Vous êtes sur la page 1sur 7

Journal of Reproductive Immunology 85 (2010) 3339

Contents lists available at ScienceDirect

Journal of Reproductive Immunology


journal homepage: www.elsevier.com/locate/jreprimm

Review

Corticotropin-releasing hormone, stress and human


reproduction: an update
S.N. Kalantaridou a, , E. Zoumakis b , A. Makrigiannakis c , L.G. Lavasidis a ,
T. Vrekoussis a , G.P. Chrousos b
a
b
c

Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Ioannina Medical School, Ioannina, Greece
Choremeio Research Laboratory, First Department of Pediatrics, University of Athens Medical School, Athens, Greece
Department of Obstetrics and Gynecology, University of Crete Medical School, Heraklion, Greece

a r t i c l e

i n f o

Article history:
Received 1 September 2009
Received in revised form 24 February 2010
Accepted 26 February 2010
Keywords:
Corticotropin-releasing hormone (CRH)
Fetal immunotolerance
Fetal programming
Implantation
Parturition
Pregnancy
Preterm delivery
Stress

a b s t r a c t
The stress system has suppressive effects on female and male reproductive function.
Corticotrophin-releasing hormone (CRH), the principal regulator of stress, has been identied in the female and male reproductive system. Reproductive CRH participates in various
reproductive functions that have an inammatory component, where it serves as an
autocrine and paracrine modulator. These include ovarian and endometrial CRH, which
may participate in the regulation of steroidogenesis and the inammatory processes of
the ovary (ovulation and luteolysis) and the endometrium (decidualization and blastocyst
implantation) and placental CRH, which is secreted mostly during the latter half of pregnancy and is responsible for the onset of labor. It has been suggested that there is a CRH
placental clock which determines the length of gestation and the timing of parturition
and delivery. The potential use of CRH-antagonists is presently under intense investigation. CRH-R1 antagonists have been used in animal studies to elucidate the role of CRH in
blastocyst implantation and invasion, early fetal immunotolerance and premature labor.
The present review article focuses on the potential roles of CRH on the physiology and
pathophysiology of reproduction and highlights its participation in crucial steps of pregnancy, such as implantation, fetal immune tolerance, parturition and fetal programming of
the hypothalamicpituitaryadrenal (HPA) axis.
2010 Elsevier Ireland Ltd. All rights reserved.

1. Introduction
The hypothalamicpituitaryadrenal (HPA) axis along
with the arousal and autonomic nervous systems consti-

Abbreviations: HPA, hypothalamicpituitaryadrenal axis; CRH,


corticotropin-releasing hormone; AVP, arginine-vasopressin; ACTH,
adrenocorticotropic hormone; CRH-BP, CRH-binding protein; GnRH,
gonadotropin releasing hormone; IUGR, intrauterine growth restriction.
The authors own the exclusive intellectual property rights of the
present review paper and they are free to reproduce it in whole or in
part (including tables and gures) in any electronic and/or printed article
of which they are authors.
Corresponding author. Tel.: +30 26510 07251; fax: +30 26510 07055.
E-mail address: Sophia Kalantaridou@hotmail.com
(S.N. Kalantaridou).
0165-0378/$ see front matter 2010 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.jri.2010.02.005

tute the stress system. The stress system is activated in a


coordinated fashion during stress, inuencing central and
peripheral functions that are important for adaptation and
survival (Chrousos and Gold, 1992). Stress has suppressive
effects on the female and male reproductive systems.
The main central regulators of the HPA axis are
corticotrophin-releasing hormone (CRH) and argininevasopressin (AVP), both produced by parvicellular neurons
of the paraventricular nucleus of the hypothalamus into
the hypophyseal portal system (Chrousos and Gold, 1992).
CRH and AVP synergistically stimulate pituitary adrenocorticotropic hormone (ACTH) secretion and subsequently,
glucocorticoid secretion by the adrenal cortex. CRH and its
receptors are also found in many extra-hypothalamic sites
of the central nervous system, playing a major coordina-

34

S.N. Kalantaridou et al. / Journal of Reproductive Immunology 85 (2010) 3339

Fig. 1. Stress and the reproductive system.

tive role for the stress response (Chrousos et al., 1998).


Three CRH receptor genes have been identied so farCRHR1, CRH-R2, and CRH-R3 (Hillhouse and Grammatopoulos,
2006; Kalantaridou et al., 2007). In mammals, only the CRHR1 and CRH-R2 receptors have been identied (Hillhouse
and Grammatopoulos, 2006), whereas the CRH-R3 has
only been identied in the catsh (Zoumakis et al., 2009).
Furthermore, the biological effects of CRH are modulated
by CRH-binding protein (CRH-BP), which controls CRH
bioavailability (Smith, 2007).
CRH and its receptors have also been identied in
the female and male reproductive system. Thus reproductive CRH is a form of tissue CRH, i.e. CRH found
in peripheral tissues. Reproductive CRH participates in
various reproductive functions with an inammatory component, where it serves as an autocrine and paracrine
modulator. These include ovarian and endometrial CRH,
which may participate in the regulation of steroidogenesis
and the inammatory processes of the ovary (ovulation and
luteolysis) and the endometrium (decidualization and blastocyst implantation) and placental CRH, which is secreted
mostly during the latter half of pregnancy and is responsible for the onset of labor.
The present review article focuses on the potential roles
of CRH on the physiology and pathophysiology of reproduction and highlights its participation in crucial steps of
pregnancy, such as implantation, fetal immune tolerance
in early pregnancy, parturition and fetal programming of
the HPA axis.
2. Effect of stress on female and male reproduction
An increased glucocorticoid activity is the hallmark of
stress. As the end product of the HPA axis, glucocorticoids
have a wide range of effects in multiple systems involved
in growth, maintenance and reproduction.
The HPA axis, when activated by stress, exerts an
inhibitory effect on the female reproductive system (Fig. 1).
CRH and CRH-induced proopiomelanocortin peptides, such
as -endorphin, inhibit hypothalamic GnRH secretion

