preterm birth ( prior to 37  weeks gestational age ) is the principle cause of neonatal morbidity and mortality in the developed world . the united states has one of the highest rates of preterm births in the developed world , occurring in 1213% of pregnancies ( goldenberg et al . , 2008 ) . 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 however , tocolytics have a variety of side effects and there is not enough evidence of benefit to the infant to justify their use ( mackeen et al . , 2011 ) . the mechanisms underlying the initiation of labor are poorly understood , which has limited progress on therapies to maintain pregnancy or stop preterm labor . the lack of a suitable animal model has limited progress toward understanding human parturition ( smith , 2007 ; velia et al . , 2009 ; hill et al . , 2010 ; nanjidsuren et al . , 2011 ) . the roles of the placenta and other reproductive tissues in parturition , as well as specific steroid and prostaglandin metabolites , differ considerably between mammalian species . furthermore , the substrate specificities and expression levels of the aldo  keto reductase ( akr ) isoforms differ considerably between species . given the discrepancies in mechanism between species , this review will focus on the akrs and their substrates and metabolites in human pregnancy . progestins play a critical role in human pregnancy , as demonstrated by the efficacy of progesterone in maintaining pregnancy and of the progesterone receptor ( pr ) antagonist mifepristone in terminating pregnancy and initiating labor ( mcgill and shetty , 2007 ; iams et al . in other species , a decline in circulating progesterone levels , mediated by distinct pathways , precedes the onset of labor at term ( smith , 2007 ; zakar and hertelendy , 2007 ) . however , serum progesterone levels do not decline during human pregnancies , suggesting that a different mechanism determines the timing of labor . the exact role of progesterone and its metabolites in determining the timing of human labor remains a mystery . proposed pathways include paracrine regulation through increased myometrial expression of progesterone metabolizing enzymes and/or changes in pr expression . in addition to direct actions of progesterone , actions of its metabolites are likely involved . in particular , 5-dihydroprogesterone ( 5-dhp ) inhibits myometrial contractility ( kubli - garfias et al . , 1979 ; grazzini et al . , 1998 ; the activities of human akr1d1 and akr1cs suggest they play critical roles in mediating these processes . upregulation of pgh2 synthase 2 occurs late in pregnancy , resulting in an increase in the synthesis of prostaglandins , particularly the pgf2 isomers ( mijovic et al . , 1999 ; activation of the f prostanoid ( fp ) receptor by prostaglandins stimulates cervical ripening and the initiation of labor ( kelly et al . , 2003 ) . akr1d1 , human 5-reductase , catalyzes the formation of 5-androstanes and 5-pregnanes and contributes to the formation of bile acids in the liver ( charbonneau and luu - the , 2001 ; chen et al . , akr1d1 catalyzes the conversion of progesterone to 5-dhp ( figure 1 ; charbonneau and luu - the , 2001 ; chen et al . , 2011 ) . 5-dhp may be a key mediator of the pregnancy maintaining effects of progesterone . while levels of progesterone do not decrease during the final week of pregnancy , levels of 5-pregnanes decline starting in week 31 ( hill et al . , 2007 ) . this decline appears to be largely the result of decreased 5-reduction , although increased downstream metabolism may also occur . although 5-dhp was proposed to bind directly to the oxytocin receptor and antagonize oxytocin binding ( grazzini et al . , 1998 ) , others have not been able to replicate this finding ( burger et al . , 1999 ; 5-dhp could also inhibit contractions through activation of the pregnane x receptor ( mitchell et al . , 2005 ) , allosteric modulation of the gaba receptor ( putnam et al . , 1991 ) , or through some as yet unknown mechanism . although the mechanism is uncertain , it is clear that 5-dhp limits myometrial contractility ; it is significantly more potent than progesterone at inhibiting the contraction of myometrial cells in vitro ( kubli - garfias et al . , 1979 ; thornton et al . , 1999 ) . progesterone metabolism by akr1d1 and akr1cs in pregnancy . akr1d1 is likely to inhibit myometrial contractions through formation of 5-dihydroprogesterone , while akr1c1 , akr1c2 , and