In this session, Dr Elias Tsakos, FRCOG, Medical Director at EmbryoClinic, Thessaloniki, Greece, provided one of his past patient diagnosed with diminished ovarian reserve, endometriosis, tubal factor and mild male factor successful story. Dr Tsakos, also explained protocols that work best in patients with (DOR) and how important pre-IVF evaluation is.
Low ovarian reserve is one of the bigger mysteries in life and fertility. It is something that has attracted a lot of interest from scientists all over the world. Dr Tsakos explained that from 2005 onwards, he and his team studied the AMH, and they performed quite a few investigations at the time, they also tried to compare the AMH with the previous assessment methods of poor ovarian reserve and low ovarian reserve. They were able to publish a few papers and produced the PhD thesis of Dr Tsakos’s business partner, Dr Tolikas, and they presented all the data in 2010-2011. Now, we know that AMH is not something new anymore, we rely on AMH to make some predictions of low ovarian reserve. This is a very significant factor in determining how we approach those women in the stimulation protocols and the expectation that we have as clinicians, and they have as patients, for their ovarian response to stimulation.
The whole issue of AMH is based on the ability we now have to predict and design adequate protocols for stimulating the ovaries of those women based on the AMH. It’s not just the AMH, we still use the FSH and LH, estradiol as a baseline, although we’re moving away from them quite rapidly at the moment. We use the AFC, the Antral follicle count, therefore, the question is: How do we define low ovarian reserve? What AMH is normal? What AMH level is suboptimal, and what AMH level is high enough to indicate an excessive ovarian response? This is very important to be aware of before stimulation and avoid the hyperstimulation syndrome, but also diagnose the polycystic ovarian syndrome that may be missed by other methods of diagnosis.
AMH has now become the standard hormonal test and measurement before IVF, and it is now recommended to be checked once or twice a year, always in conjunction with the AFC, which is a subjective method by the use of scanning technology. By combining the two, we can have an accurate prediction of ovarian reserve.
The first case presented by Dr Tsakos was a relative of his who was 38 years old at the time, with low ovarian reserve associated with severe endometriosis.
The couple never had gone through IVF, it was their first cycle which was indicated because of her tubal factor endometriosis, low ovarian reserve and a mild male factor. The woman had a normal BMI of 24, the ovarian reserve at 0.7 ng/ml is a pretty low level of AMH for a 38-year-old woman, and that was in line with AFC -4, so there were 4 potential eggs. After discussing with the couple we defined the successful outcome of stimulation of 4 eggs, secondly, we tried to do any modifications that we could do to optimize the environment before the stimulation. We evaluated the vitamin D levels, we improved the vitamin D levels at the time by giving supplementation. The woman was perfectly healthy, had a normal diet, was a non-smoker, and a non-drinker, so we didn’t have very much to do there. We discussed the value of DHEA supplementation, which we have been empirically providing for patients, in the hope that some of them would benefit from it and very few of them would have the side effects. We give this for a minimum of 6 to 8 weeks before stimulation at a dose of 25 milligrams 2 or 3 times, and we planned a stimulation protocol.
Regarding protocols, some schools are providing maximum stimulation hoping to stimulate even smaller follicles that wouldn’t stimulate otherwise, some other groups are in favour of mild stimulation, and some other ones are somewhere in the middle. Taking that into account, we thought that there was no point in excessive stimulation if we knew AFC was 4. However, because this woman hadn’t been stimulated before, we thought we would give a normal stimulation as opposed to mild stimulation, so she had taken 250 units daily of purified FSH, which we think was a standard dose, and that was an antagonist protocol. She produced 4 follicles out of those 3 mature eggs, we performed ICSI in this particular case as there was a mild male factor. We had 3 mature eggs, and out of those, we had 2 blastocysts produced. We did the first embryo transfer, we transferred 1 fresh blastocyst, and we froze the other. We had a perfect endometrium, we had the perfect level of hormones and in particular, we had low progesterone on the day of the trigger, it was under 1 ng/ml, so we had a pregnancy, however, this pregnancy ended up in an early miscarriage, it was a six-week miscarriage. We performed an evacuation of retained products, it was a clinical pregnancy, and we performed DNA tests on the concept it was normal, however, that was a miscarriage.
