gene (3q26.3), in one of nine tumors. Knocking down PTEN expression in the HEC-1B cell line, which possesses both K-Ras and PIK3CA mutations, further enhances phosphorylation of Akt (Ser 473 ), indicating that double mutation of PIK3CA and PTEN has an additive effect on PI3K activation. Our data suggest that the PI3K pathway is extensively activated in endometrial carcinomas, and that combination of PIK3CA/PTEN alterations might play an important role in development of these tumors. (Cancer Res 2005; 65(23): 10669-73)

Abstract. This study was performed to investigate the serum levels of bisphenol A (BPA), an endocrine disruptor, in women with ovarian dysfunction and obesity. Fasting serum samples were obtained from 19 non-obese and 7 obese women with normal menstrual cycles: 7 patients with hyperprolactinemia, 21 patients with hypothalamic amenorrhea, and 13 non-obese and 6 obese patients with polycystic ovary syndrome (PCOS). BPA was measured by an enzyme-linked immunosorbent assay. BPA was detected in all human sera. Serum BPA concentrations were significantly higher in both non-obese and obese women with polycystic ovary syndrome (1.05 ± 0.10 ng/ml, 1.17 ± 0.16 ng/ml; p<0.05, respectively) and obese normal women (1.04 ± 0.09 ng/ml, p<0.05) compared with those in non-obese normal women (0.71 ± 0.09 ng/ ml). There was no difference among women with hyperprolactinemia, women with hypothalamic amenorrhea, and nonobese normal women. There were significant positive correlations between serum BPA and total testosterone (r = 0.391, p<0.001), free testosterone (r = 0.504, p<0.001), androstenedione (r = 0.684, p<0.001), and DHEAS (r = 0.514, p<0.001) concentrations in all subjects. These findings show that there is a strong relationship between serum BPA and androgen concentrations, speculatively due to the effect of androgen on the metabolism of BPA.

Hoping to get more insight into a role of vascular endothelial growth factor (VEGF), a putative substance involved in the development of preeclampsia, we measured concentrations of soluble VEGF receptor-1 (sVEGFR-1), a natural antagonist of VEGF, in serum from women with (n = 31) and without (n = 52) preeclampsia. The concentrations of sVEGFR-1 in serum from women with preeclampsia (median 7791 pg/mL) were > 6-fold higher than those from control (1132 pg/mL, p < 0.0001). The levels of sVEGFR-1 decreased markedly after delivery in both groups. Serum sVEGFR-1 levels of non-preeclamptic women were positively correlated with gestational age (r = 0.570, p < 0.0001), whereas those of preeclamptic women exhibited no correlation with gestational age (r = -0.130, p = 0.476). These findings may point to an involvement of sVEGFR-1 in the pathophysiology of preeclampsia possibly by antagonizing of VEGF effects on the formation of placental vasculature and maternal endothelial cell function.

Sufficient cytotrophoblast (CT) invasion into the uterine wall and subsequent remodeling of maternal uterine vasculature is critical to establish uteroplacental circulation. The production of vascular endothelial growth factor (VEGF) family molecules is confirmed in placental cells including CTs, but it is not elucidated how the VEGF system in CTs is controlled by oxygen tension and how it is involved in the development of placental circulation. To address this, we explored the effect of oxygen tension on the expression of VEGF, placenta growth factor (PlGF), and their antagonist, soluble fms-like tyrosine kinase-1 (sFlt-1) using ELISA and real-time PCR in a primary CT cell culture. For comparison, the same was conducted in parallel using other cells comprising placenta, such as human umbilical vein endothelial cells (HUVECs) and villous fibroblasts (VFs). Reduced oxygen resulted in a pronounced increase in sFlt-1 mRNA amount and sFlt-1 release into the culture media in CTs, whereas this was not the case with HUVECs and VFs. Free (not bound to sFlt-1) VEGF was not detected in CT culture media regardless of oxygen concentration, even though VEGF expression was stimulated by reduced oxygen in CTs, which was similar to the stimulation in HUVECs and VFs. Free PlGF was also diminished in CT culture media by reduced oxygen. These results implicate that CTs possess a unique property to enhance sFlt-1 production under reduced oxygen, which could consequently antagonize angiogenic activity of VEGF and PlGF. The presented findings might provide a framework with which to understand the mechanism of uterine vascular remodeling and its perturbations as exemplified in preeclampsia.

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Previous medical treatment of endometriosis or large cyst size was a significant factor that was associated with higher recurrence of the disease. Post-operative pregnancy is a favourable prognostic factor.