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Objective: We attempted to determine whether the human placenta secretes lipid peroxides. If it does, then it could be a source of lipid peroxides in maternal blood., Study Design: In study 1 isolated human placental cotyledons (n = 7) were perfused serially for 20-minute intervals with control Krebs-Ringer-bicarbonate buffer gassed with 95% oxygen and 5% carbon dioxide and Krebs-Ringer-bicarbonate buffer with progressively increasing concentrations of t-butyl hydroperoxide added (10, 25, 50, and 100 mumol/L) to stimulate endogenous lipid peroxide production. In study 2 placental cotyledons (n = 6) were perfused serially for 20-minute intervals with control Krebs-Ringer-bicarbonate buffer, t-butyl hydroperoxide (100 mumol/L), low-dose aspirin (5 x 10(-5) mol/L), and low-dose aspirin plus t-butyl hydroperoxide. Maternal and fetal effluent samples were analyzed for lipid peroxides by hydrogen peroxide equivalents., Results: In study 1, compared with control Krebs-Ringer-bicarbonate perfusion, peroxide perfusion significantly increased, in a dose-response manner, placental lipid peroxide secretion. In study 2, aspirin completely blocked the ability of peroxide to increase the secretion of lipid peroxides. In both studies placental secretion of lipid peroxides was significantly greater toward the maternal side of the placenta than toward the fetal side., Conclusions: (1) The human placenta secretes lipid peroxides primarily into the maternal effluent. (2) Exogenous peroxide stimulates endogenous lipid peroxide production, which is blocked by aspirin, suggesting cyclooxygenase is involved in lipid peroxide production. (3) The placenta could be a source of circulating lipid peroxides in pregnant women.

Objective: Placental lipid peroxides and thromboxane are abnormally increased in preeclampsia. Thromboxane is a potent vasoconstrictor of the placental vasculature. Peroxides stimulate cyclooxygenase (prostaglandin H synthase), and thereby could increase thromboxane, to cause vasoconstriction in the placenta. This study was performed to test the hypothesis that peroxides would produce vasoconstriction in the human placenta by stimulating thromboxane production., Study Design: Isolated human placental cotyledons were perfused for 20-minute intervals with 100 mumol/L t-butyl hydroperoxide alone, and during and after perfusion with low-dose aspirin (5 x 10(-5) mol/L) (n = 6) or the thromboxane receptor blocker SQ 29,548 (n = 2). Krebs-Ringer-bicarbonate buffer gassed with 95% oxygen and 5% carbon dioxide was used for the perfusion buffer. Perfusion pressure was monitored continuously, and effluent flow rates were measured during each experimental treatment. Maternal and fetal effluent samples were analyzed for thromboxane B2 and 6-keto-prostaglandin F1 alpha., Results: Compared with control Krebs-Ringer-bicarbonate buffer perfusion, peroxide perfusion significantly increased (p < 0.05) vascular resistance (14 +/- 2 vs 25 +/- 3 mm Hg.min/ml, mean +/- SE, respectively), thromboxane B2 secretion (fetal 0.20 +/- 0.04 vs 1.65 +/- 0.26 ng/min, maternal 4.8 +/- 1.5 vs 8.1 +/- 2.1 ng/min) and 6-keto-prostaglandin F1 alpha secretion (fetal 21 +/- 5 vs 60 +/- 1.8 pg/min, maternal nondetectable). Peroxide perfusion increased the thromboxane B2/6-keto-prostaglandin F1 alpha ratio threefold on the fetal side. Subsequent perfusion with aspirin significantly blocked the peroxide-induced vasoconstriction (13 +/- 1 mm Hg.min/ml during aspirin + peroxide) and the peroxide-induced increase in the secretion of thromboxane B2 (fetal 0.52 +/- 0.12 ng/min, maternal 2.0 +/- 0.3 ng/min) and 6-keto-prostaglandin F1 alpha (fetal 30 +/- 8 pg/min). After perfusion with aspirin the thromboxane B2/6-keto-prostaglandin F1 alpha ratio declined. When the thromboxane receptor blocker was used instead of aspirin, maternal and fetal secretion rates of thromboxane were still significantly increased by peroxide perfusion, but there was no change in perfusion pressure or vascular resistance., Conclusions: (1) Peroxide induces placental vasoconstriction coincident with increased secretion of thromboxane; (2) low-dose aspirin blocks both increased thromboxane secretion and vasoconstriction, whereas a thromboxane receptor antagonist allows increased thromboxane secretion but prevents peroxide induced vasoconstriction; (3) therefore, peroxide induces vasoconstriction by stimulating thromboxane synthesis.

Problem: Interleukin-6 (IL-6) is a pleiotropic protein that functions as an immunoregulatory peptide, growth factor, and endocrine hormone. IL-6 has been shown to be produced in whole placental tissue and isolated trophoblast (TC). In addition, the villous core (VC) compartment of the placenta contains cell types (fibroblasts, macrophages) capable of IL-6 production. Consequently, the present study was designed to determine the relative contribution of the TC and VC compartments to placental IL-6 production., Method: The VC and TC compartments from term pregnancies were separated using CR-Dispase digestion and Percoll density gradient centrifugation. The VC, TC, and whole placental tissues were cultured in Dulbecco's modified Eagle's medium over a 28-h period. Relative IL-6 mRNA expression was determined by dot blot analysis and secreted IL-6 protein was determined by enzyme-linked immunosorbent assays., Results: All three tissues demonstrated linear production of IL-6 protein over the culture period. At 28 h, whole placental tissue produced the most IL-6 (5.1 ng +/- 0.8 ng/microgram/protein) followed by TC (4.0 ng +/- 1.3 ng/micrograms) and VC (0.55 ng +/- 0.24 ng/microgram). Although production rates of IL-6 were 8.4-fold higher in TC compared to VC (P < .05), steady-state IL-6 mRNA expression was 3.5-fold higher in freshly isolated VC compared to TC (P < .0001) and 13-fold higher in VC compared to TC (P < .01) after 24 h in culture., Conclusions: These results demonstrate that: (1) the placenta can produce large quantities of immunoreactive IL-6 in vitro, (2) TC produce significantly more IL-6 than VC although both compartments contribute to placental IL-6 production, (3) placental IL-6 production and secretion are probably posttranscriptionally regulated since steady-state IL-6 mRNA expression in VC and TC compartments did not correlate with IL-6 production.