We had 1 frozen blastocyst, we prepared the endometrium and we transferred that blastocyst on the frozen cycle and that resulted in another pregnancy which was ongoing and ended up with a healthy birth by Caesarean section at about 39 weeks, that was a maternal request, this C-section was based on the fact that this woman had a single kidney, we got a fit and healthy young boy.
The message from this case is that although it was a case of a relatively advanced reproductive age of 38 with compromised ovarian reserve and endometriosis, it was very important that we identified and did our best to optimize everything. It’s hard to say whether DHEA played a role or not, the good news was that 4 eggs were produced and out of those, we got 2 blastocysts.
Pre-IVF phase is everything you’ve done in your lives until now until you see a fertility specialist for the first time. All the simple things have to be optimized, lifestyle habits, and a bit of exercise, it’s of great importance to prepare your body and your soul before you embark on the IVF journey. F.e., intensive weight loss before IVF does not alter the outcome and it does not improve the outcome, however, it is essential to investigate women and men before any fertility interventions.
I see couples who’ve had multiple IVFs, multiple failures, and they have adverse factors that have been undiagnosed from the simple stuff like low vitamin D levels, normal vitamin D levels have been associated with a lot of health issues positively, so we do need to optimize as much as we can. We don’t need to go over the top, we shouldn’t try to look for rare diseases, but we should ensure that harmonically the female and the male are properly checked. Checking the thyroid, having a breast assessment to eliminate any pre-existing breast cancer, which is becoming more and more common in women in their 40s or even before that. It’s also about ensuring that you’re up to date with smears, focusing not only on the ovaries, but also on the uterus to exclude any pathology of the tubes. I cannot emphasize enough the importance of pre-IVF tests.
Low AMH and having lower ovarian reserve don’t mean that you’re sub-fertile unless you’ve tried and haven’t succeeded. It doesn’t have a huge relation with a spontaneous natural pregnancy, so if everything is normal and after 6 months or 1 year at the normal age of mid-thirties, you find low ovarian reserve, don’t be alarmed, it doesn’t mean that you’re subfertile, it may be important if you end up having IVF, but by itself, it’s not a factor of infertility, and it doesn’t hugely natural conception provided that everything else is normal.
When you identify seriously abnormal AMH at a young age, it’s essential to proceed with further investigations, there can be an autoimmune disease associated with that. You need to try to eliminate any other associated factors related to low AMH. Checking autoimmune diseases like thyroid disease or other autoimmune conditions and it’s not over the top to request a karyotype testing, DNA genetic testing to ensure that the structure of the DNA is normal. It’s very essential to sit down with your doctors when they design the stimulation protocol for you based not only on your AMH but also on your antral follicle count, which most likely will be aligned with your AMH levels but also with your age, your weight, previous performance and stimulation, and by defining the successful outcome of stimulation, you get more confidence in the overall procedure and the outcome.
It is very successful, and there’s no reason why you can’t try a natural cycle. Provided that this cycle is monitored very closely. IVF is like everything else in life, the more particular you are, the more pedantic, the more care you give to every detail, the more successful you are. Sometimes it’s a little challenging for the patients, but if you monitor your natural cycle using scans and blood tests, if your doctors can accurately monitor and time the natural ovulation, then you just have to pop in the embryo or the embryos at the right time. This way, you avoid all the medical treatment. In terms of success, if the natural cycle is proven to be normal hormonally and is controlled using scans, it can be 100 % as successful and sometimes even more successful than a medicated cycle.
I’m afraid not, there’s no link with any of that with endometrium. I would suggest having a diagnostic hysteroscopy, which I suggest to all my patients, in particular of advanced reproductive age over 38. I do it for several reasons. If you go back through the webinars, you may find the value of hysteroscopy. Ideally, it should be done 1 or 2 months before the cycle. That would ensure that the lining is normal. I’m very sceptical when I hear about patients with not so optimal endometrial lining who haven’t had hysteroscopy because they may have some pathology, some problems that have been missed. So have a hysteroscopy, and then the response of the endometrium to the natural hormones is usually linear, it’s usually normal. If there’s any doubt, you can have a bit of supplementation of oestrogens but only towards the last few days before the embryo transfer and not before, because if you do it too early, it may block your ovulation.
