In this session, Dr Alejandra Aguilar Crespo, Gynaecologist at Equipo Juana Crespo, Valencia, Spain, has discussed past patient’s case story, and explained what diagnostic tests needed to be taken, what protocols had to be changed which helped to achieve the final successful result.
Dr Alejandra Aguilar Crespo presented a study case about a Spanish couple who came to the clinic at 40, she has never been pregnant, she and her partner were trying to conceive for 3 years already, and her periods were regular, but she suffered from severe dysmenorrhea which is painful periods and dyspareunia which means pain during sexual intercourse. She was diagnosed with endometriosis, and she was psychologically affected because of her infertility, and her painful periods. The male partner was 36 years old, his sperm analysis was normal, and sometimes other semen analyses showed that he had oligospermia, a low quantity of spermatozoids.
They did previous treatments in a public hospital in Spain, they underwent 3 transfers. In the first transfer, 2 day-3 embryos were transferred, and the rest was vitrified, the transfer was very difficult, and it was painful. They performed an embryo transfer in a substituted cycle with patches, they transferred the 2 remaining day-3 embryos, but she didn’t get pregnant. Again they performed a second, and they vitrified 2 day-3 embryos, they didn’t perform a fresh embryo transfer because the patient asked for it. She didn’t feel well after the egg collection, so that’s why they vitrified the embryos. A couple of months later, they transferred those remaining embryos in a substituted cycle with estrogen pills, but she did not get pregnant.
After that, they perform a hysteroscopy just to check the endometrium, and it was normal, the biopsy showed that there was no endometritis, and they performed a karyotype and thrombotic risk profile, which were normal.
We did a vaginal examination, and we saw that the uterus was fixed, and it was very painful. This ultrasound scan was done on the 21st day in the luteal phase, she had a swollen uterus with diffuse adenomyosis, the endometrial thickness was very thick measuring, 18 millimetres, and in both ovaries, we saw 2 endometriomas and 3 antral follicles in each ovary which was a low ovarian reserve. After the previous examination, the diagnosis was deep endometriosis, adenomyosis, low ovarian reserve and a possible male factor due to his previous sperm analysis showing oligospermia.
The plan was to improve the oocyte quality, so we prescribed vitamins and antioxidants, and we recommended losing a couple of kilos because her BMI was 26. Secondly, we decided on a short protocol with letrozole, which is an inhibitor that helps to decrease estrogen levels, which is good if we are dealing with endometriosis as the oestrogens can affect the uterus. Letrozole increases the FSH and LH levels, so it can also help with the stimulation. It was a short protocol using recommended FSH and Menopur.
We did the first simulation, and the estradiol, and FSH levels were good, so we were able to start the stimulation, and we got 5 eggs, but we only got 1 day 3 embryo. We tried to make the embryos develop to the blastocyst stage, but there was no evolution. After that, we did an MRI in the luteal phase, just a couple of days after the egg collection, and it showed an anteverted uterus with a normal endometrial thickness, we also saw the endometriomas and a thickness junction zone in the fundus and the anterior wall which is a sign of adenomyosis. We also did the hysterosalpingography that showed her right hydrosalpinx was patent and a distal blockage of the left tube.
As we only had 1 embryo, we decided to perform a second stimulation with the same protocol, this time, we got 2 day-3 embryos of very good quality and 1 blastocyst of a medium-low quality. The patient wanted to do a third stimulation because she wanted to have as many embryos as possible. Therefore, we did the next stimulation, and we got 2 day-3 embryos, and 2 blastocysts (day-5 and day-6). In total, we had 5 day-3 embryos and 3 blastocysts.
We started the treatment of the uterus and the fallopian tubes treatment, we planned surgery, we did hysteroscopy to remove all fibrosis and to increase the implantation area to make some different cuts to improve the vascularization of the uterus and improve the implantation, and we also did a laparoscopy to remove both fallopian tubes, the endometriomas and the uterosacral node. The findings were as we expected, bilateral hydrosalpinx, a uterine fibroid, and a very small uterine fungus were also removed. We also found severe adherential syndrome and deep endometriosis with a vaginal node. We injected her with quarterly Decapeptyl, which is an analogue of the GnRH to treat endometriosis because they make the ovary rest, which makes the woman menopausal for at least 3 months. Endometriosis is an estrogen-dependent pathology, so if there are oestrogens and ovulation, endometriosis can get worse.