Objective: There is an imbalance of increased thromboxane and decreased prostacyclin in placentas of women with preeclampsia, but this may not be the only imbalance. There is also an abnormal increase in serum lipid peroxides in preeclamptic women. Lipid peroxides are toxic compounds that damage cells and inhibit prostacyclin synthesis. The following study examined lipid peroxides to determine if they were also increased in placentas of preeclamptic women., Study Design: Placental tissue for nine normal and eight preeclamptic women were frozen in liquid nitrogen immediately after delivery. Frozen tissue samples (1 gm) were homogenized and analyzed for lipid peroxides by malondialdehyde and hydrogen peroxide equivalents and for thromboxane and prostacyclin by radioimmunoassay of their stable metabolites, thromboxane B2 and 6-keto prostaglandin F1 alpha., Results: Lipid peroxides were significantly higher in preeclamptic placentas than in normal placentas by both analytic methods (49 +/- 5 vs 31 +/- 1 nmol/gm for malondialdehyde and 5.3 +/- 0.3 vs. 3.2 +/- 0.3 mumol/gm for hydrogen peroxide equivalent; mean +/- SE; p < 0.01, respectively). Thromboxane was significantly higher and prostacyclin significantly lower in preeclamptic placentas than in normal placentas (213 +/- 23 vs 158 +/- 14 ng/gm for thromboxane and 24 +/- 3 vs 53 +/- 7 ng/gm for prostacyclin, p < 0.05). The thromboxane/prostacyclin and lipid peroxides/prostacyclin ratios were threefold higher in preeclamptic placentas than in normal placentas., Conclusion: Placental levels of both lipid peroxides and thromboxane are increased and prostacyclin decreased in preeclampsia. We speculate that abnormally increased levels of lipid peroxides in preeclamptic placentas may be a cause of decreased prostacyclin.

Objective: Preeclampsia is associated with an imbalance of increased thromboxane and decreased prostacyclin and an abnormal increase of lipid peroxides. Lipid peroxides are toxic compounds that damage cells and inhibit prostacyclin synthesis. Low-dose aspirin therapy reduces the incidence of preeclampsia, presumably by selective inhibition of thromboxane to restore a balance between thromboxane and prostacyclin. However, the effectiveness of low-dose aspirin might also relate to inhibition of lipid peroxides., Study Design: To test this hypothesis, 10 women at risk of preeclampsia were placed on low-dose aspirin therapy (81 mg/day) between 9 and 34 weeks of gestation. Plasma samples were collected before and after 3 to 4 days and 3 to 4 weeks of aspirin therapy. Samples were analyzed for thromboxane and prostacyclin by radioimmunoassay of their stable metabolites, thromboxane B2 and 6-keto-prostaglandin F1 alpha, and for lipid peroxides by hydrogen peroxide equivalents., Results: Low-dose aspirin significantly decreased (p < 0.05) both lipid peroxides (130 +/- 18 vs 92 +/- 11 and 68 +/- 9 nmol/ml, mean +/- SE) and thromboxane (502 +/- 67 vs 138 +/- 67 and 8 +/- 5 pg/ml), but it did not affect prostacyclin (55 +/- 10 vs 41 +/- 8 and 40 +/- 11 pg/ml, p > 0.1)., Conclusion: Low-dose aspirin selectively inhibits both lipid peroxides and thromboxane without affecting prostacyclin. Inhibition of both lipid peroxides and thromboxane by low-dose aspirin reveals a new mechanism of action and may account for its effectiveness in the prevention of preeclampsia.

Although freshly obtained placenta contains little or no interleukin-1 (IL-1) mRNA, placenta and isolated trophoblast have been reported to produce significant quantities of bioactive IL-1 in vitro. The present study was designed to determine if endotoxin, a common contaminant of culture medium, and trophoblast isolation procedures could induce IL-1 expression in the placenta. Tissue-extractable IL-1 alpha and IL-1 beta immunoreactive proteins were readily detected in fresh placental membranes, but not placental villi. As little as 10 ng/mL endotoxin were found to induce the expression of IL-1 alpha and IL-1 beta mRNA in intact placental villi cultured in vitro. Intact placenta cultured in the presence of 1.0 microgram/mL endotoxin demonstrated expression of IL-1 alpha and IL-1 beta mRNA and cumulative production and release of immunoreactive IL-1 alpha and IL-1 beta into the medium during 24 h of culture. Placenta incubated in endotoxin-free medium, however, exhibited no detectable IL-1 alpha or IL-1 beta mRNA expression and little or no release of IL-1 alpha or IL-1 beta immunoreactive protein into the medium. When trophoblast cells were freshly isolated by enzymatic digestion, followed by Percoll separation at reduced temperatures to inhibit cell activation, no IL-1 alpha or IL-1 beta mRNA expression was initially detectable. However, IL-1 alpha and IL-1 beta mRNA in isolated trophoblast cells were induced after 30 min of culture in endotoxin-free medium, with maximal induction at 4 h. These results suggest that normally the placenta produces very little, if any, IL-1, and that endotoxin and trophoblast isolation procedures induce IL-1 expression in placental tissues cultured in vitro.

Fetal trophoblast is generally resistant to lysis by cytotoxic cells. We hypothesized that progesterone and estrogens secreted by the trophoblast act at the choriodecidual interface where they are present in high concentrations to provide a local, paracrine immunosuppressive effect on cellular cytotoxicity. Using peripheral blood mononuclear cells as effector cells in a cytotoxicity assay, we evaluated the effects of progesterone, estrone, estradiol and estriol, either alone or in combination, on cellular cytotoxicity. Both progesterone and estradiol suppressed cytotoxicity in a dose-dependent manner. Estrone, estriol, pregnenolone and cholesterol had no effect. A synergistic suppression of cytotoxicity was observed when estrone, estradiol, estriol and progesterone were combined. We speculate that trophoblast production of progesterone and estradiol may be an important local immunosuppressive mechanism contributing to fetal survival.

We hypothesized that foetal administration of SQ-29,548, a putative thromboxane receptor blocker, would prevent foeto-placental vasoconstriction produced by the thromboxane mimic U46619. Arterial blood gases, continuous monitoring of maternal and foetal heart rates and blood pressures were performed in chronically catheterized pregnant ewes. Foetal blood flows and vascular resistance were determined with radioactive microspheres. SQ-29,548 effectively blocked the expected vasoconstrictive effects of thromboxane. However, prolonged infusion of SQ-29,548 resulted in significant decreases in umbilical-placental blood flow and foetal mean arterial pressure. This was accompanied by a respiratory acidemia. Potential therapy for the vasoconstrictive disorders of pregnancy with SQ-29,548 awaits further investigation of its intrinsic vasoactive properties in the umbilical-placental vasculature.

