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Relaxin on induction of parturition in beef heifers.

Purified porcine relaxin (3000 U/mg) was administered into the cervical os of primiparous beef heifers on day 278 of gestation (approximately 5 days before parturition normally occurs) to determine its effects on the induction of parturition, changes in progesterone, estrone (E1), 17 beta-estradiol (17 beta-E2), cervical dilation, and pelvic relaxation. Heifers were assigned randomly to 1 of 3 treatments: relaxin-double (two infusions of 3000 U, 12 h apart; n = 17), relaxin-single (3000 U; n = 14), and PBS-gel vehicle (n = 16). Relaxin induced marked earlier calving (P less than 0.002) than PBS-gel vehicle. The intervals between the administration of relaxin or the PBS-gel vehicle and calving were 2.0, 2.5, and 5.3 days for heifers given relaxin-double, relaxin-single, and PBS-gel vehicle, respectively. The duration of gestation was significantly reduced (P less than 0.002) in relaxin-treated heifers compared with that in control heifers. A precipitous decrease in progesterone (7.1 ng/ml) occurred in peripheral blood plasma within 24 h after relaxin treatment. Coincident with a decline in levels of progesterone, E1 and 17 beta-E2 increased by 1700 and 400 pg/ml, respectively, an increase of 35% compared with the 12% increase in these steroids in control heifers. Mean deviations of cervical dilation increased 643%, 526%, and 11% in heifers given relaxin-double, relaxin-single, and PBS-gel vehicle, respectively. Relaxin induced maximum pelvic opening between 12-36 h after treatment. Although relaxin induced significantly earlier calving, there was no incidence (0 of 31 heifers) of retained placenta. We conclude from this study that purified relaxin administered intracervically to primiparous beef heifers during late pregnancy induced premature parturition. Marked shifts of progesterone, E1, 17 beta-E2, pelvic canal expansion, and cervical relaxation reflect the premature parturition induced by relaxin.

Animals↗

Activation of cFos in ovine fetal corticotropin-releasing hormone neurons at the time of parturition.

The ovine fetal pituitary adrenal axis plays an important role in parturition. While lesions of the paraventricular nucleus (PVN) in the fetal sheep delay parturition, suggesting that the PVN is necessary for the processes that lead up to parturition, evidence for stimulation of PVN neurons at time of delivery/labor is lacking. The present study tested the hypothesis that activation (evidenced by expression of the oncogene product cFos) of a specific population of PVN neurons containing CRH accompanies labor in sheep. Monitoring of uterine electromyogram activity determined the onset of labor. The brains of nine fetuses (removed by ceasarian section under anesthesia at gestational ages of 125-145 days) and four newborn sheep were perfused and stained for cFos and CRH. Before labor, less than 5% of fetal paraventricular CRH neurons expressed cFos. Verification that the CRH neurons could express cFos when adequately stimulated was made by exposing an additional group of four preterm animals (125 days gestational age) to hypoxemia; the six untreated fetuses served as controls. Activation of the CRH neurons by hypoxemia produced a rapid induction of cFos in CRH neurons, with approximately 50% of the cells strongly expressing cFos protein 1 h after exposure to hypoxia. At the time uterine contractions were first detected, 70% of CRH neurons expressed cFos, and cFos immunoreactivity persisted until just after birth. cFos staining declined rapidly, reaching prelabor levels in some animals by 2-3 h after birth. These data are consistent with the hypothesis that in addition to their potential role in the processes that initiate parturition over several days before birth, fetal CRH neurons are stimulated during labor, and termination of stimulation probably occurs rapidly after delivery.

Animals↗

A corticotropin-releasing hormone type I receptor antagonist delays parturition in sheep.

