Prostaglandins and Reproduction , pp. Labhsetwar, A. Prostaglandins and studies related to reproduction in laboratory animals. In Advances in Prostaglandin Research. Kirton, K. Prostaglandins and Reproduction in sub-human primates. Cooper, M. Veterinary uses of prostaglandins. Practical Applications of Prostaglandins and their Synthesis Inhibitors , pp.
Prostaglandins in human reproduction. Obstetric and Gynaecological Uses of Prostaglandin. Interruption of pregnancy with prostaglandins.
Bygdeman, M. Menstrual regulation with prostaglandins. Practical Application of Prostaglandins and their Synthesis Inhibitors , pp.
Singapore experience with prostaglandins. Prostaglandins in obstetrics and gynaecology. In Friebel, K. International Sulprostone Symposium, Vienna, November , pp. Termination of second trimester pregnancy with prostaglandins. Termination of second trimester pregnancy with laminaria and intramuscular phenoxy,18,19,tetranor PGE2 methylsulfonylamide Sulprostone — A randomized study. Southern, E. In the human placenta, prostacyclin consistently is the most potent vasodilator. There is little information available regarding the vascular effects of leukotrienes in the placenta.
When comparing the vasoconstrictive effect of LTB 4 , LTC 4 , and LTD 4 with that of thromboxane in the perfused human placental cotyledon, 59 we found that the leukotrienes cause vasoconstriction, but only at high doses. Their potency is considerably less than that of thromboxane. Several in vivo studies have been reported concerning the vasoactive effects of prostaglandins in the placenta. The most commonly used animal model is the chronically catheterized sheep, but other species have been used, including nonhuman primates.
With respect to vasodilatation in the fetoplacental vasculature, there is controversy and disagreement between in vitro and in vivo studies. Prostacyclin is a potent vasodilator, 24 , 25 , 26 and it consistently relaxes human placental blood vessels when tested in vitro , as discussed previously. However, when tested in vivo , infusion of prostacyclin into the ovine fetus decreases fetoplacental blood flow and results in an increase or no change in the calculated placental vascular resistance.
The in vivo placental vascular results obtained for prostacyclin in the sheep are disturbing for at least two reasons. First, they contradict the consistently potent vasodilatory effect of prostacyclin obtained in human in vitro placental studies. Second, how can a compound that is such a potent vasodilator in all other vascular beds be a vasoconstrictor in the placenta, a vascular bed that must remain dilated if the fetus is to grow and mature properly?
The aberrant effects observed for prostacyclin in vivo can be explained by Poiseuille's law as it applies to the fetal—placental circulation. The placental vascular effects observed for prostacyclin in vivo or for other vasodilators are passive changes caused by shunting of blood away from the placenta to other vasodilated vascular beds more proximal to the heart.
We have previously described this concept in detail. The placental vascular actions are due to systemic alterations in blood flow and perfusion pressure in nonplacental vascular beds rather than to direct vasoconstrictive actions of prostacyclin on the placental vasculature.
Indirect evidence suggests that prostacyclin is important for in vivo vasodilation in the human placenta. Doppler ultrasonographic measurements of umbilical blood flow in pregnant women are correlated positively with prostacyclin production in vitro by specimens obtained from the umbilical arteries. The arachidonic acid metabolites are present in abundance 82 and exert potent vasoactive effects in the fetus and on the umbilical vessels.
Thromboxane is a potent vasoconstrictor in the fetal systemic circulation, as evidenced by in vivo studies in chronically catheterized sheep fetuses. Thromboxane infusion results in a significant increase in mean fetal aortic blood pressure, renal vasoconstriction, and fetal acidosis. The leukotrienes are potent fetal pulmonary vasoconstrictors and may be the compounds primarily responsible for maintaining the high pulmonary vascular resistance during fetal life.
In newborn lambs and piglets, LTD 4 increases pulmonary and systemic vascular resistance, 93 , 94 whereas blockage of the leukotriene receptors with FPL decreases pulmonary vascular resistance, increases pulmonary blood flow, and decreases pulmonary and systemic arterial pressures in late gestational fetal lambs.
Preeclampsia is considered one of the most significant health problems in human pregnancy. It is characterized primarily by proteinuria and increased vasoconstriction leading to maternal hypertension and reduced uteroplacental blood flow. Platelet aggregation, thrombocytopenia, edema, and hyperreflexia, occasionally manifested as convulsions eclampsia , may be associated with the disease process.
