During this session, Dr Elena Santiago, Gynaecologist & Fertility Specialist at Clinica Tambre, Madrid, presented a young couple’s case where the female partner had diminished ovarian reserve at 32 years of age. Dr Santiago has explained what tests were performed on the couple, what treatment protocols were suggested and how they were able to finally have a healthy baby.
Dr Santiago started her presentation by explaining that women are born with all the eggs in their ovaries. There are around 2 million eggs at birth, and then this number is decreasing throughout life. For example, we have 2 million eggs at birth, and we will have only 400 000 in puberty, that’s when our fertility is going to begin. From then on, each month we’re going to be losing lots of eggs. When we are 37 years old, we should have around 27 000 eggs.
There are lots of women with low ovarian reserve, and the egg quality decreases at the same time. In menopause, we can still have some leftover eggs, and it’s about 1000, but these are no more going to be available because the ovaries are not going to be responding to hormonal stimulation.
What are the factors that influence ovarian reserve?
How can we check your ovarian reserve? There are 2 important tests that we should be checking in a first fertility consultation. The first thing we can do is to do an ultrasound to check the antral follicle count (AFC), we can see how many antral follicles we have in each ovary. A normal ovarian reserve should be between 10 and 20 antral follicles between both ovaries. This result we have to compare to a blood hormonal testing of the Anti-Müllerian hormone (AMH), and a normal reference is between 1 or 3.5 ng/mL. A high ovarian reserve is when we have more than 3.5 ng/mL, and a low ovarian reserve is when there is less than 1 ng/mL. It’s necessary to compare ultrasound and check AFC with AMH level. Sometimes, we may not see all the follicles during an ultrasound due to birth control pills a woman is taking, but they do have a good ovarian reserve.
The case presented a couple who have been trying to conceive for 1.5 years. The woman was 32 years old with a normal BMI, no previous treatments, no diseases or current medication, and there was no familial background of early menopause. She didn’t smoke or drink alcohol every day or several days per week, only occasionally. Her partner was also 32 years old, with no diseases or current medication or no familial background.
We started with performing a sperm analysis which was normal, with a concentration of 22.1 mil/ml, in total, he had 44 million, which is quite good, the motility was normal at 58%, it should be more than 32%, and the morphology was 4% of normal sperm which is quite common. We did a karyotype test, which was normal, and the test for infectious diseases screening was negative.
A female patient had a low AMH level at 0.5 ng/ml, such low ovarian reserve begins to appear most frequently from 38-40 years onwards. She had 1 follicle in one ovary and 4 follicles in the other ovary, so in total, there were 5 follicles which are low as well. A normal ovarian reserve should be between 10 and 20 follicles. We also checked FSH, which was high LH, normally, it should be lower than 10, and the patient had 15.2. She had a normal smear test, the infections diseases test screen was negative, she had normal blood cell count and clotting, and we also checked her thyroid, and TSH was 1.01, which was normal.
Taking into account all the factors, in this case, we decided to do an antagonist protocol which is a short protocol. Normally, we go with this protocol in almost all patients nowadays. We started medication between the 2nd – 3rd days of the cycle, and we used a medication called Choripholutropine alpha, a type of gonadotropin that we like to use in low ovarian reserve. We used a higher dose of 150 micrograms, and also we put an effect of HMG, a kind of LH effect to try to have the best quality of eggs as well as the highest number of follicles. On the 8th day of stimulation, we added FSH recombinant at 225 UI, there were 10 days of stimulation which is more or less the average, and on the 11th day, we had in total 4 follicles growing. In the right ovary, we had a greater follicle of 20 millimetres, the others were small, and in the left ovary, we also had a good follicle of 19 millimetres, and other ones were. In total, we had 5, but we had only 2 that were of good size.
We did a double trigger to provoke ovulation, for this we are using 2 medications, GnRH and hCG. We tried to increase the chances of having the maximum number of mature eggs, we had only 5 follicles, and 3 of them were very small, so we wanted to try to have more mature eggs. We performed a hormonal blood taste on the day of the trigger, we had good Estradiol at 8.68 pg/ml and progesterone level was high at 3.62 ng/ml, and when progesterone is higher than 1 ng/mL on the day of the trigger it’s preferable to do a transfer in another cycle because implantation rates are going to be lower. Sometimes we can have high progesterone because of medication, this depends on the response of the patient. We finally went for the egg retrieval, we only obtained 2 mature eggs, we performed the ICSI procedure, meaning that each egg is injected with previously selected sperm, we kept embryos in the time-lapse incubator and the next day, we saw that both eggs fertilized.
