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Deregulation of the serum- and glucocorticoid-inducible kinase SGK1 in the endometrium causes reproductive failure

last modified Dec 13, 2013 11:08 AM


09 November 2011

Dr Andrew Sharkey is a co-author of a paper published in Nature Medicine.

Human pre-implantation embryos developing in vitro.
Human pre-implantation embryos developing in vitro. Following fertilization, the embryo divides while remaining within the translucent zona pellucida (zp, arrowed). Shown are the 8 cell stage (d), the early morula stage of approximately 16 cells (e), the early blastocyst stage (f) - note the fluid filled blastocoelic cavity and the small cluster of cells at the top which will develop into the fetus. (g) shows the blastocyst hatching through the zona at the top left, and (h) shows the hatched blastocyst with the empty zona lying beneath it. The hatched blastocyst is now ready to attach to the luminal epithelium, which lines the uterus. It is this attachment process that is disrupted when SGK1 expression in the epithelium is abnormally high. (photographs courtesy of Professor Peter Braude and Professor Martin Johnson, published in Essential Reproduction).

The Nature Medicine paper resulted from a long term collaboration between Andrew Sharkey and the group headed by professor Jan Brosens at Imperial, who is the senior author of the study. This work was based on earlier findings made in the Department of Pathology by a PhD student who was working with Andrew. Dr Feroze-Zaidi, who undertook a microarray study in Andrew’s lab used microarrays printed in the Department, to compare the endometrium from women with unexplained infertility (who had at least three failed cycles of IVF), with fertile controls. They showed that transcripts of SGK1 (serum- and glucocorticoid-regulated kinase 1) were increased in the luminal epithelium, lining the endometrium of infertile women compared to controls (Feroze-Zaidi et al 2007). This is the site of embryo attachment at the start of pregnancy, and suggested that increased SGK1 in these cells somehow impaired implantation. The new Nature Medicine study demonstrates that increasing SGK1 expression in the luminal epithelium of the endometrium in the mouse, by transfection with an SGK1 expression vector, results in failed implantation by altering expression of genes which permit embryo attachment. This establishes a causal link between increased SGK1 expression in the endometrium and failed implantation leading to infertility.

The new paper also identifies a second role for SGK1 during implantation. After embryo attachment, the endometrial stromal cells undergo a differentiation process known as decidualization, which is essential for successful placental development. Implantation was unhindered in Sgk1−/−/ mice, but in the absence of SGK1, stromal decidualization was grossly impaired, with a failure of pregnancy-dependent induction of genes involved in oxidative stress defences. This resulted in bleeding at the decidual-placental interface, fetal growth retardation and subsequent demise. Relative SGK1 deficiency was also a hallmark of decidualizing stromal cells from human subjects with recurrent pregnancy loss and sensitized these cells to oxidative cell death. Thus, depending on the cellular compartment, increased SGK1 activity in the luminal epithelium endometrium interferes with embryo implantation, leading to infertility, whereas decreased levels in decidualizing stromal cells predisposes to pregnancy complications and miscarriage by rendering the feto-maternal interface vulnerable to oxidative damage.

This research has exciting translational potential because inhibition of SGK1 levels in the endometrium, prior to embryo transfer may benefit those infertile women in whom SGK1 remains too high during the implantation period. Conversely, increasing SGK1 levels transiently in the endometrium might be used as a new method of contraception."

For more information contact Dr Andrew Sharkey ()

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Deregulation of the serum- and glucocorticoid-inducible kinase SGK1 in the endometrium causes reproductive failure. Salker MS, Christian M, Steel JH, Nautiyal J, Lavery S, Trew G, Webster Z, Al-Sabbagh M, Puchchakayala G, Föller M, Landles C, Sharkey AM, Quenby S, Aplin JD, Regan L, Lang F, Brosens JJ.

The original study showing SGK1 is upregulated in endometrium from infertile women, was performed here in the department of Pathology.
Role and regulation of the serum- and glucocorticoid-regulated kinase 1 in fertile and infertile human endometrium.
Feroze-Zaidi F, Fusi L, Takano M, Higham J, Salker MS, Goto T, Edassery S, Klingel K, Boini KM, Palmada M, Kamps R, Groothuis PG, Lam EW, Smith SK, Lang F, Sharkey AM, Brosens JJ. Endocrinology. 2007 Oct;148(10):5020-9. Epub 2007 Jul 19. doi: 10.1210/en.2007-0659

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