Estetrol is a weak estrogen antagonizing estradiol-dependent mammary gland proliferation.

Estetrol (E4) is a natural estrogen produced exclusively by the human fetal liver during pregnancy. Its physiological activity remains unknown. In contrast to ethinyl estradiol and estradiol (E2), E4 has a minimal impact on liver cell activity and could provide a better safety profile in contraception or hormone therapy. The aim of this study was to delineate if E4 exhibits an activity profile distinct from that of E2 on mammary gland. Compared with E2, E4 acted as a low-affinity estrogen in both human in vitro and murine in vivo models. E4 was 100 times less potent than E2 to stimulate the proliferation of human breast epithelial (HBE) cells and murine mammary gland in vitro and in vivo respectively. This effect was prevented by fulvestrant and tamoxifen, supporting the notion that ERα (ESR1) is the main mediator of the estrogenic effect of E4 on the breast. Interestingly, when E4 was administered along with E2, it significantly antagonized the strong stimulatory effect of E2 on HBE cell proliferation and on the growth of mammary ducts. This study characterizes for the first time the impact of E4 on mammary gland. Our results highlight that E4 is less potent than E2 and exhibits antagonistic properties toward the proliferative effect of E2 on breast epithelial cells. These data support E4 as a potential new estrogen for clinical use with a reduced impact on breast proliferation.

Oxidative stress-induced S100B protein from placenta and amnion affects soluble Endoglin release from endothelial cells.

Oxidative stress with elevated intracellular Ca(2+) concentration as well as endothelial dysfunction is a component of pre-eclampsia. Our aim was to investigate the oxidative stress-dependent expression of Endoglin and Ca(2+)-binding S100B protein from villous and amniotic tissue cultures, and to assess sEng expression from S100B protein-stimulated endothelial cells. We initially examined Endoglin and Hydroxy-nonenal-(HNE)-modified proteins in the placentas and amnion obtained from women with pre-eclampsia (n = 8), and healthy controls (n = 8) by immunohistochemistry. To examine oxidative stress and the S100B protein effect on sEng expression from endothelial cells, normal villous and amniotic tissue cultures were stimulated by 4-HNE, sodium fluoride and xanthine/xanthine oxidase, whereas human umbilical vein endothelial cell cultures were treated with S100B protein in a dose- and time-dependent manner at 37 degrees C in an environment of 95% air and 5% of CO(2). Culture supernatants were assessed using ELISA. Cell viability was determined using MTS assay. The concentrations of sEng and S100B protein were significantly increased in the villous and amniotic tissue culture supernatants under oxidative stress. S100B protein-stimulated endothelial cells released sEng into conditioned media with a significantly higher expression levels at a concentration of 200 pM-20 nM S100B by 2 h, whereas treated with 200 nM of S100B endothelial cells significantly expressed sEng by 12 h and stimulated the cell proliferation by the same period of time. Our findings show that oxidative stress affects sEng and S100B protein expression from villous and amniotic tissues, and picomolar and low nanomolar concentrations of S100B protein significantly up-regulate sEng release from endothelial cells leading to endothelial dysfunction.

Amniotic fluid 'sludge' detected in patients with subchorionic hematoma: a report of two cases.

Amniotic fluid 'sludge' is defined as the presence of dense aggregates of particulate matter in close proximity to the internal cervical os. It is of clinical significance in asymptomatic patients at high risk for spontaneous delivery, and in patients with preterm labor and intact membranes. Subchorionic hematoma is another ultrasound finding that is associated with a higher incidence of threatened miscarriage and preterm delivery. We report two cases of occurrence of amniotic fluid sludge in patients with previously detected large subchorionic hematoma. In the first case subchorionic hematoma and amniotic fluid sludge were detected by ultrasonography at 13 + 1 and 18 + 6 weeks' gestation, respectively, followed by preterm premature rupture of membranes, placental abruption and emergency Cesarean section. In the second case subchorionic hematoma and amniotic fluid sludge were detected by ultrasound at 11 + 3 and 15 + 5 weeks' gestation, respectively, followed by miscarriage with histological chorioamnionitis. The coincidence of subchorionic hematoma and amniotic fluid sludge in these cases points to a possible connection between these two significant ultrasound findings.

The human tumor-associated antigen RCAS1 in pregnancies complicated by pre-eclampsia.

The human tumor-associated antigen RCAS1 (receptor-binding cancer antigen expressed on SiSo cells) is considered to play a role in the escape of tumor cells from immune surveillance and, at the same time, participates in the inhibition of the maternal immune response during pregnancy. The aim of our study was to investigate the expression of tumor-associated RCAS1 protein in the placenta and amniotic membranes and to assess and compare its concentration in amniotic fluid, maternal and cord blood sera in pregnancies complicated by pre-eclampsia. Samples were obtained from women with pre-eclampsia (N=9), pre-eclampsia with IUGR (N=4), normotensive IUGR (N=7) and healthy term controls (N=25) after delivery. Placentas were studied by immunohistochemistry, Western blot analysis and real-time (RT)-PCR. For assessment of RCAS1 protein concentrations in biological fluids, ELISA was performed. RCAS1 mRNA expression in the placentas of pre-eclamptic patients was significantly lower than in controls (p<0.01). The maternal blood serum RCAS1 protein concentration in the pre-eclampsia cases was also significantly lower than in controls (p=0.0207). The other study groups did not differ significantly. This study reveals the possible role of the RCAS1 protein in the development of pre-eclampsia through an immunological pathway.

S100B protein expression in the amnion and amniotic fluid in pregnancies complicated by pre-eclampsia.

Our aim was to investigate the expression of S100B protein in the amnion and to assess the amniotic fluid concentration in pregnancies complicated by pre-eclampsia. Samples were obtained from women who developed pre-eclampsia (n = 7), pre-eclampsia with intrauterine growth retardation (IUGR) (n = 4), normotensive IUGR (n = 7) and gestational hypertension (n = 4) during pregnancy and healthy controls who delivered at term (n = 35). To determine the difference in the expression of S100B in the amnion, we performed immunohistochemistry, western blot analysis and RT-PCR. Using enzyme-linked immunosorbent assay (ELISA), we assessed the S100B concentration in amniotic fluid. The S100B mRNA expression in the amnion of pre-eclamptic patients and patients with pre-eclampsia with IUGR was significantly higher than that in the control. The amniotic fluid S100B protein concentration of the pre-eclampsia and normotensive IUGR cases was significantly higher than that of the control. This study shows that amnion could be a source responsible for the increased concentration of S100B in amniotic fluid. In pre-eclampsia, reactive oxygen species (ROS) are generated by oxidative stress. Some pathological conditions that develop during pregnancy and are related to hypoxic stress can affect the elevation of S100B concentration in the amnion.