Professional Documents
Culture Documents
Parturition
Parturition
review article
Mechanisms of Disease
Parturition
Roger Smith, M.B., B.S., Ph.D.
T
he mechanisms that instigate parturition in humans have been From the Mothers and Babies Research
remarkably elusive, but some parts of the puzzle have begun to come together. Centre, Hunter Medical Research Institute,
John Hunter Hospital, Newcastle, Austra-
A key change in the field was the realization that human parturition is a dis- lia. Address reprint requests to Dr. Smith
tinctly human event — animal models can reveal only limited insights. Consequent- at the Mothers and Babies Research Cen-
ly, investigators of human parturition have come to understand that they must focus tre, Hunter Medical Research Institute,
John Hunter Hospital, Lookout Road, New-
on the pregnant woman, despite the ethical difficulties in conducting studies that in- castle NSW 2310, Australia, or at roger.
volve women in labor. smith@newcastle.edu.au.
Preterm birth occurs in 5 to 15% of pregnancies, depending on the population.1
N Engl J Med 2007;356:271-83.
The rates are rising in many developed countries, and there is a particularly high in- Copyright © 2007 Massachusetts Medical Society.
cidence of preterm birth among black Americans. Assisted reproduction, which can
increase the frequency of multiple gestations, is only a partial explanation.2 Birth be-
fore 37 weeks of gestation is associated with 70% of neonatal deaths, and there is a
strong inverse association between the perinatal death rate and the period of ges-
tation.
Infant morbidity is also related to a short period of gestation. In a Swedish study,
50% of children with cerebral palsy had been born prematurely.3 Although there has
been no reduction in the incidence of preterm birth over the past 30 years, the de-
velopment of neonatal intensive care has improved survival considerably. The short-
term costs of neonatal intensive care are extremely high, and the long-term costs of
medical and educational services for a child who was born prematurely make pre-
term birth particularly expensive.4
Within the class Mammalia, individual species show considerable similarity in many
aspects of physiology. Reproduction, however, is an important exception. The devel-
opment of a placenta is a common feature of reproduction in most mammals, but
variations on the theme of parturition among placental mammals are considerable.
For example, parturition in sheep is initiated by processes involving the fetal hypo-
thalamus, pituitary, and adrenal glands,5,6 whereas parturition in goats depends on
dissolution of the maternal corpus luteum.7 Haig has argued that the heterogene-
ity in mechanisms of parturition is due to a maternal–paternal genetic conflict8: pa-
ternal genes promote the provisioning of the fetus from maternal resources, whereas
maternal genes modify fetal nutrition to preserve resources for the provisioning of
later offspring, which may arise from a different father.
Comparative genomic analyses have revealed that almost 95% of human and chim-
panzee DNA sequences are shared,9,10 but one of the greatest differences between
the two species occur in genes related to reproduction. In addition, striking
changes in the female pelvis with the assumption of an upright posture by the human
ancestor australopithecus and increases in the size of the cranium as modern hu-
mans evolved have had consequences for parturition (Fig 1).11
Maternal CRH
Several studies have shown an association between
levels of maternal plasma CRH, which is of placen-
tal origin, and the timing of birth.15-19 Maternal
plasma CRH levels increase exponentially as preg-
nancy advances, peaking at the time of delivery.
In women who deliver preterm, the exponential
increase is rapid, whereas in women who deliver
after the estimated date of delivery, the rise is
slower.14,20 These findings suggest that a placental
clock determines the timing of delivery.14
Production of CRH by the placenta is restrict-
ed to primates.21-25 In monkeys, there is a mid
gestation peak in placental CRH production, but
only in great apes is there an exponential rise
similar to that in humans. Humans and great apes
also produce a circulating binding protein for
CRH (CRHBP). At the end of pregnancy, CRHBP
levels fall, thereby increasing the bioavailability of
CRH.26,27 Glucocorticoids stimulate expression of
the CRH gene and production of CRH by the pla-
centa.11,28-30 In turn, CRH stimulates the pituitary
to produce corticotropin, which causes the adre-
nal cortex to release cortisol. This arrangement
permits a positive feed-forward system that has
been shown by mathematical modeling to mim-
ic the changes actually observed in human preg-
nancy.31 Placental CRH production is also modi-
Figure 1. The Chimpanzee, Australopithecus, and Hu-
fied by estrogen, progesterone, and nitric oxide,
man Pelvises.
which are inhibitory, and by a range of neuropep-
The large aperture of the chimpanzee pelvis (Panel A)
permits easy passage of the relatively small head of the tides, which are stimulatory.32-35 In an individual
fetus in an occiput posterior position. In australopithe- woman, the rising levels of placental CRH in ma-
cus (Panel B), the widening of the ilium associated ternal blood follow an exponential function that
with upright posture and the anteroposterior narrow- is characteristic for that particular pregnancy.
ing of the pelvic aperture require delivery of the head
Small changes in the exponential function describ-
in a lateral position. The human pelvis (Panel C) has
an aperture just large enough to allow passage of the ing CRH production lead to large differences
head of the fetus in an occiput anterior position. among different women later in pregnancy. Not
all cases of preterm birth are related to changes
in placental CRH production; in particular, intra-
uterine infection, a relatively frequent cause of
C or t ic o t ropin-R el e a sing preterm birth, is not associated with elevated pla-
Hormone and the Timing of Birth
cental CRH production. For this reason, a low
Human pregnancy lasts for approximately 38 weeks level of maternal plasma CRH does not rule out
after conception, with minor variations among preterm birth. A single CRH measurement has
ethnic groups.12 The timing of birth in mice is relatively low sensitivity for predicting preterm
closely linked to the maturation of the fetal lungs.13 birth, although in an individual woman, a high
CRH level has a relatively specific association with as oxytocin and prostaglandin F2α, that promote
a greatly increased risk of preterm birth. Given the uterine contraction,44,45 but it has been difficult to
large variations among pregnant women, it is replicate these findings.
