In this session, Dr Anna Blázquez, Head of Medical Research & Specialist in Assisted Reproduction at Eugin Clinic in Barcelona, talked about low ovarian reserve, and treatment plans that can help with achieving a successful outcome. Dr Blázquez provided 5 clinical cases where all patients were suffering from low AMH and their successful outcomes.
Dr Blázquez started by explaining what low ovarian reserve means, and she explained that it is a decline in the follicular pool of the ovary. The follicle is like a balloon with the oocyte, the egg inside when the specialists do a scan and ultrasound, we measure those little black rounds, and these are the follicles, and each follicle contains one egg. The main cause of low or poor ovarian reserve is age. We know that when we are born, we have around 1 million oocytes, but each month, we ovulate only from one single egg, many others start the process of getting mature, and we lose them naturally. That’s why, each month, we lose several follicles, and finally, we reach menopause. However, not only age is causing low ovarian reserve, there are some other issues, and other pathologies that can decrease the ovarian reserve of a woman. For example, endometriosis, infections, ovarian surgery, also idiopathic causes when we don’t know what is causing that. Poor ovarian reserve decreases the chances of getting pregnant, and usually, patients with low or poor ovarian reserve need medical help to get pregnant.
To diagnose a low ovarian reserve, we need to perform a test to measure the ovarian reserve. There are some indirect signs of a low ovarian reserve, it can be the shortening of the menstrual cycle. A lot of patients say that they used to have cycles of around 28-30 days, and in the last month, their cycle shortened to 24-25 days, which could be a sign of low ovarian reserve. However, not all short cycles mean that the ovarian reserve is decreasing. There’s a test that was used in the past a lot, and it is basal FSH which is a hormone that should be measured at the beginning of the cycle, and when FSH is high, typically above 10-15 units, it could mean that the ovarian reserve is low. Two other tests that are used nowadays are: The Anti-Müllerian hormone (AMH), which is a hormone that can be measured at any point of the cycle, it should be done by a blood test, and then there is The Antral Follicle Count (AFC), that’s the count that the gynaecologist or the specialist do by ultrasound, we can check how many follicles a patient has in each ovary. We look at both tests, the lower the AMH level or lower the AFC level we have, the lower the ovarian reserve.
The main issue is that there are no universal criteria to say from which point this ovarian reserve is normal or is low. It also depends on the age of the patient. In 2011, The European Society of Human Reproduction and Embryology (ESHRE) published The Bologna Criteria to try to diagnose patients with low ovarian reserve. They say that if a patient fulfils 2 of these 3 criteria, it can be diagnosed as a poor ovarian reserve. The criteria involve:
The main issue with such patients is the time. We know that every month we lose ovarian reserve, so we should try to get those patients pregnant as soon as possible. That’s why we usually skip the first treatment, which is intrauterine insemination (IUI). We know that IUI is a very good treatment for specific patients, but the success rates are lower than with IVF cycles and in poor ovarian reserve patients, as we want to get the pregnancy as soon as possible. We typically start with IVF cycles, and the standard treatment for these patients is to do an IVF cycle with a high dose of Gonadotropins for ovarian stimulation. There are different kinds of gonadotropins, but the important thing is to start with high doses. Then we have some other strategies, for example, the modified natural cycle where the patient starts without any kind of stimulation, and once she naturally has selected 1 egg to ovulate, we give her a mild stimulation to ensure that we will have at least 1 egg and then we do the oocyte pickup to get only 1 oocyte. This strategy is for patients who have a very low ovarian reserve and we know that even if we changed the strategy, we will only get 1 egg.
Another strategy is androgen supplementation. This is a bit controversial because there’s no scientific evidence yet to show that giving androgens can increase ovarian reserve, but in some cases, we can try it. Androgens are male hormones that all women have in the blood, but the doses in women are lower, and in those patients, we can try to give a mild stimulation of testosterone to try to improve the ovarian response to the stimulation. Regarding IVF cycles, we can give the patient pre-treatment with an oral contraceptive or estrogen to try to synchronize all the follicles because, sometimes, even though the patient has a low ovarian reserve with around 4 or 5 follicles, we start with stimulation, and only 1 or 2 of these follicles grow. With this pre-treatment, we try to make all the follicles grow at the same time so we could program the oocyte to pick up to get all of them.