(Chen et al., 1992). In addition, glucocorticoids suppress the


female gonadal axis function at the hypothalamic, pituitary
and uterine level (Sakakura et al., 1975; Rabin et al., 1990).
Indeed, glucocorticoid administration signicantly reduces
the peak luteinizing hormone response to intravenous
GnRH, suggesting an inhibitory effect of glucocorticoids on
the pituitary gonadotroph (Sakakura et al., 1975). Furthermore, glucocorticoids inhibit estradiol-stimulated uterine
growth (Rabin et al., 1990). These effects of the HPA axis are
responsible for the hypothalamic amenorrhea of stress,
which is observed in anxiety and depression, malnutrition,
eating disorders and chronic excessive exercise, and the
hypogonadism of the Cushing syndrome (Chrousos et al.,
1998).
Stress exerts inhibitory effects on the male reproductive
system as well (Fig. 1). Glucocorticoids inhibit testosterone
production by Leydig cells (Orr et al., 1994). In addition, experimental evidence suggests that chronic stress
may further decrease LH secretion (Norman, 1993; Orr
et al., 1994; Almeida et al., 1998). These changes result
in diminished libido and fertility (Phillips et al., 1989).
In humans, the severe psychological stress brought on
by the death of a relative or spouse lowers sperm count
(Fenster et al., 1997). Although this effect may occur due
to the stress-induced testosterone decrease, direct effects
of stress on the seminiferous epithelium have also been
reported (Yazawa et al., 1999). The extent of glucocorticoid activity in the testis is modulated by metabolism
catalyzed by 11b-hydroxysteroid dehydrogenase (Hu et
al., 2008). This enzyme is bidirectional, with both oxidase
and reductase activities, and in the rat testis is exclusively
localized in Leydig cells where it is abundantly expressed
and may catalyze the oxidative inactivation of glucocorticoids.
Increased glucocorticoid levels are responsible for the
hypogonadism of men with Cushing syndrome (Smals et al.,
1977; Chrousos et al., 1998). Interestingly, preliminary evidence suggests that testosterone levels in adult males may
be lower after stress in individuals that had been exposed
to maternal or early postnatal stress compared to individ-

S.N. Kalantaridou et al. / Journal of Reproductive Immunology 85 (2010) 3339

uals that were not stressed prenatally (Barbazanges et al.,


1996).
3. CRH in the reproductive system
3.1. CRH in the female reproductive system
3.1.1. Ovarian CRH
Ovarian CRH is primarily localized in thecal cells surrounding the ovarian follicles, in luteinized cells of the
stroma and also in the cytoplasm of the ovum (Mastorakos
et al., 1993). In vitro experiments indicated that CRH exerts
an inhibitory effect on ovarian steroidogenesis in a dosedependent, interleukin (IL)-1-mediated manner (Calogero
et al., 1996; Ghizzoni et al., 1997), suggesting that increased
ovarian CRH concentrations might be related to premature ovarian failure observed in women exposed to high
psychosocial stress (Bromberger et al., 1997).
There is no detectable CRH in oocytes of primordial
follicles in human ovaries, whereas there is abundant
expression of the CRH and CRH-R1 genes in mature follicles,
implying that CRH may play autocrine and paracrine roles
in follicular maturation (Asakura et al., 1997). Polycystic
ovaries present diminished amounts of CRH immunoreactivity, suggesting that decreased ovarian CRH might be
related to the anovulation of polycystic ovarian syndrome
(Mastorakos et al., 1993). Finally, the concentration of CRH
is higher in the premenopausal than the postmenopausal
ovaries, indicating that ovarian CRH may be related to
normal ovarian function during the reproductive life span
(Zoumakis et al., 2001).
3.1.2. Intrauterine CRH
Intrauterine CRH appears to have a fundamental role
in the mechanisms responsible for embryo implantation
and maintenance of human pregnancy. Human and rat
uterus express the CRH gene (Makrigiannakis et al., 1995a;
Mastorakos et al., 1996). Epithelial cells are the main source
of endometrial CRH, while stromal cells do not express it,
unless differentiation to decidual cells occurs (Ferrari et
al., 1995; Makrigiannakis et al., 1995a; Mastorakos et al.,
1996; Di Blasio et al., 1997). In addition, CRH-R1 receptors are present in both epithelial and stromal cells of the
human endometrium (Di Blasio et al., 1997) and in human
myometrium (Hillhouse et al., 1993), suggesting a local
effect of uterine CRH.
In humans, initiation of endometrial stroma decidualization occurs spontaneously in the luteal phase of
the menstrual cycle. The endometrial glands are full of
CRH during both the follicular and the luteal phases of
the cycle (Makrigiannakis et al., 1995a; Mastorakos et
al., 1996). However, the concentration of CRH is signicantly higher in the luteal phase. CRH induces the
decidualization of endometrial stroma (Ferrari et al., 1995).
Progestins stimulate the expression of endometrial CRH in
a cAMP-dependent manner (Makrigiannakis et al., 1999).
In addition to progesterone, several locally produced proinammatory immune factors, such as prostaglandins and
interleukins, also exert a decidualizing effect. CRH inhibits
the production of prostaglandin E2 by human endometrial
stromal cells (Zoumakis et al., 2000). Therefore endome-

