Endometriosis in context of IVF: evidence-based management

Diana Obidniak, MD
Fertility Specialist


Endometriosis in the context of IVF: evidence-based management #IVFWEBINARS
From this video you will find out:
  • endometriosis and its clinical manifestations
  • mechanism of infertility development in patients with endometriosis
  • embryo quality in endometriosis
  • the role of implantation: receptivity and selectivity
  • the association between endometriosis and chronic endometritis
  • stages of the restoration of reproductive function in endometriosis


How to manage endometriosis during IVF treatment?

Diana Obidniak, MD, Head of International Cooperation Department at AVA-Peter, is talking about endometriosis in the context of IVF and answers questions on how to manage this condition during IVF treatment.

Endometriosis – definition

Firstly, according to the doctor, the history of endometriosis is described to be ancient since some similar conditions and clinical manifestations have been detected for centuries. By comparison, endometriosis is still considered to be a mysterious disease even in the 21st century because of a general shortage of etiology information regardless of evidence-based investigations.

Endometriosis is a chronic inflammatory disease defined as the presence of endometrial tissue outside the uterus, which causes pelvic pain and infertility.

In addition to that, endometriosis is still regarded as an actual problem as there are verifications that take place every 10 years due to clinical manifestations that delay a diagnosis. What is more, the average of verified endometriosis is 27 years old. According to the World Health Organization, more than 176 million women are believed to be affected by endometriosis.

Theories of etiology

Then, based on the session, a series of theories are analyzed in detail.

  • Implantation theory

“The theory of retrograde menstruation” ( J.A. Sampson, 1921).

By that time, It was believed that having a retrograde flow of menstruation into the abdomen could provoke the formation of heterotopic endometriosis. Also, it was added that endometrial translocation during surgical interventions on the uterus could also cause the base for the formation of heterotopics. However, a great investigation was performed in 2005 by Marsh. E.E. and Leufer M.R. demonstrated that this theory did not apply to endometriosis.

  • Coelomic metaplasia & Disontogenetic theory

Both of these theories involve an explanation of the appearance of endometriosis tissue outside of the reproductive system as other organs can also be affected such as the lungs. On the one hand, the appearance of endometrial tissue can be due to peritoneal and mesothelial metaplasia (Coelomic metaplasia). On the other hand, in dysontogenetic theory, endometriosis was explained as compromised embryogenesis with the development of endometrial tissue from abnormally located rudiments of the muller channel. Neither of these theories responded to the etiology of endometriosis in the reproductive system.

As a result, it was determined by worldwide investigators that investigation of the local disruptions was the focus of endometriosis as it was later revealed that certain hormonal disorders were involved:

  • Aberrant aromatase expression
  • Type 2 17B – Hydroxy Dehydrogenase Deficiency
  • Progesterone resistance

In conclusion, these certain hormonal disruptions provide local hyperestrogenemia which results in enhanced elevated proliferation activity.

  • Epigenetic theory

It is still a compromised theory that explains the formation of endometriosis as a result of epigenetic changes in one cell and affects the process of methylation and regulation of activity using micro RNA. Moreover, It is also said that microRNA shuts down a specific gene.

Clinical manifestations:

  • Chronic pelvic pain syndrome (Progressive worsening over time)
  • Dysmenorrhea (Primary, secondary)
  • Dyspareunia
  • Dyshesia
  • Dyspepsia (Diarrhea/ Constipation)
  • Infertility

Mechanism of infertility and endometriosis

According to the doctor, it is known that many mechanisms and tools affect the fertility system through endometriosis. These are described to be not only simple things as disruptions of the egg transport process due to adhesions that ultimately produce a mechanical obstruction of the fallopian tubes and disruptions of sperm transportation but also to the growth of oxidative stress markers in the follicular fluid that eventually result in compromised endometrial receptivity and its implantation process among others.

All in all, the endometrium is compromised not only in morphological ways but also considering its functionality and so, the implantation process is always in discussion.

Competence of embryo in patients with endometriosis

Unfortunately, a lower survival rate of embryos is perceived in patients with endometriosis along with a lower number of blastocysts at the end of embryo cultivation although there is much evidence that embryo quality is the same as in generation.

Endometrium: a role in implantation

The endometrium is known as a biosensor that receives the signaling and quality of the embryo, providing a result for the whole organism if the embryo is good enough for implantation and pregnancy. These processes are related to receptivity and selectivity and can be altered either morphologically or functionally.

Endometriosis and endometrial receptivity

Regarding receptivity, due to progesterone resistance, pretreatment of different medications such as GnRH proved to be effective in improving ART outcomes. As regards morphological disruptions and alterations are called chronic endometritis, which is strongly associated with endometriosis despite being a separate disease. The difference between both is that chronic endometritis is an inflammation as the result of a micro bacteria, while endometriosis is the inflammation that results from our own epigenetic changes.

