Q From U: Endometrial Receptivity

Submitted by FertilityLab Wed 06/27/2012

From a reader: “I have a question. My lining is not that great for this FET. Now it has grown to 7.5mm thickness but has a nice trilaminar pattern. I am planning to transfer 2 blastocysts. I have an opinion like if the embryos are competent enough the endometrial lining doesn’t matter. From your experience as an embryologist what do you think? How important is endometrial lining when doing FET or in conception as a whole? Can you please write about it? Thank you very much for listening.” The recent review, “Defective endometrial receptivity” by Ariel Revel, MD is a useful summary of various factors that determine whether the uterus will be a hospitable place for the hatching blastocyst. I will summarize the major points for you. The article is available through the journal Fertility&Sterility, Vol.97, No 5, May 2012, pages 1028-1032. There is not a single paramount factor that can predict successful implantation. The embryo must be hatched from the zona pellucida, bristling with the appropriate receptors and still aggressively dividing. The uterus must be receptive to the embryo’s attempts to attach to the cell lining. The embryo and uterus must be able to effectively “talk” to one another during the implantation process. The uterus is only receptive to the embryo for a short period of a few days called the “implantation window” during the menstrual cycle. To achieve an “open” window, the uterus must be hormonally programmed by the ovaries. The molecules (adhesion molecules, cytokines, growth factors and lipids to name a few) that actually respond to the hormonal environment and allow implantation are still poorly understood, particularly in humans since direct research is limited. Large scale intrauterine factors that can DECREASE the probability of embryo implantation include uterine polyps, septate uterus, fibroids and adhesions. Uterine Polyps. Uterine polyps are growths that take up space in the uterus, blocking implantation sites. Some polyps can become so huge, that patients suffering from them can look pregnant. Polyps are routinely detected by hysteroscopy (looking at the inside of the uterus with a camera similar to colonoscopy) and polyps may be removed surgically. Removed polyps are sent for histological analysis to rule out the presence of cancerous cells. Septate Uterus. During in utero development of the reproductive tract, there is remodeling of primitive Mullerian ducts into the mature female reproductive organs. Sometimes, a residual structure persists, a fibrous partial “wall”, effectively partitioning the uterus into two parts. The extent of this fibrous tissue may only slightly dip into the uterus or it can completely dissect the uterus into two compartments. A septate uterus clearly increases the risk of miscarriage, but it may also negatively impact implantation. The fibrous area that divides the uterus is only poorly hormonally responsive and thus may present a poor implantation region for the embryo. Depending on the extent of the septate uterus, physicians may recommend surgical removal of this abnormal structure prior to pregnancy attempts to decrease the risk of miscarriage. Fibroids or leiomyomata. Fibroids are another type of abnormal cellular growth in the uterus and may vary considerably in both size and number from patient to patient. The location and size of the fibroids can determine how much of a problem they are likely to be in terms of preventing implantation or interfering with the on-going pregnancy. More about fibroids in this earlier post, Plumbing Problems. Depending on their location, fibroids may be more or less amenable to surgical removal. More recent research suggests that fibroids may alter the expression of certain gene products (HOXA-10) in endometrial stromal cells which lie just below the epithelial top cell layer that makes first contact with the embryo during implantation. Decreased HOXA-10 mRNA and protein levels have been associated with impaired receptivity in the endometrial (epithelial) layer. If fibroids are so large or plentiful that they distort the uterine cavity, some clinical studies suggest that removal of these fibroids (myomectomy) prior to IVF can increase the success rate of IVF. Synechia-Asherman Syndrome. This is a medical condition in which adhesions/scar tissues form between opposing layers of tissue within the uterus, creating scarred regions. These areas of scarring can involve layers of the endometrium (surface epithelium) , myometrium (muscle layer) or connective tissue layer. Areas of adhesions are not areas in which the embryo can implant. Surgery can be used to try to restore the size and shape of the uterus, and locally promote regeneration of new epithelium that can become receptive to the embryo. This is a difficult condition to treat and typically recurs. Use of a gestational surrogate may be necessary in some cases to successfully carry a pregnancy. Thin Endometrium. When the cells lining the endometrium are sparse, creating a lining that is less than 7 mm thick, pregnancy generally can not occur, although a few anecdotal cases of pregnancy with thinner linings have been reported. An endometrial lining with thickness in excess of 9-10 mm is considered to indicate uterine receptivity. Endometrial thickness is detected by ultrasonagraphy. It is not understood why a thin lining is correlated with poor receptivity. One study suggested that the thin layer leads to an abnormally high concentration of oxygen in the epithelial cells, resulting in excess generation of reactive oxygen species (free radicals) which can be toxic to cells. There is no “cure” for thin endometrium. Typically, hormonal stimulation is continued to encourage the development of the lining as long as possible (before menses) with repeat