Reproductive Sciences current issue

In the Spotlight

Maduro, M. R. — 2008-06-25

{beta}-HCG/LH Receptor ({beta}-HCG/LH-R) Expression in Eutopic Endometrium and Endometriotic Implants: Evidence for {beta}-HCG Sensitivity of Endometriosis

2008-06-25

Background: Luteinizing hormone (LH) and human chorionic gonadotropin (HCG) target their receptor in gonadal and nongonadal cells to stimulate steroidogenesis and cell growth. The aim of the present study was to investigate the expression of HCG/LH-R in endometriosis to elucidate a possible impact of LH and HCG on this disease. Materials and methods: Analysis of HCG/LH-R protein expression in 23 paired samples of ectopic and eutopic tissue of cycling women with endometriosis and in endometrial samples from 22 healthy controls was conducted via immunofluorescence. HCG and HCG/LH-R gene expression in endometriotic lesions was confirmed by reverse-transcriptase polymerase chain reaction. Results: In endometriotic implants, epithelial HCG/LH-R was found in 12/23 samples. No significant differences in HCG/LH-R levels were observed when compared with glands of uterine endometrium from the same patients or healthy controls. Messenger RNA transcripts for HCG were detected in all 12 samples, whereas HCG/LH-R mRNAs were observed in 10 of the 12 endometriotic lesions investigated. Conclusions: Although HCG/LH-R was not found to be selectively upregulated in endometriosis, the mere presence of HCG/LH-R in endometriotic tissue may suggest sensitivity of endometriosis to HCG and LH that target HCG/LH-R.

Induction of Growth Inhibition and Apoptosis in Human Uterine Leiomyoma Cells by Isoliquiritigenin

2008-06-25

Isoliquiritigenin(ISL), a calchone flavonoid, has cancer-preventing properties and is often used in Chinese medicine. In the present study, the authors use ISL to determine its effect on cell proliferation and cell cycle progression in primary cultured human uterine leiomyoma cells. Cell viability and cell proliferation assays were conducted. Flow cytometry, annexin V apoptosis assay, and DNA fragmentation assay were performed to determine the effect of ISL on cell cycle and apoptosis. The expression of cell cycle regulatory—related proteins was evaluated by Western blot. The cell viability and proliferation of uterine leiomyoma cells were significantly reduced by ISL treatment in a dose-dependent manner. Flow cytometry results showed that ISL induced subG1 and G2/M arrest. DNA fragmentation assay and annexin V apoptosis assays revealed apoptosis induction. ISL-induced growth inhibition in uterine leiomyoma cells was associated with increased p21^Cip1/ Waf1 expression in a p53-dependent manner. Activation of caspase-3 and downregulation of Bcl-2, cdk 2/4, and E2F, with a concomitant increase in dephosphorylation of Rb and poly—ADP-ribose polymerase cleavage, were observed. This study demonstrates that ISL inhibits cell proliferation by initiating apoptosis in human uterine leiomyoma cells coupled with increased cell cycle arrest. These results indicate that ISL could prove to be a promising chemopreventive and therapeutic agent against human uterine leiomyoma.

Estradiol 17-{beta} and Progesterone Modulate Inducible Nitric Oxide Synthase and High Mobility Group Box 1 Expression in Human Endometrium

2008-06-25

The aim of the present study is to investigate the effects of ovarian sex steroid hormones on the expression and the release of several locally active substances by human endometrium. Specific objectives are (1) to ascertain if estradiol 17-β (E2) and progesterone modulate inducible nitric oxide synthase (iNOS) expression and nitric oxide release; (2) to determine whether human endometrium can express High Mobility Group Box 1 (HMGB1), a multifunctional cytokine, and whether sexual steroid hormones can modulate this expression; and (3) to evaluate whether nitric oxide can influence HMGB1 expression in this tissue. Endometrial tissue was obtained from 40 healthy premenopausal women who underwent hysteroscopy for suspected benign gynecological conditions. Endometrium was incubated with E2, progesterone, or sodium nitroprusside, a nitric oxide donor. Nitrite assay was used to quantify stable nitric oxide metabolites in culture medium, and Western blot analysis was used to detect iNOS and HMGB1. Incubation of endometrium with E2 results in an increase in iNOS expression and nitric oxide metabolite production. The opposite effect is obtained by incubating tissues with progesterone. HMGB1 is expressed by human endometrium, and its expression is increased by E2 and decreased by progesterone. Incubation with sodium nitroprusside results in a reduction in HMGB1 expression. Both E2 and progesterone modulate iNOS expression and nitric oxide production in human endometrium. HMGB1 is expressed in the human endometrium, and its expression is modulated by E2, progesterone, and nitric oxide.