Preeclampsia is associated with an imbalance between thromboxane and prostacyclin. The cause of the imbalance is unknown. Preeclampsia sera contain cytotoxic factors that can damage endothelial cells. Lipid peroxides can damage cell membranes, so elevated levels in the mother's blood could be related to endothelial cell injury and decreased prostacyclin in preeclampsia. This study determined maternal plasma levels of thromboxane and prostacyclin and serum levels of lipid peroxides and vitamin E in women with normal pregnancy (n = 12), mild preeclampsia (n = 16), and severe preeclampsia (n = 19) between 36 and 40 weeks' gestation. In normal pregnancy the ratio of thromboxane to prostacyclin (0.63) favored prostacyclin, and the ratio of lipid peroxides to vitamin E (0.43) favored vitamin E. Prostacyclin was significantly decreased in both mild and severe preeclampsia. Thromboxane was not increased in mild preeclampsia but was significantly increased in severe preeclampsia. The ratio of thromboxane to prostacyclin was increased in mild preeclampsia (0.77) and greatly increased in severe preeclampsia (1.94). Lipid peroxides were significantly increased in mild preeclampsia and increased further in severe preelcampsia. Vitamin E levels were unaltered in mild preeclampsia but significantly decreased in severe preeclampsia. The ratio of lipid peroxides to vitamin E was increased in mild (0.52) and greatly increased in severe (1.09) preeclampsia. We concluded the following: (1) Maternal plasma prostacyclin is decreased in both mild and severe preeclampsia, but thromboxane is increased only in severe cases. (2) Lipid peroxides are significantly increased in both mild and severe preeclampsia and vitamin E is significantly decreased in severe preeclampsia. We speculate that this imbalance could result in endothelial and platelet cell damage and in decreased prostacyclin and increased thromboxane synthesis. (3) Preeclampsia is associated with an imbalance not only between thromboxane and prostacyclin but also between lipid peroxides and vitamin E in maternal blood. The imbalances progressively favor thromboxane and lipid peroxides with the increasing severity of preeclampsia, which is consistent with the clinical symptoms of this disorder.

In normal pregnancy the vasodilating actions of prostacyclin and the antioxidant activity of vitamin E are important for normal physiologic function. Thromboxane and lipid peroxides oppose these actions by promoting vasoconstriction and peroxidation reactions, respectively. An imbalance between thromboxane and prostacyclin and between lipid peroxides and antioxidant activity is implicated in pathologic states such as preeclampsia. We hypothesized that in normal pregnancy there would be a balance in the ratios of prostacyclin to thromboxane and of vitamin E to lipid peroxides that would favor prostacyclin and vitamin E. Blood samples were collected from normally pregnant women throughout gestation and analyzed for prostacyclin, thromboxane, vitamin E, and lipid peroxides. Serum levels of lipid peroxides remained relatively stable throughout gestation, but the levels of vitamin E progressively increased. Plasma levels of prostacyclin progressively increased with advancing gestation, whereas levels of thromboxane progressively decreased. Therefore the ratios of both prostacyclin/thromboxane, and vitamin E/lipid peroxides progressively increased during pregnancy. The increase in the ratios was highly correlated, r = 0.94. We conclude that the changes in the maternal concentrations of these compounds and the progressive increase in the ratios of prostacyclin/thromboxane and vitamin E/lipid peroxides suggest that the vasodilating actions of prostacyclin and the antioxidant activity of vitamin E are progressively favored with advancing gestation in normally pregnant women.

Fetal trophoblast is generally resistant to lysis by cytotoxic cells. Trophoblast progesterone and estrogens may act at the choriodecidual interface, where they are present in high concentrations to provide a local, paracrine immunosuppressive effect on cellular cytotoxicity. However, interleukin activation of these cytotoxic lymphocytes enhances their ability to lyse trophoblast. Recent evidence suggests that immunoactivation occurs in certain aberrant pregnancy conditions, including preeclampsia. Preeclamptic placentas produce more progesterone in vitro than do normal placentas. To study the potential association between progesterone production and immunoactivation, we evaluated the immunomodulatory effect of progesterone on cellular cytotoxicity. Comparisons were made with the use of both normal and interleukin-2-stimulated peripheral blood mononuclear cells as effector cells in a cytotoxicity assay. Progesterone suppressed cytotoxicity in a dose-dependent manner. Interleukin-2 augmented cellular cytotoxicity, and higher concentrations of progesterone were required to attenuate this response. An additive suppression of cytotoxicity was also observed when estrone, estradiol, estriol, and progesterone were combined. We speculate that the higher placental production of progesterone seen in preeclampsia may be a trophoblast compensatory response to immunoactivated maternal effector cells.

Unlabelled: Arachidonic acid is metabolized by cyclooxygenase leading to prostaglandins (PG), and by lipoxygenases leading to hydroxyeicosatetraenoic acids (HETE) and leukotrienes (LT). PGs are potent uterine constrictors. 5-HETE and LTC4 also stimulate uterine contractions, but their role in labor is not known. To estimate the activities of these pathways before parturition and their relationship to uterine contractility, amniotic fluid (AF) concentrations of 5-HETE, LTC4 and PGF2 alpha were determined in 5 chronically catheterized rhesus monkeys. Uterine contractility was continually assessed by changes in AF pressure., Results: AF concentrations at the time of intrauterine surgery were 4.4 +/- 0.8 ng/ml for 5-HETE and 2.5 +/- 0.7 ng/ml for LTC4. PGF2 alpha levels were nondetectable. Indomethacin infusion into the mother, although effective in suppressing PGF2 alpha levels, did not prevent the onset of premature labor and vaginal delivery in 2 animals. PGF2 alpha did not increase in 1 monkey with term labor. Approximately 1 week before delivery, 5-HETE and LTC4 concentrations increased sharply in all animals in association with a nocturnal pattern of labor contractions. Peak AF concentrations during labor were 5-HETE: 40 +/- 8 ng/ml, LTC4: 20 +/- 4 ng/ml, and PGF2 alpha: 5.4 +/- 2.1 ng/ml., Comment: LTC4 and 5-HETE stimulate uterine contractility in vitro, and probably act in concert with PGF and PGE to stimulate uterine contractions during parturition. HETEs may also act as a signal to recruit white blood cells to the uterus and to activate them, there to augment PG and LT production and act as a first line of defense against any infection that might enter the uterus from the vagina during or after delivery., Conclusions: 1) 5-HETE and LTC4, but not PGF2 alpha, are associated with uterine contractility after preterm intrauterine surgery. Surprisingly, AF PGF2 alpha levels were nondetectable for 1 to 2 weeks after surgery. 2) 5-HETE and LTC4 are present in higher concentrations than PGF2 alpha in AF. 3) 5-HETE, LTC4 and PGF2 alpha all increase with the onset of labor. AF concentrations of 5-HETE and LTC4 are significantly higher than PGF2 alpha before and during term and preterm labor. 4) Labor can occur with suppressed PGF2 alpha levels, but with increasing 5-HETE and LTC4 levels. 5) These data suggest that 5-HETE and LTC4 are important components of the parturitional process, and they challenge the dogma that PGs are the universal mediators of labor.

Leukotrienes are synthesized during pregnancy and produce cardiovascular effects in adults. We hypothesized that leukotriene C4 would cause vasoconstriction in the fetus and placenta. Eight near-term, unanesthetized ovine fetuses were studied before and after infusion of 10 micrograms leukotriene C4 (LTC4) into the fetal vena cava. Cardiovascular monitoring of maternal and fetal arterial pressures and heart rates was performed. Fetal blood flows were measured by the radioactive-microsphere technique. Sustained elevations in systolic and diastolic blood pressure and decreased fetal heart rate began by 1 min and returned to baseline by 30 min. Arterial pH fell from 7.33 +/- 0.01 to 7.29 +/- 0.01 at 15 min (P less than 0.05) and to 7.29 +/- 0.01 at 30 min (P less than 0.05), with a significant increase in base deficit from 0.7 +/- 0.7 to 3.5 +/- 0.7 at 15 min (P less than 0.05) and to 2.9 +/- 1.0 at 30 min (P less than 0.05). Fetal PO2 and PCO2 were unchanged. Significant decreases in blood flow and resistance were seen in the umbilical placental circulation as well as in fetal skeletal muscle and intestine. Blood flow and resistance were unchanged in the renal and adrenal vascular beds. Fetal administration of LTC4 caused no changes in maternal cardiovascular parameters. These findings represent the first in vivo studies of the effects of a lipoxygenase metabolite on fetal-placental blood flow.