After 3 months, we started endometrial preparation with low doses of oestrogens, it was 2 mg. After 8 days of uterine preparation, we did a scan, and the endometrium was great, so we decided to go ahead with the embryo transfer. We did a double embryo transfer, we decided to transfer 2 day-3 embryos of the second cycle and a blastocyst of the third cycle, which means that we put 3 embryos. Why? We had to take into account that it was a woman who had 6 day-3 embryos transferred before, she had endometriosis and was 40 years old, so it meant that from those 3 embryos she would probably get 1 baby, that’s why sometimes in women with endometriosis and pathological uterus, we need to transfer more to get a pregnancy.
After 10 days, they did a positive pregnancy test, and a scan that was done a couple of weeks later showed an evolutive single clinical pregnancy, and we could see also the heartbeat, and everything was going well.
Nowadays, we are facing a delay in maternity, women are deciding to delay maternity because of several reasons including social, economic factors as well as medical reasons:
Over the last decades, we are witnessing a delay in which the woman has her first child, the average, for example, in Spain, is around 33 years old. This can have a severe implication because the older the woman is, the lower probability of pregnancy. On the graph shown, we can see that after the age of 35 years old, there is a decrease in fertility, and therefore, there is an increase in infertility. There are a lot of women going ahead with assisted reproductive techniques.
What are the causes of the decrease in fertility due to maternal age?
Normally, when a woman is born, there are 1-2 million oocytes, but then among them, only 400 000 will reach maturation and will reach puberty. However, among them, only 400 will reach ovulation, and the rest of them reach atresia. In a single menstrual cycle, for example, there is follicular recruitment, but among them, only 1 will be in charge of releasing the oocyte. If there is no fertilization, 15 days later the period starts, and the rest of the follicles die, and there is another follicular recruitment.
How can we measure ovarian reserve? We have several tools to measure it:
The increase in the FSH level is the first endocrine sign of reproductive ageing, and it explains the accelerated depletion of the follicle, the shortening of the follicular phase and the increase in the incidence of dizygotic twins.
One of the main causes of low ovarian reserve is age. The older woman is, the lower amount of eggs she’ll have, but we also need to take into account all the factors or the cause of low ovarian reserve, which could be a genetic disease such as fragile X syndrome, some autoimmune disease, environmental factors, cancer treatment, chemo- radiotherapy, ovarian surgery or idiopathic when we don’t know the cause.
The second cause is a decrease in the oocyte quality and the older the woman is, the lower amount of eggs she has and the quality of that oocyte are also worse. The older woman is a higher probability of having abnormal oocytes. If a woman has an incorrect number of chromosomes in their oocytes, the higher chance of having abnormal embryos. This will increase the implantation failure and miscarriage rate. We should take into account that at the age of 40, at least 60% of the embryos will be abnormal. If we transfer an abnormal embryo, there is a high chance that it won’t implant or end in a miscarriage. The 3rd thing and most important one is the probability of having a baby with a chromosomal abnormality, for example, Down syndrome.
The third cause of decreasing infertility by maternal age is the uterus. A woman of advanced maternal age can have:
However, endometrium remains stable through age. Women can also have a higher risk of obstetric complications, such as gestational diabetes, hypertensive disorders like preeclampsia, placenta previa, risk of instrumental delivery, preterm delivery, and fetal deaths.
Currently, we now only use Letrozole for the stimulation for 5 days of the stimulation. Letrozole will maintain the endometrial sickness and with that, we can also increase the size of the follicles in all the women. We don’t use Letrozole for more than 5 days. Sometimes Letrozole is used in patients with breast cancer, and we need to stimulate women with breast cancer, we use it but only for the stimulation.
We don’t use Letrozole for months. We also use Letrozole in people who have severe adenomyosis, and we use it with Decapeptile, then we use Letrozole for at least 15 days or a month, but no more than that. It doesn’t mean that it has bad effects, but we don’t like to use that for too long because it has been demonstrated, it can help with that kind of period. We have good results with this time frame.
After an IVF treatment, you can have some irregularities with the periods, but it’s important to understand that after the age of 40, there is a drastic drop in the ovarian reserve, and sometimes it can be a sign of perimenopause. We can check it with an ultrasound scan or a blood test. Don’t worry because we can still go ahead with an IVF round, your AMH is low, but it doesn’t mean we won’t have any eggs. However, it’s completely normal that the first two months after stimulation, the periods can be irregular or heavier. If you have hot flushes, it means that your FSH level is very high and your ovarian reserve is low, but if we know that your FSH level is very high, we’ll try to use a protocol to decrease this FSH level to get as many eggs as possible.
