In this session, Dr Mauricio Gómez, Gynaecologist, specialized in Endocrinology and Reproductive Medicine at Reproclinic, Barcelona, Spain, has shared 2 of his past patients’ cases. Both women were diagnosed with low (diminished) ovarian reserve, and Dr Gómez explained protocols, medication provided to overcome this and achieve a pregnancy.
The first case presented by Dr Mauricio Gomes was of a 34-year-old woman, with no allergies or toxic habits, no previous family history. The patient was suffering from hypothyroidism treated with Thyroxine and had low vitamin D levels treated with vitamin D supplementation once a week. One year before, she had a hysteroscopy to remove a partial uterine septum, which after another control 2 months later showed all was normal. The patient had regular menstrual cycles and has never been pregnant. Her last gynaecological examination, including pap smear, was normal. She’s married, and her husband was a healthy 35-year-old and has never had a child. They came to the office after 3 years of primary infertility and 2 previous failed IVF treatments in another centre.
In both attempts, a high dosage of gonadotropins was used. The first one was cancelled before the collection as only 1 follicle was found. In the second one, it was an antagonist cycle and an FSH plus LH combination (Menopur) of 300 units was used instead of r-FSH (Gonal). This time 2 follicles were found, and only 1 egg was retrieved, but it did not fertilize. Therefore, there was no embryo to transfer.
The results of the tests requested showed a normal spermogram and a very low AMH level of 0.2 ng/ml (1.42 pmol/l). The rest of the tests, including Karyotypes, X-fragile chromosome study, serologies, biochemistry cell scan and thyroid function were within the normal range. The gynaecological ultrasound showed very low antral follicle count (AFC), two follicles were found with normal uterus and endometrium. After studying all the results and considering that the patient didn’t want to go ahead with egg donation treatment at that moment, another IVF treatment with her own eggs was recommended and accepted by the patients.
Modified natural cycle
However, considering 2 previous failed cycles, it was a moment to change the strategy of ovarian stimulation. Dr Gomez and his team offered the possibility of doing a modified natural cycle. After the first day of menstruation, a gynaecological ultrasound was performed to see the situation of the ovaries. At the beginning of that cycle, there were 2 antral follicles, a second ultrasound was done on the 7th day of the cycle, and the ultrasound showed 1 follicle growing at the right ovary, it was 11 millimetres. After two days, an ultrasound was done again, and the follicle was 15 millimetres. That is when added Orgalutran antagonist of GnRH and Menopur to decrease the risk of spontaneous ovulation and give some extra vitamins to regulate the growth and the modulation of this egg.
After another 2 days, the follicle had become bigger at 19 millimetres, the endometrial lining was good at 9 millimetres, and it was trilaminar. At that moment, we used a dual trigger with Decapepyle and Ovitrel. The egg retrieval was done after 36 hours of the triggering, we got a mature egg which was collected and inseminated in the laboratory by ICSI with one spermatozoon. We prescribed 400 milligrams of vaginal progesterone twice a day.
The day after we had the embryo, we decided to culture it for 5 days. The patient continued her treatment with progesterone, Thyroxine, folic and antioxidative diet supplementation. We got a 4 AB blastocyst which was ready to be transferred. A pregnancy test was done 12 days after the result of the beta hCG was 350, and posterior ultrasound 2 weeks later showed an intrauterine evolution pregnancy. The pregnancy passed normally, without any complication, and at 40 weeks of pregnancy, it was a vaginal delivery of a 3-kilogram newborn.
This case report showed us that some important facts should be considered in patients with very low ovarian reserve. The first one is that more dosage of gonadotropins doesn’t mean better. It’s significant to think about controlled ovarian stimulation to achieve as many eggs as possible. It’s also crucial to inform the patients of the situation and their real chances to succeed. They have to accept a high chance of not having an egg or embryo, but at least the treatment is going to be less stressful. Finally, the most significant is the patient’s age. This case demonstrates that the main factor of a good prognosis is age, while AMH and AFC are only markers of quantity, not quality. That’s why it’s recommended to try with your own eggs for patients less than 36, even though they have a very low ovarian reserve.
