Endocrinology of Parturition1
Gerson Weiss
New Jersey Medical School, Department of Obstetrics, Gynecology and
Womens Health, Newark, New Jersey 07103-2714
Address correspondence and requests for reprints to: Gerson Weiss, M.D., New Jersey Medical School, Department of Obstetrics, Gynecology and Womens Health, 185 South Orange Avenue, Newark, New Jersey 07103-2714. E-mail: weissge{at}umdnj.edu
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Introduction
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To insure optimal survival of the neonate, the
timing of parturition must be tightly controlled. Parturition before
term dramatically increases the risk of the birth of a nonviable
premature infant. At a time after the baby is mature, the intrauterine
environment becomes hostile. Postdate fetuses have an increased
incidence of intrauterine demise. To maximize infant survival,
mechanisms have evolved to allow for uterine distention and reduced
contractions during pregnancy and the timely initiation of labor. In
women this process is only partially understood. The control of the
timing of labor is complex and involves interactions of the mother, the
fetus, and the placenta plus membranes. In women, invasive study of the
intrauterine environment is limited for ethical reasons. However, the
control of pregnancy and parturition is highly species specific.
Although much more is known about the process of parturition in rodents
and sheep than in humans, there are no good nonprimate models of human
parturition. Even subhuman primates have significantly different
endocrine environments and controls than humans. There is a complex
schema of the initiation of labor in women, and there is no simple
chain of events as there are in other species. For instance, there
cannot be shown an acute rise in circulating estrogen, nor an abrupt
decline in circulating progesterone levels to signal the onset of labor
in all pregnancies. Evidence suggests that there are multiple
paracrine/autocrine events, fetal hormonal changes, and overlapping
maternal/fetal control mechanisms for the triggering of parturition in
women.
For parturition to occur, two changes must take place in a womans
reproductive tract. First, the uterus must be converted from a
quiescent structure with dyssynchronous contractions to an active
coordinately contracting organ with complex interlaced muscular
components. This requires the formation of gap junctions between
myometrial cells to allow for transmission of the contractile signal.
The second change is that the cervical connective tissue and smooth
muscle must be capable of dilatation to allow the passage of the fetus
from the uterus. In pregnancy there is a dynamic balance between the
forces that cause uterine quiescence and the forces that produce
coordinated uterine contractility. There is also a balance between the
forces that keep the cervix closed to prevent uterine emptying and the
forces that soften the cervix and allow it to dilate. For delivery to
occur, both balances must be tipped in favor of active uterine
emptying.
Whereas there may be a final common pathway for the initiation of
labor, which involves alterations in prostaglandin and calcium
metabolism, there are multiple, sometimes complementary, initiating
factors involved in the onset of labor (1). These are
endocrine, paracrine, and autocrine. The "final common pathway" to
delivery is likely to be multiple, parallel, interactive paths that tip
the balance in favor of coordinated uterine contractility and cervical
dilation. These mechanisms involve a shift from progesterone to
estrogen dominance, increased sensitivity to oxytocin, gap junction
formation, and increased prostaglandin activity. Decreased nitric oxide
(NO) activity and increased influx of calcium into myocytes are both
required for uterine contractibility (2, 3). Complementary
changes in the cervix involving a decrease in progesterone
dominance and the actions of prostaglandins and relaxin, via connective
tissue alterations, collagenolysis, and a decrease in collagen
stabilization through metalloproteinase inhibitors, leading to cervical
softening and dilation (4).
It is clear that the above mentioned pathways are not all inclusive.
