Endocrinology ofPreterm LaborV. DANIEL CASTRACANE, PhDTexas Tech University School of Medicine, Amarillo, Texas

Preterm labor is the most serious obstetricalproblem in 7–12% of pregnancies, and de-pending on population, results in up to 75%of neonatal morbidity and mortality. De-spite many years of dedicated investiga-tions, the cause and prevention of pretermlabor still elude us. This chapter is devotedto endocrine events that are associated withpreterm labor. There are several reasons tostudy the endocrinology of this importantclinical condition. The first would be tounderstand the physiology that contributesto the development of preterm labor. Al-though we are beginning to understand theevents leading to parturition, the story is notcomplete, and whether preterm labor is in-deed identical to normal term labor butadvanced by 10 or more weeks is not clear.An understanding of the physiology mayhelp us to manage this difficult clinicalenigma. The second reason for studying theendocrine conditions surrounding pretermlabor would be for the development of di-agnostic tests that may serve as more reli-able predictors of impending preterm labor.Some of these will be discussed in this

chapter. These would include the use ofsalivary estriol as well as the increasingimportance of corticotropin releasing hor-mone (CRH). Both of these may becomeuseful although neither alone would seemto be able to predict preterm labor in themajority of cases. Development of futureendocrine markers for preterm labor or per-haps the use of a series of endocrine mark-ers with independent physiology may bemore useful as a future diagnostic test todetermine which patients are at greatest riskfor preterm labor.

Estrogen and ProgesteroneAs we try to understand the physiology ofnormal parturition, the roles of estrogen andprogesterone seem to be essential. In mostspecies below primates, there is generally adecrease in serum levels of progesteroneand an increase in estradiol. Both of thesechanges would then allow the production ofprostaglandins contributing to uterine con-tractions. In the primate, including humans,there is no decline in progesterone. Only intwo instances out of many studies ofwomen has it ever been indicated that thereis a decline in progesterone in late preg-nancy, but there is a steady increase inestradiol. The relative increases in estradiol

Correspondence: V. Daniel Castracane, PhD, Professorand Director of Laboratories, Department of Obstetricsand Gynecology and Womens Health Research Insti-tute, Texas Tech University School of Medicine, 1400Wallace Boulevard, Amarillo, TX 79106. E-mail:debbie@cortex.ama.ttushc.edu.

CLINICAL OBSTETRICS AND GYNECOLOGYVolume 43, Number 4, pp 717–726© 2000, Lippincott Williams & Wilkins, Inc.

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far exceed the relative increases in proges-terone and consequently, over the course oftime, the estrogen to progesterone ratio in-creases producing an estrogenic effect. Pre-sumably, this allows a number of things tohappen and contribute to normal parturitionincluding the development of oxytocin re-ceptors that allow in late pregnancy themyometrium to be responsive to oxytocin.The increasing estrogen environment mayeven contribute to an increase in oxytocinreleased from the pituitary. The stimulationof prostaglandins is facilitated by the in-crease in estrogen, the decrease in proges-terone, and lastly, the development of gapjunctions that facilitate coordinated myo-metrial contractions that allow the fetus tobe delivered. Whether these same condi-tions contribute to preterm labor as well hasbeen the subject of a number of studies thathave investigated the role of estrogens andprogesterone in preterm labor.

Because of the long-accepted role of estro-gen in stimulating advanced parturition andprogesterone presumably being able to sup-press those events, studies of estrogen andprogesterone have been repeatedly investi-gated during the years as tools for managingor diagnosing preterm labor. The use of pro-gestins as a means to prevent or delay pretermlabor has been studied sporadically and theuse of this approach seems to recur periodi-cally. The use of progestins, either naturalprogesterone or 17-hydroxyprogesterone ca-proate, was associated with a significant re-duction in the frequency of preterm labor,preterm birth, and babies with low birthweight.1–4 They also reported that thereseemed to be no improvement in the inci-dence of preterm premature rupture of mem-branes, indicating that infection-associatedpreterm labor may not be affected by suchtreatment. The literature presents a number ofstudies in which progestins have been suc-cessful in delaying or preventing preterm la-bor but also other cases in which progestinshave not been effective. The conclusion to bemade from these earlier studies is that pro-gesterone may have an effect, but by itself

cannot be considered an effective means in alarge percentage of patients to prevent pre-term labor.

