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The endometrial factor and recurrent failures in IVF: diagnosis and treatment options

Harry Karpouzis, MD
Founder & Scientific Director at IVF Pelargos Fertility Group, IVF Pelargos Fertility Group

Embryo Implantation, Failed IVF Cycles, Miscarriages and RPL

Recurrent failure - the endometrial factor
From this video you will find out:
  • How molecules and genetics help us to understand the endometrial factor?
  • What is the role of 3D ultrasound and hysteroscopy for diagnosis?
  • How polyps and fibroids affect your fertility?
  • How adhesions can be diagnosed and how they influence your IVF treatment?
  • How can we treat thin endometrium?

How to properly diagnose and treat endometrium before IVF cycle?

In this webinar, Dr. Harry Karpouzis, MD, Founder & Scientific Director at IVF Pelargos Fertility Group, Athens, Greece has discussed endometrial factors that cause recurrent failed IVF attempts. Dr. Karpouzis has also, provided how to diagnose it and what are the treatment options.

How to properly diagnose and treat endometrium before IVF cycle? - Questions and Answers

What do you mean when it comes to fibroid with more than 50% projection in the cavity?

We have a fibroid, as we said, that is intramural, so they start from the muscle. Some of those fibroids can protrude inside the cavity. Half of them can be inside of the womb muscle, half of them go inside the cavity. Some of them are mostly inside the womb muscle. It is less than 50%, and some are more than 50% percent inside the cavity. They are not completely inside the cavity. It’s difficult on how to remove them hysteroscopically, laparoscopically, that’s what I mean.

Given that these days you have so many instruments and test available, why the usual approach with many clinics is to wait for an ‘x’ number of failures? Instead of doing the test on the patient for everything that might be an issue from the get-go? How exactly the age plays a role in fibroids and their removal (or not)? Is it only a question of not wasting time waiting for the uterus to be ready, or are there other reasons?

It’s exactly that. If we have a very poor responder with very low AMH, and someone is close to 40-42, we understand that the laparoscopic removal of the fibroid would mean another 6 months before she tries again. This affects fertility to a very big degree after 40. We know we have a very steep reduction in fertility. Sometimes, we need to evaluate all the factors and see if it is worth doing that for a fibroid, which is intramural. Regarding the submucosal fibroids, we have clear evidence, so we need to take all the factors, this is what I mean when I talk about age.

When it comes to the first question, it’s a difficult question, all those tests cost a lot of money, you may need to pay for another IVF, for example, to do all those tests, and we don’t use them for everyone. Another reason is that we are talking about invasive tests sometimes as well, and we don’t do all those tests if we don’t have any reason suspecting that something is wrong. It increases a lot of the cost.

Some of those procedures and tests are invasive, we need to take biopsies, we need to do laparoscopies, hysteroscopies. If we know that we have very good chances of about 74% of achieving the pregnancy, then I don’t know if it would work to do those tests for everybody. If we have an unexplained failure, then yes, we need to personalize each patient and check all of those things.

Could multiple small fibroids near the uterine lining be removed without affecting fertility?

Yes, they can be removed without affecting fertility. Generally, if the surgery is done correctly, it doesn’t affect fertility. If we manage not to breach the cavity, then, of course, there’s no problem. The question is: do those need to be removed or not? As I’ve said, for a fibroid that is small in size that is close to the cavity, it is a difficult question to answer, and we would need to consider lots of factors.

If they are just touching the cavity without protruding, maybe I wouldn’t remove them from the first IVF if I knew that the cavity is free and no fibroids are protruding inside that, and it looks healthy. Yes, they can be removed if the surgery is done correctly.

Could multiple hysteroscopies damage the endometrium?

No, hysteroscopies will not damage the endometrium. Invasive hysteroscopies like adhesiolysis, removal of submucosal fibroids that are done over and over again will always be the cause of creating chronic endometritis, some adhesions, or scar tissues. It depends on the technique, it is very important the surgeon is experienced, not only that because reproductive medicine is a completely different thing than just treating for symptoms. The diagnostic hysteroscopy will not affect it, it will not cause damage to the endometrium.

How do you see if the uterus is well vascularised? And if the blood flow is not ideal, are there ways to improve this?

It’s a combination, as I’ve said, it’s the thickness, the blood flow. If the thickness is okay, the endometrium is trilaminar, then sometimes, we don’t look for blood flow. If the thickness is not ideal, then we need to check to see if it is also combined with reduced blood flow or not. The blood flow is checked with Color Doppler, so with ultrasound and if we find out that there’s no blood flow inside the endometrium, then we suspect that something is wrong, so then we need to go ahead with the hysteroscopy and see what’s the reason that it’s causing that.

