Chapter 6

The Comparative Physiology of Parturition

in Mammals: Hormones and Parturition
in Mammals
I. Ross Young,* Marilyn B. Renfree,y Sam Mesiano,** Geoff Shaw,y Graham Jenkinyy and Roger Smith***
*
Monash University, Clayton, Victoria, Australia, y The University of Melbourne, Victoria, Australia, ** Case Western Reserve University,
Cleveland, OH, USA, yy Monash Institute of Medical Research (MIMR), Clayton, Victoria, Australia, *** The University of Newcastle, NSW, Australia

investigated. Rather than surveying the physiology of

SUMMARY
The physiology of parturition in mammals is highly diverse and
parturition species by species, this contribution will attempt
almost species specific. A range of examples is presented from the to identify mechanisms that vary widely among species and
marsupial Tammar wallaby (Macropus eugenii) to the primate those that are well-conserved. This classical comparative
Homo sapiens. In some species, such as the sheep, parturition is approach explicitly assumes that highly conserved mech-
initiated by the fetus while in others, for example the goat, anisms are fundamentally important because they have
parturition is initiated by the mother. In the human and other great remained unchanged in the face of changing selective
apes parturition appears to be regulated by placental production of pressures during the course of evolution. While the
steroids from both fetal (estriol) and maternal (estradiol) origin. comparative approach on its own can tell us what is
The role of progesterone related steroids and estrogens varies fundamentally important about the process we are investi-
dramatically amongst species. In a number of mammals proges- gating, our understanding can be expanded by simultaneous
terone withdrawal initiates labor while in others a rise in estrogens
consideration of the phylogenetic relationships among the
is the precipitant. However, in other species, such as the Tammar,
neither estrogens or progestagens appear to have any role. In all
taxa we are studying. In doing so, we make an assumption
species examined to date prostaglandins play a role in the process that fundamental, conserved processes have evolved earlier
of parturition although the regulation of increases in prostaglan- and are more widespread among distantly related taxa than
dins varies with differing prostaglandin synthases involved in are processes that exhibit wider variations (Somero, 2000).
different species and differences in the tissues of origin and sites In this chapter we shall apply this style of reasoning to the
of action. The enormous variation in the physiology of parturition following questions: What determines gestation length?
is related to the high rates of perinatal death of both mother and How are fetal maturation and birth synchronized? How are
offspring and the consequent evolutionary pressures that are the uterotonic mechanisms activated?
exerted on this process. Parturition is fundamental to viviparity, but even
a cursory overview of the mammals makes it apparent that
there is huge variation. This review will draw heavily from
studies in three species: the tammar wallaby (tammar), the
1. INTRODUCTION
sheep, and the human. Tammars are marsupials with
Much of our knowledge of the physiology of parturition in a relatively brief gestation (the organogenesis phase lasts
mammals has been gained from studies of only a few barely eight days). The highly altricial neonate is barely
species, notably the sheep, pig, rat, rabbit, some nonhuman 1/10 000 of maternal weight, with many organ systems
primates, and the human. From the perspective of poorly developed, but it climbs to the pouch and finds a teat
comparative physiology, this is a poor coverage as these where it then spends around nine months of lactation
species fall into only four of the 28 orders and only half completing its development. Sheep have more extensive
a dozen or so of the ~5000 species of mammals. Moreover, development in utero and the relatively large precocial
the fundamental mechanism underlying the initiation of young are able to stand and run minutes after birth; the
parturition is not established in any species, and consider- young gain independence after a relatively short lactation.
able variation exists among the species that have been Humans too give birth to large young. However, their large

Hormones and Reproduction of Vertebrates, Volume 5dMammals 95

Copyright Ó 2011 Elsevier Inc. All rights reserved.
96 Hormones and Reproduction of Vertebrates

FIGURE 6.1 In the chimpanzee, as in all extant

primates except Homo sapiens, the fetal head
passes through the maternal pelvis with the face
in an anterior position facing the pubic
symphysis. Upright posture as present in
Australopithecus was associated with a narrow-
ing of the anterior to posterior diameter of the
pelvis, forcing the fetus at delivery to rotate to
traverse the birth canal. Further changes to the
pelvis in Homo sapiens require a series of rota-
tions to enable the large head and wide shoulders
of the human fetus to negotiate the birth passage,
placing a severe constraint on the size of the fetus
and especially the fetal brain at the time of birth.
See color plate section.

FIGURE 6.2 Various mammals adopt different strategies regarding pre- and postnatal development. Precocial species have relatively long gestational
periods and deliver relatively mature, independent young; altricial species have shorter gestational periods and deliver immature, dependent young.
Primates in general follow the precocial pattern, giving birth to relatively independent young after a long gestational period; however, humans have
a complex pattern consisting of a long gestational period with delivery of an immature offspring that is highly dependent for an extended period of time.
The human pattern seems to be a consequence of changes required for upright posture and possession of a large brain. The human brain is relatively large
compared to total body size at birth and continues to grow rapidly after birth. The relatively narrow pelvis of primates has become narrowed with the
adoption of upright posture (see Figure 6.1) in Australopithecus and modern humans, providing a physical limit on the size of the fetal brain that can
traverse the birth canal. See color plate section.
Chapter | 6 The Comparative Physiology of Parturition in Mammals: Hormones and Parturition in Mammals 97

brains provide a challenge at birth when the relatively large 2. WHAT DETERMINES GESTATION
head must fit through a pelvis designed for bipedalism
(Figure 6.1). Consequently, humans have acquired the trait
LENGTH?
of secondary altriciality, giving birth to a very immature The duration of gestation for each species is remarkably
neonate in which the brain continues to grow postnatally to constant. This suggests that some time-measuring or
a much greater extent than observed in other primates counting process may be involved. If so, the process may
(Figure 6.2). The late maturation of the brain means that involve counting the number of cell divisions that have
human offspring require prolonged maternal care during an occurred since the time of syngamy, although experimental
extended lactation and beyond, before they become confirmation of this is lacking. Alternatively, the process
independent. may involve measurement of the time elapsed since
Failure of birth means failure to pass on genes, with syngamy, which would require counting the repetitions of
likely death of both mother and offspring, so there has been an isochronous process, as occurs in clocks. This may occur
heavy Darwinian selection of the processes of parturition. in the mother, the placenta, or the fetus. If the putative time-
Because of this pressure, failsafe systems may be present keeping mechanism resides in the mother, the isochronous
with multiple pathways to fetal expulsion. Whichever of process may be the external photoperiod or some physio-
these pathways is first triggered becomes the normal logical rhythm linked to it, such as a circadian rhythm in the
‘mechanism’. The redundancy in the pathway provides concentration of a metabolic (e.g., plasma glucose), endo-
a fertile ground for evolution as secondary paths can be crine (e.g., plasma melatonin (MEL) or cortisol (F)), or
independently developed and eventually subsume the role behavioral (e.g., activity or feeding) parameter. The recent
of the previously dominant path, which may then become discovery of genes and proteins that may transduce photic
superfluous and be lost from the genome. Thus, as species information into physiological signals in the mother may
have evolved, the trigger used may have changeddso long lead to an improved understanding of the mechanisms
as one pathway is effective the genes will be passed on and underlying the establishment of 24-hour rhythms (Gekakis
different ‘mechanisms’ become normal. However, the et al., 1995; Shearman et al., 1997; Steeves et al., 1999;
various trigger mechanisms tend to converge on a smaller Zheng et al., 1999; Hida et al., 2000); however, no link has
set of final processes that stimulate uterine contractions been made to a circadian cycle-counting mechanism, which
(notably oxytocin (OXY) and prostaglandin F2a (PGF2a)), would be expected if these phenomena form the basis of
remove inhibition (notably via regulation of progesterone a clock that keeps count of days. In any case, empirical
(P4) action and nitric oxide synthase (NOS)) and facilitate evidence suggests that photoperiodic or circadian infor-
delivery (e.g., cervical ripening, facilitated by hormones mation is not a necessary determinant of gestation length in
such as relaxin and prostaglandin E2 (PGE2)). Clearly these primates and rats, although it modulates the time of day
processes need to be synchronized in order to effect birth, when births occur (Bosc, 1990; Honnebier et al., 1991;
and so a key question becomes how this synchronization is Rowland et al., 1991; Honnebier & Nathanielsz, 1994). The
achieved and how this is coordinated with fetal develop- ovine fetus can signal its own birth after destruction of the
ment, so that birth occurs when the fetus is developmentally fetal optic nerves and suprachiasmatic nuclei (SCN) (Poore
ready for delivery. et al., 1999), and maternal pinealectomy abolishes the