Similarly, for the diagnosis of pretermlabor, a number of studies have examinedserum levels of estradiol and progesteroneor the ratio of the two to determine whetherthis would be useful information. Similarly,these studies again offer us no compellingdiagnostic tool. It is interesting that salivaryestriol, which will be discussed in anothersection, seems to have some use in thisregard. Clearly, the role for estrogen is im-portant in that it facilitates prostaglandinproduction, the formation of oxytocin re-ceptors, the formation of gap junctions,probably allows interleukins to be pro-duced, and may even be responsible for theincreased production of prostaglandin pre-cursors, which seem to be an early event innormal term delivery and may also be in-volved in preterm delivery. All of thesefactors implicate estradiol as useful, butneither estradiol nor progesterone serummeasures have been uniformly useful inpredicting preterm labor.5,6

In contrast to those studies in which norole of estrogen or progesterone in pretermlabor is evident, there are reports that pro-gesterone/estradiol ratios were lower in am-niotic fluid of those who delivered preterm,that serum estradiol levels were signifi-cantly higher in serum,7 and that pretermand term parturition are two different endo-crinologic processes, based on these kindsof studies.8

The role of estradiol and progesteroneeffects has been interpreted as a change inprogesterone receptors during both pretermand term labor.9 An alternate interpretationhas been the blockade of the progesteronereceptor by cortisol, associated with thestress of labor and increased adrenalactivity.10

SALIVARY ESTRIOLFor many decades, we have known thatsaliva is a body fluid that can be used tomeasure steroid hormones and that an equi-

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librium exists between serum and saliva.Perhaps of major interest is that the equilib-rium exists between what is essentially thefree-steroid hormone in the serum and thatthose steroids that are tightly bound to serumprotein do not equilibrate. During the years, anumber of references have appeared on themeasurement of salivary steroid hormonesand their normal changes during the men-strual cycle and other physiologic conditions.In the nonpregnant patient, these assays, ofnecessity, need to be more sensitive than as-says designed for serum measurements be-cause the levels represent the free-fraction,which in the nonpregnant patient would below. In pregnancy in which the levels ofestrogens are high, the equilibrium is suchthat little change in assay sensitivity is neededto measure these salivary estrogens.

Another important aspect of measuringsalivary estriol is that estriol is a specialestrogen, “the estrogen of pregnancy.”Years ago, it was determined using labeledsteroid precursors, in studies that will prob-ably never be repeated, that approximately90% of the precursors for the production ofestriol in the maternal circulation comesfrom fetal precursors. Estriol is the endproduct of the fetal adrenal, producing de-hydroepiandrosterone sulfate (DHEAS)and then 16-hydroxylation in the fetal liver,which is a potent source of 16-hydroxylase.This additional hydroxyl group now allowsthis precursor to be converted into estriolby a series of steroidogenic reactions in theplacenta. The maternal liver has trivialamounts of 16-hydroxylase and conse-quently the mother makes little contributionto maternal serum estriol levels. For manyyears, the measurement of estriol, urinaryor plasma, was used as a marker of fetal-placental well-being. This diagnostic testhas diminished with the development offetal monitoring devices that allow instantassessment of the fetus and placenta, al-though estriol continues to be used as adiagnostic screening test as one of the se-ries of markers used in the prenatal screen-ing for Down syndrome. The importance of

estriol therefore represents fetal adrenal ac-tivity, perhaps an indication of the stressphenomenon in the fetus resulting ingreater adrenal activity, more precursors,and hence, more estriol in the maternalcirculation. Physiologists have long-soughtin the human some index of fetal contribu-tion to the timing of delivery and whetherthe increase in estriol may be a fetal signalfor both normal term labor as well as pre-term labor. Initial studies have used longi-tudinal sampling to demonstrate that thelevels of estriol are increased 2 to 4 weeksbefore delivery. This is true for both normalterm delivery as well as preterm delivery.This may be a useful test to diagnose pre-term labor in women at high-risk and whomay actually go on to deliver preterm.11

