The pleiotropic effects of human chorionic gonadotrophin (hCG), the key regulator of human pregnancy, are dependent upon cell surface expression of its functional cognate receptor LHCGR in the placental trophoblasts, corpus luteum, uterus, vascular endothelial and smooth muscle cells. Additionally, lutenizing hormone-mediated signalling failure has often been linked to activating/inactivating mutations in LHCGR. One of the intriguing aspects of these studies is that the mutations are most frequently located within C-terminal 200-350 residues of the receptor protein. In an attempt to reconcile the mechanistic basis of LHCGR regulation and mutations, we have carried out bioinformatic analyses to identify the CpG-rich regions and the major potential scaffold/matrix attachment sites (S/MARs) in LHCGR and neighbouring gene (ALF) at human chromosome 2p21. Based on these analyses, we propose a chromatin-loop model, which may explain the temporal regulation and susceptibility to mutation of the human LHCGR. One of the characteristic features of the model, is that the major potential S/MAR sequences of the human LHCGR gene (68 kb) are located at the 3' end of the gene, and unlike mouse, the transmembrane and C-terminal protein coding sequences at exon 11 are embedded in this S/MAR site. Moreover, this region is subject to antisense transcription from the neighbouring gene ALF, which is gonad-specific and is only activated in meiotic spermatocytes and oocytes. Together, these analyses suggest that exon 11 of human LHCGR could be more susceptible to mutation than the other 10 exons together and that activation of LHCGR, contingent to the somatic silencing of neighbouring ALF, could be linked to male-limited precocious puberty and pre-eclampsia.