Endometriosis in context of IVF: evidence-based management

When we are talking about egg donors, we should find the perfect donor, so we should get the information about what kind of ovarian cysts we observe because some cysts require surgical treatment. Some of them are not the basis for surgery, and we just have to wait for the next cycle. Or sometimes, we can help the donor to recover from the cyst using birth control pills because birth control pills also have a treatment indication and sometimes administration for 1 cycle is a great prevention or cyst formation. If your physician is sure that the cyst is so-called functional and there is no need for surgery, we can consider this egg donor as a perspective. We can just wait for 1 cycle, or we can prescribe birth control pills to help the donor to fix the problem as soon as possible.

Generally speaking, no. In our case report, we demonstrated the good result from the first cycle, but remember that it was the practice that was used 4 years ago. Now, we have strong evidence that there is synchronization in the maturation of endometrium and the development of embryos in patients with endometriosis. We have much better results when we do so-called delayed embryo transfer, so at first, we collect the egg, fertilize them, and cultivate the embryos. When there is a need, we implement pre-implantation genetic testing, and when we know that the embryo is good enough to be transferred, we plan to do the delayed embryo transfer. It provides better results without any doubt. The fresh cycles also can provide pregnancy. When we compare fresh cycles with delayed embryo transfer, we see better results in patients with endometriosis. Nowadays, all my physicians have standardized protocol to recommend to patients with endometriosis delayed, so-called interrupted IVF cycle in most cases.

Actually, we have 19 schemes and so-called protocols for simulations, and so we do not just take the presence of endometriosis into the account, we always consider your personal hormonal levels, your BMI, your age, your medical background, even the size of the follicles by ultrasound and only after that, we can recommend a protocol. There is no perfect protocol for everybody. The thing is that nowadays, we should have an individual approach for each person. For patients with endometriosis, we might be working even more attentive, but to tell you the truth, it’s just the normal practice. We should assess all the details, we should take into account your previous experience, and only after that, we should implement and provide a good decision. If we’re talking about the traditional approach of a patient with endometriosis for many years, there was an understanding that it’s better to use a so-called long protocol, but unfortunately, a long protocol with the GnRH is non -flexible protocol. Sometimes, it will have a good effect on endometriosis, but it will diminish your fertilization rate, so my response is that it’s not for the kind of patients with endometriosis, it’s just the good understanding of IVF practice, we should take into the account all your personal details and only after that, we should choose one among 19 protocols, so we have enough options, we will find the perfect option for you.

The common thing that we are talking about is the pathology of the uterus of the internal surface of endometria. Endometriosis has wider implications, complications for women involving the uterus. Chronic endometritis is a condition, which only involves endometria. A common thing that both conditions have is the inflammatory process in the uterus. Unfortunately, the embryo will never implant in bad conditions, so I always say to my patients, your uterus, your endometrium is an apartment for your following pregnancy. We should be sure that the conditions are good not only for implantation because our aim is not just the initiation of the pregnancy. They said that it will be a long journey for 9 months and if there are bad conditions, unfortunately, you can observe so-called biochemical or molar pregnancy. When we see the elevation of HCG, and then we see how it’s diminished and we call it implantation failure, so it’s an inflammatory process. The golden standard of diagnosis in both cases is hysteroscopy. When we can visualize the pattern, the situation in your uterus, the difference is etiology and the reason for inflammation is different. It inquires different tactics, different therapy. Sometimes, it has an association when we observe both endometriosis and chronic endometritis. We have to distinguish it by hysteroscopy and histological examination. If we have chronic endometritis of severe activity, we have to prescribe antibiotics. Not in all cases – I just want to pay your attention only in cases of severe activity of chronic endometritis. If we have endometriosis, we have to prescribe medication or therapy for endometriosis. It is considered to be pathogenic.

We can’t find chronic endometritis using blood tests. Unfortunately, all these alterations over endometria. If we’re talking about morphological alterations or functional alterations cannot be detected by blood tests. We have to do a biopsy and prove it by histological examination or immunohistochemical investigation. Or by so-called ERA test where we want to catch functional alterations. So, no we don’t have the option to check it via blood tests, all the procedures are invasive.

