The corticotropin-releasing hormone (CRH) in normal and tumoral epithelial cells of human endometrium.

Abstract

CRH is produced by several intrauterine sites, including placenta and desidua, during pregnancy. However, no data are available regarding the presence of CRH in the nonpregnant uterus. We now report that CRH is produced in the epithelial cells of normally cycling human uterus and in an endometrial epithelial cell-derived tumor. Specifically, we have found that: 1) Northern blot hybridization analysis of normal glandular endometrium as well as of Ishikawa human endometrial adenocarcinoma cells showed the presence of the CRH messenger RNA; the size of the transcript seemed to be identical to that present in human placenta and rat hypothalamus; 2) immunoreactive CRH (ir-CRH) was detectable in normal dispersed glandular endometrial cells as well as in the Ishikawa adenocarcinoma cells; 3) gel filtration chromatography of normal glandular endometrial and Ishikawa cell extracts and their culture media showed that most ir-CRH present had the mol wt of the authentic CRH peptide; in addition, a larger form of ir-CRH was also present in both normal and tumoral endometrial epithelial cell extracts; the latter most probably correspondents to CRH precursor molecules; and 4) immunofluorescence staining of CRH in normal glandular endometrial and Ishikawa cells revealed a cytoplasm rich in granules positive for ir-CRH. Our findings suggest that CRH may play an important role in the physiological events taking place within the uterine cavity, since CRH seems to be present in nonpregnant as well as pregnant uteri. Since CRH is expressed in normal endometrial epithelial cells and in an epithelial tumoral cell line, we propose the use of the Ishikawa cell line as a convenient model for the in vitro study of endometrial CRH.

Hypothalamic-pituitary-adrenal axis function during perinatal depression

“…These fi ndings suggest that CRH binding to its cognate receptor is involved in both implantation and early pregnancy immune tolerance [116] . CRH levels increase during gestation and at term; high concentrations of placental CRH (pCRH) are present in maternal and fetal blood, including the amniotic fl uid [113,116] . CRH activity in maternal plasma is attenuated by the presence of a circulating CRH-binding protein (CRH-BP) produced by the liver and placenta.…”

“…Both the rat and human uterus express the CRH gene [76,112] . Cellular studies show that epithelial cells constitute the primary source of endometrial CRH [113] and its cognate receptor, CRH-R1 [114] , is widely distributed in epithelial and stromal cells of the human endometrium [113,115] and myometrium [111] . During stromal decidualization, progestins stimulate the expression of endometrial CRH in a cAMP-dependent manner [115] , resulting in the production of large amounts of CRH [114,116] .…”

Expression and subcellular localization of CRH and its receptors in human endometrial cancer

“…Beyond hypothalamus, CRH has been found to be expressed in other sites of the nervous system, in the gastrointestinal tract (Suda et al, 1984), vasculature (Simoncini et al, 1999), skin (Slominski et al, 1998), as well as in normal human ovaries and endometrium (Makrigiannakis et al, 1995, Mastorakos et al, 1996, Di Blasio et al 1997, Florio et al, 2003. Moreover, during pregnancy the placenta becomes the major source of CRH, which seems to play a role in the timing of birth (Smith 1999).…”

“…CRH expression was also found in different human epithelial neoplasia such as thyroid , lung (Moody et al, 1994), skin (Slominski et al, 1998), and breast (Ciocca et al, 1990) cancers. As far as endometrial cancer is concerned, evidence is limited to the finding of CRH expression in Ishikawa cell line (Makrigiannakis et al, 1995). Despite such huge amount of studies addressed to localize CRH expression in normal and tumor parenchymas, no study has been devoted so far to investigate the patterns of intra-cellular CRH distribution.…”

“…In normal human endometrium, the constitutive expression of both CRH and its R1-type receptor (particularly in stroma cells) suggests an autocrine/paracrine action of CRH on endometrial cells, where the peptide elicits progesterone-like cell differentiation (Tang et al, 1993, Ferrari et al, 1995, Makrigiannakis et al, 1995, Di Blasio et al, 1997, Telgmann et al, 1997, Florio et al, 2003. As an extension of the physiological role in normal endometrium, in Ishikawa endometrial tumor cells CRH is secreted and acts locally to inhibit basal and estradiol-stimulated cell growth, as well as to promote differentiation via the activation of R1 receptors and the subsequent increase in adenylyl cyclase activity (Graziani et al, 2002(Graziani et al, , 2006.…”