We have examined factors concerned with the maintenance of uterine quiescence during pregnancy and the onset of uterine activity at term in an animal model, the sheep, and in primate species. We suggest that in both species the fetus exerts a critical role in the processes leading to birth, and that activation of the fetal hypothalamic-pituitary-adrenal axis is a central mechanism by which the fetal influence on gestation length is exerted. Increased cortisol output from the fetal adrenal gland is a common characteristic across animal species. In primates, there is, in addition, increased output of estrogen precursor from the adrenal in late gestation. The end result, however, in primates and in sheep is similar: an increase in estrogen production from the placenta and intrauterine tissues. We have revised the pathway by which endocrine events associated with parturition in the sheep come about and suggest that fetal cortisol directly affects placental PGHS expression. In human pregnancy we suggest that cortisol increases PGHS expression, activity, and PG output in human fetal membranes in a similar manner. Simultaneously, cortisol contributes to decreases in PG metabolism and to a feed-forward loop involving elevation of CRH production from intrauterine tissues. In human pregnancy, there is no systemic withdrawal of progesterone in late gestation. We have argued that high circulating progesterone concentrations are required to effect regionalization of uterine activity, with predominantly relaxation in the lower uterine segment, allowing contractions in the fundal region to precipitate delivery. This new information, arising from basic and clinical studies, should further the development of new methods of diagnosing the patient at risk of preterm labor, and the use of scientifically based strategies specifically for the management of this condition, which will improve the health of the newborn.

/pdf/endocrine-and-paracrine-regulation-of-birth-at-term-and-4igz1kdkru.pdf

Endocrine and paracrine regulation of birth at term and preterm

Parturition is the process of giving birth, and the molecular mechanisms involved are still to be elucidated. Among the various factors involved prostaglandins appear to have an important role. They are synthesized within the human fetal membranes (amnion and chorion) and decidua and act to ripen the cervix, change membrane structure and contract the myometrium. Prostaglandin concentrations increase in amniotic fluid prior to myometrial contractions, and the activity of prostaglandin H synthase (PGHS) increases in the chorion laeve and amnion at labour. This increase is due to increased expression of the PGHS-2 isoenzyme rather than the PGHS-1 isoenzyme. In animal pregnancy, there is also an increase in the expression of the PGHS-2 isoenzyme, and in both human and animal pregnancies this increase appears to occur in the fetal tissues rather than in the maternal tissues. Prostaglandin metabolism also plays an important role in altering prostaglandin output by the human fetal membranes. Prostaglandin dehydr...

The role of prostaglandins in human parturition

Epithelial and stromal cells were isolated from endometrium of cyclic heifers by enzymic dispersion. These cells exhibited specific morphological and functional properties. Epithelial cells appeared cuboidal or columnal and showed contact inhibition as they reached confluence. Stromal cells were fibroblast-like and enlarged at the time of confluence after which they overgrew in multiple layers. The presence of specific receptors for PGE-2 and beta-adrenergic catecholamines (isoproterenol) was estimated by activation of adenylate cyclase. Stromal cells had more adenylate cyclase activity (P less than 0.01) than did epithelial cells before (basal) and after stimulation with guanosine triphosphate (GTP) and PGE-2. However, epithelial cells were much more responsive to isoproterenol (P less than 0.01). Treatment of cultured cells with indomethacin to block PG synthesis increased the sensitivity and maximal response to PGE-2 in stromal (P less than 0.01) but not in epithelial (P greater than 0.1) cells. The latter result suggested autologous desensitization of the PGE-2 response resulting from synthesis of PGs in cultured cells. Both cell types synthesized PGs in culture: PGF-2 alpha was synthesized in greater quantity in epithelial than in stromal cells (P less than 0.05) while stromal cells synthesized more PGE-2 than did epithelial cells (P less than 0.001). Endometrial cells separated in this way should prove useful for study of their specific role in the processes of implantation and maternal recognition of pregnancy.