35

trial CRH, in addition to its direct decidualizing effect, may


also alter the decidualizing action of progesterone via its
inuence on the locally produced modulators, including
prostaglandin E2 . In addition, CRH stimulates the production of both IL-1 and IL-6 in human endometrial stromal
cells (Zoumakis et al., 2000). IL-1 is an important modulator
of the decidualization process, blocking the differentiation
of human endometrial stromal cells induced by ovarian
steroids or cAMP (Frank et al., 1995). The stimulatory effect
of CRH on stromal IL-1 indicates that the former may exert
its decidualizing effect either directly or indirectly as a
modulator of progesterone, which is the classical decidualizing effector. Therefore, a close interaction occurs within
the human endometrium involving CRH, prostanoids and
cytokines, which act as an endometrial network of decidualization.
3.1.3. The role of CRH in implantation, early maternal
tolerance and trophoblast invasion
The fundamental process of implantation involves a
series of steps leading to an effective cross-talk between
invasive trophoblast cells and the maternal endometrium.
The success of implantation depends on achieving the
appropriate embryo development to the blastocyst stage
and the invasion of the latter into the decidualized
endometrium (Makrigiannakis et al., 2006). During blastocyst implantation, the maternal endometrial response to
the invading fetal semi-allograft has characteristics of an
acute, aseptic inammatory response (Makrigiannakis et
al., 2001). However once implanted, the embryo suppresses
this response and prevents rejection. Simultaneously, the
mothers immune system prevents a graft vs. host reaction
deriving from the fetal immune system (Makrigiannakis et
al., 2001).
Early in pregnancy, the implantation sites in rat
endometrium contain 3.5-fold higher concentrations
of CRH compared to the interimplantation regions
(Makrigiannakis et al., 1995b), indicating that CRH might
participate in implantation. Embryonic trophoblast and
maternal decidua cells produce CRH and express Fas ligand (FasL), a proapoptotic molecule (Makrigiannakis et
al., 2001). Fas and its ligand play an important role in
the regulation of immune tolerance. The major function
of the FasFasL interaction is the induction of apoptosis in activated cells carrying Fas, that is, in cells located
at the interface between the fetal placenta and maternal
endometrium.
CRH induces the expression of apoptotic FasL on invasive extravillous trophoblast and maternal decidual cells
at the fetalmaternal interface (Makrigiannakis et al.,
2001). Furthermore, CRH increases the apoptosis of activated T lymphocytes through FasL induction, participating
in the processes of both implantation and early pregnancy tolerance. This effect of CRH is specically mediated
through CRH-R1 (Makrigiannakis et al., 2001). These ndings suggest that CRH participates in the processes of both
implantation and early pregnancy immune tolerance.
The trophoblast is the rst tissue to differentiate in
the mammalian conceptus and its normal development
is important for implantation and further survival of
the embryo. Indeed, trophoblast invasion and regulation

36

S.N. Kalantaridou et al. / Journal of Reproductive Immunology 85 (2010) 3339

is a prerequisite for a successful pregnancy. The placenta has the unique ability to proliferate and invade the
endometrium in a controlled manner. We have shown
that CRH inhibits in vitro the invasion of human extravillous trophoblast cells (Bamberger et al., 2006). This effect
is mediated by CRH-R1 and involves downregulation of
the synthesis of the carcinoembryonic antigen-related
cell adhesion molecule 1 (CEACAM1) by extravillous
trophoblast cells. CEACAM1 is a member of the carcinoembryonic antigen (CEA) family and the immunoglobulin
superfamily, which is expressed in the normal human
placenta with a specic localization in the extravillous
trophoblast cell (Bamberger et al., 2006). Thus, early in
pregnancy, locally produced CRH appears to have a dual
effect on trophoblast implantation and invasion, mediated via the R1 receptor: (1) it promotes implantation and
maintenance of early pregnancy, by killing activated T lymphocytes, and (2) it controls proper trophoblast invasion,
by regulating CEACAM1 expression.

3.1.4. Placental CRH


During human pregnancy, the placenta and fetal membranes produce large amounts of CRH (McLean et al., 1995).
Synthesis of CRH in these tissues increases with advancing
gestation and by term, it is present in high concentrations in the maternal and fetal blood, and in amniotic
uid (Frim et al., 1988). The biologic activity of CRH in
maternal plasma is attenuated by the presence of a circulating CRH-binding protein (CRH-BP), produced by the liver
and placenta (Linton et al., 1993). CRH-BP concentrations
decrease during the last 6 weeks of pregnancy, leading to
elevations of free CRH (Linton et al., 1993). Thus, placental
CRH is responsible for the hypercortisolism observed during the latter half of pregnancy. This hypercortisolism is
followed by a transient suppression of hypothalamic CRH
secretion in the postpartum period, which may explain the
blues/depression and autoimmune phenomena seen during this period (Chrousos et al., 1998).
Placental CRH induces dilation of uterine and fetal
placental vessels through nitric oxide synthetase activation (Chrousos, 1999; Smith, 2007). At term pregnancy,
placental CRH promotes myometrial contractility by stimulating prostaglandin production from the decidua and fetal
membranes (Jones and Challis, 1989) and potentiates the
contractile effects of oxytocin and prostaglandins on the
myometrium (Benedetto et al., 1994).
Placental CRH is also released into the fetus and stimulates the production of dehydroepiandrostenedione from
the fetal zone of the adrenal gland during pregnancy
(Sirianni et al., 2005). Because the placenta cannot directly
synthesize estradiol, the fetal adrenal gland is the predominant source of its precursor, dehydroepiandrostenedione.
This positive loop may also mediate other components of
labor, such as expression of oxytocin receptor, gap junctions and prostaglandins (Grammatopoulos and Hillhouse,
1999).
Placental CRH secretion is stimulated by glucocorticoids, inammatory cytokines, and anoxic conditions, including the stress of preeclampsia or eclampsia
(Robinson et al., 1988; Goland et al., 1995).

