ReceptivaDX Test and How it Can Help You with guest Dr. Bruce Lessey
I am delighted to be interviewing Dr. Bruce Lessey today. Dr. Lessey is a reproductive endocrinologist working in Winston-Salem at The Center of Infertility where he has two partners. He is the creator of the ReceptivaDx test, and he is joining me to talk about ReceptivaDx test and how it can help fertility patients.
Dr. Aimee: Welcome, Dr. Lessey! It’s such an honor and privilege to have you on the show today, because I know you personally have helped so many patients that you don’t even know with your tests. Thank you for all the work that you do and all the research that you’ve done and continue to do. I’m so excited to have this conversation today.
Why don’t you tell our audience about yourself, about your practice?
Dr. Bruce Lessey: Thank you so much for having me on the show. I recently moved from Greenville, South Carolina, where I had spent the last 15 years. I am now at The Center of Infertility, in Winston-Salem. This clinic is fabulous. It’s a brand new IVF center, and we’re having great success up here.
Dr. Aimee: Well, I love fabulous and brand new, but I mostly like great success. I’m sure your patients appreciate your hard work just as much as we do here. What made you go into medicine and more specifically fertility medicine?
Dr. Bruce Lessey: Well, I remember when I was six or seven sitting on the basement steps thinking about how much I wanted to be a scientist. I’m not sure where that came from, but it really was something that apparently drove me to what I ended up doing.
My father was a physician and I saw how hard he worked. I think being a scientist was more interesting to me. As it turned out, I did go to graduate school and became a scientist, but then went on to medical school. Because of my background in the research I was doing, I was working in the canine uterus and steroid receptors and the estrous cycle. It was quite logical for me to go into OB/GYN where those specific topics tend to come up quite a bit, especially in the infertility business. It’s worked out wonderfully and my research has supported much of the work we do in infertility today.
Dr. Aimee: Certainly. You spent so much of your research life now discovering novel therapies to help women who are suffering from infertility. I want to specifically talk about the ReceptivaDx test. Tell us, how did you discover this test?
Dr. Bruce Lessey: Well, Louis Pasteur said that “chance favors the prepared mind.” I think that this was one example of how that happens. I was studying a different molecule that was supposed to be high when this protein, BCL6, is low, and indeed when I found that the first protein was high, BCL6 was also high, which didn’t go along with what I expected. I became very interested in why BCL6 was elevated and it turned out that that became the basis for the ReceptivaDx test.
BCL6 is a lymphoma, or cancer, marker and its expression in the endometrium at such high levels was strange. As we studied it, it became obvious that it was a really good marker for the presence of inflammation, specifically endometriosis.
Dr. Aimee: Well, you said something, and that C-word that you just mentioned might scare some people, but the test doesn’t tell you if you have cancer or anything like that, right?
Dr. Bruce Lessey: No, it’s actually a protein that’s expressed at low levels in normal endometrium, but it’s high expression levels signify the presence of inflammation. As you know, cancer and other diseases can also have high inflammation. That may be why it’s associated with those.
Dr. Aimee: Got it. How is the test specifically done? How do you get those cells out to look for it?
Dr. Bruce Lessey: Well, unfortunately the test is currently based on doing an endometrial biopsy and that is a direct measure of what the endometrium looks like during the window of implantation. We take the biopsy about a week after a woman ovulates and the tissue is sent to a reference lab. They do some immunostaining and do an H score. That H score can help us know whether or not the test is abnormal or not.
The patients who have the biopsy know that it lasts about 5–10 seconds of really bad cramping, but after that, the discomfort goes away fairly quickly.
Dr. Aimee: Are here any other markers that you can have tested at the same time, aside from just BCL6?
Dr. Bruce Lessey: Well, ReceptivaDx was also based on our earlier work with the beta-3 integrin. The beta-3 integrin was one of the original biomarkers for endometrial receptivity, and it is still useful. The problem is that everyone who’s abnormal for BCL6 is not abnormal for the beta-3 integrin. We feel like if you’re going to do the test, the BCL6 is the primary marker.
You can also order the CD138, which is a way of detecting whether the patient might have a related ailment called endometritis. Endometritis can be diagnosed during the endometrial biopsy as well.