Because preeclampsia occurs only during pregnancy or in the presence of placental tissue i. The cause of preeclampsia is not known, but in recent years, a considerable amount of evidence has accrued to indicate that it is associated with an imbalance of increased thromboxane and decreased prostacyclin production, as discussed subsequently. The first evidence that prostaglandins were involved in preeclampsia came from studies involving vascular sensitivity of pregnant women to AII.
Although AII levels are not higher in women with preeclampsia than in healthy pregnant women, 99 , the vascular responsiveness to AII is increased greatly in preeclamptic women. Gant and associates demonstrated that the dose of AII required to elicit a pressor response of 20 mmHg in diastolic blood pressure was significantly less than normal as early as 23 — 26 weeks of pregnancy in women destined to develop pregnancy-induced hypertension.
This study demonstrated the increased vascular responsiveness of preeclamptic women, and it showed that this increased responsiveness was present as early as the second trimester of pregnancy, long before clinical symptoms were manifest. The mechanism for the increased vascular responsiveness is not known, but defective prostaglandin production or a loss of response to prostaglandins contributes to the development of pregnancy-induced hypertension.
In other words, by inhibiting prostaglandin synthesis, the investigators mimicked the increased vascular responsiveness of preeclampsia. Prostacyclin is a potent vasodilator, an inhibitor of platelet aggregation, 24 , 25 , 26 and an inhibitor of uterine contractility; , , thus, its combined effects favor prevention of maternal hypertension, prevention of platelet aggregation, and promotion of increased uteroplacental blood flow. A deficiency in its production during pregnancy would contribute to the clinical manifestations of preeclampsia.
The role of prostacyclin in pregnancy has been reviewed extensively. A significant amount of data indicate that prostacyclin production is decreased in preeclampsia, as reviewed comprehensively. Prostacyclin production is, therefore, decreased in umbilical arteries, placental veins, uterine vessels, and subcutaneous vessels obtained from preeclamptic women as compared with healthy pregnant women. Other studies also confirm decreased prostacyclin production in preeclampsia.
For example, urinary metabolite concentrations are depressed, as are amniotic fluid concentrations. Studies suggest that prostacyclin itself does not circulate in concentrations sufficient to produce physiologic effects, but rather that it exerts its effects locally by a paracrine mechanism between the endothelial cells and the vascular smooth muscle to relax the blood vessels in which it is produced.
Placental production of prostacyclin is decreased significantly in preeclampsia Fig. Although the production rate of prostacyclin is small when expressed per milligram of wet tissue per hour, the large placental mass makes it a formidable endocrine organ during pregnancy. A placental production rate of 6. Preeclamptic vs. Walsh SW. Preeclampsia: An imbalance in placental prostacyclin and thromboxane production.
Am J Obstet Gynecol ; With less prostacyclin being produced in preeclampsia, the vasoconstrictor effects of AII, thromboxane, and catecholamines would not be opposed efficiently, leading to hypertension.
The renin-angiotensin system is suppressed paradoxically in preeclampsia, but AII levels still are elevated over the nonpregnant state. Deficiency in prostacyclin is present before the onset of clinical symptoms. Mills et al. Thromboxane opposes the actions of prostacyclin. Thromboxane is a potent vasoconstrictor, a stimulator of platelet aggregation, 24 , 25 , 26 and a stimulator of uterine contractility.
The deficiency in prostacyclin production by preeclamptic placentas is associated with enhanced production of thromboxane similar to the imbalances in these eicosanoids that have been suggested for other pathologic states that favor the development of thrombosis, such as arterial thrombosis, venous thrombosis, myocardial infarction, diabetes, and thrombocytopenia purpura. The placental imbalance of increased thromboxane and decreased prostacyclin in preeclampsia is even more striking when one compares their production rate ratios between normal and preeclamptic pregnancies Fig.
The normal placenta produces approximately equivalent amounts of thromboxane and prostacyclin; thus, their biologic actions on vascular tone, platelet aggregation, and uterine contractility are balanced.
The preeclamptic placenta, however, produces more than seven times as much thromboxane as prostacyclin, so the balance of biologic actions would be tipped heavily in favor of thromboxane Fig. Production rates of thromboxane by normal and preeclamptic term placental tissues, as estimated by the concentrations of its stable metabolite, thromboxane B 2 TXB 2 , in the incubation media. The heavy typeface and box for thromboxane suggest an exacerbation of its actions in preeclampsia, whereas the lighter typeface and box for prostacyclin suggest a diminution of its actions.
