In our recent event, the panellists discussed options for women facing low ovarian reserve, providing valuable insights into the latest treatments and strategies.
Featuring Experts:
Dr. Nicole Mardešićová, MHA – Head Doctor of PRONATAL Group
Dr. Elena Puente – Medical Director of Clinica Fertia, Spain
Dr. Evangelos Sakkas, PhD, MSc, MD – Medical Director of Gyn Care IVF, Greece
The event was hosted by: Professor Alan Thornhill, Fertility Expert & Coach, Founder of The Fertility Guy.
Dr Nicole Mardešićová, MHA, PRONATAL Group: Ovarian reserve is a marker—the number of eggs you have left or the number of eggs you have in total. Women are born with a certain amount of eggs, and this constitutes our ovarian reserve at the beginning. As we age, the ovarian reserve diminishes, and the rate at which it diminishes is very individual and hard to predict. The older we get, the lower our ovarian reserve becomes, and of course, the lower your ovarian reserve gets, the harder it can be to get pregnant. This is also dependent on age. We will surely talk more about it later on.
Dr Elena Puente, Clinica Fertia: As Dr Nicole mentioned, we are born with a certain amount of eggs, which varies among different women. If our mothers entered menopause very early, most probably our ovarian reserve will be lower than that of a woman whose mother reached menopause in her 50s. Generally speaking, ovarian reserve declines with age. This decline starts in our 30s and then accelerates rapidly once we reach 35. The ovary is one of the organs that ages faster. We lose 80% of our ovarian function in just five years, from 35 to 40 years of age. This is why age is such an important factor. Besides ovarian reserve, age is the most important prognostic factor in terms of fertility treatment.
Dr Evangelos Sakkas, PhD, MSc, MD, Gyn Care IVF: The only tool we have, the most recent one, is the AMH, which is a simple blood test that we do on whatever day of the menstrual cycle for our patient. Before the AMH, we used to do a combination of FSH, LH, and estradiol, which are three hormones we used to measure at the beginning of the cycle. Now, we use the AMH, which, as you know, can be done in every lab, and it gives us a result. What’s very important to underline in this case is that AMH reflects ovarian reserve, but it doesn’t reflect ovarian quality. It reflects the ovarian quantity; it’s not a marker of quality. That’s something our patients should bear in mind because it’s very important. Very often, I see patients stressed about that. Of course, you have to pay attention when interpreting the result because if you see a level of, let’s say, 2 ng/mL in a 30-year-old woman, it’s quite a good result. But if you see the same result in a 20-year-old woman, maybe it’s not so good. You must also pay attention to the reference units. One thing is measuring it in ng/mL, and another is in pmol/L. So, be careful when interpreting the result.
Dr Evangelos Sakkas, PhD, MSc, MD, Gyn Care IVF: The work you have to do with the patient when she comes to your clinic always includes the AFC, which is the antral follicle count done by transvaginal ultrasound, along with the AMH. We usually also add FSH and estradiol to this. But let’s say that today, we mostly depend on AFC and AMH. Of course, many years ago, we also did the inhibin test, but it’s not done anymore.
Dr Elena Puente, Clinica Fertia: I think it’s very important to focus on the first part: she is 35 years of age, and this is the most crucial point. When you are 35, the quality of your eggs is good. As Dr Sakkas mentioned, the number of eggs and the quality are two different things. When we talk about AMH, we’re talking about ovarian reserve—about quantity, the number of eggs you have left. But it doesn’t mean that the quality isn’t good. So, her AMH is a bit lower than it should be for her age, but her age is very good, so we can expect very good quality eggs.
As for the miscarriage, we cannot say that it’s because of poor egg quality. 5% of young women experience miscarriage, so that could happen just by chance, with no relation to her situation. I don’t think it’s good advice to move to egg donation because, on one hand, her AMH suggests she could get at least 7 to 8 eggs, and we know that if you are 35 or younger and can get between 4 and 7 eggs, you can usually get at least 1 euploid embryo. Euploid means a genetically normal embryo, and the probability of implantation with such an embryo is 65%, with a good chance of a live birth. So, I think she can proceed with her own eggs. I don’t see the point in going for egg donation because, first, age is the most important prognostic factor, and this factor is good for her. It’s a different story when you’re 42 or 43 because, at that age, you have many abnormal eggs and would need at least 20 to 25 eggs to get a genetically normal embryo. But at 35, with an AMH of 1.05, I’m sure she can achieve a good pregnancy that can go to term.
Dr Nicole Mardešićová, MHA, PRONATAL Group: I’m not sure if we agree that her AMH is 1.05 nanograms, hopefully, because that would be a huge difference if this number was in picomoles. So, if it is 1.05 nanograms, then I certainly agree that she should go for IVF with her own eggs.