FIGURE 6.3 In the sheep, maturation of

the fetal hypothalamus appears to regulate
the timing of birth. ACTH, corticotropin;
CRH, corticotropin-releasing hormone;
P450C17, 17-hydroxylase 17,20 lyase;
PGE2, prostaglandin E2; PGHS2, prosta-
glandin synthase-2. See color plate
section.
98 Hormones and Reproduction of Vertebrates

diurnal MEL rhythm but does not affect the duration of postpartum estrus (Tyndale-Biscoe et al., 1988). Falling P4
gestation (McMillen & Nowak, 1989). These observations and rising E2 are known mechanisms that can activate ute-
suggest that the recognized components of the fetal or rotonic mechanisms in some eutherian mammals. However,
maternal biological clocks do not affect gestation length in these changes in P4 and E2 in tammars are not important for
the sheep. birth, since not all females have a rise in E2 and postpartum
In species such as the sheep, where the signal to end estrus (Shaw & Renfree, 1984), and, when folliculogenesis
gestation arises within the fetus (Figure 6.3), it is difficult to is blocked by passive immunization, preventing a rise in E2
conceive of a time-counting mechanism operating from the (Short, Flint, & Renfree, 1985), the timing of birth is not
time of conception, except at the cellular level. The struc- affected. Similarly, birth timing is unaffected if P4 levels
tures we associate with generating or marking the diurnal near term are manipulated (Shaw, 2006). Moreover, in many
rhythms (the SCN and pineal gland) do not differentiate nonmacropodid marsupial species, luteolysis or rising E2
until the conceptus is several weeks old. The problem are not normally closely associated with parturition (Tyn-
becomes deeper when we consider species exhibiting dale-Biscoe & Renfree, 1987).
embryonic diapause, a state of suspended development in As a time-measuring mechanism does not appear to
which the blastocyst remains quiescent in the uterus determine gestation length, we may consider the possibility
awaiting a maternal signal to recommence growth. In the that the conceptus of each species develops at a genetically
tammar, embryos may develop continuously with a gesta- determined rate and that birth occurs in response to a signal
tion length of ~27 days or, more usually, with an 11-month given when the fetus (or litter) attains sufficient size or
period of embryonic diapause when the gestation is a year. maturity. Such a signal may be transduced by the mother
In the latter case, the sum of the periods before diapause (Figure 6.4) (e.g., uterine volume), the fetus (e.g., nutrient
and after the signal to end diapause is the same as the restriction; developmental transition), or the placenta (e.g.,
uninterrupted gestation length plus a few days required to increased fetal demand for nutrients). In all of these cases, the
transmit and receive the maternal signal to reactivate the duration of gestation would ultimately depend on the genet-
embryo (Renfree, 1994). However, the timing appears to be ically determined developmental or growth rate of the
related to the developmental stage of the embryo, because conceptus, and not on any objective measurement of time.
there is a remarkably uniform period of 19 days from the Uterine volume, once considered a possible determinant of
time of a P4 pulse (which occurs four to six days after gestation length, now seems unlikely to be so, although larger
removal of pouch young) to birth, whereas the time from uterine volume (e.g., in multiple vs. singleton ovine or human
fertilization, reactivation, or artificially induced reac- pregnancy) is associated with slightly shorter gestation
tivation of the blastocyst is variable (Renfree, 1994). It is length. In the case of multiple ovine pregnancy, birth occurs
therefore unlikely that a fetal clock-like function is much closer to the time expected for singleton pregnancies
involved in determining gestation length in this marsupial. (145e150 days) than to the time (about 120 days) when the
In tammars one might argue for a clock based on the combined fetal mass reaches that of a term singleton preg-
lifespan of the corpus luteum, which undergoes luteolysis nancy. Further, dysfunction of the fetal pituitary or adrenals in
with a corresponding fall in plasma P4 at birth (reviewed in sheep is associated with prolonged gestation and continued
Shaw & Renfree, 2006). At this time there is normally also fetal growth. In this case, the ewe does not deliver the fetus
a rise in plasma 17b-estradiol (E2) in concert with the start of but eventually dies of starvation because the uterine volume

FIGURE 6.4 In rodents, the timing of

birth appears to be controlled by events in
the maternal tissues leading to luteolysis
and a fall in progesterone (P4) levels.
ACTH, corticotropin; CRH, cortico-
tropin-releasing hormone; PGF2, prosta-
glandin F2. See color plate section.
Chapter | 6 The Comparative Physiology of Parturition in Mammals: Hormones and Parturition in Mammals 99

compromises her ability to take in sufficient food (Van bandicoots, which develop an invasive chorioallantoic
Kampen & Ellis, 1972). Thus, increased uterine volume placenta in the last day or so of the 12.5 day gestation
appears insufficient to trigger birth in the sheep. In the human, (Padykula & Taylor, 1976), yet the term fetus weighs under
while twin gestations deliver prematurely at a much higher 250 mg and is at a relatively earlier stage of development
rate than singletons, this appears to be related more to than the tammar neonate.
placental hormone secretion than to increased uterine volume Since it is difficult to find conclusive support for time-
or myometrial tension (Smith et al., 2009). keeping mechanisms or fetal size as fundamental deter-
Persuasive arguments have been made that the rapid minants of the onset of parturition, other mechanisms must
accretion of fetal tissue in late gestation outstrips the ability be considered. One possibility is that the mechanism for the
of the placenta to supply substrates at the necessary rate, timing of birth is encoded in the fetal genome and is acti-
with the result that fetal substrate concentrations actually vated when certain prerequisite developmental events have
fall, activating the fetal hypothalamoepituitaryeadrenal occurred. The details of such a putative mechanism are
(HPA) axis, which, in at least some species, provides the unknown, but may be elucidated with further research, just
signal for birth. An alternative hypothesis suggests that as the molecular bases for other, previously mysterious,
the supply of fetal nutrients is maintained by adaptation of processes in the early development of the embryo are being
the placenta to the increased fetal demand, but that one of discovered.
the placental responses to that increased demand is the Human pregnancy lasts approximately 38 weeks after
secretion of a factor, hypothetically PGE2, that activates conception, with minor variations among different racial
the fetal HPA axis. Evidence that brain PGE2 modulates the groups (Patel et al., 2004). In humans, the timing of birth is
preparturient rise in corticotropin (ACTH) in the fetal sheep associated with development of the placenta and, in
has recently been published (Gersting et al., 2008). Both particular, placental synthesis of corticotropin-releasing
these hypotheses are subject to the objection that substrate hormone (CRH) (McLean et al., 1995). An association
limitation would evolve gradually and it is difficult to between levels of maternal plasma CRH, which is of
reconcile this feature with the precision that normally placental origin, and the timing of birth has been found in
characterizes the timing of birth. several large cohort studies (Hobel et al., 1999; Leung et al.,
In marsupials, the term fetus is tiny and places almost 1999; Holzman et al., 2001; Inder et al., 2001; Leung et al.,
no metabolic demands on the motherde.g., a 5000 g 2001; Ellis et al., 2002; Sandman et al., 2006; Torricelli
female tammar has a single 0.4 g fetus at term (Tyndale- et al., 2007). Maternal plasma CRH increases exponentially
Biscoe & Renfree, 1987). However, most marsupials have as pregnancy advances, peaking at the time of delivery. In
a relatively noninvasive yolk sac placenta, so it is possible women destined to deliver preterm, the exponential
that parturition occurs when the limit of placental transfer increase is more rapid, whereas in women destined to
is reached. When parturition in tammars was prevented by deliver after the estimated date of delivery the rise is slower
administration of indomethacin, dead postmature fetuses (Figure 6.5) (McLean et al., 1995; Torricelli et al., 2006).
20% heavier than normal were recovered from the uterus These findings suggest that a placental clock determines the
two days after the normal birth time (Renfree, 1994). timing of delivery in humans (McLean et al., 1995).
Whether the fetal death was attributable to toxic effects of Production of CRH by the placenta is restricted to
indomethacin or to fetal growth beyond what the placenta primates (Robinson et al., 1989; Smith et al., 1999; Bowman
could supply is not clear. However, it is hard to argue that et al., 2001) and even within the order of primates the pattern
such a limitation occurs in another marsupial group, the of production varies considerably. In New and Old World

100 FIGURE 6.5 Placentally produced corticotropin-releasing hormone

Women Who Delivered
(CRH) can be measured in maternal plasma in humans. The
Prematurely
concentration of CRH in maternal plasma follows an exponential
(Picomolesper Liter of Plasma)

curve that peaks at the time of delivery. In women who deliver

prematurely (less than 37 completed weeks of gestation), the rate of
Maternal CRH

Women Who rise of the exponential curve is greater than that observed in those that
Delivered at Term deliver at term (37e40 weeks), which is greater than that of those
50 who deliver late (more than 40 weeks). See color plate section.