Simultaneous measurements of prostacyclin and thromboxane in preeclampsia have been reported for amniotic fluid levels; umbilical, uterine venous, and peripheral plasma levels; and placental release. Maternal circulating levels of thromboxane are not increased in mild preeclampsia, , , but they are increased significantly in severe preeclampsia and in hypertensive pregnancies with insufficient fetal growth. The cause of the imbalance of increased thromboxane and decreased prostacyclin production in women with preeclampsia is not known, but it could be related to a second significant biochemical imbalance.
Women with preeclampsia have an increase in oxidative stress and lipid peroxidation; simultaneously, they have a deficiency in several important antioxidants. Low doses of aspirin also preferentially inhibit thromboxane production in the placenta. The ratio of thromboxane to prostacyclin is altered by low-dose aspirin in favor of restoring a balance between thromboxane and prostacyclin. In each of the studies cited previously, the ratio of thromboxane to prostacyclin was decreased by low-dose aspirin.
Therefore, the adverse effects of unopposed thromboxane are attenuated or eliminated. Low-dose aspirin therapy for prevention of preeclampsia Early studies evaluating low-dose aspirin therapy for the prevention of preeclampsia reported dramatic decreases in the incidence of preeclampsia. The initial report based on intent to treat of the NICHD Maternal—Fetal Medicine Unit Network trial of low-dose aspirin to prevent preeclampsia in nulliparous women found a modest reduction in the incidence of preeclampsia from 6.
If only one-half of the patients in the treatment group are compliant in taking the test compound, the effectiveness of the compound is not being adequately evaluated. Meta-analysis of low-dose aspirin trials demonstrates that aspirin is effective in preventing preeclampsia.
Incidence of preeclampsia in relation to compliance of women on low-dose aspirin therapy. Pill compliance was significantly associated with a beneficial effect of aspirin for prevention of preeclampsia. Reanalysis of the data based on percentage of pill compliance of the aspirin group revealed a significant decrease in the incidence of preeclampsia from 5.
Modified from Walsh SW. Low-dose aspirin given to pregnant women is beneficial with respect to blood pressure and vascular sensitivity to pressors. Women in whom hypertension is destined to develop in pregnancy are more responsive to the vasoconstrictive effects of AII. The ratio of thromboxane to prostacyclin is positively correlated with maternal mean blood pressure: the higher the ratio, the higher the blood pressure. Low-dose aspirin therapy to lower the ratio of thromboxane to prostacyclin results in lower blood pressure.
In women with preeclampsia, low-dose aspirin therapy decreases systolic, diastolic, and mean blood pressures. Several comprehensive reviews have been published on this subject. These should be consulted for more detailed descriptions of the role of prostaglandins in labor. Three primary lines of evidence indicate the importance of prostaglandins to the process of labor:.
Inhibition of prostaglandin synthesis with cyclooxygenase inhibitors, such as indomethacin, flufenamic acid, or aspirin, inhibits uterine contractility, prolongs the length of gestation, and prolongs the duration of labor in monkeys and women. Unlike the uterine responsiveness to oxytocin that is manifest at term, the human uterus contracts to prostaglandins at any stage of pregnancy and also during the nonfertile cycle. Prostaglandin production is increased at the time of labor but not before.
The first step in the synthesis of prostaglandins is the release of arachidonic acid from glycerophospholipids in the cell membranes. The amnion is a rich source of phosphatidylethanolamine and phosphatidylinositol, and these phospholipids appear to be the major source of arachidonate for human parturition. Phospholipase A 2 acts on phosphatidylethanolamine to release arachidonate, and phospholipase C acts on phosphatidylinositol to release arachidonate-rich diacylglycerol, which then is further metabolized by diacylglycerol and monoacylglycerol lipases to yield arachidonic acid.
The specific activities of phospholipase A 2 and phospholipase C are increased in amnion at term compared with during midgestation. In sheep, the fetus is the initiator of parturition. In a beautiful set of classic ablation and endocrine experiments, Liggins and colleagues established the sequence of events initiated by the ovine fetus that results in parturition. A summary diagram is presented in Fig. Fetal hypophysectomy or adrenalectomy results in a prolongation of gestation in sheep, whereas fetal ACTH or glucocorticoid infusion results in premature labor.
Schematic diagram of the pathway by which the fetal lamb influences endocrine events in the ewe. Also shown are experimental procedures that have been used to modify the activity of the pathway. The mechanism of initiation of parturition in the ewe.
Recent Prog Horm Res ; In primates, the role of the fetus in parturition is less clear. Human anencephalic fetuses and monkey experimental anencephalic fetuses are born at an average gestational length that is not significantly different from healthy intact fetuses. There is, however, a significant disruption in the timing of birth, with more fetuses born prematurely or postmaturely. Glucocorticoid administration to pregnant women or monkeys does not induce premature labor as it does in sheep.
