By fertility experts from Spain.
In this webinar, Dr Andrea Vidali, Endometriosis Surgeon, Reproductive Immunologist & Endocrinologist, The Owner of Braverman IVF & Reproductive Immunology, has discussed three major topics, endometriosis, fertility-related problems and immunology. Dr Vidali performs a lot of endometriosis surgery, mostly robotic surgery. He also has training in reproductive endocrinology and reproductive immunology.
Dr Vidali is also a co-founder of an organization called ‘The endometriosis summit’. It is an organization focused on putting together patients and practitioners for what pertains to endometriosis as it pertains to fertility and reproductive immunology.
Dr Vidali started by explaining that one of the issues with endometriosis and reproduction is that there’s very poor research. The reason why the research is not that great is that surgeons do not publish a lot of papers. They just are busy doing surgeries, they don’t write a lot of papers. The second dilemma is that IVF doctors do not ‘believe’ that endometriosis is associated with infertility or causes infertility, or maybe if they do believe it, they believe that IVF will bypass the problem. If you’ve had IVF or you’re dealing with IVF, and you have endometriosis, the doctor will often tell you: don’t worry, I’ve yet to bypass the issue.
The third concern is that there aren’t any good protocols that address endometriosis adequately. Even if there’s a desire to address the issue, there’s no clarity on how to address it, which is certainly a factor.
Endometriosis affects egg quality, it’s a fact. The way it affects that quality is probably by affecting somehow steroidogenesis. We know that there are alterations in cytochrome P450 and lower estrogen levels. This affects the level of the egg cell.
In the picture shown, there’s a reduced mitochondrial level. There’s a test to check for mitochondrial DNA content called Mitograde™, and Dr Vidali has been using that test at his practice. There is dark granulation in the egg, and sometimes patients with endometriosis are told they have dark eggs. It’s because of what’s happening in the cell. The hardening of the zona pellucida, the skin around the egg, gets harder to penetrate.
There’s plenty of data on how endometriosis affects oocytes. Patients going through IVF have fewer oocytes, lower estrogen levels and less mature oocytes, it’s a fact.
When it comes to implantation, there is some evidence that there are endometrial alterations that happen due to endometriosis most likely, it has to do with progesterone resistance. This is also probably related to the problems that also happen at the level of the egg. This progesterone resistance disrupts implantation to some degree. There’s also the inflammatory immunological element.
Many IVF doctors, especially European IVF doctors, will tell you that endometriosis does not affect implantation. There are one or two studies that looked at what was called ‘sibling’ egg donor oocytes. They took egg donor eggs from the same donor and gave them to two separate recipients. They fertilized them, and then they compared. One recipient had endometriosis, the other did not, and they looked at outcomes. At least in the Spanish papers, there was no difference, but then at the same time, a Greek paper from the group out in Thessaloniki, among them Dr Nikos Prapas, revealed the opposite, which showed it affected it. The verdict is not out, but you need to remember that you’ll get different opinions from different doctors.
When you look at the curve in the picture from SART, which is the American Association of Fertility Clinics. The curve has a downward slope, it shows that endometriosis is less and less diagnosed in IVF cycles. IVF clinics report the results to SART every year, and they report their data, and part of the reporting diagnosis is included. They report different diagnoses, male factor, tubal factor, egg factor, endometriosis, unexplained infertility, etc.
I have to say that I hate ‘unexplained’ as a diagnosis. In my mind, ‘unexplained’ means that the doctor hasn’t dug deep enough. Unexplained should never really be a diagnosis, but believe it or not, it’s a very common diagnosis. Endometriosis is going down as a diagnosis because nobody’s looking for it. Laparoscopy has been eliminated as part of the diagnostic testing. That doesn’t mean that it’s not there, it’s just not diagnosed.
The ultrasound is not adequate to diagnose endometriosis. If you don’t look for the problem enough, you’re not going to find it. Endometriosis sometimes can be hard to find, and the reason why it’s hard to find is, for example, individuals patients do not report their issues, their symptoms, although they have pain and cramping, they always told the pain is normal, so they’re not going to report that that pain. That’s why it comes down to this whole idea of silent endometriosis, which probably doesn’t even exist because it’s never silent, but that’s what we call it.