Women Who
Delivered Late

0
15 20 25 30
Weeks of Gestation
100 Hormones and Reproduction of Vertebrates

monkeys there is a pronounced peak in CRH production in 3. HOW ARE FETAL MATURATION
midgestation, but only in the great apes is there an expo-
AND PARTURITION SYNCHRONIZED?
nential production similar to the rise in maternal CRH
in humans (Smith et al., 1993; Smith et al., 1999). Humans The timely birth of suitably mature fetuses requires that
and other great apes also produce a circulating binding some mechanism synchronizes fetal maturation with the
protein for CRH (CRHBP). At the end of pregnancy, maternal mechanisms that effect the birth, including
CRHBP levels fall, thereby increasing the bioavailability of preparatory (uterotropic) and expulsive (uterotonic) phases.
CRH (Linton et al., 1993; McLean et al., 1995). In some species, including ruminants and the tammar, the
Glucocorticoids stimulate expression of the CRH gene synchronizing factor is glucocorticoid secreted by the fetal
and production of CRH by the placenta (Robinson et al., adrenal cortex.
1988; Cheng et al., 2000). In turn, CRH stimulates ACTH In tammars, the fetal adrenals almost double in size in
production by the pituitary and this ACTH causes release of the last two days of gestation, and their F content increases
F by the adrenal cortex. This arrangement permits a posi- 10-fold, then falls postpartum (Renfree 1994; Ingram,
tive feed-forward system that has been shown by mathe- Shaw, & Renfree, 1999). Cortisol concentrations in fetal
matical modeling to mimic the changes observed in human blood and allantoic and yolk-sac fluid follow a similar
pregnancy (Emanuel et al., 1994). Placental CRH produc- pattern. Adrenals from term fetuses secrete F in vitro, and F
tion is also modified by estrogens, P4, and nitric oxide synthesis is stimulated by ACTH and by PGE2 (Ingram
(NO), which are inhibitory, and by a range of neuropep- et al., 1999). Administration of exogenous glucocorticoids
tides, including adrenalin, noradrenalin, and acetylcholine, on day 24 precipitates premature parturition 22 hours later
which are stimulatory (Petraglia et al., 1989; Ni et al., 1997; on day 25, one day earlier than normal (Shaw, Renfree, &
2002; 2004). In each individual woman, levels of placental Fletcher, 1996). Glucocorticoids probably also synchronize
CRH in maternal blood follow an exponential function to organ development with parturition. For example, lung
produce a particular trajectory for that pregnancy so that surfactant is controlled by glucocorticoids and is activated
each woman maintains her position relative to median by the time of birth, even though the lungs are only at the
levels throughout the pregnancy. That is, if a woman has early stages of the terminal air-sac phase in tammars
relatively low levels early in pregnancy compared to her (Renfree, 1994). This rise in F is therefore clearly a fetal
peers, she will also have relatively low levels late in preg- signal for parturition in the tammar.
nancy. Small changes in the exponential function The rising glucocorticoid concentrations that charac-
describing CRH production at the beginning of pregnancy terize the late gestation fetal sheep not only accelerate the
lead to large differences in concentrations between maturation of organ systems required for extrauterine life,
different women later in pregnancy. Given the large varia- but induce placental enzymes (especially 17a-hydroxylase-
tions between individuals, it is likely that the rate of rise of C17,20 lyase (P450c17)) that increase the synthesis of
maternal concentrations of CRH, rather than absolute estrogens (potent uterotropic factors) at the expense of P4.
levels, is the signal for the onset of labor (Leung et al., These changes, in turn, lead to synthesis of uterotonins such
2001; McGrath et al., 2002). African Americans have lower as prostaglandins (PGs), with consequent activation of the
maternal plasma CRH concentrations than other racial myometrium and delivery.
groups studied to date, although among African American The F concentrations in ovine fetal plasma increase
women CRH concentrations correlate with the timing of exponentially over the last month of the 147-day gestation,
birth (Holzman et al., 2001) and African American women a phenomenon that has come to be known as the F surge
have relatively high rates of preterm birth. (Poore et al., 1998). The role of increased glucocorticoid
Thus, in humans and other great apes, it seems likely concentrations in accelerating the maturation of multiple
that the length of gestation is determined by the maturation organ systems needed for postnatal survival is well estab-
of the placenta and the developmental regulation of lished. An example is the respiratory system, where
expression of the CRH gene in the placental tissue modified glucocorticoid is needed for structural and functional
by factors that impinge on this process through stress- maturation of the lungs, a feature that has led to the
related production of glucocorticoids. The observed bias of prophylactic use of glucocorticoid treatment in cases of
human deliveries to the night time (Lindow et al., 2000) threatened premature delivery in humans. This treatment
suggests that diurnal rhythm in other factors, such as helps to mature the lung and reduce the incidence and
adrenal steroid production, provides a fine tuning to the severity of respiratory distress syndrome in the neonate.
actual time of delivery. The obligate requirement for prenatal glucocorticoid
The underlying factor determining gestation length in exposure was underlined when it was shown that neonatal
most species remains elusive, and we should remain open to mice lacking the CRH gene cannot survive birth unless they
the possibility that these factors may differ between species receive glucocorticoid via their mothers in utero (Cole
and that in all species the control may be multifactorial. et al., 1995; Muglia et al., 1995).
Chapter | 6 The Comparative Physiology of Parturition in Mammals: Hormones and Parturition in Mammals 101

It is important to establish the precise role of gluco- concentrations in fetal plasma may increase as a conse-
corticoids in fetal maturation, including whether they act to quence of the parturient mechanisms. The often poor
initiate or simply accelerate the differentiation of cells in outcome for prematurely born humans suggests it may be
the organs of interest. As a result of the mechanism of of little practical importance, although, in this case, struc-
action of glucocorticoid receptors on the genome of the tural immaturity of the lung and other vital organs may
target cell, there is a clear potential for these hormones to limit their ability to respond to glucocorticoids and it is
affect gene expression and thus to serve as initiators of important to extrapolate cautiously from pathological
cellular differentiation. Evidence acquired to date in the phenomena to normal physiology.
hematopoietic system suggests that, rather than acting in On balance, the universality of the fetal F surge
this way, glucocorticoids accelerate maturational change, preceding normal labor at term suggests that it constitutes
which is initiated by other means (Wintour et al., 1985; a fundamental signal. It is clearly linked to maturational
Zitnik et al., 1995; Wessely et al., 1997). Another issue processes in the fetus, although not universally to the
requiring resolution is the degree of prenatal glucocorticoid initiation of parturition.
exposure that is optimal. As a result of the approximately
30-fold increase in F concentration observed in fetal sheep
in the month before birth, it might be assumed that this 4. HOW DOES THE FETUS SIGNAL
degree of exposure is required. None-the-less, the F THE INITIATION OF LABOR?
concentrations of human fetuses appear to rise more slowly
The role of fetally derived glucocorticoids in initiating birth
and to a more modest extent, bringing into question the
in ruminants is well established. In species such as the
degree of F exposure needed in this species. Infants born
sheep, in which the placenta is the principal source of P4 for
with defective F synthesis, e.g., those affected by congen-
pregnancy maintenance, glucocorticoids induce the
ital adrenal hyperplasia, have low plasma glucocorticoid
expression of enzymes that redirect the steroidogenic
concentrations but do not usually come to clinical attention
pathway to favor the production of estrogens at the expense
because of lung immaturity (New & Speiser, 1986; White &
of P4 (Anderson et al., 1975; Steele et al., 1976). The
Speiser, 2000). This observation suggests that the degree of
resultant increase in the estrogen/P4 ratio causes several
glucocorticoid exposure required for organ maturation in
uterotropic changes and activates prostaglandin G/H syn-
humans may be quite small. However, studies of fetal HPA
thase in the placenta, leading to myometrial activation and
activity in humans (measured by the levels of estriol (E3) in
labor (Flint et al., 1974; Liggins, 1974; McLaren et al.,
the maternal circulation) suggest that late in the third
1996; 2000). Thus, the prepartum F surge is accepted as the
trimester maternal F crosses the placenta and enters the
fetal signal for labor in the sheep and related species as well
fetal circulation (Patrick et al., 1979). This may represent
as in the tammar, and probably in other macropodid
an adaptive trait to ensure that fetal organ systems are
marsupials (see Figures 6.3 and 6.4).
matured in situations where fetal glucocorticoid production
is compromised.
In addition to its maturational role, the F surge also 4.1. A More Complicated Case: The Corpus
constitutes the signal for parturition in the sheep and other
ruminants (Liggins et al., 1967; Liggins, 1968; Bassett &
Luteum-Dependent Species
Thorburn, 1969) (and even in the tammar, which has The goat, a close relative of the sheep, presents an
a ruminant-type physiology (Ingram et al., 1999)). Gluco- intriguing and significant difference from the sheep. In this
corticoids do not serve this role in all species, but an species, as in the sheep, the fetal F surge is indispensible for
increase in fetal glucocorticoid concentration occurs prior the initiation of labor (Currie & Thorburn, 1977a; 1977b;
to parturition in all species examined to date, indicating that Flint et al., 1978; Ford et al., 1998), yet the corpus luteum
it plays an essential role in late gestation, presumably that and not the placenta is the principal source of P4. This
of promoting organ maturation. In species such as the condition is termed corpus luteum dependence because
mouse, horse, and human, which do not rely on a fetal F removal of the corpus luteum results in loss of the preg-
signal to initiate birth, the possibility still exists for a causal nancy. To effect a decrease in P4 secretion, the fetal
relationship between fetal glucocorticoid-mediated matu- glucocorticoid signal must be transmitted to this remote site
ration and the birth process. The link involves one of the and induce luteolysis. It seems extremely unlikely that fetal
ubiquitous uterotonins, PGE2. This eicosanoid is secreted F could cross the placenta, be mixed with maternal blood in
in increasing amounts by the placenta or fetal membranes the maternal circulatory system, and reach the corpus
in many species during the prelude to labor and is a potent luteum in sufficient concentration to induce luteolysis
activator of the fetal HPA axis (Louis et al., 1976; Hol- directly. A more likely scenario is that F is the signal for
lingworth et al., 1995). Thus, even in species that do not some change in placental endocrine function leading to
rely on glucocorticoid as the signal for birth, glucocorticoid luteolysis. Induction of the placental P450c17 enzyme
102 Hormones and Reproduction of Vertebrates

