Advanced fertility assessment including invasive/surgical diagnostic methods

Elias Tsakos MD, FRCOG
Medical Director , Embryoclinic

Advanced Maternal Age, Endometriosis, Failed IVF Cycles, Fertility Assessment, Male Factor, Miscarriages and RPL, Reproductive surgery

From this video you will find out:
  • What types of tests include advanced fertility female tests? When are they indicated?
  • Which male fertility advanced tests should be performed?
  • When endoscopy is indicated?
  • What are the benefits of hysteroscopy and laparoscopy?
  • What is a Robot-assisted laparoscopic surgery called “Da Vinci system”? When can it be suggested?
  • How can endometriosis, hydrosalpinx and fibroids, myomas be treated?

When surgical diagnostic methods should be indicated?

In this session, Dr Elias Tsakos, FRCOG, Medical Director of Embryoclinic, Thessaloniki, Greece, has been talking about advanced fertility assessment and fertility surgery such as laparoscopy, hysteroscopy, but also Robot-assisted laparoscopic surgery “Da Vinci system”etc. as a valuable tool that can be used in fertility treatments.

Dr Tsakos discussed advanced and basic female assessments and emphasised that different countries and even clinics can have various approaches and include some more advanced tests as standard while others don’t. This is still controversial, and we must be aware of such differences. As per Dr Tsakos and his team at Embryoclinic experience, they have established their list of basic/ advanced female assessment tests.

Female fertility assessment

The first thing that is always checked and performed is hormonal testing, which includes the standard hormones, such as FSH, LH, estradiol, progesterone, prolactin, and TSH. It also includes advanced assessment, an AMH and some more specialized hormonal tests depending on the indications, for example, it’s best to perform more hormonal tests if there’s evidence of hormonal imbalance, like in the case of PCOS or premature failure.

The next thing would be anatomy assessment, according to Dr Tsakos, this is something that is usually overlooked. These days the anatomy assessment tends to be limited to the ultrasound scan, but despite the advance of new technologies, not all IVF units have the skills and the availability to provide a 3D scanning or very advanced ultrasound scanning, including Doppler’s. In general, anatomy assessment should not be limited just to 1 scan, no matter how good the scanning facility or the scanning technology and skills are. It can only diagnose around 80% of the things we need to know about the anatomy, and 20% of them are misdiagnosed or undiagnosed. Genetic assessment should include a blood group, but also a test for Cystic fibrosis, which is the most common gene amongst the white race, roughly 1 in 20 people are carriers of that gene. Also, Karyotype testing is important, another is electrophoresis, which is a genetic anomaly of the haemoglobin and this is related to the gene, it’s commonly known as Thalassemia, it is generally thought to be common in the south of Europe, in Italy, Spain, Portugal, Greece and France, it is a bit less common in Northern Europe, however, it’s not unheard of. Microbiology and viral screening are also very significant, so screening for Hepatitis B and C, HIV, syphilis, and also vaginal and cervical screening. The general health tests should include the cervical smear to be up-to-date, breast assessment, thyroid testing, and TSH testing on its own is not enough. It’s best to do a full screen of the thyroid function tests, but also other assessments like checking the vitamin D levels, which is becoming very popular these days.

Female fertility advanced assessment

Tests that are considered advanced assessments test should be performed on the indication, only if there’s a history of miscarriages or family history of Thrombosis, for example, failed IVF cycles, etc. That includes Thrombophilia testing, which has become very popular in the last 10 years, it is fairly common in a large proportion of the general population, and even more common in infertility patients. It should also include autoimmunity testing, genetic testing and endometrial receptivity testing. These are still controversial, however, they may be considered advanced female tests.

Male fertility assessment

Male fertility assessment includes a semen analysis, semen culture, genetic tests should also be included as well as a blood group, cystic fibrosis, whether it’s full cystic fibrosis gene testing or just a DF 508, this depends on the clinician’s protocols. Karyotype, serum viral testing is also very important for the benefit of the procedure and also the benefit of the unborn child, and a very simple hormonal assessment for the men is also important, men should also check their thyroid function, there is an association of thyroid anomaly and semen dysfunctions and the same applies with prolactin and some other tests like vitamin D and glucose.