Most of Dr Vidali’s and Dr Braven’s patients in the reproductive immunology practice come to them with unexplained infertility, recurrent miscarriage or recurrent IVF implantation failure. They’ve done multiple IVF cycles unsuccessfully, and there are no explanations for it. Many of these patients, when tested appropriately, suffer from an autoimmune disease. They might also have the pre-clinical stage of autoimmune diseases.
The basis of immune rejection is that the embryo is similar to a transplant, with half of the embryo coming from the father and ‘foreign’ to the maternal immune system. It normally tolerates the embryo because of immune privilege in the pregnant uterus. However, immune privilege can be disrupted by the presence of inflammatory and autoimmune conditions. The loss of immune privilege can lead to rejection of embryo, unexplained infertility, recurrent implantation failure (RIF), recurrent pregnancy loss (RPL) and complications of pregnancy (IUGR, preeclampsia, etc.)
Endometriosis is associated with peritoneal inflammation and altered cellular and numeral immunity:
These alterations likely lead to both pain and reproductive failure. Endometriosis is associated with autoimmune diseases, for example, Hashimoto’s thyroiditis, lupus, antiphospholipid syndrome, scleroderma.
Autoimmune diseases are associated with various combinations of HLA alleles. Like autoimmune diseases, endometriosis is associated with particular alleles of HLA genes. Some HLA haplotypes found in endometriosis patients overlap with autoimmunity.
We often suspect endometriosis in patients who do not have the classic symptoms and signs like pain, the menstrual cramps. We call this ‘silent’ endometriosis. In reality, when we start asking questions, true ‘silent’ endometriosis is relatively uncommon. These patients have mild symptoms when the proper questions are asked. Nevertheless, they are mild enough that they do not affect their everyday life. This is why we still call it ‘silent, and it’s not that silent because the main symptom is a reproductive failure.
There are several clinical indicators of ‘silent’ endometriosis:
This is basically what is now known as personalized medicine. Over the years, we have developed testing panels, which are very valuable in our database, and we are developing a new panel that is going to be very valid, and it is an immunological Assessment Report that will help identify patients in a risk and tailor treatment and also quantify based on artificial intelligence the chance of pregnancy loss with a prediction tool. This will help assist these patients physicians in tailoring treatment of reproductive failure, pregnancy loss and identify the presence of endometriosis.
Whenever endometriosis is suspected, laparoscopy should be considered. Surgical treatment combined with immunotherapy significantly improves fertility and pregnancy outcomes in these at-risk patients.
I think immunology plays a major role in this whole process, endometriosis is an inflammatory condition, after all. The whole immune discourse around how those present macrophages migrate into the uterus, and it ultimately affects implantation.
There are two non-invasive tests used nowadays, Bcl6 testing and the ReceptivaDXTM test. The whole idea is that if you have elevation in Bcl6, it is associated with endometriosis. Based on Dr Vidali’s data, patients who had either miscarriages or failed implantations, above 70% had endometriosis, so you’re in a high-risk group. If you’re not getting pregnant, you may have ‘silent’ endometriosis, you should have a laparoscopy.
Endometrial Receptivity Test (ERA) is extremely popular now, and many IVF centres use it when you have failed cycles. ERA does not correlate with endometriosis, so it doesn’t help. The majority of patients are pre-receptors. When people are non-receptive, they’re mostly pre-receptive, and the correlation with an endometrial biopsy is not there.
When it comes to endometriosis and IVF, medications to suppress endometriosis. Hormones treat pain, not fertility. If you take birth control pills or Lupron, when you stop the birth control pills or the Lupron, you’re going to be better because you suppress the endometriosis, that’s not true. You just wasted three months. Whether there is a reset of the endometrium or not, that may help implantation, it’s a possibility not very solid data, but it’s there, and it’s possible that if you’re doing IVF that a couple of months of lupron or oral contraceptives or progestins will reset the endometrium. Otherwise, doing it therapeutically, it’s not going to help you.
The questions regarding the ideal IVF stimulation protocol for endometriosis is hard to answer. There may be, but the protocol you’re going to use to improve your egg retrieval may not help your implantation. If you have endometriosis or you think you have endometriosis, you should probably consider doing an all-free cycle, banking and then a frozen embryo transfer later. This is what almost every IVF centre does in The United States today, with a few exceptions. If you have endometriosis, a minimal stimulating protocol or an estrogen suppressing protocol that’s going to focus on egg quality will be best, and then go for the frozen embryo transfer because those protocols are not good for implantation.