may act, as it does in the sheep, to redirect steroidogenesis 4.2. The Role of the Fetal Hypothalamoe
from P4 to E2 synthesis (Flint et al., 1978). The caprine pituitaryeadrenal (HPA) Axis in the Initiation
placenta synthesizes as much P4 as the ovine placenta, but it
of Parturition
does not secrete sufficient P4 to maintain pregnancy
because the P4 is metabolized before it can be secreted Although the sheep and the goat differ in the way in which
(Sheldrick et al., 1980; 1981). As fetal glucocorticoid fetally derived F signals the induction of the uterotonic
secretion induces placental P450c17 activity in this species mechanisms, there is general agreement that, in these and
(Flint et al., 1978), the induction of this enzyme may lead to most other ruminant species, the fetal F surge is indeed the
the synthesis of E2, using either pregnenolone or P4 as its signal for birth. In keeping with this view, exogenous
substrate. Exogenous E2 can induce luteolysis in nonpreg- glucocorticoid induces labor in both species, whether it is
nant does and labor in pregnant does (Currie et al., 1976), administered to the fetus or the mother. In species other
although the mechanism by which it does so is not fully than the even-toed ungulates (Artiodactyla), the role of the
established. fetal HPA axis in the initiation of parturition is less clear.
When maternally administered E2 was used to induce For example, in the horse, an odd-toed ungulate (Peri-
parturition in does, the latency to parturition was about ssodactyla), the fetal F profile increases only in the last 48
three days and peripheral plasma P4 concentrations started hours before delivery and maternally administered gluco-
to decrease about 40 hours after the commencement of the corticoid does not induce labor as it does in sheep and
E2 infusion. Uteroeovarian venous PGF2a concentrations goats (Silver, 1990; Silver & Fowden, 1991). Similarly,
subsequently increased markedly in association with labor; there is little evidence for glucocorticoids as inducers of
however, episodes of PGF2a secretion were seen earlier, parturition in rodents. Mice lacking a functional CRH
about 30 hours into the infusion period, and these may have gene have atrophic adrenal cortices, yet are born at the
induced luteolysis (Currie et al., 1976). Consistent with this normal time (Muglia et al., 1995) and the timing of birth
interpretation, direct infusion of PGF2a into the uteroe in guinea pigs is unaffected by ablation of the fetal pitu-
ovarian vein induced labor in 30e36 hours, after a precip- itary (Donovan & Peddie, 1973) or maternal administra-
itous decrease in plasma P4 concentrations during the first tion of dexamethasone (Donovan & Peddie, 1973;
six hours of PGF2a infusion (Currie & Thorburn, 1973). Illingworth et al., 1974). Data from other species are
These data suggest that, in the normal doe at term, an equivocal and it is probably unsafe to assume that fetal
increase in endogenous E2 secretion could induce PG glucocorticoids play a causative role in parturition in
synthesis, leading to luteolysis and labor, although exper- eutherians generally.
imental corroboration of this hypothesis has been difficult Since fetal glucocorticoids signal birth in only
to obtain. When larger numbers of does were studied after a restricted range of eutherian species, it is noteworthy that
a longer period of postoperative equilibration, it became there is strong evidence for this phenomenon in a marsupial
apparent that P4 decreases over the last ten days of gestation species, the tammar. The marsupial lineage diverged from
with a more rapid decline in the last three days. This that of the Eutheria during the Cretaceous period between
latter change coincides with an increase in E2 concentra- 148 and 125 million years ago (Luo et al., 2003; Bininda-
tion as expected, but no evidence of increased pulsatile Emonds et al., 2007), before the major radiation that gave
or mean PGF2a secretion was found until the final, labor- rise to the Artiodactyla and most other extant eutherian
associated increase on the day of birth (Ford et al., orders. Notwithstanding the distance of their phylogenetic
1998; 1999). relationship, the tammar conforms to the artiodactyl pattern
Further studies are needed to clarify the nature of the in that the concentration of F in fetal fluids increases in the
luteolytic signal(s) in the goat. This information may have last two days of the ~27 day gestation period (Ingram et al.,
considerable economic importance as the physiology of 1999). Exogenous glucocorticoid induces premature birth
parturition in the goat parallels that in cattle. Increasingly, with maternal endocrine profiles closely matching those
large dairy herds in developed countries use synchronized, associated with spontaneous birth (Renfree & Shaw, 1996;
artificially assisted breeding programs with consequent Shaw & Renfree, 2001), and inhibition of glucocorticoid
synchronization of calving. None-the-less, there is still synthesis may delay delivery (Renfree, 1994; Shaw et al.,
considerable variability in calving dates, resulting in 1996). Whether this physiological similarity between two
significant costs to producers in terms of the human widely separated groups is an example of convergent
workload needed to minimize and manage obstetrical evolution or represents the persistence of a primitive
mishaps. Improved understanding of the normal physiology condition that has been replaced in many other eutherian
of parturition in corpus luteum-dependent species may taxa is open to debate. In either case, the induction of labor
permit more effective strategies for manipulation of calving as a result of the ubiquitous prepartum increase in fetal F is
dates with economic benefits to producers and improved not a highly conserved mechanism across taxa and there-
welfare for their stock. fore appears not to be a fundamental one.
Chapter | 6 The Comparative Physiology of Parturition in Mammals: Hormones and Parturition in Mammals 103

In primates, the fetal adrenal cortex contains a specific Median curves for progesterone, estriol and estradiol
functional compartment known as the fetal zone, which in 400 singleton pregnancies delivering at term.
produces the C19 androgen dehydroepiandrosterone sulfate 800

(nanomoles per Liter of Plasma)

P
(DHEA-S) in response to ACTH. The fetal zone grows E3
disproportionately from around the 10th week of gestation. E2

Maternal P, E2, E3
Dehydroepiandrosterone sulfate is 16-hydroxylated in the
fetal liver to form 16-OH-DHEA-S, which is then con-
verted by sulfatase and aromatase into E3 in the placenta. 400

As the 16-hydroxylase enzyme is only expressed by the

fetal liver, the production of E3 by the placenta is reflective
of the steroidogenic activity of the fetal HPA axis. Some
DHEA-S, after removal of the sulfate, is also converted to
estrone (E1) and E2 by the placenta. Thus, the estrogens of 0

human pregnancy (E1, E2, and E3) are produced by the 15 20 25 30 35 40

placenta from C19 substrate provided by the fetal zone of Gestational age (weeks)
the fetal adrenal cortex, although production of E2 and E1
Median curves for ratios of progesterone to
also occurs from maternal adrenal DHEAs.
estriol and estriol to estradiol in 400 singleton
Placental CRH is also released into the fetus. Although pregnancies delivering at term
the concentrations of CRH in the fetal circulation are lower 10
than in the maternal circulation, they still rise with E3 / E2
advancing gestation (Nodwell et al., 1999). In the fetus, P / E3

CRH receptors are present in the pituitary (Asa et al., 1991) Maternal P, E2, E3 Ratio
and on fetal zone cells in the adrenal cortex (Smith et al.,
1998). Based on the known effects of CRH on the HPA
axis, it is thought that stimulation of the fetal pituitary by 5
CRH increases ACTH production and consequently the
synthesis of F by the fetal adrenal gland and maturation of
the fetal lung. In turn, the rising F concentrations in the
fetus further stimulate placental CRH production. This
leads to an exponential increase in placental CRH 0
production and is reflected by increasing levels in the 15 20 25 30 35 40
maternal and fetal circulations. Corticotropin-releasing Gestational age (weeks)
hormone may have direct effects on fetal organ maturation FIGURE 6.6 In human pregnancy, estriol (E3) derived from fetal adre-
as well as promoting the steroidogenic activity of the fetal nal dehydroepiandrosterone sulfate (DHEA-S) increases as pregnancy
HPA axis. In baboons, CRH directly stimulates fetal lung advances under the drive from the exponential increase in placental
development and strongly induces surfactant phospholipid corticotropin-releasing hormone (CRH) production. This leads to an
increase in the ratio of E3 to 17b-estradiol (E2) (which is derived from
synthesis (Emanuel et al., 2000) but it is not clear if this maternal sources). The increase in E3 also increases the ratio of E3 to
occurs in humans. Interestingly, CRH also directly affects progesterone (P4) in maternal plasma. Together, the changes in these ratios
fetal zone function by interacting with specific receptors on increase the biologically effective estrogen action at estrogen receptors and
fetal zone cells that lead to increased DHEA-S production change the balance of estrogenic to progestational actions to favor estrogen
(Smith et al., 1998). The fetal zone of the adrenal involutes and promote the onset of labor. See color plate section.
rapidly after delivery of the placenta in association with the
decline in circulating CRH levels, which is consistent with rather than the E3 produced from adrenal precursors stim-
the idea that placental factors, such as CRH, maintain the ulated by CRH in the great apes (Smith et al., 1999). These
fetal zone. contrasting patterns in monkeys and great apes are likely
In New and Old World monkeys the situation is more related to the complex actions of the different estrogens at
complex as peak fetal zone size occurs at midgestation. In the estrogen receptor (ER). Individually, E1, E2, and E3 are
the New and Old World monkeys, E1 and E2 are the all effective agonists at the ER but act as mutual antagonists
dominant estrogens of pregnancy. The two estrogens, at equimolar concentrations (Melamed et al., 1997). In the
however, follow very different patterns: E2 peaks in great apes, in which the major estrogens are E3 and E2, the
midgestation while estrone increases progressively to peak exponential increase in placental CRH drives a late preg-
at parturition. Maternal plasma CRH concentrations in nancy increase in E3 derived from fetal adrenal androgens,
these species peak at midgestation (Smith et al., 1993), which leads to a molar excess of E3 over E2 and the
suggesting that in monkeys CRH drives E2 production estrogenic environment required for labor (Figure 6.6).
104 Hormones and Reproduction of Vertebrates