We report the effect of high glucose infusion on vascular resistance in isolated human placental cotyledons perfused with Krebs-Ringer-bicarbonate solution containing 80 mg/dl (4.4 mmol/L), 160 mg/dl (8.8 mmol/L), or 320 mg/dl (17.6 mmol/L) D-glucose (n = 6). Placental vascular resistance remained constant during 25-minute perfusion periods with 80 mg/dl followed by 160 mg/dl glucose solution. Subsequent perfusion with 320 mg/dl glucose produced a significant increase in placental vascular resistance. Placentas were also studied in which the placental cotyledon was sequentially perfused for 25-minute periods with solutions containing glucose at 80 mg/dl followed immediately by 320 mg/dl (n = 5). Placental vascular resistance remained constant throughout perfusion with 80 mg/dl glucose solution but increased significantly after beginning perfusion with 320 mg/dl glucose. We conclude that the increase in placental vascular resistance appears to be a function of the high glucose level rather than the duration of glucose perfusion.

We hypothesized that streptozocin-induced ovine diabetes would cause alterations in the placental production of thromboxane and prostacyclin. With a tissue incubation technique, we examined the placental production of thromboxane and prostacyclin in cotyledons from seven normal near-term ewes (127 +/- 3 days' gestation) and six streptozocin-induced diabetic ewes (125 +/- 3 days' gestation). Diabetic status was verified with serial fasting blood glucose assessments. Placental tissue was incubated in Dulbecco's modified Eagle's medium for 48 hours at 37 degrees C with 95% oxygen and 5% carbon dioxide. Samples were collected at 0, 1, 2, 4, 8, 20, 32, and 48 hours. Radioimmunoassay of the stable metabolites thromboxane B2 and 6-keto-prostaglandin F1 alpha were used to determine thromboxane and prostacyclin production, respectively. Placental thromboxane production was reduced in diabetic animals when compared with control animals (5.63 +/- 2.81 vs 7.32 +/- 1.37 pg/mg per hour, respectively; p less than 0.05). Prostacyclin production was also significantly reduced in the diabetic placentas compared with control placentas (11.44 +/- 4.06 vs 16.29 +/- 4.59 pg/mg per hour, respectively; p less than 0.05). We conclude that the ovine placenta produces thromboxane and prostacyclin. The ovine thromboxane production rate is comparable to that of the human placenta but the prostacyclin production rate is approximately two to three times higher. The observed decrease in the placental production of thromboxane and prostacyclin may reflect an adverse effect of hyperglycemia directly on eicosanoid production or indirectly through decreased placental cellular proliferation.

Pulsed and continuous-wave Doppler ultrasonography was used to assess blood velocities in the ductus arteriosus and the pulsatility index of the umbilical artery in 20 fetuses (1 pair of twins and 18 singletons) at 23 to 33 weeks' gestation during maternal indomethacin therapy for preterm labor or polyhydramnios. There was no statistically significant difference in the pulsatility index of the umbilical artery during maternal indomethacin treatment (mean +/- SD, 1.11 +/- 0.20) when compared with baseline values (1.12 +/- 0.19) in all 20 fetuses studied. An increase in the peak systolic and diastolic blood velocities in the ductus arteriosus consistent with ductal constriction was noted in 9 fetuses. Analysis of the umbilical artery pulsatility index values before and during indomethacin in this subgroup of fetuses failed to reveal a statistically significant change (1.12 +/- 0.19 vs. 1.11 +/- 0.20). Indomethacin therapy does not influence the pulsatility index of the umbilical artery at the gestational ages studied.

Arachidonic acid is metabolized by cyclooxygenase leading to prostaglandins and by lipoxygenases leading to hydroxyeicosatetraenoic acids (HETE) and leukotrienes (LT). Prostaglandins are potent uterine constrictors. 5-HETE and LTC4 also stimulate uterine contractions but their role in labor is not known. To estimate the activities of these pathways before parturition and their relationship to uterine contractility, amniotic fluid concentrations of 5-HETE, LTC4, and prostaglandin F2 alpha (PGF2 alpha) were determined in five chronically catheterized rhesus monkeys. Uterine contractility was continually assessed by recording changes in amniotic fluid pressure. The results obtained indicate the following conclusions: (1) 5-HETE and LTC4, but not PGF2 alpha, are associated with uterine contractility after preterm intrauterine surgery. Surprisingly, amniotic fluid PGF2 alpha, levels were nondetectable for 1 to 2 weeks after surgery. (2) 5-HETE and LTC4 are present in higher concentrations than PGF2 alpha in amniotic fluid. (3) 5-HETE, LTC4, and PGF2 alpha all increase with the onset of labor. Amniotic fluid concentrations of 5-HETE and LTC4 are significantly higher than those of PGF2 alpha before and during term and preterm labor. (4) Labor can occur with suppressed PGF2 alpha levels but with increasing 5-HETE and LTC4 levels. (5) These data suggest that 5-HETE and LTC4 are important components of the parturitional process.

Placentas obtained from women with preeclampsia produce more thromboxane, a potent vasoconstrictor, and less prostacyclin, a potent vasodilator, than normal. Although the factors responsible for this are not known, steroids are known to affect eicosanoid production, and the placenta is a rich source of progesterone and estradiol. If placental steroids contribute to the imbalance of increased thromboxane/decreased prostacyclin in preeclamptic placentas, then their placental production might also be abnormal. The following study was performed to see whether the placentas of preeclamptic women produce progesterone or estradiol abnormally. Fresh human term placentas were obtained immediately after delivery from normal and mild preeclamptic pregnancies. Whole placental tissues (350 mg) were incubated for three hours. Samples were collected and analyzed for progesterone and estradiol-17 beta by radioimmunoassay. Progesterone production was significantly higher in preeclamptic than in normal placentas without the addition of a precursor and with the addition of pregnenolone sulfate as a precursor, but not with the addition of pregnenolone alone. Both normal and preeclamptic placentas converted pregnenolone sulfate into progesterone as efficiently as they converted pregnenolone into progesterone. Estradiol production rates were similar in both preeclamptic and normal placentas, regardless of whether dehydroepiandrosterone sulfate was added as a precursor. These data indicate that placentas of women with mild preeclampsia produce more progesterone than normal, probably because they contain more pregnenolone sulfatase and larger stores of endogenous cholesterol. Higher concentrations of progesterone in the preeclamptic placenta could contribute to lower prostacyclin production because progesterone inhibits placental prostacyclin production.

