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322 S. Mesiano, T.N. Welsh / Seminars in Cell & Developmental Biology 18 (2007) 321331

progesterone withdrawal and estrogen activation initiate parturi-

tion by transforming the myometrium to a highly contractile and

excitable state. This review focuses on recent progress in under-

standing of how progesterone maintains myometrial relaxation

for most of pregnancy and how estrogens promote a contractile

state. We also examine recent data regarding the mechanism for

progesterone withdrawal and estrogen activation in human par-

turition and how these key events are mediated, coordinated and

controlled.

2. The relaxatory actions of progesterone

Progesterone affects myometrial contractility through

genomic and non-genomic pathways. Genomic pathways func-

tion by altering the expression of specific contraction associated

genes to modulate the long-term contractile phenotype. Non-

genomic pathways in contrast are more rapid and directly affect

the contractile machinery by modulating intracellular signal

transduction pathways.

2.1. Genomic actions of progesterone

Genomic actions of progesterone are mediated by the classic

nuclear progesterone receptors (nPRs) that function as ligand-

activated transcription factors. The human nPR gene encodes

two major products, the full-length PR-B and the truncated (by

164 N-terminal amino acids) PR-A, under the control of two

separate promoters [25]. Other proteins generatedby exondele-

tions and intronic insertions have also been reported (see[6]for

review); however, their physiological roles are uncertain. Mul-

tiple in vitro studies suggest that PR-B is the principal mediator

of genomic progesterone actions. PR-A also modulates the tran-scription of some genes; however, it mainly acts to repress the

transcriptional activity of PR-B [79]. Theextent to which PR-A

decreases PR-B activity depends on its amount relative to PR-

B. Thus, genomic progesterone responsiveness is determined

by the dual and opposing actions of PR-A and PR-B, and is

inversely related to the PR-A/PR-B ratio.

The induction of labor and delivery by treatment with

nPR antagonists such as RU486, reflects the importance of

nPR-mediated progesterone actions for the maintenance of

myometrial relaxation during pregnancy. The principal genomic

mechanism by which progesterone represses myometrial con-

tractility is by modulating the expression of genes encoding

contraction-associated proteins (CAPs). Some important CAPsinclude the oxytocin receptor (OTXR) and the prostaglandin

(PG)-F2 (PGF2) receptor (FP), the gap-junction protein

connexin-43 (Cx43) and the PG-metabolizing enzyme 15-

hydroxy-PG-dehydrogenase (PGDH). Progesterone decreases

myometrial OT and PGF2responsiveness by inhibiting OTXR

and FP expression, respectively [1014]. In pregnant rats,

removal of endogenous progesterone by ovariectomy or inhi-

bition of progesterone action with RU486 treatment increases

myometrial OTXR expression and OT responsiveness. Pro-

gesterone decreases myometrial OTXR levels indirectly by

inhibiting estrogen-induced OTXR expression [15,16]. Inter-

estingly, progesterone also inhibits stretch-induced myometrial

OTXR expression in rats [17,18], suggesting that it represses

multiple pathways that induce OTXR expression. Adminis-

tration of RU486 [19] or epostane [20,21] (a progesterone

synthesis inhibitor) to pregnant women at early and mid-

gestation increases the effectiveness of PG treatment to induce

labor, indicating that progesterone represses PG responsive-

ness. Importantly, progesterone also increases the inactivation

of PGs by increasing expression of PGDH in the myometrium

and chorion[2225].

Progesterone also decreases the development of coordinated

uterine contractions by inhibiting expression of Cx43, a major

component of myometrial gap-junctions that serve to synchro-

nize contractions over the entire uterus. Expression of Cx43 in

the human pregnancy myometrium increases with the onset of

labor[26], and in human myometrial cell cultures its expres-

sion is up-regulated by estrogen and inhibited by progesterone

[27,28]. Studies in rats showed that progesterone not only

decreases expression of Cx43 but also its translocation through

the Golgi and its assembly into functional gap-junctions at the

plasma membrane[29].Thus, progesterone decreases contrac-tile capacity by inhibiting Cx43 expression and gap-junction

formation.