3.1.5. The role of CRH in normal parturition and preterm


delivery
Placental CRH appears to play an important role in coordinating the transition of the uterus from a relaxation state
to a contraction state during labor (Grammatopoulos and
Hillhouse, 1999). During the nal 3 weeks of the gestation, the process of parturition takes place. Parturition
the process by which the fetus is expelled from the uterus
to the extrauterine environment is a result of a complex interplay of fetal and maternal factors. This process
requires that the uterus develops coordinated contractility
and the cervix dilates, in order to allow passage of the fetus
through the birth canal. CRH and its related peptide urocortin 1 (Ucn1), may control human parturition not only
by affecting myometrial contractility, but also by increasing local matrix metalloproteinase-9 (MMP-9) activity in
placenta and fetal membranes (Li and Challis, 2005), thus
contributing to membrane rupture with the onset of labor.
It has been demonstrated that CRH plasma levels are
signicantly higher in women delivered preterm and signicantly lower in women delivered after term than in
women delivered at term (McLean et al., 1995). It should
be pointed out that in nonprimate mammals, end of pregnancy is associated with a fall in maternal progesterone
concentration, which contributes to the initiation of labor
(Karalis et al., 1996). In the human placenta cortisol is able
to compete with the action of progesterone in CRH regulation (Yang et al., 2006). Therefore, cortisol blockade of
progesterone is a possible mechanism in labor initiation.
The etiology and initiation of preterm labor is a complex phenomenon. Factors such as genital tract infection,
spontaneous rupture of membranes and premature activation of normal parturition may all by involved in preterm
delivery. In some women with idiopathic preterm labor,
concentrations of CRH increase up to 10 weeks before the
development of any symptoms or signs (McLean et al.,
1995). Indeed, it has been suggested that there is a CRH
placental clock which is active from the early stages of
human pregnancy and determines the length of gestation
and the timing of parturition and delivery (McLean et al.,
1995). These data suggest that the timing of labor is related
to processes that occur early in pregnancy and that parturition is the nal step of a longitudinal process in the
feto-placental unit, activated at a predetermined stage of
gestation. We have shown that increased plasma CRH and
ACTH levels may be associated with idiopathic preterm
labor (Makrigiannakis et al., 2007); thus maternal CRH and
ACTH levels may be useful predictors for the timing of parturition in a woman who has been diagnosed with preterm
labor.
3.1.6. The potential role of CRH in spontaneous abortions
Human reproduction is remarkably inefcient, with
more than half of spontaneous conceptions failing to complete the rst trimester. We demonstrated that abortive
deciduas contain leukocytes that are positive for FasL and
extravillous trophoblasts, which show increased expression of Fas and increased rates of apoptosis (Minas et al.,
2007). We hypothesized that CRH, and its related peptide
Ucn1, may mediate these phenomena. Indeed, we found
that CRH and Ucn1 expression was up-regulated in abor-

S.N. Kalantaridou et al. / Journal of Reproductive Immunology 85 (2010) 3339

tions (Minas et al., 2007). In vitro, these peptides induced


the expression of FasL in decidual lymphocytes obtained
from elective termination of pregnancy placentas and
thus potentiated the cells ability to induce Fas-mediated
apoptosis in an extravillous trophoblast-choriocarcinoma
hybrid cell line. Finally, decidual lymphocytes from abortion sites effectively induced apoptosis of extravillous
trophoblasts without prior treatment. It is possible that
these events may impede successful early placentation and
thus contribute to the pathophysiology of human abortion.
These effects were mediated by CRH-R1, since the addition
of a CRH-R1 antagonist completely reversed these events.
3.1.7. The potential role of CRH in placental dysfunction
associated with preeclampsia and intrauterine growth
retardation
Preeclampsia is a leading cause of maternal and neonatal morbidity and mortality, characterized by hypertension,
proteinuria, and edema. In severe cases, impaired liver
function, activation of the clotting system, renal failure
or pulmonary edema may also be present. Intrauterine
growth restriction (IUGR) is another major cause of perinatal morbidity and mortality, characterized by failure
to attain optimal intrauterine growth and development.
Shallow trophoblast invasion and subsequently decient
remodeling of spiral arteries have been associated with
preeclampsia and/or IUGR (Schiessl, 2007).
Normally, the pregnant uterus exerts remarkable vascular remodeling and the most important change is the
transformation of the uterine spiral arteries into lowresistance ow vessels that allow large volumes of blood
to enter the placental intervillous space (Rusterholz et al.,
2007). CRH participates in the maintenance of vascular tone
by activating a guanylate cyclase/nitric oxide pathway in
the human placenta (Clifton et al., 1995). Indeed during
blastocyst implantation, EVT invasion leads to replacement
of the endothelium of the uterine arteries, thus modifying
the high-resistance, non-pregnant circulation to a lowresistance system in order to facilitate nutrient exchange
(Rusterholz et al., 2007). In pre-eclamptic and growthrestricted pregnancies, the maternal plasma levels of CRH
are signicantly elevated (Perkins et al., 1995), whereas
placental CRH-R1 expression is reduced (Karteris et al.,
2003). The pathophysiologic basis of the inverse correlation
between CRH and CRH-R levels in these complicated pregnancies is unknown. One possibility is that elevated levels
of placental CRH may down-regulate its own receptor.
Alternatively, defects causing preeclampsia and/or IUGR
may result in reduced CRH-R expression, and the concomitant increase in CRH production may represent a regulatory
mechanism to compensate for the decreased signaling efciency. Indeed, dysregulation of the CRH/CRH-R1 system
has been suggested to play a role in the pathophysiology
of placental ischemia, which is observed in preeclampsia
(Karteris et al., 2005). Thus it is possible that abnormal
rst trimester trophoblast invasion due to a dysregulated
CRH/CRH-R1 system may lead to placental dysfunction
associated with preeclampsia and/or IUGR.
It is tempting to speculate on the pathophysiologic
network system between rst trimester improper trophoblast invasion, CRH and FasFasL interaction, IUGR

