Placental synthesis of estrogens at parturition and during placental retention in the cow

Nine cows were submitted to lutectomy at 250 or 270 d of pregnancy and catheters were implanted in the jugular, carotid, uterine artery and uterine vein to determine endocrine changes following lutectomy and throughout parturition. Blood samples were collected at 8-h intervals and assayed for estrogens. Fetal and maternal placental tissues were also collected at parturition and 3 d postpartum for incubation studies on estrogen synthesis. Based on plasma concentrations, the uterus is able to secrete considerable quantities of unconjugated and conjugated estrone (E1) and estradiol 17 μ (E2α) at both 250 and 270 d of gestation. In vitro conversion of androstendione to total estrogens averaged 32.4% and 16.8% for fetal and maternal tissues at parturition, respectively. Incubation of placental tissues collected from animals with placental retention on Day 3 postpartum resulted in conversion of 3.2 and 4.6% of androstendione by fetal and maternal tissues, respectively. One cow which retained the placenta was sampled until 3 d postpartum and assay of the plasma estrogen content indicated that there was always a higher concentration of estrogen in the uterine vein than in the uterine artery, supporting the in vitro incubation data.     

Progesterone and the initiation of parturition in the goat

The corpora lutea were surgically removed from 6 goats between 134 and 136 days of pregnancy and progesterone was administered daily. Pregnancy was prolonged past normal term in 4 goats receiving 25 mgs. of progesterone daily as a split dose. However, eventual delivery following progesterone withdrawal was abnormal and foetal mortality high.The progesterone therapy regime maintained maternal jugular plasma concentrations of progesterone in excess of 3 ng/ml. In normal untreated goats, maternal plasma concentrations of progesterone declined over the last 6 days of gestation. In treated goats, plasma concentrations of progesterone fell only after the cessation of therapy. Maternal plasma concentrations of estrogen rose within 24 hours of parturition in normal untreated goats. In the 4 goats in which pregnancy was prolonged, by progesterone administration, maternal plasma concentrations of estrogen were elevated for several days in the period before eventual foetal delivery.     

Effects of periconceptional undernutrition on the initiation of parturition in sheep

In sheep, parturition is initiated by increased fetal hypothalamic-pituitary-adrenal axis (HPAA) activity leading to PGE(2) and PGF(2alpha) production and a rise in the 17beta-estradiol-progesterone (E(2)/P(4)) ratio. Uteroplacental PG production can also increase fetal HPAA activity. Periconceptional maternal undernutrition accelerates fetal HPAA maturation resulting in preterm labor. We determined whether preterm labor was preceded by an increase in PG concentrations and E(2)/P(4) ratio and whether these increases preceded or followed the corresponding rise in cortisol concentrations. Singleton-bearing ewes were nourished ad libitum (N, n = 9) or undernourished (UN, n = 10) to reduce maternal weight by 15% from -61 days (d) to +30 d after mating with ad libitum intake thereafter. Paired maternal and fetal blood samples were collected from 126 d until delivery. Half the UN group delivered prematurely (>2 SD below mean gestation for the flock). PG and cortisol concentrations and E(2)/P(4) ratio increased before delivery in the same way in both groups. However, the increases occurred 7-10 d earlier in UN than in N animals. In both UN and N fetuses cortisol concentrations rose before fetal and maternal PG concentrations and maternal E(2)/P(4) ratio. Periconceptional maternal undernutrition induces preterm delivery in sheep by advancing the expected prepartum rise in cortisol and PG concentrations and E(2)/P(4) ratio. The rise in fetal cortisol concentration precedes the rise in fetal and maternal PG concentrations and maternal E(2)/P(4) ratio, suggesting that the underlying mechanism is likely to be acceleration of fetal HPAA maturation, resulting in initiation of the normal process of parturition.     