Is there anything we can do to improve our endometrium before transfer?

All those things that we are discussing are things that we try to do to improve the endometria. Usually, the endometrium doesn’t need any improvement, it goes thicker by itself if everything is nice and everything is normal, and we don’t have any issues. In a natural cycle or estrogen cycle, the endometrium will get thicker if it is normal. If there are problems with endometrium thickness, for example, you should check the growth factor with the hysteroscopy. Some research talks about Sildenafil, Viagra, all those things that can affect it, but to be honest with you, the endometrium is a very difficult factor to treat, and most of those treatments do not have conclusive evidence behind it. They have important evidence that they may help.

If there is a thick junctional zone in adenomyosis, how much of an impact would GnRH treatments have in reducing this make pregnancy possible, and in turn, how thin is it likely to need to be for success?

Adenomyosis is a difficult thing as well. Most of the time, it cannot be operated on, so the only option is to try and make it better with GnRH. Many times they do not help. In adenomyosis, you cannot judge the excess of it from an ultrasound. When you suspect endometrial regions as well is hysteroscopy and check if the endometrium is affected as well, and the part of the adenomyosis just try to regulate, this may minimize a bit the thickness the muscle of the womb, check with a hysteroscopy to make sure that you don’t have any problems inside the endometrium and this is what you can do. I wouldn’t be able to give you a figure of how thin the junctional zone should be.

Do you have any views on taking prenatal vitamins before ET, and which ones like folate are crucial for a successful pregnancy and birth?

First of all, every woman who is trying to get pregnant should take folic acid, which protects from birth abnormalities of the baby. There are many multivitamins for men and women on the market that advertise they can improve the egg quality. There is no strong evidence behind it, but there are some vitamins that can be used. For example, for PCOS patients, it’s inositol, or for poor responders – the DHEA. There are many of those in the market, depending on the case, you don’t have anything to lose by making sure that you take a bit of vitamin D, folic acid and taking the rest of the things that are needed. To make sure that you are well prepared for the embryo transfer. Vitamin E can help, as well.

During my 3 FET on day 12th of taking estrogen, I start to bleed, and my endometrial thickness reduces. I have abandoned the cycle twice, most recently, we continued and had a transfer but have had a chemical miscarriage. Do you know what could be a reason why I keep bleeding at this point in the cycle? What effect does it have on the cycle?

That’s a very difficult question, we need to go through the whole medical history. In your case, I would do a natural cycle to see what is exactly happening in the natural cycle. Most of the time, this is a matter of uterine defect, which means it is progesterone-related. Unless there is a reason that is causing the bleeding, so one of the things that I would first check is to make sure that there are no adhesions with hysteroscopy. You need to make sure that everything is okay inside, and then depending on what is exactly happening on a natural cycle, maybe I would try to do a transfer of natural cycle, not a hormonal cycle. Sometimes, in cases like it’s related to that, it can help.

Could Intramural fibroids near the uterine lining(endometrium) grow fast with or after several stimulations?

Fibroids are estrogen-related, so pregnancy can increase them because, in pregnancy, estrogens are increased. IVF increases the estrogen, so yes, at the time of stimulation, it can get increased. Usually, they are not increased a lot, and they go back to normal after we start the hormones, but sometimes we do see that we have an increase in their size. Rarely, it is something that causes problems.

My clinic is adamant that progesterone measured in the blood is not indicative of the progesterone in the uterus, so they don’t test for it. Should I insist they do a test for it?

It’s the policy of each clinic. We do a lot of blood testing during our IVFs, and so at the time of the stimulation, we check the progesterone as well. Some data shows that we need to have specific levels, they are not completely indicative of the progesterone, that’s true.

Some other data shows that if the progesterone is less than a specific level, the chances are getting less in a frozen cycle and higher from a specific level in the fresh cycle, the chances are reduced, so why not check it.

Do you think it’s important to check the NK cells in the uterus before IVF?

This is again a difficult question, yes, you could do it if we have a recurrent failure of implantation. The thing is that reproductive immunology is a very complicated and difficult thing, not all people know what’s the exact significance of each of those factors. Steroids coverage, for example, which is a very cheap medication together with a combination of intralipid infusions covers about 90% percent of the cases of the immunological factors that can affect the implantation, and it cost much less than the testing, on a protocol that is given correctly. There is another 10% that may need extra treatments like immunoglobulin infusion and things like that.