37

and preeclampsia that might underlie these ndings. A


large scale prospective study, evaluating pregnant women
from the rst trimester and throughout pregnancy, will
be required to determine the clinical implication of this
relationship.
3.2. CRH in the male reproductive system
3.2.1. Testicular CRH
CRH is present in the testis of several animal species,
localized in Leydig and germ cells and in spermatozoa
(Fabbri et al., 1990). A major stimulus for Leydig-cell
derived CRH is luteinized hormone, which results in CRH
secretion in a dose-dependent fashion (Fabbri et al., 1990).
In the rat testis, CRH acts as an anti-reproductive hormone, exerting autocrine inhibitory actions on Leydig cell
steroidogenesis (Fabbri et al., 1990; Dufau et al., 1993).
4. Interactions between the mother and the fetus:
inuence of maternal stress and adverse
intrauterine environment on the development of
the offspring
Epidemiological and experimental studies suggest that
environmental events acting in the developing embryo in
utero are crucial determinants for disorders later in life
(Fowden et al., 2006), a phenomenon known as fetal programming.
Life exists through maintenance of a dynamic equilibrium called homeostasis, which is constantly challenged
by adverse forces, the stressors. Stress is dened as a state
of threatened homeostasis. Abnormal trophoblast invasion,
decient remodeling of spiral arteries with high-resistance
placental vessels and subsequent placental dysfunction,
leading to preterm labor and/or fetal growth restriction
and/or preeclampsia, may reect a state of threatened
homeostasis for the fetus that responds to intrauterine
stressors by increasing its CRH levels. However, a fundamental question that remains to be answered is whether
the elevated concentrations in CRH are a cause of preterm
labor and/or fetal growth restriction and/or preeclampsia or consequence of an underlying pathophysiology. It
has been suggested that the fetus might respond to an
adverse intrauterine circumstance through increased placental CRH levels. Inappropriate elevations of fetal cortisol
generate a common pathway to growth restriction and
to elevations of placental CRH. In addition, abnormally
increases in fetal cortisol may impair fetal growth and
predispose to later life diseases, such as insulin resistance and cardiovascular disease. Indeed, this relationship
is exacerbated in cases of placental or uteroplacental
dysfunction. Interestingly, a recent epidemiological study
suggested that preterm birth is associated with diminished long-term survival and reproduction (Swamy et al.,
2008).
It is possible that abnormal endometrial environment
during implantation and trophoblast invasion may predispose to placental dysfunction associated with later
appearance of preeclampsia and/or IUGR and/or preterm
labor. Determining the mechanisms that control implantation and invasion may have implications for therapeutic

38

S.N. Kalantaridou et al. / Journal of Reproductive Immunology 85 (2010) 3339

intervention in preeclampsia, intrauterine growth retardation, infertility and spontaneous abortions.


Apart from the adverse intrauterine stressors, maternal gestational stress has also been linked to development
of insulin resistance and cardiovascular disease, as well as
to development of a diverse range of neurodevelopmental disorders in later life (Phillips et al., 2005). Maternal
prenatal stress, anxiety, depression and unbalanced diet
during pregnancy (Reynolds et al., 2007) have been associated with preterm delivery (Ruiz et al., 2003), low birth
weight (Kinsella and Monk, 2009), and adult offspring
insulin resistance (Entringer et al., 2008). In humans, low
birth weight has been correlated with adult increased
plasma cortisol levels and risk for developing glucose intolerance, hypertension and dyslipidemia, i.e. components
of the metabolic syndrome (Chrousos and Kino, 2007). In
addition, prenatal maternal stress and anxiety have been
associated with increased risk for impaired cognitive development, behavioral problems, autism and schizophrenia
(ODonnell et al., 2009). Animal data indicate that prenatal maternal stress alters the activity of the placental
barrier 11-betaHSD2 enzyme, which metabolizes cortisol
(ODonnell et al., 2009). Future studies are needed to elucidate the mechanisms by which in utero stress hormones
affect fetal programming and to investigate the potential
use of CRH-antagonists in the prevention of adult offspring
long-term diseases, from metabolic syndrome to psychiatric disorders.
5. Conclusions
Hypothalamic CRH, the principal regulator of stress, has
suppressive effects on female and male reproductive function. CRH has been identied in both the female and male
reproductive systems. CRH participates in various reproductive functions that have an inammatory component,
where it serves as an autocrine and paracrine modulator.
CRH has a fundamental role in the mechanisms responsible
for embryo implantation and maintenance of human pregnancy. It has been suggested that there is a CRH placental
clock which is active from the early stages of human pregnancy and denes the length of gestation and the onset
of parturition and delivery. Abnormalities of decidual, trophoblast and placental CRH have been implicated in several
common disease processes of pregnancy, including spontaneous abortions, preeclampsia and intrauterine growth
restriction. Further study is required into the clinical applications of CRH-receptor antagonists in the management of
pathophysiological states associated with abnormal CRH
levels during pregnancy, such as preeclampsia/eclampsia,
intrauterine growth restriction, and preterm labor. In addition, more research is needed to elucidate the mechanisms
by which in utero stress hormones affect fetal programming
and to investigate the potential use of CRH-receptor antagonists in the prevention of adult offspring long-term diseases, from metabolic syndrome to psychiatric disorders.
References
Almeida, S.A., Anselmo-Franci, J.A., Rosa e Silva, A.A., Carvalho, T.L., 1998.
Chronic intermittent immobilization of male rats throughout sexual
development: a stress protocol. Exp. Physiol. 83, 701704.