likely that the rate of increase in maternal CRH
levels is the most accurate predictor of the outcome CRH in the Fetus
of pregnancy and is the critical variable.36,37 In Placental CRH is also released into the fetus, and
assessing CRH values, it is necessary to adjust for although the concentrations are lower in the fetal
race or ethnic group. Black American women have circulation than in the maternal circulation, they
lower maternal plasma CRH levels than other still rise with advancing gestation46 (Fig. 2). In the
racial or ethnic groups, although among black fetus, CRH receptors are present in the pituitary47
American women, CRH concentrations do corre- and on the cells that form the fetal zone of the ad-
late with the timing of birth.38,39 renal gland.48 Stimulation of the fetal pituitary by
CRH increases corticotropin production and, con-
CRH Receptors sequently, the synthesis of cortisol by the fetal ad-
CRH is secreted from the placenta predominant- renal gland and maturation of the fetal lungs. In
ly into the maternal blood, but it also enters the turn, the rising cortisol concentrations in the fe-
fetal circulation.40 CRH acts primarily by bind- tus further stimulate placental CRH production.
ing to the CRH type 1 receptor, a member of the The maturation of the fetal lungs as a result of in-
seven-transmembrane G protein–coupled recep- creasing cortisol concentrations is associated with
tor superfamily.38 In the mother, CRH receptors increased production of surfactant protein A and
are present in the pituitary, the myometrium, phospholipids, both of which have proinflamma-
and probably the adrenal glands. In the fetus, tory actions and may stimulate myometrial con-
there are CRH receptors in the pituitary, the ad- tractility through increased production of prosta-
renal glands, and perhaps the lungs. Rising lev- glandins by fetal membranes and the myometrium
els of CRH can therefore act at multiple sites in itself. In baboons, CRH directly stimulates fetal
mother and fetus to initiate the changes associ- lung development and strongly induces surfactant
ated with parturition. phospholipid synthesis,49 but it is not clear wheth-
Increased placental CRH levels drive the rise in er this occurs in humans.
maternal cortisol and corticotropin levels as ges- CRH stimulation of fetal adrenal zone cells,
tation advances, although the effect is moderated which lack 3β-hydroxysteroid dehydrogenase, pref-
by the circulating binding protein and the desen- erentially causes placental formation of DHEA, the
sitization of CRH receptors by continuous expo- precursor of estrogen and an important hormone
sure to high levels of CRH.39,41 The increased levels in pregnancy.48 The fetal zone of the adrenal
of CRH and corticotropin promote the production glands involutes rapidly after delivery of the pla-
of cortisol and dehydroepiandrosterone sulfate centa, indicating that placental factors, such as
(DHEAS) by the maternal adrenal glands; the in- CRH, maintain the fetal zone (Fig. 2). Thus, CRH
creased cortisol may stimulate further placental may stimulate adrenal steroidogenesis, thereby
release of CRH, and DHEAS provides a substrate providing the substrate for the placental produc-
for placental estrogen synthesis. tion of estrogens, which favor parturition by in-
There are several forms of CRH receptors in the ducing contraction.43
myometrium.42 Ligand binding to the most com- In summary, it appears that positive feed-
mon form, CRHR1α, causes the dissociation of the forward systems in the mother and fetus drive
α subunit of the G protein, which relays signals an exponential increase in placental CRH produc-
from the CRH receptor to intracellular effectors. tion as gestation advances. Increased placental
These signals culminate in relaxation of the myo- CRH production, in turn, instigates a change in
metrial cell. At term, CRH receptors change to a fetal cortisol concentrations, fetal lung matura-
form that is less efficient in activating relaxation tion, amniotic fluid proteins, phospholipids, and
pathways in the myometrium. Instead, the recep- myometrial receptor expression, which combine,
tors activate the Gαq pathway, which is linked to through a set of independent activating pathways,
protein kinase C activation, and the contractile to precipitate labor and delivery. These pathways,
pathways.43 CRH has been reported to potentiate each capable of stimulating parturition, make the
the contractile effects of several uterotonins, such mechanism of labor robust.
