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Endocrine and Paracrine Regulation of Birth at Term and Preterm¹

Departments of Physiology (J.R.G.C., S.G.M., W.G., S.J.L.) and of Obstetrics and Gynaecology (J.R.G.C., S.G.M., S.J.L.), University of Toronto, Toronto, Ontario, Canada M55 1A8; Program in Development and Fetal Health (J.R.G.C., S.J.L.), Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5; MRC Group in Fetal and Neonatal Health and Development (J.R.G.C., S.J.L.); Department of Obstetrics and Gynaecology, and Cellular and Molecular Medicine (W.G.), University of Ottawa, Ottawa, Ontario, Canada K1H 8L6

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.