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The role of prostaglandins E1 and E2, dinoprostone, and misoprostol in

cervical ripening and the induction of labor: a mechanistic approach

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Arch Gynecol Obstet
DOI 10.1007/s00404-017-4418-5
REVIEW
The role of prostaglandins E1 and E2, dinoprostone,
and misoprostol in cervical ripening and the induction of labor:
a mechanistic approach
Ronan Bakker1 • Stephanie Pierce1 • Dean Myers2
Received: 31 March 2017 / Accepted: 30 May 2017
Ó Springer-Verlag GmbH Germany 2017
Abstract
Purpose Prostaglandins play a critical role in cervical
ripening by increasing inflammatory mediators in the cer-
vix and inducing cervical remodeling. Prostaglandin E1
(PGE1) and prostaglandin E2 (PGE2) exert different
effects on these processes and on myometrial contractility.
These mechanistic differences may affect outcomes in
women treated with dinoprostone, a formulation identical
to endogenous PGE2, compared with misoprostol, a PGE1
analog. The objective of this review is to evaluate existing
evidence regarding mechanistic differences between PGE1
and PGE2, and consider the clinical implications of these
differences in patients requiring cervical ripening for labor
induction.
Methods We conducted a critical narrative review of peer-
reviewed articles identified using PubMed and other online
databases.
Results While both dinoprostone and misoprostol are
effective in cervical ripening and labor induction, they
differ in their clinical and pharmacological profiles. PGE2
has been shown to stimulate interleukin-8, an inflammatory
cytokine that promotes the influx of neutrophils and indu-
ces remodeling of the cervical extracellular matrix, and to
& Ronan Bakker
ronan-bakker@ouhsc.edu
1
Fellow, Maternal Fetal Medicine, Department of Obstetrics
and Gynecology, University of Oklahoma Health Sciences
Center, 800 Stanton L. Young Blvd., Suite 2400,
Oklahoma City, OK 73104, USA
2
John W. Records Chair in Maternal-Fetal Medicine,
Maternal-Fetal Medicine Fellowship Member, Harold Hamm
Diabetes Center, Department of Obstetrics and Gynecology,
University of Oklahoma Health Sciences Center,
Oklahoma City, OK, USA
induce functional progesterone withdrawal. Misoprostol
has been shown to elicit a dose-dependent effect on
myometrial contractility, which may affect rates of uterine
tachysystole in clinical practice.
Conclusions Differences in the mechanism of action
between misoprostol and PGE2 may contribute to their
variable effects in the cervix and myometrium, and should
be considered to optimize outcomes.
Keywords Prostaglandin
Misoprostol
Dinoprostone

Cervical ripening
Labor induction
Mechanisms
Introduction and development of prostaglandins
Induction of labor occurs in up to 25% of all term preg-
nancies around the world [1, 2]. In the United States, the
latest numbers point to an overall induction rate of 23% for
all pregnancies [3]. The extent of cervical ripening is one
of the most important factors in predicting the success of
labor induction [4]. Cervical ripening is a complex process
involving extensive remodeling and dynamic anatomic and
physiologic alterations governed by hormonal changes,
inflammatory responses, vasodilatory changes, and other
biological processes [5–7]. Prostaglandins, produced both
locally in the cervix and uterus as well as originating from
the fetal membranes, play a critical role in cervical ripening
and other processes related to parturition, including uterine
contractility and the induction of labor.
Prostaglandins are eicosanoids, formed from the
20-carbon unsaturated fatty acid, arachidonic acid, which is
liberated from membrane phospholipids via phospholipase
A2. Arachidonic acid is initially converted to prostaglandin
H2 (PGH2) via the sequential reactions of prostaglandin
G/H synthases-1 or -2 (PGHS-1 or PGHS-2), also known as
123

cyclooxygenase-1 and -2 (COX-1 and COX-2) [8, 9].
Subsequently, specific isomerases and synthases convert
labile PGH2 to active prostanoids, including prostaglandin
E2 (PGE2; via prostaglandin E synthase), prostaglandin F2
(PGF2; via PGF synthase), and prostacyclin (via pros-
taglandin I synthase) [10]. COX-2 couples preferentially
with prostaglandin I synthase and the microsomal pros-
taglandin E synthase isozymes (PGES 1 and 2) [10].
There are five primary types of prostaglandins: PGE2,
prostaglandin F2a (PGF2a), prostaglandin D2, pros-
taglandin I2, and thromboxane A2. PGE2 and PGF2a are
the two key prostaglandin types involved in cervical
ripening and parturition. PGE2 acts on the prostaglandin
type E prostanoid (EP) family of receptors, while the
effects of PGF2a are primarily mediated through pros-
taglandin FP receptors [8, 11]. Numerous sources of PGE2
and PGF2a in the reproductive system have been identi-
fied, including the cervix, uterus, placenta, and fetal
membranes [8, 11]. Receptors for prostaglandins have been
localized to the myometrium, cervix, trophoblast, decidua,
and fetal membranes [7, 12–16].
The roles of PGE2 and PGF2a have been extensively
studied in parturition. Research on the potential impact of
prostaglandins on labor and delivery began in the 1930s
when human semen was found to cause uterine contrac-
tions, leading researchers to coin the term ‘‘prostaglandin’’
to describe the biologically active substance in the extracts
[17–19]. Subsequent research demonstrated that pros-
taglandin levels in labor also act on the myometrium to
increase its contractility, promoting the onset and pro-
gression of labor [20]. Specifically, PGE2 levels are
markedly increased in the amniotic fluid and fetal mem-
branes during labor and in term pregnancies [21], and they
are significantly higher during term births compared to
preterm births [22]. While PGF2a levels also increase once
labor is established [8], and both PGE2 and PGF2a cause
myometrial contractions, PGE2 has also been shown to
promote cervical ripening and rupture of the fetal mem-
branes [8, 23].