toward the end of pregnancy, and the consequent creased myometrial stretching that occurs with
increasing tension of the uterine wall signals the multiple or abnormally large fetuses or excess am-
onset of parturition. On average, labor starts ear- niotic fluid.74 In most smooth-muscle organs,
lier with twins than with singletons and earlier stretching leads to contraction.75 The switch from
with triplets than with twins, and fetuses with the growth-accommodating behavior of the uter-
macrosomia or polyhydramnios are often prema- us during most of pregnancy to the stretch induced
ture; these trends are probably related to the in- by the cessation of uterine growth at labor appears
to be regulated by progesterone.76 It is likely that activity falls, exposing the underlying decidua,
progesterone withdrawal increases the attachment cervix, and myometrium to the proinflammatory
of myocytes to the intercellular matrix, through in- actions of prostaglandin E2.86 Prostaglandins
tegrins, and this process promotes activation of mediate the release of the metalloproteases that
mitogen-associated protein kinase and increases weaken the placental membranes, thereby facili-
contractility.77 tating membrane rupture. CRH also stimulates
As term approaches, there are increasing con- the secretion of membrane matrix metalloprote-
centrations of placental CRH, a boost in the syn- ase-9.87
thesis of corticotropin by the fetal pituitary, and
heightened steroidogenesis in the fetal adrenal Cervical Softening
glands. The DHEA produced in increasing amounts A critical component of normal parturition is the
in the fetal zone is rapidly metabolized by the pla- softening of the cervix. Parturition is associated
centa into estrogens. Concurrently, cortisol pro- with movement of an inflammatory infiltrate into
duction is increased in the definitive zone of the the cervix and the release of metalloproteases that
fetal adrenal glands.78 Rising fetal concentrations degrade collagen, thus changing the structure of
of cortisol induce maturation of many fetal tis- the cervix.88-90 During this process, the junction
sues, especially the lungs.79 The maturing fetal between fetal membranes and the decidua breaks
lungs increase production of the surfactant pro- down, and an adhesive protein, fetal fibronectin,
teins and phospholipids that are critical for lung enters vaginal fluids. The presence of fetal fibro-
function. The surfactant proteins also enter the nectin in cervical fluids is a clinically useful pre-
amniotic fluid, where they have macrophage-acti- dictor of imminent delivery.91,92
vating properties. In the mouse, surfactant pro-
tein A activates amniotic fluid macrophages, and Progesterone Withdrawal
these cells play a critical role in the onset of la- Progesterone plays a critical role in the develop-
bor.13 In humans, the amniotic fluid surfactant ment of the endometrium by allowing implanta-
proteins may well stimulate the inflammation tion and, subsequently, the maintenance of myo-
that is observed in the adjacent fetal membranes, metrial relaxation.93,94 In many mammals, a drop
cervix, and underlying myometrium at the time in circulating progesterone levels precipitates par-
of labor. There is considerable evidence that this turition; in humans, the progesterone antagonist
inflammatory process is one of the elements lead- RU486 can initiate parturition at any time during
ing to the onset of labor.80 During the last weeks pregnancy.95 A characteristic of human pregnan-
of pregnancy, CRH levels also rise in the amniotic cy is that the level of circulating progesterone does
fluid, which is in direct contact with the underly- not fall with the onset of labor.96 A search for
ing amnion.81,82 mechanisms that could account for a functional
withdrawal of progesterone has identified several
Fetal Membrane Activation forms of the progesterone receptor. These variants
The amnion lies in direct contact with the amniotic arise from transcription of the single progester-
fluid, giving constituents of the amniotic fluid un- one receptor gene at alternative start sites.97,98 Pro-
restricted access to the amnion (Fig. 2). The pro- gesterone receptor B, the most common transcript,
duction of surfactant proteins, phospholipids, and mediates many of the actions of progesterone; there
inflammatory cytokines in the amniotic fluid in- are shorter transcripts, however, including proges-
creases as cyclooxygenase-2 (COX-2) activity and terone receptors A and C. These variant receptors
prostaglandin E2 production increase in the am- lack an N-terminal–activating domain, and in some
nion. Concurrently, levels of cortisol and CRH, settings they function as dominant repressors of
both of which stimulate the production of COX-2, the function of the progesterone receptor B.97,99
rise in the amniotic fluid.81,83,84 These redundant With the onset of labor, the proportions of proges-
actions increase prostaglandin E2 and other me- terone receptors A, B, and C change in a way that
diators of inflammation in the amnion.85 could constitute a mechanism of progesterone
The chorion underlies the amnion (Fig. 2). It withdrawal.100,101 In addition, the function of pro-
produces the enzyme prostaglandin dehydroge- gesterone receptors requires specific coactivators,
nase (PGDH), which is a potent inactivator of including the progesterone receptor coactivators
prostaglandins. Late in pregnancy, chorionic PGDH cAMP-response element-binding protein and ste-
roid receptor coactivators 2 and 3,102 which de- tions, which implies a degree of reversibility of the
crease in abundance with the onset of labor.102 Pro- process, at least in the early stages. Tissue from
gesterone can be metabolized to products with human myometrium removed at cesarean section
different biologic properties. For example, at the before the onset of labor and placed in an organ
time of labor, the potent relaxation-inducing ste- bath under tension exhibits regular synchronized
roid 5β-dihydroprogesterone decreases as steroid contraction74; evidently, the contractile machin-
5β-reductase expression and activity drop.103 Nu- ery is present and capable of activity before the
clear transcription factor κβ may also be impor- physiologic activation of labor. A study compar-
tant in blocking the action of progesterone at the ing myometrial tissue samples obtained at cesar-
receptor level.85 ean section from women in labor with samples
obtained before the onset of labor has shown
Inflammation and the Onset of Labor that in both sets of samples, genes that encode
In rhesus monkeys and baboons, parturition at participants in inflammation, notably interleu-
term lasts for several days. Synchronized uterine kin-8 and superoxide dismutase, are consistent-
contractions occur each night, disappearing dur- ly up-regulated.96
ing the day, until delivery.104,105 Humans also have Understanding the progression to labor in hu-
the potential to go into and out of active contrac- mans has proven difficult because of the lack of
Figure 5. Maternal and Fetal Endocrine Systems Involved in Increased Placental Production of CRH.