The fetus of primates does not play the key role in initiating labor as it does in sheep. However, the primate fetus does play an important role in influencing the timing of birth to ensure that it is not born too early or too late. The mechanisms through which the primate fetus influences the timing of birth are not known, but they may involve nocturnal activity of the fetal adrenal glands.
In the monkey, fetal adrenal activity increases at night because of the release of negative feedback inhibition from transplacental passage of maternal cortisol. Dexamethasone administration not only suppresses fetal adrenal activity, but also abolishes the nocturnal increase in uterine activity, as does death of the fetus. Women, if allowed to deliver naturally, also have a nocturnal rhythm in uterine activity, with the onset of labor contractions being most frequent at night.
The fetal adrenal glands appear to control the nocturnal increase in uterine contractility by supplying precursors for estrogen biosynthesis. Studies in nonhuman primates demonstrate that the increase in fetal adrenal activity at night results in an increase in the circulating levels of dehydroepiandrosterone sulfate DHEAS and androstenedione, which then are converted to estrogens by the placenta. For example, estrogen stimulates the maternal secretion of oxytocin and increases the number of receptors for oxytocin in the myometrium.
Estrogen also stimulates the production of prostaglandins and the formation of gap junctions in the myometrium. Uterine muscle becomes more irritable under the influence of estrogen. The nocturnal rhythm in uterine contractility is under the influence of a nocturnal increase in the maternal circulating levels of oxytocin.
Several other stimulators of prostaglandin synthesis have been identified. Epidermal growth factor EGF stimulates PGE 2 output by amniotic cells, increases the rate of synthesis of cyclooxygenase in amnion, and stimulates uterine contractility in estrogen-primed rats.
Neutrophils are also a source of prostaglandins at the time of labor. Labor is associated with extensive infiltration of neutrophils into the decidua and myometrium.
Interleukin-8, a potent neutrophil chemokine, and COX-2, the inducible form of cyclooxygenase, were two key inflammatory genes with increased expression early in the labor process. An alternative hypothesis to parturition being initiated by stimulators of prostaglandin synthesis is that pregnancy is maintained until the time for delivery by inhibitors of prostaglandin synthesis.
At the time of delivery, the inhibitors are removed or overwhelmed by the appearance of prostaglandin stimulators. Inhibitors of prostaglandin synthesis have been identified in human amniotic fluid. This corresponds to a simultaneous increase in the activity of stimulators of prostaglandin synthesis in the amniotic fluid. The inhibitory actions appear to be exerted either at the cyclooxygenase enzyme or at the phospholipase A 2 enzyme.
The chemical identities of the inhibitors are not known, but at least one appears to be similar to lipomodulin lipocortin, macrocortin , the inhibitory protein active against phospholipase A 2 that is stimulated by the glucocorticoids. The pregnancy factors responsible for regulating the prostaglandin synthesis inhibitors are not known. In many nonprimate species e.
Overt changes such as these in maternal peripheral blood do not occur in human or nonhuman primate pregnancy, so the concept that progesterone withdrawal precedes labor has been questioned for primates. Progesterone withdrawal may, however, occur locally within the intrauterine tissues.
Estrogens also are formed in these tissues, and they inhibit this enzyme system. At the time of labor, there is a decrease in the formation of progesterone from pregnenolone within the decidua and chorion.
At the same time, there is an increase in the activity of the estrone sulfatase enzyme in decidua and chorion. Another possibility for progesterone withdrawal involves an alteration in progesterone receptors in the myometrium. Progesterone maintains uterine quiescence by binding to the progesterone receptor PR -B isoform.
Presence of the PR-A isoform antagonizes the relaxing action of progesterone. Evidence suggests that the change in progesterone receptors is mediated by prostaglandins. Most of the work relating arachidonic acid metabolites to parturition has focused on the cyclooxygenase metabolites, the prostaglandins. PIP: Clinical uses of prostaglandins include induction of abortion and of labor, treatment of uterine bleeding, and cervical dilatation.
The author reviews currently recognized indications for these uses, local and systemic administration, dosages, possible complications, and side effects. Prostaglandins F2alpha and E2 are the most frequently used, although an analog of prostaglandin F2alpha is also increasingly used. PGE2 has been used in 3 cases of hydatidiform mole. In all these cases the mole was delivered within 12 hours of starting the infusion. Abstract PIP: The prostaglandins PGs , a group of pharmacologically active and modified fatty acids, were first discovered in association with male sex organs and their secretions, and have subsequently been shown to be widely distributed in mammalian tissues and fluids.
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