The last step that we can always use is egg donation. It’s the most effective treatment because the patients are usually 40 or above, and with oocyte donation, they have a higher chance of getting pregnant. There are 2 main advantages of egg donation, we have often more quantity of eggs, but also the quality of those eggs is better because donors are young, they are between 18 and 34 years old, and that’s what gives us better quality and more chances of getting pregnant.
The first case presented by Dr Blázquez was about a patient who came to the clinic when she was 43 after 11 years of trying to get pregnant. She had never been pregnant, and after the evaluation, she had 4 follicles, 2 in the right ovary and 2 in the left. Her AMH level was low at 0.8 ng/ml, so we suggested starting an IVF cycle due to her age, the years of infertility and her ovarian reserve. We did a cycle with a high dose of Menopur – 300 units per day.
We retrieved 3 oocytes, 1 of these oocytes was mature, we did the insemination with the ICSI technique with her partner’s sperm, we had 1 embryo that was transferred, it was a fresh transfer on day-2, and she got pregnant and delivered a healthy girl at 36 weeks. The baby was a little premature, but this is normal because with the age the rates of prematurity are a little increased.
The second case was about a younger patient of 36 years old, she was single, and she wanted to be a single mother. We started with intrauterine insemination with donor sperm, but after 5 unsuccessful failed cycles, we suggested going through an IVF cycle, she was then 37, and we re-evaluated her ovarian reserve, and we saw 6 follicles in the ovaries. We started with an IVF cycle with a high dose of Menopur, and after the oocyte pickup, we only got 2 oocytes, only 1 was mature. We did the ICSI technique, we had 1 embryo that was transferred on day-3 without success.
For a second attempt, we wanted to improve the ovarian reserve as we counted 6 follicles, but we only got 2 eggs, so we tried transdermal testosterone during the first 5 days of the ovarian stimulation again with high doses of Menopur. From this attempt, we got 8 oocytes, and all of them were mature. We did the ICSI technique, we had 4 embryos, 2 of them were transferred fresh, the first attempt wasn’t successful again, and two other embryos were frozen, then thawed and transferred without success.
The patient was not tired yet, and she did a 3rd attempt, we repeated the same strategy as in the second attempt because the results were much better than in the first one with testosterone, high doses of Menopur, and we had 8 oocytes, 6 mature, we did ICSI with the donor sperm, we had 3 embryos, and after the first transfer of 2 embryos on day-3, she got pregnant, and she delivered a girl.
The 3rd case presented the youngest patient of 5, cases the patient was 33 years old and came to the clinic after 2 years of trying to conceive without success. We evaluated her ovarian reserve, and we saw that she had 4 follicles, and her AMH level was 1.2 ng/ml, so we suggested the couple start IVF cycles and skip IUI.
We started the first attempt with a high dose of gonadotropins, and we saw that during ovarian stimulation only 1 follicle was growing. Therefore, before the oocyte pick-up, we cancelled the cycle because we thought that in this patient who had 4 follicles, we could have a better ovary response. In the second attempt, we tried a pre-treatment with oestrogens orally 1 week before starting the stimulation, then again, we did stimulation with a high dose of Menopur, but only 1 follicle was growing. This was the second attempt, so we decided to continue, and we did the oocyte pick-up, we got 1 mature egg that was fertilized with her partner’s sperm, and we did a single embryo transfer on day-3 without success.
For the 3rd attempt, we suggested trying a modified natural cycle, as we knew that only 1 oocyte was possible to achieve in this specific case. She started the cycle without any kind of stimulation, we did the follicular controls, and once we saw that 1 follicle reached 40 millimetres, we started a more mild stimulation, we did the oocyte pickup, and we got only 1 follicle, which we expected. We did a single embryo transfer, and in the end, we were successful, and she had a baby boy.
The 4th case was of a 41-year-old patient who came after secondary infertility of 1 year. The couple already had 1 daughter of 13 years old, they came to the clinic, and after evaluating her ovarian reserve, we saw that her Antral Follicle Count was 6 and her AMH level was 1 ng/ml.
We tried the first IVF cycle with the standard protocol with high doses of gonadotropins, and we saw that only 1ne follicle was growing, so again, we cancelled before the oocyte pickup as we thought that a better result could be achieved in this patient. In the second attempt, we gave her oral estrogens 1 week before starting the stimulation, then again, we did the simulation with high doses of Menopur, but on this occasion, we had 5 oocytes, 3 were mature, 2 correctly fertilized, and we did a double embryo transfer on day-3, and she got pregnant and delivered a healthy boy.