In the setting of fetal death the drop in E3 likely leads to an development of an inflammatory response in the gestational
excess of E2 and the onset of labor. In the monkeys, tissues, especially the fetal membranes and perhaps the
a midgestation rise in E2 opposes the actions of E1 at the myometrium. This may impact on the sensitivity of the
level of the estrogen nuclear receptor. The subsequent fall gestational tissues to inflammation-induced parturition. An
in E2 as E1 is maintained allows a single estrogen (E1) to interesting twist to this paradigm is the observation that the
become dominant, creating an estrogenic environment that fetal membranes express SP-A in response to glucocorti-
coincides with the onset of labor. coid and that SP-A induces PG synthesis by chorionic
Thus, the complex functional interaction between trophoblasts (Sun et al., 2006).
placental CRH and the fetal HPA axis represents a potential In summary, the synchronization of fetal maturation
link between the putative placental clock, reflected by with birth is probably achieved through increased fetal
placental CRH and the production of glucocorticoids glucocorticoid secretion in the prelude to labor. This is also
needed for fetal organ maturation and estrogens needed for the signal for labor in a minority of species. In the
the process of parturition. sheep, the glucocorticoid signal is transduced by the
placenta and the chain of events leading from this step to
myometrial activation is well defined. In corpus luteum-
4.3. Signals from the Fetal Lungs
dependent ruminants, the F signal is also transduced by the
Birth should not occur until the fetal lungs (and other organ placenta, but the mechanism linking this step to P4
systems that are needed for extrauterine life) are suffi- withdrawal requires further definition. In most other
ciently mature that the newborn is capable of air breathing. species glucocorticoids do not provide the signal for labor,
As described above, in most species F produced by the fetal but their concentrations in fetal plasma may be increased in
adrenals stimulates lung maturation and in some animals response to spillover of uterotonins such as PGE2 from
it ensures that the timing of birth is synchronized with placental tissues into the umbilical vasculature.
the functional development of organ systems (especially
the lungs) that the newborn will need to survive outside the
uterus. Recent studies in rodents (Condon et al., 2004) have 5. HOW ARE THE UTEROTONIC
indicated that the fetal lungs contribute to the parturition MECHANISMS ACTIVATED?
process. In this species, surfactant protein-A (SP-A),
During gestation, the uterus grows to accommodate the
a critical lung surfactant protein, produced by the fetal lung
increasing mass of its contents and, as term approaches, it
epithelium is secreted into the amniotic fluid where it
prepares for labor by increasing its ability to contract and
activates fetal macrophages and causes them to migrate to
expel those contents. The preparatory changes are
the myometrium. In the myometrium the increased
described as uterotropic, while the mechanisms that effect
production of cytokines by the fetal macrophages induces
myometrial activation and contraction are called utero-
activation of the transcription factor NFkB in the myo-
tonic. Clearly, both types of mechanism are important for
metrial cells, which opposes the transcriptional activity of
the successful delivery of healthy young and frequently
nuclear P4 receptors (PRs), leading to functional P4 with-
they are coordinately regulated, so it is somewhat artifi-
drawal (see Section X) and parturition (Condon et al.,
cial to separate them. The following sections concentrate
2004). This interaction ensures that fetal lung maturation,
on the uterotonic factors but also refer to uterotropic
indicated by SP-A production, and birth timing are coor-
mechanisms.
dinated. However, evidence for a similar system is not
apparent in the human. The trafficking of fetal macro-
phages in humans and mice differs substantially. However, 5.1. The Sex Steroids: Progesterone (P4)
this does not discount the possibility that SP-A, or some
and Estrogens
other signaling factor produced by the developing fetal
lung, affects myometrial contractility. In-vitro studies have In common laboratory and domestic species such as the rat,
shown that SP-A may activate the inflammatory process by mouse, rabbit, sheep, goat, cow, and dog, P4 is required for
interacting with cell surface receptors CD14 and toll-like the maintenance of pregnancy. It is secreted into the
receptor (TLR)-2 (TLR2) (Murakami et al., 2002; Sato maternal circulation from the corpus luteum of pregnancy
et al., 2003) and TLR4 and MD-2 on macrophages and, in some species, the placenta takes over this role at
(Yamada et al., 2006). In addition, some studies suggest some stage in gestation. The high P4 concentrations ach-
that SP-A interacts directly with human myometrial cells ieved during pregnancy generally favor myometrial quies-
via a specific receptor to increase prostaglandin production cence. Progesterone is thought to achieve this effect via the
and contractile capacity (Garcia-Verdugo et al., 2008). classic genomic mode of steroid hormone action whereby
Thus, SP-A produced by the human fetal lungs may directly its interaction with nuclear PRs leads to their activation as
affect myometrial contractility and the capacity for the transcription factors that modulate the expression of
Chapter | 6 The Comparative Physiology of Parturition in Mammals: Hormones and Parturition in Mammals 105

specific genes, the products of which promote a relaxed rigid. At parturition, the relaxatory actions of P4 are with-
myometrial phenotype. In addition, some studies have drawn and the stimulatory actions of estrogens prevail to
indicated that P4 also binds to membrane-associated PRs transform the myometrium to a highly contractile and
(mPRs) and that this directly affects intracellular signaling excitable state and promote cervical softening. In this
cascades that hyperpolarize myometrial cells, thus context the key event in the hormonal control of parturition
opposing the generation of electrical and mechanical is the mechanism by which P4 withdrawal is mediated and
activity within the tissue (Kuriyama & Suzuki, 1976; Par- controlled and how this is coordinated with increased
kington, 1983), although there are long-standing technical estrogenic drive to the myometrium and cervix. This event
difficulties in establishing this with certainty (reviewed in appears to be fundamental across multiple viviparous
Finn & Porter, 1975). In contrast to the relaxatory actions of species but with variability existing in the physiology and
P4, estrogens (mainly E3 in the human) promote labor and biochemistry of P4 withdrawal and estrogen activation.
delivery by favoring the synthesis of contractile proteins in In many species, the maternal plasma P4 concentration
myometrial cells and enhancing electrical coupling through decreases shortly before the onset of labor, and P4 with-
connexin 43 and the expression of OXY receptors, leading drawal before term results in premature labor (see
to well-propagated, coordinated contractions. Thus, the Figure 6.7).
general consensus is that through most of pregnancy the In others, such as the guinea pig and human, no such
influence of P4 dominates to maintain the uterus in marked decrease in plasma P4 occurs, yet preterm treatment
a relaxed and quiescent state with the cervix closed and with antiprogestogens induces premature labor, at least

