Dr Elias Tsakos MD FRCOG, Medical Director of Embryoclinic, discussed the latest treatments and strategies for managing endometriosis and overcoming subfertility.
Reproductive surgery and endometriosis represent the most common indications for reproductive surgery. Endometriosis is not endometrial tissue but endometrial-like tissue that, instead of being where it should be, is located in various other positions. This causes inflammation and fibrosis. It’s a strange disease that can affect many women, presenting in different ways. It could present with endometrioma or other subtypes of endometriosis. About 20 to 45% of endometriosis cases involve endometriomas and cysts on the ovary. These can be multiple or single, causing inflammation and distortion of the anatomy.
The prevalence of endometriosis is elusive; some estimate millions of women worldwide are affected. It affects about 10% of women in the general population, with around 50 women per 100,000 being diagnosed each year. It is more common during reproductive age, particularly in the 30 to 40 age group. However, it can present much earlier, even in teenage or prepubertal years, and it can appear after menopause.
Endometriosis is a chronic disease and a disability, with over 2 million life years lost annually due to disability and even death caused by the disease. It’s a very serious chronic condition.
The symptoms of endometriosis can vary widely—tiredness, lack of energy, pain, dysmenorrhea, painful periods, pelvic pain, lumbar pain, abdominal bloating, painful intercourse, painful urination, or no symptoms at all. Some women with advanced endometriosis may have no symptoms and may be diagnosed accidentally during a laparoscopy, ultrasound, or infertility investigation. It can disguise itself in many ways and can be misdiagnosed for many years, taking up to 7 or 8 years on average for a correct diagnosis.
Women with infertility have a 30 to 50% chance of being affected by endometriosis, which is a significant burden. The incidence of endometriosis in infertile women is 5 times higher than in the normal population. There are various mechanisms by which endometriosis may affect fertility. Those include:
In the past, some people thought that having endometriosis wouldn’t matter much for IVF, assuming it only affected the tubes or caused a cyst or two of deep endometriosis. However, it does matter. It is proven that implantation rates can be 16% lower in the endometriosis group, and the number of oocytes retrieved can be 50% lower. As per Dr Tsakos, at Embryoclinic the team recently retrieved oocytes from a young patient, aged 31, with endometriosis. She had only 1 viable embryo—just 1 normal blastocyst at the age of 31. Therefore, it’s crucial to remember that endometriosis lowers the number of oocytes. Interestingly, the multiple pregnancy rate is 21% higher in the endometriosis group, mainly due to the team’s stress on improving outcomes by implanting 2 embryos, which is not always good practice. The ectopic pregnancy rate is 16% higher, which may be associated with adhesions and inflammation in the tubal area.
What are the pregnancy outcomes? Placenta previa is 3 times higher in the endometriosis group. Even if a pregnancy is achieved despite the challenges and lower chances of success, these pregnancies are high-risk, complicated pregnancies. Postpartum haemorrhage is 25% higher, which is a serious complication, as are placenta previa and haemorrhage.
What are the outcomes of IVF and ICSI? There are fewer oocytes if you have endometrioma, fewer in total, and fewer normal mature oocytes. However, the overall number of embryos and high-quality embryos shows no difference.
How do we treat women with endometriosis? Firstly, preservation of fertility. When endometriosis is diagnosed, whether this young woman—any reproductively young woman under the age of 50—is concerned, I would always include fertility in the counselling and consultation. If there is a wish to preserve fertility or to increase the number of family members, that’s always part of the equation in managing those patients. The factors determining the plan include the age of the patient, the condition, additional factors, the severity, and extent of the disease, and the severity of symptoms, particularly pain.
The treatment options include medical and surgical treatments, fertility options, and some emerging treatments. Medical treatments are more or less familiar: suppression of the ovaries, GnRH analogues, contraceptives, anti-inflammatories, and various other pills, which overall are not recommended for fertility management patients.
Fertility treatment options are crucial. PRF testing and fertility counselling are very important to assess fertility before embarking on any discussion of fertility options. Egg donation may always be an option, and even surrogacy may be valid for some complex and challenging cases.
What about surgical treatments? Surgery is important because many times, patients’ pain needs to be alleviated. Many times, patients have tried a lot of previous options, and of course, it’s necessary to improve pain, diagnose the disease correctly through histology, and improve access to the ovaries.
In the last 30 to 40 years, minimally invasive options like laparoscopy have become established, and more recently, robotic surgery has improved the ability to better manage more challenging and complex cases of endometriosis. While robotic surgery isn’t new—it’s been around for about 25 years—it has significantly expanded over the last 10 years, especially in the Western world and Europe. It is becoming the most popular and technologically advanced option for endometriosis patients.
There are other emerging treatment options, which are very promising, however they are still experimental. These include:
Endometriosis is a complex condition that not only impacts fertility but also affects overall quality of life. Understanding the multifaceted nature is crucial for improving outcomes and supporting women through their fertility journey.