Clinical Application of Pulse Transit Time and Correlation With Intrapartum Fetal Heart Rate Monitoring: A Preliminary Study of 18 Full-Term Infants

Kawagoe, Y., Sameshima, H., Ikenoue, T. — 2008-06-25

The authors show that pulse transit time and blood pressure are reciprocal in fetal goat models. They applied this technique in clinical settings to correlate changes in pulse transit time with fetal heart rate monitoring patterns and acid-base status. In 18 uncomplicated pregnancies, pulse transit time was obtained from electrocardiograms to pulse oximeter waveform and averaged during each baseline period, defined by the interpretation of fetal heart rate monitoring. According to a > 10% change from the control value, chronological changes were categorized into shortened, unchanged, and prolonged. Pulse transit time was available in 82% ± 11% of the recordings. In 15 fetuses, 2 (13%) showed prolonged, 7 (47%) showed shortened, and 6 (40%) showed unchanged conditions. Comparisons of the shortened and unchanged categories revealed that severe variable deceleration was significantly increased, and half or more fetuses showed hypoxemia in the shortened category. Shortening of pulse transit time, theoretically indicating a hypertensive condition, was more frequently associated with severe variable decelerations, suggesting that the pulse transit time may supplement the interpretation of fetal heart rate monitoring.

ECG and Heart Rate Variability Changes in Preterm and Near-Term Fetal Lamb Following LPS Exposure

Blad, S., Welin, A.-K., Kjellmer, I., Rosen, K.G., Mallard, C. — 2008-06-25

The aim of this study is to evaluate the myocardial response in the preterm and near-term fetal lamb with infection. Chronically instrumented fetal lambs were exposed to lipopolysaccharide (LPS), and the fetal electrocardiogram (FECG) ST waveform was examined using STAN. Fetal heart rate variability (FHRV) was automatically analyzed by adapting a polynomial function to the RR sequence in the FECG. Preterm fetuses exposed to >90 ng/kg LPS died within 8 hours of LPS administration, a response not seen in near-term fetuses. In both surviving and nonsurviving preterm fetuses, cardiovascular responses were characterized by decreased arterial pressure, negative T waves, and tachycardia accompanied by an increase in FHRV. Similar changes were not observed in the near-term fetuses after LPS. The study shows that preterm lambs are more sensitive to LPS in terms of myocardial/cardiovascular response than the more mature fetuses are. High FHRV and negative ST waveform seem to characterize the LPS-induced stress response in preterm fetuses.

The Increase of Blood Flow in the Fetal Middle Cerebral Artery Correlates With the Onset of Labor at Term

2008-06-25

The objective of this cohort study is to evaluate the relationship between blood flow resistance in the fetal middle cerebral artery (MCA) and the beginning of spontaneous labor. A group of consecutive women (n = 664) with a singleton pregnancy was submitted to Doppler examination of fetal MCA between 24 and 41 weeks' gestation (median, 35 weeks). The study population was later divided into 2 groups according to the MCA pulsatility index (PI), expressed in multiples of the median (MoM) for each gestation week. The median time elapsed between the Doppler examination and the onset of spontaneous labor (which eventually occurred in 302 women, of whom 291 were at term) was significantly shorter in the group with MCA PI <0.74 MoM (5.5 days; interquartile interval, 2-10 days) than in the group with MCA PI ≥0.74 MoM (22.5 days; interquartile interval, 5-37.5 days; P < .001). Survival analysis and Cox regression confirmed that the MCA PI was independently associated with the number of days elapsed from Doppler to spontaneous labor (P < .001; Exp[B], 2.77; 95% confidence interval, 1.95-3.90) after correction for birth weight and umbilical artery PI. The present data suggest that, at term of pregnancy, a gestation-independent decrease of fetal cerebral vascular resistance precedes the onset of spontaneous labor.