Progesterone also augments activity of the cAMP/protein

kinase-A (PK-A) signaling cascade in myometrial cells. The

cAMP/PK-A pathway promotes smooth muscle relaxation in

part by PK-A-mediated inhibition of the phospholipase C

(PLC)/Ca2+ pathway (for reviewsee [30]; seealso Lopez Bernal,

this issue;Sanborn,this issue). Activityof PK-A is modulatedby

its association with A-kinase anchoring proteins (AKAPs) that

localize PK-A to specific intracellular compartments and facili-

tate its capacity to phosphorylate specific targets, especially PLC

[3133]. In rats, labor is preceded by a decrease in PK-A associ-ation with the AKAP complex[34],and progesterone treatment

prevents the parturition-related PK-A/AKAP decline [35]. Thus,

progesterone, through its effects on the PK-A/AKAPinteraction,

augments PK-A-mediated inactivation of PLC. This opposes

the capacity for stimulatory uterotonins such as OT and PGF2to increase intracellular Ca2+ levels, via the PLC/Ca2+ path-

way. That this action of progesterone was inhibited by RU486

suggests that it is nPR-mediated[35].

Thus, progesterone via its interactions with nPRs, maintains

myometrial relaxation by: (1) directly inhibiting CAP expres-

sion; (2) decreasing estrogen-induced CAP expression, and (3)

increasing the effectiveness of PK-A to inhibit PLC activity. In

vitro studies suggest that these actions are most likely medi-ated by PR-B in the human pregnancy myometrium[3638].

However, in PR-B-knockout mice, PR-A alone is sufficient to

mediate the pro-gestational actions of progesterone [39,40], sug-

gesting that species diversity exists in the role of the two nPRs

in pregnancy and parturition.

2.2. Non-genomic actions of progesterone

Non-genomic actions of progesterone are characterized by:

(1) a rapid time-course for response with a latency of min-

utes, rather than hours; (2) no requirement for nPR activity

or occupancy; (3) no requirement for RNA or protein synthe-

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S. Mesiano, T.N. Welsh / Seminars in Cell & Developmental Biology 18 (2007) 321331 323

sis; and (4) occurrence in response to conjugated progesterone

(e.g., progesterone-BSA) that cannot enter the target cell. These

effects are potentially mediated by the interaction of proges-

terone with specific mPRs that are coupled to intracellular

signaling pathways; activation of Src/MAPK cascade intracel-

lular signaling pathways by ligand activated nPRs, and/or by

progesterone interaction with neurotransmitter and peptide hor-

mone receptors (e.g., GABAAand OTXR).

Studies examining the rapid effects of progesterone on iso-

lated myometrial strips from various species generally showed

that it inhibits OT-induced contractions and that it uncouples

the excitationcontraction process (for review see [41]).How-

ever, in vitro studies using human pregnancy myometrium

yielded mixed results with some investigators reporting a rapid

relaxatory effect of progesterone and progesterone metabolites

[4246]while others reporting that progesterone augments con-

traction frequencybut decreases duration, amplitude and activity

area in term myometrial strips[4749].The reason for this vari-

ability is not readily apparent but could be due to difference in

theprogestins used andhow they were prepared,and thecontrac-tile state of the tissue before it was mounted on the myograph.

Nonetheless, the studies clearly demonstrated that progesterone

has a rapid non-genomic affect on myometrial contractility.

Several in vivo studies support the hypothesis that proges-

terone non-genomically influences myometrial contractility. In

one of the first clinical trials of progestin tocolysis, Hendricks

et al. [50] found that administration of a large bolus of pro-

gesterone into the amniotic fluid of women at term decreased

the frequency of spontaneous contractions and attenuated OT

responsiveness. The tocolytic effect of intra-amniotic proges-

terone therapy was rapid and in some women persisted for

several days. However, the number of subjects was small andthe data were somewhat anecdotal. In the mid-1960s Pinto et al.