FIGURE 6.7 Pattern of circulating levels of progesterone (P4) and estrogens in the rat, rabbit, sheep, cow, tammar, guinea pig, and tree shrew throughout
gestation. See color plate section.
106 Hormones and Reproduction of Vertebrates

under some conditions. This apparent paradox may be hypothesis, which posits that P4 withdrawal in human
resolved in the case of the guinea pig by the observation parturition is mediated by an increase in the myometrial
that, although the circulating steroid concentrations do not PR-A/PR-B ratio. In support of this hypothesis, several
change, the abundance of PRs decreases while ERs studies have found that PR-A levels (and the PR-A/PR-B
increase near term (Glasier & Hobkirk, 1993). This ratio) increase in the human pregnancy myometrium in
suggests that functional P4 withdrawal in species with association with advancing gestation and the onset of labor
persistent exposure of the uterus to high P4 levels is (Mesiano et al., 2002; Merlino et al., 2007). Interestingly,
mediated by decreased myometrial P4 responsiveness. a similar labor-associated increase in the myometrial PR-A/
Myometrial P4 responsiveness is determined primarily by PR-B protein ratio has been observed in the rhesus monkey
the extent of expression of specific PRs and in particular the (Haluska et al., 2002), a species that also lacks a systemic
nuclear PRs. The fact that labor is initiated by adminis- P4 withdrawal at parturition.
tration of specific PR antagonists (e.g., mifepristone Other mechanisms also may facilitate functional P4
(RU486)) reflects the importance of nuclear PR-mediated withdrawal at parturition. The transcriptional activity of the
P4 actions for the maintenance of pregnancy. Moreover, it PRs requires specific coregulators that form the nPR-
shows that inhibition of this signaling pathway is sufficient induced transcriptional complex. These include cAMP
to trigger the full parturition cascade. Based on this (cyclic-3’,5’-adenosine monophosphate)-response-element-
reasoning, it is hypothesized that human parturition binding protein (CREB)-binding protein and steroid receptor
involves a functional nuclear PR-mediated P4 withdrawal coactivators 2 and 3 (Condon et al., 2003). Studies in human
whereby genomic P4 responsiveness in myometrial cells is term myometrium have shown that the levels of these critical
abrogated (Mesiano et al., 2002). coactivators decrease with the onset of labor (Condon et al.,
The human PR exists as two major forms: the full- 2003) and as such the capacity for ligand-activated PR-B to
length PR-B and the truncated (by 164 N-terminal amino control gene expression could be compromised. Proges-
acids) PR-A (Kastner et al., 1990). Many in-vitro studies terone may also be metabolized to products with diminished
have led to the concept that PR-B is the principal mediator progestin activity. For example, at the time of labor, the
of P4 actions, whereas PR-A decreases P4 responsiveness potent relaxatory steroid 5b-dihydroprogesterone decreases
by repressing the transcriptional activity of PR-B (Haluska along with a reduction in steroid 5b-reductase expression
et al., 2002; Mesiano, 2004; Merlino et al., 2007). Thus, and activity (Sheehan et al., 2005). The transcription/activity
genomic P4 responsiveness may be related to the PR-A/ of factor NFkB in myometrial cells may also be important in
PR-B ratio in target cells. This has led to the PR-A/PR-B blocking the action of P4 at the receptor level (Kalkhoven

FIGURE 6.8 The onset of labor

in humans. Placental production of
corticotropin-releasing hormone (CRH)
leads to a change in the balance of
estriol (E3) to 17b-estradiol (E2) and of
E3 to progesterone (P4). Contraction-
associated proteins (CAPs) include
connexin 43. Caþþ; cAMP, cyclic-
3’,5’-adenosine monophosphate;
cGMP; CAP, contraction-associated
protein; ER, estrogen receptor; IkBa;
NFkB; PG, prostaglandin; PGRMC;
PR, progesterone receptor. See color
plate section.
Chapter | 6 The Comparative Physiology of Parturition in Mammals: Hormones and Parturition in Mammals 107

FIGURE 6.9 In the Tammar fetal

production of cortisol is a dominant signal
to the onset of parturition. Cortisol
promotes placental transcription of the
PGHS2 gene leading to increased prosta-
glandin production. Both PGE2 and
PGF2a are produced within the placenta.
PGE2 feeds back to promote ACTH
release from the fetal pituitary promoting
the rapid rise in fetal cortisol that precedes
parturition. PGF2a is released from the
placenta into the maternal circulation
where it promotes parturient behaviours
and myometrical contraction. Other
placental factors may stimulate nitric
oxide synthase (NOS) which promote
myometrial relaxation during pregnancy.
Mesotocin from the mother also plays
a role in promoting myometrial contrac-
tion. The increase in mesotocin and
PGF2a prior to delivery occurs as a brief
peak (approximately one hour). See color
plate section.

et al., 1996; Lindstrom & Bennett, 2005). This may be 1994). Indeed, in this and related species the duration of
a critical mechanism for infection-induced preterm labor, gestation and the estrous cycle are the same and the P4 and
since NFkB is a major mediator of the inflammatory estrogen profiles during pregnancy do not differ. Neither
response; one of its actions in myometrial cells may be to blocking P4 nor increasing it via exogenous injection, or
block the transcriptional activity of PR-B. Taken together, removal of estrogens, has any influence on the timing of
the current data indicate that in human parturition the P4 parturition (Ward & Renfree, 1984; Short et al., 1985).
block to the onset of labor is removed by specific Further comparative studies are needed to determine
biochemical events in myometrial cells that abrogate the whether P4 or related progestogens play an obligatory role
capacity of ligand-activated PR-B to promote relaxation (see in the maintenance of pregnancy across the mammalian
Figure 6.8). subclasses and orders.
In the horse, circulating P4 concentrations are low in Estrogens promote protein synthesis, tissue growth, and
late gestation, while high concentrations of 5a-reduced P4 blood flow in the uterus, and, in the common laboratory and
metabolites are found (Holtan et al., 1975; 1991). Inhibi- domestic species, they favor the synthesis of uterotonins,
tion of P4 synthesis with the 3b-hydroxysteroid dehydro- including prostaglandins. They also promote the expression
genase (3b-HSD) inhibitor, epostane, does not induce of receptors for uterotonins (PGs and OXY) in the myo-
premature labor in mares even though plasma P4 concen- metrium. As such, they oppose P4 action, and the simul-
trations fall (Fowden & Silver, 1987). Interestingly, in taneous prepartum decrease in circulating P4 and increase
those studies epostane also inhibited estrogen synthesis, in estrogen concentrations in the sheep are regulated
complicating the interpretation of the outcomes, as the coordinately through the activation of placental P450c17.
estrogen/P4 ratio may be more important than the absolute While it is generally true that estrogens predispose the
concentrations of the individual steroids in the equine. myometrium to contract, they are not essential for partu-
Estrogens are synthesized by the equine placenta using as rition in all species. Antagonism of estrogen actions delays
the principal substrate DHEA-S derived from the fetal but does not abolish the birth process in rats (Fang et al.,
gonads (Raeside et al., 1979). If the fetal gonads are 1996) and pregnancy and parturition proceed in women
removed, the estrogen/P4 ratio falls dramatically but the when placental aromatase is lacking (Shozu et al., 1991;
timing of parturition is unaffected, suggesting that even the 1992). Similarly, exogenous estrogens do not induce or
estrogen/P4 ratio is relatively unimportant, although there accelerate labor in humans, and other data indicating that
is some contradictory evidence (Haluska & Currie, 1988). estrogens are not essentially linked to the onset of human
Considered together, these findings suggest that the clas- labor have been reviewed previously (Liggins & Thorburn,
sical roles of the sex steroids in the physiology of partu- 1994). Despite these findings, studies in the rhesus monkey
rition may not apply in the horse. Similarly, there is no suggest that increased estrogen synthesis due to increased
prepartum change in P4 in the tammar (Ward & Renfree, availability of C19 precursors may precipitate parturition
1984; Tyndale-Biscoe, Hinds, & Horn, 1988; Renfree, (Giussani et al., 1996; Mecenas et al., 1996; Nathanielsz
108 Hormones and Reproduction of Vertebrates