Yes, it is a test that can be used if we are planning to properly evaluate it and properly give other treatments than intralipids and steroids because those can be given without the testing that costs a lot of money.

Is it necessary to re-biopsy following treatment for chronic endometritis?

We don’t regularly do it unless there is a case of repeated failure. We usually combine it with a test which is called ALICE, which is the same as the ERA test. The biopsy can be taken either at the time of hysteroscopy or as an outpatient procedure. If we do it at the time of hysteroscopy, we don’t repeat the hysteroscopy, but as an outpatient just to make sure that it hasn’t shown the histological signs again, yes, we can do it. The truth is that when we cover for the specific bacteria with triple antibiotic or the specific antibiotic for a specific period, we don’t usually repeat the test, we just give the antibiotics, and we do the embryo transfer. In some cases where we have an unexplained failure, we check it.

About herpes, is it possible to have it with no symptoms? I have low uterine NK cell activity but high activity in my blood. Would this indicate herpes? How do you get tested for herpes?

It doesn’t go like that, it can be associated with many other things as well. Yes, you may have herpes inside without really having symptoms of herpes outsider, so it can happen. It doesn’t mean that it’s related only to that. There are blood tests that you can do to see if you have herpes. If you have any immunity for herpes if you had it in the past, or if you have it now, there are antibodies that you can check. This is for genital herpes, and this is for herpes in the lips. For specific herpes, you can check for those in endometrial culture.

Can endometriosis affect the microvilli of the fallopian tube? I was just wondering about how I’ve had a tubal ectopic with a normal external appearance of the fallopian tubes.

Endometriosis can do many things, it can also affect the tubes either by distorting them with adhesions or anything like that, but it can cause a hostile environment too. The tubes are a patent, and they communicate with the cavity, they communicate with the womb, and if there is endometriosis inside the cavity, this hostile environment can affect the transfer of the sperm, and anything that can play with the tubes can cause and increase the risk of an ectopic pregnancy.

Can endometriosis affect uterine lining thickness?

Endometriosis can cause increased immunological activity, natural killer cells, inflammation inside the womb. It doesn’t usually cause a reduction in uterine thickness unless it is related to some surgery inside the cavity that can cause that as a medical consequence.

What are your thoughts on platelet plasma infusions for chronically thin endometrium?

There is some data for that as well. We use it as well, but in comparison to the CGSF and the PRP, the data and the evidence that I’m familiar with, and we usually prefer it in comparison to the PRP, but yes, it can be used, and there is research that shows that it can help, there is no significant difference in comparison to CGSF though. Those 2 are used as a last resort before we go through surrogacy and things like that, so you can try that.

Does mild adenomyosis affect embryo implantation? If so, how much? And also, is it possible to treat adenomyosis?

It is not possible to operate the adenomyosis. Down-regulation with GnHR can help a bit to suppress the disease. Usually, mild adenomyosis does not affect implantation, but many times it is associated with endometriosis. We have seen that people who have adenomyosis also have comorbidity factors. Endometriosis can affect it.

I had done uterine artery embolization because of a 5 cm fibroid in the isthmic area of the uterus. UAE (Uterine artery embolization) caused a premature ovarian failure. Nothing happened to the fibroid. What examinations and tests would you recommend being done concerning uterus before IVF with donor eggs or own eggs if I manage to grow those?

Embolization can affect your own eggs, can sometimes cause premature ovarian failure, so it’s not the best thing to do for a 5-centimeter fibroid. If it is just a 5 centimeters fibroid that is not affecting the endometrium, I wouldn’t remove it or anything like that. It depends on the location of it, though. The hysteroscopy should be done to make sure that it doesn’t affect the cavity, it is something that can be done, and then you need to make a very good decision if you need to remove it or not. If it doesn’t affect the endometrium and it’s just 5 centimeters in size, I could go ahead with a transfer.

What does it mean if the endometrium shrinks during stimulation from 11mm to 8mm? Does that suggest overstimulation?

It depends sometimes, this happens in patients with polycystic ovaries. If you are talking about having an ovarian stimulation and the endometrium was 11 and then 8, then maybe something has gone wrong with the protocol or doses or premature ovulation, for example, has happened.

There could be many things. A drop in the endometrium sometimes may make us think about freezing the embryos. If you have embryos in the end and do the transfer in a frozen transfer after we create a normal endometrium that is increasing.

Does endometrial hyperplasia affect embryo implantation? What treatment options do you recommend to cure endometrial hyperplasia?