[51]re-addressed the issue and reported that large amounts of

progesterone(100200 mg bolus iv; this is almost as much as the

placenta produces in 24 h at term) administeredto women in term

labor inhibited the frequency and intensity of uterine contrac-

tions within minutes. In one woman, progesterone completely

silenced the laboring uterus within 10 minutes of administra-

tion. In two other women, progesterone inhibited spontaneous

contractions but failed to decrease the intensity of contractions

elicited by OT. Those data demonstrated direct non-genomic

relaxatory actions of progesterone at high doses; however, study

cohorts were small. Importantly, Pinto and colleagues later

found the same effects of progesterone on isolated myometrialstrips[46].

Two recent clinical studies reported that administration of

moderate doses of progesterone (100 mg daily by vaginal

suppository) or 17-hydroxyprogesterone caproate (250 mg intra-

muscular injection in oil weekly) starting at 16 weeks gestation

to women at high risk for preterm birth reduced the incidence

of preterm birth and improved neonatal outcome[52,53].The

mechanism by which progestin supplementation decreased the

rate of preterm birth is uncertain. Interestingly, da Fonseca

et al. [52] reported that women receiving progesterone via

vaginal suppositories and who presented with preterm labor

responded more favorably than women in the placebo group

to tocolytic treatment with -mimetics. It appeared that pro-

longed exposure of the myometrium to exogenous progestin

improved the effectiveness of tocolytic therapy. This was also

observed by Chanrachakul et al. [42] who reported that in

isolated term myometrial strips, progesterone, albeit at high

doses, decreased contractility and augmented the capacity for

ritodrine, a -mimetic commonly used for tocolytic therapy,

to block OT-induced contractions. They concluded that the

mechanism for this action is through a non-genomic path-

way, as it occurred soon after progesterone exposure. However,

using a similar approach, Sexton et al. [54] reported that 17-

hydroxyprogesterone caproate had no effect on spontaneous

or OT-induced contractions in myometrial strips. They sug-

gested that 17-hydroxyprogesterone-caproate affects the rate

of preterm birth via long-term genomic affects rather than by

direct non-genomic mechanisms. Clearly, further studies are

needed to determine the mechanism by which progestin treat-

ment decreases the incidence of preterm birth and in particular

whether this occurs through genomic or non-genomic pathways.

Several groups have reported that progesterone interacts withthe OTXR and that this interaction decreases contractility by

inhibitingOT-induced inositol triphosphate production and Ca2+

mobilization [5557]. However, this effect was species-specific;

Grazzini et al. [57]reported that progesterone interacted with

the rodent but not with the human OTXR. The human OTXR

instead interacted with 5-dihydroprogesterone, a 5 reduced

progesterone metabolite. This observation is consistent with

myograph studies showing that 5-dihydroprogesterone, but

not progesterone or 5-reduced progesterone metabolites, is a

potent myometrial relaxant that decreases basal and OT-induced

contractile activity[45,5860].Thus, progesterone could relax

the myometrium in an intracrine manner through its conversionto 5-dihydroprogesterone. Sheehan et al. [61] found that in

human pregnancy, circulating levels of 5-dihydroprogesterone

and expression of the 5-reductase enzyme in the placenta

and myometrium decrease in association with the onset of

labor. Mitchell et al.[62]also found that the human pregnancy

myometrium expresses the 5-reductase enzyme and has the

capacity to generate 5-dihydroprogesterone.However,whether

5-dihydroprogesterone interacts with the human OTXR is con-

troversial, as others [63,64] could not confirm the outcome

reported by Grazzini et al. [57] and instead reported that the

human OTXR does not bind 5-dihydroprogesterone. This sug-

gests that 5-reduced metabolites of progesterone relax the

myometrium by interacting with other receptors. One possibilityis that the gamma butyric acid-A (GABAA) receptor is involved.

5-Dihydroprogesterone binds to the GABAAreceptor and this

interaction is in part responsible for the anesthetic effect of

these steroids [65]. Putnam et al. [66] found that in the rat

myometrium, a GABAA-specific antagonist blocked inhibition

of contractility by progesterone and its 5-reduced metabo-

lites suggesting that the relaxatory actions of those steroids

were mediated by the GABAA receptor. Importantly, GABAAreceptors have been identified in the human uterus [67].Thus,

progesterone metabolites, especially-reduced forms,may non-

genomically relax the myometrium by interacting directly with

the OTXR or with the GABAA receptor.