So, hysteroscopy, standard vitamins, although there’s no relation with endometrial thickness and hopefully normal trilaminar appearance on the scan, normal hormones, good timing because you want to time the embryo transfer with the ovulation. You may have to have scans daily from perhaps day 9 or day 10 onwards, to align the embryo transfer, maybe a tiny touch of estrogen and progesterone before the embryo transfer.
I think 25 is too little, 75 is the right dosage, and the question is how long you take it for, and these are the questions we haven’t answered yet. If I am to give DHEA for 6 weeks, I would probably give 50 to 75 milligrams, 2 or 3 times a day. If it’s for a shorter time, I may suggest a higher dose of DHEA. For example, sometimes we have a couple who flew in from Canada, with whom we had a Skype a week before, and they knock on our door and say, ‘here we are, my period is starting tomorrow’. In two days, it’s a little too late, so I may give a higher dose of DHEA. It depends on how long we give it. If we have 6 weeks, I would probably give it 4 to 6 weeks, I would probably give 50 to 75 milligrams depending on your weight and age. For a younger slim woman, I would give 50 for over 38 perhaps or with a history of low response and a bit higher BMI, I would probably give 75. If I were to give DHEA for a longer time, I would probably stick to 50. I wouldn’t give it longer than three months anyway. So 50 to 75 and not 25.
I don’t think it makes a huge difference whether we use Menopur or Gonal-F or Pergoveris or anything else. It wouldn’t make a visible difference to us. There is some evidence, however, that perhaps adding LH, which is another hormone, to the FSH may improve the response of women with a low ovarian reserve and in advanced reproductive age, over 35 or 37, depending on how you define it. In general, in the 40+ age group, I would probably use a bit of LH. Menopur is also a nice drug because it contains a component like LH. Although it is considered to be the previous generation drug. It wouldn’t be a bad choice. I would try to optimize the lifestyle as much as I can without fluctuations in weight, I would probably use DHEA for 4 to 6 weeks at 50 to 75 milligrams per day, I would optimize the vitamin D levels, I would do a hysteroscopy if the patient hasn’t had one within a year, because things change in the uterus.
If everything looks normal on the scan, hysteroscopy may show some factors that are not visible on the scan. Every diagnostic method we use has a certain accuracy. The gold standard is a hysteroscopy, and if it’s combined with a biopsy, with histology report, it is even better. Even the visualization alone without biopsy is not 100% sure, and if we want to go to the around 100% chance of success, we may need to do some microbiology cultures as well. So visualization, histology, and microbiology would probably give us the best approach clinically we could have at the moment. In the future, we will be able to do more genetic tests. We can do more elaborate tests on the endometrium, but for now, that’s probably enough.
As far as I’m aware, the oldest woman in the world who delivered a healthy child through IVF with her own eggs is 46. I’ve never had anyone through IVF 46, and I always quote that to my patients if they insist on using their own eggs. I do have some anecdotal reports from my colleagues that had successes with 47 -48-year-olds. I challenged them to publish it, and that is the publication I haven’t seen. So, at 45, yes you do have a chance. AMH 0.6 is normal for a 45-year-old. If you haven’t tried IVF with your own eggs before, I would probably encourage you to proceed with that. Applying all the rules that we mentioned before, ensuring that all the pre-IVF assessment is normal, you have done all that, and you have optimized your body and soul before the stimulation, and you use the appropriate stimulation protocol, which should be not a very high dose of hormones.