ultrasound measurements to detect when the desired thickness is achieved. Altered expression of adhesion molecules. At the cellular level, receptivity is invisible, but it involves a highly orchestrated cast of molecular molecules which scientists are only beginning to characterize. As the embryo enters the uterus, it soon frees itself from the confines of the zona pellucida, its pre-implantation home for the first five days of the embryo’s existence. But now the embryo has another problem. Receptors on it’s surface must signal and bind to complementary receptors on the epithelial cells lining the uterus. Then, once a foothold is established, the embryo burrows into the underlying layers of stromal cells until the stromal cells signal “enough is enough” and stop the cellular invasion. Failure to stop this invasion can result in rare forms of placental cancer. Once in place, the continued growth of the embryo unfolds in step with the parallel growth of the placenta that forms the embryo/fetus’s second home until the full term fetus is expelled at birth. This complex highly orchestrated production that is implantation occurs at the invisible sub-microscopic layer and requires the interaction of a variety of molecules including adhesion molecules, cytokines (cell-to-cell signalling molecules), various growth factors and lipids (fatty molecules). Even my own post-doctoral research in the late nineties, looked into the question of cell-cell signalling between layers of the uterus during implantation using a mouse cell co-culture model. In the almost two decades since, our understanding of the complexity and scope of the problem has increased, but with little progress that can be directly translated into effective clinical treatments. Currently, the focus of implantation research is identification of molecular markers of receptivity that could be used to better identify the window of receptivity. Some of the molecules identified may then become targets of therapy to replace or regulate these molecules to restore a state of receptivity. But for now, we can merely measure the thickness of the endometrium via ultrasound to predict whether the uterus may be receptive to the embryo. Endometriosis. Endometriosis is a medical condition in which epithelial cells establish themselves abnormally in places outside of the uterus where they proliferate and respond to hormones in a cyclical manner, even dying and bleeding in spots outside the uterus. This abnormal cell behavior causes pain and can result in poor egg quality or poor embryo quality. More recently, some studies suggest that endometriosis may also alter the expression of implantation molecules during the implantation window, interfering with receptivity. Local hormonal dysregulation may also occur. Normally, the estrogen receptor is down regulated during implantation but in some women with endometriosis, the estrogen receptors may actually be up-regulated, which does not allow progesterone to dominate as needed for implantation. Hydrosalpinx. Hydrosalpinx is a condition in which the Fallopian tubes fill up and become distended with abnormal, possibly toxic, serous fluid, which can seep into the uterus and interfere with implantation, either via mechanical means or by altering the expression of receptivity markers such as avb3 integrins. Whatever the mechanism, a comprehensive Cochrane review of the literature has demonstrated that pregnancy rates are improved when patients had hydrosalpinx surgically removed prior to IVF. Removal of the hydosalpinx means removal of the abnormal tube. If both tubes are removed, the patient is effectively sterilized unless IVF is used. Gonadotrophin ovarian stimulation for IVF. The controlled ovarian hyperstimulation (COH) protocols that are necessary prior to IVF to produce a large cohort of mature eggs may upset the delicate hormonal balance necessary for optimal implantation. This may explain in part why some patients fail to become pregnant from their fresh IVF cycle, then become pregnant on a subsequent frozen embryo transfer cycle using the “lesser quality” embryos from the same cohort. The high levels of estrogen reached in some cycles may interfere with the precise expression of some receptivity markers, leading to reduced receptivity. Currently, there is little effective targeted treatment to induce, detect or restore receptivity. A better understanding of the molecular mechanisms underlying receptivity is the first step in developing new treatments. One product available through Vitrolife and named (no kidding) Embryo Glue has been used with favorable results based on reports from some programs. It is a thick viscous fluid rich in the glycosaminoglycan, hyaluronan. Hyaluronan is normally found in the female reproductive tract and has been proposed to help implantation by increasing cell-cell adhesion of the embryo and the uterine lining, interacting with growth factors that mediate implantation, indirectly promote the growth of new blood vessels which encourage and support implantation, interacting with receptors on the embryo and generally promoting implantation. A small volume of Embryo Glue is added to the embryo’s culture medium in the last few hours before transfer and then the embryo is picked up in this medium in the transfer catheter. I have used this product in the past with our IVF patients and it, at least, did not seem to diminish our pregnancy rates. It may have helped but determining efficacy in a clinical situation is a difficult experiment to conduct. Who wants to be the control subject and not use something called Embryo Glue? I have no financial interest in this product. So in summary, for successful implantation to occur, both the embryo and the uterus have to be in good shape and talking to one another.

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