The first thing we need to understand when we see an infertile couple is the reason the woman doesn’t get pregnant. Is it because of the male factor or her endometriosis, etc.? For example, just at the first consultation, we know that the woman didn’t get pregnant because she had severe and deep endometriosis and a possible male factor, and of course, an advanced maternal age. In your case, even if your embryos were euploid, it doesn’t guarantee a pregnancy 100%. We need to understand that because the quality of the embryo is important. Sometimes a low-quality embryo that suffers during a biopsy, then it’s frozen and thawed, because of that, we can lose potential implantation.
We need to check the quality of the embryos, and of course, it’s mandatory to check the fallopian tubes and the uterus. We use hysteroscopy as a diagnostic technique, we can see inside the uterus and try to widen the endometrial cavity, to make the uterus more receptive.
Not everybody can do the hysteroscopy, everybody knows how to do a hysteroscopy, but doing it well and performing hysteroscopy to try to direct the embryo to the area so it can implant is very difficult. If there are no experts at hysteroscopy at your clinic, my advice is not to do it. A good option is to check it with an MRI or with Hysterosalpingography (HSG) if there is any problem that can lead to the implantation failure.
One thing to check is to perform an ultrasound scan just to confirm the ovulation, this is the first thing that can do. If you don’t have regular periods and don’t know if you are ovulating, they can give you the contraceptive pill, and therefore you can start with Diphereline.
Normally in a long protocol, we prefer not to give the contraceptive pill, but sometimes in people with very irregular periods or people with polycystic ovaries who have periods for 3-4 months, we give the contraceptive and therefore, we can plan the treatment.
This is something that we should be aware of, it’s very simple to talk to a patient and say, you have to lose weight, but it’s never simple. We do need to know that a BMI over 32 decreases the number of eggs, the probability of implantation and increases the risk of miscarriage. Age is the most important factor, luckily you have embryos when you were 36, I don’t know your BMI. If it is your first embryo transfer, of course, and, your BMI is lower than 32, I would try to transfer an embryo.
If not, we need to focus on losing weight. If, for example, you’re worried about those 3 embryos, you can do and also it’s another stimulation to get as many embryos as possible, but from my point of view, we have a lot of people with high BMI that get pregnant as well, but they need to know that they have a 5% probability of bad luck, in that case, taking into account your BMI. If it’s over 35, my recommendation is to lose weight otherwise, the results will be probably bad.
The dose of estrogen depends on every woman. If we see that your endometrium is very thick, it means that we need to decrease the dose of estrogen. If we see that the endometrium is not thick enough, we need to increase it a little or change the way of the uterine preparation.
As you had 2 embryo transfers with an egg donation, we need to understand why they failed, we may be facing a uterine problem. We need to check the quality of the embryos, but I assume that as it was from an egg donor, the quality was fine. I assume that you got 4 blastocysts and 2 with a single embryo transfer, probably, so you only have two blastocysts left. I know you are 50 years old, and we always recommend doing a single embryo transfer, but in that case, as you have the only remaining blastocysts, which probably will be of worse quality, my advice would be to transfer both of them.
Regarding the uterine preparation, if they’ve done 2 FET attempts and they have not been successful, they need to change something, they need either change the uterine preparation, you can go ahead with a natural cycle or with a different way of taking oestrogens like vaginally, patches and they also need to study your uterus. If you have fibroids, you need to check where those fibroids are, if they are touching the endometrial lining if they are close to the endometrial cavity, this is very important. We need to check the fallopian tubes, also your thrombotic risk profile.
It depends on the woman, I would never recommend a protocol without seeing a woman. It has been demonstrated that a long protocol in a low ovarian reserve has good results. In our clinic, we like to personalize the protocols, but it depends, most of the women coming to our clinic had previous failed treatments, so we need to change the protocol, we need to do something different. If they got a very good number of embryos or oocytes in the previous treatment, we will repeat it. We will change it if they had not been successful. The type of protocol depends on the characteristic of the patient, her ovarian reserve, her previous treatments and her age.
This is one of the things that happen a lot. People are very afraid of the polycystic ovary, and we don’t have to be afraid of it. In your case, you have a very good ovarian reserve, which means that we need to take advantage of that. We won’t give you super-high doses of hormones because we don’t want to cause a severe hyperstimulation syndrome, but in that case, with an AMH of 20 and having only 4 eggs, it means that the stimulation was done very badly. We need to take into account that in the polycystic ovary, the LH levels are very low, so it means that they need LH, they need, for example, Menopur.
They have changed to a long protocol, I think it’s a good solution because in your case, probably they gave you Decapeptyl, they didn’t give you Ovitrelle, that’s why you didn’t reach the LH level, so that’s why they retrieved only 4 eggs. That’s why it’s better to do a long protocol this time.