Increased placental synthesis of CRH drives increased corticotropin and cortisol production in both mother and fetus. Increased cortisol
stimulates further production of CRH, generating a positive feed-forward loop and a consequent exponential rise in CRH synthesis. The
increased fetal cortisol leads to lung maturation, increased lung surfactant, and phospholipid production. Cortisol and surfactant proteins
activate inflammatory pathways in the amnion, leading to both cervical softening and myometrial activation. The myometrial activation
involves progesterone withdrawal and increased production of COX-2, which synthesizes prostaglandins and promotes contraction. Fetal
growth and consequent uterine myometrial stretching combine with progesterone withdrawal to further promote uterine contractility.
a good experimental model, but improved mod- levels in the maternal or fetal compartments and
eling techniques may advance our knowledge of consequent increases in placental CRH expres-
the processes involved (Fig. 5). Directed graphs sion.107-109 Infection activates inflammation and
(showing the direction of influence between vari- may stimulate prostaglandin synthesis in fetal
ables) that model competing hypotheses can be membranes. Abruption appears to affect the myo-
used to determine the compatibility of a particular metrium directly through the release of thrombin,
causal pathway with data from a group of sam- a potent stimulator of myometrial contraction.110
ples in a statistically rigorous manner.106 With In the case of multiple gestation and polyhydram-
this approach, it appears that increases in inflam- nios, increased uterine stretching activates myo-
matory factors such as COX-2 and interleukin-8 metrial contractility (Fig. 4).
are early events in the progression to active labor. The road to an understanding of human birth
These increases antedate changes in progesterone is circuitous and challenging. The goal is to pre-
receptors, which instigate alterations in estrogen dict which pregnancies carry a risk of preterm
receptors and, as a consequence, expression of birth and to intervene with appropriate measures.
connexin 43 and the oxytocin receptor (Fig. 5). The benefit will be substantial if we are able to
A better understanding of the pathway to nor- reduce the incidences of cerebral palsy and cog-
mal birth should provide the basis for identifying nitive impairment associated with preterm birth.
points along the pathway at which a pathological Supported by the Andrew Thyne Reid Trust.
process may precipitate preterm birth. The effects No potential conflict of interest relevant to this article was re-
ported.
of stress may be mediated by increased cortisol
References
1. Slattery MM, Morrison JJ. Preterm de- 12. Patel RR, Steer P, Doyle P, Little MP, ability to predict preterm delivery. Am J
livery. Lancet 2002;360:1489-97. Elliott P. Does gestation vary by ethnic Obstet Gynecol 2002;186:94-9.
2. MacDorman MF, Martin JA, Mathews group? A London-based study of over 20. Torricelli M, Ignacchiti E, Giovannelli
TJ, Hoyert DL, Ventura SJ. Explaining the 122,000 pregnancies with spontaneous on- A, et al. Maternal plasma corticotrophin-
2001-2002 infant mortality increase in the set of labour. Int J Epidemiol 2004;33:107- releasing factor and urocortin levels in
United States: data from the linked birth/ 13. post-term pregnancies. Eur J Endocrinol
infant death data set. Int J Health Serv 13. Condon JC, Jeyasuria P, Faust JM, 2006;154:281-5.
2005;35:415-42. Mendelson CR. Surfactant protein secret- 21. Smith R, Chan EC, Bowman ME,
3. Himmelmann K, Hagberg G, Beck- ed by the maturing mouse fetal lung acts Harewood WJ, Phippard AF. Corticotro-
ung E, Hagberg B, Uvebrant P. The chang- as a hormone that signals the initiation of pin-releasing hormone in baboon preg-
ing panorama of cerebral palsy in Sweden. parturition. Proc Natl Acad Sci U S A 2004; nancy. J Clin Endocrinol Metab 1993;76:
IX. Prevalence and origin in the birth-year 101:4978-83. 1063-8.
period 1995-1998. Acta Paediatr 2005;94: 14. McLean M, Bisits A, Davies J, Woods R, 22. Smith R, Wickings EJ, Bowman ME,
287-94. Lowry P, Smith R. A placental clock con- et al. Corticotropin-releasing hormone in
4. Petrou S. The economic consequences trolling the length of human pregnancy. chimpanzee and gorilla pregnancies. J Clin
of preterm birth during the first 10 years Nat Med 1995;1:460-3. Endocrinol Metab 1999;84:2820-5.
of life. BJOG 2005;112:Suppl 1:10-5. 15. Wolfe C, Poston L, Jones M. Digoxin- 23. Bowman ME, Lopata A, Jaffe RB, Go-
5. Liggins GC. Premature parturition like immunoreactive factor, corticotro- los TG, Wickings J, Smith R. Corticotro-
after infusion of corticotrophin or corti- pin-releasing factor, and pregnancy. Lan- pin-releasing hormone-binding protein in
sol into foetal lambs. J Endocrinol 1968; cet 1987;1:335-6. primates. Am J Primatol 2001;53:123-30.
