In this webinar, Dr Halyna Strelko, the Co-founder & Leading Reproduction Specialist at IVMED Fertility Center, Kyiv, Ukraine, presented a real-life patient story who suffered from a poor ovarian reserve. Dr Strelko explained in detail what tests were performed, what protocols have been undertaken, and how, in the end, she managed to get pregnant.
Low ovarian reserve – real-life case
- a 29-year-old female with poor ovarian reserve after chemotherapy (Hodgin Lymphoma), fertility preservation before chemotherapy
The patient came to the clinic (IVMED) with 5 frozen eggs (3 mature) preserved before her chemotherapy. When she came to the clinic, her AMH was 0.2, and on the ultrasound, only 1 antral follicle and 1 corpus luteum was found.
All the investigations were done, infections were negative, coagulation tests found increased fibrinogen, but it may happen in such conditions, the general blood test was also normal as well as hormonal levels. The patient’s husband had a bit decreased sperm quality, only 3% of normal morphology and a decreased motility, a bit low count of sperm cells probably due to varicocele, which is the enlargement of the testis.
We discussed what is the best approach in this case and concluded that the stimulation is probably useless because of only 1 antral follicle, which means that stimulation will not increase the number of oocytes. Therefore, we decided on the natural IVF cycle and thawing these frozen oocytes, fertilising them, and performing a fresh transfer.
We received 1 egg, we are thawing 3 eggs MII and 2 MI. The embryologists tried to make the MI mature, and they were successful, they became MII. The ICSI procedure was done, but unfortunately, only 1 4AB blastocyst was obtained and transferred, however, the result was negative.
The couple came back after a few months on day five of the cycle so that we could try to receive 1 more egg. On day 5, a dominant follicle of 23 millimetres was seen, and it was ready to ovulate, which is very early, but this is the problem of a woman with very poor ovarian reserve where the follicles start to grow even in the previous cycle before menstruation. At the beginning of this cycle, we can see that they have 2-3 follicles, but one of them is big, another one is average, and one of them is little, so in the end, we cannot receive more than one.
We decided not to take this follicle and wait for the ovulation. We prescribed estrogens because we wanted to decrease the FSH level. After ovulation, progesterone was added, and in 2 weeks, we have seen 4 antral follicles. We started a new stimulation with Clomid + FSH and triggering with hCG, we received 4 mature oocytes and 2 blastocysts. The results were very good, with 2 blastocysts of very good quality 5AA and 4AA. One of them was transferred, and one frozen. We received a positive result, and the couple got pregnant with twins. It was monozygotic twins, and she had delivered two healthy boys.
Poor ovarian response: Bologna criteria
There is an official recommended criteria called Bologna criteria, established in 2011. During an ESHRE meeting, a guideline has been created to define poor ovarian reserve.
- advanced maternal age or any other risk factor for POR
- previous poor response to stimulation (POR), less than 3 oocytes in a normal stimulation
- an abnormal ovarian reserve (i.e., AFC 5-7 follicles or AMH 05-1.1 ng/ml)
It is necessary to have at least 2 of those 3 points to say that this patient has a poor ovarian reserve. Why is ovarian reserve testing so important? It’s because each egg at any age has a probability of live birth of around 4-6%, the more eggs we will retrieve, the higher chance of pregnancy. The ovarian reserve permits us a prognosis, for example, the number of follicles, probability of pregnancy, what should be the starting and total dose of medication we use, and success rate. In some cases, when we see that the probability of pregnancy is very low, less than 1%, we can discuss it with the couple and suggest egg donation or just the opposite if there is still a good probability of achieving pregnancy with our own eggs.
Ovarian reserve markers
There are a lot of markers of ovarian reserve and lots of possibilities to measure the number of follicles and oocytes. The first is age, then some hormonal tests like FSH, estradiol, Inhibin, and AMH. There are some dynamic tests, which means that we give something to the female and then measure what happens, like The Clomiphene Citrate Challenge Test (CCCT), and the GnRH agonist stimulation test (GAST). We can use ultrasound, we count the number of antral follicles, ultrasound machines are quite sensitive, and if we have follicles of more than 2 millimetres in diameter, we can see them on an ultrasound.
Another important marker is genetic tests because, in some cases, women can have a good number of antral follicles, but her receptors are not correct, they don’t see an FSH or LH molecule. In this case, the response to stimulation will be much lower than expected. The most precise method is histological, where it is necessary to take some part of the ovary and then see the number of follicles however, normally, we don’t do that.
Ovarian reserve vs. age
Why is age the first predictor of ovarian reserve? It’s because we know that age of women correlates with the probability of pregnancy. It is always individual, but in most cases, the number of follicles decreases with advancing age. Age is the most reliable predictor of pregnancy and live birth rate, not the number of follicles. Taking age into account, along with other markers, gives a better prognosis. In most cases, the limit of receiving a live birth with own eggs is 40 to 43 years old. This is mostly due to the genetic problem of eggs.