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Non-genomic actions of progesterone can also be mediated

by nPRs. PR-A and PR-B have proline-rich motifs in their N-

termini that, upon ligand binding, interact with the Src tyrosine

kinaseat the plasmamembrane to activate the Ras/Raf-1/MAPK

pathway [68,69]. Src is a key intermediate that couples hormone

signals at the plasma membrane with intracellular transduction

pathways involved in regulating a variety of cellular processes

including proliferation, differentiation, adhesion, migration, and

apoptosis[68].This may be an important mechanism by which

progesterone exerts tropic action on the pregnancy myometrium.

Whether this pathway affects contractility is uncertain. Putnam

et al. [66] found that RU486 reversed the rapid inhibition of

spontaneous contractility by progesterone in myometrial strips

from non-pregnant rats, suggesting that non-genomic relaxatory

actions of progesterone involve nPRs.

A number of unique membrane associated PRs (mPRs) have

recently been identified and characterized. Progesterone recep-

tor membrane component-1 and -2 (PGRMC1 and PGRMC2)

have single transmembrane spanning domains and interact with

plasminogen activator inhibitor of RNA binding-1 (PAIRBP1),which recruits the mPRs to form a multimeric progesterone-

binding complex on the plasmamembrane [7076]. In granulosa

cells, binding of progesterone to the PGRMCPAIRBP1 com-

plex activates protein kinase G and decreases intracellular Ca2+

levels [77]. The role of these mPRs in the onset/process of

labor and whether the human pregnancy myometrium expresses

PAIRBP1 is not known at this stage.

mPR,mPR and mPR are structurally related to G-protein

coupled receptors, having a typical seven-transmembrane

domain structure [78,79]. mPR and mPR are coupled

to inhibitory G-proteins and therefore, upon ligand binding

decrease intracellular cAMP levels [80]. Several studies haveshown that mPR and - are expressed in the human pregnancy

myometrium, whereas mPR expression is barely detectable

[8082]. Karteris et al. [80] found that ligand activation of

mPR and mPRin primary cultures of human term myome-

trial cells decreased cAMP levels and increased phosphorylation

of myosin. They proposed that these effects (decreased cAMP

and activation of myosin) augment contractility. However, they

also found that mPRand mPRincreased the transcriptional

activity of ligand-activated PR-B, which would be expected

to decrease contractility via the genomic pathway. To recon-

cile those opposing activities, they proposed that for most of

pregnancy the genomic actions of PR-B dominate to relax the

myometrium, and that mPR and mPR augment this pathwayby augmenting PR-B activity. At parturition, functional proges-

terone withdrawal (see below) negates PR-B actions, allowing

non-genomic actions mediated by mPR and - to prevail,

and therefore increase contractility by decreasing cAMP and

increasing myosin phosphorylation. This model proposes that

for most of pregnancy non-genomic and genomic actions of

progesterone conspire to relax the myometrium, whereas non-

genomic pathways mediated by mPRand mPRprevail after

functional progesterone withdrawal and promote contraction.

This may explain reports of progesterone increasing contractil-

ity of isolated strips of term human myometrium[49,83].This

would occur if the tissue was procured after genomic proges-

terone withdrawal. The idea of functional cross-talk between

the genomic and non-genomic pathways and the notion that

progesterone switches from promoting relaxation to enhancing

contraction are novel concepts that warrant further investigation.

However,Krietschet al. [84] haverecentlysuggested thatmPR,

-and -are not activated by progesterone and do not localize

to the plasma membrane. Clearly, further studies are needed to

confirm the model proposed by Karteris et al. and determine the

roles of mPRand -in the pregnancy myometrium.

3. Transformation to a contractile phenotype

Transformation of the myometrium from a relaxed to a

highly contractile state is an early and key event in the

parturition process. The biochemical and physical changes

include: increased Cx43 expression leading to increased cou-

pling between myocytes so that contractions are synchronized

across the whole uterus; increased sensitivity and contrac-

tile responsiveness to stimulatory uterotonins such as OT and

PGF2 due respectively to increased OTXR and FP expres-sion; increased production of PGs by the gestational tissues

and decreased inactivation of PGs in the myometrium; low-

ered threshold for myocyte excitability; and decreased capacity

for the cAMP/PK-A signaling pathway to maintain relaxation.