Asakura, H., Zwain, I.H., Yen, S.S., 1997. Expression of genes encoding
corticotropin-releasing factor (CRF), type 1 CRF receptor, and CRFbinding protein and localization of the gene products in the human
ovary. J. Clin. Endocrinol. Metab. 82, 27202725.
Bamberger, A.M., Minas, V., Kalantaridou, S.N., Radde, J., Sadeghian, H.,
Loning, T., et al., 2006. Corticotropin-releasing hormone modulates
human trophoblast invasion through carcinoembryonic antigenrelated cell adhesion molecule-1 regulation. Am. J. Pathol. 168,
141150.
Barbazanges, A., Piazza, P.V., Le Moal, M., Maccari, S., 1996. Maternal glucocorticoid secretion mediates long-term effects of prenatal stress. J.
Neurosci. 16, 39433949.
Benedetto, C., Petraglia, F., Marozio, L., Chiarolini, L., Florio, P., Genazzani, A.R., et al., 1994. Corticotropin-releasing hormone increases
prostaglandin F2 alpha activity on human myometrium in vitro. Am.
J. Obstet. Gynecol. 171, 126131.
Bromberger, J.T., Matthews, K.A., Kuller, L.H., Wing, R.R., Meilahn, E.N.,
Plantinga, P., 1997. Prospective study of the determinants of age at
menopause. Am. J. Epidemiol. 145, 124133.
Calogero, A.E., Burrello, N., Negri-Cesi, P., Papale, L., Palumbo, M.A., Cianci,
A., et al., 1996. Effects of corticotropin-releasing hormone on ovarian
estrogen production in vitro. Endocrinology 137, 41614166.
Chen, M.D., OByrne, K.T., Chiappini, S.E., Hotchkiss, J., Knobil, E., 1992.
Hypoglycemic stress and gonadotropin-releasing hormone pulse
generator activity in the rhesus monkey: role of the ovary. Neuroendocrinology 56, 666673.
Chrousos, G.P., 1999. Reproductive placental corticotropin-releasing hormone and its clinical implications. Am. J. Obstet. Gynecol. 180,
S249S250.
Chrousos, G.P., Gold, P.W., 1992. The concepts of stress and stress system
disorders. Overview of physical and behavioral homeostasis. JAMA
267, 12441252.
Chrousos, G.P., Kino, T., 2007. Glucocorticoid action networks and complex
psychiatric and/or somatic disorders. Stress 10, 213219.
Chrousos, G.P., Torpy, D.J., Gold, P.W., 1998. Interactions between
the hypothalamicpituitaryadrenal axis and the female reproductive system: clinical implications. Ann. Intern. Med. 129, 229
240.
Clifton, V.L., Read, M.A., Leitch, I.M., Giles, W.B., Boura, A.L., Robinson, P.J.,
et al., 1995. Corticotropin-releasing hormone-induced vasodilatation
in the human fetal-placental circulation: involvement of the nitric
oxide-cyclic guanosine 3 ,5 -monophosphate-mediated pathway. J.
Clin. Endocrinol. Metab. 80, 28882893.
Di Blasio, A.M., Pecori Giraldi, F., Vigano, P., Petraglia, F., Vignali, M., Cavagnini, F., 1997. Expression of corticotropin-releasing hormone and
its R1 receptor in human endometrial stromal cells. J. Clin. Endocrinol.
Metab. 82, 15941597.
Dufau, M.L., Tinajero, J.C., Fabbri, A., 1993. Corticotropin-releasing factor:
an antireproductive hormone of the testis. FASEB J. 7, 299307.
Entringer, S., Wust, S., Kumsta, R., Layes, I.M., Nelson, E.L., Hellhammer,
D.H., et al., 2008. Prenatal psychosocial stress exposure is associated
with insulin resistance in young adults. Am. J. Obstet. Gynecol. 199,
498 e17.
Fabbri, A., Tinajero, J.C., Dufau, M.L., 1990. Corticotropin-releasing factor
is produced by rat Leydig cells and has a major local antireproductive
role in the testis. Endocrinology 127, 15411543.
Fenster, L., Katz, D.F., Wyrobek, A.J., Pieper, C., Rempel, D.M., Oman, D., et
al., 1997. Effects of psychological stress on human semen quality. J.
Androl. 18, 194202.
Ferrari, A., Petraglia, F., Gurpide, E., 1995. Corticotropin releasing
factor decidualizes human endometrial stromal cells in vitro. Interaction with progestin. J. Steroid Biochem. Mol. Biol. 54, 251
255.
Fowden, A.L., Giussani, D.A., Forhead, A.J., 2006. Intrauterine programming of physiological systems: causes and consequences. Physiology
(Bethesda) 21, 2937.
Frank, G.R., Brar, A.K., Jikihara, H., Cedars, M.I., Handwerger, S., 1995.
Interleukin-1 beta and the endometrium: an inhibitor of stromal
cell differentiation and possible autoregulator of decidualization in
humans. Biol. Reprod. 52, 184191.
Frim, D.M., Emanuel, R.L., Robinson, B.G., Smas, C.M., Adler, G.K., Majzoub, J.A., 1988. Characterization and gestational regulation of
corticotropin-releasing hormone messenger RNA in human placenta.
J. Clin. Invest. 82, 287292.
Ghizzoni, L., Mastorakos, G., Vottero, A., Barreca, A., Furlini, M., Cesarone,
A., et al., 1997. Corticotropin-releasing hormone (CRH) inhibits steroid
biosynthesis by cultured human granulosa-lutein cells in a CRH
and interleukin-1 receptor-mediated fashion. Endocrinology 138,
48064811.