The last and final 5th case was about a woman of advanced maternal age, she was 44 when she came to the clinic with her partner. They had a miscarriage 3 years before. When we evaluated her ovarian reserve, we saw that it was very low, she had only 2 follicles in the ovaries, and her AMH level was 0.5 ng/ml. The couple already had 2 IVF cycles. In the 1st one with high doses of stimulation, she only got 2 follicles, 1 mature, they did a single embryo transfer without success and on the second attempt with the same protocol, they only got 1 mature egg, but there was a fertilization failure, so no embryo was available to be transferred.
At this point, we suggested doing egg donation treatment because this was the best treatment for them. She underwent an endometrial preparation with transdermal estrogen and vaginal progesterone, and we selected a donor for her. From the donor, we obtained 8 oocytes, 7 were mature, and after the second nation with her partner’s sperm, we had 5 embryos, and we left those embryos until the blastocyst stage, we finally had 4 blastocysts, and we transferred only 1 embryo because it was an embryo on day-5 with oocytes from a donor and she is now pregnant.
Indeed, it’s not always as successful as in these cases, it’s difficult for patients with low ovarian reserve to achieve a pregnancy. We always have the option of oocyte donation, but it’s crucial to remember that in patients with low ovarian reserve, especially if they are young, we can try to do many strategies to achieve a pregnancy.
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Low Ovarian Reserve and IVF With Donor Eggs
DHEA won’t increase the risk for cysts or polyps, but we don’t usually recommend it to our patients because there’s no scientific benefit of taking this medication to increase the ovarian reserve or even to increase the quality of the eggs. However, it won’t do any harm. If you want to take it, you can. We don’t think that it could increase the results substantially.
It depends a lot on the clinic because some clinics only do day-5 transfers, but as you have seen in my cases, we have done a lot of day-2, -3 embryo transfers. That’s because we know that between day-2 or day-3 until day-5, an embryo inside an incubator might not survive. An incubator is not the natural environment for the embryo, it’s the uterus.
We know that day-5 is a better stage to transfer the embryos because the implantation rate is higher. However, if there is a risk and from day-2 until day-5, we might lose some embryos putting them in a uterus can give us a very healthy baby. We decide if we take the risk for them to arrive until day-5, depending on the number of embryos we have.
If we have a lot of embryos, let’s say around 4 embryos or more, we take the risk to arrive until day-5 because maybe we will only get 1 at the end, but this embryo has a high potential of pregnancy. Usually, if we have 3 or 4 embryos or a lower number, we prefer to be conservative, and we transfer the embryos on day-2, -3 because we don’t want to lose a healthy embryo.
The embryologists are the ones that give us the recommendation depending on the number of embryos and on the quality of those embryos, and if we have 3 very good quality embryos, we can take the risk of arriving until day-5.
We are maybe a little conservative, but it’s true that maybe the patient will have more failed transfers, and it’s difficult to cope with, but we prefer not to lose any good embryo in the lab. That’s why if we have 3 embryos or fewer, we always do the transfer on day-3.
The best option in your case is egg donation, that’s true, because in the best scenario, maybe you can try with some strategy and a modified natural cycle or even with testosterone. I think the best response that we can have in your case is possibly one egg, so we can try with an embryo transfer, but the effectiveness after 3 failed different cycles with no embryos to transfer, with different strategies, different doses, the best option is egg donation.
Egg donation is a change of mind, some patients prefer to try all the options they have before changing to egg donation, which depends a little on you. If you are tired of negative results, if you can cope with more cycles and possibly bad results, then as you are 38, we can try. I would suggest trying a different strategy to see if we can have at least 1 egg, knowing that possibly only one egg might be obtained. If you are looking for the most effective treatment, it’s for sure egg donation.
At 49, we always do an egg donation or double donation depending on if the patient is in a relationship or not, but with egg donation, the chances of getting pregnant are around 60% at the first attempt. In cases, we don’t have a pregnancy in the first attempt, and a patient needs a second cycle, 85% of patients get pregnant, and in the number of cases that need a third egg donation cycle, 90% of patients get pregnant, so those are the chances of getting pregnant.
It all depends a little on if you have any basal pathology and if you have any uterine malformation, but if everything is okay, your chances are more than around 60-65% of getting pregnant in the first attempt.