These events are controlled primarily by the combined effects

of progesterone withdrawal and estrogen activation.

3.1. Progesterone withdrawal

In most animals the onset of labor is preceded by a fall in

circulating maternal progesterone levels (i.e., a systemic pro-

gesterone withdrawal). In some species this is due to decreasedplacental progesterone secretion (e.g., sheep), while in others

(e.g., rabbit, mouse, rat) it is caused by regression of the corpus

luteum (CL)[8588]. The mechanism by which progesterone

withdrawal increases myometrial contractility is not clearly

understood. As mentioned above, studies with the progesterone

antagonist RU486 demonstrate that inhibition of nPR-mediated

progesterone action induces the full parturition cascade. This

suggests that withdrawal of genomic progesterone actions is a

key parturition-triggering event. Whether withdrawal of non-

genomic progesterone actions, including those mediated by

nPRs, is also required for myometrial transformation is uncer-

tain.

Themechanism for progesterone withdrawal in human partu-rition is uncertain. Unlike most other species, labor and delivery

in humans occur without a decrease in maternal, fetal and

amniotic fluid progesterone levels[8991],suggesting that pro-

gesterone withdrawal is not necessary. However, as RU486

treatment induces labor at all stages of human pregnancy, it is

generally considered that human parturition involves a form of

progesterone withdrawal that does not depend on a decrease in

circulating progesterone levels. Proposed mechanisms include:

(1) sequestration of free active progesterone by a circulating

progesterone binding protein; (2) intracrine inactivation of local

progesterone bioactivity by myometrial cells; (3) production

of an endogenous progesterone antagonist; and (4) decreased

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myometrial progesterone responsiveness (i.e., a functional pro-

gesterone withdrawal) mediated by changes in the levels of

specific nPRs or nPR co-activator/co-repressors (for review see

[92,93]). Indirect evidence for each of these mechanisms has

been reported but their definitive roles in human parturition

remain uncertain.

Several research groups, including ours, have tested the

hypothesis that functional progesterone withdrawal is mediated

by specific changes in myometrial nPR expression. Studies of

nPR protein[37,38,94]and mRNA[95]levels in myometrial

biopsies indicated that human parturition involves an increase

in the myometrial PR-A/PR-B ratio due to increased expression

of PR-A. Functional studies in myometrial cells showed that

an increase in the PR-A/PR-B ratio decreased genomic proges-

terone responsiveness mediated by PR-B [37,38]. We found that

PR-A and PR-B were exclusively expressed in myocytes in the

human pregnancy uterus and that the PR-A/PR-B protein ratio

was 0.5 (a PR-B-dominant state) at around 30 weeks, increased

to 1.0 (equal amounts of PR-A and PR-B) at term before labor

onset and increased further to around 3 (a PR-A-dominant state)in laboring myometrium[37].The pregnancy stage- and labor-

associated increase in the PR-A/PR-B ratio was almost identical

to data reported by Haluska et al. [94] in the rhesus monkey

(Fig. 1),a species that also lacks a systemic progesterone with-

drawal at parturition. Another truncated nPR, known as PR-C,

that also represses PR-B activity, has been found to increase

in fundal myometrium in association with labor at term [36].

Thus, studies so far suggest that functional progesterone with-

drawal in human parturition is mediated by an increase in the

myometrial PR-A (or PR-C)/PR-B ratio and that regionalization

exists in the uterus such that progesterone responsiveness is dif-

ferentially regulated in fundal (by PR-C) and lower segment (byPR-A) myometrium.