Other factors, such as endothelin, are involved in uterine changes
conducive to increased blood flow and myometrial activity
(5). It is also clear that with many overlapping
mechanisms, decrease or absence of a single component can be
compensated by changes in other paths. By way of analogy, in mice with
specific gene knockouts, CRH and oxytocin are not necessary for normal
delivery. Although knockouts of cyclooxygenase (COX)-1, COX-2,
phospholipase A2, and relaxin do alter the timing of labor, they do not
preclude uterus emptying and cervical dilation in all animals
(6). Thus, complementary actions for the system must come
into play. It is also quite likely that many of the causes of preterm
parturition differ from the initiators at term. In fact, there seem to
be multiple causes of preterm parturition. For example, infection may
overwhelm one or more control mechanisms of normal labor. Or, more
specifically, a deficiency of a choriodecidual enzyme (such as
15-hydroxy-PG-dehydrogenase) may alter the metabolism of prostaglandin
E2 (PGE2) resulting in
excess and, ultimately, onset of labor (7, 8). On the
other hand, in a novel and as yet undetermined way, prematurity in
patients whose ovulation induction included human menopausal
gonadotropins is associated with hyperrelaxinemia (9).
Many initiating mechanisms may be involved in prematurity due to other
causes, such as premature membrane rupture or the prematurity
associated with uterine anomalies. Thus, whereas the onset of term
labor seems to be a fairly predictable chain of events, preterm labor
is as if the normal chain of events was entered at a site dependent on
the etiology.
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Estrogen
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Estrogen is essential for uterine development and function.
Estrogens are responsible for the synthesis of the contractile proteins
and the regulatory enzymes necessary for uterine contractility. In
prepubescent girls, the uterus is small. It is only after estrogen is
secreted that the uterus increases in size and develops the ability to
respond to stimulants and inhibitors of contractions. Estrogen
increases the concentration of receptors for oxytocin and
-adrenergic agents, which modulate membrane calcium channels
(10). Estrogens are critical for intracellular
communication. Estrogens increase connexin 43 synthesis and gap
junction formation in the myometrium (11). This allows for
coordinated uterine contractions. Estrogen also stimulates the
production of prostaglandins F2
and E2, which
stimulate uterine contractions (12). In women, although
estradiol continues to remain high, it does not have a sharp
predelivery increase as in sheep, where it is responsible for the onset
of labor.
Estrogens control cervical ripening. This may be associated with the
down-regulation of the estrogen receptor. The control of the softening
of the cervix, which involves rearrangement and realignment of
collagen, elastin, and glycosaminoglycans such as decorin, is not well
studied and is poorly understood (4).
The metabolism of estrogens during pregnancy in humans and in other
higher primates differs from that of all other species. The human
placenta lacks significant amounts of 17-hydroxylase/1720 lyase. This
enzyme is needed in the synthetic pathway of estradiol from
progesterone. Progesterone is synthesized from acetate and cholesterol
in the placenta. Human pregnancy estrogen production is complex. The
fetal zone of the adrenal gland produces dehydroepiandrosterone sulfate
(DHEAS), which may be hydroxylated to 16-OH-DHEAS in the fetal liver.
The 16-OH-DHEAS may be aromatized by the placenta to produce estriol,
the major circulating estrogen of human pregnancy. In contrast to the
nonpregnant state, during late human pregnancy the ovary is a minor
source of circulating estrogens. Estradiol and estrone are synthesized
by placental aromatization of DHEAS from both maternal and fetal
sources; however, more than 90% of estriol is derived from fetal 16-OH
DHA (13).
Estriol concentrations in serum and saliva increase during the last
46 weeks of pregnancy. Throughout the last two fifths of pregnancy,
levels of salivary estriol in women destined to have preterm deliveries
are higher than in control women having term deliveries. There seems to
be a 4-week advancement in the higher levels in women who will deliver
preterm. Salivary estrogen has been suggested as a screen for the
potential of preterm labor risk (14).
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Progesterone
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During late pregnancy in women the placenta is the major source of
circulating progesterone; the ovarian contribution is slight. In
species in which pregnancy is luteal dependent, such as the rodent,
progesterone withdrawal initiates the onset of labor. In women there is
no confirmed prelabor fall of circulating progesterone. Serum
progesterone levels do not vary significantly between women in labor
and those not in labor.
