Signal Transduction Pathways Activated by Chorionic Gonadotropin in the Primate Endometrial Epithelial Cells1

Abstract

Successful implantation requires synergism between the developing embryo and the receptive endometrium. In the baboon, infusion of chorionic gonadotropin (CG) modulates both morphology and physiology of the epithelial and stromal cells of the receptive endometrium. This study explored the signal transduction pathways activated by CG in endometrial epithelial cells from baboon (BE) and human (HES). Incubations of BE and HES cells with CG did not significantly alter adenylyl cyclase activity or increase intracellular cAMP when compared with Chinese hamster ovarian cells stably transfected with the full-length human CG/luteinizing hormone (LH) receptor (CHO-LH cells). However, in BE and HES cells, CG induced the phosphorylation of several proteins, among them, extracellular signal-regulated protein kinases 1 and 2 (ERK 1/2). Phosphorylation of ERK 1/2 in uterine epithelial cells was protein kinase A (PKA) independent. This novel signaling pathway is functional because, in response to CG stimulation, prostaglandin E(2) (PGE(2)) was released into the media and increased significantly 2 h following CG stimulation. CG-stimulated PGE(2) synthesis in epithelial cells was inhibited by a specific mitogen-activated protein kinase (MEK 1/2) inhibitor, PD 98059. In conclusion, immediate signal transduction pathways induced by CG in endometrial epithelial cells are cAMP independent and stimulate phosphorylation of ERK 1/2 via a MEK 1/2 pathway, leading to an increase in PGE(2) release as the possible result of cyclooxygenase-2 activation.

Expression of LH receptor in nonpregnant mouse endometrium: LH induction of 3β-HSD and de novo synthesis of progesterone

“…In mouse uterus, a binding study and in situ hybridization technique revealed that LHR is localized in endometrial stromal cells (Zheng et al 2001). Several groups also proposed different paracrine functions of LH/HCG in endometrium-like prostaglandin and cytokine biosynthesis (Zhoi et al 1997, Rao 1998, Zhou et al 1999, Srisuparp et al 2003, and modulation of decidualization and implantation of the embryo into the uterus (Han et al 1999, Banaszak et al 2000, Licht et al 2002, Das et al 2009). The present study using RT-PCR and real-time PCR demonstrates a clear and distinct expression of Lhr mRNA in mouse endometrium at each stage of the estrous cycle with a maximum at metestrus.…”

“…Contrary to this conventional belief, numerous studies demonstrated that the LH receptor (LHR)/HCG receptor is also present in a variety of non-gonadal tissues, particularly in the female reproductive tract (Bonnamy et al 1990, Reshef et al 1990, Lei et al 1993, Mukherjee et al 1994, Shemesh et al 1997, Ziecik et al 2005. Activation of this receptor in vivo and in vitro resulted in a wide variety of responses, which can be attributed to initiation and maintenance of pregnancy (Banaszak et al 2000, Srisuparp et al 2003, Lin et al 2005, Ziecik et al 2005.…”

“…Reports are even available that HCG does not directly affect in vitro decidualization of human endometrial stromal cells (Kasahara et al 2001). It has also been shown that although LH and FSH evoke a growth response in different endometrial cell lines, their stimulation does not appear to be via the classical gonadotropin receptor pathway, and all these together indicate a contradictory role of LHR in the endometrium (Davies et al 2000, Srisuparp et al 2003.…”

“…Moreover, although different paracrine functions of LH in the endometrium like prostaglandin biosynthesis (Srisuparp et al 2003) or modulation of decidualization (Banaszak et al 2000, Licht et al 2002 have been proposed, LH-induced steroid biosynthesis in nonpregnant mouse endometrium is little understood.…”

Human choriogonadotropin prior to controlled ovarian stimulation and in vitro fertilization improves implantation, and pregnancy rates

“…Luteinizing hormone/hCG receptors are expressed in many reproductive organs and within specific regions within these organs. Endometrial tissues from numerous species have been reported to contain LH/hCG receptors [43][44][45]. In the human and nonhuman primate LH/hCG receptor expression appears to be cycle-dependent with secretory endometrium expressing higher levels compared to proliferative endometrium [46,47].…”