If women have an average response, so 7 -10 eggs before turning 39 years old, almost 100% of these women will have at least 1 genetically normal embryo. However, if we have poor responders, 1-3 eggs at 42-43, only 17% of embryos will be genetically normal, and only 37% of women will have a minimum of 1 genetically normal embryo.
Ovarian reserve – AFC & AMH
Another marker of ovarian reserve is the Antral Follicle Count, which is the number of antral follicles, which we can find on the ultrasound. This is a very important marker and has a low variability between cycles. Between antral follicle count measurement and a number of eggs in poor response and ovarian hyperstimulation syndrome, we can see a very high sensitivity, therefore, it is a very good method.
Why is AMH the best marker of ovarian reserve? If we compare, for example, AMH with FSH at 30 and 40, we can see FSH is normal. Then, when the age is near 50, we have mostly 0 ovarian reserve, it quickly goes up. One day it is okay, but it may be absolutely out of normal range the next day. It’s difficult to understand the moment we start to lose our eggs with FSH. The same is with estradiol and progesterone, the range is normal and then when we are going into menopause, it drops. When we look at the AMH level, the curve decreases progressively, and it permits us to measure it in the current situation.
If we compare the prediction of live birth rates in a fresh cycle, antral follicle count, AMH and age, we can mostly see the same result. The AMH level correlates with the number of follicles which we can receive. When we’re measuring AMH, it is always necessary to think about the laboratory variability of this measurement. It may be due to pre-laboratory preparation of blood, some temperature conditions, tests used in the laboratory, and in some cases, the results may be different from what you have in your plasma, so it is always important to have 2-3 different methods of measuring the ovarian reserve to be more exact.
What is the normal AMH level? The level depends on the goal and why we are measuring AMH level. It is better to talk about the possibility to receive some amount of eggs according to the AMH level. If we have less than 1 ng/ml, it is considered a reduced ovarian reserve, if we have less than 0.5 ng/ml, it is a very reduced ovarian reserve, from 1 till 2.5 ng/ml, it is more or less okay, it means that we expect to receive 10-15 eggs if it is more than 3 ng/ml, we expect to have a high response, and more than 3.5 ng/ml, suggests a risk of ovarian hyperstimulation. However, it is only concerning further stimulation.
The theory of the follicular waves
There is also a new theory of follicular waves. In the past, doctors were thinking that follicles are constantly growing, but it was discovered that follicles are growing by waves. In some cases, during one cycle, we can have 2 waves, in some other cases, we can have 3 waves. According to this, there is a time that will be good to adopt our stimulation protocol and find the moment when the wave of the growing follicle will be the most important, and it may permit us to receive more eggs.
On the slide shown, there is a change in FSH level during this cycle, and we can see the growing follicle. That’s why we have used these estrogens in our clinical case after ovulation, it decreased FSH level and the difference in the size of follicles a bit. Sometimes, we can 2 waves, sometimes 3 waves in the cycle, but the lower the ovarian reserve we have, the more difference in the size of follicles we can see at the beginning of the cycle. This is one of the biggest problems in patients with poor ovarian reserve. They come first on the second day of the cycle, and we cannot start the stimulation although we can see follicles, those follicles have different sizes, and sometimes we can start stimulation in the second phase of the cycle, sometimes just after ovulation. Therefore, it is important to look for these waves and find the best moment to start the stimulation.
Nowadays, the cryopreservation of embryos and oocytes works extremely well, at our clinic (IVMED), we’re doing around 85% to 90% of cryotransfers. The survival rate is around 99%, so there is no risk of the embryo not surviving the freezing, and it permits to start of stimulation any day of the cycle. Then we can freeze the embryos, wait for the optimal moment to thaw and then do the transfer.
The next slide presented the comparison of stimulations with estrogen priming
, which means giving estrogens after ovulation. It can decrease FSH levels a bit, and antral follicles grow in a more homogenous way. The number of follicles received is better, the maturation rate is higher, and the clinical pregnancy rate is mostly two times higher as well as the live birth rate. It may be a good method to receive more follicles and more eggs.
Improving the results
How to improve the result of simulation for poor responders? There are a lot of methods available, and we try to use them all. However, there are some that we use more often:
- adding estradiol in the luteal phase to receive a more homogeneous cohort of oocytes for stimulation
- adding recombinant LH because
- growth hormone to improve the quality and sensitivity of follicles
- androgens, aspirin to improve blood circulation
- specific protocols of stimulation
- natural IVF cycle
- oocyte cryopreservation
The poor ovarian response is a very typical situation in the reproductive clinic, and ovarian reserve testing is one of the most important parts of infertility evaluation because it permits us to understand what to do and how quickly we should start and which protocol, and which medication we should use. The essential markers of ovarian reserve are age, Anti-Müllerian Hormone (AMH) and Antral Follicle Count (AFC). AMH indicates an only number of antral follicles and is not related to quality. Age is the most important predictor of the quality of eggs, and in difficult cases, we should use an individual approach for each patient because it is essential for successful treatment.