Reproductive Sciences

Objective: Atherosclerosis is a complex process characterized by an increase in vascular wall thickness owing to the accumulation of cells and extracellular matrix between the endothelium and the smooth muscle cell wall. There is evidence that females are at lower risk of developing cardiovascular disease (CVD) as compared to males. This has led to an interest in examining the contribution of genetic background and sex hormones to the development of CVD. The objective of this review is to provide an overview of factors, including those related to gender, that influence CVD. Methods: Evidence analysis from PubMed and individual searches concerning biochemical and endocrine influences and gender differences, which affect the origin and development of CVD. Results: Although still controversial, evidence suggests that hormones including estradiol and androgens are responsible for subtle cardiovascular changes long before the development of overt atherosclerosis. Conclusion: Exposure to sex hormones throughout an individual’s lifespan modulates many endocrine factors involved in atherosclerosis.

Objective: Progesterone supplementation prevents preterm birth (PTB) in some high-risk women, but its mechanism of action is not known. One third of PTB is associated with preterm premature rupture of membranes (PPROM). We hypothesize that progesterone may block proinflammatory cytokine-induced apoptosis of fetal membrane, thereby preventing PPROM and PTB. Methods: Fetal membranes were collected at elective repeat cesarean at term (no labor, no infection [n = 12]), washed, and cultured with/ without progesterone (125-500 ng/mL), 17α-hydroxyprogesterone caproate (125-500 ng/mL [17P]), or medroxyprogesterone acetate (10^-7-10 ^-6 mol/L [MPA]) for 24 hours. Membranes were then treated with/without lipopolysaccharide ([LPS] 100 ng/mL) or tumor necrosis factor alpha ([TNF-α] 50 ng/ mL) for 24 to 72 hours, harvested, and homogenized. Apoptosis was determined by evaluating caspase-3, -8, and -9 activities. Caspase activity in relative light units was measured on a luminometer and corrected for total protein. Results: Both TNF-α and LPS significantly increased caspase-3, -8, and -9 activity in term fetal membranes in a time-dependent fashion. Progesterone, 17P, and MPA significantly reduced TNF-α, but not LPS, induced caspase-3 activity. Interestingly, progesterone and MPA, but not 17P, also inhibited basal caspase-3 activity. Conclusion: Progesterone inhibits basal and TNF-α-induced apoptosis in term fetal membranes. This novel observation may explain in part the mechanism by which progesterone supplementation prevents PPROM and PTB in some high-risk women. The effect of progesterone on the basal levels of apoptosis suggests that this mechanism may also be important for normal labor at term.

The prevalence of cerebral palsy (CP) shows little temporal or geographic variation and is associated with preterm birth, maternal/fetal infection/inflammation, and fetal growth restriction (IUGR), a potential surrogate for chronic fetal hypoxemia (CHX). We previously demonstrated CHX causes a fetal inflammatory response syndrome (FIRS). Herein, we test the hypothesis that CHX may cause fetal brain injury by upregulating inflammatory cytokine cascades, culminating in apoptosis pathway activation. Time-mated guinea pigs were housed in 12% or 10.5% O₂ for the last 21% of gestation. Chronic fetal hypoxemia increased the lactate/pyruvate and decreased the glutathione (GSH)/oxidized glutathione (GSSH) ratios, confirming a shift to a prooxidant state. The end result was a >30% decrease in hippocampal neuron density. Based on a microarray spotted with 113 cytokines and receptors, 22 genes were upregulated by CHX in proportion to the degree of hypoxia; the findings were confirmed by quantitative polymerase chain reaction (PCR). Thus, CHX triggers fetal brain inflammation inversely proportional to its severity characterized by increased apoptosis and neuronal loss. We suggest CHX fetal brain injury is not directly caused by oxygen depravation but rather is an adaptive response that becomes maladaptive.

Our goal was to compare the expression of plasma monocyte chemotactic protein 1 (MCP-1) and the gene polymorphism in patients with pelvic inflammatory disease (PID) and healthy controls. The enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) were, respectively, used to measure the plasma MCP-1 level and MCP-1 polymorphism in 70 healthy controls and in 64 patients with PID before and after they received routine treatment protocols. We found plasma MCP-1 was significantly elevated in patients with PID compared to that in normal controls and decreased significantly compared to that in patients with PID after they received treatment. The increased expression of plasma MCP-1 was significantly correlated with the cell counts of white blood cells (WBCs) in blood and the level of plasma C-reactive protein (CRP) of patients with PID before they received treatment. There was no association between MCP-1 -2518G/A SNP and its gene expression levels and PID susceptibility. Elevated plasma MCP-1 could be a biological marker for the diagnosis and to be a new strategy for target therapy of pelvic inflammatory disease.

