Role of Aldo–Keto Reductase Enzymes in Mediating the Timing of Parturition

Michael C Byrns

doi:10.3389/fphar.2011.00092

Abstract

A better understanding of the mechanisms underlying parturition would provide an important step toward improving therapies for the prevention of preterm labor. Aldo–keto reductases (AKR) from the 1D, 1C, and 1B subfamilies likely contribute to determining the timing of parturition through metabolism of progesterone and prostaglandins. Placental AKR1D1 (human 5β reductase) likely contributes to the maintenance of pregnancy through the formation of 5β-dihydroprogesterone (DHP). AKR1C1, AKR1C2, and AKR1C3 catalyze the 20-ketosteroid and 3-ketosteroid reduction of progestins. They could therefore eliminate tocolytic progestins at term. Activation of the F prostanoid receptor by its ligands also plays a critical role in initiation of labor. AKR1C3 and AKR1B1 have prostaglandin (PG) F synthase activities that likely contribute to the initiation of labor. AKR1C3 converts PGH2 to PGF2α and PGD2 to 9α,11β-PGF2. AKR1B1 also reduces PGH2 to PGF2α, but does not form 9α,11β-PGF2. Consistent with the potential role for AKR1C3 in the initiation of parturition, indomethacin, which is a potent and isoform selective inhibitor of AKR1C3, has long been used for tocolysis.

Highlights

Preterm birth is the principle cause of neonatal morbidity and mortality in the developed world
Placental tissues obtained from pregnancies at term reduce progesterone to 20α-hydroxyprogesterone at five times the rate of placentas from the first trimester and there is a further increase in activity with the onset of labor (Milewich et al, 1978; Diaz-Zagoya et al, 1979)
Very little is known about the roles of the Aldo–keto reductases (AKR) in mediating signaling during preterm labor, which may be very different than what occurs at term

Summary

INTRODUCTION

Preterm birth (prior to 37 weeks gestational age) is the principle cause of neonatal morbidity and mortality in the developed world. Preterm deliveries account for 75% of perinatal mortality and surviving preterm infants are at risk for neurological, respiratory, and gastrointestinal complications (Goldenberg et al, 2008; Iams et al, 2008) Treatments such as intravaginal progesterone can be effective at maintaining pregnancies in women at increased risk for preterm labor. Tocolytic therapies to stop active labor do not delay parturition long enough to allow further fetal development, but do provide time for transportation to a hospital with a neonatal intensive care unit (Iams et al, 2008; Mackeen et al, 2011). Serum progesterone levels do not decline during human pregnancies, suggesting that a different mechanism determines the timing of labor. AKR1B1 and AKR1C3 are the enzymes that form the PGF2 isomers in humans

AKRs in parturition

Findings

CONCLUSION