In sheep, corticotropin-releasing hormone (CRH) can stimulate the fetal release of ACTH to produce a cortisol surge which leads to the onset of parturition. We tested the hypothesis that fetal CRH is a primary factor in the onset of parturition in sheep by using a Type I CRH receptor antagonist, antalarmin, to block the endogenous action of CRH. Pregnant ewes were cannulated at 130-135 days of gestation. Five catheters were placed into the amniotic sac, fetal femoral artery, fetal tarsal vein, maternal jugular vein and carotid artery. After 5 days' recovery, blood samples from maternal and fetal vessels were collected at the following times: a day before the start of infusion, at [-1, 0, 1, 2, 4, 8 and 24]h, on the first day of infusion, and thereafter daily throughout a 10-day infusion. Animals (n=6 per group) received infusions into a fetal vein of either a vehicle comprising 1:1 mixture of ethanol and polyethoxylated castor oil (Cremophor EL) or antalarmin (50 g/L) in the vehicle at a rate of 0.3 mL/h. The plasma samples were assayed for ACTH and cortisol using commercial RIA kits. Fetuses infused with vehicle delivered at a mean gestational age of 141.8 +/- 0.9 days compared with antalarmin-infused sheep at 148.8 +/- 1.6 days (P = 0.0036, unpaired Student's t-test). Fetal ACTH and cortisol did not change in the antalarmin-infused sheep after 3 days' infusion compared to significant increases in vehicle-infused sheep (P=0.004 and P = 0.016 respectively, ANOVA). These data show that CRH receptor antagonism in the fetus can delay the onset of parturition. It supports the hypothesis that hypothalamic CRH drives fetal production of ACTH and is essential for the onset of parturition triggered by a surge in fetal cortisol.

Adrenocorticotropic Hormone↗

Daily hormonal changes in the maternal, fetal, and amniotic fluid compartments before parturition in a primate species.

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.

Amniotic Fluid↗

A role for the 72 kDa gelatinase (MMP-2) and its inhibitor (TIMP-2) in human parturition, premature rupture of membranes and intraamniotic infection.

OBJECTIVE: Degradation of the extracellular matrix in fetal membranes has been implicated in the process of parturition and rupture of membranes. Matrix metalloproteinases (MMPs) are enzymes capable of degrading extracellular matrix including collagen. Tissue inhibitors of matrix metalloproteinases (TIMPs) inhibit the activity of MMPs by covalently binding to the enzymes. MMP-2 degrades Type IV collagen and TIMP-2 is its specific inhibitor. The objective of this study was to determine if human parturition, rupture of membranes (term and preterm) and microbial invasion of the amniotic cavity (MIAC) are associated with changes in the concentrations of MMP-2 and TIMP-2 in amniotic fluid. STUDY DESIGN: A cross-sectional study was conducted with women in the following categories: 1) term with intact membranes, in labor and not in labor; 2) preterm labor and intact membranes who delivered at term, who delivered preterm and preterm labor with MIAC; 3) preterm premature rupture of membranes (PROM) with and without infection; 4) term and preterm PROM not in labor; and 5) midtrimester. MMP-2 and TIMP-2 concentrations in amniotic fluid were determined using sensitive and specific immunoassays. RESULTS: The concentration of TIMP-2 increased with advancing gestational age (r = 0.6, p < 0.001). No correlation was found between MMP-2 concentrations and gestational age. Human parturition and rupture of membranes (term and preterm) and in patients with intact membranes were not associated with changes in the amniotic fluid MMP-2 concentrations. In contrast, 1) patients with spontaneous labor (term and preterm) had significantly lower median concentrations of TIMP-2 compared to those not in labor (p < 0.05 for both); 2) MIAC in women with preterm labor and preterm PROM was associated with a significant decrease in amniotic fluid TIMP-2 concentrations (p < 0.04 for both comparisons); 3) Rupture of the membranes (term and preterm) was also associated with a significant decrease in the amniotic fluid TIMP-2 concentrations (p < 0.05 and p < 0.03, respectively). CONCLUSIONS: Human parturition (preterm and term), rupture of fetal membranes (term and preterm) and intraamniotic infection are associated with a significant decrease in amniotic fluid TIMP-2 concentrations.

Amniotic Fluid↗

The influence of drugs on the kinin-forming system in relation to pregnancy and parturition in the rat.