Those 2 embryos developed into blastocysts of good quality, we achieved a day-5 blastocyst of 3BA and another 6-day blastocyst which was 3BB, both embryos were frozen for a deferred transfer. We did an endometrial preparation with oestrogens of 6 milligrams per day for 12 days, we did an ultrasound to see if everything was okay, we started with oestrogens, and did a second scan for 12 days after, we had a trilaminar endometrium of 9 millimetres. We started the luteal phase support by adding progesterone pessaries of 400 mg every 12 five days before the transfer. We recommended going for a single embryo transfer, and 11 days after, we did the pregnancy test, which was positive with a very good hCG level of 326 UI/ ml, a good prognosis is 100 hCG or more. There were no fetal or maternal complications during the pregnancy, and 9 months later, a healthy baby girl was born. It was 2 years already, and the couple came back to the clinic because they wanted to try for another child as they had the frozen blastocyst left, so we did a very similar endometrial preparation, but in this case, the pregnancy test turned to be negative.
We count antral follicles when they are lower than 10 millimetres, but we do count all because if, for example, we’re doing an ultrasound on the 13th day of the cycle, we’re going to have a great follicle in one of the ovaries for sure, we do count with that follicle too.
It’s the other way around. We normally try to trigger when we have follicles at a minimum of 18 millimetres at least, but if we have other lower size follicles, we try maybe to wait for a little and see if we can get more follicles of good size, let’s say from 16-17 millimetres onwards. In this case (in my presentation), as you’ve seen, we had 2 follicles with good sizes, but the other ones were too small, and we couldn’t wait for them anymore. As I said, after 10 days of stimulation, on the 11th day, the trigger was off, we don’t go for the trigger before because we don’t think that this is going to help.
It seems that there’s bad quality of the eggs. It could be related to age and other factors that we don’t know the reason for bad quality. As you’ve mentioned that you had more or less the same result with a normal cycle and mild cycle, you could go ahead with another stimulation and try a natural cycle, possibly.
You have to decide whether you have the strength to go ahead with it because you’ve seen that 2 times, the results were very similar, so sometimes we can get better results, but it’s very difficult to do something medically that is going to improve that result. You have to see uh whether you want to try again, as I said, mild stimulation or even a natural cycle could be an option, or if not, the other option would normally be egg donation donated eggs. With egg donation, you will have much more chances of pregnancy for sure.
Nowadays, at our clinic, we don’t do that, it’s something that we don’t have enough evidence on yet.
It’s hard to give you the cause. It has to be related to egg quality. We normally say that the first days of division when we don’t have good results, it’s more because of the egg than the sperm, but here we would need to see more details about the male and female factor to have more information.
We do lots of PGS testing, nowadays, but in this particular case, we didn’t advise doing it because it was a 32-year-old woman. At this age, you are going to have at least 50% of healthy embryos. The idea was that we were not going to have loads of blastocyst, let’s say to select them with PGS, that’s why we decided not to go ahead with PGS, but it’s something that you can always do if you want. In this case, it wasn’t indicated.
It was the next cycle for the stimulation, we waited to have a period, and we did a scan with that period, we saw that ovaries were already resting. We did go ahead directly with a transfer. Sometimes, stimulation can cause the ovaries are not resting with a period, and we have to wait 1 month more to have a good situation and start the endometrial preparation.
We started them on the 5th day because we already had one follicle at 14 millimetres, so our idea is to start antagonists when we have at least 1 follicle of a minimum of 14 millimetres. If not, another way is doing it on the 6th day of the stimulation. We normally go for the first option with 14 millimetres, but sometimes we do have patients that have very small follicles during the first 5-7 days of stimulation, and we do have to wait a little more to add the antagonist, in this case, it was the 5th day.
Optimally, we need to have 3 layers to go for transfer and no signs of ovulation in the ultrasound, but I don’t know if they did this, but you have to check that there hasn’t been any spontaneous ovulation before doing the trigger. You check it by doing a progesterone test, so I don’t know if this was done. If you don’t have 3 layers shown on the ultrasound, you have to check if there has been any premature ovulation.
This is very important, sometimes we do have endometrium that is not trilaminar, and there hasn’t been ovulation, it happens as well. This depends on each case, sometimes you can have ultrasounds where the angle of the uterus is not perfect to see a trilaminar endometrium, so this is something to take into account as well.
It’s very difficult to put a limit, you’re still very young with a good prognosis, but it’s true that after 2 failed attempts if there are no other known factors egg donation could be an option. However, I don’t know if you had a good embryo quality or if there’s a need to do some other tests, we have to check, it depends on the case. After 2 or 3 attempts, we do always recommend egg donation if we see, for example, that the egg quality is not so good according to your age before doing anything. If you’ve done 2 cycles and we see that egg quality is not good, then we do recommend going for an egg donation.