Is there a good protocol for implantation? When you look at the data, it’s all over the place. According to Dr Vidali, it’s probably more important to focus on egg production, quality than focusing on the protocol for implantation. If you did the ERA, follow the ERA test.
There’s plenty of data where the surgical excision may enhance implantation, but it’s not extensive data. Regarding endometriomas – if you have an endometrioma, it is a big dilemma. When you take out the endometriosis, you damage the ovary. However, the presence of an endometrioma per se already damages the ovary, there’s pretty clear evidence that endometriosis affects both endometrioma, egg quality and implantation. The key is how to perform the surgery and the patients who are better suited for this. It’s most likely that the younger patient will benefit the most, the older patient has to be a little bit more careful. Nevertheless, the key here is who operates, but the idea to take out the endometriosis and leave the endometriomas inside not to damage the ovary, it’s not an acceptable question, and that’s an unacceptable issue.
It’s a very loaded question because you have several issues here. The first issue is the two laparoscopies for excision, we have to assume they were excision, and sometimes people call excision, but then they don’t do it. My advice would be to review them with your doctor to make sure that it was indeed excision. It looks like the symptoms are coming back, so that’s a factor. That’s like a big deal to have 4 chemicals on PGS normal embryos, that’s an issue. I would seriously consider the immunological evaluation. I don’t know if you’ve done that or if your doctor believes in this, but with 4 PGS normal embryos implanted and only biochemicals, I would say that probably, that’s like a factor.
When it comes to Decapeptyl, I’m not sure that it would make a difference because you implanted, but then you had the biochemical, so it’s not like you did not implant. It looks like it’s beyond that. Decapeptyl or oral contraceptives do the same thing. You could do like 2 months of oral contraceptive, which is the same as Lupron basically for what pertains to this the resetting of the lining or Aygestin norethindrone acetate 10 milligrams a day. I think that that’s sort of how I would do it, but I would certainly consider an immunological evaluation.
Adenomyosis is associated with reduced implantation, it’s unquestionable and very clear. Doctors under-diagnosed adenomyosis, they don’t see it, they don’t look for it, sometimes it’s there, and they don’t see it, sometimes they see it, but they ignore it, mostly because of the answer, and it’s a little like the answer of the other individual earlier who said my doctor said that people with lupus have a normal pregnancy, not all of them, it’s like telling people I know somebody who smoked their whole life and never developed lung cancer, not every smoker gets lung cancer, but if you smoke you are increasing the risk of lung cancer. Everything has to be looked at as per in risk, not in terms of possible or impossible. Everything is possible, nothing is impossible, but the point being whenever you have a failure, you have to look at your overall chance of success.
You have to say what are the factors that can affect my success, there may not be one factor, it could be a combination of factors, it could be like one factor is endometriosis, one factor is adenomyosis, one factor is an autoimmune condition, one factor is there you have a thin lining and so on and so on. You have to tackle each one of these factors. This is what we call personalized medicine. If you go to a doctor, a fertility doctor that has one of those: everybody’s the same approach, cookie-cutter, you’re not going to find your solution. Maybe you’ll be lucky, you’ll get pregnant on the first shot, but once you start failing, you need to start breaking it down and look at all the different factors, and that’s what you need to do.
Adenomyosis certainly plays a role, and I think that on adenomyosis, there’s pretty substantial data. Number one, you got to do a frozen embryo transfer, you can’t do a transfer on a fresh transfer, you’re just not going to get pregnant if you have significant adenomyosis. Second, you’re going to do hormone suppression before the next transfer. You got to do a transfer, either a natural transfer or a transfer with Letrozole, which suppresses estrogen to get your best possible opportunity for implantation.
There’s plenty of data that looked at the association between endometriosis and adenomyosis. They’re cousins, so they’re very tightly associated, and I want to say 30%, but I wouldn’t tell you the exact number, but the answer is, it is very common. Ultrasonography helps, but MRI also helps. I also want to add something else with the diagnosis of adenomyosis, the advantage you have when you have me here is I know a little of something about everything because I’m a surgeon, I know immunology and IVF, so I get a global picture. Sometimes, people don’t get this global picture.
