By fertility experts from Spain.
Endometriosis is a painful and distressing condition that may affect up to 10% of the female population. It has a significant, adverse effect on fertility – if left untreated, it may lower your chances of conception to around 2-10% each month. Exactly how endometriosis affects fertility depends on the stage and severity of the condition.
IVF treatment is usually the first-choice option for those affected by endometriosis. If you have been diagnosed or suspect that you might have it, it is of utmost importance that you find a specialist that understands this condition well. Dr Harry Karpouzis from IVF Pelargos joined our IVF Webinars series recently to talk to us about endometriosis and how IVF treatments may help.
Endometriosis is the condition in which endometrial tissue is present outside the uterus. It is a difficult condition to manage and it often negatively impacts on the quality of life of those affected. It is present in around 7 to 10% of women of reproductive age.
The exact causes of endometriosis are not entirely clear. There are a variety of suggested explanations – from genetic causes, through immunological reasons, to endocrinology. The most common theory has to do with retrograde menstruation – an inflammatory process in the pelvis caused by endometrial cells being sent “the wrong way” during menstruation.
Endometriosis usually presents itself with these symptoms:
The precise impact of endometriosis on fertility varies from patient to patient; it can cause mechanical changes such as altered tub ovarian relationships due to scarring or adhesions. Immunological responses, peritoneal fluid and hormone levels can also be disrupted by the condition.
The American Reproductive Society introduced a grading system which allows specialists to estimate the severity of the condition. In this system, four stages of the condition are distinguished; classification depends on the amount, size, location, depth, and adhesions. A laparoscopy is required to measure all of these parameters.
Laparoscopies are sometimes called “minimally invasive surgeries” – they involve creating very small incisions, no larger than 15 millimetres, in order to insert a small surgical camera. In cases of endometriosis, a laparoscopy is not just a diagnostic technique. In mild to moderate cases, the surgeons can treat the condition at the time of diagnosis, without the need for a separate surgery. Unfortunately, this does not extend to more serious cases of endometriosis which require more advanced surgical techniques.
Dr Karpouzis described some real-life cases of endometriosis he has helped to treat. The first case involved a 34 year old woman who had been suffering from secondary infertility for two years. After giving birth to her first child, she started trying for a second pregnancy with her husband to no effect. Six months of attempts gave no results. Although her cycle was normal, she started noticing a mild degree of dysmenorrhea – painful menstrual cramps. Her husband’s sperm analysis came back normal, as did her own HSG and hormonal tests. Her ovarian reserve was also good, with an AMH of over 2.2 ng/ml. So, what was wrong?
In order to solve this puzzle, we need to go back seven years – to the patient’s first attempt at pregnancy. A year of unsuccessful attempts led the patient to seek medical advice. While all the usual tests came back normal, a small complaint of painful menstruation led her doctors to recommend a laparoscopy, which revealed a mild degree of endometriosis, which was cauterised. The patient then tried again unsuccessfully. She ended up trying without a result for three years before she and her husband decided to try using intrauterine insemination (IUI). It took three attempts, but eventually she got pregnant and delivered a healthy child.
Back to the present day she repeated many of the same steps from the previous pregnancy. Her HSG and ultrasound scans came back normal. Three IUIs with an additional course of Letrozole failed, as did two further attempts using gonadotrophins. IVF was advised to her as a possible further course of action.
Following a long protocol, twelve eggs were retrieved, of which ten were fertilised. Five blastocysts were generated, with two of them being transferred. This resulted in the patient achieving pregnancy with twins – which she delivered through a caesarean section at 38 weeks.
The conclusion from this case is that the patient should have undergone another laparoscopy during her second attempt – because she didn’t, she tried unsuccessfully for a full year before achieving success. A laparoscopy would have saved her that year, as it permits both the correct diagnosis and treatment at the same time. Their decision to pursue IUI and other fertility treatments without checking for and dealing with endometriosis first cost the patients a lot of time and effort.
Another factor was attempting IUI instead of going for IVF – although IUI worked previously, the patient was considerably older by this point, with a known history of endometriosis. IVF was the best option for the patient, as it circumvents the toxic pelvic environment, especially following a laparoscopy.
Research shows that properly treated cases of endometriosis increase the spontaneous pregnancy rates in those afflicted by the condition. Even NICE and ESHRE guidelines recommend performing laparoscopies in order to increase pregnancy rates.
The second case recalled concerned a 35 year old woman with severe rectovaginal endometriosis – between stage 3 and four. Additional complications were present in the form of a frozen pelvis and mild ovarian disease. She underwent a laparoscopy for pain five years prior; adhesions were separated, ovaries mobilised, one tube removed.
