These are 2 pictures of the endometrium, or uterine lining, as seen under a microscope with special stains to highlight the cells, each with a bright purple nucleus. These pictures are substantially different: the one on the left has 2 simple round glands that look like “blue donuts”. The picture on the right shows dilated branching glands, with debris or secretions contained within. Interestingly, the uterine lining for most reproductive-aged women will be similar to the picture on the left during the first 2 weeks of the menstrual cycle; and will be similar to the picture on the right during the last 2 weeks of the menstrual cycle. This is an extraordinary amount of change in a short period of time that no other tissue in the body exhibits. The secretions in the glands of the uterine lining on the right can provide the nutrition needed for an embryo to implant. “The Window of Implantation” refers to the few days in a normal menstrual cycle whereby the endometrial development is sufficient to permit the implantation of an embryo, whether this is a natural conception or an IVF conception.
Estrogen secreted from the ovary in the first half of the menstrual cycle, helps the uterine lining build-up, or “proliferate” and thicken. Progesterone secreted from the ovary, in the second half of the menstrual cycle, after ovulation, will “mature” the lining such that the glands branch and become enlarged with glycogen secretions. When someone does not ovulate normally, fertility medications serve the dual purposes of permitting the release of the egg so it may be fertilized and assisting the ovary in making progesterone to support the development of the uterine lining. When a fertility patient participates in a frozen embryo transfer cycle, the hormonal protocols are designed to expose the uterus to a medium amount of estradiol daily, for approximately 2 weeks, with the initiation of progesterone once the lining has thickened sufficiently, and with the timing of the embryo transfer to be day 6 of progesterone exposure. This type of hormonal synchronization is most likely to yield the “window of implantation.”
However, with the best quality, chromosomally normal embryos, successful implantation rates are in the department of 60-65% per single embryo transferred. We still do not know everything we need to know about the endometrium. While implantation rates are substantially better than what they were 20 years ago, we would like them to be better yet. And certainly, it takes two to tango. Implantation rates have improved as we have learned how to facilitate a better-quality embryo, as well as a better-quality endometrium. There are some patients who fail to implant with multiple attempts. Much research has been dedicated to this group of patients with “Recurrent Implantation Failure.” It is possible to provide more advanced endometrial and uterine testing to patients with recurrent implantation failure or RIF. Testing can include assessing the overall anatomy of the uterine cavity with ultrasound, Xray, or MRI. Testing of the actual uterine lining, or endometrium, can be done with a sampling, or aspiration, or biopsy of the uterine lining, provided the patient has premedication to minimize cramping. An endometrial biopsy can reveal basic information as the pictures presented above; or additional special stains can be added to the microscopy slide of embedded tissue to highlight whether there are inflammatory cells. Should inflammatory or plasma cells be revealed with special stains (CD-138 staining) the patient would be best treated with a full course of antibiotics. An endometrial biopsy can also be sent to a specialty lab to analyze the molecular markers to see if there was a successful development of the window of implantation. We know there are certain molecules that should be present during this time, and that too much or too little exposure to progesterone may influence the presence of these molecules that are associated with the adhesion of the embryo to the uterine lining. This results in a more customized hormonal preparation of the window of implantation. There is an additional molecular marker that is associated with active endometriosis; the marker is called BCL-6. If this should be reported as abnormally high, then that patient would benefit from hormonal treatment to quiet down the endometriosis prior to the embryo transfer.
There is currently ongoing research to determine whether certain growth factors might assist with the implantation of embryos. It is important to gather an extensive amount of data from clinical trials to determine which patients would benefit; what are the potential risks and side effects. When we learn from our complex patients, such as those with recurrent implantation failure, everyone benefits.