akr1c3 are likely to stimulate contractions through the elimination of progesterone and 5-dihydroprogesterone . the placenta appears to be the major site of akr1d1 expression , although it is also expressed in the myometrium ( sheehan et al . , 2005 ) . the decline in 5-dhp levels during labor are accompanied by a significant decline in akr1d1 mrna levels . the effect was particularly pronounced in the myometrium , which demonstrated a sevenfold reduction in akr1d1 levels ( sheehan et al . , 2005 ) . decreased synthesis of relaxatory pregnanes by akr1d1 may play an important role in the onset of labor . akr1d1 exhibits potent substrate inhibition by -ene steroids due to binding in a non - productive conformation ( di costanzo et al . , 2008 ; faucher et al . , 2008 ; chen et al . , 2011 ) , suggesting a second mechanism for the regulation of its activity . the presence of other -ene steroids , particularly 11-deoxy - corticosterone and 4-androstene-3,17-dione ( chen et al . , 2011 ) , would be anticipated to potently decrease the formation of 5-dhp by akr1d1 . 4-androstenedione levels are slightly elevated during labor , while levels of its aromatase product estrone are very high during labor ( hill et al . , 2010 ) . given the permissive ligand binding pocket of akr1d1 ( di costanzo et al . , 2008 ) , it is likely that steroids that are not substrates , including estrogens , will serve as inhibitors . although it is found in higher concentrations than 5-dhp throughout pregnancy , 5-dhp formation does not appear to contribute to the timing of labor . 5-dhp is completely unable to inhibit myometrial contractility in vitro ( kubli - garfias et al . , 1979 ) . ratios of progesterone to 5-dhp remain constant throughout pregnancy and it appears that expression levels of 5-reductase enzymes remain elevated throughout pregnancy ( hill et al . , 2010 ) . much of the work that has investigated 5-reduced pregnanes in pregnancy has focused on their neuroendocrine effects , including their anxiolytic and anesthetic effects in the mother , and their important role in protecting the developing nervous system of the neonate ( amin et al . both 5- and 5-progestins , particularly allopregnanolone and pregnanolone , act as allosteric modulators of gabaa receptors ( reddy , 2010 ) . members of the akr1c subfamily are likely to help initiate labor by catalyzing the formation of inactive progestin metabolites , leading to paracrine suppression of pr signaling ( figure 1 ) . akr1c1 , akr1c2 , and akr1c3 eliminate progesterone , 5-dhp , and 5-dhp through their 20-ketosteroid reductase activities ( penning et al . furthermore , they possess substantial 3-ketosteroid reductase activities that provide another pathway for the metabolism of 5-dhp and 5-dhp ( jin et al . , 2011 ) . the 20- , 3- , and 3-hydroxy - progestin products of akr1c enzymes have reduced tocolytic activities and are substrates for elimination through glucuronidation or sulfation . the 3-hydroxy products , such as pregnanolone and allopregnanolone , are neuroactive and could contribute to analgesic and anxiolytic effects in the mother and neuroprotection of the fetus ( steckelbroeck et al . , 2004 ; amin et al . , 2006 the stereochemistry for the reduction of 3-ketosteroids varies between akr1c isoforms and between 5-dhp and 5-dhp , while reduction of the ketone at the 20 position exclusively forms the 20-stereoisomer ( jin et al . , akr1c1 , akr1c2 , and akr1c3 are expressed in reproductive tissues , including the placenta , myometrium , and cervix ( nishizawa et al . 2008 ; lee et al . , 2008a ; hevir et al . , 2011 ) . placental tissues obtained from pregnancies at term reduce progesterone to 20-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 . it is not known whether expression levels of the akr1c enzymes correspond to the observed activity . expression of mrna encoding akr1c1 is elevated in the myometrium during spontaneous , but not oxytocin induced , labor ( lee et al . , 2008a ) . akr1c1 has the highest catalytic activity toward 20-ketosteroids , and this enzyme likely plays an important role in the inactivation of myometrial progesterone during spontaneous labor ( penning et al . , 2000 ; placental expression of akr1c3 during pregnancy has primarily been examined in the context of its prostaglandin metabolizing effects and is discussed below . akr1c2 expression in placenta is the lowest of the three peripheral akr1c isoforms ( nishizawa