/pdf/specific-properties-of-epithelial-and-stromal-cells-from-the-411lzkl1jy.pdf

Specific properties of epithelial and stromal cells from the endometrium of cows

The discovery in 1910 (see Liggins, 1988, for historical review) of the dependence of continuing pregnancy in rodents on the corpus luteum and the subsequent isolation of progesterone seemed to provide a sound basis for the mechanism initiating parturition. The ‘progesterone withdrawal’ hypothesis gained widespread acceptance regardless of whether the maintenance of pregnancy was corpus luteum dependent or placenta dependent. Because the luteotrophic complex of hormones in rodents is of maternal origin, little reason existed to depart from the traditional view that the mechanism resided in the mother rather than the conceptus. However, the 1950s saw increasing awareness of the evidence that fetal genotype in farm animals and certain fetal malformations in both man and farm animals influence the duration of pregnancy. With the unequivocal demonstration in 1967 that hypophysectomy in fetal sheep abolishes the initiation of parturition, the pendulum swung decisively away from maternal control towards fetal control and the fetal endocrine system became the focus of attention of most investigators.

Initiation of parturition.

PGs are important regulators of reproductive processes At the time ofluteolysis in vivo, PGF2alpha is produced by endometrial cells, in response to oxytocin (OT) The mechanism by which OT induces the release of PGF2alpha remains to be defined We have used 13 different cultures of bovine epithelial endometrial cells to study the effect of OT on the regulation of PGF2alpha and to identify the possible involvement of cyclooxygenases (COXs) OT induced a dose-dependent increase of both inositol phosphates (IPs) and [Ca2+]i concentration in epithelial cells labeled with [3H]-myoinositol or loaded with fura-2 (using a fluorescent microscope imaging system), respectively OT induced a dose-dependent increase of both PGF2alpha production and COX-2 gene expression (as demonstrated by RT-PCR and Northern blots) PGF2alpha production was increased from 133 +/- 20 to 1668 +/- 225 ng/ml (P < 00001) On the other hand, COX-2/beta-actin mRNA gene expression (as determined by densitometric analysis) was increased 51 +/- 07-fold (P < 0001) with OT (10[-7] M) treatment, compared with control Addition of indomethacin (1 microM) and a specific COX-2 inhibitor (NS-398, 1 microM) blocked the OT-induced PGF2alpha production COX-1 and phospholipase A2 mRNA were expressed at steady-state levels, but no effect of OT was detected on their regulation Combined to OT, 10 microq/ml of recombinant ovine interferon-tau (roIFN-tau) was able to decrease significantly (P < 00001) the dose-dependent increase of PGF2alpha production Furthermore, partial bovine COX-1 (777 pb) and COX-2 (449 bp) cDNAs were cloned and sequenced An homology of 83% and 97% was found in relation with rat and sheep, for COX-1, respectively COX-2 was found to bear 84%, 86%, and 87% of homology in relation to rat, guinea pig, and human, respectively Collectively, these results demonstrate, for the first time, that COX-2 is involved in the mechanism by which OT regulates PGF2alpha production in the endometrium

Cellular mechanisms involved during oxytocin-induced prostaglandin F2alpha production in endometrial epithelial cells in vitro: role of cyclooxygenase-2.

The effects of gestational age on concentrations of prostaglandin E (PGE), PGF, 6-oxo-PGF, � (the hydrolysis product of PGI2) and thromboxane B2 (TxB2), measured by radioimmunoassay (RIA), in amniotic and allantoic fluids and in tissues collected from different areas of myometrium, endometrium, cotyledons, chorioallantois and amnion were examined in sheep. The output of prostanoids (PG) in vitro, from dispersed cells from cotyledons, chorioallantois and amnion collected from sheep at different gestational ages was also determined in an attempt to estimate basal prostanoid production by these tissues. For myometrium, analysis of variance indicated that prostanoid concentrations were significantly different in miduterine areas than elsewhere in the uterus at all gestational ages and that concentrations of TxB2, but not other prostanoids, were lower on Day 145 than at earlier stages of pregnancy. For cotyledons and chorioallantois, analysis of variance indicated significantly lower prostanoid concentrations on Days 50 and 100, and on Day 50 respectively, than in later stages of pregnancy. Concentrations of PGE, but not other prostanoids, were also significantly lower in amnion collected on Days 50 and 100 than in later stages of pregnancy. Similarly, prostanoid output in vitro from dispersed cells was significantly lower on Days 50 and 100 for cotyledons, and on Day 50 for chorioallantois and amnion than in later stages of pregnancy. For amnion, PGE was the major prostanoid produced, while for other tissues, outputs of 6-oxo-PGF1 a’ PGE and PGF were similar. In amniotic and allantoic fluids, 6-oxo-PGF, a was the major prostanoid found; concentrations of all prostanoids were significantly higher on Day 145 than at earlier stages of pregnancy. Concentrations of PGF and TxB2, but not other prostanoids, were significantly lower on Day 100 than at other gestational ages in these fluids. These results indicate that prostanoid production by fetal and maternal intrauterine tissues is, in general, lower on Day 50 than at the other times of pregnancy studied. An increase in tissue prostanoid concentrations, and in prostanoid output in vitro occurs during the last third of pregnancy. The highest concentrations of prostanoids were found in chorioallantois and cotyledons, and isolated cells from these tissues also produced the greatest amounts of prostanoids in vitro.