Specifically, PGE2 has been shown to regulate the
synthesis of hydrophilic glycosaminoglycans and increa-
ses the activity of elastin, both of which induce cervical
ripening by separating and dispersing collagen bundles
[24–26]. The application of PGE2 to the human cervix
has been reported to increase collagenase activity in
cervical biopsies [27]. In addition, PGE2 modulates the
inflammatory response that characterizes cervical ripening
and remodeling [28]. This inflammatory response consists
of an influx of inflammatory cells, an increase in
inflammatory mediators such as interleukin-8 (IL-8),
tumor necrosis factor-a (TNF-a), and IL-1b, and an
increase in matrix metalloproteinase (MMP) activity
[9, 29, 30].
123
Arch Gynecol Obstet
Despite the impact of prostaglandins on cervical ripen-
ing and the induction of labor, the development of clini-
cally useful prostaglandin formulations was a long and
challenging process [17]. Natural prostaglandins have
several drawbacks that thwarted their development into
viable clinical compounds. They are rapidly metabolized,
making them orally inactive, with a short half-life when
administered parenterally. They also have numerous side
effects and are chemically unstable [17].
These limitations have been addressed through changes
in the delivery system and modifications to the pros-
taglandin molecule. The two key prostaglandin formula-
tions used today to promote cervical ripening and induce
labor are dinoprostone and misoprostol (Fig. 1). Dinopro-
stone is a synthetic preparation chemically identical to
PGE2 that is delivered by cervical gel or vaginal insert and
provides sufficient quantities of PGE2 to local tissues to
induce cervical ripening [31]. Misoprostol is a methyl ester
analog of prostaglandin E1 (PGE1), a naturally occurring
form of prostaglandin E that was initially developed to
prevent and treat gastric ulcers [17, 32, 33]. Misoprostol is
a methyl ester that is enzymatically cleaved to misoprostol
acid, the active drug [17]. When used to promote cervical
ripening and induce labor, misoprostol can be administered
orally, rectally, sublingually, or vaginally.
In clinical use, PGE1 has the same limitations as other
prostaglandins: it is rapidly metabolized, chemically
unstable, and has numerous side effects [17]. Misoprostol
was designed to be an orally active and chemically
stable form of PGE1. While misoprostol did show
improved selectivity with regard to its side effect profile as
a treatment for gastric ulcers, one side effect that was not
eliminated was its ability to induce uterine contractile
activity [17]. The uterotonic effects of misoprostol and its
impact on cervical softening have made misoprostol a
widely used therapy in obstetrics and gynecology [33].
Misoprostol has been shown to have two primary effects
when used in labor induction: to increase uterine contrac-
tility and to soften the cervix, primarily through its ability
to degrade collagen in the connective tissue stroma of the
cervix [29, 33, 34]. However, it should be noted that the
effects of endogenous PGE1 in the parturition process
remain enigmatic.
Despite the widespread use of prostaglandins and pros-
taglandin analogs in labor induction, the mechanistic dif-
ferences between these drugs, and the general role of
prostaglandins in labor, have not been fully elucidated. The
objective of this review is to evaluate existing evidence on
the roles of PGE1, the PGE1 analog misoprostol, and PGE2
in cervical ripening and parturition, including their differ-
ential effects on prostaglandin receptors and cell signaling
responses, and to consider the clinical implications of these
differences for using dinoprostone and misoprostol to
Arch Gynecol Obstet
Dinoprostonea
O O
O O
O O
O O
Misoprostolc
O O
CH1
O O
H 1C CH
CH1
HO
Fig. 1 Structures of dinoprostone, PGE2, misoprostol, and PGE1.
The chemical structure of dinoprostone is identical to that of
endogenous PGE2. The primary differences between misoprostol
and endogenous PGE1 are the relocation of the 15-hydroxy group to
the adjacent 16 position and the addition of a methyl group at the
same position [17]. aNational Center for Biotechnology Information.
PubChem Substance Database; CID = 5280360, https://pubchem.
ncbi.nlm.nih.gov/substance/134337670 (accessed Dec. 20, 2016).
b
National Center for Biotechnology Information. PubChem Substance
induce labor, including the impact of prostaglandins on
neonatal outcomes.
The prostaglandin EP receptor family and its
ligands
The prostaglandin EP receptor family consists of 4 sub-
types [7]: EP1, EP2, EP3, and EP4, each of which has been
shown to have a variety of effects [7, 35]. These receptors
are G protein-coupled receptors (GPCRs) that mediate
smooth muscle cell contractility and relaxation (Fig. 2)
[23, 36].
Prostaglandin receptors are located in the myometrium,
trophoblast cells, amnion, cervix, and decidua [7, 12–14].
The EP receptor protein family is encoded by distinct
genes, which themselves show significant variability
through alternative splicing at the carboxy-terminal tail of
some isoforms [37, 38].