FSH at a standard dose would probably give you a fair chance to at least produce eggs. You must be aware that the chance of a clinical pregnancy is 3 to 4% maximum. The chance of ongoing pregnancy is maybe 1%, and the chance of delivering a healthy child is probably less than that. However. I don’t think anyone could prevent you from trying, as long as you do not compromise your health. As long as you enter this journey having been thoroughly checked for general conditions, like breasts, general tests, some heart and lung tests. You need to make sure that you’re healthy. Whether you use your own eggs or egg donation, you need to be aware of the very poor outcome. However, I don’t think anyone could prevent you from trying, as long as you haven’t tried before. At the age of 45, there’s always the debate about genetic testing. Discuss that with your doctors, whether it would be indicated or not. In my opinion, it’s probably indicated. I would feel very uncomfortable implanting an untested embryo at this age, given the fact that the majority of the embryos, if we manage to produce any blastocyst, could be chromosomally abnormal. There’s still a journey ahead of you, so give it your best shot.
I would complete the basic investigations of you and your partner. Make sure all basic investigations are normal, and if you haven’t been trying naturally for a long time, keep going. Nothing and nobody prevents you from trying naturally. It’s just that IVF may give you a little extra add-on to the natural conception chances.
In that case, the chance of natural pregnancy at your advanced reproductive, with unexplained infertility, is also in the region of one per cent, the same as maybe IVF pregnancy, so it’s your call to make your choices.
It may not just be the protocol, it may be the timing. Let’s put it this way, when we see 18 follicles on the scan, we tend to get a little scared because we don’t want hyperstimulation. Hyperstimulation is something bad. We’ve been taught that we must avoid that. I have seen many times my colleagues in some units respond a little abruptly when they see potential hyperstimulation. Sometimes we alter the protocol midway by perhaps reducing the dose of stimulation or increasing the dosage of the antagonist, which in a way burns the follicles, and therefore we do not get the full potential. So I would be very interested in looking into your protocol to see exactly how the cycle was managed. It’s like flying the plane, when the plane dives nose down, the automatic reflex of the pilot is to bring it up and stall it, and that’s the worst thing you can do.
The right thing to do is to accelerate and gain some speed so that you keep flying. Sometimes we do not respond as clinicians, we do not respond well to the potential hyperstimulation. If you have 18 follicles, I would expect to receive more eggs, and if you didn’t, I would like to look very carefully into how the cycle was managed in terms of dosages, duration, stimulation, coasting, increasing the antagonist, in terms of how you trigger the final ovarian maturation and how long after the final maturation trigger the collection takes place and so forth. So, I would be very intrigued to look into your protocols.
It’s fine. 2 months is fine, and I would probably give a smaller dose. There are some research projects underway where they are trying to identify how long to administer it, at what dose and who will benefit from it. I was hoping that this summer, they would be out. Until then, we just use 25, 2 times per day for 2 months.
Most people do not test progesterone at all. We do. The vast majority of people, units, doctors never test on the day of oocyte retrieval, so I’m very intrigued, and I would like to congratulate you on coming to this piece of fine information. Many people don’t even do progesterone measurements on the day of trigger, never mind on the day of retrieval. To my knowledge, there’s no scientific evidence of what is the cut-off level on the day of the retrieval. We do have some data unpublished in my unit that the limit is 10 on the day of retrieval. But that depends on how many follicles we have and a bit on the age of the patient. We try to correlate that level with the trigger day. The cut-off on trigger day is between 1 and 1.5 nanograms. Unfortunately, the assessments we use, the microbiology labs are not designed for very small levels of progesterone, so it’s been debated whether there is any accuracy possible between 1 and 1.5. So that’s why perhaps we have a second chance of measuring it on the day of oocyte retrieval.
To conclude, I think I wouldn’t transfer ever if I had on the day of the trigger more than 1.5. The question is, what do I do when it’s between 1 and 1.4, and the answer is I compare the results with the day of retrieval. So if it’s a single figure and it’s less than 1.5, I probably transfer on the first cycle if everything else is normal. However, if it’s in the grey zone (when on trigger day progesterone is 1.1 to 1.4) and I have a double-figure on the day of retrieval (10 or more), I wouldn’t transfer. Then again, we take into account other situations as well, such as the risk of hyperstimulation. If there’s a risk of hyperstimulation and I’m like in the grey zone, I probably wouldn’t transfer. It’s also the proximity of the patients. We had a patient last week, a single lady doctor who travels around the world through some organizations, and she would be in Guinea next week. So she said, ‘if I don’t do a transfer now, I would next come to Greece at Easter.’ We have to take into account those factors, and we have to factor in our patients as well. We need to share our knowledge, our uncertainties, the grey zones, and another important factor for me is whether we have a second embryo transfer. So if I’m in the grey zone and I have one blastocyst, I probably wouldn’t transfer it on the first cycle.