The duration of normal gestation and parturition in the rat can be changed by treatment with drugs which alter the equilibrium of the kallikrein-kinin system. The kallikrein inhibitor, aprotinin, when given from Days 19-22 of pregnancy prolongs gestation. Treatment with aprotinin from Days 20-22 of pregnancy prolongs the parturient process, as does a single dose given on the morning of Day 22. Kallikrein, when administered from Days 19-22 of pregnancy, results in a prolongation of gestation and abolishes the pre-parturient behaviour ('labour'). Parturition is prolonged and many fetuses are stillborn. Soya bean trypsin inhibitor when given from Days 19-22 of pregnancy delays and prolongs parturition; maternal haemorrhage occurs during birth and many fetuses are born dead or are abandoned at birth. It is suggested that the kallikrein-kinin system plays a functional role in the normal process of parturition in the rat.

Animals↗

Influence of meclofenamic acid on the initiation of parturition and lactation in the sow.

The effect of inhibition of prostaglandin (PG) synthesis on the initiation of parturition was studied in 4 groups of 16 sows each. Oral administration of meclofenamic acid (5.0 mg/kg body weight/day) on Days 112, 113 and 114 of pregnancy significantly delayed parturition compared to controls (P less than 0.001). Exogenous PGF-2 alpha after meclofenamic acid treatment synchronized parturition 20.4 +/- 1 h later. Functional luteolysis as indicated by a decline in maternal progesterone levels began during meclofenamic acid treatment; the fall in progesterone was then arrested in sows treated only with meclofenamic acid. Meclofenamic acid treatment in late pregnancy modified the normal initiation of lactation, as indicated by the high concentration of lactose and low concentrations of protein and Na+ in colostrum in treated sows compared to controls. We suggest that PG synthesis is required for the initiation of parturition in the sow and that luteal regression may involve two stages: the first which may be independent of prostaglandin, and the second, dependent on prostaglandin.

Animals↗

Effect of relaxin on parturition and frequency of live births in pigs.

Gilts on Day 105 of gestation were sham ovariectomized (Group C, N = 5); ovariectomized and given i.m. injections of 100 mg progesterone twice daily from Day 105 to 112 (Group OP, N = 5); or ovariectomized and given progesterone and i.m. injections of 1 mg highly purified porcine relaxin 4 times/day from Day 105 until the end of parturition (Group OPR, N = 5). Concentrations of progesterone in peripheral plasma of gilts in Group OP were similar to those in Group C. Relaxin was undetectable in peripheral plasma of gilts in Group OP which also showed prolonged parturition (P less than 0.001) and impaired frequency of live births (P less than 0.001), although onset of lactation was not affected. In Group OPR the duration of parturition and frequency of live births were similar to those observed for gilts in Group C. These results indicate that the ovarian hormone relaxin is necessary for normal duration of parturition and frequency of live births and that the onset of lactation is not prevented by an absence of relaxin.

Animals↗

Effects of removal in late pregnancy of the corpus luteum, graafian follicle or ovaries on plasma progesterone, oestradiol, LH, parturition and post-partum oestrus in the tammar wallaby, Macropus eugenii.

Concentrations of oestradiol-17 beta, progesterone, and luteinizing hormone (LH) were measured in plasma collected at 6- to 12-h intervals from tammars around the time of parturition and post-partum oestrus. Parturition occurred on Day 26 or 27 after reactivation of lactation-delayed pregnancy and coincided with a precipitous decline in progesterone levels. A sharp rise in oestradiol, from basal concentrations of less than 10 pg/ml to a peak of 13 to 32 pg/ml, as well as oestrus, followed the drop in progesterone by 8.3 and 9.8 h, respectively. The LH surge was dependent on the oestradiol rise and followed it by 7 h. Ovulation followed mating by about 30 h and the LH surge by 24 h. Removal of the ovary with the large Graafian follicle prevented the oestradiol rise, oestrus and the LH surge, but not parturition. Peripartum changes in peripheral oestradiol do not appear to be involved in initiation of parturition but the oestradiol rise and associated change in the oestradiol:progesterone ratio are important signals for post-partum oestrus and the LH surge.