et al . , 2000 ) and the contribution of akr1c2 to parturition may be less critical than akr1c1 and akr1c3 . ( 2008 ) used intact tissues from combined hysterectomy and cesarean section to examine the role of akr mediated 20-ketosteroid reductase activity in cervical ripening . they observed mrna transcripts corresponding to akr1c1 , akr1c2 , and akr1c3 in cervix , with akr1c1 exhibiting the highest expression . cervical tissue from patients in active labor exhibited considerably faster progesterone 20-ketosteroid reduction relative to patients who were not in labor . however , cervical expression of mrna for the three akr1c isoforms did not change with labor onset . the increased reductase activity was proposed to result from decreased expression of type 2 17-hydroxysteroid dehydrogenase , which catalyzes the opposing oxidation reaction ( andersson et al . , 2008 ) . the timing of parturition is the release of calcium due to fp receptor activation . unlike pge2 , which has receptors that inhibit contractions and others that induce them , pgf2 has only labor promoting effects ( brodt - eppley and myatt , 1999 ) . the principle phenotype of fp receptor knockout mice is the inability to deliver young at term , which is rescued by the administration of oxytocin ( sugimoto et al . , 1997 a selective fp receptor antagonist inhibits myometrial cell contractility in vitro ( friel et al . , 2005 ) . regulation of fp signaling is partially via control of its expression levels and partially through the levels of its pgf2 ligands , which are determined by the expression of pgh2 synthase 2 , and akr1b1 and/or akr1c3 ( figure 2 ; mijovic et al . , 1999 ; slater et al . , 1999 ; mitchell et al . , 2005 ; lee et al . , 2008b ; smith et al . , 2011 ; transcript for the fp receptor is suppressed throughout pregnancy , declining with gestational age until immediately before the initiation of labor , when expression levels spike ( brodt - eppley and myatt , 1999 ; olson et al . , 2003 ) . in sheep corpus luteum and rat myometrium , expression of the fp receptor is upregulated by estradiol administration , while progesterone has a suppressive effect , suggesting that steroids may regulate receptor levels during pregnancy ( hoyer et al . , 1999 ; both akr1c3 and akr1b1 form pgf2 from pgh2 , while akr1c3 also forms 9,11-pgf2 and akr1b1 may also contribute to the formation of pgd2 the traditional ligand for the fp receptor is pgf2 , although its stereoisomer 9,11-pgf2 is also a potent ligand ( mitchell et al . , 2005 ) . levels of pgf2 in amniotic fluid are low throughout the first 36  weeks of pregnancy before rising during the last few weeks of pregnancy ( lee et al . , 2008b ) . samples from patients at term indicated a substantial increase in pgf2 from no labor ( 250  pg / ml ) to early labor ( 640  pg / ml ) and advanced labor ( 4300  pg / ml ) , which was far greater than the increase in pge2 levels . these measurements were performed with a commercial immunosorbent assay with an antibody against pgf2 , but cross - reactivity with 9,11-pgf2 was not ruled out . pg / ml ) were detected in amniotic fluid samples from patients undergoing labor at term using an assay with an antibody that had limited cross - reactivity with pgd2 , but not pgf2 , suggesting that both isomers may play an important role in labor ( mitchell et al . , 2005 ) . pg / ml ) were detected in patients at term who were not undergoing labor , while levels of this isomer were suppressed in patients prior to 36  weeks , including those undergoing preterm labor . the absence of increased 9,11-pgf2 in preterm labor could be the result of low levels of pgd2 synthase or low akr1c3 activity . the enzymes responsible for the increased synthesis of pgf2 products at term have not been conclusively identified . however , both of the proposed prostaglandin f synthases are aldo  keto reductases ( smith et al . , 2011 ; watanabe , 2011 ) . akr1c3 has substantially higher catalytic activity for the reduction of pgd2 to 9,11-pgf2 relative to its other endogenous substrates , while the conversion of pgh2 to pgf2 is also faster than for its steroid substrates ( matsuura et al . , 1998 ; suzuki - yamamoto et al . , 1999 involvement of the akr1b family has only recently been recognized , with the bovine akr1b5 isoform first shown to synthesize pgf2 ( madore et al . , , akr1b1 exhibits a higher catalytic activity for the conversion of pgh2 to pgf2 than akr1c3 , but