Preeclampsia is associated with increased thromboxane and decreased prostacyclin production by the placenta. Low-dose aspirin can selectively inhibit thromboxane production in the adult circulation, but its effects on placental vascular production of thromboxane and prostacyclin are incompletely understood. We therefore studied the effects of low-dose aspirin on the production rates of prostacyclin and thromboxane, with and without vasoconstricting doses of angiotensin II, in human placental arteries. Chorionic plate arteries were incubated and samples were assayed for thromboxane and prostacyclin by radioimmunoassay of their stable metabolites. Production rates for prostacyclin were similar in the control, aspirin, angiotensin II, and angiotensin II plus aspirin groups. Mean (+/- SEM; n = 8) thromboxane production rates in the aspirin (1.4 +/- 0.5 pg/mg/hr) and angiotensin II plus aspirin (2.9 +/- 0.6 pg/mg/hr) groups were significantly lower (p less than 0.05) than values in the control (8.6 +/- 2.7 pg/mg/hr) and angiotensin II (6.7 +/- 1.3 pg/mg/hr) groups. We conclude that low-dose aspirin significantly decreases production of thromboxane in placental arteries both with and without vasoconstricting doses of angiotensin II.

Unlabelled: Placentas obtained from women with preeclampsia produce more thromboxane and less prostacyclin than normal. They also produce more progesterone than normal. This study tested whether a progesterone concentration equivalent to that in the medium after in vitro incubation of placentas from women with preeclampsia (greater than or equal to 1.5 x 10(-5) mol/L) could cause an imbalance of increased thromboxane and decreased prostacyclin production by normal placentas. Fresh term placental tissues were incubated for 48 hours in the absence or presence of various concentrations of progesterone and/or estradiol. Prostacyclin and thromboxane were determined by radioimmunoassay of their stable metabolites, 6-keto-prostaglandin F1 alpha and thromboxane B2. A progesterone concentration of 1.5 x 10(-5) mol/L significantly (p less than 0.001) inhibited prostacyclin production, compared with control, but lower concentrations did not. Estradiol at concentrations present in the medium after incubation of either normal or preeclamptic placental tissue did not significantly affect prostacyclin production, nor did it prevent progesterone at 1.5 x 10(-5) mol/L from inhibiting prostacyclin. Thromboxane production was not affected by either progesterone or estradiol., Conclusion: In vitro addition of progesterone at a concentration equivalent to that in the medium after incubation of preeclamptic placentas inhibited prostacyclin production by normal placentas to a rate characteristic of preeclampsia. However, it did not increase thromboxane., Speculation: Increased trophoblast progesterone in preeclampsia may act by a paracrine mechanism to inhibit prostacyclin synthesis in placental vasculature. Progesterone's selective inhibition of prostacyclin without affecting thromboxane may be due to the compartmentalization of thromboxane production to trophoblast and stroma and prostacyclin production to placental vasculature.

The vasodilator prostacyclin is produced by fetal tissues and may serve to protect umbilical blood flow. We hypothesized that prostacyclin could reverse fetoplacental vasoconstriction produced by a thromboxane mimic (U-46619). Fetal regional blood flow was measured by the radioactive microsphere technique in six unanesthetized, near-term ovine fetuses. Measurements were made in the control period, again 20 minutes after a fetal infusion of U-46619 was begun, and finally 20 minutes after prostacyclin was added to the U-46619 infusion. Mean arterial pressure rose significantly in response to U-46619 (38 +/- 1 to 51 +/- 2 mm Hg, p less than 0.01) and returned to baseline after prostacyclin (42 +/- 2 mm Hg). Renal resistance was increased from 0.16 +/- 0.01 to 0.22 +/- 0.01 mm Hg.ml-1.min.100 gm-1 (p less than 0.05) by U-46619 and decreased significantly (p less than 0.05) below baseline by addition of prostacyclin (0.10 +/- 0.02 mm Hg.ml-1.min.100 gm-1). Placental resistance also increased significantly (p less than 0.03) in response to U-46619 (from 0.15 +/- 0.01 to 0.21 +/- 0.01 mm Hg.ml-1.min.kg-1 fetal weight) but was further increased to 0.29 +/- 0.03 mm Hg.ml-1.min.kg-1 fetal weight by the addition of prostacyclin. Umbilical placental blood flow decreased significantly (p less than 0.03) when prostacyclin was added to U-46619 (315 +/- 40 to 195 +/- 30 ml.min-1.kg-1 fetal weight). Whereas U-46619 had no effect on fetal arterial blood gases, the addition of prostacyclin resulted in significant fetal acidosis (p less than 0.03). We conclude that thromboxane mimic causes fetal hypertension and renal and placental vasoconstriction. Prostacyclin reverses hypertension and renal vasoconstriction but, unexpectedly, worsens fetal placental vasoconstriction produced by thromboxane. It is likely that the observed fetal acidosis is a result of compromised placental function.

The eicosanoids are ubiquitous metabolites of arachidonic acid that possess an array of biological actions including marked vasoactivity. They are produced in significant quantities by the fetus, chorion, amnion, placenta, and maternal vascular tissues, and they have many important functions in the development and maintenance of normal vascular tone in human gestation. Imbalances in the production of certain eicosanoids may lead to failure of appropriate fetal growth and development, as well as to certain maternal vasoconstrictive disorders, such as preeclampsia. There is evidence that the eicosanoids have powerful vascular effects on both sides of the placental circulation, so it is likely that the control of blood flow in this vascular bed is largely dependent on eicosanoid metabolites. Current knowledge of production, regulation and physiologic actions of the lipoxygenase metabolites as they relate to pregnancy is in the embryonic stage of development. It will be necessary to learn more about the factors that regulate both eicosanoid production and action before a better understanding of the complexities involved in the control of the placental circulation will be achieved.

Preeclampsia is characterized by imbalances in the production rates of several arachidonic acid metabolites. There is a considerable amount of evidence to indicate that PGI2 production is decreased in preeclampsia. PGI2 is a potent vasodilator, an inhibitor of platelet aggregation, and an inhibitor of uterine contractility. Evidence is accumulating that TX production in preeclampsia is either increased or unchanged so that the ratio of TX to PGI2 favors TX. TX opposes the actions of PGI2 in that it is a potent vasoconstrictor, a stimulator of platelet aggregation, and a stimulator of uterine contractility. Therefore, an imbalance of increased TX/decreased PGI2 production can account for the major clinical symptoms of preeclampsia. There is now preliminary evidence that the placenta produces lipoxygenase, as well as cyclooxygenase compounds. The hydroxyeicosatetranoic acids (5-HETE, 12-HETE, 15-HETE) and LTB4 have been identified as placental products. The preeclamptic placenta appears to be deficient in the 5- and 12-lipoxygenase enzymes, as indicated by placental production of 5-HETE and 12-HETE. Little is known about the regulation of arachidonic acid metabolites in normal or preeclamptic pregnancies. Steroids are known to affect cyclooxygenase product production. Progesterone, for example, inhibits PGI2 production. Although circulating and urinary concentrations of progesterone do not differ between normal and preeclamptic pregnancies, there is one report that placental progesterone concentrations are higher in preeclampsia; this may partially explain the decreased placental production of PGI2. There is a considerable amount of evidence in various tissues that regulatory interactions exist between the cyclooxygenase and lipoxygenase metabolites of arachidonic acid, but the role of these interactions in preeclampsia is not known. There is still much to be learned about the etiology of preeclampsia, but it is certain that aberrations in the production of arachidonic acid metabolites play an important role. It is likely that the effective treatment of preeclampsia will come from understanding the regulation of the arachidonic acid metabolites during pregnancy, and, therefore, the ability to specifically treat the production imbalances that characterize this disorder.