EP receptors can generally be categorized into those that
facilitate smooth muscle contractility (EP1 and EP3) and
PGE2b
O O
PGE1d O
O
O
O
Database; CID = 5280360, https://pubchem.ncbi.nlm.nih.gov/sub
stance/134337670 (accessed Dec. 20, 2016). cNational Library of
Medicine ChemIDPlus, a TOXNET database. Registry Number
59122-46-2. https://chem.nlm.nih.gov/chemidplus/rn/59122-46-2
(accessed Dec. 20, 2016). dNational Center for Biotechnology
Information. PubChem Substance Database; CID = 5280723, https://
pubchem.ncbi.nlm.nih.gov/substance/134337669 (accessed Dec. 20,
2016). PGE1 prostaglandin E1, PGE2 prostaglandin E2
those that promote smooth muscle relaxation (EP2 and
EP4). All four EP receptor types are expressed in
myometrial samples from pregnant women [37]. Signaling
through EP1 increases phosphoinositol turnover and cal-
cium mobilization, leading to smooth muscle contraction
(Fig. 2) [37, 39–41]. In contrast, EP3 inhibits adenylate
cyclase and cAMP production via G proteins and inhibits
smooth muscle relaxation [39–41]. EP2 and EP4 stimulate
adenylate cyclase and cAMP production via G proteins,
leading to smooth muscle relaxation [39–41].
EP receptor subtypes show differential spatial expres-
sion in the uterus and cervix that may vary, depending on
the species studied, pregnancy status, and gestational stage
[42]. This differential distribution may facilitate location-
specific effects such as the remodeling of the cervix, the
relaxation of the lower reproductive tract, and the simul-
taneous contraction of the fundal myometrium [24, 43]. In
fact, one determining factor for the reactivity of these tis-
sues at a given stage of gestation may be the relative
expression of each receptor type at that stage [42, 44]. For
example, EP3 expression in the myometrium is reduced in
123

Fig. 2 PGE2 signaling pathways [119]. PGE2 signals by binding to
its G protein-coupled receptors: EP1-4. Activation of EP1 (coupled to
Gq) increases intracellular Ca2? via PLC. Activation of EP3 (coupled
to Gi) increases intracellular Ca2? via PLC and/or inhibits cAMP
production via adenylate cyclase. Activation of EP2 or EP4 (both
early pregnancy compared to the nonpregnant state, sug-
gesting that downregulation of EP3 receptors during
pregnancy may help maintain quiescence in the myome-
trium [45]. However, in later pregnancy, upregulation of
contractile EP3 receptor mRNA has been reported in the
myometrium of pregnant rats, ewes, baboons, and women
[46–49]. Moreover, baboons in labor have higher
myometrial mRNA expression of EP1 and EP3 in the
fundus compared to the lower uterine segment [24, 49].
Expression of EP3 variants may also differ in the myo-
metrium of pregnant and nonpregnant women. In one
study, EP3-2 mRNA was reduced and EP3-6 mRNA was
increased in gravid samples vs nongravid samples [50].
These data suggest that EP3-mediated contractile activity is
upregulated during parturition to facilitate delivery of the
infant.
Generally, EP1 receptor expression is lower compared
with the other EP subtypes. In one study, EP1 mRNA was
not evident in the myometrium from guinea pigs at a late
gestational age, but was observed in nonpregnant animals.
However, in labor in humans, EP1 expression was signif-
icantly increased in the lower uterine segment compared
with individuals not in labor [12, 38]. If these receptors are
functional, they would complement the increased expres-
sion of EP3 receptors, which promote uterine contraction.
Temporal and regional variations in myometrial EP2
receptor expression may also affect the maintenance of
pregnancy and the induction of labor [51]. EP2 receptor
expression in the myometrium declines at the end of ges-
tation compared to early pregnancy and stabilizes during
labor and parturition [44, 51, 52], suggesting the end of
123
Arch Gynecol Obstet
coupled to Gs) stimulates cAMP production via adenylate cyclase.
ATP adenosine triphosphate, Ca2? ionized calcium, cAMP cyclic
adenosine monophosphate, EP E prostanoid, PGE2 prostaglandin E2,
PLC phospholipase C. Gi, Gq, and Gs are G-protein subtypes Adapted
from [119]. ÓThe American Physiological Society
uterine quiescence in preparation for labor. Changes in EP2
mRNA corresponded to a decline in contractile respon-
siveness to PGE2, again suggesting that EP2 receptors may
play a role in maintaining uterine quiescence [38, 44, 51].
Nonetheless, a study by Mosher and colleagues of EP
receptor activity in myometrial cells from pregnant women
at term found that EP2 was the most highly expressed of all
four EP receptors [53]. Immunocytochemistry analyses
also demonstrated that EP2 protein was abundantly present
throughout myometrial cells at term [53]. While additional
research on changes in EP4 expression over the course of
pregnancy is needed, Mosher and colleagues confirmed the
expression of EP4 receptor mRNA in myometrial cells in
pregnant women at term.
EP receptor distribution and the effects of pregnancy
status have also been evaluated in the cervix in animal and
human studies. In the rat cervix, EP2 and EP4 expression
appears to change with duration of gestation, peaking at
parturition, while EP1 and EP3 receptors show no change
in their expression with advancing gestational age [54, 55].
In baboons, expression of EP1 receptors increased with
gestational age before labor, while expression of EP2 was
four times lower among animals in labor compared to those
not in labor [56].