In early pregnancy, removal of the corpus luteum, the major source of
progesterone at that stage of pregnancy, results in pregnancy loss
(15). Progesterone receptor blockers such as RU486 result
in the initiation of labor (16). This may be because RU486
stimulates CRH messenger RNA, suggesting that a progesterone decrease
will result in an increased CRH effect (17). However, the
actual amount of circulating progesterone throughout pregnancy is in
excess of the concentration needed for uterine inhibition. Women with a
ß-lipoproteinemia, who have circulating progesterone levels of less
than 10 ng/mL throughout pregnancy, maintain their pregnancies normally
and deliver normally at term (18).
In pregnancy, progesterone is in dynamic balance with estrogen in the
control of uterine activity. Progesterone in vitro decreases
myometrial contractility and inhibits myometrial gap junction formation
(2). Progesterone activity stimulates the uterine NO
synthetase, which is a major factor in uterine quiescence. Progesterone
down-regulates prostaglandin production, as well as the development of
calcium channels and oxytocin receptors both involved in myometrial
contraction (2). Calcium is necessary for the activation
of smooth muscle contraction. In the cervix, progesterone increases
tissue inhibitor of matrix metalloproteinase 1 (TIMP-1)
(19). TIMP-1 inhibits collagenolysis. Thus, it is clear
that progesterone is a major factor in uterine quiescence and cervical
integrity. The factors that result in parturition must overcome the
progesterone effect that predominates during the early pregnancy period
of uterine quiescence. The activity of 17,20 hydroxysteroid
dehydrogenase in fetal membranes increases around the time of
parturition, leading to an increase in net 17ß-estradiol and
20-dihydroprogesterone (20). This is a factor in altering
the estrogen/progesterone balance. There may be decreased progesterone
receptor levels at term resulting in a diminished progesterone
effect.
In summary, estrogen and progesterone activities are critical
determinants of the balance between uterine quiescence and the factors
that produce labor. Labor stimulation or inhibition will generally be
produced by agents that alter this critical balance.
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Oxytocin
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Available evidence suggests that oxytocin performs an important,
but not critical, role in the initiation of labor. Patients will
deliver after hypophysectomy. Circulating oxytocin does not increase in
late pregnancy. It does not increase in labor until after full cervical
dilatation (21). However, the concentration of uterine
oxytocin receptors increases toward the end of pregnancy
(22). This results in increased efficiency of oxytocin
action as pregnancy progresses. Estrogen increases oxytocin receptor
expression and progesterone suppresses such estrogen-induced increase
in cultured human myometrial cells (23).
Oxytocin induces uterine contractions in two ways. Oxytocin stimulates
the release of PGE2 and prostaglandin F2
in
fetal membranes by activation of phospholipase C. The prostaglandins
stimulate uterine contractility (24). Oxytocin can also
directly induce myometrial contractions through PLC, which in turn
activates calcium channels and the release of calcium from
intracellular stores (25, 26).
Oxytocin is locally produced in the uterus (27). The role
of this local endogenous oxytocin is unknown. Nor is the direct effect
of oxytocin on cervical dilatation well understood. Oxytocin infusion
is used clinically to induce uterine contractions and labor. Oxytocin
may accelerate cervical ripening at term, but it does not effectively
or efficiently ripen an unripe cervix taking a long time at a low dose.
Oxytocin is also less effective in causing uterine contractions in
midpregnancy than at term.
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Prostaglandins
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There is good evidence that prostaglandins are involved in the
final pathway of uterine contractility and parturition. Prostacyclins,
inhibitory prostaglandins present throughout early pregnancy, are also
responsible for uterine quiescence during pregnancy. Arachidonic acid
is the obligatory precursor of PGE2 and F2
,
the major stimulatory prostaglandins (28). Although
prostaglandins may not be obligatory for labor, as has been shown in
knockout mice, they are of major importance in women (6).