Diagnosis guidelines

  • Diagnosis based on symptoms, in the presence of any of them (Dysmenorrhea, acyclic pelvic pain, infertility, fatigue, among others.)
  • Diagnosis in women of reproductive age with clinically manifested symptoms (Dyshesia, dysuria, hematuria, rectal bleeding.)

In addition, speaking of the diagnosis of external genital endometriosis, the gold standard to go is a laparoscopy while a hysteroscopy is said to be the most effective standard regarding internal genital endometriosis (adenomyosis).

Stages of restoration of reproductive function in endometriosis:

  • I Stage surgical treatment
  • II Stage Conservative Therapy
  • III Stage pregnancy achievement
    • natural conception
    • ovulation induction
    • IVF

The main goal of endometriosis management

Above all, according to the doctor, the first goal is the removal of endometroid foci, which is the tissue growing outside the reproductive system as a means of reducing pain. Afterwards, the following steps should be considered:

  • Anti-recitative therapy
  • Fertility recovery

It is believed that the most important thing in surgery and ART for endometriosis is age as performing surgery on a patient below the age of 28 years old enhances the possibility of natural conceiving while assisted reproductive technology would be highly suggested for patients over the age of 28 years old because of better results concerning the number of embryos. Finally, with patients over 43 years old surgery is the standard recommendation although not highly suggested because of the likelihood risk of cancer.

Real-life cases

Case 1 – a 29-year-old woman, with endometriosis at stage IV, she already had surgical treatment of endometrioid cysts of both ovaries, with AMH= 0.31

After the surgery, she did not receive conservative treatment. After she came to the clinic, the patient and her partner were once again screened, and sperm analysis was normal, however, after performing the MAR test, which is used to detect IgG and IgA class anti-sperm antibodies in semen, it was at 80%. Another thing suggested and conducted was the application of Dienogest during 4 cycles and after that, a controlled ovarian stimulation and short protocol with an antagonist was performed through IVF/ICSI. Four oocytes were received, and one embryo was transferred on day 5. Another two embryos were vitrified. The patient got pregnant after her first attempt.

Case 2 – a 41-year-old woman, with endometriosis at stage IV, had a combined surgical treatment of endometrioid cysts of both ovaries and hormonal treatment with GnRH agonist for 6 months without add-back therapy.

The treatment was however stopped due to the severity of side effects. There was no response to controlled stimulation. Her AMH = 0.31, FSH = 22.3. When she came to the clinic (Ava Peter), Dienogestan for 3 cycles was suggested, and then IVF/ICSI treatment in the natural cycles was performed as part of the embryo banking (embryo accumulation) program. Three viable embryos were vitrified, one was transferred and once again the patient got pregnant after her first attempt.

Related reading:

- Questions and Answers

If an egg donor has a cyst, what should the doctor do to prepare her for a donation? Should the donor wait for the next cycle, how should she get rid of it?

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.

Is a fresh transfer good for patients with endometriosis?

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.

What protocol is better for patients with endometriosis?

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.

What do endometriosis and chronic endometritis have in common?

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.

Can we find out (check) for chronic endometritis from blood tests? Or only from tissue tests? What tests are available for chronic endometritis?

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.

How should we cure light chronic endometritis? Without antibiotics?

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.

Is it possible to reduce inflammation caused by endometriosis? Would this improve egg quality? Is there any pre-treatment (before egg retrieval) to improve the egg quality for patients with endometriosis? Is it common that eggs have a hard time to mature evenly for such patients?

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.

What can be done against adenomyosis?

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.

Is immunology important before transfer when you have endometriosis?

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.

Do painful periods lead to endometriosis? I have quite painful, 1st day of my periods, but I have had such painful periods 3-4 times in my life that I had to be assisted by medical stuff with intramuscular painkiller injections. I am 44. What could be the reason for such a painful 1st day of the menstruation? Later on, I had a polyp removed, could this by myoma?

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.

I did a hysteroscopy, and we found that I have endometritis. My doctor gave me antibiotics (Floxaval 500mg for 10 days, Vibramycin 100mg for 3 weeks, and estrogen for 2 weeks). After this treatment, can I proceed immediately with IVF, or do I have to make sure that the infection is gone?

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.

Once stage 1 of endometriosis is removed, how long before it can come back?

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.

I am 35 years old and have endometriosis. I have only achieved a biochemical pregnancy using PGD. The other negative transfers. My last transfer will be in the natural cycle. What do you think? Why don’t I get pregnant, and when I do, I lose it right away?

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.

Does endometriosis cause raised TNF alpha?

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.
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Diana Obidniak, MD

Diana Obidniak, MD

Dr Diana Obidniak, MD is the Head of ART of Birth Clinic in St. Petersburg, Russia. Dr Obidniak is a Fertility Specialist, Affiliated Professor at St. Petersburg State University. She is also a member of the American Society for Reproductive Medicine and the European Society of Human Reproduction and Embryology (ESHRE). She is also a National Representative of Russia at the ESHRE Committee.
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Caroline Kulczycka

Caroline Kulczycka

Caroline Kulczycka is managing MyIVFAnswers.com 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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