Being unable to become pregnant can be devastating for couples that want to have children. Fortunately, the causes of so-called unexplained infertility are becoming increasingly clear. A common cause of infertility is endometriosis, which can impair implantation of the embryo on the wall of the uterus. A new test called ReceptivaDx tests for levels of a biomarker called BCL6 in menstrual fluid. It is thought that many cases of endometriosis are not accompanied with any symptoms, so having a noninvasive test like this can avoid surgery such as laparoscopy.

We asked Dr. Aimee Eyvazzadeh some questions. She was very good to get back to us quickly, but I felt that she didn’t really answer many of the questions such as the false positive and false negatives rates, and risks of hormone therapy for mild nonsymptomatic endometriosis.

It seems that depending on the results of the ReceptivaDx test, the method of IVF is adjusted. Given that the lack of clarity on the accuracy and specificity of the test, it’s hard to say whether it would be useful to pay for it, and whether it would help. Nevertheless, this is another option to ask your doctor about if you have unexplained infertility. Below you’ll find the questions to Dr. Eyvazzedeh and the answer kindly provided.

UPDATED: Dr. Lessey has provided additional information to supplement Dr. Eyvazzedeh’s answers. You will find the answers from Dr. Lessey below. The answers provided by Dr. Lessey seem to be more quantitative and may be of particular value to patients assessing whether to ask their doctor about this test. I still feel the discussion around the risk of continued hormone therapy in the background of asymptomatic endometriosis was not properly addressed and these risks, among others, should be carefully discussed with your physician.

Dr. Lessey is the Scientific Advisor for CiceroDx, Inc. and is an internationally recognized leader in uterine receptivity research and the identification of markers associated with unexplained infertility. Dr. Lessey’s research background includes published research on Beta 3 Integrin and BCL6, the two key components of the current ReceptivaDxTM Assay. Dr. Lessey is a practicing Ob-Gyn at The Fertility Center of the Carolinas in Greenville, SC.

IVF patient with doctor

1)      What sort of symptoms can indicate that a person has endometriosis–do women with symptoms of endometriosis still need to be tested for the BCL6 marker?

Dr. Eyvazzedeh: “That’s why I recommend the ReceptivaDx test because endometriosis isn’t anything you can see with ultrasound unless it’s very obvious as cysts in the ovary or by symptoms. This marker is changing lives one test at a time. I have helped women who may have otherwise needed to use a gestational carrier by doing this test, treating them and then seeing them get pregnant right after treatment.

When you get a woman’s uterus prepped for embryo transfer, we do many checks on the lining of the uterus. One of the most frustrating problems in IVF medicine is when everything looks absolutely perfect and still doesn’t work. It’s frustrating and depressing. Having this test to be able to guide women about why things aren’t working and then having a treatment has been able to change my fertility practice in ways that are unimaginable. Imagine telling someone you have a less than 20% chance of pregnancy if we didn’t catch this and now you have over 70%. It’s wonderful.”

Dr. Lessey: “Many women with endometriosis have dysmenorrhea or pain, pain with intercourse or bowel movement. Infertility can be the only symptom and many women with unexplained infertility have endometriosis and don’t know it. Irritable bowel syndrome is an example where may women have endometriosis that accounts for their symptoms. In response to this specific question of who deserves to be tested, the primary group would be those with unexplained infertility or IVF failure, but other women with chronic symptoms who need an answer might also select this test.”

2)      What percentage of women test positive for the BCL6 marker with your test, but do not have physiological endometriosis upon closer examination? Related to this question, what percentage of women who test negative for the BCL6 marker with your test are found to have endometriosis upon closer examination?

Dr. Eyvazzedeh: “In the “old days” we used to do a laparoscopy on everyone! Anyone who has IN-Fertility (note I don’t like to use the word infertility but think of my patients of being in fertility)  would get booked for a laparoscopy after their first visit. That’s another great reason to do this test: you can diagnose endometriosis without doing surgery. Who wants to have surgery when you can have a much simpler biopsy in an office setting?”

Dr. Lessey: “Less than 5% did not have visible endometriosis. Some had other conditions known to be associated with infertility such as hydrosalpinges or adenomyosis. [regarding false negatives] We don’t know that answer. The test seems to detect all stages of endometriosis and BCL6 negative women usually get pregnant quickly naturally or in IVF.”