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The simple answer is that they work by regulating the cycle, either by diminishing the cycle or suppressing the areas of endometriosis. In my opinion, there is a limited place for medical management because, for several reasons, it is an adjunct treatment. For example, if we do surgery and for some reason we’re not able to excise all the lesions, or we don’t see all the lesions, we may think we’ve removed them all. That’s why endometriosis is a very complex condition and disease.
It’s not being managed properly, in my opinion. Overall, it is considered a benign condition. It’s not oncology, so it doesn’t have priority in funding or government planning. As a result, many patients with endometriosis are not managed properly by surgery, leading to either residual disease or an incorrect diagnosis, meaning that certain areas haven’t been addressed. For example, we might perform endometriosis surgery for ovarian cysts but miss deep endometriosis that may also be present. So, these patients might still be in pain three to four months after surgery.
Yes, there is a place for medical management in these patients. It’s a limited place, perhaps only in terms of time, because we can’t keep them on medication forever. However, it can be useful until we decide on the next steps. Are we going to focus on fertility preservation if they desire fertility, or move towards more radical surgery in a specialized centre? Sometimes I consult world-class specialists and invite them to operate with me on difficult cases.
I think it’s important to address that, locally, as a surgeon, endometriosis surgery is more challenging than cancer surgery. The impact of endometriosis on tissues is worse than that of cancer, in my personal opinion, after 30 years of dealing with both endometriosis and cancer cases.
There is a place for medical management, but it’s an adjunct place—it’s not the main approach. Perhaps it’s useful until the next surgery, until IVF, or until fertility preservation. It might also have a longer-term role in older patients who don’t desire pregnancy. For example, I currently have several cases of women in their late 40s who are menstruating and have endometriosis. After counselling, they opted against treating their deep endometriosis or having bowel resection surgery, which is major surgery. These patients allowed us to remove as much as possible without undergoing more extensive procedures, and we are managing their remaining deep endometriosis conservatively, hoping it will improve as they age.
It’s not easy, and it doesn’t happen automatically once they reach 50. I have a 52-and-a-half-year-old patient who is still in pain if we stop GnRH analogues. The bottom line is that there is a place for medical management, but as a team, we need to discuss this with you. We have to understand your wishes, beliefs, and boundaries, and then tailor our treatments to your individual needs.
Firstly, thank you for sharing your case, and congratulations on being so brave after so many attempts; you’re still in the game. This is all inspiring, and congratulations. If I did IVF with your eggs, I would do pre-genetic testing. After so many transfers, you must ensure that you have genetically normal embryos, which we call euploid. That’s one factor. Factor number two is to ensure that I have no problems with Ryeqo, although I don’t have huge experience with it. I don’t think anyone in the world has, as it’s a new drug, so I would have no problems using it for a few months.
First, ensure good quality embryos that are genetically tested. Number two, ensure that the pelvic anatomy, the pelvic condition, is reasonable. A proper ultrasound scan, 3D/4D ultrasound scan, hysteroscopy, and maybe a tubal test are necessary to exclude hydrosalpinges and endometritis. I would like to make sure that the uterus is all well and the surrounding area is too. If that’s the case, definitely consider the microbiome. I’m not sure about the immune system check. Most people would probably dispute this a little bit. I wouldn’t disregard it 100%, but I would probably leave it to the end.
Endometrioma needs to be considered. If I have ensured that the endometrium is reasonably good, excluded hydrosalpinges, and have good quality euploid embryos, I would keep going. Maybe before the implantation, I would disconnect a collection from implantation because I would probably like to suppress you with GnRH analogues for a few weeks, if not a few months, before the embryo transfer to reduce the inflammation before the embryo transfer. That’s what I would do in the next phase.
There are a lot of reasons. I’m not going to go into detail, but one main reason is that endometriosis itself is locally damaging via many mechanisms. The most obvious mechanism is that the inflammation damages the primordial follicles, damages the ovarian reserve, eats away and destroys the normal ovarian tissue, and the normal ovarian function, which is the production of oocytes.
Secondly, surgery may also harm. Unless you are very meticulous with your surgery and respectful with the oocytes, you need to be very cautious with the ovaries. We shouldn’t be cauterizing the ovaries abundantly when we do surgery. All these factors affect not only the number but also the quality of the eggs. These are the clear mechanisms, and that’s why the overall number of oocytes retrieved is very small.
It’s also very clear that when you see the histology, many times you see the histology of an endometrioma, and together with the endometrioma, you see a few follicles, a few healthy ovarian tissue follicles that have been removed as well. Think of a flower that’s eaten away by bugs—sometimes, in trying to kill the bug, you destroy the flower as well. Ovaries can be very robust, but they are also very sensitive. The number, quality, and quantity of the eggs are diminished with endometriosis plus/minus surgery.