A 2013 study evaluated the concentrations and distri-
bution of cervical EP mRNA in pregnant, nonpregnant, and
postpartum women to determine how reproductive status
affects EP receptors. As expected, levels of EP1-4 varied
between pregnancy states and cell types [57]. Relaxatory
EP2 and EP4 mRNA levels were lowest before the onset of
cervical ripening in women with term pregnancies and
Arch Gynecol Obstet
were higher among postpartum women immediately after
parturition, when the uterus is most relaxed and initiating
involution [57].
EP receptor status in women treated
with prostaglandins
Although induction of labor is among the most common
obstetric procedures, up to 33% of patients who are
induced do not respond to induction with prostaglandins or
oxytocin [58, 59]. To gain a better understanding of the
role of PG receptors on cervical ripening and remodeling,
several investigators have evaluated the expression and
localization of these receptors in the human cervix after
failed and successful induction of labor with dinoprostone
(PGE2) [60].
In one study in cervical tissue, contractile EP1 mRNA
expression was inversely related to the response to dino-
prostone. All patients who did not respond to dinoprostone
showed upregulated EP1 mRNA expression [7]. In the
analysis of myometrial EP gene expression, significantly
higher expression levels of EP3 mRNA were observed in
women treated with dinoprostone, independently of
responsiveness. Women receiving dinoprostone showed
3.6-fold higher levels of EP3 mRNA expression compared
to women experiencing spontaneous labor, indicating that
dinoprostone may regulate EP3 at the transcriptional level
[58]. In a second study of EP expression in cervical tissue,
Roos et al. found increased expression of contractile EP3
and decreased expression of relaxatory EP4 in women who
did not respond to induction with a local PGE2 compared
to those who were successfully induced [60]. The differ-
ences in EP1, EP3, and EP4 expression in the cervix
between those who did and did not respond to dinoprostone
suggest that these receptors have an important role in
parturition. Consequently, upstream signals regulating the
expression of these receptors may be critical for successful
cervical ripening and may provide potential therapeutic
targets.
Misoprostol and PGE2 may have different binding
affinities and exert different effects on each of these
receptors in a variety of tissues [61–63]. For example,
misoprostol is a potent EP3 receptor agonist and may also
have affinity for the EP2 receptor [45]. In one study of the
effect of misoprostol in the uterus and cervix of rats,
misoprostol induced elevations of EP3 mRNA expression
in the myometrium but not in the cervix. Misoprostol also
induced PGE2 secretion at doses of both 50 and 100 pg/mL
in the myometrium, but only at a dose of 100 pg/mL in the
cervix [45]. These findings may account, in part, for the
ability of misoprostol to stimulate myometrial contractility
more potently when it is used for cervical ripening [45].
Prostaglandins and myometrial contractility
While misoprostol and PGE2 are both associated with
cervical remodeling [64–66], studies have demonstrated
the differential effects of these agents in the myometrium
in term pregnancies. In in vitro studies, PGE2 did not affect
contractility in uterine tissue obtained from term preg-
nancies in women with scheduled cesarean sections
[67, 68]. However, both contractile and relaxation
responses have been observed with PGE2 in myometrium
samples from nonpregnant women [64, 67, 68]. Additional
research is needed to clarify how PGE2 affects myometrial
contractility in nonpregnant and pregnant women and how
its action varies by gestational age.
The effects of misoprostol and PGE2 on myometrial
contractility and uterine structure have been compared in
two in vitro studies of myometrial tissue from women
undergoing scheduled repeat cesarean sections [64, 69]. In
both studies, misoprostol elicited greater increases in
myometrial contractility compared to PGE2 [64, 69].
Chiossi and colleagues found that myometrial contractions
were linked to a decrease in total myometrial collagen and
connective tissue, and exposure to misoprostol may add to
this effect. PGE2, on the other hand, had no such effect
[64]. Studies in pregnant women have shown that higher
concentrations of PGE2 have inconsistent effects on
myometrial contractility. Gordon-Wright et al. found that
high PGE2 concentrations either induced a transient
decrease in uterine contractions or no changes at all, con-
cluding that the initiation of uterine contractions observed
during PGE2 therapy may represent an indirect response to
cervical ripening rather than a direct effect on the myo-
metrium [67]. The difference in myometrial contractility in
response to dinoprostone and misoprostol could explain
some of the differences in outcomes and some of the safety
concerns, such as uterine tachysystole [69].
Prostaglandins and functional progesterone
withdrawal
Prior to the onset of labor, a dynamic balance exists
between the mechanisms that maintain uterine quiescence
and those that coordinate cervical ripening and uterine
contractility, including changes in progesterone and pros-
taglandin activity. However, during pregnancy, uterine
quiescence is mediated by progesterone. In other mam-
malian species, cervical ripening and increased myometrial
contractility are preceded by a considerable decline in
progesterone, a phenomenon not seen in humans [5].
Instead, a ‘‘functional’’ progesterone withdrawal is thought
to occur before labor in humans [70].
123

During functional progesterone withdrawal, proges-
terone activity is reduced and estrogen activity is increased
in the myometrium [71]. This increases the production of
estrogen-dependent molecules, such as prostaglandins, that
promote uterine contractility.
The exact mechanism of this proposed functional pro-
gesterone withdrawal is unclear; however, it is thought to
possibly be related to differential expression of the two main
isoforms of the nuclear progesterone receptor (PR), classi-
fied as PR-A and PR-B. In general, PR-B is thought to
mediate positive progesterone-induced changes in genes that
are responsive to the hormone, while PR-A is thought to
play an inhibitory role. Specifically, PR-A has been shown
to be a potent repressor of PR-B transcriptional activity
[58, 72]. Based on these earlier data, it has been postulated
that PR-A and PR-B have opposing transcriptional activity,
and thus the end result of PR activation depends on the ratio
of PR-A to PR-B. Other data indicate that both PR-A and
PR-B are transcriptionally active at various endogenous
promoters [73, 74]. With this, a new paradigm has been
proposed, asserting that progesterone exerts its effects
through the combined actions of PR-A and PR-B [75].