3) What are the risks of receiving hormone therapy for endometriosis if there is no physiological endometriosis? Do patients require further clinical examination with laparoscopy if they test positive for the BCL6 marker with your test?

Dr. Eyvazzedeh: “The way I think of this test is, I’m getting the uterus ready for the most important house guest of it’s life 🙂 This is what I tell patients. I do the following:

  • Step 1 : IVF
  • Step 2: Make sure embryos are genetically normal
  • Step 3: Do the ReceptivaDx test and then make the most successful transfer calendar possible. Checking BCL6 tells me the protocol that will be the most successful for the patient. There are several protocols and some include Lupron Depot and some don’t, but the Lupron Depot patients take active birth control pills (I.e. pregnancy readiness pills in IVF medicine) so that they don’t suffer the horrible side effects of the medication: hot flashes, mood changes vaginal dryness, thinning bones, etc.

I tell patients to take the time and spend the money on the test so you don’t have to take the time and spend money on more IVF cycles. Spend 10% of what you will on your IVF to give yourself the absolutely highest chance of pregnancy the first time.”

Dr. Lessey: “This is a good question. The patient with known endometriosis by previous laparoscopy doesn’t need more surgery since there are effective strategies for management. For pain, turning off the menstrual cycle is important with continuous OCPs or Mirena IUD. For fertility patients, especially those in IVF programs, freeze all cycles with Lupron suppression for 2 to 3 months has yielded very high pregnancy rates and is our preferred approach. Long term suppression with medications like Depot Lupron with appropriate addback is also safe and effective.”

4) What percentage of women with unexplained infertility are found to have undiagnosed endometriosis, and of these patients, what percentage would be detected with your biomarker test?

Dr. Lessey: “As we showed in our original BCL6 paper, we found over 80% of unexplained infertility had undiagnosed endometriosis. There were also a high percentage of women with unexplained recurrent pregnancy loss that test positive (77%) and these were also found to have endometriosis. The literature suggests that 30 to 50% of unexplained infertility have endometriosis but given the subtle forms of endometriosis that exist, we can say based on our BCL6 studies that the rate is closer to 80%. Therefore, unexplained infertility patients are a good group to use the test in.”

5) If a patient tests positive for the BCL6 marker, what treatments can the patient undergo to increase the probability of successful fertilization via in vitro methods or sexual intercourse?

Dr. Eyvazzedeh: “I recommend:

  1. Anti-inflammatory diet and guide patients about this as well
  2. Anti-inflammatory supplements that can also reduce endometriosis
  3. Making sure the transfer protocol addresses the BCL6 level

If a patient doesn’t want to do IVF, that’s OK too! Consider treating the BCl6 level and giving yourself the highest chances for pregnancy at home ,too! And I agree. It’s way more romantic to get pregnant at home than in my office.”

Dr. Lessey: “We are about to report our data on surgery versus Lupron suppression before transfer in IVF and find that both work well. As mentioned above, if a women has already had surgery, we think medical suppression is better (and equivalent) in terms of success. The same may be true for natural intercourse but those studies have not been done to the same degree. Interestingly, a large number of subjects conceive after having the biopsy, which has been reported. This may be another short term benefit from having the test.”

6) What are other causes of unexplained infertility, and what is the recommended next step for a patient who does not test positive for the BCL6 marker with your test?

Dr. Eyvazzedeh: “First of all, there’s no such thing as “unexplained” to me. Unexplained means no one took the time to explain it to you. In 2017 we have so many diagnostic tools that I have yet to find a patient that is truly unexplained with current tests like:

I can truly pinpoint what the fertility factors are for my patients and give them treatment plans based on what we have learned about them, so they feel like they know everything up front at the start of the fertility path. I’d much rather take a path than a journey.”

Dr. Lessey: “In our IVF program, the BCL6 negative women have an excellent pregnancy rate of over 60%. Male factor issues and age related embryo issues need to be pursued in those cases.”

Thank you to both Dr. Eyvazzedeh and Dr. Lessey for taking the time to answer these questions for BoxRoundup.

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