42:323-9. 16. Warren WB, Patrick SL, Goland RS. 24. Goland RS, Wardlaw SL, Fortman JD,
6. Liggins GC, Fairclough RJ, Grieves SA, Elevated maternal plasma corticotropin- Stark RI. Plasma corticotropin-releasing
Forster CS, Knox BS. Parturition in the releasing hormone levels in pregnancies factor concentrations in the baboon dur-
sheep. Ciba Found Symp 1977;47:5-30. complicated by preterm labor. Am J Ob- ing pregnancy. Endocrinology 1992;131:
7. Cooke RG, Knifton A. The effect of stet Gynecol 1992;166:1198-204. 1782-6.
intra-aortic prostaglandin F-2 alpha on 17. Hobel CJ, Dunkel-Schetter C, Roesch 25. Power ML, Bowman ME, Smith R, et al.
uterine motility in pregnant goats. J Re- SC, Castro LC, Arora CP. Maternal plasma Pattern of maternal serum corticotropin-
prod Fertil 1980;59:347-50. corticotropin-releasing hormone associ- releasing hormone concentration during
8. Haig D. Genetic conflicts in human ated with stress at 20 weeks’ gestation in pregnancy in the common marmoset
pregnancy. Q Rev Biol 1993;68:495-532. pregnancies ending in preterm delivery. (Callithrix jacchus). Am J Primatol 2006;
9. Cheng Z, Ventura M, She X, et al. Am J Obstet Gynecol 1999;180:S257-S263. 68:181-8.
A genome-wide comparison of recent chim- 18. Wadhwa PD, Porto M, Garite TJ, 26. Linton EA, Behan DP, Saphier PW,
panzee and human segmental duplications. Chicz-DeMet A, Sandman CA. Maternal Lowry PJ. Corticotropin-releasing hor-
Nature 2005;437:88-93. corticotropin-releasing hormone levels in mone (CRH)-binding protein: reduction
10. Chimpanzee Sequencing and Analysis the early third trimester predict length of in the adrenocorticotropin-releasing ac-
Consortium. Initial sequence of the chim- gestation in human pregnancy. Am J Ob- tivity of placental but not hypothalamic
panzee genome and comparison with the stet Gynecol 1998;179:1079-85. CRH. J Clin Endocrinol Metab 1990;70:
human genome. Nature 2005;437:69-87. 19. Ellis MJ, Livesey JH, Inder WJ, Prickett 1574-80.
11. Rosenberg KR, Trevathan WR. The evo- TC, Reid R. Plasma corticotropin-releas- 27. Linton EA, Perkins AV, Woods RJ, et
lution of human birth. Sci Am 2001;285: ing hormone and unconjugated estriol in al. Corticotropin releasing hormone-bind-
72-7. human pregnancy: gestational patterns and ing protein (CRH-BP): plasma levels de-
crease during the third trimester of nor- Mood changes, obstetric experience and 54. Moran CJ, Friel AM, Smith TJ, Cairns
mal human pregnancy. J Clin Endocrinol alterations in plasma cortisol, beta-endor- M, Morrison JJ. Expression and modula-
Metab 1993;76:260-2. phin and corticotrophin releasing hormone tion of Rho kinase in human pregnant
28. Robinson BG, Emanuel RL, Frim DM, during pregnancy and the puerperium. myometrium. Mol Hum Reprod 2002;8:
Majzoub JA. Glucocorticoid stimulates J Psychosom Res 1990;34:53-69. 196-200.
expression of corticotropin-releasing hor- 40. Goland RS, Jozak S, Warren WB, Con- 55. Parkington HC, Coleman HA. Excit-
mone gene in human placenta. Proc Natl well IM, Stark RI, Tropper PJ. Elevated ability in uterine smooth muscle. Front
Acad Sci U S A 1988;85:5244-8. levels of umbilical cord plasma corticotro- Horm Res 2001;27:179-200.
29. Cheng YH, Nicholson RC, King B, pin-releasing hormone in growth-retard- 56. Asboth G, Phaneuf S, Lopez Bernal
Chan EC, Fitter JT, Smith R. Glucocorti- ed fetuses. J Clin Endocrinol Metab 1993; AL. Prostaglandin E receptors in myome-
coid stimulation of corticotropin-releas- 77:1174-9. trial cells. Acta Physiol Hung 1997;85:39-
ing hormone gene expression requires a 41. Owens PC, Smith R, Brinsmead MW, 50.
cyclic adenosine 3',5'-monophosphate reg- et al. Postnatal disappearance of the preg- 57. Lopez Bernal A. Mechanisms of la-
ulatory element in human primary pla- nancy-associated reduced sensitivity of bour — biochemical aspects. BJOG 2003;
cental cytotrophoblast cells. J Clin Endo- plasma cortisol to feedback inhibition. 110:Suppl 20:39-45.
crinol Metab 2000;85:1937-45. Life Sci 1987;41:1745-50. 58. Shlykov SG, Yang M, Alcorn JL, San-
30. Korebrits C, Yu DH, Ramirez MM, 42. Grammatopoulos D, Thompson S, born BM. Capacitative cation entry in hu-
Marinoni E, Bocking AD, Challis JR. An- Hillhouse EW. The human myometrium ex- man myometrial cells and augmentation
tenatal glucocorticoid administration in- presses multiple isoforms of the cortico- by hTrpC3 overexpression. Biol Reprod
creases corticotrophin-releasing hormone tropin-releasing hormone receptor. J Clin 2003;69:647-55.