Inhibition of progesterone secretion by a 3 beta-hydroxysteroid dehydrogenase inhibitor in late pregnant sheep

The role of progesterone in the initiation of parturition in the sheep is unclear. Whether a decrease in plasma progesterone is the essential prerequisite for the initiation of parturition or whether other factors also maintain uterine quiescence until delivery is not known. The effect of withdrawal of progesterone on the initiation of parturition has been investigated by intravenous administration of trilostane, a 3 beta-hydroxysteroid dehydrogenase delta 5-4 isomerase inhibitor, to late pregnant sheep. Twenty-five or 100 mg trilostane caused a precipitous decrease in plasma progesterone to about 30% of preinjection levels. Progesterone remained depressed for up to 7 days after treatment. 13,14-Dihydro-15-keto-prostaglandin F2 alpha (PGFM) became elevated between 7 and 36 h after trilostane injection but gradually returned to preinjection levels during the subsequent 36 h, at a time when plasma progesterone was still depressed. Four of 11 animals treated with 100 or 200 mg trilostane aborted prematurely at a time when plasma PGFM was maximal and plasma progesterone minimal. There were no consistent changes in plasma estradiol-17 beta or ovine placental lactogen concentrations after treatment with trilostane. It is suggested that a decrease in plasma progesterone will cause a transient increase in plasma PGFM concentrations which can lead to the premature initiation of parturition. In some instances the myometrium does not appear to respond to the elevated PGFM concentrations even when the estrogen:progesterone ratio is elevated by a decrease in plasma progesterone.     

Altered fetal pituitary-adrenal function in the ovine fetus treated with RU486 and meloxicam, an inhibitor of prostaglandin synthase-II

Term and preterm labor are associated with increased fetal hypothalamic-pituitary-adrenal (HPA) activation and synthesis of prostaglandins (PGs) generated through the increased expression of prostaglandin H synthase-II (PGHS-II) in the placenta. Inhibition of PGHS-II has been advocated as a means of producing uterine tocolysis, but the effects of such treatment on fetal endocrine functions have not been thoroughly examined. Because PGE(2) is known to activate the fetal HPA axis, we hypothesized that administration of meloxicam, a PGHS-II inhibitor, to sheep in induced labor would suppress fetal HPA function. Chronically catheterized pregnant ewes were treated with RU486, a progesterone receptor antagonist, to produce active labor, and then treated with either high-maintenance-dose meloxicam, graded-maintenance-dose meloxicam, or a saline infusion. Maternal uterine contraction frequency increased 24 h after the RU486 injection and the animals were in active labor by 48 +/- 4 h. RU486 injection led to increased concentrations of PGE(2), ACTH, and cortisol in the fetal circulation, and increased concentrations of 13,14 dihydro 15-ketoprostaglandin F(2 alpha) (PGFM) in the maternal circulation. Uterine activity was inhibited within 12 h of beginning meloxicam infusion at both infusion regimes. During meloxicam infusion there were significant decreases in fetal plasma PGE(2), ACTH, and cortisol concentrations, and PGFM concentrations in maternal plasma. In control animals, frequency of uterine contractions, maternal plasma PGFM, fetal plasma PGE(2), ACTH, and cortisol concentrations increased after RU486 administration, and continued to rise during saline infusion until delivery occurred. We conclude that RU486-provoked labor in sheep is associated with activation of fetal HPA function, and that this is attenuated during meloxicam treatment to a level considered compatible with pregnancy maintenance.     

Influence of the fetal pituitary-adrenal axis on fetal and maternal progesterone and unconjugated oestrogen concentrations in the pig

Fetal and maternal plasma progesterone and unconjugated oestrone and oestradiol-17 beta concentrations were measured in intact pig fetuses and those in which the pituitary had been destroyed. Progesterone concentrations were significantly higher (P less than 0.05) and oestrogen concentrations significantly lower (P less than 0.01) in hypophysectomized fetuses than in intact fetuses. When fetuses in one uterine horn only were hypophysectomized, oestrogen concentrations in the uterine vein draining this horn were lower than those from the contralateral vein. The results indicate that both fetal and maternal oestrogen concentrations are influenced by the fetal pituitary. When dexamethasone was infused (at 27 micrograms/h for 96 h) into 5 chronically-catheterized hypophysectomized fetuses no changes in peripheral fetal progesterone or oestrone were observed.     