et al., 1998). Recent work in the human suggests a critical mutual antagonism of E3 and E2, and to the inhibition of
role for the ratio of E3 to E2, with a marked rise in E3 myometrial ERa expression by P4. Thus, P4 may not only
occurring just prior to delivery that is correlated with inhibit the expression of contraction-associated genes, such
increasing concentrations of CRH (Smith et al., 2009). This as connexin 43, but also decrease myometrial estrogen
finding indicates a physiological link between the activity responsiveness by inhibiting ERa expression. Studies of
of the fetal HPA axis and the timing of parturition in PR and ERa expression in the term human pregnancy
primates. A unique feature of the primate fetal adrenal myometrium support this hypothesis and suggest that
cortex is the fetal zone and its abundant production of functional P4 withdrawal mediated by increased expression
DHEA-S. Dehydroepiandrosterone sulfate is the principal of PR-A (and the PR-A/PR-B ratio) leads to increased
source of C19 steroids for placental estrogen production. expression of ERa. In this scenario the circulating estro-
The principal placental estrogen of human pregnancy is E3. gens could promote contractility once the P4 block has
As the placenta lacks the 16-hydroxylase enzyme, it can been removed.
only produce E3 from a 16-hydroxylated C19 steroid
precursor (Diczfalusy et al., 1964). Most of the DHEA-S 5.2. Inflammatory Mediators: Prostaglandins
produced by the fetal zone is converted to 16a-hydroxy-
DHEA-S by the fetal liver and to a lesser extent within the
(PGs) and Cytokines
adrenal itself (Seron-Ferre, 1981). The maternal adrenal Some of the changes seen in uterine and cervical tissues in
also makes a substantial contribution to DHEA-S produc- the period surrounding the onset of labor resemble changes
tion but the maternal tissues lack the 16-hydroxylase that typically occur in response to tissue damage. These
enzyme. In the placenta, the sulfatase enzyme removes the include tissue edema, neutrophil infiltration, and expression
sulfate moiety from DHEA-S and 16a-hydroxy-DHEA-S, of chemical mediators of the inflammatory reaction, of
producing DHEA, which is aromatized to E1 and E2, and which cytokines and PGs are key players (Kelly, 1996). The
16a-hydroxy-DHEA, which is aromatized to E3. Thus, E3 case for inflammatory mediators as effectors in parturition
production is exclusively from fetal sources while E2 and is strengthened by the observation that stimuli such as
E1 may originate from either maternal or fetal precursors. mechanical or chemical trauma, or infection, which
In primates, the placenta lacks P450c17 throughout gesta- commonly induce the expression of these agents, are
tion; therefore, P4 production does not decline at the end of associated with premature delivery and are often effective
pregnancy as it does in sheep. as abortifacients.
Androgens may be important for the initiation of In considering the roles of proinflammatory agents in
primate parturition. Infusion of androstenedione (AND) parturition, it is useful to distinguish between their effects
into pregnant rhesus monkeys late in gestation increased on the body of the uterus and the cervix. The body of the
maternal estrogens and nocturnal OXY concentrations and uterus consists principally of the endometrium and the
induced cervical dilation and normal parturition (Mecenas myometrium, while the cervix is unlike either of these
et al., 1996). Thus, in primates, androgen, produced by the tissues, being composed mainly of collagenous connective
fetal adrenals as a source of aromatizable substrate for tissue. Cytokines and PGs are implicated in the activation
estrogen synthesis by the placenta, may be the link between of the myometrium, but they play an equally important role
fetus and mother in the initiation of parturition. However, in cervical ripening. This process is characterized by
removal of the fetus (fectectomy) in baboons does not hydration of the ground substance, together with enzymatic
prolong retention of the placenta, and administration of E2 unlinking and loss of orientation of the collagen fibers that
prevents placental delivery and prolongs gestation in compose the bulk of the cervical tissue, with consequent
fetectomized baboons, indicating that in this species softening and increased compliance of the cervix. This
estrogens produced by the fetoeplacental unit may actually allows transformation of the entire structure from an
inhibit parturition. However, the interpretation of these data unyielding, tubular one into a compliant, effaced opening
needs to be conducted in the light of the likely role of allowing the safe exit of the fetus (Calder & Greer, 1990;
changing ratios of different estrogens close to the onset of Denison et al., 1999).
labor in primates. The questionable importance of estrogen Among the cytokines, interleukins (ILs)-1, -6, and -8
for parturition in horses and wallabies (Shaw & Renfree, and tumor necrosis factor (TNF)-a are implicated in
1984) already has been discussed. cervical ripening and in the prelude to myometrial activa-
In human pregnancy, maternal estrogen levels begin to tion, although they do not exert uterotonic effects directly
increase from around the 10th week of gestation and (Romero et al., 1991; Romero & Tartakovsky 1992; Elliott
continue to be elevated up to delivery. Thus, for most of et al., 1998; Denison et al., 1999). Interestingly, evidence
pregnancy, the myometrium is exposed to large amounts of suggests that IL-6 is secreted in response to tissue damage
estrogens, yet it remains in a relaxed and quiescent state. but acts to mitigate the inflammatory response (Wu et al.,
This apparent refractoriness may be attributable to the 2004). The neutrophils that infiltrate the cervical tissue are
Chapter | 6 The Comparative Physiology of Parturition in Mammals: Hormones and Parturition in Mammals 109

probably responsible for the enzymatic unlinking of 2005). The predominant location of PGHS-2 in a fetal
collagen fibers although fibroblasts that are also abundant structure (the amnion) may reflect the need for a fetal signal
express collagenases and may participate in this process to initiate labor, but the amnion is relatively distant from
(Calder & Greer, 1990; Kelly, 1996). the site of PG action in the myometrium, and the PGs
In the myometrium, PGs induce muscle contraction. would need to diffuse through the chorion containing the
Prostaglandin E2 does not elicit contraction in all species or dehydrogenase that inactivates them. In the tammar, PGs
at all stages of gestation, but PGF2a is secreted into the accumulate in the yolk sac fluid, and the placenta appears to
uterine veins during labor in all species studied to date be the site of synthesis (Shaw, 1983; Shaw & Bell, 1999)
including marsupials, and appears to act as a universal These PGs are critical for the induction of normal birth
myometrial contractant. Accordingly, disruption of the behavior as well as for uterine contractility (Hinds et al.,
genes encoding the inducible PG synthase (PGHS)-2 or the 1990; Shaw, 1990) (see Figure 6.9).
PGF receptor is associated with disordered labor in mice Data from studies of human myometrial cells suggest
(Dinchuk et al., 1995; Morham et al., 1995; Sugimoto et al., that PGs play a critical role in the induction of parturition
1997). Similarly, direct infusion of PGF2a (and, in some by inducing P4 withdrawal via their induction of PR-A
species, PGE2) induces labor whereas pharmacological expression (Madsen et al., 2004). Several observations
inhibition of PGHS-2 inhibits it (Poore et al., 1999). provide clues as to the hormonal regulators of myometrial
Proinflammatory cytokines in the parturient process appear PR expression. Prime candidates include locally produced
to promote induction of PGHS-2, the expression and immune/inflammatory cytokines, particularly PGE2 and
activity of which increase at the onset of labor with PGF2a, that may be involved in normal term birth and
consequent increases in PG production by intrauterine infection-associated preterm birth. In women, exogenous
tissues. Positive feedback of PGs on cytokine expression PGs induce the full parturition cascade at all stages of
also has been demonstrated (Denison et al., 1999). pregnancy (Robins & Mann, 1975; Jain & Mishell, 1994).
Although it may not cause uterine contraction in all species, However, in contrast to the potent and almost instantaneous
PGE2 is secreted in large amounts from the placenta in late uterotonic actions of PGs when administered to women
gestation in many species and is effective in inducing already in active labor, the induction of labor in a quiescent
cervical ripening. Thus, uterine activity and cervical uterus by exogenous PGs occurs after a latency of 15e20
compliance are affected simultaneously by the comple- hours (Robins & Mann, 1975; Jain & Mishell, 1994). This
mentary actions of PGF2a and PGE2. These effects seem to likely represents the time needed for the myometrium to
apply in all species studied to date. transform to a contractile state. Thus, PGs may first act as
The sites of PG synthesis within the uterus and the uterotropins to transform the myometrium to a contractile
means by which these cytokines reach the myometrium phenotype, and then exert potent uterotonic actions once
have been the subject of investigations. Contrary to earlier the contractile state is established. Consistent with this
expectations, the myometrium does not generally exhibit hypothesis is that, in a human myometrial cell line, PGF2a
increased expression of PGHS-1 or -2 at labor in the sheep increases the PR-A/PR-B mRNA ratio by specifically
(McLaren et al., 1996; Gibb et al., 2000; McLaren et al., increasing expression of PR-A but not PR-B expression
2000) or the rat (Myatt et al., 1994), raising questions about (Madsen et al., 2004). This finding suggests that increased
where these PGs are synthesized and how they reach the local PGF2a production and/or increased PGF2a accessi-
target tissue. In the sheep, the only tissue showing increased bility to the myometrium from the amnion through
expression of PGHS-2 at spontaneous or glucocorticoid- decreased PG dehydrogenase in the chorion could initiate
induced labor appears to be the placenta (McLaren et al., labor by modulating myometrial PR expression to induce
1996; 2000). Prostaglandins may reach the myometrium functional P4 withdrawal. Indeed normal labor at term is
from the 80e100 placentomes by diffusion, either directly associated with increased PG production by the fetal
through the basal plates of the placentomes or from the membranes and decidua (Mitchell et al., 1995) and
many small veins draining the placentomes. Thus, in the abnormal parturition, particularly infection/inflammation-
sheep, the signaling pathway from the fetus to the placenta associated preterm labor, could involve the same process. In
via glucocorticoids and from the placenta to the myome- this regard, the link between the local immune/inflamma-
trium via PGs appears reasonably straightforward. In tory response within the gestational tissues and myometrial
humans, the situation is much less clear. The human fetal PR expression becomes an important issue. Activation of
HPA axis probably plays an important role in normal the NFkB transcription factor complex (a key mediator of
parturition but is not essential in signaling the onset of labor the inflammatory response) stimulates expression of PRs in
(reviewed in Liggins & Thorburn, 1994) and the principal myometrial cells (Condon et al., 2006). Thus, current data
site of PG production is believed to be the amnion suggest that local immune/inflammatory cytokines, and in
(Sadovsky et al., 2000), although PGHS-2 increases in the particular PGF2a, converge on myometrial PR expression to
human myometrium at labor (Chan et al., 2002; Bisits et al., modulate P4 responsiveness and potentially initiate labor by
110 Hormones and Reproduction of Vertebrates