it is not involved in the formation of 9,11-pgf2 ( kabututu et al . , 2009 ) . in addition to synthesizing pgf2 , a recent report indicates that in the absence of cofactor , akr1b1 can catalyze the rearrangement of pgh2 to form pgd2 ; akr1c3 did not exhibit this activity ( nagata et al . akr1b1 and akr1c3 are expressed in reproductive tissues during pregnancy and both likely synthesize pgf2 during pregnancy . both akr1b1 and akr1c3 were cloned based on placental dna libraries ( grundmann et al . most of the early work on akr1b1 focused on its role in regulating glucose metabolism , although it has many additional endogenous substrates ( srivastava et al . , 2005 ) . its roles in prostaglandin signaling have only recently been described ( kabututu et al . , 2009 ; bresson et al . , 2011 ) . akr1c3 also catalyzes the reduction of a wide variety of substrates in addition to prostaglandins ( matsuura et al . , 1998 ; suzuki - yamamoto et al . , 1999 ; byrns et al . , 2010 ) . expression of akr1b1 and akr1c3 were recently examined at the mrna and protein levels in placenta ( breuiller - fouch et al . , 2010 ) . based on immunohistochemistry , both enzymes were expressed throughout the fetal membranes , but the highest expression was in chorionic trophoblasts and in decidual stromal cells . western blot and quantitative rt - pcr indicated that akr1b1 was primarily expressed in the choriodecidua , while akr1c3 exhibited similar expression levels in both choriodecidua and amnion . lipopolysaccharide stimulation did not upregulate either protein , suggesting that their expression levels do not contribute to preterm labor induced by intrauterine infection . changes in placental expression of these enzymes over the course of pregnancy have not been examined . further research is needed to understand the contribution of the akrs to the induction of normal labor . furthermore , very little is known about the roles of the akrs in mediating signaling during preterm labor , which may be very different than what occurs at term . evidence supports a role for declining placental and myometrial akr1d1 expression in the initiation of labor . increased paracrine inactivation of progestins by akr1cs may also be an important step in parturition . formation of increased levels of pgf2 isomers stimulates labor , although a major unresolved question is whether changes in the placental expression of akr1b1 and/or akr1c3 contribute to this effect . changes in levels of steroid and prostaglandin products could also result from changes in other enzymes involved in upstream and downstream metabolism . although the contribution of akr1c3 to labor initiation has not been the subject of much research , its enzymatic activities suggest an important role . each of its enzymatic activities has the potential to contribute to the initiation of parturition . akr1c3 can eliminate progesterone and its 5- and 5-reduced products and can synthesize estradiol and both prostaglandin f2 isomers ( byrns et al . furthermore , it is potently inhibited by the tocolytic drug indomethacin ( byrns et al . , 2008 ) . it is expressed in several reproductive tissues during pregnancy , although it is not known whether expression levels change , except in the cervix where it does not ( nishizawa et al . , 2000 ; andersson et al . , 2008 ; breuiller - fouch et al . , akr1d1 inhibitors might be useful for inducing cervical ripening or given along with oxytocin for the initiation of labor . inhibitors of the akr1b and akr1c enzymes might have benefits for the maintenance of pregnancy or for tocolysis . given that mammals have distinct mechanisms of parturition and akr substrate specificities , it is not clear that effects in animal models will apply to human pregnancies . another potential issue is that the akr1c and akr1d enzymes contribute to the synthesis of neuroactive steroids , such as allopregnanolone and pregnanolone . given the neuroprotective effects of these steroids , inhibition of these enzymes in the fetal compartment may be undesirable . the author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest .
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 5 reductase ) likely contributes to the maintenance of pregnancy through the formation of 5-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 pgf2 and pgd2 to 9,11-pgf2 . 
 akr1b1 also reduces pgh2 to pgf2 , but does not form 9,11-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 .