When we’re talking about advanced male fertility assessments, those are performed if there are some abnormal findings on the basic test. If there’s relevant history and that includes anatomy testing, referral to an andrologist, hormonal testing, DNA fragmentation testing and in some cases Y Chromosome microdeletion tests and so forth.

Fertility Endoscopy

The majority of IVF clinics don’t require a tubal test before performing IVF on the basis. However, there are cases in which the tubes have hydrosalpinx, and they are not always picked up by scans, apart from the cases in which the uterine cavity has anomalies, which have not been picked up by the scan. Let’s not forget that the scan is not the panacea, it’s not the gold standard for anatomy assessment of the female reproductive tract. The gold standard is a hysteroscopy and laparoscopy.

When is an endoscopy indicated? When there’s unexplained infertility, if it’s a tubal factor, endometriosis, fibroids, polyps prior, before IVF, after failed IVF, after miscarriages and after a mild male factor, which would not justify going straight for IVF. The fertility endoscopy includes hysteroscopy and laparoscopy, either the standard one or the da Vinci laparoscopy.

- Questions and Answers

Does full thyroid testing include reverse T3? It’s difficult to find this as a part of testing?

In thyroid function testing, I would include TSH, T3, T4, Anti-TPO and anti-G antibodies. If everything is normal, in my opinion, you don’t need to do anything else. TSH levels need to be optimal, which is a maximum of 2.5- 2.9, but less than 3. Although the normal TSH range is up to 4 for fertility patients or patients wishing for pregnancy or pregnant women, we would like this to be ideally 2.5, so if the TSH is higher than 2, 3, for example, if it’s 2.9, and everything else is normal. I would just repeat it in six months, and that’s it.

Now, if it’s more than 3, if one of the antibodies is high or both of them, then I would perform a thyroid scan because that may reveal some other anomaly. I would advise talking with your GP. Thyroid function has to be perfect for everyone. It is even more important for fertility patients and pregnancy. I would urge my patients, all the viewers, all the listeners tonight to ensure that they’ve seen your GP, your family doctor, to make sure your thyroid is functioning normal and 100%.

I have Anti-TPO around 59, TSH was tested six months ago- 2.49. When it was tested on day 10 of stems, TSH was 3.6. Is it possible it was due to stims?

It’s difficult to say. I can’t remember the levels, every lab has different levels for Anti-TPO, so if it appears within the normal range for your lab, then that’s fine. If it’s higher and that together, with the TSH is occasionally at 3.6, it may mean that it was too high. You probably tend to suffer from what we call Hashimoto’s disease. I would suggest seeing your GP and organize a scan of the thyroid gland and if the scan is normal, which hopefully it will be, but if it’s abnormal, of course, the GP will advise you.

However, if it’s normal, I would just keep measuring the TSH. You have two options. One is to keep measuring TSH and ensure that it’s under 3, and the other is to take supplementation of thyroid hormone, T4 hormone, not to bring the antibodies down, but to ensure that you will not have fluctuation of your TSH. The standard fertility advice for women who are even starting Hashimoto’s disease is to supplement the thyroid gland with a very small dose depending on your weight. The dose between 25 and 50 micrograms of the T4 hormone to ensure that the TSH level is within the normal range. Keep checking them every six months.

I had an HCG done, and the gynaecologist saw something in the uterus on the scan. He said I need to do a hysteroscopy. What is this, and what could be in the uterus?

As I showed you on my slide, hysteroscopy is an outpatient procedure where a specialist is inserting a fine tube with the camera and the light into the uterus to examine the cavity. It’s a similar procedure to a gastroscopy, which examines the stomach, or a colonoscopy which examines the bowel. Hystero in Greek is the uterus, so it’s a uterine endoscopy, and I would highly recommend doing it.

Can TSH be too low?

Yes, it can. It’s not as common as being too high, but anything outside the range requires a visit to the GP, or the endocrinologist if you’re in Europe.