Your FSH seems very high, I’m not sure if this was done at a good time of your cycle, but as I said, it’s normally not important. AMH, I think you’re talking possibly about picomoles, not nanograms, so 2.1 picomoles, is quite low with only 1 antral follicle. Even if you are very healthy with good immunity, good body weight, your age is not a very good prognosis because we can go ahead with the stimulation, we could achieve a follicle growing after stimulation, possibly we could retrieve an egg, and it could fertilize, and we could have a good blastocyst, but you have to take into account that getting there is quite difficult, even if we have an embryo chance of pregnancy are low because of your age.
Instead of having, for example, 50% chances of success with 1 embryo, you’re going to have around 20% chances, because as I said, egg quality is going to be lower, and they are going to be chromosomally abnormal embryos. You are in a situation where you could try with your own eggs to see what happens. My advice is to be very conscious of the situation. You need to be aware that if it doesn’t work, you should go for egg donation.
Both things. If you are using Time-lapse, you have to take into account that if you had normal divisions, you are going to have a morphological classification. However, if that embryo had abnormal divisions during, for example, the first days, that is something you have to take into account for sure. If at last, you have a very good quality blastocyst, but not very good divisions and you have other blastocysts to choose from, then you will perhaps choose the one that didn’t divide correctly, the last one.
This is something that you have to take into account in the final classification, which is normally morphological. However, if there are very bad divisions, let’s say, or abnormal divisions in the first days, it’s something that we have to take into account in the final classification for sure.
Normally, we don’t use Duphaston for the luteal phase support. We use micronized natural progesterone, these are different pharmaceutical combinations, Duphaston, we don’t use it.
At first, I would like to have more information, but at first, it seems that it’s not a bad sperm count, and for an IVF, we don’t need lots of sperm, we can do IVF as you’ve seen we are going to select only one sperm of all normally millions that we have. If you have good progressive motility and I hope that normal morphology, but don’t worry, even if you have an abnormal morphology, you have 1-2%, it’s fine for an IVF treatment and ICSI.
Yes, normally, we give 2 together 36 hours before the egg retrieval. There are cases, if unfortunately, we had, for example, spontaneous ovulation, and we don’t understand why this happened, maybe we were changing the timing and giving these drugs a little later, changing the timing, but that’s not the standard case. Normally, we give both of them 36 hours before.
This is very individualized. At our clinic, we normally add LH from the beginning. It’s true that perhaps if we have a patient who you started with FSH only for whatever reason and we see that the response is not very good, and we want to increase the dose or whatever, we can add that LH during the first ultrasound before starting with stimulation, it’s around the 5th day of the stimulation cycle. Normally, we give it from the start, but there are other options where we can add Menopur or LH later on.
We’re doing quite a lot nowadays because, for example, we have lots and lots of patients with a low ovarian reserve, unfortunately, and normally as I said, we are doing PGS from 38 years old onwards. If we think that we are going to achieve 1-2 blastocysts in each cycle, we do recommend trying Duo-stim from the start. We think it works quite well.
The results show that the response, so the final number of eggs, is the same as in the previous stimulation cycle or even a little higher. Whenever we can, we do recommend going ahead with the duo-stim. Another advantage is that you don’t have to wait 1 month and a half to go ahead for another stimulation, you start 5 days after the first egg retrieval.
Yes, we measure progesterone before the transfer when we do the trigger as you’ve seen, and we do measure it before doing the transfer, for example, after endometrium preparation for frozen embryo transfer. Before adding up the progesterone pessaries, there are also shots, we always measure progesterone even in a natural cycle.
There’s no protocol for everyone, as I said, we try to individualize it. If you mean which protocol we use comparing antagonists or agonists, as I said, normally antagonist, it depends on the person, age. The idea or the recommendation is to try to have between 12-1 5 mature eggs so we can have maximum chances of success in the future.
You can do a single trigger or a double trigger as well whatever you prefer, there is no inconvenience in, for example, putting hCG before the second stimulation. You can trigger with whatever you think is going to be best, we do lots of dual triggers in duo-stim as well as we do have a low ovarian reserve, we do it a lot. If you have a patient that has a very high response, a very high number of follicles, and there is a risk of getting hyperstimulation, then we only use the agonist of GnRH, Decapeptyl. You won’t have that added risk of hyperstimulation, but as I said, you can use both of them if you want.
We normally do lots of combined treatments. We put in FSH and HMG or LH effect because nearly all our patients are aged more than 35 years old, and we believe that we try to increase egg quality by putting both medications, so normally we go with both of them.