Prostaglandins are produced in the placenta and fetal membranes. The
membranes, consisting of amnion and chorion form the amniotic sac. On
the maternal side, the chorion is adherent to the decidua.
Prostaglandin levels are increased before and during labor in the
uterus and membranes (29, 30). Many factors affect the
production of prostaglandins. Levels are decreased by progesterone and
increased by estrogens (31, 32, 33, 34). Several
interleukins result in an increase in prostaglandin production
(35). This may be the mechanism by which inflammatory
cytokines result in premature labor. A leukocyte influx at the time of
infection releases inflammatory cytokines that increase production of
stimulatory prostaglandins. A significant proportion of cases of
prematurity are related to intrauterine or cervical infection. CRH also
increases prostaglandin production (36, 37). An increase
in the circulating concentration of prostaglandin metabolites is found
at the onset of labor (28).
Prostaglandin is formed from arachidonic acid that is converted to
prostaglandin H2 by the enzyme prostaglandin H synthetase (PGHS).
PGHS-2 is an inducible form of the enzyme. PGHS-2 and COX-2 are the
same enzyme but both are referred to in different papers and so is
included here under both names. Cytokines increase the concentration of
this enzyme 80-fold. Prostaglandins are degraded by 15-
hydroxy-prostaglandin dehydrogenase. COX-2, the cyclooxygenase
isoform that is cytokine inducible, is increased by NO. This is another
mechanism by which prostaglandin production increases during
inflammation. Inflammation-induced increase in prostaglandins can
result in stimulation of uterine activity and cervical ripening
(28).
Local application of PGE1 and
PGE2 is used clinically to induce cervical
ripening. Prostaglandin F2
increases total glycosaminoglycan
activity. PGE2 dilates cervical small blood
vessels. PGE2 leads to cervical ripening
associated with collagen degradation (4). There is
controversy as to whether the action of prostaglandin on the cervix is
direct or indirect. The prostaglandin effects on myometrium are, at
least in part, direct actions.
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CRH
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CRH is the hypothalamic hormone responsible for control of ACTH.
It, in turn, is modulated by a typical long loop feedback system
involving adrenal cortisol. Thus, is the mother ACTH stimulates the
adrenal that makes cortisol, which decreases the production of CRH
(negative feedback), resulting in a decrease in ACTH secretion. In
human pregnancy, from the onset of the second trimester, the placenta
is a major source of CRH secretion (38). Paradoxically,
cortisol increases CRH production by the placenta (positive feedback)
(39). Positive and negative feedback may be controlled by
different signal transduction mechanisms. CRH stimulates fetal ACTH
release. The resultant fetal adrenal steroidogenesis results in
increased production of DHEA and DHEAS. These compounds
are placental precursors of estrogens, including estradiol. It is
postulated that increased placental CRH results in an estrogen-dominant
environment conducive to parturition (40). Stimulation of
the fetal adrenal also increases glucocorticoid production.
Glucocorticoids are responsible for fetal lung maturation. Thus, CRH
synchronizes maturation of the fetal lung with forces that induce the
onset of labor. CRH of hypothalamic origin is a stress-induced
hormone. With stress, cortisol is secreted, which increases placenta
CRH production. This may be a factor in premature birth
(41). Actions of CRH include dilation of the uterine
vessels and stimulation of smooth muscle contractions, dilation of the
fetal placental vessels via NO synthetase activation; and
stimulation of prostaglandins F2
and E2
production by fetal membranes and decidua (42, 36, 37).
Prostanoids increase CRH production by decidua and membranes
(43). These are all actions conducive to the initiation of
labor. CRH is also stimulated by inflammatory cytokines
(43). However, the administration of cortisol does not
induce labor in women.
CRH rises in maternal serum starting at approximately the 16th week of
gestation (44). Some data demonstrate that CRH increases
at a more acute rate in the last 68 weeks of pregnancy. Before
delivery, CRH binding protein decreases, resulting in more effective
unbound CRH in maternal circulation (45). Women destined
to have premature delivery have higher midpregnancy CRH levels than
those who deliver at term (46). This higher level of CRH
may be used as a marker for women at risk for prematurity. This
elevated CRH may accelerate the timing of the process of parturition
(43).