Do you recommend going straight to hysteroscopy? I think I will go with this first rather than Aqua scan?

I don’t know the answer. It depends on your circumstances. I mean, in general, if you have no history of failed IVFs or miscarriages, if you are under the age of 40, if you have no other indications on the scan, I would not go straight to hysteroscopy. However, I would do some further scanning assessment. The aqua scan might be an option for you if hysteroscopy is not indicated. If there is an indication for hysteroscopy, in my opinion, it is advanced reproductive age.

If somebody is over 40, the chance of having pathology which is missed is higher, so perhaps screening hysteroscopy might be a good idea before IVF. It would increase your pregnancy chances, that’s for sure. We have published a 10% increase in our egg donation program if we perform hysteroscopy. If you had a miscarriage, and you’re 40, go ahead and have it done, but remember that the hysteroscopy is only assessing the lining of the uterus It does not check the tubes. If you have a history of miscarriages, you’re over 40, and you haven’t had a tubal assessment, I would probably suggest a standard X-ray tubal assessment. This is better, if not much better, compared to an Aqua scan in diagnosing hydrosalpinx, which you would like to exclude before moving on.

My TSH was 3, and I am now on thyroxine. My Anti-TPO antibodies were 498( normal is 0-60 U/ml). I was told not to worry about the antibodies, as it just shows I have had thyroid issues in the past. Should I challenge this? 

I have to be diplomatic here. Perhaps there’s been confusion between antibodies. People think of antibodies like antibodies against coronavirus is indicating an infection. It doesn’t work like this on the thyroid. The presence of anti-TPO antibodies means that your body somehow is fighting your thyroid gland, that’s why it’s called thyroiditis, as in an inflammation of the thyroid. However, it’s not a virus, related inflammation is an autoimmune inflammation. The presence of Anti-TPO antibodies means that your thyroid gland is constantly under attack, not in the past, now. Every time it identifies that your thyroid is being attacked, that’s why it is a very good measure to go on thyroxine to ensure that the thyroid is functioning normally, despite the attack.

In my opinion, it doesn’t have to do anything with the past, it’s a current situation, it would probably not change. I would keep on the supplementation, checking the thyroid tests perhaps. In Greece, we’re a little too alerted about it, we do the test every six months, but once a year is a must to ensure that the doses are correct. I would also have a thyroid scan to ensure that there’s no anatomy damage. Taking 25 micrograms is fine, it’s probably a low-ish dose, but it’s fine. If you weight 50 kilos or 60 kilos, it’s fine because the TSH levels are normal. Generally, yes, we treat between 25 and 15, but this is something to be discussed with your doctor.

Would you recommend removing the rectovaginal endometrial nodule, which has been noted on an ultrasound I had?

This is tricky, I would suggest a laparoscopy to assess that. Now, removing a nodule in that area could be tricky, complex and challenging. Even in the best surgeons hands, it could be associated with more endometriosis cancer all over your pelvis. I don’t want to scare you. I would suggest a laparoscopy, perhaps, in the first instance to see or exclude if there’s more endometriosis. Whether I would remove that or not, depends on the skills and the expertise of the surgeon. In my opinion, yes, if I had a laparoscopy and if the nodule is there and if it’s causing problems and if it’s painful, I would probably attempt to remove it. Although it could be a very challenging procedure.

I had ectopic pregnancy previously. Then, I had Hy-Co-Sy and was advised it wasn’t possible to see the liquid going through the tube, but it spilt out without issue, which indicated a tube was open. Is there any reason that could cause this? Secondly, I was advised after an ectopic that the HyCoSy test wasn’t useful, and I should have had HSG. What are your thoughts?

I would probably align with the second opinion. The HyCoSy can tell us if the tube is open, but it cannot tell us if the tube has hydrosalpinx, if it’s bloated. The gold standard for this is laparoscopy. The second-best is the X-ray HSG, so in my opinion, I would also consider going straight for a laparoscopy instead of messing around with tubal assessments, which even in the best hands cannot be accurate by definition as a method. As a second option, I would do X-ray HSG.

