The Failed IVF Patient Does Not Have to Be a Conundrum

In Greenville SC, we have increased our In Vitro Fertilization (IVF) success rate by 30% in 2017 over historic averages (70% vs 54%).  In part, this is due to our ability to stratify our incoming IVF patients with unexplained infertility into good and poor prognostic groups as recently reported (http://www.fertstert.org/article/S0015-0282(17)31944-1/fulltext). We are using a simple test that measures the protein BCL6 that detects endometriosis (ReceptivaDx).  Not surprisingly, most UI patients test positive for BCL6 75% of the time.  In this blog I will provide some science, some history, some myth busting and some solutions. The decision to test for BCL6 is ultimately yours and your patient but the evidence is growing rapidly on the utility of endometrial testing using this protein.

HISTORY

As background, endometriosis has been my scientific passion for over 30 years. While I still have an active infertility practice, my research hat has always been focused on implantation and why embryos don’t attach.  Before there was a test for endometriosis, clinicians were in the dark regarding their patients’ risk for having the disease. Many women too, endured years of pain or infertility before their diagnosis of endometriosis was made.  In fact, even today the average time to diagnosis of endometriosis is 11 years in the US!  Many symptoms exist that can clue the doctor about the existence of endometriosis, including the 3 Ds, dysmenorrhea, dyspareunia, and dyschezia, but other signs are often ignored including spotting before menses, deviation of the cervix, menstrually related irritable bowel syndrome (IBS) or interstitial cystitis (IC), or unexplained infertility. The current gold standard for diagnosis remains surgical confirmation of the presence of endometrial glands or stroma through laparoscopy.  But surgery, while reliable, has fallen out of favor in many IVF centers because of expense, delay of treatment and conflicting opinions on the relationship between endometriosis and IVF failure.  That is all changing and relatively quickly.

MYTH BUSTING

The group of IVF patients with “unexplained” infertility represents a majority share of the proportion of those heading to IVF, and more often than not, are the same group that fail IVF and never understand why.  Clinicians cannot be blamed. The teaching has become dogma, stating that endometriosis does not affect IVF outcomes.  This conclusion is, not surprisingly, based on faulty assumptions and our own self-fulfilling prophecies.  For instance, women with an existing endometriosis are compared to women without endometriosis. Those with the diagnosis may have already undergone laparoscopy and therefore treatment. Many of those without the diagnosis have active endometriosis that is never counted.  Those with the diagnosis are now in a statistically favorable group when it comes to IVF success, giving clinicians the false impression that endometriosis is of no concern.

In support of this is the vanishingly small proportion of women with “endometriosis” listed in the SART statistics.  How can only 3% of women going to IVF have endometriosis, when 75% of unexplained cases of infertility have this disease? Unexplained categories account for over 50% of the groups on the SART database, suggesting we are missing the boat entirely on this disease.  I know it is reassuring for patients and doctors alike, to believe that all variables are being addressed, but this could not be farther from the truth.

In our study that came out this week in Fertility and Sterility, we demonstrated that women with UI often tested positive for the BCL6 biomarker and therefore had underlying endometriosis.  But we already knew that women who fail IVF often have endometriosis and that their IVF outcomes can have improved outcomes with surgical treatment of their disease (Littman and Giudice). Similarly having pretreated women with suspected endometriosis with letrozole during their IVF stimulation improves outcomes and pregnancy rates (Miller 2012).  GnRH agonist therapy has also been shown to improve outcomes when used before embryo transfer (Surrey).  So why the reluctance to act on this information and improve IVF outcomes?

There may be many reasons but complacency should not be one of them. Our field should not be content with pregnancy success rates of only 30 to 40%.  Overall, every women who takes a child home from an IVF cycle, there are two more that don’t.  When I ask my female patients if they want to leave it to chance, they definitely do not.  A couple that pays $15 to 20K for an IVF attempt expects to conceive and it’s our responsibility to do what we can to make it happen. Couples can now expect better results, thanks to our ability to predict endometriosis and IVF outcomes prior to taking the first shot of gonadotropins.

SCIENCE

In a recent study ( http://www.fertstert.org/article/S0015-0282(17)31944-1/fulltext ), we describe a group of women with UI that underwent testing using the ReceptivaDx test. This minimally-invasive test provides an HSCORE for the oncogene, BCL6, which is normally expressed at a low level in normal women. In women with endometriosis, the level of BCL6 is extremely high providing a reliable way to screen your patients for endometriosis. In my last blog, I described the science on why BCL6 is an important link in the progesterone resistance pathway and a likely cause of a non-receptive endometrium, through binding to another protein SIRT1. Together, SIRT1 and BCL6 turns off genes that progesterone is trying to turn on. As a critical hormone in pregnancy, progesterone is the key to endometrial receptivity.

By studying the BCl6 in the endometrium of women prior to IVF, we were able to show that over-expression of this signal gene leads to a take home baby rate of 11%, while normal (low) BCL6 expression was associated with a nearly 60% rate of success.

SOLUTIONS

Having a test for endometriosis is only as good as the strategies for using that information. As I stated upfront, in my practice, where intervention for high BCL6 has been incorporated into our work-up, our pregnancy rates are approaching 70% for 2017. In women with unexplained infertility and especially unexplained IVF failure, endometriosis can be identified and treated prior to the next transfer.  Ongoing studies in our laboratory show that 2 months of Lupron prior to frozen embryo transfer or surgery for endometriosis prior to IVF both overcome this type of implantation failure.  As previously published by our group, inflammation, particularly IL-17 cytokine, is high in endometriosis and reduced by treatment. Knowing who has endometriosis prior to starting IVF can offer a new storyline for your patients and improve your IVF outcomes as well.

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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