The role of prostaglandins in mediating progesterone
withdrawal has been investigated in several studies. In one
study, Madsen and colleagues evaluated the ability of PGE2
to alter ratios of PR-A and PR-B in myometrial cells from
pregnant women and found that PGE2 dose-dependently
increased mRNA encoding PR-A and PR-B. While activa-
tion of the protein kinase-A signaling pathway did not affect
the PR-A/PR-B ratio, activation of the protein kinase-C
(PKC) signaling pathway increased expression of PR-A
without affecting PR-B, and therefore significantly increased
the PR-A/PR-B expression ratio. The authors concluded that
PGE2, acting via the PKC pathway, may facilitate functional
progesterone withdrawal by increasing the myometrial PR-
A/PR-B expression ratio [76]. As such, there may be
reciprocal interactions between progesterone signaling and
prostaglandin signaling. Another theory to explain mecha-
nisms underlying functional progesterone withdrawal in the
cervix proposes an increase in progesterone metabolism
during the cervical ripening process [77]. Mice deficient in
the type 1 isozyme of steroid 5a-reductase, an enzyme
responsible for metabolizing progesterone, fail to exhibit
cervical ripening at term despite a decline in serum pro-
gesterone, suggesting that local progesterone metabolism is
fundamental for cervical ripening [78]. The human cervix
expresses 20a-hydroxysteroid dehydrogenase (HSD) and 5a
steroid reductases, which convert progesterone to the inac-
tive C21-steroid 20a-hydroxyprogesterone and 5a-dihy-
droprogesterone, respectively [77]. The cervix also
expresses 17b HSD type 2, which converts 20a-hydrox-
yprogesterone back to progesterone. However, in the human
cervix at term, 17b HSD type 2 is downregulated, favoring
123
Arch Gynecol Obstet
the conversion of progesterone to its inactive forms [77].
The activity of 20a-HSD is mediated by members of the
aldo–keto reductase (AKR) 1C family, primarily AKR1C1,
but also AKR1C2 and AKR1C3 [79]. The proinflammatory
cytokine IL-1b may facilitate progesterone metabolism by
increasing the expression of AKR1C1 and AKR1C2, thus
promoting progesterone metabolism in human cervical
fibroblasts [79]. The interactions between PGE2, the inter-
leukins, and other inflammatory markers in cervical
remodeling will be explored in the section that follows,
‘‘Prostaglandins and inflammation in cervical remodeling.’’
In addition, PGE2 is a regulator of the expression of
15-hydroxyprostaglandin dehydrogenase (15-PGDH) via
its actions at the EP2 receptor [80]. An antagonist of EP2
blocked PGE2 suppression of 15-PDGH, while butaprost (a
selective EP2 agonist) and misoprostol mimicked PGE2.
Thus, PGE2 seems to regulate its own metabolism in the
cervix via induction of 15-PGDH in an EP2-mediated
manner. Based on these observations, it is relevant to note
that cervical fibroblasts from nonpregnant women expres-
sed the EP2 receptor at levels 30 times higher than levels of
EP1, EP3, or EP4 receptors [80].
Because functional progesterone withdrawal is thought
to be important for successful labor, several investigators
have evaluated progesterone activity in women undergoing
labor induction who did and did not respond to dinopros-
tone [58, 81]. A reduction in serum progesterone levels
from admission to birth was observed in women who
responded to dinoprostone, but not among those who failed
to respond and not among those who experienced sponta-
neous labor or who underwent cesarean delivery without a
trial of dinoprostone [58]. These data suggest progesterone
‘‘withdrawal’’ in patients who responded to dinoprostone.
However, in women who experienced a normal sponta-
neous labor, a functional progesterone withdrawal (such as
a change in PR-A vs PR-B expression or progesterone
metabolism) may have created a change in responsiveness
to progesterone that precipitated labor. Similar findings
were reported in a study of term women who successfully
responded to dinoprostone for cervical priming, as indi-
cated by a decrease in total cervical progesterone receptor
A and B protein levels compared to nonresponders [81]. A
comparable reduction in progesterone levels was not
observed in women who did not respond to treatment or in
women who underwent spontaneous labor.
Prostaglandins and inflammation in cervical
remodeling
PGE2 plays a pivotal role in the inflammatory processes
that trigger cervical ripening and the initiation of labor
[28]. This inflammatory response is characterized by the
Arch Gynecol Obstet
differentiation of fibroblast cells into activated myofi-
broblasts, an influx of inflammatory cells into the cervix,
increased expression of inflammatory cytokines, and
increased production of MMPs [30]. Key inflammatory
mediators include IL-8, IL-1, TNF-a, and PGHS-2 (leading
to increased prostaglandin synthesis) [9, 30]. Other
cytokines involved in cervical remodeling include IL-6,
platelet-activating factor (PAF), and monocyte chemoat-
tractant protein-1 (MCP-1) [9, 66, 82, 83].