Dr. Aimee: What makes BCL6 elevated? You mentioned inflammation, but are there any other conditions that can do it as well?
Dr. Bruce Lessey: Well, we know from our work with the integrins that tubal disease, specifically hydrosalpinx, which is a blocked fallopian tube, causes that test to be abnormal. It affects the BCL6 as well. Endometritis is another inflammatory condition, which I just mentioned. I suppose there could be people with systemic inflammation, rheumatoid arthritis, or something like that that could also trigger this, although it has not really been well studied so far.
Dr. Aimee: A lot of the research that you have done has been looking at endometriosis and BCL6, right?
Dr. Bruce Lessey: Yes.
Dr. Aimee: Can you stage a woman’s endometriosis by telling her what her H score is?
Dr. Bruce Lessey: When we did our original studies, we noticed that the highest specificity, which means the ability to detect a woman with a disease, was with an H score of 1.4 or greater. Now, in truth, most women have much higher H scores than that. But when we looked at all the patients, we found that the H score itself did not predict the stage of disease, but any score above 1.4 signified the patient was likely to have endometriosis.
Since many of these women are infertile and have failed things like in vitro fertilization, it’s not unexpected that many of these women will have endometriosis, since that’s a disease that’s been largely overlooked by our colleagues in the infertile world, since endometriosis requires laparoscopy and laparoscopy is now less common.
Dr. Aimee: How do you approach treatment for the different scores? Can you take us through your decision tree if a patient has a score of two or three or four? I know it’s not just a one size fits all answer, but I’d love to hear your approach.
Dr. Bruce Lessey: Well, my approach is focused on what the patient’s symptoms are more than what the H score is. If a woman has terrible dysmenorrhea or dyspareunia, which is pain with intercourse, or has a lot of spotting before the period starts, I’m more likely to do surgery in those patients, since that’s an immediate cure.
On the other hand, a patient who’s failed IVF, who has some euploid embryos in the freezer, who has no symptoms whatsoever, I would be hard pressed to recommend laparoscopy when, in fact, those patients benefit equally simply with Lupron suppression. GmRH antagonist for a couple of months, will help reduce the inflammation and temporarily restore them to normal so that they could go ahead and do the frozen embryo transfer. So a lot of it depends on symptomatology, not the H score itself.
Dr. Aimee: Right. How would you explain this to a patient? She sees the report and then on the report, it says you could have a dilated fluid-filled fallopian tube, which is the hydrosalpinx, and then she says too you, “But Dr. Lessey, I’m doing IVF. How does that matter?”
Dr. Bruce Lessey: The fluid in the fallopian tube is trapped and it becomes like a water balloon. That fluid is highly inflammatory and it can leak back into the uterus. Just having fluid in the uterus will make an embryo transfer very difficult. It was studied early on when we were doing the integrin work that taking the fallopian tube out restored the IVF failures to normal success. That’s become standard of care by this point.
Dr. Aimee: Do you ever repeat the biopsy for patients who have gone through treatment just to see if the H score is better?
Dr. Bruce Lessey: We certainly did a lot of repeat biopsies back in the integrin days to evaluate whether or not this was a reversible condition. We found that doing surgery or suppression would, in fact, return these patients to normal. We published many of those findings.
What I’m finding now, however, is that after two months of Lupron treatment, by taking a patient and then letting them return to normal cyclicity and performing a timed endometrial biopsy, we actually may hurt the patient in the sense that the inflammation that accompanies menstruation might tend to recur. Whereas if you take that patient and simply go straight into a a frozen embryo transfer your success rate may in fact be higher.
Dr. Aimee: What advice would you have for a patient who’s, let’s say, 42 years old, she has one frozen embryo and her Receptiva H score is 4.0. and an AMH of 0.3. Would you tell her to do more cycles ahead of time? Or would you tell her to try and treat the inflammation first?
Dr. Bruce Lessey: If a patient has a good embryo and you know it’s normal and you know she has an endometrial receptivity problem, I would recommend she go ahead and do the treatment and do the transfer. I think our own success rates have shown that those patients get pregnant at the same rate as a much younger patient. As long as they have a normal embryo we can treat them and we would expect good success rates in the 70–80% range.