Gestational changes in prostanoid concentrations in intrauterine tissues and fetal fluids from pregnant sheep, and the relation to prostanoid output in vitro.

Concentrations of prostaglandin E (PGE), PGF, and 6-oxo-PGF1 alpha (the hydrolysis product of PGI2) were measured by RIA in different areas of myometrium, endometrium, cotyledons, amnion, and chorioallantoic membrane taken from chronically catheterized sheep. The animals were 130 days pregnant and had been treated for 70 h with continuous intrafetal infusions of either ACTH-(1-24) or saline. Maternal and fetal plasma samples were collected at 8-h intervals beginning 48 h before the start of infusion, and maternal plasma progesterone, estrone, and estradiol and fetal plasma cortisol concentrations were estimated by RIAs. As suggested by a significant fall in maternal plasma progesterone and rises in maternal plasma estrone and fetal plasma cortisol concentrations, sheep receiving intrafetal ACTH were in early labor at the time tissue samples were taken for PG determinations. For myometrium, analysis of variance indicated a significant effect of uterine area on PG concentrations. Concentrations of 6-oxo-PGF1 alpha were elevated toward the cervical end of the myometrium in ACTH-treated animals. PGF and PGE concentrations were higher at the tubal and cervical ends of the myometrium in both groups of animals. In the endometrium of treated animals, concentrations of PGE, but not PGF or 6-oxo-PGF1 alpha, were elevated significantly. For cotyledons and chorioallantois, concentrations of PGF and 6-oxo-PGF1 alpha, but not PGE, were elevated significantly in ACTH-treated animals. PG concentrations were not elevated in amnion taken from ACTH-treated animals. For both groups, the areas of highest PG concentrations were cotyledons and chorioallantois, suggesting that these may be major sites of synthesis.

Uterine Prostaglandin Concentrations in Sheep during Late Pregnancy and Adrenocorticotropin-Induced Labor

To assess the importance of endogenous prostaglandins in parturition, we have examined the effects of indomethacin on maternal steroid concentrations and on the frequency and maximum amplitude of uterine contractions during delivery induced by administering adrenocorticotrophic hormone (ACTH) to fetal sheep. Uterine contractions were evaluated by measuring amniotic fluid pressure in chronically catheterized sheep, 130-days pregnant treated for 70 h with continuous infusions of intrafetal ACTH1–24, and with indomethacin or vehicle into the maternal femoral vein. Maternal plasma progesterone and estrone concentrations and fetal plasma Cortisol concentrations were estimated by radioimmunoassays (RIAs). Concentrations of prostaglandin E (PGE), PGF, and 6-oxoPGF1α (the hydrolysis product of PGI2) were measured by RIAs in myometrium, endometrium, cotyledons, amnion, and chorioallantois at different locations of the uterus. Labor was initiated after 70 h intrafetal ACTH treatment as indicated by a significant fa...

The effects of indomethacin on uterine activity and prostaglandin (PG) concentrations during labor induced by administering ACTH to fetal sheep.

The role and regulation of prostaglandins in late pregnancy and parturition in sheep

Uterine prostaglandin concentrations following fetal death in sheep

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