We should assess how your lab approves superficial chronic endometritis. There are strict criteria when we are trying to assess if chronic endometritis is superficial, or if it is a severe disease. There are four stages, the first stages even don’t inquire about specific therapy, but if we talk about strong activity, we have to prescribe antibiotics. If we’re talking about long-lasting chronic endometritis, we don’t expect severe activity. If we observe severe fibroid implications, we see connections, adhesions and we see that endometrium is not functional. That’s why we have to prescribe so-called recovery therapy, we implement PRP, platelet-rich plasma to enhance the resources of the endometrium, so we help to recover the endometrium to enhance its functional abilities. If we talk about just very superficial chronic endometritis, we even don’t have to treat it.

Not only it’s possible to reduce inflammation, but we have to reduce it before, we have to implement pre-treatment. The evidence-based pre-treatment, we implement Dienogest or so-called Decapeptyl, so as we have mentioned in both case reports, we have to do pre-treatment from 3 to 6 months of pre-treatment depending on the stage of the endometriosis. If it’s severe, sometimes we even have to make pre-treatment for 6months, but usually, as we have to shorten the time to pregnancy, we don’t wait, we are very accurate with the occurrence of this pre-treatment. Usually, such pre-treatment takes 3 or 4 months, in that first line of pre-treatment we give is Dienogest, it’s a tablet, it’s very comfortable for patients, it has just little side effects, not in all the cases. This results in an enhancement in our outcomes, but not really in egg quality because to tell you the truth, we don’t have an evidence-based tool for improvement of egg quality. We lower this oxidative stress, so we expect that endometriosis will not have this bad installation during this period of pre-treatment, so that’s why we usually observe more embryos and as a result, more chances of the pregnancy. In regards to maturation, there is no proof that endometriosis causes disrupted maturation, but there is a tricky moment that sometimes when a physician recommends some kind of protocol for ovarian stimulation, there is a bigger risk to have a slow maturation, usually, we assess this risk beforehand, that’s why we provide as a trigger, so-called double- trigger, it’s like our insurance that we will have proper maturation. It’s not about the endometriosis, it’s about shaping your ovarian stimulation protocol, but for sure, we should take this risk into the account beforehand and individualize ovarian stimulation.

The thing is that our approach is individualized, but we have to go through the standardized approved stages. Adenomyosis is the endometriosis of your uterus. What does this mean? The uterus becomes a little bit bigger, it’s not that strong, it’s the result of the progression of endometriosis, you should understand that endometriosis, unfortunately, progresses for a long time. From the very beginning during each time of your menstruation, endometriosis has an elevated activity during your menstruation. That’s why the therapy for endometriosis requires pausing your menstruation, so we stop your menstruation for 3 months. We have observed that it is benign in fact on your uterus, but we also have to assess the quality of the condition of your uterus from inside, so adenomyosis is a general word for endometriosis on the uterus, so we have to prepare it in the muscle layer concerning your endometrium. That’s why the best tactics are to do hysteroscopy to assess the stage of adenomyosis, how severe it is. After that, if there are some problems inside the uterus like, for example, micro polyps, we remove them. After that, we recommend therapy of endometriosis like this Dienogest or another type of medication, we also understand that there is a risk of chronic endometritis. So if there are signs of chronic endometritis approved by morphological examination, we also implement some kinds of therapy for that like antibiotics or enzymes or PRP therapy.

We suppose that there is some immunological defect when we talk about endometriosis but when we’re talking about defects of the human system, you should understand that in most cases, we have no ability to fix it because it’s the feature of our organism. Some cases with immunological problems involve not only the uterus but also, for example, thyroid because there is an association like a triangle, we call it, uterine, thyroid, and ovaries, we have to fix some problems like this function of thyroid though we have endometriosis but if we talk about immunological defects in the uterus as we observe antibodies in the endometrium as a sign of immunological defects. Unfortunately, there is no strong evidence of the implementation of some tools. In severe cases, we recommend intravenous immunoglobulin, but it’s still experimental, it’s still under discussion, there is no great meta-analysis. We always communicate with the patient and describe why we want to recommend this tool because we understand that it’s safe, and it can provoke complications, but it can help us. Unfortunately, we still have to investigate this, we have to assess if it works on big populations.