in maternal plasma. Br J Obstet Gynaecol Endocrinol Metab 1995;80:2388-93. 59. Blanks AM, Thornton S. The role of
1998;105:556-61. 43. Grammatopoulos DK, Hillhouse EW. oxytocin in parturition. BJOG 2003;110:
31. Emanuel RL, Robinson BG, Seely EW, Role of corticotropin-releasing hormone Suppl 20:46-51.
et al. Corticotrophin releasing hormone in onset of labour. Lancet 1999;354:1546- 60. Oldenhof AD, Shynlova OP, Liu M,
levels in human plasma and amniotic fluid 9. Langille BL, Lye SJ. Mitogen-activated pro-
during gestation. Clin Endocrinol (Oxf) 44. Quartero HW, Fry CH. Placental corti- tein kinases mediate stretch-induced c-fos
1994;40:257-62. cotrophin releasing factor may modulate mRNA expression in myometrial smooth
32. Ni X, Hou Y, Yang R, Tang X, Smith R, human parturition. Placenta 1989;10:439- muscle cells. Am J Physiol Cell Physiol
Nicholson RC. Progesterone receptors A 43. 2002;283:C1530-C1539.
and B differentially modulate corticotro- 45. Benedetto C, Petraglia F, Marozio L, 61. Chapman NR, Smyrnias I, Anumba
pin-releasing hormone gene expression et al. Corticotropin-releasing hormone DO, Europe-Finner GN, Robson SC. Ex-
through a cAMP regulatory element. Cell increases prostaglandin F2 alpha activity pression of the GTP-binding protein (Gal-
Mol Life Sci 2004;61:1114-22. on human myometrium in vitro. Am J Ob- phas) is repressed by the nuclear factor
33. Ni X, Hou Y, King BR, et al. Estrogen stet Gynecol 1994;171:126-31. kappaB RelA subunit in human myome-
receptor-mediated down-regulation of 46. Nodwell A, Carmichael L, Fraser M, trium. Endocrinology 2005;146:4994-5002.
corticotropin-releasing hormone gene ex- Challis J, Richardson B. Placental release 62. MacDougall MW, Europe-Finner GN,
pression is dependent on a cyclic adenos- of corticotrophin-releasing hormone across Robson SC. Human myometrial quies-
ine 3',5'-monophosphate regulatory element the umbilical circulation of the human cence and activation during gestation and
in human placental syncytiotrophoblast newborn. Placenta 1999;20:197-202. parturition involve dramatic changes in
cells. J Clin Endocrinol Metab 2004;89: 47. Asa SL, Kovacs K, Singer W. Human expression and activity of particulate type
2312-8. fetal adenohypophysis: morphologic and II (RII alpha) protein kinase A holoen-
34. Ni X, Chan EC, Fitter JT, Smith R. Ni- functional analysis in vitro. Neuroendo- zyme. J Clin Endocrinol Metab 2003;88:
tric oxide inhibits corticotropin-releasing crinology 1991;53:562-72. 2194-205.
hormone exocytosis but not synthesis by 48. Smith R, Mesiano S, Chan EC, Brown 63. Chanrachakul B, Matharoo-Ball B,
cultured human trophoblasts. J Clin En- S, Jaffe RB. Corticotropin-releasing hor- Turner A, et al. Immunolocalization and
docrinol Metab 1997;82:4171-5. mone directly and preferentially stimu- protein expression of the alpha subunit of
35. Petraglia F, Sutton S, Vale W. Neu- lates dehydroepiandrosterone sulfate se- the large-conductance calcium-activated
rotransmitters and peptides modulate the cretion by human fetal adrenal cortical potassium channel in human myometri-
release of immunoreactive corticotropin- cells. J Clin Endocrinol Metab 1998;83: um. Reproduction 2003;126:43-8.
releasing factor from cultured human 2916-20. 64. Brainard AM, Miller AJ, Martens JR,
placental cells. Am J Obstet Gynecol 1989; 49. Emanuel RL, Torday JS, Asokanan- England SK. Maxi-K channels localize to
160:247-51. than N, Sunday ME. Direct effects of cor- caveolae in human myometrium: a role
36. McGrath S, McLean M, Smith D, Bis- ticotropin-releasing hormone and thyro- for an actin-channel-caveolin complex in
its A, Giles W, Smith R. Maternal plasma tropin-releasing hormone on fetal lung the regulation of myometrial smooth mus-
corticotropin-releasing hormone trajecto- explants. Peptides 2000;21:1819-29. cle K+ current. Am J Physiol Cell Physiol
ries vary depending on the cause of pre- 50. Lye SJ, Ou C-W, Teoh T-G, et al. The 2005;289:C49-C57.
term delivery. Am J Obstet Gynecol 2002; molecular basis of labour and tocolysis. 65. Challis JRG, Lye SJ. Parturition. In:
186:257-60. Fetal Matern Med Rev 1998;10:121-36. Knobil E, Neil JD, eds. The physiology of
37. Leung TN, Chung TK, Madsen G, Lam 51. Yu JT, Lopez Bernal A. The cytoskele- reproduction. New York: Raven Press, 1994:
PK, Sahota D, Smith R. Rate of rise in ma- ton of human myometrial cells. J Reprod 985-1031.
ternal plasma corticotrophin-releasing hor- Fertil 1998;112:185-98. 66. Chanrachakul B, Pipkin FB, Khan
mone and its relation to gestational length. 52. Macphee DJ, Lye SJ. Focal adhesion RN. Contribution of coupling between
BJOG 2001;108:527-32. signaling in the rat myometrium is abrupt- human myometrial beta2-adrenoreceptor
38. Hillhouse EW, Grammatopoulos DK. ly terminated with the onset of labor. En- and the BK(Ca) channel to uterine quies-
The molecular mechanisms underlying the docrinology 2000;141:274-83. cence. Am J Physiol Cell Physiol 2004;287:
regulation of the biological activity of cor- 53. Sanborn BM, Ku CY, Shlykov S, Babich C1747-C1752.
