Peripheral CRH and its receptors have been identified in most female reproductive tissues, including ovary, uterus and placenta (67, 68, 31, 32, 35, 16). Οvarian CRH is primarily found in the theca and stroma and also in the cytoplasm of the oocyte (31, 32). Corticotropin-releasing hormone type 1 receptors are also detected in the ovarian stroma and the theca and in the cumulus oophorus of the graafian follicle (31, 69). Granulosa cells are devoid of the expression of CRH and CRH-R1 genes and peptides (69). Epithelial cells of the human endometrium and differentiated stromal cells also express the CRH gene (35, 70, 71). In addition, CRH-R1 are present in both epithelial and stroma cells of human endometrium and myometrium (72-74). Although it is known that CRH is expressed in myometrial smooth muscle cells with CRH transcript and immunoreactive peptide increasing significantly with pregnancy, it is not clear whether the peptide responsible for the direct activation of myometrial CRH receptors is circulating placental CRH acting by paracrine diffusion, or endogenous myometrial CRH acting locally, or a combination of both (75,76). Placental CRH is synthesized in syncytiotrophoblast cells, in placental decidua and fetal membranes (77, 78) and is secreted into the maternal circulation during gestation. Its concentrations increase exponentially as pregnancy progresses(79). Non-pregnant human myometrium expresses three CRH receptor subtypes, namely 1α , 1β and 2β. Αs pregnancy progresses, the myometrium starts to express the 2α receptor. In addition, at term the myometrium expresses the 1c and 1d receptor subtypes, indicating a possible functional role for these receptor subtypes at the end of pregnancy (80). The syncytiocytotrophoblasts of the placenta and the fetal membranes express the 1α, 1c, 1d and 2β subtypes (81) and the fetal adrenal glands express both the 1α and 2α subtypes (82).

It appears that the effects of CRH in the reproductive tract are carried out mainly via its proinflammatory properties as in the case of ovulation, luteolysis (31, 32) and blastocyst implantation (71). The abundant expression of the gene encoding CRH and CRH-R1 in mature follicles compared to that in small antral follicles indicates that the CRH-CRH-R1 system in the thecal cells may play autocrine and paracrine roles in steroidogenesis and follicular maturation. Several studies have reported that CRH suppresses ovarian steroidogenesis in vitro (83-85). Both Calogero et al.(83) and Ghizzoni et al.(84) demonstrated that CRH exerts an inhibitory effect on estrogen and progesterone production in human granulosa-luteal cells isolated from the follicular fluid upon oocyte retrieval (83-85). Likewise, Erden et al. demonstrated that CRH inhibited LH-stimulated DHEA and androstenedione production in isolated follicular thecal cells. Recently, CRH and CRH receptors were shown to be predominantly expressed in luteinized thecal cells of the early degenerating corpus luteum, which were losing their steroidogenic function (86). This finding may be one of the pieces of evidence suggesting that CRH could be linked to the processes of follicular atresia and luteolysis.

Endometrial CRH participates in the regulation of intrauterine inflammatory processes such as stroma decidualization, blastocyst implantation and early maternal tolerance (87). The progesterone induced decidualization is modulated by locally produced inflammatory factors. Epithelial and stromal CRH affects decidualization of stromal cells by regulating local modulators i.e. prostanoids (PGE2) and cytokines (IL-1 and IL-6). The net effect of its actions is the fine–tuning of the decidualizing effect of progesterone (88). The blastocyst may modulate the expression of endometrial CRH through IL-1 and/or PGE2 secretion. Subsequently, endometrial CRH, in association with other local factors, may participate in a local inflammatory response at the site of implantation, rendering the endometrial surface adhesive for the attachment of the blastocyst (89). Ιn line with this hypothesis, a significantly higher concentration (3.5-fold) of the CRH transcript and its peptide product were shown at the early implantation sites of pregnant rats compared to the interimplantation uterine regions (71). Furthermore, it has been suggested that CRH participates in the nidation of the fertilized egg by inhibiting the local maternal immune response to the implanted embryo. Indeed, CRH of maternal (decidua) and fetal (trophoblast) origin acts in an autocrine/paracrine fashion, through CRH-R1, to stimulate FasL protein expression and to potentiate the ability of these cells to induce apoptosis of the surrounding maternal T lymphocytes activated by the presence of the embryo (90). Abnormalities of maternal tolerance pointing at inadequate CRH-mediated self induction of FasL in extravillous trophoblasts and decidual cells may have deleterious consequences for the developing fetus. In line with these findings, female rats treated with a CRH antagonist in the first six days of gestation had a dose-dependent decrease of endometrial implantation sites and markedly diminished FasL protein expression (91).

Placental CRH, which is upregulated by both fetal and maternal cortisol, may participate in the physiology of pregnancy and the onset of parturition. By mid gestation, CRH levels are correlated inversely with gestational length making this peptide a unique candidate for regulation of fetal endocrine systems (92, 93). In addition, the placental CRH/CRH-R system has been associated with the pathological mechanisms leading to peeclampsia. A reduction of both CRH-R1 and CRH-R2 might result in a disturbance of the balance controlling vascular tone toward vasoconstriction. Although very little is known regarding regulation of expression of CRH-Rs in intrauterine tissues, it is possible that chronic exposure to elevated levels of placental CRH in preeclampsia or IUGR might downregulate its own receptors (94). It is not surprising that cumulative impact of enduring stress such as economic position and racism may condition or unmask neuroendocrine mechanisms ‘priming’ the likelihood of preterm delivery. A US study reported an association between low family income and high maternal CRH (95). In addition reported findings from the Black Women Health Study show an impact of individually directed racism on the risk of preterm delivery (96). Additionally, infection and inflammation of the maternal genital tract believed to account for 20-30% of preterm deliveries are more prevalent among black women (97). Taking into account that placental CRH plays a central role in modulating the effects of hypoxia, infections, possible decidual haemorrhage and psychosocial stress per se on prematurity-related outcomes, it is likely that placental CRH levels are related to the length of gestation and fetal growth either directly by participating in physiologic processes involved in parturition and fetal maturation, or indirectly by bringing to light anterpartum conditions priming for prematurity.