One thing about adenomyosis is that when the radiologists read your MRI, some of them are old-school, they don’t know the modern way to look at it, they’re just looking at the junctional zone, which is like the zone by the endometrium and close to the endometrium. We don’t look at that anymore, there can be islands of adenomyosis, so you could have a normal junctional zone which is what they measure but then have islands of adenomyosis, and I see that all the time. I review all my MRIs, and I see tons of adenomyosis that were missed by radiologists, it’s crazy.
Endometrioma is a manifestation of endometriosis in the pelvis. It’s because of the way endometriomas happen, and this has been demonstrated over and over again. You have your ovulation, the egg pops out, there’s a little of a breach inside the ovary that has just ovulated, there’s endometriosis in the pelvis because that’s where endometriosis lives. Endometriosis is not endometrial tissue, by the way, and is not caused by retrograde menstruation. It’s the tissue that resembles the endometrium, but it’s not endometrium, it does not come from reverse menstruation, it comes from cells that are there from the early stages of embryo development, and they grow progressively over time. It’s sitting in the pelvis, and it climbs into the ovary, so whenever you have a recurrence of an endometrioma very soon after the surgery, there are two possibilities.
One is that a little of the endometrioma was left behind, which is a possibility, and you can’t blame the doctor in a sense that the doctor may be trying to be conservative on the ovary not to break it, to rip it and all that stuff. The second one is that endometriosis was left in the pelvis, so the instant you drop the ovary back in, you take out the endometrioma, you drop it in you got a raw surface whatever endometriosis is under climbs right back in, and there you have it, you have endometriosis again.
Do I recommend a new lap after a fairly recent one or IVF, provided he endometrioma is relatively small? I think that it depends on your age, but I would probably tell the person to do an IVF cycle and bank those embryos, see how many you have and then make a decision on what to do, that’s what I would recommend. At this point, I think I wouldn’t recommend another surgery right away, get some embryos out, make some embryos, bank them and then figure it out. I know these can be problems in Europe where they don’t like embryo banking, there are all sorts of rules everywhere, so it may not be feasible, I’m just talking in terms of generic terms.
Ubiquinol is a form of Coq10. The whole idea about behind ubiquinol is that part of the lecture that I did earlier you saw where I said that eggs have lower mitochondrial content. The whole idea is that by supplementing mitochondria, you’re increasing the egg energetic component. The mitochondria are like the engine of the cells, that’s one of the reasons. In terms of other supplements, NAC is a possibility, mostly on the pain side though. What I would probably suggest is to consider anything that lowers inflammation. I personally like tree bark, also called Pycnogenol, and I like curcumin, melatonin, so those are kind of the elements that are key there.
If you’re going to take one supplement that I think helps infertility, in my opinion, the one supplement should be fish oil, just because it’s both a blood thinner and an inflammation reducer. I don’t like it when people come with a list like this long of all these supplements because I feel that sometimes they fight against each other. If I should recommend 1 or 2, I guess I would recommend vitamin D3, we know that low vitamin D3 levels affect miscarriage, so I would seriously consider taking at least 5000 a day of vitamin D3. I would certainly consider taking at least 2000 fish oil.
That’s a very good question. Endometriosis is a disease, which is not as progressive as some think it, but it certainly progresses from the adolescent ages to adulthood, and those years are crucial in the development of endometriosis. My perspective as a physician but also the perspective of the endometriosis summit as an organization is that endometriosis should be treated whenever it presents itself. If, of course, the symptoms are severe enough. I feel that it’s essential to treat it the sooner, the better, we treat our adolescents, we treat young teens because the more you wait, the more you develop chronic problems, and there’s a chance to have a very different outcome in life if it gets treated early enough.
There’s a lot of parts in it. This is a very difficult question for me because obviously, I can’t comment on what’s worth or not worth it because that’s a personal decision. There’s no pressure for egg donation because it would have a similar outcome at 41 as at 43. In my experience, egg donation you could access later. I would say to try to get the surgery earlier, maybe go to another province. The advantage in Canada is that you could go to a different province, and if you push hard enough, you could get your laparoscopy earlier.
It’s a question that doesn’t have an automatic answer because it depends on one’s history, how severe the endometriosis is, your age. There isn’t a solution for everybody, but I’m going to try to sum it up. If you have very extensive endometriosis and an endometrioma, I would recommend excising the endometriosis first because if you have all those endometriomas, it’s going to be a mess, you’re not going to get a good result. The stimulation will indeed make the endometriosis worse for sure.
