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Review
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-
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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.
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