Pregnancy management in the bitch

Pregnancy management to optimize maternal and neonatal health begins with breeding management and the selection of normal, healthy brood stock in ideal body condition. After breeding, a commercial diet appropriate for reproduction and lactation should be fed. Typically these contain 29-32% protein of animal source, at least 18% fat, 20-30% carbohydrate, and essential vitamins, minerals and fatty acids. Pregnancy is confirmed approximately 25 d after breeding. A "maternity ward" and whelping box should be provided. Steady increases in caloric intake and body weight are expected as pregnancy progresses. Weight loss should not occur. Throughout pregnancy, changes in the bitch's attitude, activity, appetite, body weight, and physical findings should be monitored by the owner. If appetite and body weight do not continue to increase, or if any signs of illness develop, maternal health should be assessed with a complete physical examination and a CBC, biochemical profile, and free-catch urinalysis. Fetal health should be assessed with ultrasonography. Maternal or fetal abnormalities will put the pregnancy at risk. Impending parturition and the progress of labor and delivery can be monitored by assessing rectal temperature, serum concentrations of progesterone, and/or uterine and fetal monitors. This article reviews the physiology of canine pregnancy and parturition, and typical schemes used to manage normal canine pregnancy to optimize maternal and puppy health.     

Plasma Levels of Progesterone and Oestradiol-17 β in Reindeer (Rangifer Tarandus Tarandus) During Pregnancy

The plasma concentrations of progesterone and oestradiol-17p during pregnancy and the first 20 days after parturition were estimated in reindeer. The concentration of progesterone in the period 75–25 days prior to parturition was significantly higher than in the period 200– 75 days prior to parturition (P < 0.001). During the last 25 days before parturition the concentration decreased significantly. The concentration of oestradiol-17β was in most cases below 70 pg/ml until 50 days prior to parturition. During the last 25 days of pregnancy there was a significant increase in oestradiol-17β and the ratio progesterone/ oestradiol-17β was markedly lower than in the period 75–25 days before calving.     

Fetal responses to maternal and intra-amniotic lipopolysaccharide administration in sheep

A link between intrauterine infection and premature labor is widely accepted, yet the fetal inflammatory responses to such infections are not well understood. Our aim was to use a sheep model in which an inflammatory state was induced by lipopolysaccharide (LPS) administration during pregnancy to the maternal systemic, intra-amniotic or extra-amniotic compartments. Fetal and maternal blood gases and uterine electromyographic activity along with fetal and maternal circulating concentrations of prostaglandins PGE2 and PGFM, cortisol, and interleukin-6 were determined. Maternal systemic LPS treatment resulted in mild maternal hypoxemia, a rise in temperature, greater fetal hypoxemia, and a marked rise in fetal cortisol and PGE2 concentrations that persisted for 48 h. Intra-amniotic administration of LPS at doses higher than those used systemically caused an increase in fetal cortisol and PGE2 concentrations as well as a rise in uterine activity, but these were lesser in magnitude. Extra-amniotic LPS administration caused no overt fetal or maternal inflammatory responses. We conclude that maternal LPS treatment markedly elevated fetal cortisol and PGE2 concentrations. This may be a potential protective mechanism that aids the fetus in the event of premature delivery. The attenuated fetal response to intra-amniotic LPS treatment, despite the much higher dose used, may support a role for the amniotic fluid in protecting the fetus from endotoxin exposure during pregnancy.     

Effects on maternal and fetal steroid concentrations of induction of parturition in the sheep by inhibition of 3 beta-hydroxysteroid dehydrogenase

Changes in circulating steroid hormones, the incidence of myometrial contractions, and the onset of labour were all monitored after administration of the 3 beta-hydroxysteroid dehydrogenase inhibitor, epostane, to chronically catheterized ewes and fetuses near term. In all animals the drug induced delivery 33-36 h after injection or infusion into the ewe with the birth of live healthy lambs which showed normal subsequent development. Epostane induced immediate, permanent falls in both maternal and fetal plasma progesterone concentrations, accompanied by increased PGF metabolite concentrations in the uterine vein beginning 15 min after treatment. Of the other hormonal changes observed, the most striking was the pronounced drop in both maternal and fetal plasma cortisol. In the fetus this fall was followed by increasing concentrations of circulating ACTH which eventually restored the cortisol levels. By 12-24 h after epostane a substantial overshoot had occurred and at 27-30 h the fetal plasma cortisol concentrations were as high as those seen during normal parturition at term. No significant changes in maternal plasma oestradiol-17 beta could be detected after epostane treatment or during labour. The incidence of slow myometrial contractions increased significantly during the second 3-h period after epostane, although their duration did not change. Contraction patterns typical of first stage labour were seen from 20 to 24 h. These results show that epostane may be used as a safe, predictable inducing agent in sheep if given 6-10 days before term; the lambs showed no signs of prematurity despite their lowered plasma cortisol concentrations which persisted for some hours before labour was induced.     