Painful periods are not a specific sign, but it’s very characteristic of endometriosis for sure. Sometimes, it can be a result of myoma, of the special place of myoma, or some disruptions with your intestine. Because the intestine functions during your period maybe you have seen that there is a kind of some gas in the intestine during your period. So it also can result in a rather strong pain during your period. To tell you the truth in many cases, a painful period is a sign of endometriosis, but it’s not the basis for verification of endometriosis. When we suppose that it can be endometriosis, we start to diagnose it, we seek the approval that it is endometriosis proactively.

When we talk about the investigation, studies, trials when we perform scientific work, we always make a second sample to investigate if our therapy was sufficient to treat these conditions. According to worldwide practice for sure, we don’t want to provide additional interventions. When we are wondering if the infection has gone, we have to do another sample of biopsy of the endometrium. Sometimes, we face patients, especially when we talk about recurrent implantation failure, we see that these patients have already several hysteroscopies, several biopsies, and their medical background that’s why we don’t want to make an additional intervention. We can do it just after this treatment, and to tell you the truth, this treatment is rather good, without any doubt. I think your physician has experience in treating chronic endometritis, so I would recommend doing embryo transfer just after this treatment. Do not wait to do the biopsy and then wait to recover, then waste the menstrual cycle because we cannot do the biopsy to prove that the infection has gone to do embryo transfer within 1 month. We have to pass this menstrual cycle and wait for another, so I think that there is a great chance that therapy was sufficient to treat endometritis if the stage was not very severe.

It depends on the severity of the process because sometimes it takes several years to keep the same stage of endometriosis. You should understand that sometimes there are forms of endometriosis where we see the patient, and it can be quite different within two months after, so it’s a very personal situation. The thing is that endometriosis cannot come back, unfortunately, it’s not gone anyway. We can just minimize its activity for a certain time. We cannot remove it because we do surgical removal only of the tissue, only of pathological samples of tissue that we can observe during the surgical treatment. Unfortunately, it takes a long time, sometimes a month, sometimes some years from the formation of endometriosis, it can come back very soon. In most cases, especially if we implement therapy, it will reabsorb more benign form of endometriosis, unfortunately, it will minimize only when your menstrual period is gone, so only at the stage of menopause.

As I understand you had several transfers, you are 35 years old, and I have no information if your couple has a male factor also because when we talk about recurrent implantation failure and unfortunately, it’s your case, we shouldn’t focus only on endometriosis, we should focus on all these details, we should consider if the embryo is good, so for sure I would recommend doing pre-implantation genetic testing of the embryos, without a doubt. Another thing, I would do hysteroscopy to assess if the condition of the uterus is good. A very good thing that you already had biochemical pregnancy, biochemical pregnancy is like the first meeting and the first interaction between embryo and endometrium. If you already had a positive HCG level, it’s very likely to get pregnant, we just have to find the small features, small problems, which certainly can be fixed, but we should do our best to find it. Also, you should understand that there is some concomitant pathology that can diminish your chances to get pregnant. The first line is the thyroid, but also we assess our blood condition and so on. I would recommend assessing the embryos, the condition of the endometrium and to assess if you have some risky points like concomitant pathology, but I want to inspire you that as you already have biochemical pregnancy for sure, you’re able to get pregnant and to carry the pregnancy, so just wait for a Little, natural cycle it’s a very good thing. I love natural cycles, it’s not the kind that they are better than hormonal replacement therapy because talking about big data and great trials and large meta-analyses, the outcomes, and pregnancy rates it’s just quite the same. Natural cycles allow us to diminish our hormonal stress, we don’t have to prescribe a lot of medication. That’s why I love natural cycles, but unfortunately, we should assess if it’s applicable personally for you because in some cases, the natural cycle is not a good thing, so it depends if it’s applicable for you. Such cycles, allow us to diminish our intervention, but sometimes it’s better to prescribe medication. In terms of endometriosis, we are not talking about the total natural cycle because we have to support the pregnancy properly so we have to add medications of progesterone, but the natural cycle as an idea is a good sign. I would recommend spending some time on diagnosis, you should understand the reason for negative transfers, and only after fixing this problem or enhancing the conditions, move on with the embryo transfer maybe with a natural cycle.

There are some data that TNF-alpha is elevated in the peritoneal fluid, so it’s still under investigation. If we can use it, it is a kind of minimally invasive lab test but talking about practical implementation, we don’t have an established reference range. We cannot use it, and we don’t have any practical guidelines for that. In general, yes there is an association that in the case of severe endometriosis, we observed elevated TNF-alpha.