For people with polycystic ovaries, the long protocol is very good. Some clinics refuse to do it because of the risk of hyperstimulation syndrome. However, if we vitrify eggs, check estradiol level in each follicular tracking scan, if we try to prevent this hyperstimulation, I think we will have a good amount of eggs and therefore a good amount of embryos. At 40, we need to take into account your AMH level, and for that, we need to get as many eggs as possible and, therefore, as many embryos as possible.
My advice is, if you have more than 4 blastocysts, do PGS just to confirm that you have normal embryos, but don’t be afraid, you will feel bloated, you can feel a bit of discomfort, but just for a couple of days, we have several drugs to avoid this hyperstimulation syndrome.
Yes, of course, it can happen, not that the egg quality can drop significantly, but it has been demonstrated that in people with a low ovarian reserve and older women, giving more than 300 units is a waste of money, and also it can cause adverse events. It can also impair the uterine quality, and it’s important not to increase the dose in older women. If the woman has a high BMI, we need to adjust these doses, but no more than 225 or 300 in that kind of patient.
Since they were blastocysts, and it was from an egg donor, it means that you have an implantation failure, and the reason is not the ERA test. The reason is beyond that, we need to check the uterus by doing an MRI, by performing a hysteroscopy just to rule out adenomyosis, endometriosis, endometritis, which is an inflammation or infection of the endometrium. We need to check the fallopian tubes, which are very often omitted and sometimes there is a hydrosalpinx or something wrong there that provokes this implantation failure. Once we remove these fallopian tubes, women get pregnant. We need to study the uterus, fallopian tubes, also check your thrombotic risk profile to be sure that there is no problem with your coagulation.
It’s important to check the quality of the embryos, if it was an egg donor, it would be good to check if this donor has previous pregnancy or previous cycles, we need to check if the quality is okay.
When we have 2 failed embryo transfers, it means that there is something wrong, and we need to focus on different things because it’s not just bad luck, it means that we are doing something wrong, and we need to investigate in other ways to find this issue.
In that case, it can be an embryo quality, the first thing is to perform PGS to confirm that the embryos are normal because, for example, if we do a cycle and we see that the embryos are chromosomally abnormal, it means that we are facing a problem of the ovarian quality. That is the reason for implantation failures. If we perform a cycle and you have normal embryos, it means that your previous embryo transfer was probably with normal embryos. We should investigate the other cause of implantation failure.
In our clinic (Juana Crespo), we don’t use the ERA test because it was a promising technique 10 years ago, but now it has been demonstrated that it doesn’t change anything. There are a lot of papers that confirm that the ERA test doesn’t increase the probability of pregnancy. We had a lot of patients who did the ERA test, and we decided to transfer the embryo when the patient was ready, and she got pregnant without taking the ERA test into account. Therefore, I do not recommend the ERA test because it won’t change it.
If you are planning to do an ERA test, you can. ALICE and EMMA are complementary techniques, they can check the microbiota, which is completely fine because if they see that there is something wrong, they can give you probiotics, or if there is an infection, they will give you antibiotics. If you are planning to do the ERA test, it is the same technique, so you can also do the ALICE and EMMA.
It’s the ultrasound scan and the hysteroscopy. I mean the eyes of the gynaecologist and the experience of the gynaecologist. In our clinic, for example, before putting an embryo the day of scheduling the embryo transfer, we perform a diagnostic hysteroscopy, and we check the endometrium if this endometrium is fine without signs of endometritis, with a good shape and good colour, for us, it is more reassuring than the ERA test because it analyses a couple of genes but the endometrium changes every month. If your endometrium is pre-receptive, you don’t know if it will be the same next month. The best technique is to do the scan, and the hysteroscopy, which will show us that this endometrium will be in charge of allowing the pregnancy in the same cycle.
If your TSH level is okay, your eggs will be completely normal. Hypothyroidism hasn’t been related to bad egg quality, it can imply during the pregnancy or the neural development of the baby. A complete hypothyroidism disorder with a super high TSH level can compromise fertility because your menstrual cycle can alter, but if your periods are regular, don’t worry, the egg quality will not be affected because of it.
The answer is yes. It has been demonstrated that it can increase the oocyte number. For women with low ovarian reserve, every oocyte matters, so we give DHEA, we prefer DHEA to testosterone because sometimes the testosterone can provoke ovarian cysts which is not malignant. DHEA should be administered at least 21 days before the stimulation, so we start taking them the previous month of the stimulation and continue until we get embryos.