The vasodilator prostacyclin is produced by many fetal tissues and may serve to protect umbilical placental blood flow. We hypothesized that prostacyclin could reverse fetoplacental vasoconstriction produced by angiotensin II (ANG II). Studies were done in eight unanesthetized near-term ovine fetuses. After a control period, ANG II was infused into the fetal inferior vena cava at a rate of 0.5 microgram/min for 40 min. Twenty minutes after starting the ANG II infusion, an infusion of prostacyclin at a rate of 5 micrograms/min was added to the ANG II infusion. Blood flows were measured by the radioactive microsphere technique. Blood flow measurements were made during the control period, 20 min after starting the ANG II infusion, and 20 min after adding prostacyclin to the ANG II infusion. ANG II produced significant fetal hypertension and renal, intestinal, and placental vasoconstriction. Placental vascular resistance rose from 0.14 +/- 0.01 to 0.18 +/- 0.01 mmHg.min.kg fetal wt.ml-1 during the ANG II infusion period (P less than 0.05). The addition of prostacyclin to the ANG II infusion resulted in a return to control values for fetal blood pressure and renal and intestinal resistance. However, placental vasoconstriction was not reversed by addition of prostacyclin as placental vascular resistance remained significantly elevated over the control value (0.17 +/- 0.01 mmHg.min.kg fetal wt.ml-1). Although unchanged by ANG II infusion, fetal pH decreased significantly during the ANG II plus prostacyclin infusion period. We conclude that ANG II causes fetal hypertension and renal and intestinal vasoconstriction, which are reversed by prostacyclin.(ABSTRACT TRUNCATED AT 250 WORDS)

The discovery of the imbalance of increased thromboxane and decreased prostacyclin production in preeclamptic women has explained the cause of the major clinical symptoms of this disorder and has formed the basis and rationale for clinical studies with low-dose aspirin to treat preeclampsia. Low doses of aspirin (60 to 81 mg/day) have a remarkable ability to inhibit thromboxane production selectively without significantly inhibiting prostacyclin production. Therefore the actions of thromboxane to increase vasoconstriction, stimulate platelet aggregation, increase uterine contractility, and decrease uteroplacental blood flow are attenuated, and the ratio of thromboxane to prostacyclin is altered in favor of prostacyclin. Prostacyclin promotes vasodilation, inhibits platelet aggregation, decreases uterine contractility, and increases uteroplacental blood flow. The initial clinical studies with low doses of aspirin are very encouraging with respect to the treatment and prevention of preeclampsia. Substantial evidence already indicates that low-dose aspirin therapy decreases the incidence of preeclampsia; it decreases the maternal systemic arterial pressor response to angiotensin II; and it does not seem to be harmful to the fetus. Treatment of preeclampsia with prostacyclin appears to be contraindicated because prostacyclin is a potent systemic vasodilator and the clinical outcome of preeclamptic women infused with prostacyclin has been poor. The mechanism whereby low-dose aspirin preferentially inhibits thromboxane synthesis is not known.(ABSTRACT TRUNCATED AT 250 WORDS)

Low-dose aspirin has been used as prophylactic treatment for preeclampsia and fetal growth retardation, but the physiologic mechanisms for the beneficial effect of this therapy are unknown. We studied the effects of aspirin on eicosanoid production by different compartments of normal term human placental villi. Duplicate parallel incubations (n = 7) of whole villi, villous core tissues, and trophoblast were established on Millicell platform dishes in minimum essential medium in the presence or absence of 1 x 10(-4) or 1 x 10(-5) mol/L aspirin. Production rates of thromboxane A2 and prostacyclin were estimated by radioimmunoassay of their stable hydrolysis products, thromboxane B2 and 6-keto-prostaglandin F1 alpha, respectively. Our results indicate that 1 x 10(-4) mol/L aspirin inhibits thromboxane production in whole villi and villous core tissues denuded of their trophoblast layer but not in isolated trophoblast cells. The same concentration of aspirin also inhibits prostacyclin production in the isolated villous core but not in whole villi and not in isolated trophoblast. We conclude that aspirin can selectively inhibit thromboxane production in whole placental villi and differentially affects thromboxane and prostacyclin production by the trophoblast and villous core compartments.

Five monkeys with amniotic pressure catheters were placed in restraining chairs on days 127 to 131 of gestation (term = 167 days) for examination of circadian patterns in uterine activity. Uterine activity (total area under the contraction curve) was recorded continuously for 3- to 9-day intervals while the animals were exposed to a 16-hour:8-hour light:dark photoperiod. A ratio of hourly contraction area to mean hourly contraction area was established for each individual, and a circadian pattern was observed, with the occurrence of peak uterine activity between 2200 and 0200 hours (analysis of variance, P less than 0.01). An unrestrained animal equipped with a telemetry device and monitored for 23 days demonstrated a similar pattern. Four other catheterized, chair-restrained, pregnant monkeys were used to examine the effects of dexamethasone on uterine activity rhythms. After a 48-hour control period, dexamethasone (0.1 mg/hr) was infused via a maternal venous catheter for 48 hours. Fetal and maternal estrone and estradiol levels and total uterine activity were significantly reduced during dexamethasone infusion (P less than 0.05). In the 48 hours after dexamethasone infusion, mean uterine activity returned to preinfusion levels but the nocturnal peak remained ablated. Therefore, dexamethasone, alters the magnitude, as well as the circadian pattern, of uterine activity in association with reduced estrogen biosynthesis by the fetoplacental unit. Since the effect on uterine activity is biphasic, dexamethasone probably acts by more than one mechanism.