Endometrial hyperplasia, most of the time, is related to obesity, for example, and increases weight. If it is a histological diagnosis, we need to make sure that it is not associated with any activity. It can be a precancerous lesion as well, it depends. If it’s just simple endometrial hyperplasia sometimes, you don’t need to do anything. If it is complex hyperplasia or has abnormal cells, for example, the Mirena coil, increased progesterone doses are things that you can consider.

When it comes to endometrial hyperplasia outside the stimulation to affect the embryo implantation, then no. If you are talking about the endometrium that is getting very thick at the preparation time, you need to make sure that there is no hidden polyp. Hysteroscopy would be good to make sure that it’s nothing like that. The second thing is that if the endometrium gets more than 15-16 millimeters, some research shows that it can reduce the chances. The ideal thickness at the time of the stimulation is between 9 and 14.

I’ve heard that vitamin B6 is useful for the uterine lining. Is that true?

Not to my knowledge that it really can make a significant difference to be taken before the embryo transfer to increase the uterine lining.

Could Ubiquinol 50 mg taken daily for more than 3 months improve the overall health before stimulation?

We do give it to poor responders, especially and women that have problems with quality embryos, we use it. Some data suggests it can help.

Is better to take progesterone suppositories or injections? In the US, they always talk about these ‘PIO’ injections, while in Europe, they seem to prefer suppositories. Are these effective in the same way?

Adrenal progesterone is not getting absorbed in a balanced way sometimes. This can cause issues with the levels of progesterone. That’s why we usually prefer in our clinic to give a higher dose of progesterone. We can make sure that the levels are maintained because they don’t always have to be completely absorbed. On the other hand, it means you need to have injections daily, which is not ideal because you do many injections during IVF.

It has better pharmacokinetics with the progesterone level. You can even do a combination of those two. Sometimes, we do use subcutaneous progesterone combined with vaginal one. They can get from two roots, and we don’t have any issues with just choosing one.

Next month I am going to have FET in a natural cycle. I have regular cycles and regular ovulation, but my endometrium is usually thin (about 7mm). What do you suggest? Is adding estrogen a good idea? How many days and how much?

If there is an issue with the endometrium, the first thing would be to go with an estrogen cycle. Even with a frozen cycle, and hormonal replacement, the estrogen does not go more than 7 millimeters, this is a different case, and we can think about going back to the natural cycle. The first option, in our clinic and to my belief, is a cycle with hormones.

I would like to know if a small polyp (less than 1 cm) could be eliminated with drug treatment?

It’s not guaranteed, you could lose time. Hysteroscopy is a very straightforward day-case, actually, so sometimes, with high progesterone treatment, the polyps can go, but usually, it’s more difficult to go with treatments, and the easiest way to remove it is by doing hysteroscopy.

Is there any dietary change you recommend to help implantation in someone with endometriosis? I would like to do everything I can.

A healthy lifestyle, antioxidants, Vitamin E, C, reducing smoking and alcohol, it’s equally important for people with endometriosis. It has not been proven it can affect the chances of success significantly regarding diet.

When should the endometrium thickness be measured before or after ovulation, and why?

We usually check it at the time of the trigger, at the time of the ovulation. In some cases, there is a point of checking after that to see what is happening if it is changing in pattern and things like that. Usually, we check it on the day of the trigger. On the day of the ovulation to see what’s the thickness size. This is the cut-off limit of more than 7, but ideally more than 9.

Harry Karpouzis, MD

Harry Karpouzis, MD

Dr. Harry Karpouzis is an Obstetrics and Gynecology Consultant, specialized in Reproductive medicine/infertility and minimally invasive surgery, with over 7 years of full-time experience in the field of assisted reproduction. Dr. Karpouzis was fully trained and specialised in the UK. He has worked at some of the busiest hospitals in London (Guy’s & St. Thomas NHS Trust, King’s College Hospital, Newham University Hospital, University College Hospital, Homerton University Hospital. He has been a member of the Royal College of Obstetricians and Gynecologists since 2011 and is a scientific director and founder of IVF Pelargos Fertility Group.
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Caroline Kulczycka

Caroline Kulczycka

Caroline Kulczycka is managing and has been hosting IVFWEBINARS dedicated to patients struggling with infertility since 2020. She's highly motivated and believes that educating patients so that they can make informed decisions is essential in their IVF journey. In the past, she has been working as an International Patient Coordinator, where she was helping and directing patients on their right path. She also worked in the tourism industry, and dealt with international customers on a daily basis, including working abroad. In her free time, you’ll find her travelling, biking, learning new things, or spending time outdoors.
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