IVF Failure: Sometimes the Answer is So Obvious, We Simply Ignore it.

Victor Hugo is quoted as saying “Nothing is more powerful than an idea whose time has come”. Well, we’ve been promoting an “idea” for the last 10 years that data are now finally proving out. Simply put, endometriosis is the major cause of failed IVF cycles and a leading cause of unexplained infertility (UI) and unexplained pregnancy loss (uRPL). Most women who fail IVF for unexplained reasons, are the same as those who fail to get pregnant (UI and uRPL). Even when normal genetically screened embryos are put back, IVF success rates remain at only 50% (1). So why is that?

The problem, more often than not, resides with defective endometrial receptivity. We previously explained our theory of progesterone resistance and its relationship to endometriosis (2). Based on the use of a novel biomarker, BCL6, we find that whenever there is no apparent reason(s) for achieving or maintaining an early pregnancy, it is almost always endometriosis! (3).    No other condition can explain so much of what is happening out there to women having difficulty conceiving. Our mantra is “There is no such thing as unexplained infertility”.

Victor Hugo is quoted as saying “Nothing is more powerful than an idea whose time has come”. Well, we’ve been promoting an “idea” for the last 10 years that data are now finally proving out. Simply put, endometriosis is the major cause of failed IVF cycles and a leading cause of unexplained infertility (UI) and unexplained pregnancy loss (uRPL). Most women who fail IVF for unexplained reasons, are the same as those who fail to get pregnant (UI and uRPL). Even when normal genetically screened embryos are put back, IVF success rates remain at only 50% (1). So why is that?

The problem, more often than not, resides with defective endometrial receptivity. We previously explained our theory of progesterone resistance and its relationship to endometriosis (2). Based on the use of a novel biomarker, BCL6, we find that whenever there is no apparent reason(s) for achieving or maintaining an early pregnancy, it is almost always endometriosis! (3).    No other condition can explain so much of what is happening out there to women having difficulty conceiving. Our mantra is “There is no such thing as unexplained infertility”.

In addition, there appears to be no safe amount of endometriosis that can be said to be OK, at least in susceptible women. Endometriosis has been shown to cause problems with endometrial receptivity at incredibly low amounts. Dr. M. Canis from France published a paper showing that invisible endometriosis, seen only using blue dye, was associated with infertility. After removal of these areas of blue staining, nearly 70% of women conceived successfully without IVF (4). We found similar results in our blue dye study for pain, where many of those women conceived after resection of blue stained peritoneum (5).  If very subtle or invisible endometriosis can cause infertility, then leaving even small amounts of endometriosis behind after surgery may be why pregnancy rates aren’t as good as we might expect after laparoscopy for mild disease (6).

What do we know now that we didn’t know before?  Based on available data the American Society for Reproductive Medicine maintained guidelines that, in my opinion, underestimated the impact of endometriosis (7). Studies of women with UI has been the key to expanding our understanding of endometriosis.

BCL6 is the primary biomarker in the ReceptivaDx test for detection of endometriosis. This protein is an “oncogene” associated with lymphoma, and involved with inflammation. We found in our research that BCL6 pairs with another protein called Sirtuin 1 (SIRT1), and together these proteins appear to block the action of progesterone in the endometrium (8). As most know, the actions of progesterone are critical to successful pregnancy and “progesterone resistance”, as it is called, and appears to be a primary mechanism involved in endometriosis and its pathophysiology leading to infertility.

With that said, let’s look at new clinical data. Women with unexplained infertility have a very high prevalence of elevated BCL6 staining (3). We see the same finding of elevated BCL6 in most women with unexplained IVF failure (9).  Both these groups (UI and Failed IVF) had endometriosis as a common finding at laparoscopy. Unfortunately, laparoscopy is being performed less and less in most IVF centers. This has led to a vast under-reporting of endometriosis in the SART database that is published online each year (www.sart.org), perpetuating a false conclusion among many Reproductive Endocrinologists that endometriosis is not a major cause of failed IVF and frozen embryo transfer (FET) cycles. The opposite is likely to be true.

Figure 1: The percentage of women with the diagnosis of endometriosis undergoing IVF has fallen steadily over the years. This does not mean that endometriosis is less common; it means that laparoscopy is becoming a procedure that is omitted from the infertility workup.  Endometriosis still is a major cause of infertility, just most women with this disease don’t know they have it. (Source: ART Surveillence and Research Team, CDC, Atlanta, GA).