Pregnancy management in the bitch

Pregnancy management to optimize maternal and neonatal health begins with breeding management and the selection of normal, healthy brood stock in ideal body condition. After breeding, a commercial diet appropriate for reproduction and lactation should be fed. Typically these contain 29–32% protein of animal source, at least 18% fat, 20–30% carbohydrate, and essential vitamins, minerals and fatty acids. Pregnancy is confirmed approximately 25 d after breeding. A “maternity ward” and whelping box should be provided. Steady increases in caloric intake and body weight are expected as pregnancy progresses. Weight loss should not occur. Throughout pregnancy, changes in the bitch’s attitude, activity, appetite, body weight, and physical findings should be monitored by the owner. If appetite and body weight do not continue to increase, or if any signs of illness develop, maternal health should be assessed with a complete physical examination and a CBC, biochemical profile, and free-catch urinalysis. Fetal health should be assessed with ultrasonography. Maternal or fetal abnormalities will put the pregnancy at risk. Impending parturition and the progress of labor and delivery can be monitored by assessing rectal temperature, serum concentrations of progesterone, and/or uterine and fetal monitors. This article reviews the physiology of canine pregnancy and parturition, and typical schemes used to manage normal canine pregnancy to optimize maternal and puppy health.     

Induction of parturition by cortisol: effects on negative feedback sensitivity and plasma CRF.

In fetal sheep, plasma concentrations of both adrenocorticotropic hormone (ACTH) and cortisol increase at the end of gestation. The increase in fetal plasma cortisol concentration induces placental 17 alpha-hydroxylase and 17, 20 lyase activities and therefore stimulates the placenta to secrete relatively more estrogen and relatively less progesterone. The resultant increase in the estrogen-to-progesterone ratio is thought to increase uterine contractility and initiate labour. We had previously demonstrated that the efficacy of cortisol-induced suppression of ACTH secretion at the end of gestation was reduced. We hypothesized that cortisol-induced stimulation of placental steroidogenesis promoted the secretion of a steroid hormone which reduced negative feedback efficacy, and therefore allowed both ACTH and cortisol secretion to increase simultaneously. Others had proposed that cortisol stimulates the placental secretion of corticotrophin releasing factor, which might also stimulate fetal ACTH secretion. This study was designed to test the hypotheses that cortisol reduces its own feedback efficacy or stimulates CRF secretion. Five pregnant ewes with twin pregnancies were studied after chronic catheterization. One fetus was subjected to infusion of hydrocortisone sodium succinate (10 micrograms/min, iv) and the other to infusion of saline. After 5 and 53 h of infusion, each fetus was subjected to a period of hypotension produced by infusion of sodium nitroprusside. The infusion of hydrocortisone sodium succinate decreased plasma progesterone concentrations in the fetal circulation into which the steroid was infused, and in the maternal circulation. Fetal plasma CRF concentrations were increased on the third day of infusion, the day in which the fetuses went into labour.(ABSTRACT TRUNCATED AT 250 WORDS)     

Thromboxane B-2 in the plasma and amniotic fluid of late pregnant and periparturient sheep.

The concentration of thromboxane (TX) B-2 was similar in plasma from all sources but was significantly greater (P less than 0.01) in amniotic fluid. Fetal hypophysectomy was without effect on maternal or fetal levels of TXB-2 (P greater than 0.1). Neither normal parturition at term nor prematurely induced delivery was associated with any significant trend in TXB-2 levels. During late pregnancy (105--145 days of gestation) the concentrations of TXB-2 and 13, 14-dihydro-15-keto-prostaglandin F (PGFM) in maternal and fetal plasma were significantly correlated (P less than 0.001). There was, however, no correlation between TXB-2 and PGFM levels in samples taken during the 36 h before delivery. These data suggest that thromboxanes play little part in the mechanism of parturition in sheep.     