Normal pregnancy is the controlled state of inflammation and this systemic inflammatory response is reported to be more intense in preeclampsia. The current study tested the hypothesis that maternal serum stimulates interleukin 6 (IL-6) production from endothelial cells and that nicotine inhibits these effects. Human umbilical vein endothelial cells (HUVECs) were incubated with or without 0.5% serum from healthy pregnant women at term (n = 5) and treated with or without nicotine (10^-9 to 10^-6 mol/L) in the presence of 0.5% serum. Cell survival was determined by colorimetric assay. Interleukin 6 concentration and nuclear transcription factor kappa B (NF-kB) activities were determined by enzyme-linked immunosorbent assay (ELISA)-based method. Interleukin 6 production by endothelial cells was significantly stimulated in the presence of maternal serum. Nicotine significantly preserved cell survival and suppressed IL-6 production from endothelial cells. Nicotine also significantly inhibited NF-kB activation in endothelial cells. Nicotine inhibited inflammatory reaction through NF-kB suppression in vitro model of maternal vascular endothelium, and this effect may be one of the explanations for the reduced risk of preeclampsia in smokers.

Up to 10% of women of reproductive age in our country are carriers of hepatitis B virus. This study examined whether maternal hepatitis B carrier status has any effect on markers used in first-trimester screening for Down syndrome. Records for 2 major Taiwanese hospitals were retrospectively examined to identify women with singleton pregnancies resulting in normal live births from June 2002 through 2008. Maternal hepatitis B data were used to define 3 groups: seronegative women, inactive carrier women, and active carrier women. Women with active or inactive carrier status were significantly older than seronegative women. The results of the study show that maternal hepatitis B carrier status does not influence first-trimester levels of maternal serum free beta-human chorionic gonadotropin (free β-hCG) multiples of the median (MoM), pregnancy-associated plasma protein A (PAPP-A) MoM, and median fetal nuchal translucency and screening false-positive rate; therefore, correction in the risk calculation algorithm for maternal hepatitis B carrier status is not necessary.

Genistein has previously been shown to cause regression of endometriotic lesions. In the current study, we investigated whether this observation is due to the antiangiogenic activity of genistein. Endometrial fragments and ovarian follicles were transplanted into dorsal skinfold chambers of hamsters, which were treated with genistein (50 and 200 mg/kg) or vehicle (control). Vascularization and blood perfusion of the grafts was analyzed over 14 days using intravital fluorescence microscopy and histology. Genistein inhibited angiogenesis neither in endometriotic lesions nor in ovarian follicles. This was indicated by a final microvessel density of the grafts, which was comparable to that of controls. Blood perfusion was not affected by genistein treatment. At day 14 after transplantation, the grafts of genistein- and vehicle-treated animals exhibited a histomorphology, which was typical for well-vascularized endometriotic lesions and ovarian follicles without any signs of regression. Thus, genistein may not be considered for the development of antiangiogenic treatment strategies in the therapy of endometriosis.

Blood matrix metalloproteinase 9 (MMP-9) level is a promising new diagnostic marker. The aim of the current case—control study is to investigate the correlation between the serum MMP-9 level with occurrence and progression of breast cancer. The serum MMP-9 level was investigated by gelatin zymography in 100 patients with breast cancer and 120 healthy participants. The average value of MMP-9 activity was significantly higher in patients with breast cancer than in control ( P < .002), this value correlates with tumor stage ( P = .005) and tumor size ( P = .012). Our results suggest serum MMP-9 level is a potential diagnostic marker for predicting breast cancer occurrence and progression.

The changes in transcript profile induced by vascular endothelial growth factor (VEGF-A) and serum withdrawal in primary human endometrial endothelial cells (ECs) were investigated using microarrays, gene ontology and pathway analysis. Vascular endothelial growth factor A altered the levels of transcripts involved in angiogenesis, cell survival, and apoptosis, including up-and downregulation of AKT1, BAD, MIF, and IGFBP3 and ANGPT2, respectively. Serum deprivation induced downregulation of cell-cycle-related transcripts such as mitosis regulators CDC20 and SPC25. Of the transcripts regulated by both VEGF-A and partial serum deprivation, remarkably 88 of 89 showed reciprocal regulation (p < 1 × 10 ^-49). These are predominantly cell-fate-associated transcripts and this novel observation suggests that endometrial ECs may be particularly dependant on the levels of these transcripts. Our results show that in addition to the known role of VEGF-A as an EC growth and survival promoter, it also regulates apoptosis-related messenger RNAs (mRNAs), many of which were reciprocally regulated following serum withdrawal.