Unfortunately, the test is not foolproof anddoes not detect every patient who may de-liver preterm, probably because there aremultiple causes at the basis of preterm la-bor. In a typical early study of salivaryestriol as a diagnostic screen for pretermdelivery, there was a false-positive rate ofonly 26% but a negative predicative valueof 95%.12

CORTICOTROPIN-RELEASINGHORMONECorticotropin-releasing hormone was identi-fied as a hypophysiotrophic hormone in 1980.As postulated, this hormone was found inhypothalamic extracts and demonstrated to bethe trophic hormone that stimulated adreno-corticotrophic hormone (ACTH) productionin the pituitary. Surprisingly, the next year,CRH was identified in the placenta andwithin 2 years it demonstrated that levels in-crease 100-fold in maternal serum in the thirdtrimester before parturition. The roles thatCRH have in pregnancy indicate that thismay be one of the more important compo-nents leading to parturition and data clearlyassociate increasing CRH in patients withpreterm labor. It was found that if one mea-sured CRH levels throughout pregnancy, afamily of curves would be generated and thehighest levels of CRH, even early in preg-

Endocrinology of Preterm Labor 719

nancy well-before the timing of preterm de-livery, demonstrated that women who deliverprematurely had increased levels of CRH.These data suggested that the placenta and itsincreased ability to synthesize CRH is de-cided before the establishment of other fac-tors that may lead to preterm delivery.13 Sev-eral other studies have demonstrated thatincreased levels of CRH indicate a higher riskfor preterm delivery.14–16 Corticotropin-re-leasing hormone is bound to a circulatingbinding protein (CRHBP) which decreasesthe biologic activity of CRH. Later in gesta-tion, serum levels of CRHBP decrease, allow-ing the increase in serum levels of free-CRHand a greater biologic effectiveness at term.The decrease in CRHBP may be related to itsbinding with CRH and a more rapid clearancefrom the circulation.

Corticotropin-releasing hormone is notonly present in the maternal circulation, butalso crosses the placenta so that there areincreases in the fetal circulation. In the fetalcirculation, CRH stimulates both the fetalpituitary and the fetal adrenal to stimulateandrogen precursors to increase the placen-tal production of estrogens. Interestingly,CRH not only stimulates the adrenal butalso preferentially stimulates the produc-tion of dehydroepiandrosterone sulfate(DHEAS), the preferred precursor for theproduction of estrogens in the placenta.17

There are other actions of CRH that alsomay contribute to preterm labor, includingthe stimulation of myometrial contractionsbecause CRH receptors have been found inthe myometrium. This certainly may be anunexpected but important finding for itsrole in normal parturition as well as pretermlabor.

The commercial availability of a diag-nostic test for CRH has not been developed.Part of the problem may be that the vari-ability of CRH in individual patients maymake interpretation of serum levels difficultagainst the population with a broad normalrange.18 Clearly, this marker gives promisefor the future of a diagnostic test that can becommercially used. Clinical results and

predictions of preterm labor are required,and it may take several years. It is impor-tant to remember that the other availabletests, eg, salivary estriol or fetal fibronectin,by themselves do not have a high positivepredictive value, and some combination oftests may become essential, perhaps sali-vary estriol, fetal fibronectin, and maternalserum CRH may serve as a battery of tests,but together would have an increased pre-dictive value. An initial study to demon-strate the effectiveness of such an approachhas recently been reported.19

PROSTAGLANDINSWe have known for many years how effec-tive prostaglandins of both the E and F seriescan be in stimulating myometrial contrac-tions. In most species lower than the primates,there is a decrease in progesterone and anincrease in estrogen which facilitates the pro-duction of uterine prostaglandins, resulting inparturition. In primates, whereas the dramaticchanges in estrogen and progesterone foundin the lower vertebrates are not seen, there isa steady increase in the estrogen to progester-one ratio which facilitates the production ofprostaglandins along with other biochemicalchanges to facilitate the process. Prostaglan-dins are probably the most important agentsfor stimulating myometrial contractions atterm and probably preterm as well. We haveknown for many decades that prostaglandinsof both the E and F series are able to stimulateuterine contractions at any stage of pregnancyand indeed have been used for early andmidtrimester termination of pregnancy. Themyometrium is always able to respond toprostaglandins.