Circadian rhythms and hormonal interactions among the maternal, fetal, and amniotic fluid compartments were studied in long-term catheterized rhesus macaque monkeys between days 127 and 138 of gestation (term = 167 days). Blood samples were collected at 3-hour intervals for 48 hours and analyzed by radioimmunoassay for estrone, estradiol, cortisol, progesterone, dehydroepiandrosterone sulfate, and prolactin. Distinct circadian rhythms were present for cortisol and progesterone in the maternal circulation and for progesterone and dehydroepiandrosterone sulfate in the fetal circulation (p less than 0.05). Although maternal and fetal estrogen levels were higher in AM samples than in PM samples, a statistically significant circadian rhythm was not present (p greater than 0.10). Fetal levels of progesterone and dehydroepiandrosterone sulfate and maternal levels of progesterone were highest between 9:00 PM and 3:00 AM and lowest between 9:00 AM and 3:00 PM. Maternal levels of cortisol were highest between 6:00 AM and 9:00 AM and lowest between 6:00 PM and 12 midnight. The circadian patterns of maternal cortisol and progesterone were inversely related to each other (r = -0.68; p less than 0.01). Amniotic fluid cortisol levels were highest between 9:00 AM and 12 noon and lowest between 6:00 PM and 3:00 AM (p less than 0.10). With the possible exception of cortisol, amniotic fluid steroid hormones did not demonstrate distinct diurnal fluctuations, nor did they correlate with steroid changes in maternal or fetal blood. Because the rhesus placenta is permeable to glucocorticoids it is likely that transplacental passage of maternal cortisol influences the activity of the fetal pituitary and adrenal so that the circadian rhythm in the fetal axis is 180 degrees out of phase with that of the maternal axis. The circadian rhythms in fetal dehydroepiandrosterone sulfate and progesterone in late gestation parallel the biorhythm in uterine contraction frequency and amplitude, with peaks during periods of darkness between 9:00 PM and 3:00 AM.

The daily hormonal fluctuations that occur simultaneously in the fetus, mother, and amniotic fluid during late gestation and before preterm parturition were studied in long term catheterized rhesus macaques. Blood and amniotic fluid samples were collected twice daily and analyzed by RIA for estrone, estradiol, dehydroepiandrosterone sulfate (DHEAS), progesterone, cortisol, and prostaglandin F2 alpha metabolite (PGFM). Vaginal delivery in monkeys with live fetuses was preceded by rising concentrations of DHEAS in fetal, but not maternal, blood. Parallel increases in fetal plasma estrone, maternal plasma estrone and estradiol, and amniotic fluid estrone preceded the rise in amniotic fluid PGFM (P less than 0.005, by analysis of variance). Cortisol levels remained stable in maternal blood and amniotic fluid, but increased before delivery in fetal blood. Nocturnal progesterone peaks in both fetal and maternal blood increased progressively in magnitude in fetuses before parturition. Rising concentrations of fetal DHEAS, estrone, and progesterone indicated an increase in adrenal activity before parturition in the rhesus fetus. PG production, reflected in amniotic fluid PGFM concentrations, was temporally related to increasing amniotic fluid concentrations of estrone. Although progesterone withdrawal may occur at a local tissue level, parturition occurred without an apparent decrease in circulating maternal, circulating fetal, or amniotic fluid progesterone concentrations.

The detailed anatomy of arteries and veins in the testicular pedicle of the rhesus monkey, with special emphasis on an area of extensive surface contact between these vessels in the spermatic cord, is described. The mean plasma testosterone concentration in blood from the testicular artery was significantly greater than the mean for samples collected simultaneously from the contralateral femoral artery in 11 monkeys. These observations are interpreted as supportive of the hypothesis that a hormone concentrating mechanism involving the local transfer of testoterone between the vessels of the pampiniform plexus and the spermatic artery exists in the male-rhesus monkey.

Preeclampsia is characterized by increased vasoconstriction frequently associated with increased platelet aggregation, reduced uteroplacental blood flow, and premature delivery. Because prostacyclin antagonizes the vasoconstrictor, platelet-aggregating, and uterine-activating actions of thromboxane, we considered the hypothesis that placental production of thromboxane was increased coincident with decreased production of prostacyclin in preeclampsia. Fresh human term placentas were obtained immediately after delivery from 11 normal and 10 preeclamptic pregnancies (blood pressure greater than or equal to 140/90 mm Hg, urinary protein greater than 0.3 gm/24 hr). Tissues (350 mg) were incubated sterilely in 6 ml of Dulbecco's Modified Eagle's Medium for 48 hours at 37 degrees C with 95% oxygen and 5% carbon dioxide in a metabolic shaker. Samples were collected at 8, 20, 32, and 48 hours and analyzed for thromboxane by radioimmunoassay of its stable metabolite, thromboxane B2, and for prostacyclin by radioimmunoassay of its stable metabolite, 6-keto prostaglandin F1 alpha. The production of thromboxane was significantly increased in preeclamptic versus normal placental tissue (22.9 +/- 4.7 versus 6.3 +/- 1.5 pg/mg/hr, mean +/- SE, p less than 0.01), whereas the production of prostacyclin was significantly decreased (3.0 +/- 0.3 versus 6.7 +/- 0.5 pg/mg/hr, p less than 0.001). In both normal and preeclamptic placentas, the production rates of thromboxane and prostacyclin were inhibited by indomethacin (5 mumol/L) and not affected (p greater than 0.50) by arachidonic acid (100 mumol/L). Therefore, during normal pregnancy, the placenta produces equivalent amounts of thromboxane and prostacyclin, so that their biologic actions on vascular tone, platelet aggregation, and uterine activity will be balanced. In preeclamptic pregnancy, however, the placenta produces seven times more thromboxane than prostacyclin.

Prostacyclin is a potent vasodilator and inhibitor of platelet aggregation. Because toxemia is characterized by increased vasoconstriction frequently associated with increased platelet aggregation and reduced uteroplacental blood flow, a deficiency in prostacyclin production during pregnancy could contribute to the development of toxemia. Placentally produced prostacyclin could have both local effects on the uteroplacental vasculature and systemic effects because prostacyclin, unlike the other prostaglandins, is not extensively metabolized by the lungs. Fresh human term placentas were obtained immediately after delivery from 12 normal and 12 toxemic (blood pressure greater than or equal to 140/90 mm Hg, urinary protein greater than 0.3 gm/24 hours) pregnancies. Tissues (300 mg) were incubated in a sterile manner in 5 ml of Dulbecco's Modified Eagle's Medium for 48 hours at 37 degrees C with 95% oxygen and 5% carbon dioxide in a metabolic shaker. Samples were collected at 8, 20, 32, and 48 hours and analyzed for prostacyclin by radioimmunoassay of its stable metabolite, 6-keto-prostaglandin F1 alpha. Prostacyclin production was significantly decreased in toxemic placental tissue compared with normal placental tissue (2.72 +/- 0.49 versus 7.22 +/- 0.44 pg/mg/hr, mean +/- SE, p less than 0.01). In both normal and toxemic placentas, prostacyclin production was inhibited by indomethacin (5 or 50 mumol/L) and not affected (p greater than 0.10) by arachidonic acid (5 or 100 mumol/L). Lowering the oxygen concentration from 95% to 20% significantly (p less than 0.01) decreased prostacyclin production in normal but not toxemic placentas. Prostacyclin production rates in the amnion and chorion were not affected (p greater than 0.10) by toxemia. The amniotic and chorionic prostacyclin production rates were not different from each other (p greater than 0.10) and were only one seventh of the normal placental production rate. These data indicate that placental prostacyclin production is decreased in toxemia; therefore, this vasoactive prostaglandin may be involved in the causation and the associated hypertension and coagulation abnormalities of this disorder.