Detection and Identification of Novel Metabolomic Biomarkers in Preeclampsia

2008-06-25

In a previous study, the ability of gas chromatography time-of-flight mass spectrometry to detect potential metabolic biomarkers in preeclampsia was demonstrated. In this study, the authors sought to validate their preliminary findings in an entirely different patient cohort using a complementary, novel, and powerful combination of analytical tools (ultra performance liquid chromatography and LTQ Orbitrap mass spectrometry system). Eight metabolites that appeared in the authors' previous patient cohort were identified as being statistically significant (P < .01) as discriminatory biomarkers. The chemical identities of these 8 metabolites were established using authentic chemical standards. They included uric acid, 2-oxoglutarate, glutamate, and alanine. This is the first study to identify, in an unbiased manner, a series of small-molecular-weight metabolites that effectively detect preeclampsia in plasma. The identity of these metabolites provides new insights into the pathology of this condition and raises the possibility of the development of a predictive test.

Thyroid Hormone Regulates Renocortical COX-2 and PGE2 Expression in the Late Gestation Fetal Sheep

Carey, L. C., Valego, N. K., Kai Chen, , Rose, J. C. — 2008-06-25

Cyclooxygenase 2 (COX-2) is important for development of the fetal kidney. Precisely how renal COX-2 expression is regulated in fetal life is unclear. The hypothesis that thyroid hormone positively regulates COX-2 and PGE₂ levels in the late gestation fetal kidney cortex was tested. Sham, thyroidectomized (TX), and TX + thyroid hormone replacement (R) fetal sheep were studied. TX was performed at 120 days gestational age (dGA). TX + R fetuses were continuously infused with thyroxine from 3 days after surgery until study completion. Fetal kidney cortex was obtained at 137 dGA for measurement of renal cyclooxygenase type-2 (COX-2) protein and PGE₂ metabolites. Renocortical COX-2 and PGE₂ levels were significantly lower in TX compared with sham and TX + R fetuses. There were no differences between sham and TX + R fetuses. These findings demonstrate that thyroid hormone positively regulates renal COX-2 and PGE₂ expression in the late gestation fetal sheep kidney.

The Relation Between Venous Reserve Capacity and Low Plasma Volume

2008-06-25

Objective: Prepregnant low plasma volume (LPV) is associated with subsequent gestational hypertensive disease. It is unknown to what extent an LPV affects the venous reserve capacity (VRC). We tested the hypothesis that LPV reduces the VRC, as indicated by presyncope or altered cardiovascular changes in response to head-up tilt. Study design: In 52 nonpregnant women with a history of preeclampsia or recurrent miscarriage, the authors assessed plasma volume, stroke volume, and cardiac output and determined blood pressure, heart rate, and autonomic responses to stepwise inflicted head-up tilt. Results: 12 participants had LPV, which related to presyncope when compared with subjects with normal plasma volume (NPV). Women with LPV without presyncope demonstrated a circulatory response comparable to NPV women at the expense of consistently higher heart rate. Conclusion: LPV decreases the capacity to cope with head-up tilt without affecting the response pattern, suggesting reduced VRC.

Reduction of Brain Injury in Neonatal Hypoxic--Ischemic Rats by Intracerebroventricular Injection of Neural Stem/Progenitor Cells Together With Chondroitinase ABC

2008-06-25

Perinatal hypoxia—ischemia (HI) remains a critical issue. Cell transplantation therapy could be a potent treatment for many neurodegenerative diseases, but limited works on this kind of therapy have been reported for perinatal HI. In this study, the therapeutic effect of transplantation with neural stem/ progenitor cells (NSPCs) and chondrotinase ABC (ChABC) in a neonatal HI rat model is evaluated. Histological studies showed that the unaffected area of the brain in animals treated with NSPCs together with ChABC was significantly larger than that in the animals treated with vehicle or NSPCs alone. The wet weight of the brain that received the combined treatment was also significantly higher than those of the vehicle and their individual treatments. These results indicate that intracerebroventricular injection of NSPCs with ChABC reduces brain injury in a rat neonatal HI model.