HB-EGF but Not Amphiregulin or Their Receptors HER1 and HER4 Is Altered in Endometrium of Women With Unexplained Infertility

Abstract

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) and its receptors (HER1 and HER4) play a role in the human implantation process. Amphiregulin is a member of the EGF family but with unknown function in human fertility. It has been suggested that some women with unexplained infertility have defective endometrial development. The aim of this study is to determine the presence of amphiregulin and the receptors HER1 and HER4 in normal human endometrium throughout the menstrual cycle. In addition, the present study aims to compare endometrium from women with unexplained infertility with endometrium from women with male factor infertility and healthy fertile controls. Immunohistochemistry and real-time polymerase chain reaction were used to determine the expression of HB-EGF, HER1, HER4, and amphiregulin. The stromal staining of HER1 and the epithelial staining of HER4 were most intense in the mid- and late-secretory-phase endometrium. Amphiregulin did not vary during the menstrual cycle. In the mid-secretory phase, the protein expression of HB-EGF was lower in endometrium from women with unexplained infertility versus normal endometrium and endometrium from women with male factor infertility. HB-EGF and HER4 mRNA expression in mid-secretory endometrium of women with unexplained and male factor infertility were increased compared with normal controls. Impaired endometrial expression of certain members of the EGF family may contribute to infertility in some women with unexplained infertility.

Molecular Evidence for Differences in Endometrium in Severe Versus Mild Endometriosis

“…Epidermal growth factor receptor (ERBB1) expression in normal eutopic endometrium on the mRNA and protein levels during different menstrual cycle phases was demonstrated herein and confirms earlier reports. 31-33 We have observed that EGFR gene expression is increased in eutopic endometrium of women with severe endometriosis compared to women without disease in ESE and MSE, but not PE, and is not regulated in mild endometriosis versus nonendometriosis samples throughout the cycle (Aghajanova et al, unpublished data). Herein, we have found that EGFR is dysregulated in severe versus mild endometriosis throughout the menstrual cycle on both mRNA and protein levels, with the most dramatic difference (upregulation) in ESE.…”

Cell signaling in trophoblast-uterine communication

“…It remains to be established whether the reduced expression of HBEGF precedes the onset of preeclampsia or if it is merely associated with late placental demise. There is also clinical evidence of HBEGF disruption associated with infertility in women (Aghajanova et al, 2008). The decreased HBEGF expression in infertile couples was not confirmed in a larger clinical study, but it was noted that a significant increase between the early and mid secretory phases was absent in the infertile patients (Leach et al, 2012).…”

Physiological and molecular determinants of embryo implantation

“…HB-EGF activation of ErbB1/4 receptors involves bidirectional interactions between the blastocyst and the uterus prior to implantation in mice (Das et al, 1994; Hamatani et al, 2004b; Paria et al, 1999a; Paria et al, 2001a; Raab et al, 1996; Wang et al, 2000; Xie et al, 2007), and a similar machinery functions during human implantation and placentation (Birdsall et al, 1996; Chobotova et al, 2005; Chobotova et al, 2002a; Chobotova et al, 2002b; Gonzalez et al, 2011; Jessmon et al, 2009; Leach et al, 1999; Lessey et al, 2002; Yoo et al, 1997). Moreover, aberrant expression of HB-EGF in human trophoblasts is associated with preeclampsia (Aghajanova et al, 2008a; Leach et al, 2002). In addition, homeobox transcription factors and developmental morphogenesis genes essential for uterine function and implantation in mice exhibit dynamic expression patterns in human endometrium and potential association with certain pregnancy complications (Bombail et al, 2010; Cheng et al, 2008; Kodama et al, 2010; Koler et al, 2009; Li et al, 2007; Mirkin et al, 2005; Taylor, 2000; Taylor et al, 1998; Taylor et al, 1997; Tulac et al, 2006).…”