The patient had no allergies or toxic habits, her last gynaecological examination, including pap smear and mammography, was normal. Her husband was 49 years and was a healthy patient, he also had a daughter from a previous relationship. The patient got spontaneously pregnant two times. First, she had to do a voluntary interruption of the pregnancy at 14 weeks after Edward’s syndrome diagnosis. The second pregnancy was a twin pregnancy that finished in abortion at 12th week. The Chromosomal study of one of these embryos diagnosed Patau’s Syndrome (a 13 chromosome), the other was euploid. The test requested showed a normal spermogram, and DNA Double Chain Fragmentation was also normal. The patient’s AMH level was very low (0.06 ng/ml). Other tests, including Karyotypes, thyroid function and vitamin D level, were within the normal range. The gynaecological ultrasound showed only 1 follicle.
Minimal/Mild Combined Stimulation Cycle
The couple wasn’t ready to go ahead with egg donation, that’s why IVF treatment with PGT-A was offered. After analysing all the results and considering a very low ovarian reserve, a combined treatment with Letrozole 5 milligrams a day in 2 doses and 150 units of Menopur. The idea was to stimulate the recruitment from 1 different mechanism following the previously described protocol. The answer was surprisingly good, 3 follicles were found. The ovarian triggering was based on Ovitrel and Decapeptyle. We’ve managed to retrieve 3 eggs, and 2 of them were fecundated. Finally, we got 1 embryo that arrived at the blastocyst stage, it was biopsied and frozen. Four days after the egg collection, another ultrasound was done. We saw 2 follicles of 6 and 8 millimetres and decided to start another ovarian stimulation with 225 units of Menopur the day after.
The idea was to get more embryos at the same cycle, considering a low chance of having a euploid embryo in a 42-year-old patient with a clinical history. After 5 days of stimulation, the first ultrasound control was done. Two follicles had grown, one in each ovary, and after another two checkups, they were ready to be collected. The dual triggering was done again in the same way, and two eggs were collected. All of them were fecundated, unfortunately, 1 of them became a blastocyst. That’s why it was biopsied and frozen.
After three weeks PGT-A result showed that the first blastocyst was aneuploid, the second one retrieved after the luteal phase stimulation was euploid. The chances of a successful pregnancy were much higher now, the most difficult step was done. We decided to do an extra study of the endometrial receptivity that showed us 24 hours before the implantation window. According to this result, we started a substituted cycle with 60 milligrams daily dose of oral oestrogens at the beginning of the next cycle. When the endometrial line reached 8 millimetres, we started progesterone treatment vaginally, and after 6 days, 1 day more than usual considering the result of the ERA test, we transferred this euploid embryo.
After 2 uncertain and stressful weeks, the pregnancy and test were positive, and after that, the patient finally delivered a healthy baby delivered by Caesarean section at 40 weeks of pregnancy. By contrast with the first case, this patient had an extra factor that added more difficulty to achieve pregnancy. She was more than 40, it’s important to know that the average number of eggs required to get a healthy euploid embryo at the 42 patient is more than 15 eggs more or less. However, in this case, we were only able to collect 5 eggs between 2 procedures at the same cycle. That’s why, considering these 15 eggs required, we were really lucky.
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In the first case, considering the patient was 34 years old and considering the statistics, we should have collected between 3 or 4 eggs to assure 1 healthy embryo. We only get 1, but at 34, we didn’t recommend performing a genetic study. We were lucky in both cases, but sometimes this luck deserves to be solved.
In the second case, the decision of trying a non-conventional ovarian stimulation protocol has been decided because of the patient’s very low ovarian reserve. The idea of accumulating embryos was obvious, so we could get as many embryos as possible. PGT-A is strongly recommended from the 38 years old and older it’s very important to share
We also need to remember to do an extra study of the endometrial receptivity to prepare the best endometrium for the best embryo. That’s why we prefer to do the ERA test before the transfer.
It’s difficult to give the best advice only with the information I have, but regarding the eggs, theoretically, the quality of this egg might be good. When we are talking about recurrent implantation failure, it’s important to take into consideration the possibility of doing an extra study on these embryos to assure that they are healthy. One question is the information at the laboratory just the day of the transfer, but another question is to be sure that the internal quality of this embryo is okay. The main cause of recurrent implantation failure is the quality, that’s why considering that you had 3 attempts without success, it would be good to do PGT-A on the embryos if they weren’t previously tested. It’s time to change that and study it deeper.