Prostaglandins have generally been re-ported to be increased in preterm labor,either with or without any associated infec-tion. The physiology of these increases maybe related to cytokines which represent an-other regulatory mechanism for the produc-tion of prostaglandins. A number of studieshave now demonstrated that interleukinsand tumor necrosis factor may be importantregulators of prostaglandins in preterm la-

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bor and may actively contribute to theirproduction.

Early reports of MacDonald et al indicateda role of prostaglandins in human parturitionand an increase in essential enzymes, andprostaglandin biosynthesis were noted duringthe process.20 Whether prostaglandin in-creases are the consequence of labor or actu-ally are biochemical events that precede aninitiation, this process has become an area ofcontroversy21 and most recently Casey andMacDonald22 concluded that infection-drivenprostaglandin release is a result rather than acause of preterm birth. A variety of factorsseem to be involved in the regulation of pros-taglandin production at preterm or termdelivery.23,24

The recent identification of two differentisoforms of cyclooxygenase (I and II), theenzymes essential for prostaglandin synthe-sis, now will change our interpretation ofthese events. Cyclooxygenase II seems to berapidly up-regulated in infections and may bea more important factor in infection-initiatedpreterm labor.

Because prostaglandins are importantmediators of preterm labor, it seems reason-able that inhibitors of prostaglandin synthe-sis may be effective in preventing or delay-ing preterm labor. There have beennumerous studies during the years demon-strating the effectiveness of compounds,such as indomethacin, to inhibit labor. Avariety of potentially serious side effectshave been implicated with the use of pros-taglandin synthetase inhibitors (eg, oligo-hydramnios, ileal perforation, prematureclosure of the ductus) particular if admin-istered less than 48 hours before delivery.This has dampened enthusiasm for the useof compounds such as indomethacin andhas generally limited their use to 34 weeksor earlier.25 Recently, the use of intravagi-nal indomethacin has been found to be aneffective route of administration associatedwith delaying preterm labor, higher birthweights, and shorter neonatal intensive careunit (NICU) stays.26 There may still be a

role for indomethacin in the management ofpreterm labor.

OXYTOCINFor many years, it was presumed that oxy-tocin had a minor role in normal term de-livery. This was based on the inability tomeasure appreciable changes of oxytocin ina standard daytime sample. Over the courseof the years, we have come to learn thatoxytocin has a greater involvement. Wenow recognize that oxytocin receptors areformed late in gestation, probably in re-sponse to increasing estrogen levels. Thisaccounts for the fact that oxytocin will notinduce delivery except in late gestationwhen estrogen has had the ability to inducethese oxytocin receptors. There are noctur-nal increases in oxytocin in late gestationassociated with nocturnal increases in es-trogen that may participate in the increasingrole of oxytocin at term.27,28 In addition,several studies have demonstrated that thenature of oxytocin release may be pulsatile,which may have accounted for some stud-ies not observing oxytocin increases in lategestation.29 In addition, the fetal hypothal-amus has also been shown to produce oxy-tocin30 as well as an expression of oxytocinmRNA demonstrated in human chorion,amnion, and decidua, with an increase indecidual levels at the onset of parturition.31

This information, most of it relatively re-cent, has made a stronger case for oxytocinas a normal participant in the timing of termand, perhaps, preterm deliveries.