Dr Evangelos Sakkas, PhD, MSc, MD, Gyn Care IVF: I agree with my colleagues. The only thing I would like to add is that given her mother got into menopause very early, the advice I would add is to not lose too much time. It’s better to begin now with IVF rather than finding herself at 40 years old with early menopause. In that case, maybe I would also add genetic counselling, just to add a karyotype and other exams that we ask for in those cases.
Dr Evangelos Sakkas, PhD, MSc, MD, Gyn Care IVF: I love this question. AMH isn’t 100% reliable. When a patient comes into our clinic, I think it’s a huge mistake to construct a protocol for IVF stimulation based only on AMH. I know there are many universities, schools, or clinics that tend to do that, but I’m convinced that you cannot rely solely on AMH. So, yes, it’s not 100% reliable, but it’s the only biochemical marker we have today. If tomorrow I have to construct my IVF protocol, I’m going to consider it, but I’m also going to consider the AFC (antral follicle count) and the IVF history of my patient. If she’s coming for her first IVF, that’s one thing, but if she’s had two or three attempts, I have more information in my mind for how to construct the protocol. So yes, it’s reliable, but not the most reliable thing we have today—it’s just the only thing we have, so we should use it.
Dr Nicole Mardešićová, MHA, PRONATAL Group: That’s a complicated question because there’s more information we need from this patient. Now, if I answer the question purely from a medical point of view, which is usually impossible, unfortunately, this woman—she’s 41, that means the quality of her eggs will already be quite compromised because egg quality is mainly determined by the age of the patient. We know that at this age, almost 80% of the embryos resulting from stimulation will be genetically unhealthy, so-called aneuploid. Given that this patient has a very low AMH combined with her age, the chances for success with her own eggs are very low. But now, let’s focus on the patient—on the woman. If she has never tried it before, as a woman, I completely understand that she would like to try an IVF cycle first. There are many factors we don’t know—what is her sensitivity to FSH stimulation? Maybe she will react a little better; maybe we can use a soft or mild stimulation to lower the costs. There are options we can consider for her stimulation. Even though we know her chances for success are low because of her low AMH and age, if she has never tried before, I understand she would like to try.
From a purely medical perspective, it’s better to use donor eggs, but if she has never tried before, we can attempt IVF stimulation with PGT-A (Preimplantation Genetic Testing), which involves genetic testing of the embryos before implantation into the uterus.
Dr Evangelos Sakkas, PhD, MSc, MD, Gyn Care IVF: Of course, exercise is only beneficial. There’s no connection between exercise, even extreme exercise, and ovarian reserve. Exercise means vascularization, blood flow, and all the health benefits for the patient and the ovarian reserve. Just to be clear, it doesn’t mean that we can improve ovarian reserve. If I start jogging or running tomorrow, that won’t improve my ovarian reserve, but it won’t deteriorate it either. Of course, extreme conditions, like an extremely low BMI, could impact ovarian reserve, but all the other conditions—no.
It’s very often that we hear patients who do extreme exercise, like those training for the Olympics, for example. They may not have their period, but not having a period doesn’t mean you don’t have a good ovarian reserve. It doesn’t mean you’re harming the reserve. It’s another mechanism, a bit more complicated, that interrupts your cycle, but the ovarian reserve is still there.
Dr Nicole Mardešićová, MHA, PRONATAL Group: Difficult question; there’s not much there. Well, there is one thing that we should ask this patient: How many kids do you wish to have? If this patient wants to have just 1 child, maybe she still has a bit of time to try to conceive naturally. If she tells me, “I would like to have 2, ideally 3 children,” then with this ovarian reserve, which is diminished—AMH 0.74 ng/mL at the age of 32 is lower than it should be—, if she wants more than 1 child, then some kind of fertility preservation is advisable. In that case, I wouldn’t recommend postponing the first pregnancy for longer.
Dr Elena Puente, Clinica Fertia: Yes, but as Dr Sakkas mentioned, we cannot base our treatment or evaluation of the patient just on the level of AMH. We need to know more things about this patient. It would be very important to check her antral follicle count (AFC). Maybe she’s been on contraception for a long time; this can affect the level of AMH. For sure, she should try with her own eggs. We should tailor an appropriate treatment for this lady. Maybe we should think about different protocols, like double stimulation. When you have a very low ovarian reserve, the most important thing is what can you do for the patient because every egg matters, especially at this age. If we can get maybe one or two eggs from one cycle, we will improve the probability of a live birth. The main thing is to establish the best protocol for her. Should we use some kind of therapy to synchronize her follicles? Should we do a mild stimulation with higher doses of analogues like Q10 or other antioxidants? Many things can be done, but we need more information. It seems like it’s something inherited, as her mother already had a proven low reserve.