Theoretically, it’s possible to collect these spermatozoa with this treatment. We need to be sure that this spermatozoon has the same quality as normal spermatozoa from a normal ejaculation. Sometimes we have found that the internal quality of these spermatozoa is not the same, and that’s why if it’s impossible to get this sperm, this is very good news, but I think more studies will be needed to assure that this quality of the embryo is good. Not only by the external embryo at day-5 of development, but it’s also important to do this before to assure that in this case, its chromosomal structure, its karyotype is good.
Depending on the patient’s age, if we’re talking about the antral follicles count, 2 eggs if the patient is younger than 35-36 years old. As I told you before, the most important question is the quality of this possible egg. Indeed, we are not going to retrieve so many eggs considering the low ovarian reserve, but theoretically, if we can stimulate with small doses of medication 1 or 2 follicles by a natural cycle and we can retrieve 1 healthy mature egg if the sperm sample is good. We are talking about an ICSI, and for an embryologist, it’s not difficult to take 1 healthy and mobile spermatozoa to fertilize this egg. This is a chance of having a healthy embryo with some chances of success.
The chances are low, and that information must be given to the patients to accept that there is a possibility of not having an embryo. When we talk about a younger patient, we recommend doing a fresh transfer if the sperm sample has been previously frozen, once it is thawed, the transfer can be done after 5 of ICSI, it’s not a problem.
This is connected with the reported case of the 2nd patient. It could be a similar case, first, the statistics say that we would need more than 20 eggs to have 1 healthy euploid embryo, but this is only statistics. For example, in our case, from 5 eggs, we had 1 healthy embryo. The problem is that every year from 40, the prognosis is decreasing dramatically. That’s why at 45 years old, the statistics are terrible, I’m afraid. In my experience for patients older than 43-44 years old, the recommendation from the beginning is donor eggs, respecting the idea of trying with own eggs at least once. In this case, the issue is that at 45 years old, we are talking about a low ovarian reserve, that’s why we might need to do many cycles to accumulate eggs and embryos to have some healthy embryo without certainty.
That’s why it’s very difficult to be optimistic. To try once, it might be possible to collect 1 or 2 eggs, but you have to realize that it might be very hard to achieve 1 healthy embryo. It’s a complicated case, the age of 45 is not the same as 42, which is the age of my patient. The ovarian reserve is more or less the same, but the difference of 3 years is very important.
Regarding the fibroids, it’s essential to know the size of the fibroids, and when it comes to this intramural fibroid, it depends on the location inside the uterus. It’s not the same as an intramural fibroid near the endometrium. If you are deciding to do the egg donor treatment, the embryo quality should be assured, the receptivity of the endometrium is strongly related to the location and the size of the fibroid. That is why it’s significant to check it to be sure that the endometrium is okay.
This case is similar to the first case I presented. The number of eggs is going to be low, and this is the right example to show us that giving the right amount of medication doesn’t mean more eggs. That’s why, in this case, it would be interesting to change the strategy and think about a natural cycle or a minimal stimulation cycle.
Regarding 1 maybe 2 follicles, theoretically, we don’t need more follicles to have 1 healthy embryo, and at that age, we could get a mature egg. It’s time to change the strategy, there is no sense to repeat and give a higher dose of size Gonal-F, it will have the same result. Sometimes we see that the medication can be stressful for the ovaries and can decrease the quality of the eggs. That’s why my recommendation would be to possibly try again for the last time depending on the patient, but changing this strategy and talking about stimulating with less medication or maybe doing this natural cycle. If 1 follicle is growing, go on.
Theoretically, when it comes to the size of these fibroids, there’s no reason to worry about the progress and the bad prognosis. This is a normal size, it’s not recommended to do surgery before the transfer. I would need more information not only on the location of the uterus of these fibroids, it would be good to know about the distance from the endometrium.