Lets look a little deeper. As you can see from the CDC data presented over 20 years, the Society for Assisted Reproductive Technologies (SART) there has been a steady downward trend in the percent of women listed as having endometriosis (Fig. 1). Currently less than 10% of women undergoing embryo transfer are listed as having endometriosis. The prevalence of endometriosis in the normal fertile population is 5 to 10% and up to 70% of women with unexplained infertility have endometriosis. Further, all of the women who have been diagnosed in the IVF CDC data set have already been laparoscoped and therefore treated for endometriosis.  Since the majority of active cases of endometriosis are no longer being counted, the favorable outcomes listed in SART for IVF success rates in women with endometriosis is artificially high. In fact, we recently reported that woman thought to have endometriosis based on ReceptivaDx, did very poorly in IVF (9). (Based on conservative estimates, a majority of women with endometriosis undergoing IVF don’t know they have the disease; this is a problem that is affecting success rates, treatment protocols, and obviously patient bank accounts.

The good news, and the idea whose time has come, is that a test now is available to identify these women before embryo transfer. The response by many physicians to ReceptivaDx testing has been very positive.  The idea that a majority of unexplained cases can finally be explained is changing the face of IVF treatment. When confronted with the options of doing more IVF and having a low success versus identification and treatment of endometriosis before the next transfer, patients recognize the choice as a “no-brainer”.  Early data from our center clearly shows that treatment of high BCL6 levels in women with suspected endometriosis improves outcomes by over 50%. Treatment options include a few months of medical suppression of endometriosis with depot Lupron® (leuprolide acetate) or laparoscopy to identify and treat underlying endometriosis. Future studies may also find that Orilissa® (elagolix), an orally active GnRH antagonist, may also be helpful. The chance of finding endometriosis at laparoscopy is close over 90 % in women who test positive with high endometrial BCL6 levels.  Reducing inflammation is likely the reason these treatments improve implantation and explains why the majority of women conceive with the next embryo transfer after treatment. These data are being submitted for publication and should be available to the interested physicians and patients soon.

Endometriosis is a terrible, often silent disease that deserves more funding and more respect from clinicians.  Women with infertility, especially unexplained infertility need to know about this condition. ReceptivaDx can detect all stages of this disease. The idea that we should ignore endometriosis in the setting of IVF is simply wrong and misguided. We need to do the opposite and expose it to the light of day.

References

1 -Harton GL, Munne S, Surrey M, Grifo J, Kaplan B, McCulloh DH et al. Diminished effect of maternal age on implantation after preimplantation genetic diagnosis with array comparative genomic hybridization. Fertility and sterility 2013;100:1695-703

2 -Lessey BA and Kim JJ. Endometrial receptivity in the eutopic endometrium of women with endometriosis: It is affected, and let me show you why. Fertil Steril. 2017 Jul;108(1):19-27.

2017

3 -Evans-Hoeker E, Lessey BA, Jeong JW, Savaris RF, Palomino WA, Yuan L, Schammel

DP, Young SL. Endometrial BCL6 Overexpression in Eutopic Endometrium of Women

With Endometriosis. Reprod Sci. 2016 Sep;23(9):1234-41.

4 – Manhes H, Shulman A, Haag T, Canis M, Demontmarin JL. Infertility due to

diseased pelvic peritoneum: laparoscopic treatment. Gynecol Obstet Invest.

1994;37(3):191-5.

5 -Lessey BA, Higdon HL 3rd, Miller SE, Price TA. Intraoperative detection of

subtle endometriosis: a novel paradigm for detection and treatment of pelvic pain

associated with the loss of peritoneal integrity. J Vis Exp. 2012 Dec 21;(70).

6 -Marcoux S, Maheux R, Bérubé S. Laparoscopic surgery in infertile women with

minimal or mild endometriosis. Canadian Collaborative Group on Endometriosis. N

Engl J Med. 1997 Jul 24;337(4):217-22.

7 – https://www.sart.org/globalassets/asrm/asrm-content/news-and-publications/practice-guidelines/for-non-members/endometriosis_and_infertility_a_committee_opinion-noprint.pdf

8 – Yoo JY, Kim TH, Fazleabas AT, Palomino WA, Ahn SH, Tayade C, Schammel DP,

Young SL, Jeong JW, Lessey BA. KRAS Activation and over-expression of SIRT1/BCL6

Contributes to the Pathogenesis of Endometriosis and Progesterone Resistance. Sci

Rep. 2017 Jul 28;7(1):6765.

9 – lmquist LD, Likes CE, Stone B, Brown KR, Savaris R, Forstein DA, Miller PB,

Lessey BA. Endometrial BCL6 testing for the prediction of in vitro fertilization

outcomes: a cohort study. Fertil Steril. 2017 Dec;108(6):1063-1069.

Bruce Lessey, M.D., Ph.D. – Scientific Advisor
Lessey’s Corner

The ReceptivaDxTM Test was developed by CiceroDx in conjunction with Pathology Consultants, Inc. of Greenville, SC. Pathology Consultants, Inc. is a laboratory certified under the Clinical Laboratory Improvement Amendments (CLIA). As with other laboratory-developed tests, this testing service has not been cleared or approved by the US FDA or any other federal regulatory agencies. Data have not been submitted to or evaluated by Federal regulatory agencies and the test is not for sale as an In Vitro Diagnostic (IVD) in the US or the EU.


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