S.N. Kalantaridou et al. / Journal of Reproductive Immunology 85 (2010) 3339


Goland, R.S., Conwell, I.M., Jozak, S., 1995. The effect of pre-eclampsia
on human placental corticotrophin-releasing hormone content and
processing. Placenta 16, 375382.
Grammatopoulos, D.K., Hillhouse, E.W., 1999. Role of corticotropinreleasing hormone in onset of labour. Lancet 354, 15461549.
Hillhouse, E.W., Grammatopoulos, D.K., 2006. The molecular mechanisms underlying the regulation of the biological activity of
corticotropin-releasing hormone receptors: implications for physiology and pathophysiology. Endocr. Rev. 27, 260286.
Hillhouse, E.W., Grammatopoulos, D., Milton, N.G., Quartero, H.W., 1993.
The identication of a human myometrial corticotropin-releasing hormone receptor that increases in afnity during pregnancy. J. Clin.
Endocrinol. Metab. 76, 736741.
Hu, G.X., Lian, Q.Q., Lin, H., Latif, S.A., Morris, D.J., Hardy, M.P., et al.,
2008. Rapid mechanisms of glucocorticoid signaling in the Leydig cell.
Steroids 73, 10181024.
Jones, S.A., Challis, J.R., 1989. Local stimulation of prostaglandin production by corticotropin-releasing hormone in human fetal membranes
and placenta. Biochem. Biophys. Res. Commun. 159, 192199.
Kalantaridou, S.N., Zoumakis, E., Weil, S., Lavasidis, L.G., Chrousos, G.P.,
Makrigiannakis, A., 2007. Reproductive corticotropin releasing hormone, implantation, and fetal immunotolerance. Crit. Rev. Clin. Lab.
Sci. 44, 461481.
Karalis, K., Goodwin, G., Majzoub, J.A., 1996. Cortisol blockade of progesterone: a possible molecular mechanism involved in the initiation of
human labor. Nat. Med. 2, 556560.
Karteris, E., Goumenou, A., Koumantakis, E., Hillhouse, E.W., Grammatopoulos, D.K., 2003. Reduced expression of corticotropinreleasing hormone receptor type-1 alpha in human preeclamptic and
growth-restricted placentas. J. Clin. Endocrinol. Metab. 88, 363370.
Karteris, E., Vatish, M., Hillhouse, E.W., Grammatopoulos, D.K., 2005.
Preeclampsia is associated with impaired regulation of the placental nitric oxide-cyclic guanosine monophosphate pathway by
corticotropin-releasing hormone (CRH) and CRH-related peptides. J.
Clin. Endocrinol. Metab. 90, 36803687.
Kinsella, M.T., Monk, C., 2009. Impact of maternal stress, depression and
anxiety on fetal neurobehavioral development. Clin. Obstet. Gynecol.
52, 425440.
Li, W., Challis, J.R., 2005. Corticotropin-releasing hormone and urocortin induce secretion of matrix metalloproteinase-9 (MMP-9)
without change in tissue inhibitors of MMP-1 by cultured cells from
human placenta and fetal membranes. J. Clin. Endocrinol. Metab. 90,
65696574.
Linton, E.A., Perkins, A.V., Woods, R.J., Eben, F., Wolfe, C.D., Behan, D.P., et
al., 1993. Corticotropin releasing hormone-binding protein (CRH-BP):
plasma levels decrease during the third trimester of normal human
pregnancy. J. Clin. Endocrinol. Metab. 76, 260262.
Makrigiannakis, A., Zoumakis, E., Margioris, A.N., Theodoropoulos, P.,
Stournaras, C., Gravanis, A., 1995a. The corticotropin-releasing hormone (CRH) in normal and tumoral epithelial cells of human
endometrium. J. Clin. Endocrinol. Metab. 80, 185189.
Makrigiannakis, A., Margioris, A.N., Le Goascogne, C., Zoumakis, E., Nikas,
G., Stournaras, C., et al., 1995b. Corticotropin-releasing hormone
(CRH) is expressed at the implantation sites of early pregnant rat
uterus. Life Sci. 57, 18691875.
Makrigiannakis, A., Margioris, A.N., Chatzaki, E., Zoumakis, E., Chrousos,
G.P., Gravanis, A., 1999. The decidualizing effect of progesterone may
involve direct transcriptional activation of corticotrophin-releasing
hormone from human endometrial stromal cells. Mol. Hum. Reprod.
5, 789796.
Makrigiannakis, A., Zoumakis, E., Kalantaridou, S., Coutifaris, C., Margioris, A.N., Coukos, G., et al., 2001. Corticotropin-releasing hormone
promotes blastocyst implantation and early maternal tolerance. Nat.
Immunol. 2, 10181024.
Makrigiannakis, A., Minas, V., Kalantaridou, S.N., Nikas, G., Chrousos, G.P.,
2006. Hormonal and cytokine regulation of early implantation. Trends
Endocrinol. Metab. 17, 178185.
Makrigiannakis, A., Semmler, M., Briese, V., Eckerle, H., Minas, V., Mylonas,
I., et al., 2007. Maternal serum corticotropin-releasing hormone and
ACTH levels as predictive markers of premature labor. Int. J. Gynaecol.
Obstet. 97, 115119.
Mastorakos, G., Webster, E.L., Friedman, T.C., Chrousos, G.P., 1993.
Immunoreactive corticotropin-releasing hormone and its binding
sites in the rat ovary. J. Clin. Invest. 92, 961968.
Mastorakos, G., Scopa, C.D., Kao, L.C., Vryonidou, A., Friedman, T.C., Kattis,
D., et al., 1996. Presence of immunoreactive corticotropin-releasing
hormone in human endometrium. J. Clin. Endocrinol. Metab. 81,
10461050.