ticotropin-releasing hormone receptors: L. Molecular signaling through G-protein- 67. Doheny HC, Lynch CM, Smith TJ,
implications for physiology and patho- coupled receptors and the control of in- Morrison JJ. Functional coupling of beta3-
physiology. Endocr Rev 2006;27:260-86. tracellular calcium in myometrium. J Soc adrenoceptors and large conductance cal-
39. Smith R, Cubis J, Brinsmead M, et al. Gynecol Investig 2005;12:479-87. cium-activated potassium channels in hu-
man uterine myocytes. J Clin Endocrinol evidence of inflammatory activation in centrations of vaginal fetal fibronectin as
Metab 2005;90:5786-96. gestational membranes with term and pre- a predictor of deliveries occurring after 41
68. Sigger JN, Harding R, Jenkin G. Rela- term parturition. Am J Obstet Gynecol weeks. Am J Obstet Gynecol 1994;171:1-
tionship between electrical activity of the 1999;181:1530-6. 4.
uterus and surgically isolated myometri- 81. Alvi SA, Brown NL, Bennett PR, Elder 93. Csapo A. Progesterone “block.” Am J
um in the pregnant and nonpregnant MG, Sullivan MH. Corticotrophin-releas- Anat 1956;98:273-92.
ewe. J Reprod Fertil 1984;70:103-14. ing hormone and platelet-activating factor 94. Csapo AI, Knobil E, van der Molen HJ,
69. Duquette RA, Shmygol A, Vaillant C, induce transcription of the type-2 cyclo- Wiest WG. Peripheral plasma progester-
et al. Vimentin-positive, c-kit-negative in- oxygenase gene in human fetal mem- one levels during human pregnancy and
terstitial cells in human and rat uterus: branes. Mol Hum Reprod 1999;5:476-80. labor. Am J Obstet Gynecol 1971;110:630-
a role in pacemaking? Biol Reprod 2005; 82. Laatikainen TJ, Raisanen IJ, Salminen 2.
72:276-83. KR. Corticotropin-releasing hormone in 95. Mazouni C, Provensal M, Porcu G, et
70. Eswaran H, Preissl H, Wilson JD, amniotic fluid during gestation and labor al. Termination of pregnancy in patients
Murphy P, Lowery CL. Prediction of labor and in relation to fetal lung maturation. with previous cesarean section. Contra-
in term and preterm pregnancies using Am J Obstet Gynecol 1988;159:891-5. ception 2006;73:244-8.
non-invasive magnetomyographic record- 83. Challis JR, Smith SK. Fetal endocrine 96. Mesiano S. Myometrial progesterone
ings of uterine contractions. Am J Obstet signals and preterm labor. Biol Neonate responsiveness and the control of human
Gynecol 2004;190:1598-602. 2001;79:163-7. parturition. J Soc Gynecol Investig 2004;
71. Lowery CL, Eswaran H, Preissl H, 84. Whittle WL, Patel FA, Alfaidy N, et al. 11:193-202.
Wilson JD, Robinson S, Murphy P. First Glucocorticoid regulation of human and 97. Wei LL, Hawkins P, Baker C, Norris B,
magnetomyographic recordings of uter- ovine parturition: the relationship be- Sheridan PL, Quinn PG. An amino-termi-
ine activity with spatial-temporal infor- tween fetal hypothalamic-pituitary-adre- nal truncated progesterone receptor iso-
mation using 151 channel sensor array nal axis activation and intrauterine pros- form, PRc, enhances progestin-induced
(SARA). J Ark Med Soc 2003;100:90-1. taglandin production. Biol Reprod 2001; transcriptional activity. Mol Endocrinol
72. Garfield RE, Maner WL, MacKay LB, 64:1019-32. 1996;10:1379-87.
Schlembach D, Saade GR. Comparing 85. Lindstrom TM, Bennett PR. The role 98. Conneely OM, Maxwell BL, Toft DO,
uterine electromyography activity of ante- of nuclear factor kappa B in human la- Schrader WT, O’Malley BW. The A and B
partum patients versus term labor patients. bour. Reproduction 2005;130:569-81. forms of the chicken progesterone recep-
Am J Obstet Gynecol 2005;193:23-9. 86. Johnson RF, Mitchell CM, Clifton V, tor arise by alternate initiation of transla-
73. Young RC, Zhang P. Inhibition of in Zakar T. Regulation of 15-hydroxyprosta- tion of a unique mRNA. Biochem Biophys
vitro contractions of human myometrium glandin dehydrogenase (PGDH) gene ac- Res Commun 1987;149:493-501.