Functional progesterone withdrawal could also be medi-

ated by the inhibition of nPR interaction with target DNA.

nPR binding to nuclear extracts of term human decidua is

reduced in laboring compared with non-laboring tissue indi-

cating that the onset of labor involves changes in the nPR

Fig. 1. Comparison of the PR-A/PR-B protein ratio in human and rhesus mon-

key pregnancy myometrium. *P < 0.001 (Adapted from Merlino et al.[37]and

Haluska et al.[94]).

transcriptional complex[96].In the myometrium, labor is asso-

ciated with a decline in specific nPR co-activators, particularly

cAMP-response element-binding protein-binding protein and

steroid receptor coactivators-2 and -3 [97]. The reduction in

co-activators may decrease histone acetylation that effectively

closes chromatin around the progesterone response element,

making it inaccessible to the nPR transcriptional complex. Such

a scenario would explain the decrease in nPR binding to nuclear

response elements in decidual cells[96].As a variation on this

theme, Dong et al.[98]identified a protein known as polypirim-

idine tract-binding protein-associated splicing factor (PTB) that

specifically inhibits nPR transactivation and whoseexpression in

rat myometrium increasesat term. They proposed that this factor

contributes to functional progesterone withdrawal by acting as

an additional nPR co-repressor. Interestingly, PTB also controls

the splicing of myosin phosphatase targeting protein mRNAs,

and therefore the functional activity of myosin phosphatase, a

key determinant of smooth muscle contractility [99]. These data

demonstrate the complexity that underlies the genomic actions

of progesterone on myometrial contractility and the multiplelevels at which functional progesterone withdrawal could occur.

3.2. Estrogen activation

In 1967, Pinto et al. [46] examined the role of estrogens

in human parturition by administrating a large amount of

17-estradiol (200 mg intravenously in 1 h) to non-laboring

pregnant women at term. They found that estradiol treatment

increased uterine contractility and OT responsiveness within

46 h and accelerated the time to delivery. Those findings were

consistent with the stimulatory actions of estrogens on myome-

trial contractility and showed that the progesterone block isnot absolute and can be overcome by estrogenic drive. Stud-

ies in rats and sheep also demonstrated that treatment with

estradiol at mid-gestation induces preterm labor [100102].

Interestingly, Pinto et al.[46]also found that administration of

progesterone rapidly (within 10 minutes) blocked the stimula-

tory actions induced by 17-estradiol, supporting the hypothesis

that progesterone acts non-genomically to promote relaxation.

In the rhesus monkey, Nathanielsz et al. found that augment-

ing placental estrogen production (by the administration of

androstenedione, which is readily converted to estrogens by

the placenta) increases myometrial contractility and OT respon-

siveness and induces preterm birth [103,104]. Inhibition of

aromatase activity eliminated the induction of parturition byandrostenedione, confirming that its conversion to estrogens was

essential for the initiation of parturition[105].However, others

found that estradiol treatment alone had no effect on parturition

in the rhesus monkey even though circulating estradiol levels

weremarkedlyelevated [106]. Those inconsistent outcomes sug-

gest that local production of estrogens from androgen precursor

is more important than circulating estrogen levels. Further stud-

ies are needed to resolve this controversy. Nevertheless, data so

far demonstrate the critical role of estrogenic drive (i.e., estrogen

activation) for myometrial transformation to a contractile state.

In most species estrogen activation is mediated by an increase

in circulating estrogen levels and is coordinated with systemic

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progesterone withdrawal[85].However, in humans (and higher

primates) circulating estrogens increase at around mid-gestation

and continue to rise gradually until birth[8991].This has led

to the concept that estrogen activation in human parturition,

as with progesterone withdrawal, is mediated at the functional

level, by an increase in myometrial estrogen responsiveness.

Thus, for most of pregnancy the human myometrium appears

to be refractory to estrogens at least in terms of CAP gene

expression, and parturition involves functional estrogen acti-

vation whereby the myometrium becomes estrogen-responsive.

Refractoriness of the myometrium to estrogens for most of

pregnancy is likely due to very low levels of ER and ER.

Importantly, we found that ER expression is low in non-

laboring term myometrium and increases in association with

labor onset, suggesting that functional estrogen activation is

mediated by increased ER expression[95].We also found that

ERmRNA levels correlate with the PR-A/PR-B mRNA ratio

[95]indicating a functional link between the nPR and ER sys-

tems. This association is consistent with studies in a variety

of species showing that progesterone decreases uterine estrogenresponsiveness by decreasing ER expression [107110]. In the

