2019 Volume 65 Issue 1 Pages 12-19
In humans, the incidence of embryo wastage and pregnancy loss is extraordinarily high; therefore, pregnancy loss commonly occurs in reproductive women. Furthermore, some women suffer from recurrent pregnancy loss (RPL). In over 50% of RPL cases, no specific cause is identified even after detailed examinations. Impaired decidualisation of uterine endometrium with aberrantly high uterine natural killer (uNK) cell density is associated with unexplained RPL. Glucocorticoid includes active cortisol and inert cortisone, which are mutually catalysed by 11β-hydroxysteroid dehydrogenase (11βHSD). 11βHSD isoform type 1 activates cortisone to cortisol, which binds glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). During decidual transformation in human endometrial stromal cells (HESCs), 11βHSD1, but not type 2, is particularly induced by progesterone, leading to the local production of active cortisol and regulation of GR and MR gene networks. 11βHSD1/GR signalling is a significant pathway for the regulation of uNK cells and inflammatory reaction upon decidualisation of HESCs, whereas the MR gene network includes retinoid metabolism. Retinol (vitamin A), which is hydrolysed from retinyl ester, is transformed to retinaldehyde (Rald) and generates retinoic acid (RA) following two-step oxidation. RA binds to CRABP2 and activates retinoic acid receptor (RAR), leading to cell apoptosis and senescence, whereas RA-dependent activation of PPARβ/δ is mediated through FABP5, leading to cell differentiation. The decidualisation of HESCs decreases the expression of CRABP2 and FABP5 and down- and upregulates RAR and PPARβ/δ, respectively. In addition, decidualisation is associated with the upregulation of retinoid metabolism-related genes, including retinol-binding protein 4 (RBP4), cytochrome P450 26A1 (CYP26A1), RDH12 and DHRS3, suggesting that decidualisation suppresses RA signalling by decreasing key cytoplasmic-binding proteins and upregulating retinoid metabolism. Taken together, corticosteroid signalling via 11βHSD1 induction regulates GR-specific gene networks including inflammation and angiogenesis at the implantation site. Furthermore, retinoid metabolism signalling is controlled via 11βHSD1/MR signalling, leading to an optimal balance of cell differentiation and apoptosis, such as decidualisation of HESCs. Recently, for the treatment of unexplained RPL, the GR and MR gene networks are targeted via corticosteroid signalling, leading to modulation of uNK cells as well as retinoid metabolism signalling.