Animals↗

Aromatase activity and oestrogen concentrations in bovine cotyledons and caruncles during gestation and parturition.

Two peaks of aromatase activities were detected in bovine cotyledons, 2.76 +/- 0.96 pmol min-1 mg-1 protein at month five of gestation and 3.62 +/- 0.78 pmol min-1 mg-1 protein immediately after parturition, but aromatase activity in caruncles was very low throughout gestation. Oestrone concentrations in the cotyledons and caruncles were 0.93 +/- 0.50 and 1.51 +/- 0.69 ng mg-1 protein at month five of gestation, but 4.31 +/- 1.66 and 3.36 +/- 0.98 ng mg-1 protein immediately after parturition, indicating a biphasic pattern. Our findings suggest that oestrogen synthesis in the bovine placenta increased to a maximum at least twice during the period from gestation to parturition; at month five of gestation and at parturition the changes in aromatase activity may only be partially explained by changes in oestrogen production.

Animals↗

Changes in content of mRNA encoding oxytocin in the pig uterus during the oestrous cycle, pregnancy, at parturition and in lactational anoestrus.

The aim of this study was to show that the pig uterus synthesizes oxytocin. Uteri were obtained from 2-7 pigs at regular intervals during the oestrous cycle, throughout pregnancy, at parturition and in lactational anoestrus. Localization of mRNA encoding oxytocin was by in situ hybridization and oxytocin concentrations were measured by radioimmunoassay. As reproductive status changed, mRNA encoding oxytocin varied significantly (P < 0.05). Uterine tissue type was a significant factor in determining synthesis of mRNA encoding oxytocin (P < 0.001). In luminal epithelia, concentrations of mRNA encoding oxytocin were greater at oestrus than during day 14 of the luteal phase (P < 0.01) or at any stage of pregnancy (P < 0.05), with concentrations minimal at parturition. This trend was also exhibited in uterine circular muscle. In longitudinal muscle, concentrations of mRNA encoding oxytocin were lower during late pregnancy than at oestrus (P < 0.05) or during the luteal phase (P < 0.05). Concentrations were minimal at parturition. The oxytocin content in endometrial and myometrial tissue was positively correlated across reproductive status (P < 0.02, r = 0.402, n = 35). These data are the first indication that the uterine endometrium and musculature of the pig express mRNA encoding oxytocin. The luminal epithelium of animals at oestrus was particularly rich in mRNA encoding oxytocin, whilst late pregnant and parturient animals did not show a rise in mRNA encoding oxytocin. Local uterine synthesis of oxytocin may therefore be more important in control of the oestrous cycle than in pregnancy or at parturition in pigs.

Animals↗

Effect of progesterone on the activation of neurones of the supraoptic nucleus during parturition.

Parturition is driven by a pulsatile pattern of oxytocin secretion, resulting from burst firing activity of supraoptic oxytocin neurones and reflected by induction of Fos expression. Rats were injected with progesterone on day 20 of pregnancy to investigate the role of the decreasing progesterone:ratio oestrogen ratio, which precedes delivery, in the activation of supraoptic neurones. Progesterone delayed the onset of birth by 28 h compared with vehicle (control) and prolonged the duration of delivery, which was overcome by pulsatile injections of oxytocin, indicating that the slow delivery may reflect impaired oxytocin secretion. Parturient rats pretreated with progesterone had fewer Fos immunoreactive nuclei in the supraoptic nucleus than did parturient rats pretreated with vehicle. The number of Fos immunoreactive nuclei was not restored after oxytocin injection, indicating that appropriate activation of oxytocin neurones is impaired by progesterone and also that there is a lack of stimulatory afferent drive. Fos expression increased in the nucleus of the tractus solitarius during parturition in rats pretreated with either vehicle or progesterone, but not in rats that had been pretreated with progesterone and induced with oxytocin, indicating that this input was inhibited. Endogenous opioids inhibit oxytocin neurones in late pregnancy and the opioid antagonist, naloxone, increases Fos expression in supraoptic nuclei by preventing inhibition. However, progesterone attenuated naloxone-induced Fos expression in the supraoptic nucleus in late pregnancy and naloxone administered during parturition did not accelerate the duration of births delayed by progesterone administration, indicating that progesterone does not act by hyperactivation of endogenous opioid tone. RU486, a progesterone receptor antagonist, enhanced supraoptic neurone Fos expression in late pregnancy, indicating progesterone receptor-mediated actions. Thus, progesterone withdrawal is necessary for appropriate activation of supraoptic and tractus solitarius neurones during parturition.

