Prostaglandin dehydrogenase and the initiation of labor

Abstract

In summary, these studies have suggested that prostaglandin dehydrogenase may have a central role to play in the mechanisms which determine biologically active prostaglandin concentrations within human fetal membranes and placenta at the time of labor, at term or preterm. Moreover, our studies indicate that the regulation of PGDH may by multifactorial (figure 3). In certain regions of the membranes, we suggest that PGDH expression may be influenced by levels of anti-inflammatory and pro-inflammatory cytokines. In other regions of the membranes, we suggest that PGDH may be regulated at a transcriptional level by competing activities of progesterone and cortisol. The action of progesterone could be effected through systemically-derived steroid, or by locally synthesized steroid, acting in a paracrine and/or autocrine fashion. The effects of cortisol in placenta must be due to glucocorticoid derived from the maternal or fetal compartment, since the placenta lacks the hydroxylases required for endogenous cortisol production. However, metabolism of cortisol by 11 beta-HSD-2 reduces the potency of this glucocorticoid in placental tissue. In chorion however, cortisol may be formed locally, from cortisone, in addition to its being derived from the maternal circulation and/or from the amniotic fluid. Our current studies do not allow us to delineate whether the effects of progesterone and cortisol on PGDH are exerted through the glucocorticoid receptor (GR) or progesterone receptor (PR) or both. It is possible that through pregnancy, PGDH activity is maintained by progesterone acting either through low levels of PR in membranes, or, more likely, acting through GR. At term, elevated levels of cortisol compete with and displace progesterone from GR, resulting in inhibition of PGDH transcription and activity. In this way, local withdrawal of progesterone action would be effected within human intrauterine tissues, without requiring changes in systemic, circulating progesterone concentrations. Since glucocorticoids appear also to increase expression of prostaglandin synthesizing enzymes within the amnion and chorion, directly by upregulating PGHS-2, or indirectly through the intermediary action of a paracrine effector such as CRH, their role in coordinating processes of parturition remains central. Further understanding of the regulation of PGDH may be of therapeutic importance. For example, it is possible that PGDH activity in lower segment chorion may be reduced in those patients with premature cervical softening, or may be particularly high in those patients with an unfavorable cervix, presenting with a low Bishop score and poor progression at the time of labor. If the enzyme in this region crucially determines the passage and availability of biologically active prostaglandins from amnion and chorion to underlying cervix, then pharmacologic manipulation of PGDH activity may effectively regulate PG transfer in these clinical conditions. Glucocorticoids appear to have a central role in promoting production of agents that are u...

Course of placental 11beta-hydroxysteroid dehydrogenase type 2 and 15-hydroxyprostaglandin dehydrogenase mRNA expression during human gestation

“…In our opinion, this supports the hypothesis that increased oxidation of cortisol to inactive cortisone allows PGDH activity to increase with advancing gestation. Increasing PGDH activity provides an increasing capacity for prostaglandin metabolism to decrease myometrial contractility until term (25).…”

Prostaglandin dehydrogenase is a target for successful induction of cervical ripening

“…Increases in cervical PGE 2 are prevented not only by low levels of COX-2 but also by high levels of the enzyme 15-prostaglandin dehydrogenase (15-PGDH) that inactivates PGE 2 by converting it to inactive 15-keto-PGE 2 (4)(5)(6). Hence, tissue levels of PGE 2 are regulated by the relative abundance of COX-2 and 15-PGDH enzymes.…”

Hormones and Calcium: Mechanisms Controlling Uterine Smooth Muscle Contractile Activity

“…The regulation of the expression of signalling molecules themselves is critical to the initiation of labour (Challis & Lye, 1994;Challis et al 1999), but that subject is beyond the scope of this discussion. While there are species-specific differences in relative importance and timing, in general, the components of the signalling pathways favouring contraction and parturition are enhanced in myometrium late in pregnancy or in labour (Challis & Lye, 1994;Fuchs, 1995;Challis et al 1999).…”

“…While there are species-specific differences in relative importance and timing, in general, the components of the signalling pathways favouring contraction and parturition are enhanced in myometrium late in pregnancy or in labour (Challis & Lye, 1994;Fuchs, 1995;Challis et al 1999). FP receptor RNA in pregnant human myometrium is low relative to non-pregnant myometrium (Matsumoto et al 1997) but increases in a number of species in labour (Brodt-Eppley & Myatt, 1998Ma et al 1999).…”