The role of oxytocin in preterm labor isalso of recent interest and data are still inthe early stage. There are reports of in-creased oxytocin levels in women destinedfor preterm labor, and increased oxytocinreceptor concentrations were noted inwomen in preterm labor.32 The appearanceof increased oxytocin receptors may be lim-ited to subsets of the population and maynot represent the mechanism whereby allpatients become responsive to oxytocin asan initiator of preterm labor.

Perhaps the most compelling piece of

Endocrinology of Preterm Labor 721

information for the importance of oxytocinin preterm labor is the use of oxytocinantagonists and their ability to delay pre-term labor. Several oxytocin antagonistshave been developed in the past decade.The one that seems to have been developedfirst and to have the most clinical data col-lected, generally begun in Europe with clin-ical trials and now in the United States, isatosiban. The characteristic of this antago-nist is that the amino acid structure is sim-ilar to oxytocin, usually differing in twoamino acids, that renders these compoundsresistant to oxytocinase, and the longerhalf-life then contributes to their more po-tent antagonist action. Treatment withatosiban results in a significantly greaterdecrease in contraction frequency than withplacebos (55% vs 27%). Contractions werecompletely prevented in 14 of 56 womenreceiving atosiban and in only 3 of 56women that received placebo, with no sig-nificant adverse events in these studies.33

The future of oxytocin antagonist therapyas a means to prevent or delay pretermlabor is in doubt because the Food andDrug Administration has recently decidednot to approve the drug for use in theUnited States. This decision was based pri-marily on the observation that there was noimprovement in outcomes and questions ofadverse outcomes at lower gestational ageswere not clear. More clinical trials havebeen suggested.34

It is difficult to find an animal model ofpreterm labor that is useful for experimen-tal manipulation with enough relevance tothe human situation. In the rhesus monkey,the infusion of androstenedione results inpreterm labor because it serves as a precur-sor for estrogen synthesis and also in-creased oxytocin levels which eventuallyinduce preterm labor. It is interesting that inthis experimental model the nightly infu-sion of the oxytocin antagonist, atosiban,was able to interrupt the progression lead-ing to preterm labor. This information andthe animal model suggest that oxytocinmay be an important component in the

management of preterm labor. This animalmodel may be useful in our further under-standing of factors involved in the initiationof preterm labor. At the present time, theuse of atosiban remains questionable andfurther trials may be necessary.

RELAXINRelaxin is a protein hormone produced bythe corpus luteum and is secreted into theperipheral circulation. Levels of relaxinduring pregnancy are increased in the firsttrimester and slightly decreased thereafter,but remain increased in the second andthird trimester, above normal luteal phaselevels. Serum levels of relaxin are predom-inantly, if not exclusively, from the corpusluteum. We do know, however, that thereproductive tract, particularly the placentaand decidua, have the ability to synthesizerelaxin, but this seems to be maintainedwithin the reproductive tract, probably for aparacrine regulation of reproductive tissues.Relaxin does have a role in pregnancy andit seems to synergize with progesterone tosuppress myometrial contractions but moreimportantly it may be one of the majorcomponents involved in cervical ripening.Many years ago, it was observed that re-laxin was increased in most patients thatexperienced preterm labor.35,36 These weresmall studies but the suggestion was im-planted early.

In ovulation induction cycles in whichwomen are stimulated to ovulate multiplefollicles by treatment with exogenous go-nadotropins, multiple corpora lutea areformed and levels of serum relaxin aremarkedly increased in these patients whohave had in vitro fertilization. It is wellknown that patients with in vitro fertiliza-tion have a high incidence of preterm laborand it was suggested by Weiss et al37 thatrelaxin may be a contributing factor to thisearly labor. Serum levels of relaxin at 6 to12 weeks of gestation are indeed higher anddo correlate with earlier labor. Of course,the corpus luteum produces many sub-stances, and other endocrine factors may

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also contribute. Further studies are requiredto determine the role specifically of relaxinand/or other substances in the initiation ofpreterm labor. The demonstration of in-creased relaxin mRNA in decidua of pa-tients in preterm labor, even in the absenceof infection, is an even stronger indicationfor a relaxin role in preterm labor.38