Vasoactive effects of leukotrienes and thromboxane mimic were tested in the perfused human placental cotyledon. Tissue viability was demonstrated by oxygen consumption and by carbon dioxide and lactate production. Vasoconstrictive effects of leukotrienes B4, C4, and D4 were compared with those of a known potent vasoconstrictor, thromboxane mimic (U 46619). The leukotrienes and thromboxane mimic were administered as bolus injections into a chorionic plate artery in doses ranging from 10(-6) to 25 micrograms. In each placenta only one leukotriene was compared with thromboxane mimic. Vasoconstrictive effects were determined by maximum increases in resistance occurring after each injection. Thromboxane mimic caused significantly greater increases in resistance than any of the leukotrienes (p less than 0.001). Thromboxane mimic and leukotriene D4 had significantly lower threshold doses than leukotriene B4 or C4 (p less than 0.001). We concluded: (1) Thromboxane mimic is a potent vasoconstrictor in the human placental vasculature; (2) leukotrienes also cause vasoconstriction but are much less potent than thromboxane; (3) thromboxane mimic and leukotriene D4 have vasoconstrictor effects at significantly lower (p less than 0.001) concentrations than leukotriene B4 or C4.

Seven adult female rhesus monkeys were laparotomized at days 22, 42, and 157 of pregnancy and blood was collected from the uterine vein and peripheral circulation. Plasma samples were analyzed for monkey chorionic gonadotropin (mCG), monkey chorionic somatomammotropin (mCS), and prolactin by radioimmunoassay. Levels of mCG at day 22 of pregnancy were approximately 250 ng/ml; however, during the later stages of gestation mCG was either nondetectable or less than 0.7 ng/ml. There was no statistical difference in prolactin concentrations between days 22 and 42 of pregnancy, mean levels being between 176-424 ng/ml, but by day 157 prolactin levels of greater than 2,000 ng/ml were recorded. No statistical difference existed between peripheral and uterine vein concentrations of either mCG or prolactin at any of the stages of gestation examined. At day 22, mCS was not detectable; however, at day 42 of gestation mCS titers averaged 1.5 micrograms/ml and 2.3 micrograms/ml in the peripheral and uterine vein plasma, respectively. A statistically significant mCS increase occurred by day 157, levels in the periphery and uterine vein averaging 11.0 micrograms/ml and 16.3 micrograms/ml, respectively. Uterine vein titers of mCS were significantly higher than peripheral titers at both days 42 and 157. Thus, the highest levels of mCG were present during early pregnancy, whereas the highest levels of mCS and prolactin were present during late pregnancy.

Cytotoxicity of peritoneal cells in a HSV-infected murine model is attenuated in late pregnancy. Prostacyclin (PGI2) is elevated at this time in reproductive tissues and has been implicated in the regulation of the immune response. The purpose of this study was to estimate PGI2 in the peritoneal wash or culture supernatants of peritoneal cells obtained from uninfected and HSV-infected pregnant and virgin mice using a radioimmunoassay for 6-keto-prostaglandin F1 alpha. The peritoneal wash of uninfected pregnant and virgin mice contained high levels of 6-keto-PGF1 alpha, 505 +/- 51 pg/100 microliters, (mean +/- S.E., n = 15), and 200 +/- 19 pg/100 microliters, (n = 30), ad did peritoneal effector and target cell cultures (1,159 +/- 118 pg/100 microliters, n = 6, and 1,057 +/- 207 pg/100 microliters, n = 7), respectively. HSV-infection induced in vitro cytotoxicity and suppressed the release of 6-keto-PGF 1 alpha (r = -0.897, P less than 0.05, n = 18). Its concentration was significantly higher (14-fold, P less than .05) in the peritoneal wash, but not in the cell culture, of pregnant (212 +/- 29 pg/100 microliters, n = 19) as compared to virgin mice (18.5 +/- 3.4 pg/100 microliters, n = 27). The levels of 6-keto-PGF1 alpha were inversely correlated (P less than .05) with the combined effects of HSV-infection and cytotoxicity.

To determine the effects of suppressing fetal and maternal adrenal activity on parturition, we treated pregnant rhesus macaques with dexamethasone (0.25 to 4.0 mg, twice a day) from gestation day 130 until delivery (term = 167 days). Long-term dexamethasone treatment increased gestation length: 71% of fetuses were born postmaturely (after day 175 of gestation; X2 = 52.6; P less than 0.001). The dexamethasone decreased basal levels of maternal estradiol and cortisol, but not progesterone, and abolished the prepartum estrogen and prolactin surges; doses greater than 0.16 mg/kg per day resulted in fetal death but not premature delivery. That vaginal delivery was induced by estradiol benzoate in monkeys with prolonged pregnancy and dead fetuses, but not in those with live fetuses, suggests active fetal inhibition of prostaglandin synthesis. The dexamethasone retarded fetal growth (410 +/- 16 gm versus 501 +/- 5 gm for controls; P less than 0.001) and decreased thymus, spleen, and adrenal weights (P less than 0.01). A less significant decrease in brain weight was noted (P less than 0.1), as were decreases in biparietal diameter, occipitofrontal diameter, and head circumference (P less than 0.05). These results indicate that corticosteroids do not induce premature labor in primates. On the contrary, long-term dexamethasone administration is associated with prolonged pregnancy and suppression of estrogen biosynthesis.

The hormonal regulation of corpus luteum (CL) function during late pregnancy was studied in hypophysectomized monkeys. Between days 149-154 of gestation, 9 days after hypophysectomy, progesterone in the uteroovarian vein (UOV), uterine vein (UV) and peripheral circulation (P) averaged 179.7 ng/ml, 38.9 ng/ml and 5.5 ng/ml, respectively. Amniotic fluid prolactin ranged from 2150-6700 ng/ml and monkey chorionic somatomammotropin (mCS) in mothers carrying live fetuses ranged from 11.4-30.8 micrograms/ml in the UV and P. Prolactin and monkey chorionic gonadotropin in the UV and P were low or nondetectable as was mCS in 2 mothers carrying dead fetuses. CL function was further studied 7 and 39 days after removal of the fetus alone or both the fetus and placenta. Placental delivery was extremely variable, ranging from 2-greater than 63 days post-fetectomy. Although progesterone was not detectable in the P7 days after cesarean section in those animals in which both fetus and placenta were absent, surprisingly, progesterone was measurable in the UOV (range 1.6-48.2 ng/ml). At 39 days, progesterone was either nondetectable or very low. We have interpreted these data to mean: 1) neither the maternal pituitary gland nor a live fetus is necessary for placental or corpus luteum production of progesterone during late pregnancy, 2) the presence of high levels of circulating prolactin and mCS are apparently not necessary for continued secretion of progesterone from the CL during late pregnancy, 3) the fetoplacental unit may be the source of the luteotropic stimulus of late pregnancy since progesterone in the UOV decreases markedly in the absence of the fetoplacental unit or disruption of the unit brought about by fetectomy, and 4) regression of the CL following cesarean section in hypophysectomized monkeys is exceedingly slow when compared to the precipitous regression characteristic of the CL of the nonfertile menstrual cycle.