Do you recommend the ERA test as a standard? Does it need to be repeated?

It’s a very simple answer, absolutely not. I don’t think the ERA test should be a standard, and I challenge whether it should be even an advanced test. I don’t think, at the moment, scientifically, we’re convinced of its value, of course, it’s there, but to be honest, I think there’s a lot of means to assess the implantation window. We can do this very successfully without resorting to controversial and expensive tests. Not as a standard and maybe not even as an advanced test.

 My ovarian reserve is low, just turned 44, eating healthy, taking supplements, and I’m not ready to do donor egg yet. I’ve had two IVF cycles and had only one retrieval but did not create an embryo. What other things I could do to improve my egg quality?

Unfortunately, there’s no huge effect on anything we could suggest. However, it is important to be healthy, to take supplements, consider DHEA perhaps, and what is low ovarian reserve for a 44-year-old is variable. If there is difficulty with producing eggs, I would just have natural cycles and aim to collect as many successful cycles as possible. I would grow the eggs to the blastocyst stage, and I would even consider PGT-A to know that these are euploid embryos. In my opinion, you should take DHEA, do natural cycles or mild, very mild stimulation cycles aiming to produce one or two eggs, blastocyst culture, PGT-A screening. And of course, if you have euploid embryos before you implant them, ensure that you have a normal cavity with the hysteroscopy before implantation.

If during the thyroid scan damage is detected, can this impact fertility or recorrect it somehow?

What is worrying us the most is a lack of knowledge, and that is our constant concern. When we’re designing fertility testing for every woman, every couple, this is something that’s always bothering us. Are we cutting corners? Are we for the sake of the economy, the sake of cost-effectiveness, are we doing good or bad for our patients? Don’t worry about discovering something. These are very standard things thyroid gland is very important for our health, our well-being, metabolism, and of course, fertility, so don’t worry, have a scan, and whatever is found. I’m sure can be treated successfully.

Is there any link to NK cells? I have had 3 miscarriages in the past?

I have a very clear answer, at the moment, there’s no scientific evidence about the value of either testing or treating NK cells. In my practice, I don’t check for it, to be honest.

How do you determine the correct window of implantation without using the ERA test?

That’s a very short and very important question. We do it by intensive hormonal measurement, we take great care not to subject the endometrium to high levels of estradiol, and of course, not to very high levels of progesterone. This is how we determine that, and of course, this is doubled by high technologically advanced scanning done by expert consultant gynaecologists. This is how we would justify the implantation window, so harmonically and anatomically. We define this by measuring the estradiol, progesterone, LH levels. We do it every single time we do scanning before the embryo transfer. We ensure that the lining is not just size-wise normal, but also the morphology is normal. Now, what we also keep in mind is that it’s not just the anatomy and the physiology that are important, embryo transfer technique is important as well, who does it, how you do it.

There are still people in Europe, I don’t know about the US, but I do know people in Europe, Western Europe, in The European Union that perform embryo transfers without ultrasound guidance. That could be a factor, I still know people in clinics in Europe where they don’t do mock transfers before the embryo transfer either because they don’t believe it’s important or because they want to save some time and energy or because it’s not feasible. For example, you have your clinic here, and then the patient is stimulated 500 kilometres down the road, and you only see them on the egg collection and embryo transfer, and you’ve never had the chance to do the mock transfer, so embryo transfer is also very important and let’s not forget that.

One of the mechanisms by which the hysteroscopy is increasing the success is ensuring that the embryo transfer would be easy. Why? If we see the stenosis in the cervix on the hysteroscopy and treat it there and then, we ensure that we have an easy embryo transfer even if everything else is normal. It’s not just the window, it’s the embryo transfer, which is important.

Would there be anything different to all these tests that you could add for using a surrogate, or the same test/ checks should be done, as if carrying the pregnancy on its own?