IL-8, a critical mediator of cervical remodeling, is pro-
duced by numerous types of cervical cells, including
endocervical epithelial cells, cervical stromal fibroblasts,
leukocytes, and macrophages [30]. IL-8 production is
believed to begin in cervical stromal cells and is aug-
mented through the recruitment of numerous immune cells
that produce IL-8 and its receptors after activation by IL-8
[30]. IL-8 has two key functions: to induce neutrophil
activation and migration, and to cause degranulation,
releasing collagenase. IL-8 concentrations rise as labor
progresses [8].
Studies have shown that TNF-a and IL-1b act on
prostanoid biosynthesis at multiple points in a coordinated
fashion (Fig. 3). These cytokines have been shown to
increase the expression of PGHS-2 and subsequently
increase the production of prostaglandins at various tissue
sites during pregnancy [84]. High doses of IL-6 have also
been shown in amnion and decidua tissue to stimulate the
production of prostaglandins [85]. The aforementioned
Fig. 3 Cytokine-prostaglandin
interactions. Proinflammatory
cytokines such as TNF-a act in
a coordinated fashion to
upregulate prostanoid
biosynthesis and downregulate
metabolism [84, 120]. cPLA2
cytosolic phospholipase A2, IL-
1b interleukin-1b, PG
prostaglandin, PGDH
15-hydroxyprostaglandin
dehydrogenase, PGG2
prostaglandin G2, PGH2
prostaglandin H2, PGHS-2
prostaglandin H synthase-2,
TNF-a tumor necrosis factor-a
Reprinted from [84], Copyright
(1999), with permission from
Elsevier, and from [120],
Copyright (2003), with
permission from Elsevier
cytokines have also been implicated in effecting the pro-
duction of MMPs by cervical fibroblasts [86, 87]. PGE2
has been shown to elicit anti-inflammatory responses to
these cytokines by repressing the IL-1b-induced release of
IL-8, MCP-1, and granulocyte macrophage colony-stimu-
lating factor (GMC-SF). These and other effects of PGE2
on IL-b have been shown to be mediated by EP2 and/or
EP4 receptors [53, 88].
Evidence suggests that there is a positive feedback
mechanism between prostaglandins and the inflammatory
cytokines released by infiltrating leukocytes during cervi-
cal remodeling [89, 90]. For example, outside the uterus, a
synergy may exist between PGE2 and IL-8 to facilitate the
recruitment of neutrophils. Moreover, PGE2 can upregulate
IL-8 release in a dose-dependent manner [6, 91]. PGE2
may also stimulate vasodilation and increase vascular
permeability for IL-8-directed recruitment of neutrophils
[6]. In addition, myometrial cell cultures indicate that pro-
inflammatory cytokines may upregulate prostaglandin
receptors, such as EP4 [38, 92]. The proinflammatory
cytokine IL-1b has also been shown to facilitate cervical
ripening by inducing progesterone metabolism in cervical
fibroblasts, leading to functional progesterone withdrawal
[79].
In a study of post-term women who received dinopros-
tone for cervical priming post-term, the influx of leuko-
cytes as assessed by leukocyte common antigen (CD45)
was strongest in women who responded to therapy and
cPLA2
PGG2/PGH2
123

significantly lower in women who did not respond [66].
Cervical leukocyte influx was intermediate in women who
achieved labor spontaneously. Decreased immunostaining
for IL-8, PAF-receptor, and MMP-9 was also observed in
nonresponders. The authors suggested that decreased
leukocyte influx may partly explain the failed cervical
ripening [66].
While accumulating evidence indicates that PGE2
mediates inflammation, limited data on the impact of PGE1
on inflammation in the cervix are available. One study in
pregnant women at 8–12 weeks of gestation did find that
orally or vaginally administered misoprostol was associ-
ated with a greater expression of inflammatory cells and a
higher degree of MMP-8 and MMP-9 staining in the cervix
compared to controls [29]. Misoprostol also is known to
affect inflammation in other organ systems, including in
patients with nonsteroidal anti-inflammatory drug
(NSAID)-induced gastric ulcers [93]. Additional research
on the impact of PGE1 and misoprostol on the inflamma-
tory processes involved in parturition is needed.
Prostaglandins currently used in labor
and delivery
Because endogenous prostaglandins are short-lived and
rapidly metabolized, several synthetic analogs of the nat-
urally occurring isoforms PGE1 and PGE2 have been
developed and are stable enough for therapeutic use [94].
The most commonly used prostaglandin therapies for cer-
vical ripening in clinical practice are dinoprostone (Cer-
vidil, Ferring Pharmaceuticals Inc., Parsippany, NJ, USA;
Prepidil, Pharmacia & Upjohn Company, Division of Pfi-
zer, Inc, New York, NY, USA) and misoprostol (Cytotec,
G. D. Searle, Division of Pfizer, Inc, New York, NY,
USA).
Dinoprostone
Dinoprostone is FDA-approved for cervical ripening. It is
identical to the body’s own PGE2 and is available in 2
formulations: a vaginal insert (Cervidil) and a cervical gel
(Prepidil). Dinoprostone has a sustained and controlled
onset of action and duration of effect, with a half-life of
approximately 2.5–5 min [31]. Both formulations require
cold storage to keep the compound chemically
stable [31, 95].
The cervical gel releases dinoprostone more rapidly than
the vaginal insert. Consequently, the dinoprostone vaginal
insert provides a more gradual increase in plasma PGE2
levels and a longer duration of action [96]. The vaginal
insert releases dinoprostone at a rate of 0.3 mg/h for 12 h
123
Arch Gynecol Obstet
[31]. It has been suggested that the vaginal insert is more
convenient than the cervical gel because it can be easily
removed, is less invasive, and requires fewer vaginal
examinations [96].