She then decided to start tryfor a pregnancy. She underwent four IVF treatments – all of which failed. Deeper investigation into the patient’s health revealed a relatively good ovarian reserve, normal levels of hormones, and the sperm used in her treatment did not present any outstanding issues. An ultrasound, however, revealed two endometriomas – one on each ovary. This was probably the reason for every failure. Dr Karpouzis theorizes that none of the doctors previously wanted to operate on a patient who previously had rectovaginal endometriosis, and whose endometriomas were relatively small in size. Was that the correct decision, however?
The specialists at the Pelargos clinic decided to recommend an operation to the patient. A laparoscopy and cystectomy then took place, during which endometriosis deposits were cauterised. Once the patient recovered, another IVF cycle was scheduled, which resulted in two blastocysts of good quality being generated. Both were transferred at the same time, resulting in a pregnancy.
Research shows that endometriomas have a large impact on IVF success rates. Between 17 and 44% of all endometriosis case result in endometriomas – as such, advisory bodies such as ESHRE have laid down protocols for treating them with surgery.
Surgery, however, carries with it some consequences. Depending on the severity of the condition, the patient may be left with a lowered AMH or diminished antral follicle count. They may also experience less of a reaction to controlled ovarian hyper-stimulation treatments – limiting the amount of eggs they can produce during a stimulation cycle. It doesn’t, however, affect fertilization, implantation or pregnancy chances. The presence of endometriomas, however, does have a negative impact on oocyte quality, and obviously it’s better to have some viable eggs rather than a whole lot of low quality ones. Because endometriosis is an inflammatory condition, it deregulates the immune system; the levels of immune cells, macrophages, NK and T cells et cetera are wildly imbalanced.
Once our patient’s endometriomas were removed, her egg quality suddenly improved. This demonstrates that surgery does have a point even on small endometriomas, if the embryo quality is severely impaired despite the patient having normal AMH and antral follicle count.
The last case presented concerned a single woman, aged 39, who sought IVF treatment with donor sperm. She had a history of endometriosis; four years prior, a laparoscopy confirmed a stage 3 condition. A cystectomy removed her endometrioma and cauterised her peritoneal endometriosis. Her initial tests revealed a low AMH (0.4 ng/ml), normal levels of hormones – everything was within expectations until the ultrasound, which showed that the endometrioma came back. It came as a surprise to the patient because her condition was completely asymptomatic – no pain or any other symptoms.
She attempted and failed an IVF cycle and was advised to undergo a laparoscopy to remove the endometrioma before trying an egg donation cycle. She decided to visit the Pelargos clinic for advice.
The doctors at Pelargos recommended against removing the endometrioma; instead, they recommended a different protocol for own egg IVF. Although immunological testing was recommended to the patient, she did not proceed with that, citing cost reasons. A hysteroscopy revealed no polyps and a healthy endometrium – an endometrial scratch was also performed for good measure. Before the IVF cycle, she underwent eight weeks of pre-treatment using COCP.
Then, the real cycle came. A higher dose of hormones (450 units versus 300 units used in the previous attempt) combined with a slightly different timing resulted in 5 eggs being retrieved. Four embryos were created, which resulted in three embryos of top quality on day three. Out of those three, only two were transferred after reaching the blastocyst stage. The patient was also put on a course of intralipids, aspirin, and steroids in an attempt to balance out any immunological overreactions. The treatment was a success – a twin pregnancy was established, which ended in a caesarean.
Removing endometriomas located on the ovaries can result in ovarian tissue being removed therefore the patient should be fully informed before they decide whether or not to agree to the operation. The patient’s previous attempt indicated that the problem was with the number of eggs, not with their quality. In addition, her endometrium was healthy. Research shows that repeated surgery for endometriomas on patients with already diminished ovarian reserves can further compromise AMH and AFC – as such, the best decision was to leave the endometrioma as it was especially as the patient was asymptomatic and didn’t feel pain.
Dr Karpouzis concluded his presentation with a number of recommendations:
in order to fully treat endometriosis, a deep understanding is required; as such, the patient requires care from experts who understand the condition. Mistreatment or wrong decisions can cause further harm. Every case is different, which is why treatment of endometriosis requires doctors to think outside the box instead of falling into established patterns.
This is a pelvis in which all the organs are stuck to each other and nothing is moving – sometimes we do a laparoscopy and we see that the bowels are stuck to the womb, the womb is stuck to the ovaries, and the ovaries are stuck to the tubes. It is not very common, but can sometimes happen in stage 3 or stage 4 disease, and it can be a very difficult surgery to separate all these adhesions.
