Glucocorticoids have been implicated in many processes including successful embryo implantation, placentation, and the growth and development of the fetus. Glucocorticoid treatment has been advocated as a treatment to improve reproductive outcome for a number of reasons. Prednisolone treatment has been associated with improvement in clinical outcome in women with recurrent miscarriage and improvement in outcome of In Vitro Fertilisation. Steroids have been found to reduce the high levels of uterine natural killer cells which have been associated with recurrent miscarriage and recurrent implantation failure. Glucocorticoids stimulate peri-implantation human chorionic gonadotrophin secretion from trophoblast of early human embryo and accelerate trophoblast growth and invasion. Elevated uterine NK cell levels during the implantation window are associated with reproductive failure and can be repressed by oral glucocorticoids. We have shown that decidualizing human endometrial stromal cells profoundly up regulate the expression and activity of 11beta-hydroxysteroid dehydrogenase type 1, the enzyme that converts inert cortisone to active cortisol; thus establishing a local cortisol gradient and activation of glucocorticoid and mineralocorticoid receptors. We also found that elevated levels of uterine natural killer cells in the stroma underlying the surface epithelium of endometrium are associated with defective decidualization of resident stromal cells, inadequate cortisol biosynthesis and suboptimal induction of corticosteroid-dependent enzymes involved in lipid droplet accumulation and retinoid transport pathway. Thus, impaired decidualization limits the induction of a local cortisol gradient in the stroma underlying the surface epithelium. This in turn accounts for possible inappropriate recruitment of uterine natural killer cells and suboptimal expression of metabolic genes involved in lipid biosynthesis and retinoid storage pathway. Based on the findings, we postulate that patients suffering recurrent miscarriage associated with high uterine NK cell density may benefit from corticosteroid treatment in early pregnancy; although this assumption will need to be tested in a larger clinical trial.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:618961 |
| Date | January 2014 |
| Creators | Venkatakrishnan, R. |
| Publisher | University of Warwick |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://wrap.warwick.ac.uk/62785/ |
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