CYTOKINESPerhaps the area of most recent interest andpotential diagnostic usefulness has been therole of cytokines in preterm labor. Gener-ally, our understanding of physiology pro-ceeds from the basic to the pathologic. Inthis case, we would expect that an under-standing of normal term parturition and therole of cytokines would lead us to an un-derstanding of these agents in preterm la-bor. Conversely, because of the tremendousclinical importance of preterm labor, cyto-kines have been studied in the pathologiccondition, preterm labor and delivery, andare only now beginning to be applied tonormal term labor. The role of cytokinesmay be most effective in the diagnosis ofchorioamnionitis because the productsof infection may include any of a variety ofcytokines. It has been demonstrated that avariety of cytokines are detectable in amni-otic fluid and an increased production ofmany of these cytokines is observed in as-sociation with intrauterine infection. Thesewould include IL-1, IL-2, IL-6, IL-8, tumornecrosis factor-a (TNF-a), and granulo-cyte-macrophage colony stimulating factor(GM-CSF).39

There are now numerous studies to dem-onstrate that, in amniotic fluid, IL-6 is areliable index of intrauterine infection andits levels are increased and can predict pre-term labor in these cases. The further in-creases in IL-6 as well as other interleukinsseem to be related to more active stages oflabor.40–44 The role of other interleukins inbeing able to detect preterm infections hasalso been initiated. TNF-a would seem tobe second most important in terms of stud-ies performed and its use as an indication of

infections,43,41,45 although initial reports formany other interleukins would indicatesimilar diagnostic usefulness.46–49 Thespectrum of interleukins seems to groweach year and a recent report on IL-16demonstrating amniotic fluid concentra-tions being increased with preterm laborleading to preterm delivery50 indicates thescope of potential interleukin indicators. Atthe present time, IL-6 and TNF-a seem tobe the most promising in this literature, butan array of interleukin diagnostic tests areindicated and available.

A controversy still exists whether interleu-kins represent only infection-initiated pretermlabor and whether these agents initiate laboror are an accompaniment of the labor pro-cess.51 Certainly, we must focus on those thatare most reliable and the next few years willdefine these actions. It is important to remem-ber that these interleukins are produced by avariety of tissues and different effects in dif-ferent tissues may be an expression of local orparacrine actions. Amniotic fluid levels maynot always explain actions within the repro-ductive tract. Serum levels are too far re-moved from the site of action to be reliableindices for this test. There are several meth-ods to obtain amniotic fluid and some reportshave used cervicovaginal fluid as a means toobtain this biologic sample. Others have usedtransabdominally-obtained amniotic fluid.Obviously, the route of collection may con-tribute to an effect on culture results andperhaps even on cytokine levels. Initial stud-ies clearly indicate a role for cytokines asso-ciated with infection.52 Whether cytokineshave a role in normal term delivery is notclear, but this is an active area of investiga-tion. The future of preterm labor therapy willprobably involve some anticytokine therapy,and the route of administration will have to beanatomically correct for these agents to beeffective.

SummaryThe clinical importance of preterm laborand delivery dictates that we understand the

Endocrinology of Preterm Labor 723

physiology and diagnostic usefulness of en-docrine as well as other agents that may behelpful in this regard. Clearly, estrogen andprogesterone establish the environment thatallows parturition and probably preterm la-bor to occur. The use of salivary estriol,though not a foolproof test, is becomingmore frequent and is commercially avail-able. Fibronectin, though not an endocrinetest, has a similar diagnostic usefulness. Inthe future, we would expect to see CRH andeven the use of selective cytokines, proba-bly IL-6, as possible diagnostic tests.Whereas all of these agents have some di-agnostic usefulness, none of them can beexpected to predict every case of pretermdelivery and some battery of tests, not un-like the triple or quadruple tests that areused for prenatal diagnosis of Down syn-drome, may be effective and should be ex-amined in the future. The use of these tests,salivary estriol and fetal fibronectin in par-ticular, has already had an effect on man-agement and decision making involved inpreterm labor, and the future should give usmore options and hopefully, better choicesto manage this most difficult condition.

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