Analysis of Variance↗

The importance of oxytocin mechanisms in the control of mouse parturition.

The role of oxytocin in parturition in mice was investigated. Pup birth profiles, blood samples and brains were collected from parturient mice observed under red light conditions in a reversed light:dark photoperiod. Peripheral administration of an oxytocin antagonist in a dose-dependent manner delayed the birth of subsequent pups, indicating that oxytocin is required for a normal pup birth profile. Oxytocin neurones were activated during birth as shown by both increased immediate early gene ( Fos) expression in oxytocin neurones in the supraoptic nucleus and increased plasma oxytocin concentrations during birth. In addition, the nucleus of the tractus solitarius and the olfactory bulbs, sites that process inputs to oxytocin neurones, become activated during parturition. Exposure to stress during parturition halted subsequent deliveries; at this stage plasma oxytocin concentrations were not higher than those of virgin mice, and birth was restored by administration of oxytocin. Administration of beta-adrenergic antagonist (propranolol) also restored stress-delayed birth, whereas administration of ritrodrine (beta-agonist) delayed birth in non-stressed mice, indicating that adrenergic mechanisms contribute to stress-delayed births in mice. Administration of morphine (mu-opioid agonist) delayed births transiently, but naloxone (opioid antagonist) did not prevent stress-delayed birth, indicating that endogenous opioids do not appear to contribute to neuroendocrine or uterine mechanisms that promote birth in mice. Therefore, despite evidence in oxytocin knockout mice that oxytocin is not essential for parturition in this species, the results of the present study indicate that oxytocin neurone activity and secretion contribute to the birth process in normal mice.

Adrenergic beta-Agonists↗

Inflammatory mediators and parturition.

A role for inflammatory mechanisms in ovulation and parturition has been proposed on many occasions. In addition, many agents directly implicated in parturition, such as cytokines and prostaglandins, can be pro-inflammatory. The cervix can be softened and labour induced in women by mechanical trauma (sweeping the membranes), prostaglandins, antiprogestins or chemokines such as interleukin 8 (IL-8). This review presents evidence that invading cells, such as neutrophils, may be involved in the softening of the cervix and the onset of birth, and describes pathways in which this action can be controlled by cytokines and vasodilatory agents such as prostaglandins. Such mechanisms may, in turn, be controlled by steroids. The role of progesterone is enigmatic since progesterone concentrations do not fall in the peripheral circulation of women at the time of birth and yet antiprogestins soften the cervix in a manner indistinguishable from that seen during parturition. Prostaglandin E (PGE) can be both pro-inflammatory and anti-inflammatory, the former action probably occurs at the level of the blood vessel, whereas the latter is associated with the change in cytokine profile induced by PGE. This latter effect may contribute to pregnancy maintenance by maintaining a favourable cytokine profile in decidua. In contrast, the pro-inflammatory action of PGE may be involved in a synergistic action with chemokines such as IL-8 and play a role in parturition. In early pregnancy decidua, this pro-inflammatory action is likely to be controlled by progesterone-dependent prostaglandin dehydrogenase associated with the small blood vessels in decidua.

Animals↗

What knockout mice can tell us about parturition.