The main difference when we use a surrogate is that the surrogate is a fertile woman, that’s the main difference between using a surrogate and using an infertile patient. A surrogate by definition, especially in Greece, where, by definition, they have to have one child of their own, and they have to be of reasonable age between 25-45, they’re fertile women. The indications of performing tests on fertile women are not there. However, we still do many tests, advanced tests, and of course, we equally test the intended parents, especially if they’re providing their genetic material.

When it comes to endometriosis, are there different ways to treat this surgically, possibly cutting away or burning off if I have read it correctly? What is the best option to avoid decreasing fertility?

The condition of endometriosis decreases fertility. Now, of course, surgery can be very challenging for endometriosis. Endoscopic surgeons have to be very experienced in endoscopic surgery to perform it in such a way so that surgery itself will not damage it. The main and the major damage is done by endometriosis itself. Especially if endometriosis is left either undiagnosed or if we delay the treatment after the diagnosis. It’s not clear-cut whether we should always operate if we have a cyst of two centimetres or five centimetres. Should we operate easier the first time and less easy the second time?

However, I think the take-home message is that endometriosis as a condition is detrimental to fertility. If surgery is advocated, it has to be performed by a very skilled surgeon in a very skilled and technologically advanced environment. In my experience with endometriosis surgery, I think robotic surgery, robotic approach “Da Vinci” is providing us with amazing results, much better than the traditional laparoscopy, especially for challenging cases.

I have not been diagnosed with endometriosis but looking to explore this. Would it be okay on NHS or better to seek someone else, as you mentioned a very skilled doctor?

If you have not been diagnosed with endometriosis and if you have no clear indication that you may have endometriosis, the chance is that you will not have it. You may only need a diagnostic laparoscopy, a diagnostic laparoscopy does not need the best experts in the world. I would talk to the GP and see if you can get some health authorities. They’re a little more relaxed about offering a diagnostic laparoscopy to women more than others.

I think the first door is to your GPs door, if it’s a friendly GP just mention that you’re really worried that you have endometriosis because of infertility, abdominal pain, dysmenorrhea, sometimes a little abnormal bleeding. Most women have these symptoms anyway, and if you’re lucky, they can list you and perform a diagnostic laparoscopy. If you have no other clear signs, the chance of having advanced endometriosis that would require advanced surgery is very low.

I had these diagnostic tests done 5 years ago, but nothing was found. I was diagnosed with unexplained infertility. I had failed IVF treatment last year. Would you recommend redoing these tests, or would you have other suggestions? I am 38, so I don’t have a lot of time.

Make sure you’ve had what I have on my list of tests. Some of them are valid for life, so the genetic tests are valid for life if you’ve had them done, you don’t have to repeat them. Some of them are valid for six months or a year, depending on the results, so that’s my answer whether you need to repeat them or not. We’re always puzzled by the diagnosis of unexplained infertility, I mean, the American colleagues of ours say that there’s no such thing as unexplained fertility, just people who haven’t been investigated enough, so I would just move on. I mean, have some more tests.

On the other hand, the IVF attempt itself is not a huge piece of history to be desperate. I don’t know what your circumstances are, how supportive your environment is and so forth, and of course, the details of your IVF would also guide us. For example, there are different test protocols if you’ve had 5 normal embryos that just didn’t implant versus having had 1 embryo that was not of good quality and didn’t implant. I think someone has to look into your history, tests you’ve done and into the IVF details to form a little protocol for your assessment. I would advise being tested before the second assessment. You’re very welcome to email me if you wish to look into your files and provide further advice.

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Elias Tsakos MD, FRCOG

Elias Tsakos MD, FRCOG

Dr Elias Tsakos, FRCOG, is a Medical Director of Embryoclinic - Assisted Reproduction Clinic in Thessaloniki, Greece. He has received extensive and certified training in the United Kingdom and is a Fellow of the Royal College of Obstetrics & Gynaecology. Dr Tsakos is also a Board Member Representative of the Royal College for Greece and Cyprus and a Board Member of the Hellenic Society of Assisted Reproduction. He is a Member of the British, European and American Fertility Societies (BFS, ESHRE, ASRM). Dr Tsakos has been living and working in Thessaloniki, Greece, since 1999.
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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.