by mibefradil, a T-type calcium channel tivity, messenger ribonucleic acid process- 99. Giangrande PH, Kimbrel EA, Edwards
blocker: support for a model using excita- ing, and protein abundance in the human DP, McDonnell DP. The opposing tran-
tion-contraction coupling, and autocrine chorion in late gestation and labor. J Clin scriptional activities of the two isoforms
and paracrine signaling mechanisms. J Soc Endocrinol Metab 2004;89:5639-48. of the human progesterone receptor are
Gynecol Investig 2005;12:e7-e12. 87. Li W, Challis JR. Corticotropin-releas- due to differential cofactor binding. Mol
74. Wood C. Physiology of uterine con- ing hormone and urocortin induce secre- Cell Biol 2000;20:3102-15.
tractions. Br J Obstet Gynaeol 1964;71: tion of matrix metalloproteinase-9 (MMP- 100. Condon JC, Hardy DB, Kovaric K,
360-73. 9) without change in tissue inhibitors of Mendelson CR. Upregulation of the pro-
75. Renfree MB. Maternal recognition of MMP-1 by cultured cells from human pla- gesterone receptor (PR)-C isoform in la-
pregnancy in marsupials. Rev Reprod centa and fetal membranes. J Clin Endo- boring myometrium by activation of nu-
2000;5:6-11. crinol Metab 2005;90:6569-74. clear factor-kappaB may contribute to the
76. Lye SJ, Mitchell J, Nashman N, et al. 88. Ledingham MA, Denison FC, Riley onset of labor through inhibition of PR
Role of mechanical signals in the onset of SC, Norman JE. Matrix metalloproteinas- function. Mol Endocrinol 2006;20:764-75.
term and preterm labor. Front Horm Res es-2 and -9 and their inhibitors are pro- 101. Mesiano S, Chan EC, Fitter JT, Kwek
2001;27:165-78. duced by the human uterine cervix but K, Yeo G, Smith R. Progesterone with-
77. Loudon JA, Sooranna SR, Bennett PR, their secretion is not regulated by nitric drawal and estrogen activation in human
Johnson MR. Mechanical stretch of hu- oxide donors. Hum Reprod 1999;14:2089- parturition are coordinated by progester-
man uterine smooth muscle cells increas- 96. one receptor A expression in the myome-
es IL-8 mRNA expression and peptide syn- 89. Thomson AJ, Telfer JF, Young A, et al. trium. J Clin Endocrinol Metab 2002;87:
thesis. Mol Hum Reprod 2004;10:895-9. Leukocytes infiltrate the myometrium 2924-30.
78. Yoon BH, Romero R, Jun JK, et al. An during human parturition: further evi- 102. Condon JC, Jeyasuria P, Faust JM,
increase in fetal plasma cortisol but not dence that labour is an inflammatory pro- Wilson JW, Mendelson CR. A decline in
dehydroepiandrosterone sulfate is fol- cess. Hum Reprod 1999;14:229-36. the levels of progesterone receptor coacti-
lowed by the onset of preterm labor in 90. Osman I, Young A, Ledingham MA, et vators in the pregnant uterus at term may
patients with preterm premature rupture al. Leukocyte density and pro-inflamma- antagonize progesterone receptor func-
of the membranes. Am J Obstet Gynecol tory cytokine expression in human fetal tion and contribute to the initiation of par-
1998;179:1107-14. membranes, decidua, cervix and myome- turition. Proc Natl Acad Sci U S A 2003;
79. Garbrecht MR, Klein JM, Schmidt TJ, trium before and during labour at term. 100:9518-23.
Snyder JM. Glucocorticoid metabolism in Mol Hum Reprod 2003;9:41-5. 103. Sheehan PM, Rice GE, Moses EK,
the human fetal lung: implications for 91. Giles W, Bisits A, Knox M, Madsen G, Brennecke SP. 5 Beta-dihydroprogester-
lung development and the pulmonary sur- Smith R. The effect of fetal fibronectin one and steroid 5 beta-reductase decrease
factant system. Biol Neonate 2006;89:109- testing on admissions to a tertiary mater- in association with human parturition at
19. nal-fetal medicine unit and cost savings. term. Mol Hum Reprod 2005;11:495-501.
80. Keelan JA, Marvin KW, Sato TA, Cole- Am J Obstet Gynecol 2000;182:439-42. 104. Morgan MA, Silavin SL, Wentworth
man M, McCowan LM, Mitchell MD. Cy- 92. Lockwood CJ, Moscarelli RD, Wein R, RA, et al. Different patterns of myome-
tokine abundance in placental tissues: Lynch L, Lapinski RH, Ghidini A. Low con- trial activity and 24-h rhythms in myome-
trial contractility in the gravid baboon trial activation tested using directed graphs. infant outcome. Ann N Y Acad Sci 1997;
during the second half of pregnancy. Biol PLoS Comput Biol 2005;1:132-6. 814:266-75.
Reprod 1992;46:1158-64. 107. Hobel CJ, Arora CP, Korst LM. Corti- 109. Sandman CA, Wadhwa P, Glynn L,
105. Bievenue AM, Jenkins SL, Nathan- cotrophin-releasing hormone and CRH- Chicz-Demet A, Porto M, Garite TJ. Corti-
ielsz PW. The effects of photoperiod on binding protein: differences between pa- cotrophin-releasing hormone and fetal
the switching of myometrial contractility tients at risk for preterm birth and responses in human pregnancy. Ann N Y
patterns of pregnant baboons: relation- hypertension. Ann N Y Acad Sci 1999;897: Acad Sci 1999;897:66-75.
ship to surgery and parturition. J Soc Gy- 54-65. 110. Elovitz MA, Baron J, Phillippe M. The
necol Investig 2002;9:27-31. 108. Sandman CA, Wadhwa PD, Chicz- role of thrombin in preterm parturition.
106. Bisits AM, Smith R, Mesiano S, et al. DeMet A, Dunkel-Schetter C, Porto M. Am J Obstet Gynecol 2001;185:1059-63.
Inflammatory aetiology of human myome- Maternal stress, HPA activity, and fetal/ Copyright © 2007 Massachusetts Medical Society.