The truth is that a lot of doctors say they are endometriosis specialists but they are not – it depends on the country. For example, in the UK, there are specific doctors who are allowed to treat severe endometriosis – mild endometriosis is not a problem, but stage 3 or stage 4 disease have to be treated by doctors that have vast experience in cases like that. Endometriosis surgery is very difficult and a steep learning curve, and stage 3 or 4 disease, like rectovaginal endometriosis, for example, is not very easy to find, so there are a few centres that have access to all those cases, therefore there are not many doctors are endometriosis specialists. About the number, I’m not sure if that’s the exact number or not, but the truth is, not all the doctors who say they are, are endometriosis specialists. Also, it would be good for an endometriosis surgeon to have some fertility experience as well, or work in a team with a fertility specialist, because you treat endometriosis differently in terms of pain, but also differently in terms of fertility. Sometimes the most important thing in treating fertility in endometriosis is the answer to the question “do we need to operate or not?”
Well, yes, but this is another question where we need some more details about this specific case – what is the AMH? What is the age of the woman? Was she operated on before? I cannot give a clear answer, and as I said, we need to treat every case differently. If we cannot do an egg collection because the ovaries are so displaced or we have a high risk of injuring the bowel, then maybe the only option would be to mobilise the ovaries. The decision of whether or not to remove the endometriomas from the ovaries depends on many things: the AMH, whether or not it was operated on before and other factors.
Yes, egg quality which is to do with age is mostly irreversible, so if we talk about a patient who is 43 or 44 years old, even if you remove the endometriomas, then this will not change the egg quality. Sometimes, but not always, we find that if we remove an endometrioma in a young patient who does not have any other reasons causing poor egg quality, and we treat the endometriosis, then it can improve the quality of the eggs, because the environment becomes less toxic. In cases like that, when we can see quality problems in young patients and when using normal sperm, it may be a solution.
When we talk about stage 3 or stage 4 disease, sometimes this can affect the lining of the womb as well. First of all, a hysteroscopy is very important to find out if the lining of the womb is okay, or if there are any endometrial problems. Also, the fact that there is a generally unhealthy environment in the pelvis can compromise the chances of success of egg donation and generally, we have less chance of success for pregnancy with donor eggs in a patient with endometriosis than without. For example, if there is a hydrosalpinx, then this has to be removed before the donor IVF, but if it is an open tube without hydrosalpinx but there is an element of severe disease in the pelvis, then sometimes the best solution would be not to operate, but to down-regulate and give the patient some pre-treatment for a couple of months before the embryo transfer. Generally, as much as we down-regulate the very unhealthy environment, or as much as we operate on this environment, then this can help with chances of success off egg donation. If we’re talking about stage 1 or 2, then it actually shouldn’t play a big role.
What happens sometimes, is that immediately after the surgery, we usually have a drop [inaudible] six months, and we may have an increase and it can reach the same levels as before the surgery. Also, it depends on the surgery. Like I said, the technique, the doctor and the way that we remove an endometrioma is very important – if it is done correctly, with proper hemostasis and not a lot of bleeding, then the AMH can come back to the same levels as before. Higher levels? Not sure, but AMH is difficult to test in laboratories as well, and so a result showing a small increase can be insignificant. Here I was talking about surgery of endometriomas (chocolate cysts), but if we’re talking about the disease in the pelvis, without endometriomas, then possibly, if we treat it, then AMH levels can get higher.
It is not possible to diagnose endometriosis without a laparoscopy, I’m afraid. Ca 125 is a marker, and it can be increased by many things. Even having your period can increase the levels of Ca 125. Also, if it is very highly increased, then we need to check what sort of cyst it is, as the ultrasound only gives us a general view. If you want to know if you have endometriosis or not, then you need to have a laparoscopy to check this, otherwise, the diagnosis cannot be conclusive. If you need to do a laparoscopy before your IVF, then this is something different, and we need to go through your history to find out if this would be the appropriate thing to do or not, because I’m not sure if the reason that the embryo transfers were failing was due to this suspected endometriosis or something else, like the quality of the embryos etc.
I was partially trained at UCH, and this is a very good endometriosis centre in London, for example.
Endometriosis is a disease that is causing painful periods, pain during intercourse and is usually in the pelvis, in the ovaries, and inside the womb. Adenomyosis means “thick wall” of the womb – it can be related to fibroid tissue as well as endometriosis. Both of them can play a role in egg donation outcomes – if we are talking about severe endometriosis, then this can affect the chances of pregnancy, as well as adenomyosis – if it affects the endometrium, then it can play a big role, but if it is restricted to the muscle of the womb, they shouldn’t really affect chances of pregnancy unless it co-exists with endometriosis.
Yes, we do, especially in the UK and for example Belgium, Qatar or Dubai – we have colleagues that we cooperate with abroad to do the initial ultrasounds and scans.