When we’re talking about intramural fibroids, there are different types 3,4,5 depending on the length, the distance from the endometrium, it’s not the same having 1 intramural fibroid of type 3 or type 5, it’s a very strict concept of the situation. However, theoretically, there is no problem to do an egg donation treatment and transferring a good embryo with good chances of success. When the size is more than 4-6 cm, surgery is indicated, this is not a consensus, but over 5-6 cm, it is recommended when we’re talking about intramural fibroids. If the fibroids are touching the endometrium or are submucosal, they must be removed after IVF treatment.
In this luteal phase, stimulation, considering there are high levels of progesterone that can decrease the risk of spontaneous ovulation. When we find 1 or 2 follicles in the last days before the retrieval, we like to have bigger follicles, more than 15-16. We want to make sure there is not an extra risk of spontaneous ovulation.
Several studies show 2 ways of stimulating the final maturation of these eggs with an agonist of GnRH and Ovitrel, where we have better results with the quality of the egg and the maturity and the health of this embryo. It’s difficult to assure, but there are no problems adding some extra medication. In my experience, I have had good results in such cases as these two. I’m not able to tell you if it’s been due to this dual triggering, but considering the scientific evidence, the results are interesting.
In this case, we have a normal ovarian reserve at 40 years old, it should be good to have more eggs to try to have more embryos. Our recommendation is to do a biopsy with PGT-A considering the risk of aneuploidy. That’s why, in these cases, it’s better to have more eggs. That’s why I would try with a medium, but the higher dosage of gonadotropins, because as I told you before, more doesn’t mean better. If you’ve done 2 previous treatments with a high dosage of medication with success, we could try a softer stimulation. I think doing a natural cycle if there is the possibility of having more eggs is a bit risky.
It would be good to know the combination of ovarian stimulation you did to be able to make some changes. There are many factors of the stimulation that are not reflected here, so I would need more details. To sum up, I would try again with your own eggs, but not in a natural cycle.
It would be good to know when it was done. For example, if we see fluid during ovarian stimulation, sometimes it’s related to the process of stimulation. If you see fluid between the ovary and the uterus, it’s very important to be sure that it’s not hydrosalpinx. Sometimes when we find that there is some amount of liquid in the fallopian tube, it can be dangerous or damage the embryo implantation. If there is a suspicion of fluid inside the fallopian tube, we need to check it because, in these cases, laparoscopy is recommended before the transfer.
If the liquid is in the Pouch of Douglas and the gynaecologist is sure it’s not related to the liquid inside fallopian tubes, there is no reason to worry about it.
The main probability that you did not become pregnant and had an ongoing pregnancy with success may be related to the internal quality of these embryos. As I told you before, implantation failure or this biochemical pregnancy is related to the problem of the embryo. PGT-A is very important to us and helps us avoid repeated failures. It would help us to see whether these embryos are healthy, but the issue is that if they are frozen, we would need to thaw the embryos so we can get the results, and after that, freeze them again so we can transfer. If they were of good quality, you could try again.
The main hypothesis is that the issue related to the immunological factor is very controversial. It’s hard to justify that this implantation failure happened due to immunological issues. The treatment with corticoids, antibodies can be dangerous for the patient, that’s why it’s significant to be sure that there are no other issues before thinking about the immunological issues. That’s why in a 42-year-old patient who is trying with a normal or suboptimal ovarian response, the most important thing is to study these embryos before transferring.
If these are your last two embryos, their quality is not the best, typically the worst of all, but there is no direct relationship between the external quality and the internal quality. I have seen that sometimes after 2 or 3 attempts with theoretically better embryos, the patient has not become pregnant, and after the transfer of the last blastocyst of worse quality, the patient has become pregnant.
That’s why I would possibly try an empiric treatment to cover all these hypotheses, but we always offer some medication like aspirin, corticoids, we are working with a small dose of prednisone, sometimes we offer heparin, however, if there is any thrombophilia or any vein problems, there’s no sense to add more medications and increase the risk for the patient. Therefore, it’s difficult to give the best advice. Thinking about the immunological disorders can be taken into account, but after we are sure that the embryos are internally healthy. Many centres don’t study the embryos properly before transferring them, and when they are frozen, the situation is more complicated.