Misoprostol
Misoprostol is a synthetic analog of PGE1 that is stable at
room temperature [45, 96]. It is approved by the FDA for
the prevention and treatment of gastrointestinal (GI) ulcers
and peptic ulcer disease caused by prostaglandin inhibitors,
such as NSAIDs [97]. However, it is widely used for the
off-label indications of cervical ripening, labor induction,
termination of pregnancy, and managing post-partum
hemorrhage. Misoprostol has several potential advantages:
significantly lower cost and longer shelf life than dino-
prostone, and no need for refrigeration.
Misoprostol can be administered via several possible
routes (oral, rectal, sublingual, and vaginal); however,
absorption is variable. With oral administration, plasma
concentrations rise quickly, peak between 12.5 and 60 min,
and fall steeply by 120 min [98]. With vaginal tablet
administration, levels gradually increase to a maximum
between 60 and 120 min and decline slowly to about 60%
of the peak level at 240 min [98]. Because misoprostol
tablets are not designed for vaginal administration,
absorption may be slow or erratic [96]. The bioavailability
of vaginal misoprostol is 3 times higher than that of oral
misoprostol [98]. A study comparing the pharmacokinetic
profile of a vaginal misoprostol insert (100–400 mcg) and
oral misoprostol (200 mcg) in nonpregnant women repor-
ted a mean half-life of 44–50 min for the vaginal insert and
37 min for oral misoprostol [99]. The standard dosage,
regimen, and safety of misoprostol administered by the
buccal or sublingual routes have not been fully ascertained.
Consequently, these routes of administration are not yet
recommended for routine use [100].
Efficacy and safety of prostaglandin formulations
in cervical ripening and labor induction
Both dinoprostone and misoprostol facilitate the remodel-
ing of cervical extracellular collagen, increasing water
content and promoting changes in the glycosaminoglycan
content of the cervical extracellular content [94]. Together,
these effects cause the softening, effacement, and dilation
of the cervix. However, the previously discussed differ-
ences in biochemical activity and receptor activation and
inhibition between PGE1 and PGE2 may have important
implications for the clinical activity of dinoprostone and
misoprostol.
Arch Gynecol Obstet
Efficacy
Compared to placebo or no treatment, dinoprostone has
been shown to enhance cervical effacement and dilation,
reduce the rate of failed inductions, shorten the interval
between induction and delivery, reduce oxytocin use, and
reduce the rate of cesarean delivery [100, 101]. A Cochrane
review of trials comparing dinoprostone formulations
found that PGE2 formulations were similarly effective,
with no differences in rates of cesarean delivery [102].
Multiple studies have shown that misoprostol tablets
administered vaginally or orally are either superior or
equivalent in efficacy to the dinoprostone gel
[100, 103, 104]. In fact, clinical trials and meta-analyses
have shown that vaginal use of misoprostol improved
cervical ripening and reduced the rate of failure to achieve
vaginal delivery [100, 105, 106]. Compared with other
vaginal prostaglandins, vaginal misoprostol was more
effective in facilitating vaginal delivery within 24 h and
reduced the need for oxytocin supplementation
[100, 104–106]. Moreover, a Cochrane review of 76 ran-
domized trials reported that oral misoprostol was at least as
effective as vaginal misoprostol [103]. Finally, a meta-
analysis of 96 randomized controlled trials reported that
vaginal dinoprostone was more effective than oral miso-
prostol in reducing the number of vaginal deliveries not
achieved in 24 h, but oral misoprostol was the most
effective in reducing cesarean section rates [104].
Safety
Key safety considerations with the use of prostaglandins in
cervical ripening include an increased risk of tachysystole,
which could potentially lead to a non-reassuring fetal heart
rate and to fetal hypoxemia. Studies suggest that women
receiving misoprostol may be at greater risk for these
complications than those receiving dinoprostone
[103, 104, 107]. Misoprostol is also associated with an
increased incidence of meconium-stained amniotic fluid. In
addition, there have been reports of uterine rupture after
misoprostol administration in women with a history of
prior cesarean delivery [103, 104, 107].
Rates of cesarean delivery for the indication of fetal
distress have been shown to be higher among multiparous
women who received misoprostol compared to those who
received dinoprostone [108]. Because misoprostol also
directly stimulates EP3-mediated uterine contractions and
EP3 receptors tend to be upregulated during labor, differ-
ences between the potencies of misoprostol and dinopros-
tone as EP3 receptor agonists and their selectivity for EP3
may help explain why deliveries occur more rapidly with
misoprostol and why rates of adverse events are lower with
dinoprostone.
Uterine hyperstimulation can result in fetal hypoxemia,
which can manifest as an abnormal heart rate and other
signs of fetal distress, including meconium staining [109].
Rates of uterine tachysystole, with or without changes in
fetal heart rate, are related to dose and route of adminis-
tration of misoprostol and dinoprostone, with higher rates
observed at higher doses [110]. In a recent network meta-
analysis, vaginal misoprostol at doses of 50 mcg or greater
was associated with a nearly 3-fold increase in the risk of
hyperstimulation compared to the vaginal dinoprostone
insert [111]. A comparison of misoprostol, dinoprostone
gel, and dinoprostone insert found that misoprostol was
associated with increased incidence of uterine tachysystole
compared with dinoprostone gel or insert [112]. However,
no differences in rates of cesarean delivery or reduced
neonatal Apgar scores were observed among the groups.