Clinical, biological and hormonal study of mid-pregnancy termination in cats with aglepristone

In order to evaluate the efficacy, the safety and the variation in plasma concentrations of estrogens, progesterone, PGFM, oxytocin, cortisol and prolactin after mid-pregnancy termination induced by aglepristone, 61 pregnant queens (33.3 + 4.2 days), were injected subcutaneously with 15 [corrected] mg/kg aglepristone, (Alizine) [corrected] repeated once 24 h later. Five queens served as control and received a placebo. The efficacy of aglepristone was 88.5% and termination of pregnancy was achieved in 50% of the queens within 3 days. Brief periods of depression and anorexia were noted in 9.3% of the queens before fetal expulsion (these symptoms were attributed to the phenomenon of fetal expulsions). Not one of the queens that aborted developed uterine disease. There were no changes in plasma concentrations of estrogen, prostaglandin, prolactin or oxytocin following aglepristone administration. However, there were significant increases in plasma concentrations of progesterone and cortisol 60 and 30 h, respectively, after aglepristone administration. Termination of pregnancy occurred with high plasma progesterone concentrations. Fetal expulsion was characterised by an increase in estrogen, PGFM and oxytocin concentrations, whereas prolactin and cortisol levels remained at a basal level.     

Spontaneous uterine activity and plasma progesterone and oestrogens in the ewe with live and stillborn lambs

Peripheral plasma progesterone and oestrogen concentrations were measured during late pregnancy and the parturient period in 12 ewes producing live lambs and three others producing stillborn lambs. Progesterone values started declining by 10 days before lambing but at minus 24 hours were still 6.1 +/- 3 ng/ml in the ewes bearing live lambs; during the last 24 hours progesterone was significantly lower in the ewes producing stillborn lambs. Oestrogens reached a maximum level of 550 +/- 280 pg/ml at the time of delivery and declined rapidly to basal values shortly after lambing. Oestrogens did not rise at lambing in the ewes producing stillborn lambs. In seven of the 12 ewes bearing live lambs, uterine activity, as determined by intrauterine pressure changes, was recorded throughout parturition and compared with the plasma values for progesterone and oestrogens. It was found that there was a highly significant positive correlation between uterine activity and plasma oestrogen concentrations, and a highly significant negative correlation between uterine activty and both plasma progesterone concentrations and the progesterone: oestrogen ratio.     

Peripartal changes in plasma progesterone and 15-keto-13,14-dihydro-prostaglandin F2α concentrations in Holstein cows with or without retained foetal membranes

Peripheral blood plasma concentrations of progesterone and the main metabolite of prostaglandin F_2α, (15-keto-13,14-dihydro-PGF_2α) PGFM, were determined in 10 Holstein cows with retained foetal membranes (RFM) and 12 Holstein cows without RFM (NRFM) during the peripartal period. The rate of uterine involution in the postpartum cows was monitored.There was no difference in the rate of uterine involution between cows with or without RFM. Cyclical ovarian activity was resumed within a month after parturition in both group. Increases in the mean peripheral plasma PGFM concentrations were evident in the RFM cows 6 days before parturition, compared to 48 h before parturition in the NRFM cows. A gradual decline in PGFM to prepartum concentrations occurred in both groups by Day 12 after parturition, although in the RFM cows, PGFM concentrations remained high until the placenta was shed.In both groups, the mean peripheral plasma concentrations of progesterone showed a marked decline beginning 48 h before partusition. The mean plasma progesterone concentrations were less than 1 ng/ml during the immediate postpartum period.     