Dr. Aimee: I know you mentioned, for example, Depot Lupron and surgery. Are there any novel therapies that we can look forward to from a physician community and certainly patients as well that might be coming out soon?
Dr. Bruce Lessey: Well, there was an interesting paper by Steiner et all in fertility and sterility back in July of last year, which I think was a well performed controlled study, where they compared Lupron to Lupron plus Letrozole, which many patients know as Femara. They use the combination of the GnRH antagonist with this aromatase inhibitor, Letrozole, and the two drugs together had a much higher success rate than just Lupron alone. I think, although the symptoms might be greater with the combination, the results argue that there may be some benefit in combining those two drugs.
Dr. Aimee: That is something that I sometimes do for patients also. I used to do a lot of repeat biopsies when I started doing the test and I don’t do them as often, but sometimes I do a repeat biopsy, for example, if the patient is over 40 with just one embryo with an H score of 4.0, and certainly that combination approaches something that I’ve seen can help as well.
What do you say to a patient who gives you this feedback? The feedback is, “I talked to my doctor about this test and they told me that there’s no science that shows that this is a valid test that patients should be offered.”
Dr. Bruce Lessey: Well, unlike many of the receptivity tests out there, ours actually has a lot of science behind it. We were able to show early on that BCL6 was associated with infertility and endometriosis. We went on to show that IVF failure was associated with high BCL6 levels. More recently, in a paper by Creighton Likes, he showed that both surgery and Lupron suppression had similar cure rates and success rates after either treatment.
I think the studies have been coming and I think we have a randomized controlled trial looking at this new drug, Elagolix, which is an orally active Lupron, which will be very exciting to see if that with the fewer side effects, it has might be a better treatment or at least equivalent to Lupron for two months. Those studies are starting now, both here and at Stanford.
Dr. Aimee: I would say anyone who has a physician that says, I don’t believe in this test and there’s no research to show that it works, maybe they’re saying they haven’t seen the research. I always tell people, have them reach out to me. I’d love to talk to your physician about my experience because certainly I didn’t start doing this test from the very beginning. I actually had a patient who had, I think it was 11 failed transfers, who brought me this test and I was skeptical. Then I treated her with depot Lupron just one month and she had her first live birth. I was just floored that such an amazing thing had happened for her and I certainly wanted other patients to have the same benefit to this technology.
What does the research show about pregnancy outcomes after treatment? I know you touched on it a little bit. Can you tell us a little bit more?
Dr. Bruce Lessey: Well there’s certainly, if you have in the setting of euploid embryo transfers, it becomes quite obvious that endometrial receptivity problems do exist and that these patients need to be treated or else they’ll go through another unfortunate loss. Without embryo testing you’ll still get the normal 20% loss because of chromosomal abnormalities in the embryo, but the success rates continue to go up. I think in the future, we will be testing patients before they even start IVF so that we don’t have to wait for an IVF failure to suggest treatment. There may be better ways to test in the future. Those are part of a NIH sponsored grant that we’re now currently working on.
Dr. Aimee: That’s great. You just touched on something that I wanted to ask you, that was, is this test only for IVF patients? What is your experience with that?
Dr. Bruce Lessey: Well, it’s certainly a good idea to treat anyone with unexplained infertility with this test, patients who don’t have the means to do IVF now could still benefit from potential treatment, either surgical or medical treatment for unsuspected endometriosis. I would remind your listeners that most of the patients who go to IVF or even most of the patients in the infertility clinic with unexplained infertility have undiagnosed endometriosis, at least 70–80% do.
The studies that have shown that endometriosis doesn’t affect IVF outcome are all based on patients that have previously been diagnosed and therefore previously treated. You really can’t use them as examples of what endometriosis does. I think this is an area where it’s rapidly expanding. I think the word is getting out that undiagnosed endometriosis is bad and it needs to be addressed early in the infertility workup.