No, if you have menopause, it’s impossible. In those cases, even in younger patients with early menopause, the only option is to go through an egg donation. If it’s menopause, that means one year or more without your cycles.
Accumulating embryos is an option that many patients want to try to have more options because if we have more embryos, we have more chances of having 1 embryo that can implant. It’s a good strategy in your case. I don’t know why they have always done modified natural cycles, maybe because of your ovarian reserve.
Even with trying other strategies, only 1 egg can be achieved, but, of course, you are 41, and you are not in menopause, so we can try different strategies to see if instead of 1, 2 or 3 eggs can be retrieved. Possibly 2 embryos can be obtained and frozen. It’s a good strategy, Gonal F with Menopur.
Don’t worry about those 4 cycles, it’s not going to increase cancer risk, but, indeed, Clomid is used for milder stimulation, so in your case, I will suggest stopping with Clomid and trying with gonadotropins, I think it’s the best treatment in your case.
Unfortunately, no, there isn’t any kind of treatment that could improve AMH levels, there’s no treatment to improve ovarian reserve. There are some experimental therapies, but they have not been shown or proved to be used in clinical practice. After 2 years of trying naturally without success, I would suggest starting with medical treatment. I don’t know your AMH level, but if it’s low and you’ll be trying for 2 more years, it will decrease even more, and then maybe it will be late to do a treatment.
The international medical association says that when a patient is 35 or younger after one year of trying without success, they should start treatment. If the patient is older than 35, they should go to a doctor to study and try to diagnose the cause of infertility. In your case, yes, I would suggest starting a fertility treatment.
Perhaps, we can. There’s always a chance of doing another cycle, but to recommend another cycle, I would need more information about these previous cycles because what we don’t recommend is to do the same things after 4 failed cycles. We can do something else to try to improve the results. If there’s nothing else that we can do, then we skip to an egg donation.
I need more information about these previous cycles, if there’s something that could improve the ovarian response or the egg quality, then I would suggest it. You are 39, and you have a chance of getting pregnant, so if there’s something that can improve the response, I would suggest doing another cycle with your own eggs, but again I need more information about the previous cycles.
That depends on the ovarian reserve of the patient, that’s how we determine the dose. Also, depending on the age, we use some kinds of gonadotropins or some other. It also depends on when we do the ultrasound and the antral follicle count. If we, for example, see that there are follicles of very different sizes, maybe we receive 2 and if the patient has a low ovarian reserve, we decide to start with pre-treatment.
Usually, it depends on the age, ovarian reserve, the experience of the doctor with each medication, that’s important too, and the last and very important factor is if the patient has done previous cycles because that gives us a lot of information and we will know if it’s better to change the kind of gonadotropin or not.
It’s different if you have an empty follicle syndrome because you had a low number of follicles growing, and they weren’t able to recover any eggs from these 1 or 2 follicles, or if you had a very good amount of follicles, and no egg was recovered. Some strategies can improve or try to avoid this empty follicle syndrome. One of them is changing the gonadotropin and using a dual trigger.
\We do the ovulation trigger with two different medications, and we program the ovum to pick up a little earlier than in the first attempt. That’s the strategy that we use when a patient has had an empty follicle syndrome, but it’s not the same to have an empty follicle syndrome if a patient has a low ovarian response to the medication or if it’s after unexpected empty follicle syndrome.
That depends on what you want. If it’s to stimulate the ovaries, it won’t be a substantial change, achieving regulation of the cycle before the stimulation. If it’s to prepare your uterus, the endometrium before an embryo transfer, sometimes we need to regulate the cycle to have a good endometrium that can achieve a good thickness to receive the embryo.
If it’s about starting another stimulation, we don’t try to have a regular cycle before. Once the patient is ready to start, we try to evaluate the point of the cycle the patient is with a blood hormone test. Depending on the result, we tell the patient to start with stimulation or we provoke the cycle to start afterwards. In my opinion, there’s no need of having 3 or 4 regular menses before starting the stimulation because it won’t improve the ovarian response.
We usually start the first treatment with a stimulation treatment because possibly instead of 1 egg that we are going to get with a natural modified treatment, we will have 2 or 3.
When we talk about 2 or 3, it makes a difference, so yes, in your case, I would start at least at the first attempt with a high dose of stimulation, and if it doesn’t work, then we always have the option of the natural modified cycle.