The receptive endometrium : the thinner the better?
It is well established that the maximal endometrial thickness a woman reaches in an IVF cycle is associated with the chance of successful implantation. Virtually every reproductive endocrinologist has debated whether to proceed to embryo transfer when the endometrium is thinner than ideal. Once a thickness of 7 or 8 mm is reached, we all breathe a sigh of relief and happily proceed to transfer. At that point, we know the outcome is mostly up to the embryo. But what if there is more to the story?
In this issue of Fertility and Sterility, Haas et al. from Toronto present retrospective data suggesting that endometrial compaction, or thinning, after progesterone starts may result in optimal pregnancy rates. They reviewed 274 frozen embryo transfers (FETs) of single blastocysts and found lower ongoing pregnancy rates from cycles in which the endometrium did not compact between the end of the proliferative phase and the day of embryo transfer.
This difference was most pronounced in cycles that reached a thicker peak endometrium of at least 8 mm or 11 mm. In those cycles reaching 8 mm, the ongoing pregnancy rate was 54.1% if there was at least 10% compaction
versus only 21.8% if the endometrium did not compact. For those reaching 11 mm, the difference was even more pronounced at 62.5% vs. 18.5%.
In natural cycles, the secretory phase heralded by a rise in circulating progesterone from the corpus luteum induces changes in the endometrium. Proliferation ceases and the tissue becomes denser, as evidenced by a more homogeneous echogenic pattern on ultrasound. The endometrium normally compacts around implantation, but compaction has not routinely been assessed as a positive biomarker in IVF cycles.
Some centers assess the endometrium before thawing for embryo transfer, typically as a perfunctory check. This provides a chance to confirm the transfer plan and that the patient has been compliant with her progesterone regimen. If a patient somehow did not start progesterone, the thaw could be cancelled. Beyond proving medication compliance, it is controversial whether the actual progesterone level before transfer is predictive. A recent study suggested
that a low serum progesterone level might be associated with lower success in recipients of egg donation with the use of vaginal progesterone. Another retrospective study suggested that higher progesterone levels could be associated with a lower chance of success when euploid embryos are replaced in FET cycles using intramuscular progesterone.
Abnormal patterns or the presence of fluid in the lining also could be cause for concern when checking the endometrium before transfer. One center was concerned that if the endometrium thinned too much it might be associated with
lower success. They found that even>5mmdecrease in thickness did not affect pregnancy outcomes.
The idea that compaction may be a positive biomarker is novel and deserves further study. There are some concernswith the current study design that could be addressed in prospective studies. Patients with thinner linings (<7 mm) were
excluded, so we do not know if there is a point where the endometrium may be too thin at the time of transfer. The study was restricted to medicated FETs with the use of single-blastocyst transfer, so it is not clear if these findings apply to fresh ET or natural-cycle FET. A study exclusively using PGT-A would help to isolate the effect of the compacted endometrium by controlling for embryo quality. In the current study, the ultrasound assessment was performed transabdominally, which may not be as accurate as a transvaginal scan, especially in women with higher body mass indices or uterine fibroids. The authors plan to address these concerns in a prospective study.
Even if the findings of this study are confirmed, the question remains of what to do about the noncompacted endometrium. Although the positive correlation of endometrial thickness and IVF outcomes is well established, it has never been conclusively shown that an individual patient benefits from cancelling her transfer and repeating a cycle in the hope that the lining will thicken further. We obsess over these markers, but we lack prospective data that any intervention
improves the outcomes in women with a thin lining, echogenic pattern, or hypercontractile endometrium.
The authors suggest cancelling if compaction does not occur, but most patients did not have an endometrium that compacted by 10%. What intervention will enable it to compact in the subsequent cycle? They hint at some possible interventions—increased dose or duration of progesterone, decreased dose of estrogen, switching to a more natural FET—but these are not proven to help. It may be interesting to correlate the noncompacted endometrium with results from the endometrial receptivity array. Could a noncompacted endometrium be more likely to be ‘‘prereceptive’’?
Rather than cancelling the transfer, should the transfer be delayed and the endometrium reassessed 24 hours later? More than 7 years after Bob Casper—the senior author of this study—announced that ‘‘It’s time to pay attention to the endometrium,’’ it’s still a mystery but we’re paying more attention and getting closer to understanding how to optimize its role in implantation.