39

McLean, M., Bisits, A., Davies, J., Woods, R., Lowry, P., Smith, R., 1995. A
placental clock controlling the length of human pregnancy. Nat. Med.
1, 460463.
Minas, V., Jeschke, U., Kalantaridou, S.N., Richter, D.U., Reimer, T., Mylonas,
I., et al., 2007. Abortion is associated with increased expression of FasL
in decidual leukocytes and apoptosis of extravillous trophoblasts: a
role for CRH and urocortin. Mol. Hum. Reprod. 13, 663673.
Norman, R.L., 1993. Effects of corticotropin-releasing hormone on
luteinizing hormone, testosterone, and cortisol secretion in intact
male rhesus macaques. Biol. Reprod. 49, 148153.
ODonnell, K., OConnor, T.G., Glover, V., 2009. Prenatal stress and neurodevelopment of the child: focus on the HPA axis and role of the placenta.
Dev. Neurosci. 31, 285292.
Orr, T.E., Taylor, M.F., Bhattacharyya, A.K., Collins, D.C., Mann, D.R., 1994.
Acute immobilization stress disrupts testicular steroidogenesis in
adult male rats by inhibiting the activities of 17 alpha-hydroxylase
and 17,20-lyase without affecting the binding of LH/hCG receptors. J.
Androl. 15, 302308.
Perkins, A.V., Linton, E.A., Eben, F., Simpson, J., Wolfe, C.D., Redman,
C.W., 1995. Corticotrophin-releasing hormone and corticotrophinreleasing hormone binding protein in normal and pre-eclamptic
human pregnancies. Br. J. Obstet. Gynaecol. 102, 118122.
Phillips, D.M., Lakshmi, V., Monder, C., 1989. Corticosteroid 11 betadehydrogenase in rat testis. Endocrinology 125, 209216.
Phillips, D.I., Bennett, F.I., Wilks, R., Thame, M., Boyne, M., Osmond, C.,
et al., 2005. Maternal body composition, offspring blood pressure
and the hypothalamicpituitaryadrenal axis. Paediatr. Perinat. Epidemiol. 19, 294302.
Rabin, D.S., Johnson, E.O., Brandon, D.D., Liapi, C., Chrousos, G.P., 1990.
Glucocorticoids inhibit estradiol-mediated uterine growth: possible
role of the uterine estradiol receptor. Biol. Reprod. 42, 7480.
Reynolds, R.M., Godfrey, K.M., Barker, M., Osmond, C., Phillips, D.I., 2007.
Stress responsiveness in adult life: inuence of mothers diet in late
pregnancy. J. Clin. Endocrinol. Metab. 92, 22082210.
Robinson, B.G., Emanuel, R.L., Frim, D.M., Majzoub, J.A., 1988. Glucocorticoid stimulates expression of corticotropin-releasing hormone gene
in human placenta. Proc. Natl. Acad. Sci. U.S.A. 85, 52445248.
Ruiz, R.J., Fullerton, J., Dudley, D.J., 2003. The interrelationship of maternal stress, endocrine factors and inammation on gestational length.
Obstet. Gynecol. Surv. 58, 415428.
Rusterholz, C., Hahn, S., Holzgreve, W., 2007. Role of placentally produced
inammatory and regulatory cytokines in pregnancy and the etiology
of preeclampsia. Semin. Immunopathol. 29, 151162.
Sakakura, M., Takebe, K., Nakagawa, S., 1975. Inhibition of luteinizing hormone secretion induced by synthetic LRH by long-term treatment
with glucocorticoids in human subjects. J. Clin. Endocrinol. Metab. 40,
774779.
Schiessl, B., 2007. Inammatory response in preeclampsia. Mol. Aspects
Med. 28, 210219.
Sirianni, R., Mayhew, B.A., Carr, B.R., Parker Jr., C.R., Rainey, W.E., 2005.
Corticotropin-releasing hormone (CRH) and urocortin act through
type 1 CRH receptors to stimulate dehydroepiandrosterone sulfate
production in human fetal adrenal cells. J. Clin. Endocrinol. Metab. 90,
53935400.
Smals, A.G., Kloppenborg, P.W., Benraad, T.J., 1977. Plasma testosterone proles in Cushings syndrome. J. Clin. Endocrinol. Metab. 45,
240245.
Smith, R., 2007. Parturition. N. Engl. J. Med. 356, 271283.
Swamy, G.K., Ostbye, T., Skjaerven, R., 2008. Association of preterm birth
with long-term survival, reproduction, and next-generation preterm
birth. JAMA 299, 14291436.
Yang, R., You, X., Tang, X., Gao, L., Ni, X., 2006. Corticotropin-releasing hormone inhibits progesterone production in cultured human placental
trophoblasts. J. Mol. Endocrinol. 37, 533540.
Yazawa, H., Sasagawa, I., Ishigooka, M., Nakada, T., 1999. Effect of immobilization stress on testicular germ cell apoptosis in rats. Hum. Reprod.
14, 18061810.
Zoumakis, E., Margioris, A.N., Stournaras, C., Dermitzaki, E., Angelakis,
E., Makrigiannakis, A., et al., 2000. Corticotrophin-releasing hormone
(CRH) interacts with inammatory prostaglandins and interleukins
and affects the decidualization of human endometrial stroma. Mol.
Hum. Reprod. 6, 344351.
Zoumakis, E., Chatzaki, E., Charalampopoulos, I., Margioris, A.N., Angelakis, E., Koumantakis, E., et al., 2001. Cycle and age-related changes in
corticotropin-releasing hormone levels in human endometrium and
ovaries. Gynecol. Endocrinol. 15, 98102.
Zoumakis, E., Kalantaridou, S.N., Makrigiannakis, A., 2009. CRH-like peptides in human reproduction. Curr. Med. Chem. 16, 42304235.