pregnant rhesus monkey, treatment with RU486 at mid-gestation

increased myometrial ER expression indicating that proges-

terone decreases ER expression through an nPR-mediated

process[111].Taken together the current data suggest that pro-

gesterone via its interaction with PR-B inhibits myometrial ER

expression and causes the myometrium to be refractory to circu-

lating estrogens. The increase in myometrial PR-A expression

with advancing gestation decreases PR-B transcriptional activ-

ity and eventually eliminates the PR-B-mediated inhibition of

ER expression. According to this model (Fig. 2) functional

progesterone withdrawal, mediated by increased PR-A, induces

functional estrogen activation mediated by increased expression

of ER and therefore coordinates these critical parturition-

triggering events. Circulating estrogens can then transform the

myometrium to a contractile state. This paradigm implies that

a fundamental mechanism by which progesterone maintains

myometrial relaxation in human pregnancy is by blocking the

stimulatory actions of estrogens and that functionalprogesterone

withdrawal induces functional estrogen activation. This phys-

iologic interaction explains why inhibition of nPR-mediated

progesterone actions triggers the full parturition cascade, espe-

ciallyas estrogensare readily available to acton themyometrium

for most of human pregnancy. It also implies that human par-

turition is triggered by any event (e.g., local PGs, myometrial

stretch, inflammation) that increases myometrial PR-A expres-sion and induces functional progesterone withdrawal. Thus,

multiple parturition trigger pathways may converge on myome-

trial PR-A expression. A more detailed understanding at the

molecular level of how the myometrial progesterone-nPR and

estrogen-ER signaling pathways interact and are regulated

in human pregnancy may reveal novel targets to therapeuti-

Fig. 2. Schematic model of the genomic and non-genomic pathwaysby whichsteroid hormonesaffect contractility of the human pregnancy myometrium. For most of

pregnancy progesterone, via its interaction with PR-B in myometrial cells, inhibits expression of CAP genes and decreases responsiveness to estrogens by inhibiting

ER expression. Progesterone and/or its metabolite 5-dihydroprogesterone also exert non-genomic effects on the pregnancy myometrium by interacting with a

variety of mPRs. The effects of non-genomic progesterone actions on myometrial contractility are not well understood but it is generally considered that progesterone

decreases contractility via this pathway. At parturition PR-A expression increases until the PR-A/PR-B ratio reaches a point whereby the relaxatory actions mediated

through PR-B are repressed, i.e., functional progesterone withdrawal. As a consequence ERexpression increases and the myometrium becomes more responsive

to circulating estrogens which increase CAP expression and transform the myometrium to a highly contractile and excitable phenotype leading to the onset of labor.

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cally control human labor and address the problem of preterm

birth.

3.3. Genomics of myometrial transformation

Determination of the human genome sequence has led to the

development of novel and cutting-edge technologies to charac-

terize the relationship between global gene transcriptional status

(i.e., the transcriptome) and phenotype in cells and tissues speci-

mens. Techniques such as suppression subtractive hybridization

[112] and multidimensional cDNA and oligonucleotide array

platforms [113117] have been used to determine changes

in the myometrial transcriptome, encompassing thousands of

genes, that may account for its contractile transformation at

parturition (for review see [118]). The fundamental hypothe-

sis tested by these powerful techniques is that transformation

of the pregnancy myometrium from quiescence to contraction

involves changes in specific gene expression in myometrialcells.

Although many of these genes have been identified using more

conventional assay techniques, the global approach incorporatesthe entire transcriptome and therefore provides the opportu-

nity to reveal the complete spectrum of genes involved. This

approach generates novel hypotheses, which can then be tested

using regular approaches.

Studies so far have used a variety of platforms to compare the

transcriptome in myometrial biopsy specimens obtained before

and after the onset of labor at term [113116] and from the

fundal and lower uterine segments [117].Most analyses iden-

tified multiple genes whose expression changed (increased or

decreased by at least twofold) in association with the onset

of labor, however, there was little overlap between the cohorts

of genes identified in different studies. There was also markedvariation between some studies. Notably, Havelock et al. [117]

foundlittle difference in gene expression profiles between fundal

and lower uterine segment and in association with labor onset,

whereas Charpigny et al.[115]found that labor was associated

with a down-regulation of a large number of developmental-,

cell adhesion- and proliferation-related genes and a concomitant

increase in inflammatory- and contraction-associated genes. The

differences between study outcomes likely stem from variabil-

ity due to methodological factors related to the array platform,

the number of samples studied in each of the experimental

groups and the purity of the biopsy samples with respect to

myometrial cell content (biopsy specimens contain multiple and

varied cell types that contribute to total RNA content of theextract). These problems will likely be overcome as the array

technology improves and price of microarrays decreases, allow-

ing more replicates of laboring and non-laboring specimens to

be performed. Thus, at this stage the body of data regarding the

relationship between the myometrial transcriptome and contrac-

tile phenotype is inconclusive and no specific labor-associated

genomic pathways have been identified.