Progesterone Receptor Expression Declines in the Guinea Pig Uterus during Functional Progesterone Withdrawal and in Response to Prostaglandins

Progesterone withdrawal is essential for parturition, but the mechanism of this pivotal hormonal change is unclear in women and other mammals that give birth without a pre-labor drop in maternal progesterone levels. One possibility suggested by uterine tissue analyses and cell culture models is that progesterone receptor levels change at term decreasing the progesterone responsiveness of the myometrium, which causes progesterone withdrawal at the functional level and results in estrogen dominance enhancing uterine contractility. In this investigation we have explored whether receptor mediated functional progesterone withdrawal occurs during late pregnancy and labor in vivo. We have also determined whether prostaglandins that induce labor cause functional progesterone withdrawal by altering myometrial progesterone receptor expression. Pregnant guinea pigs were used, since this animal loses progesterone responsiveness at term and gives birth in the presence of high maternal progesterone level similarly to primates. We found that progesterone receptor mRNA and protein A and B expression decreased in the guinea pig uterus during the last third of gestation and in labor. Prostaglandin administration reduced while prostaglandin synthesis inhibitor treatment increased progesterone receptor A protein abundance. Estrogen receptor-1 protein levels remained unchanged during late gestation, in labor and after prostaglandin or prostaglandin synthesis inhibitor administration. Steroid receptor levels were higher in the non-pregnant than in the pregnant uterine horns. We conclude that the decreasing expression of both progesterone receptors A and B is a physiological mechanism of functional progesterone withdrawal in the guinea pig during late pregnancy and in labor. Further, prostaglandins administered exogenously or produced endogenously stimulate labor in part by suppressing uterine progesterone receptor A expression, which may cause functional progesterone withdrawal, promote estrogen dominance and foster myometrial contractions.     

Hormonal concentrations in bitches with primary uterine inertia

Normal labor is accompanied by sequential changes in blood concentrations of prostaglandin F2α (measured as 15-ketodihydro-PGF2α = PGFM), progesterone, estradiol, oxytocin, vasopressin, and of elevated cortisol levels. The aim of this study was to investigate hormone concentrations in dogs diagnosed with primary uterine inertia before and during treatment by cesarian section. The hypothesis was the dogs would have abnormally low plasma concentrations in one or several of the hormones involved in parturition. The study comprised seven bitches with total primary uterine inertia (dystocia group) treated with cesarian section and six healthy bitches (control group) subjected to planned cesarean section. Blood samples were taken before anesthesia, before surgery started, on delivery of the first puppy and on delivery of the last puppy. The progesterone:PGFM ratio in plasma was higher in the dystocia group than in the control group, but the serum estradiol concentration did not differ between groups. The plasma concentrations of oxytocin and vasopressin increased in both groups when the first puppies were delivered, but both hormones were more elevated in the control group than in the dystocia group on delivery of the last puppies. The plasma cortisol concentration increased to the same level in both groups. In conclusion, the ratio between progesterone and PGFM was higher and the oxytocin and vasopressin concentrations lower in the dystocia dogs than in the control dogs. The findings indicate that these hormones are involved in the pathophysiology of total primary uterine inertia in bitches.     

Induction of labour in sheep by inhibition of 3-beta hydroxysteroid dehydrogenase: role of the fetal adrenal.

In sheep parturition may be induced within 33 h in late gestation by inhibiting progesterone production with the 3 beta hydroxysteroid dehydrogenase inhibitor Epostane. Its effect has now been investigated in ewes carrying adrenalectomised (n = 5), hypophysectomised (n = 4) or intact (n = 5) fetuses to determine the role of the fetal adrenal during this type of maternally-induced delivery. Epostane was infused i.v. (1.5 mg/kg) into each group of ewes at 137-156 days gestation. Fetus and mother were sampled from the time of administration until delivery. Measurements of plasma ACTH, cortisol, progesterone and PGF2 alpha metabolite (PGFM) were made and intrauterine pressure was monitored. Epostane induced delivery significantly later in the adrenalectomised (44 h) and hypophysectomised (52 h) animals compared with the controls (33 h). The drop in maternal plasma progesterone was similar in all 3 groups, but the subsequent increases in arterial and uterine venous PGFM were smaller in the adrenalectomised and hypophysectomised ewes than in the controls. The large escalation in fetal plasma cortisol before birth in controls was absent in adrenalectomised and hypophysectomised fetuses. The slight rises in plasma cortisol observed in the latter from about 24 h after Epostane, were related to the concomitant increases in maternal plasma levels (r = 0.76, P less than 0.01). No fetuses became hypoxic or acidotic during the period of induction despite the prolonged labour of hypophysectomised and adrenalectomised fetuses.(ABSTRACT TRUNCATED AT 250 WORDS)