Dr. Aimee: I get fired up about this a lot because I have patients that say, “Well, I was told…” Because I do a lot of second, third opinion consults, like I’m sure you do. I ask patients, I say, “Ask your doctor to do this test.” And the doctor says, “Well, everyone comes back positive for it.” I’m like, “I know. That’s the point.” It’s because it’s so common of a problem and it’s something that we have a strategy for. There’s treatment out there that you can use to treat it, so knowing if you’re positive can actually be very helpful.
Can you share some patient stories of yours? Patients who’ve done the test and then had treated and had success?
Dr. Bruce Lessey: Well, I would immediately think of my first patient who came from France. Her name was Beatrice. Because she was a scientist, she was very active in this research as a patient and would allow me to do the repeat biopsies and then do treatment. She had unexplained infertility. After her laparoscopy, she ended up having a child. She came back later and ended up just needing progesterone for her second boy. Her third son was born without any treatment at all, which illustrates how many of these patients do get better with subsequent pregnancies.
The most dramatic patient was Beth. I’ve talked about Beth in many of my talks. Beth was an example of how infertility clinics typically ignore the presence of endometriosis and push on ahead needlessly, burdening patients with unnecessary costs.
Beth had a small endometrioma, so right from the beginning, it was obvious she had endometriosis. She did multiple cycles back in Maryland. Didn’t get pregnant. Went out to Stanford and because of a low AMH did a donor egg cycle, got 22 top quality blastocysts, kept putting them back and having failures. Ended up coming to me and getting tested. We did a laparoscopy, removed a little endometrioma and then she had her first set of twins after putting back two of her beautiful embryos from San Diego.
She then came back later and had infertility again. I operated on her a second time and then she had her little girl. Now she’s totally happy and has her family. But it was just ridiculous that this endometriosis was being ignored and could have been treated much earlier, saving her countless heartaches.
Dr. Aimee: I agree. What exciting research can you tell us about? I know there’s more that you’re doing. What else is out there that we might see down the pipes, even maybe five years from now?
Dr. Bruce Lessey: Well, we are working on a partner protein that pairs with BCL6. We applied to and were awarded an NIH grant to study this. This grant is now being actively looked at. We’re working with Stanford to reproduce the data using this second biomarker in IVF patients. Then we’re doing the Elagolix trial that I mentioned.
But we’re also doing biopsies at the time of retrieval with the thought that in the future, we might be able to do the egg retrieval, do the biopsy while the patient’s asleep, and therefore the biopsy would be painless, and then before we do the embryo transfer already know ahead of time which patients are going to be successful and which ones aren’t. That would be a wonderful thing. I think realistically we and others should be able to get our IVF success rates up around the 90% mark in the next three or four years.
Dr. Aimee: I have to tell you, I have been doing my biopsies during the retrieval time too, so I’m glad to say that there will be some really good research out there to show [crosstalk 00:21:40] Absolutely. Yes.
I also want your website and I saw that you have an app that’s just come out. Can you tell us about your ReceptivaDx app as well?
Dr. Bruce Lessey: This is the app that Cicero Diagnostics has published and it’s on through your app store, ReceptivaDx. It’s for patients and doctors. Each of them have their own part. You can get a lot of information on what the test can do, how to use the test and how to interpret the results. That’s very exciting. I think it’s going to make it a lot easier for clinicians to get acclimated to this very exciting test.
Dr. Aimee: Thank you so much for coming on the show. I really appreciate you sharing all your wisdom and knowledge. And of course all the research you’re doing I know is going to help women for generations to come. I see family trees filled up with babies, all thanks to you and your hard work.
But before we sign off, can you tell our audience where people can find you, if people want to get a second opinion consult or just see you as a new patient?
Dr. Bruce Lessey: Well, you can certainly find me online, but the Center for Infertility, Endocrine, and Menopause is the name of our clinic in Winston-Salem.
Dr. Aimee: We’re going to put all your information on the article that will go with this podcast and show so people can reach out and find you super easily. Thank you for everything that you do. Thank you for coming on the show. For everyone who’s listening, please subscribe to my YouTube channel, the Egg Whisperer Show, and tune in next time. Thanks everyone. Have a great day.
Dr. Bruce Lessey: Thank you, Dr. Aimee. Thanks for having me.
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