Similar results were reported in a 2015 meta-analysis
demonstrating lower rates of uterine hyperstimulation with
fetal heart rate changes with intracervical dinoprostone
compared with oral and vaginal misoprostol and with
vaginal dinoprostone compared with vaginal misoprostol
[104].
Misoprostol is associated with a higher rate of meco-
nium staining compared with dinoprostone and oxytocin,
although no association has been found with other adverse
neonatal outcomes [103]. It is possible that meconium
staining is a direct effect of misoprostol on the fetal gut,
since misoprostol is known to stimulate the GI tract and
can lead to diarrhea [94, 103, 105, 106]. However, some
differences in other indicators of fetal distress have been
observed between women who received oral vs vaginal
misoprostol, and among women who received higher (e.g.,
50 mcg) vs lower (e.g., 25 mcg) doses of vaginal miso-
prostol [103, 113]. Data indicate that vaginal misoprostol is
associated with a greater incidence of 5-min Apgar scores
\7 [103]. Higher doses of vaginal misoprostol may also be
associated with increased meconium staining and increased
rates of NICU admissions [113]. Few differences in cord
blood pH, an indicator of fetal oxygenation status, have
been observed in studies comparing different prostaglandin
preparations. However, it should be noted that studies
comparing prostaglandin formulations have not been
powered to detect differences in neonatal outcomes.
Misoprostol is not recommended in women at term with
a previous cesarean delivery due to increased risk of
uterine rupture [114]. However, other prostaglandins and
mechanical options may be considered after extensive
counseling on risk and benefits [100]. In a recent review of
outcomes in women attempting labor after cesarean
delivery, incidences of uterine rupture were 1.1% with
oxytocin, 2.0% with dinoprostone, and 6.0% with miso-
prostol [115]. A systematic review of cervical ripening
agents in the second trimester of pregnancy in women with
123

a history of cesarean delivery found that misoprostol was
associated with an increased risk of uterine rupture in
women with C2 cesarean sections but not among women
with only 1 cesarean section; PGE2 was not associated
with an increased risk of uterine rupture [116]. The use of
both misoprostol and dinoprostone is avoided in women
with a history of cesarean section at term [31, 114]. These
factors should be considered when selecting a cervical
ripening agent, particularly in patients at risk for the
adverse effects of prostaglandin therapies.
Tolerability
Because prostaglandin analogs exert their effects in the
median preoptic nucleus—the chief mediator of fever in
the hypothalamus—some women who are induced by
misoprostol or dinoprostone may experience chills or fever
[94, 117]. Other dose-dependent effects include diarrhea
and nausea, both of which are well-known side effects of
prostaglandin administration thought to be caused by the
impact of prostaglandins on the smooth muscle of the GI
tract [17, 118]. Each of these side effects appears to be
dose-dependent and much more common with oral miso-
prostol than with vaginal preparations [94]. In registration
studies, GI adverse effects were reported in 5.7% of
women assigned to dinoprostone gel vs 2.6% assigned to
placebo [95], while nausea, vomiting, diarrhea, and
abdominal pain were noted in less than 1% of patients who
received the dinoprostone vaginal insert [31].
Conclusions
While the two prostaglandin therapies (dinoprostone and
misoprostol) commonly used to facilitate cervical ripening
and induce labor have been in use for decades, the differ-
ences in their mechanisms are still under investigation.
Dinoprostone is a formulation of PGE2, while misoprostol
is a synthetic analog of PGE1. Each of these formulations
may have different effects on receptor expression, inflam-
mation, and myometrial contractility.
Although misoprostol has not been approved by the
FDA for use in labor induction, considerable evidence has
shown that oral or vaginal misoprostol and the dinopros-
tone gel or insert are effective for this indication. Both
dinoprostone and misoprostol are more effective than
oxytocin alone for cervical ripening. While some studies
have shown that women receiving misoprostol may be
more likely to deliver vaginally and may require less
oxytocin compared to dinoprostone, they may be at greater
risk for complications, including uterine hyperstimulation,
meconium-stained amniotic fluid, and uterine rupture in
women with a history of cesarean delivery. It is thought
123
Arch Gynecol Obstet
that the increase in rates of uterine hyperstimulation with
misoprostol may be due to its increased impact on uterine
contractility via the EP3 receptor.
Today, induction of labor occurs in more than 1 in 5
births in the United States. With the current range of
pharmacological and nonpharmacological options for cer-
vical ripening and induction of labor, it is critical for
clinicians to understand how the mechanisms of action of
these agents affect their efficacy, safety, tolerability, and
acceptability when making treatment decisions for their
patients. Additional research on the mechanisms underly-
ing cervical ripening and labor and the role of pros-
taglandins in these processes may help inform patient
management.
Acknowledgements The authors wish to thank Nicole Cooper of
MedVal Scientific Information Services, LLC, Princeton, NJ, USA,
for providing medical writing and editorial assistance funded by
Ferring Pharmaceuticals. This manuscript was prepared according to
the International Society for Medical Publication Professionals’ Good
Publication Practice for Communicating Company-Sponsored Medi-
cal Research: GPP3.
Author contributions All authors: project development, data col-
lection, data analysis, manuscript writing and editing.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
Funding Medical writing and editorial assistance on this manuscript
were funded by Ferring Pharmaceuticals.
Ethical approval Due to the retrospective nature of this review,
Ethics Committee approval is not relevant.
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