When a couple facing infertility makes the decision to embark upon a treatment of IVF at Sher Fertility Institute New York, if they eventually fail to meet with success it is usually attributable to a paucity of healthy embryos to work with. Healthy embryos are those that are, at a minimum, chromosomally normal, or “euploid”. Creating such embryos gets more challenging as a woman ages due to a natural fragility of eggs that only grows more problematic with time.
But what about those couples that transfer very healthy appearing embryos (i.e. those that have reached the expanded blastocyst stage) that still do not conceive? These developmentally normal embryos have an elevated chance to be euploid certainly, but it is not a guarantee. This leads some to genetically screen their embryos to more fully understand what they are capable of producing. Such screening involves an embryo biopsy on day 3 or day 5 of its development and then a chromosomal numerical assessment through a technique called NGS. Embryos that look developmentally appropriate and test normal via the NGS technique have minimally about a 65% chance of making a baby. This is about as good as one’s starting materials can ever be.
But what about those couples who on one or more occasions transfer such sound quality, normal testing embryos but still fail to implant? Should we just ascribe it to bad luck and keep transferring? I recommend that when such a scenario occurs, before more transfers are done, the uterine environment should be strongly considered as the source of failure and deserves more scrutiny and attention.
Does the lining of the uterus (endometrium) achieve an adequate thickness?
If the substrate for implantation is not adequate, the embryo may not implant or fail to thrive if it does. We like to see the lining at a minimum of 9mm thick. A trilaminar appearance is reassuring, but is not a mandate for a good outcome. Certainly if the lining is less than 7mm we think a fresh transfer is going to be compromised and will vitrify our embryos until we can get the lining better in the context of a frozen transfer. Data supports the use of vaginal sildenafil (Viagra) as one means to enhance the lining, presumably working through the enhancement of blood flow to the pelvic organs. Sometimes by merely increasing the duration of estrogen exposure, as can only be done in the context of a frozen embryo transfer, one can enhance the lining thickness. Finally, a hysteroscopy to look into the uterine cavity directly is worth considering as the presence of scarring might be the reason for the thin lining. Such scarring can often be cured through careful resection at the time of hysteroscopy.
Is the lining (endometrium) receptive?
We know from years of studying the physiology of early pregnancy that a uterine “window of implantation” exists in which there is a relatively short period of time during a woman’s menstrual cycle in which her uterine lining will be receptive to an embryo. Embryos placed into the uterine cavity before or after this period won’t implant. Protein secretion in the endometrial cells is altered in response to the post-ovulatory hormonal changes that occur (the main one being a surge in progesterone) and it is this new protein profile that characterizes the “window of implantation”. For example, a protein called cyclin is markedly diminished while another protein called integrin is markedly increased. Occasionally the normal protein fluctuations that engender receptivity in the lining do not occur despite what appears to be a perfectly normal hormonal pattern during natural or medicated treatment cycles. To diagnose such issues, a protein analysis of lining samples obtained via endometrial biopsy can be implemented. The reasons for a receptivity failure can be mysterious, but such aberrations tend to be more frequent in women with inflammation of the endometrial lining (endometritis), endometriosis, or tubal disease. Therefore treatments including antibiotics, a lowering of estrogen influence (as with long-acting Lupron or the aromatase inhibitor letrozole), or surgical removal of dysfunctional tubes (salpingectomy) can be very helpful. In the context of a fresh IVF cycle, it is critical to measure progesterone levels during the later days of stimulation. Premature increases of progesterone can sometimes occur and when present can shift the window of implantation. This leads to embryos which are no longer developmentally in sync with their lining. Freezing all the embryos and performing a later frozen embryo transfer should be considered when there are progesterone elevations greater than 2.5 ng/mL before egg retrieval.
What else can be done for the seemingly refractory uterine lining?
Recent data has accrued for some newer techniques that have been postulated to help implantation. One technique is called an “endometrial scratch biopsy” in which the lining of the uterus is biopsied about a month before transfer, not strictly for diagnostic purposes, but rather merely to irritate the lining a bit. Such a thing sounds very counter-productive, but nonetheless the data show otherwise, and this effect has been attributed to the fact that an irritated lining secretes many proteins and growth factors that may prove chemically alluring to the embryo. Another potentially promising technique is the injection of a dilute amount of hCG directly into the uterine cavity a short while before an embryo transfer. A recent study (Reproductive Biology and Endocrinology 2014, 12:9) demonstrated an increase in the implantation rate from 36% to 52%, and such an improvement has been attributed to the ability of hCG to influence inflammatory factors and blood vessel development in the lining. These techniques require further corroboration but appear encouraging and we shall follow the literature closely to see if they deserve more application.
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