inducing functional P4 withdrawal. This may be a central complete than that obtained in rats, but is broadly consis-
pathway in the hormonal control of human parturition. tent with this hypothesis.
The OXY gene is expressed in the uterus itself as well as
the hypothalamus, raising the possibility that OXY synthe-
5.3. Oxytocin (OXY)
sized within the uterus could participate in the initiation or
The data currently available are consistent with a role for the accomplishment of parturition (Mitchell et al., 1998).
OXY in the second stage of labor in all or most mammalian The expression of the OXY gene as measured by mRNA
species, while its putative role in the onset of labor in any concentration peaks some three to four days before labor in
species awaits confirmation. During established labor, the rat uterus, although this timing raises questions about the
OXY is secreted episodically from the posterior pituitary of role and mechanism of action of OXY in the initiation of
most if not all species in response to cervicoevaginal birth (Fang et al., 1996). The prepartum increase in OXY
stretch and acts on the myometrium to increase the gene expression in the rat uterus depends on estrogen action,
frequency and force of contractions. Physiological to being abolished by the ER antagonist tamoxifen. Signifi-
supraphysiological concentrations of exogenously admin- cantly, even when OXY gene expression was suppressed by
istered OXY are used clinically to induce labor in women at tamoxifen, labor was eventually initiated, although it was
term. However, the role of OXY appears more subtle than delayed. This delay was associated with suppression of the
that of PGs since it does not normally induce preterm labor tissue PGE2 concentration immediately before the expected
and, even at term, it is unreliable unless some procedure time of delivery, and a restoration of this parameter by the
inducing tissue damage (such as amniotomy) is also per- time of labor. These observations are consistent with
formed. Similarly, pharmacological inhibition of OXY a complex positive regulatory interaction between estro-
action may delay but does not abolish delivery in rats and gens, PGHS, and the uterine OXY system, and are consis-
guinea pigs (Chan & Chen, 1992; Schellenberg, 1995), and tent with the proposed role of PGs as the final common
OXY-null mice deliver spontaneously at the expected time effector in myometrial activation. They also suggest regu-
(Nishimori et al., 1996; Young et al., 1996). lation of PGHS expression or activity by factors other than
The expression of OXY receptors in the pregnant uterus estrogens and OXY since normal PGE2 concentrations were
is increased at term in humans, rats, and all other species reached despite significant downregulation of uterine ERs
studied to date (Alexandrova & Soloff, 1980a; 1980b; and OXY gene expression. This action could be exerted by
1980c; Fuchs et al., 1982). In the tammar, a similar increase cytokines, as discussed previously.
has been reported in the concentration of receptors for In the tammar, uterine contractility is mediated by
mesotocin (8-Ile-oxytocin (MST)), the tammar equivalent a decrease in NOS and NO in conjunction with an increase
of OXY (Parry et al., 1996; Renfree et al., 1996; Parry et al., in MST, both probably stimulated by local fetaleplacental
1997; Sebastian et al., 1998), and blocking MST inhibits signals in concert with the rapid PG pulse at parturition
parturition (Renfree et al., 1996). The consistency of this (Ingram, Renfree, & Shaw, 2001). In the pig, the OXY gene
phenomenon across taxa suggests a fundamental role for is expressed in the myometrium and the endometrium,
OXY, although it does not argue specifically for a role in the although the tissue mRNA concentration does not increase
initiation of labor. The induction of OXY receptors (OXY- as labor approaches. These data lend mixed support for the
R) at term in the rat can be inhibited by blocking PGHS notion that intrauterine OXY gene expression is an
(Chan, 1980), and this treatment is associated with pro- important step for the initiation of labor.
longed gestation and inefficient uterine contractions (Chan
& Chen, 1992). In the same study, specific OXY-R blockade 5.4. Electrical Conductivity of the
did not prolong gestation but interfered with the process of
Myometrium
delivery. Together, these observations suggest that PGs are
positive regulators of OXY-R expression, that the uterotonic It has long been known that propagation of action potentials
action of PGs depends partly on OXY action, and that PGs, through the myometrium of rabbits is inhibited by high P4
but not OXY, are involved in the initiation of labor. concentrations and that the ‘P4-blocked’ uterus is charac-
Oxytocin also stimulates PG release from the endo- terized by a reduction in both the amplitude of contraction
metrium of the pregnant rat and the OXY-R type mediating and intrauterine pressure (Csapo, 1977). These phenomena
this response may be pharmacologically differentiated from were confirmed in the tammar (Ingram et al., 2001; Shaw,
the myometrial receptors responsible for the utertonic 2001) and sheep (Lye & Porter, 1978) for uterine contrac-
actions of oxytocin (Chan, 1980; Chan & Chen, 1992; Chan tions induced by both oxytocin and PGF2a, although the
et al., 1993). These observations suggest the existence of explanation for this phenomenon at the cellular or tissue
a positive feedback control mechanism with PGHS as the level was not established at that time. It was subsequently
controlling variable and endometrial OXY-R expression as shown that the numbers of gap junctions on myometrial
the controlled variable. Evidence from other species is less cells of guinea pigs increase at parturition (Garfield et al.,
Chapter | 6 The Comparative Physiology of Parturition in Mammals: Hormones and Parturition in Mammals 111

1982) and that these are permeable to ions, intracellular mechanisms at the level of the myometrium. Prosta-
signaling molecules, and dyes. They also constitute high glandin F2a and PGE2 are universally involved in direct
conductance pathways to facilitate electrical coupling activation of the myometrium and also in preparation of
between adjacent cells and provide an anatomical basis for the cervix and other components of the birth canal. The
the increased conductivity of myometrial tissue obtained importance of gap junction proteins has not been
from pregnant animals at term, relative to other times. assessed in many species, but it may be a widespread
The gap junctions are formed by oligomers of a protein feature of uterine activation. Oxytocin plays a role in
called connexin 43. The expression of connexin 43 inducing uterine contractions in most, if not all, species,
increases at term or labor in the myometrium of the human although this role is not responsible for the initiation of
(Garfield & Hayashi, 1981; Chow & Lye, 1994; Sparey parturition.
et al., 1999), sheep (McNutt et al., 1994), rabbit (Nnamani 6. The physiology of parturition in humans is not well
et al., 1994), and rat (Orsino et al., 1996); is positively represented by any animal model and application of the
regulated by estrogens in the rat (Lefebvre et al., 1995) and methods of comparative physiology suggests that we
cow (Doualla-Bell et al., 1995); and is inhibited by P4 in the should exercise caution in extrapolating knowledge
rat (Orsino et al., 1996; Risek & Gilula, 1996; Ou et al., gained in laboratory, domesticated, or captive animal
1997). In the human, connexin 43 expression correlates species to humans. This caution applies increasingly as
with ER-A expression in the myometrium (Bisits et al., one considers mechanisms more distant from the level
2005) and explanted cells increase their expression of of the myometrium.
connexin 43 in response to exogenous estrogens (Kilarski
et al., 2000). Progesterone may not regulate connexin 43 in
ABBREVIATIONS
the human myometrium (Geimonen et al., 1998; Kilarski
et al., 2000). The human myometrium shows greater 16-OH DHEA-S 16-Hydroxy dehydroepiandrosterone
expression of connexin 43 in the fundal than the cervical 3b-HSD 3b-hydroxysteroid dehydrogenase
region, suggesting that contractions may be propagated ACTH Corticotropin
AND Androstenedione
from the former zone to the latter, which would be expected
cAMP Cyclic-3’,5’-adenosine monophosphate
to aid expulsion of the fetus (Sparey et al., 1999). It is
CAP Contraction-associated protein
highly likely that connexin 43 and other gap junction CREB cAMP-response-element-binding protein
subunit proteins are important for parturition in humans but CRH Corticotropin-releasing hormone
the factors regulating their expression in humans require CRHBP Circulating binding protein for CRH
elucidation. The distribution and regulation of gap junction DHEA-S Dehydroepiandrosterone sulfate
proteins appears not to have been studied systematically E1 Estrone
beyond the standard laboratory and farmed species, but the E2 17b-estradiol
consistency of the scenario across those that have been E3 Estriol
studied suggests that these proteins play a fundamental and ER Estrogen receptor
generalized role in the physiology of parturition. F Cortisol
HPA Hypothalamoepituitaryeadrenal
IL Interleukin
6. CONCLUSIONS MEL Melatonin
mPR Membrane-associated progesterone receptor
1. There appears to be a general requirement for ante- MST Mesotocin
natal exposure of the fetus to glucocorticoid, which NO Nitric oxide
promotes the maturational changes needed for extra- NOS Nitric oxide synthase
uterine life. OXY Oxytocin
2. The prepartum increase in glucocorticoid concentra- OXY-R Oxytocin receptor
tions in fetal plasma constitutes the signal for myo- P4 Progesterone
metrial activation in only a few species, although not all P450C17 17-hydroxylase 17,20 lyase
these species are closely related. PG Prostaglandin
PGE2 Prostaglandin E2
3. Progesterone is required for the maintenance of uterine
PGF2a Prostaglandin F2a
quiescence and its action is withdrawn at term by
PGHS Prostaglandin synthase
decreased secretion or receptor downregulation in PR Progesterone receptor
many, but not all, species. RU486 Mifepristone
4. Estrogens generally favor myometrial activation. SCN Suprachiasmatic nucleus
5. Although there is considerable interspecific diversity SP-A Surfactant protein-A
in the ultimate determinants of parturition, there is TLR Toll-like receptor
much more consistency when it comes to the effector TNF Tumor necrosis factor
112 Hormones and Reproduction of Vertebrates

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114 Hormones and Reproduction of Vertebrates

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Chapter | 6 The Comparative Physiology of Parturition in Mammals: Hormones and Parturition in Mammals 115

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