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Maternal progesterone and fetal cortisol responses to hypoxemia in pregnant sheep Wu, Li-Hua


The placenta is an important endocrine organ producing large amounts of steroid and protein hormones which are released into the maternal and fetal circulations. Moreover, it has a very high metabolic rate and consumes a significant proportion of the oxygen and glucose delivered to the uterus and its contents. However, while there have been many studies on the effects of hypoxemia on fetal cardiovascular, metabolic and endocrine functions, there are limited data on the effects of reduced oxygenation on placental endocrine activities. In the present study, we examined the effects of acute (2-h) moderate (maternal Pao₂ lowered by 27-35%, n=5) and severe (maternal Pao₂ lowered by 41-58%, n=4) hypoxemia on placental progesterone output into the maternal circulation in 7 chronically instrumented pregnant sheep (125 to 136 d). Hypoxemia was achieved by lowering maternal inspired O₂ concentration and the hypoxemia period was preceded and followed by 2 h pre-hypoxia and recovery periods, respectively. Control experiments (n=4), involving 6 h periods of normoxia were also carried out. Samples were taken simultaneously at predetermined time periods from maternal femoral arterial and uterine venous catheters for measurement of progesterone concentration. Blood flow to the uterine horn containing the operated fetus was measured continuously, and utero-placental progesterone output was calculated as the uterine venous - arterial difference in progesterone concentration times uterine blood flow. Blood samples were also collected from the fetal femoral artery and umbilical vein, and in these samples, as well as in the maternal samples, the following variables were measured: PO₂ , PCO₂ and pH, hemoglobin concentration, blood O₂ saturation and content, glucose and lactate concentrations and fetal plasma Cortisol level. The following variables were calculated from these data: uteroplacental oxygen delivery and consumption and glucose uptake and lactate flux. Maternal and fetal arterial pressure and heart rate were continuously monitored. In sheep carrying twin fetuses compared to those with a single fetus, the average progesterone concentrations of maternal arterial (6.53±0.19 versus 4.27±0.13 ng/ml) and uterine venous plasma (21.05±0.56 versus 17.82+1.17 ng/ml) were significantly higher and associated with significantly higher values of uterine blood flow (549.5±17.9 versus 339.6±6.2 ml/min) and progesterone output (8,156±426 versus 4,720±243 ng/min). In the moderate hypoxia experiments, maternal arterial P0₂ was lowered by 27- 35% (mean = 30.7±1.8%) or 38.9±4.7 mmHg. This resulted in a fall in fetal arterial oxygen tension by 19.7±2.4% or 4.1±0.5 mm Hg. This was associated with similar decreases in fetal blood O₂ saturation and content, and with a rise in lactate concentration and Cortisol level. There were no consistent changes in fetal PCO₂ or pH. Similar changes in the fetal variables were observed with severe hypoxia, when maternal P0₂ fell by 41- 58% (mean = 48.5±3.5%) or 59.4±6.6 mmHg, except that in this case the decrease in fetal P0₂ was greater (28.6±2.0% or 4.8±1.0 mmHg) and there was a significant decline in fetal arterial pH and larger increases in fetal lactate and Cortisol levels. Likely as a consequence of the acidemia, the fall in O₂ saturation (44.7±5.5%) and content (41.8±9.0 mM) was greater than with moderate hypoxemia. With both degrees of hypoxemia, there was a tendency for the umbilical veno-arterial lactate difference to increase during hypoxemia, suggesting increased utero-placental lactate production. Severe hypoxia was associated with an increase in maternal heart rate, but no change in arterial pressure, whereas neither variable was altered with moderate hypoxia. Severe hypoxia was associated with fetal hypertension and bradycardia, but these changes did not occur with moderate hypoxia. There were no changes in the maternal and fetal variables during the control, normoxia experiments except for a slight but significant decrease in fetal plasma Cortisol concentration. Uterine blood flow, O₂ delivery and O₂ consumption were not consistently changed during the moderate and severe hypoxia experiments, nor during the control, normoxia protocol. There were also no significant changes in maternal arterial and uterine venous progesterone concentrations. However, with moderate hypoxemia, the progesterone concentration in uterine venous blood increased in 4 of the 5 experiments, and the mean percentage increase was 16.2±7.3%. There was a similar trend for a rise in utero-placental progesterone output, which increased by 18.6±10.5%. However, neither change was statistically significant. Overall, the results indicate that acute hypoxemia results in significant alterations in fetal cardiovascular, metabolic and endocrine functions, with limited effects on the uteroplacental variables measured. Thus the placenta may be more resistant to reduced oxygenation than the fetus. The trend for an increase in utero-placental progesterone production with moderate hypoxia is similar to data in published reports. If such an increase does in fact occur, it may be due to the elevation in placental PGE₂ production that occurs with hypoxia, since PGE₂ has been shown to increase ovine placental progesterone synthesis in vitro. The lack of any evidence for a rise in progesterone production with severe hypoxia may reflect an inhibitory effect of severe decreases in maternal and/or fetal oxygenation on placental progesterone production. However further studies are necessary to confirm the results of the current and previous studies and in this regard the effects on placental progesterone output of other methods of inducing fetal hypoxemia, which have a greater impact on uterine O₂ delivery (e.g. maternal anemia, reduced uterine blood flow), would seem worthy of investigation.

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