When people ask me whether the fresh or frozen cycle is best. I say it depends. It depends on what you compare with. If you compare a perfect fresh cycle, I prefer a perfect fresh cycle to a perfect frozen cycle. For various reasons. One significant reason is that my time to pregnancy is shorter. I’d rather get the pregnancy now than two months later. So if I have one blastocyst or if I have the chance of one embryo transfer, I would probably keep it for a frozen cycle. If I’m in the grey zone. If I have 2 transfers again, there’s a fine element of what kind of quality blastocyst we have and which one we sacrifice in a grey zone fresh cycle and which we keep in the frozen cycle. This is why my embryo transfer consultation sometimes takes two hours.
I will talk about my daughter. I’m not suggesting this to everyone, and it depends on how expensive it is in your area. In Greece, it’s about 100 pounds, so it’s not that expensive. So I would like my daughters to know their AMH levels at the age of 18, 25, 30 because some conditions are associated with low AMH, and I would like them to get into this fertility kind of game. Teaching teenagers we focus on sexuality and fertility education should be a part of teenage education as early as possible. It’s only a matter of cost, it’s not a big deal, it’s only a blood test. I’m a big fan of preventative medicine. I’m a big fan of patient education and lay, people, education. My dad is 96, he survived because he had lots of interventions before they became a problem. He’s a living example of someone who was saved by medicine, by science and technology. He suffered from major health issues starting from the heart going downwards, but we managed to discover all those through prevention tests.
I think having a test of AMH is a good idea. AMH may even be associated with breast cancer, believe it or not. In the modern world, if women take their health in their hands, they have regular checkups like a cervical smear. Most women in the western world do not rebel against their mammogram guidelines. I’m aware that mammogram checking starts at 45 when we know that 17%of breast cancer, almost 1 in 5, occurs in women under 40. So I’ve seen women in their mid-40s who’ve never had a mammogram or never had a breast assessment. My mother had breast cancer at 39. She discovered it early, and she survived breast cancer, she died of other causes later. I don’t want to be political here, but I think it’s unfair that the health of our women and our health relies on the guidelines of our countries. The guidelines are not necessarily tailored to our health. I think we should take care of our own health, and I think we should read at least the basic stuff. The basic stuff is a cervical smear, thyroid check, AMH check, standard blood test, both for men and women. Let’s take control of our own health, not just fertility health.
Yes, I tend to give it. When I get hold of women who are just planning an IVF cycle and have proven low ovarian reserve or are of advanced reproductive age over 35-37years old. Even a small dose may make a small difference. That would not be visible, there’s no way for us to identify the impact on the individual patient. We need to wait for the big papers and the research, but, I think, there’s no harm in giving them perhaps 75 milligrams for two to three weeks. The theory behind it is that it may improve the reception and it may improve the receptor response to stimulation afterwards. If you have the chance to even give it for 2 to 3 weeks, there’s no harm, there is added value there. One of the problems is that we don’t know how long or how much should be given. In my empirical feeling about the DHEA and androgen, supplementation is probably beneficial to maybe 10 or 20 per cent of the patients, but we cannot identify who they are at the moment. There’s no harm in giving this to everyone at the moment until we have more data.
I can’t answer the specific question. I don’t know if it was an immunity response. I don’t know if that was related to the vaccine or just associated with the vaccine. I have been reading as much as I can. I’m by no means an expert. I don’t know anything more than most of you know about COVID, however, I know this is a war situation. We need to take the vaccine for ourselves, and we need to take them for society. I don’t want to be personal. My 12-year-old daughter, when she got the message from the government here in Greece that her age group is eligible for the vaccination, came and said: ‘Dad, let’s go, take the vaccine. I’m doing it for grandparents”. We’re all afraid, but we should all have the vaccine. Only if about 85% of us have the vaccine, we can be free. We can just move on with our lives. I would highly recommend that you move on and have your next dose.