If you have done cycles before and poor egg quality, obviously go ahead and have the surgery, it makes no sense. If you have mild to minimal endometriosis and you and the doctor say, let’s bank some eggs first, and then you’ll do the surgery, then you’ll do the transfer, that’s also an option, so I would say severe, extensive disease surgery first just because you’re not going to have a good cycle. If you have like milder disease, the decisions should be based on your age.
Kudos to you for having endured such a tough seven cycles without, unfortunately, any good result. You’re asking me possibilistic questions, and anything is possible, so I can’t tell you.
You have a good AMH of about 1.24, which is a good value, and your question is: what do I do, do I go with donor eggs, or do I keep on trying. I can’t answer that question for you. I think that you’re getting close to where probably using an egg donor, if available to you, is a reasonable option. It’s already endometriosis-related, but definitely, that’s what it is.
One of the things to consider is that there is the possibility that you have an immunological problem, an autoimmune problem. What I think is that you probably should consider having some kind of immune evaluation. The other part of it is that fresh transfers can always be problematic. I would always try to go with a frozen cycle. I wouldn’t tell you to give up, if you haven’t tried, I would say to try with an all freeze option and maybe some immune support, whether its blood thinners. As I said, we’re going to come out with our immune panels soon, but I think that certainly, an immune evaluation may be worth it given the losses and 4 IVF cycles.
I always tell people that it depends on how you decide on donor eggs. If you decide to go ahead with donor eggs because of age or failed cycles, miscarriages, all the other stuff, it’s a separate story. The verdict with donor eggs and endometriosis is not out that much yet. I told you there are those two studies, the one from Carlos Simone and the other one. The chances depend on your age, you may not need a lot of support, so that would be the standard fertility doctor question, but if you had miscarriages, I would need more information, but in general, I would go with that.
We have to separate the use of GnRH agonists or antagonists in the context of suppression of pain where they’re completely worthless. Lupron or Orilissa, all these drugs, we never use them, or we seldom use them, I should say. We certainly do not recommend them, and within the context of IVF trials, I can tell you that there are limited data on the use of ovarian suppression, and the reason for that is to reprogram the uterus because of progesterone resistance.
The issue that I have with Lupron is that you do the retrieval, that’s like a month, then you do 3 months of Lupron, that’s another 3 months, and then you do the transfer, that’s another month, if you’re not successful, you wasted 6 months. Maybe you’re older, and you wasted 6 months just put yourself on Lupron where your ovaries may not even bounce back. To me, it’s not the best idea, I’ll be honest with you, but as I said, everything depends on your age and all other factors. The answers are very general certainly, if you had a history of depression, Lupron could affect you psychologically, why not do a couple of months of Progestins, it would be a similar effect on the lining.
We could have a whole thing on reproductive immunology, which could be fascinating but needs to look at different factors. First, check the compatibility between the couple, to look at HLA and see how the different HLA’s, the major compatibility complexes of the couple relate to each other. Make sure that there are no HLA mismatches and things like that. You have to look at serology, we have to look at the presence of any autoantibodies like antiphospholipid antibodies, anti-nuclear antibodies, rheumatoid factors. There’s like a whole number of other antibodies associated with autoimmunity.
There are some kinds of cellular factors that are associated with inflammation. The elevation of natural killer cells is one of them. Natural killer cells activity and TH1, TH2 ratios. Those are like T helper cells that play a role. There’s a panel that your doctor can order. In most countries, doctors can order these tests. Clexane is a blood thinner, like Heparin or Lovenox, which are blood thinners that may help but are used empirically. If it works, you don’t know that it worked because of that, and if it doesn’t work, you don’t know why it didn’t work.
When it comes to breast/ovarian cancer, I think the evidence is pretty clear that it does not increase the chance of recurrence or having cancer. When it comes to endo flare, for sure a 100% is the answer. I’ve seen so many individuals who, for example, were completely fine, maybe they knew that in mild endometriosis, they went to an IVF cycle and then after that, they developed severe pain, it became symptomatic, asymptomatic endometriosis became symptomatic. I see this all the time, so yes, you cannot ignore that, but you have to be on top of it. You have to communicate with your doctors, you’re sort of responsible to talk to your doctors and tell them that you have endometriosis, these protocols can affect you, and so that’s how you have to present it.