Interpretation of outcomes from array-based studies largely

depends on the existing knowledge-base of specific gene

function and the power of the computational and statistical tech-

niques to analyze and align gene expression data, which often

comprises large numbers of genes with unknown function, into

functional networks. Advances in clustering and hierarchical

techniques have allowed for the organization of gene expres-

sion data into functional networks; however, many of the genes

identified as altered by labor onset have unknown functions and

their relationship to phenotype is ambiguous at best. Clearly,

this will be less of a problem as understanding of individual

genes and gene networks advances.The useof multidimensional

statistical analyses, such as directed graphs and principal com-

ponent analysis, have been applied to determine how theoretical

causal pathways generated by microarray data sets interact to

impact on phenotype[119,120].This approach utilizes proba-

bilistic and statistical analyses of the expression data to develop

hierarchical causal pathways for a particular phenotype or con-

dition. For example, our analysis of qRT-PCR-based data-sets

using directed graphs suggested a causal relationship between

the activation of inflammatory pathways and functional proges-

terone withdrawal [119] whereby inflammation precedes and

possibly causes functional progesterone withdrawal. That con-

clusion is consistent with our earlier study using the PHM1-31

immortalized human pregnancy myometrial cell line in whichwe found that PGF2 preferentially increases PR-A expres-

sion[121].Thus, locally produced PGs may initiate myometrial

transformation and the onset of labor by first inducing func-

tional progesterone withdrawal via increased myometrial PR-A

expression. This approach exemplifies the advantage of inte-

grating outcomes from specific cause-effect studies (e.g., from

animal models, cell lines, tissue specimens and clinical studies),

multidimensional cDNA/oligonucleotide array studies and com-

putational analyses of theoretical causal pathways in an iterative

and informative paradigm to unravel the physiology of human

parturition.

4. Conclusions

In an evolutionary context, physiological triggers for partu-

rition would have been subjected to strong selective pressures

so that the timing for birth favors species survival by optimizing

neonatal outcome and minimizing risks to themother (and there-

fore future pregnancies) imposed by the pregnant and parturient

states. This perspective helps explain the remarkable diversity

in gestation length/birth timing and parturition control across

viviparous species. In contrast, the physiologic systems that

establish and maintain pregnancy exhibit relatively little diver-

sity. In this case a single hormone, progesterone (and possibly

its metabolites) maintains pregnancy and promotes myometrialrelaxation through a combination of genomic and non-genomic

mechanisms. In fact, theprogesterone block appears to be a com-

mon trait among viviparous species. As pregnancy advances,

stimulatory influences build up to progressively challenge the

progesterone block. Although the principal stimulatory drive to

myometrial contractility is imparted by estrogens (a trait that

also appears to be conserved), other important factors such as

uterine stretch, myometrial response to the intrauterine cytokine

milieu and the activity of a fetal and/or placenta-based physi-

ologic clock mechanism, are also involved. The combination

of estrogenic and other physiologic stimulators for parturition

and the level of co-operativity, functional overlap and redun-

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dancy between them, appear to be species-specific and were

likely selected based on their overall impact on reproductive

efficiency. Parturition initiates when the combined effect of all

stimulatory influences overcomes the progesterone block. Thus,

progesterone and estrogens play central roles in pregnancy and

parturition and the mechanisms that control and coordinate their

actions on the pregnancy myometrium are critical processes in

the physiology of birth timing.

Acknowledgements

Dr. Mesiano is supported by grants from the March of Dimes

Birth Defects Foundation (#6-FY05-68) and the National Insti-

tutes of Health (HD051563).

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