If there is endometrioma, there are clear guidelines, but they are not always followed. For the first surgery and first diagnosis, to be honest, I don’t sit around with endometriomas for a very long time. If I’m fairly convinced by the ultrasound evidence, which can be as accurate as perhaps 85–90%, and if I’m convinced it’s endometrioma, and it’s growing—3, 4, 5 centimetres—I don’t hesitate to do surgery. Not only to evaluate the rest of the pelvis, but also to remove the endometrioma before it causes too much damage to the ovary. Also, to make a diagnosis, because although rare, endometriosis-type ovarian cancer is something that all of us have seen in young women. In our attempt to be conservative, sometimes we risk their lives, and I don’t want to be faced with this again.
I can’t say much about the quality—The answer is I don’t know the clear answer. PRP is not for everyone; it’s not a panacea, as we say in Greek. It’s not a solution for everything. It sounds perfect, the theory behind it is fantastic, but the evidence is not 100% there yet. There is more evidence of endometrial PRP improving implantation than there is of ovarian PRP. I think we ought to acknowledge that. On the other hand, the technology is there, we can do it. It’s not difficult, challenging, or risky. We have to counsel our patients very carefully about the expectations they should have.
For example, yesterday I had a patient from Serbia with endometriosis affecting her tubes. She had a couple of surgeries in the past, nearly lost one ovary, had a streak ovary on one side, and perhaps 30% of ovarian tissue on the other side with massive adhesions. It took us about two hours to access her ovaries. I regretted not doing it robotically due to cost-saving reasons and did it with conventional laparoscopy. In her case, once we cleared the endometriosis, removed the tubes, and removed the adhesions, I did PRP on the ovaries as well. She’s only 35, so I thought it wouldn’t harm her. I will monitor the outcome, hoping it will make a small difference. Whether it’s the quantity or quality, we don’t have crystal clear scientific evidence yet.
It depends. The answer depends on the severity of the disease and the extent of the surgery. I would hope it’s a minimal access surgery, keyhole, either conventional or robotic. It also depends on how you feel. If everything is normal and the recovery is good, I’m very happy to proceed within six to eight weeks. It also depends on whether there’s residual disease or inflammation. I would like to downregulate. A reasonable plan would be to downregulate, which I like, not just for endometriosis but for adenomyosis as well, which very commonly is present. Sometimes we see it, sometimes we don’t, but even if we don’t see it, we have to presume it’s likely there, even if mild. I would downregulate for six to eight weeks and then go for the transfer.
I wouldn’t worry too much about the ovarian reserve or the effect of suppression on it. Suppression is like makeup on your face—it’s there as long as you freshen it up. If you wipe it off, it’s gone. I wouldn’t worry too much about that. If you’re thinking of IVF soon, you can have suppression for a bit of time. If you’re not thinking of IVF soon, I would probably go for egg preservation or oocyte preservation sooner rather than later because the effect of age on the genetic dynamics, on the quality of the eggs, is there whether they’re suppressed or not. If you’re not considering IVF soon, I would proceed with stimulation and oocyte preservation, and then go back on suppression.
You’re very well-read. As far as I know, I have no experience with nanoparticles. My understanding is that it’s only being used in the context of research at the moment. I don’t think there are clinical indications to use it on our day-to-day patients at present. Let’s watch this space and hope that they will give us some evidence to utilize clinically.
Failed implantation can be due to embryo factors or endometrium factors. My advice would be the same as I gave to the previous attendee. If you have more IVF, make sure you have PGT-A. After 2, 3, and 4 implantation failures, I think PGT-A is indicated regardless of age. For two reasons: one, diagnostically, it gives us information about the embryos we’re transferring, so we’re not in the dark; and two, it has been proven in recent research that if we test genetically, the age of the woman doesn’t play much importance in the success rate. We eliminate the age factor by using euploid embryos. That’s what I would suggest.
At 41, you can presumably have had your surgery. I don’t particularly like long-term GnRH analogues before surgery, especially before fibroid surgery, but that’s a personal preference. You can solve the mystery by having a scan and a hormonal blood test to understand what’s happening with the hormones and why they are being blocked. There’s a possibility that your AMH was very low even before surgery and downregulation, and maybe for some reason, it takes a little longer to recover. But AMH, FSH, LH, estradiol, progesterone, thyroid, and prolactin testing should be enough to help you understand what’s happening.
I’m sorry to hear that. I think egg donation IVF is the way forward; you’re on the right path. That takes away the embryo quality issue. I would suggest using a very young donor in their 20s to ensure top-quality blastocysts and embryos. Then, I would concentrate on the uterus—hysteroscopy, microbiome testing, high-resolution ultrasound for adenomyosis, myomas, and endometriosis, and perhaps downregulation for six to eight weeks before embryo transfer. And don’t forget the tubes. Don’t forget to exclude hydrosalpinges because I see them very often. An amazing patient I had yesterday had multiple embryo transfers with abnormal tubes, and there’s no hope there. Think of the tubes as a source of infection, like implanting a beautiful new tooth next to a rotten one—it’s not going to take. Make sure your uterus is normal—high-resolution ultrasound, hysteroscopy, and hysterography should ensure normality. Then, follow very tight protocols and monitoring of the embryo transfer process, perhaps with longer use of estrogens, monitoring estrogen and progesterone levels, and of course, getting the best person to do the transfer.
