Endocrine and Paracrine Regulation of Birth at Term and Preterm*

Abstract

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.

Prostaglandin F2α regulates the expression of uterine activation proteins via multiple signalling pathways

“…Such changes are associated with the expression of a group of proteins known as the uterine activation proteins (UAPs) which includes (GJA1) connexin 43 (CX43), prostaglandin endoperoxide synthase 2 (PTGS2), ion channels and the receptors of uterotonic agonists such as oxytocin receptor (OTR) and prostaglandin F2a (PGF2A) receptor (PTGFR) (Fuchs et al 1995, Challis et al 2000, Kamel 2010). Thus, understanding the mechanisms responsible for controlling the expression of these proteins during pregnancy would gain deep insights into the mechanisms underlying the onset of human parturition.…”

“…PGs, which are produced within the intrauterine tissues of pregnancy, play important roles in all the physiological processes of parturition, but the most studied is myometrial contraction (Caldwell et al 1973, Challis et al 2000, Olson 2003). Elevated uterine PGs or enhanced sensitivity of the myometrium to PGs leads to contractions and labour (Romero et al 1996, Challis et al 2000.…”

“…Elevated uterine PGs or enhanced sensitivity of the myometrium to PGs leads to contractions and labour (Romero et al 1996, Challis et al 2000. Among the family of PGs, PGF2A increases the intracellular calcium concentration by stimulating the release of stored calcium, which produces a phasic contraction that permits blood flow to the foetus between contractions and optimises the ability of the uterus to expel the foetus (Luckas et al 1999).…”

Surfactant protein secreted by the maturing mouse fetal lung acts as a hormone that signals the initiation of parturition

“…In mammalian pregnancy, uterine quiescence is maintained by elevated circulating levels of progesterone (P 4 ) (1) whereas parturition is associated with a decline in maternal levels of circulating P 4 (2). However, in humans, levels of circulating P 4 and of uterine progesterone receptor (PR) remain elevated throughout pregnancy and into labor (1). Nonetheless, a critical role for functional inactivation of PR in the initiation of labor in humans is supported by the finding that treatment of pregnant women with RU486, a PR antagonist, increases uterine contractility and initiates labor (3).…”

Dydrogesterone has no effect on uterine fibroids when used to prevent miscarriage in pregnant women with uterine fibroids

“…However, the mechanism by which progesterone prevents premature birth or prolongs gestation is unknown. The conventional belief is that progesterone prevents miscarriage via the inhibition of preterm contractions of uterine muscle fibres or via the inhibition of the expression of factors involved in uterine contractions in the myometrium, such as prostaglandin, oxytocin receptor, and gap protein [18]. Increasingly, researchers believe that progesterone exerts both immunomodulatory and anti--inflammatory effects [19].…”