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Relaxin
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Relaxin is a peptide hormone that is a member of the insulin
family. Relaxin consists of A and B peptide chains linked together by
two disulfide bonds. In women, circulating relaxin is a product of the
corpus luteum of pregnancy, which is present in the ovary for the
duration of pregnancy. Circulating relaxin is secreted in a pattern
similar to that of human CG. That circulating relaxin is not critical
for pregnancy maintenance is demonstrated by pregnancies generated by
egg donation, which have no maternal circulating relaxin and are able
to go to term and deliver spontaneously. However, relaxin is also a
product of the placenta and decidua. Relaxin from these sources, which
may act locally, is not secreted into the peripheral circulation
(47).
Premature birth is associated with increased circulating relaxin levels
(48). Women who have superovulation with human menopausal
gonadotrophins for either ovulation induction or in vitro
fertilization have a significantly higher risk of premature birth.
These women, who have multiple corpora lutea, have significant levels
of hyperrelaxinemia. Logistic regression analysis has demonstrated that
the extent of hyperrelaxinemia in these women is associated with
increased levels of prematurity (9). Additional support
for a role of relaxin in prematurity is that in spontaneous pregnancies
women destined to have premature delivery have higher levels of relaxin
at 30 weeks gestation than women who deliver at term (48).
A potential mechanism for this relationship may be the action of
relaxin on the cervix. Relaxin has been associated with cervical
softening. Relaxin receptors are present on the human cervix
(49). Some of the effects of relaxin include stimulation
of procollagenase and prostromelysin, as well as a decrease in TIMP-1
(50). Relaxin is also capable of inhibiting contractions
of nonpregnant human myometrial strips (51).
Paradoxically, relaxin does not inhibit contractions of pregnant human
uterine tissue (52). This may be because of the
competitive effects of progesterone.
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Conclusion
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It is vividly clear that a variety of endocrine systems play a
role in the maintenance of uterine quiescence and the onset of
parturition, with its attendant increase in uterine contractility and
cervical ripening (Fig. 1
). However,
there is little doubt regarding the primacy of the balance between
estrogen and progesterone. There are many factors that can tip the
balance in favor of delivery early, late, or on time. These factors,
such as prostaglandins or inflammatory cytokines, may directly affect
the contractile mechanisms (53, 54). Other factors, such
as oxytocin, CRH, or relaxin, may indirectly alter the actions of
complementary systems. Physiologically, there may be many parallel
operative systems that can compensate for anomalies or imbalance in
other systems. However, our information is incomplete at present. We
have only fragmentary data regarding the interaction of these systems
and how the organism compensates for imbalances. For instance,
exogenous estrogen cannot induce labor and exogenous progesterone
cannot stop prematurity, yet both steroids are critical for the control
of uterine activities.

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Figure 1. Simplified scheme of the endocrinological
control of pregnancy and parturition in women. The balance between the
effects of estrogen and progesterone is critical to maintenance of
pregnancy and the onset of labor. Other important hormonal factors
modulate this balance as shown in the scheme. Not all factors are
represented. Those shown are endocrine factors demonstrated to be
significant.
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Ignorance of the control mechanisms carries significant costs. There
are as yet no clinically effective and useful agents to delay the onset
of preterm labor. Available methods of labor induction, while clearly
effective, are neither completely dependable nor safe. The cost of our
inability to prevent prematurity is heartbreaking pregnancy loss or
prolonged infant occupancy of neonatal intensive care units. It is only
with increased understanding of the processes of parturition that we
will be able to further improve the safety of the birth process.
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Footnotes
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1 Supported by NIH Grant HD22338. 
Received June 14, 2000.
Revised September 5, 2000.
Accepted September 8, 2000.
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