GnRH signaling in intrauterine tissues

Abstract

Type I GnRH (GnRH-I, GNRH1) and type II GnRH (GnRH-II, GNRH2), each encoded by separate genes, have been identified in humans. The tissue distribution and functional regulation of GnRH-I and GnRH-II clearly differ despite their comparable cDNA and genomic structures. These hormones exert their effects by binding to cell surface transmembrane G protein coupled receptors and stimulating the Gq/11 subfamily of G proteins. The hypothalamus and pituitary are the main origin and target sites of GnRH, but numerous studies have demonstrated that extra-hypothalamic GnRH and extra-pituitary GnRH receptors exist in different reproductive tissues such as the ovary, endometrium, placenta, and endometrial cancer cells. In addition to endocrine regulation, GnRH is also known to act in an autocrine and paracrine manner to suppress cell proliferation and activate apoptosis in the endometrium and endometrial cancer cells through several mechanisms. Both GnRH-I and GnRH-II exhibit regulatory roles in tissue remodelling during embryo implantation and placentation, which suggests that these hormones may have important roles in embryo implantation and early pregnancy. The presence of varied GnRH and GnRH receptor systems demonstrate their different roles in distinct tissues using dissimilar mechanisms. These may result in the generation of new GnRH analogues used for several hormone-related diseases.

Endocannabinoids and Kisspeptins: Two Modulators in Fight for the Regulation of GnRH Activity

“…Despite in hypophysectomised animals GnRH agonist administration induces steroidogenesis and GnRH like molecules have been detected in the main circulation of elasmobranches, in tetrapods the peptide has never been detected in plasma (King et al, 1992). Extra brain synthesis and function of GnRH -expecially GnRH2 -and GnRHRs (both mRNA and protein) have been detected in vertebrate gonads, humans included, endometrium, placenta, and endometrial cancer cells Ramakrishnappa et al, 2005;Singh et al, 2007;Wu et al, 2009). …”

“…Besides testis, in the ovary GnRH activity highly depends on the state of maturation (Guilgur et al, 2009;Pierantoni et al, 2002;Uzbekova et al, 2002;Wu et al, 2009). In lamprey, GnRH induces both steroidogenesis and ovulation, whereas in teleost fish different GnRH molecular forms differentially modulate both meiosis resumption and steroidogenesis (Nabissi et al 2000;Pati & Habibi, 2000).…”

“…In human ovary, GnRH acts as an autocrine modulator of granulosa cells and has the ability to inhibit progesterone biosynthesis (Peng et al, 1994). Lastly, in addition to endocrine regulation, GnRH is also known to act in an autocrine and paracrine manner in order to suppress cell proliferation and to activate apoptosis in the endometrium and endometrial cancer cells through several mechanisms (Wu et al, 2009). In human ovary cell lines, such a mechanism involves GnRH2 and not GnRH1, and opens question of a functional GnRHR2 in humans (Leung et al, 2003).…”

“…However, both GnRH1 and GnRH2 exhibit regulatory roles in tissue remodelling during embryo implantation and placentation, which suggests that these hormones may have important roles in embryo implantation and early pregnancy (Wu et al, 2009). …”

Is the metalloendopeptidase EC 3.4.24.15 (EP24.15), the enzyme that cleaves luteinizing hormone-releasing hormone (LHRH), an activating enzyme?

“…In human gynaecological tumours, LHRH-I signalling neutralises epidermal growth factor tyrosine kinase activity and down regulates its receptors via the activation of phosphotyrosine phosphatase (Imai et al 1996). This occurs via coupling to the Gai protein, one explanation of this differing effect (Wu et al 2009). The emerging evidence regarding LHRH-(1-5) suggests that this active peptide fragment has a proliferative effect on tumour cells.…”