Human endometrial KISS1R inhibits stromal cell decidualization in a manner associated with a reduction in ESR1 levels

Defective endometrial stromal cell decidualization is a major cause of recurrent implantation failure (RIF), a condition with a prevalence of ∼15%. To treat RIF, a stronger understanding of the endometrial factors that regulate decidualization is required. Here we studied the role of the kisspeptin receptor (KISS1R) in regulating human endometrial stromal cell (HESC) decidualization. Our data revealed KISS1R inhibits HESC decidualization in vitro in a manner associated with a striking reduction in ESR1 protein levels. To determine whether KISSR inhibition of decidualization results from reduced ESR1 levels we expressed the dominant negative ESR1-46 isoform in decidualizing HESCs. We found that expression of ESR1-46 in decidualizing HESCs ablated the expression of ESR1-66 and ESR1-54 isomers, and blocked decidualization. Interestingly, when ESR1-64 was co-expressed with ESR1-46, ESR1-66 and ESR1-54 expression was restored and decidualization was rescued. Taken together, these results suggest that KISS1R inhibits HESC decidualization by downregulating ESR1 levels. Based on our findings, we suggest that by inhibiting HESC decidualization, KISS1R regulates the depth of embryo invasion of the stroma, a requirement for a successful pregnancy. ### Competing Interest Statement The authors have declared no competing interest. * db-cAMP : N6,2’-O-dibutyryladenosine 3’:5’-cyclic monophosphate DCN : Decorin ESC : Endometrial stromal cell ESR1 : Estrogen receptor alpha, ERα FOXO1 : Forkhead box protein O1 HESC : Human endometrial stromal cell IGFBP1 : Insulin-like growth factor binding protein 1 KISS1 : Kisspeptin 1 gene KISS1R : Kisspeptin receptor KP : Kisspeptin protein KRT7 : Cytokeratin 7 KRT18 : Cytokeratin 18 LEFTY2 : Left-right determination factor 2 LH : Luteinizing hormone MPA : Medroxyprogesterone acetate MMP2 : Matrix metallopeptidase 2 MMP7 : Matrix metallopeptidase 7 PGR : Progesterone receptor gene PR : Progesterone receptor protein PRL : Prolactin WNT4 : Wingless-type MMTV integration site family member 4