The main problem is again that you’re 42 years old and have a very low ovarian reserve. As I’ve mentioned, theoretically, according to the statistics, between 10 and 50 eggs would be needed to obtain at least 1 healthy euploid embryo. That means you would need to do between 4 and 5 ovarian stimulation cycles, according to the statistics.
If you would like to try with your own eggs, you would need to consider doing PGT-A to be sure that you’re able to have a healthy embryo because there’s no sense to transfer an aneuploid embryo. I know it’s difficult to accept that the chances are low and to consider egg donation.
If you would like to do another treatment with your own eggs, you should ask your doctor and check the genetics of these embryos before transfer. There is no sense to transfer 1 or 2 embryos on day-2 without having more information about them because they probably are not going to arrive at day-5 of development. I think it’s better to inform the patient even though it’s difficult, but it’s better to tell them about their real chances. Thinking about donor eggs is not a bad idea.
With ageing, the cycles start to be shorter. Depending on the number of eggs, they are growing faster, and that’s why the quality is starting to decrease. This accelerated follicular phase means that the egg doesn’t have time to wait. I have seen some patients at 42-44, and they had a higher number of eggs than expected for their age, but it’s not correct to compare these patients with younger patients. It is giving some expectations that are not certain for these patients.
We cannot change age, and the quality is strongly related to age. The number is important, but finally, in a 43-year-old patient, the chances of having 1 healthy embryo are more difficult. Theoretically, if the reserve is good, in this case, it could be good to try a cycle with a medium or maybe higher dosage of stimulation considering that it’s possible to collect a good number of eggs.
First, it depends on if the patient is interested in having 2 children at the same time or they prefer to assure a good number of embryos. Theoretical, the quality of donor’s eggs is good, the point of starting is about, for example, 8 mature eggs from a donor, of course, not all of those 8 eggs are going to give 8 food quality embryos. That’s why, if a patient wants to have more chances for another child in the future, I would recommend having at least 15 eggs to get at least between 2-4 healthy blastocysts.
If you transfer 2 embryos at the same time, you may have more chances, but the difference is smaller than you think, and you are adding an extra risk of a successful pregnancy. The risk of a twin pregnancy is higher than you can imagine over the age of 40 when we talk about egg donation. The most important risk is related to prematurity. If this problem occurs in a twin pregnancy and, for example, you would start to deliver them at the 6-7 months of pregnancy, you have to consider the risk or the prognosis for these babies that are born 2 or 3 months before, is not good, that’s very significant to know. Therefore, my recommendation is to transfer 1 and then another 1.
We recommend culturing these embryos until day-5 of development because these embryos are stronger at that moment. They have more than 200 cells, between 100 and 200 cells, and a biopsy doesn’t cause a risk to its structure. After the biopsy, these cells are studied in a genetic department to be sure that they are healthy and euploid.
This process and getting the report takes about 2 or 3 weeks. That’s why when this biopsy is done, all the blastocysts must be frozen while we are waiting for the result. Freezing is not damaging the quality of these embryos. We have found that the pregnancy rates after a transfer of an embryo previously biopsied and frozen are the same if we transfer them fresh. The most important thing with this biopsy is that we are sure which of them are healthy and euploid, and we are going to be sure which embryos we are not going to transfer to avoid implantation failure or miscarriage, the rates of successful ongoing pregnancy are going to increase considerably.
Nowadays, laboratories with very sophisticated equipment and artificial intelligence are trying to understand the growth of the embryo process. They are trying to understand if these embryos are euploid without doing this biopsy. This growing process of these embryos is not controlled in these tiny labs, structures, cultural media, it’s giving us more exact precision if these embryos are healthy or not, but it’s not 100% like the embryo biopsy.
After 2-4 years we may get some more results, this is something that is researched. That’s why you need to be sure about the chromosomal health of this embryo. A biopsy is needed in this case.
In this case, I would recommend thinking about doing a cycle without the stimulation from the beginning and waiting to see how it’s growing. If it’s growing over 14 millimetres, add a bit of Menopur 150 units with Orgalutran to decrease the risk of spontaneous ovulation. When this follicle will be 19-20 millimetres through the dual triggering, collect 1 egg and let’s see.