Many molecules, including steroid and peptide hormones, prostaglandins and cytokines, regulate the preparation, initiation and progression of parturition in mammals. Gene targeting studies show that, in the knockout mice of steroid 5alpha-reductase type 1 gene, prostaglandin F2alpha receptor gene and cytosolic phospholipase A2 gene, parturition was severely disturbed, although live offspring were delivered by Caesarean section. Relaxin gene-disrupted mice also showed protracted labour. However, most knockout mice in which the steroid hormone, prostaglandin, cytokine or peptide hormone (for example, oxytocin, corticotrophin releasing hormone and endothelin) endocrine-paracrine systems are disrupted are inadequate for analysis of the mechanism of parturition because they die before reaching reproductive age or are infertile, or because they reproduce normally. A conditional knockout strategy, for example, using the Cre-LoxP system, should be considered for investigating the biochemical background of parturition to overcome these problems.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

Changes in bone mineral density of lumbar vertebrae after parturition in African green monkeys (Cercopithecus aethiops).

We examined the effect of lactation on the maternal bone components in laboratory-bred African green monkeys. Bone mineral density (BMD) with bone mineral content (BMC), bone area and mean width of lumbar vertebrae (L3-L5) were measured by dual-energy X-ray absorptiometry (DXA). Measurements were conducted at two-week intervals from parturition up to 40 weeks after parturition. The BMC and BMD values gradually decreased during the lactation period and then gradually increased after weaning, but the BMC and BMD of the maternal lumbar vertebrae did not recover completely to the values at parturition even at 40 weeks after parturition.

Absorptiometry, Photon↗

[Pattern of pregnancy and parturition in Sprague-Dawley rats (author's transl)].

Several parameters on pregnancy and parturition of primiparous Sprague-Dawley rats were examined. Interval between placing with males and pregnancy averaged 7.4 +/- 1.1 days and 75% of rats became pregnant within 10 days after mating (Fig. 1). Presence of sperms in the smears showed much higher pregnancy ratio than the other two indices, vaginal plug and the last estrus (Table 1). Pregnancy period was mostly 23 days when the day of appearance of each copulation signs was designated as 1 day of pregnancy (Table 2) and all rats started parturition during light time of animal room (7:00 AM approximately 9:00 PM) on both 22 and 23 days of pregnancy (Fig. 2). Average time required for parturition was 105 +/- 10 minutes and mostly less than 2 hours (Fig. 3). There was no correlation between litter size (12.6 +/- 0.5 : Fig. 4) and the time required for parturition. The ratio of still-born pups was 1%.

Animals↗

Oestrogen, progesterone and corticosteroid concentrations in peripheral plasma of sows during pregnancy, parturition, lactation and after weaning.

Steroid hormone concentrations in plasma have been measured in blood samples taken from conscious sows with ear vein catheters. In late pregnancy, the plasma progesterone concentration ranged from 6 to 12 ng/ml and it decreased in all animals before the onset of parturition. Total unconjugated oestrogens increased to high values of up to about 3 ng/ml in late pregnancy and then declined after the onset of parturition. Oestrone was the predominant unconjugated oestrogen measured. Plasma corticosteroid (mainly cortisol) concentration was about 33 ng/ml and showed no consistent change at the time of parturition. During lactational anoestrum the plasma concentration of progesterone and total unconjugated oestrogens was very low, while that of corticosteroids was 21 ng/ml. When the piglets were weaned at 26-31 days, sows came into oestrus 4-12 days later, and this was preceded, or accompanied by, an increase in plasma oestrogens. In the luteal phase, plasma progesterone concentrations rose to 20-35 ng/ml. A sow whose piglets were removed at birth, showed signs of oestrus (vulval enlargement and a lordosis response), but a lack of receptivity to the boar associated with no detectable changes in the plasma oestrogen concentration; however, ovulation probably occurred since plasma progesterone values increased in a manner comparable to that found after the formation of normal corpora lutea in other sows. After a second non-receptive cycle, the sow was mated and became pregnant at the third post-weaning oestrus. At parturition the concentration of progesterone and total unconjugated oestrogens was greater in placental venous plasma than in maternal jugular plasma, which indicates placental synthesis of these hormones. A greater concentration of plasma corticosteroids in foetal blood than in placental venous or maternal jugular plasma suggests foetal synthesis in late pregnancy.

Adrenal Cortex Hormones↗