First, we need to check the genetics and have a karyotype if she is fragile before we start thinking about the stimulation. That’s the basics: have a good diagnosis and then, of course, try to perform the best therapy for her particular case. Also, never forget that we don’t only need a good embryo; we also need a good uterus where the embryo can be implanted, and we should check for that as well. But I think, even with her low reserve at this age, she should try with her own eggs because, as we’ve all mentioned before, the main prognosis factor is age. If you are 41 and your AMH is very low, then no, it’s not very good. But it’s different when you’re younger.
Dr Evangelos Sakkas, PhD, MSc, MD, Gyn Care IVF: I agree. I would just advise the patient if she could repeat the AMH measurement because it’s extremely, let’s say, low—1 picomole. So just to be sure, maybe in another lab, it wouldn’t be a bad idea to repeat it, just to be sure.
Dr Evangelos Sakkas, PhD, MSc, MD, Gyn Care IVF: Actually, I wouldn’t be so stressed about this small reduction. I mean, 1.38 to 1.05—it’s not something that stresses me. Okay, at 36 years old, it can be many things, okay? From lab to lab, there are many factors. Even the medical technology that we use in the labs may change from lab to lab. So this reduction doesn’t stress me, and at that age, I would be calm. As we said before, it’s not only the AMH. So I would just keep in mind that I’m 36, and I have an average, let’s say, mean value of 1.2, 1.1, so it’s more or less 1 point something, which means if I do an IVF, a production of about 8, 9 eggs. If I don’t do an IVF, also a good chance of being pregnant naturally. So it wouldn’t be something that would stress me more than that. I would just take into consideration the other factors, and I would decide based on the whole image of the couple.
Dr Nicole Mardešićová, MHA, PRONATAL Group: I wanted to add one more thing. I see it quite often, and probably my colleagues as well, that people get fixed on numbers. We are not machines; we are humans. We are biological living things. That means no number is ever the same. Spermiogram is never the same, FSH is never the same. Even if we measure it at the same time in the next cycle, you see, we are living human beings. Don’t get fixed too much on little differences. Like for me, 1.3 and 1.1, basically for me, it’s the same. Because as I’m saying, and as Dr Evangelos says as well, AMH is fluctuating as well. I mean, if you look in the data, if you look in the studies, what you read is that AMH is stable; it doesn’t fluctuate intra-cyclically, or inter-cyclically. All of us, who test AMH regularly daily, know that it does. I mean, you can test a patient five days later, and it is not the same number again. And I think the reason behind this is biology. So of course, it is good to test in a different lab, or you can test a bit later, a couple of months ago or 3 weeks later, but still, we are only living humans. So don’t get too fixed on little things in the numbers.
Dr Nicole Mardešićová, MHA, PRONATAL Group: This is quite a controversial theme. So maybe my colleagues will not agree with me; we will see. I think we have nothing to offer. If we look at the data, we tried almost everything that could work to make the oocyte quality better: DHEA, antioxidants, estrogens before the cycles, whatever. Then, if you look at the RCT and the data, it does not work, unfortunately. I think we have nothing to offer; there is no rejuvenation. Although you can read about rejuvenation being studied, and some colleagues try rejuvenating the ovaries or with ovarian tissue and so on—it does not work. We don’t have anything reliable. That’s my opinion.
Dr Evangelos Sakkas, PhD, MSc, MD, Gyn Care IVF: I agree with Nicole. I think it was 2 or 3 years ago at the ESHRE Congress in Milan, Italy, where they took into consideration all the RCTs—RCTs means all the randomized control trials, so the strong trials, the most reliable trials—based on what can be done to improve egg quality. As Nicole told us: GH, rejuvenation, antioxidants, all the stuff you can imagine, DHEA. No, none of them showed superiority as far as the result of the egg quality is concerned. No one. Perhaps, there’s some stuff going on about the ovarian quantity, and maybe the rejuvenation could help us a bit, or maybe the DHEA. However, the ovarian quality—I agree with Nicole—that no improvement can be done.
Dr Elena Puente, Clinica Fertia: As both my colleagues mentioned, there’s no proven drug that can improve egg quality. No randomized control trial can prove that we can improve egg quality. Perhaps, we can improve with different strategies, possibly get 1 or 2 extra eggs, but even when we have therapy, stem cell therapy, or all kinds of ovarian activation, all that stuff trying to rejuvenate the ovary, which I think is a wrong term that we are using because we are not making the ovary younger. If you are 42, around 80-85% of your eggs are going to be genetically abnormal, so you are not making it younger; you are not improving quality. You cannot do that. You can add one extra egg, but it will be the same percentage of genetically abnormal. We cannot improve egg quality. Some strategies could try to get perhaps 1 or 2 extra eggs, but we are giving the idea to our patients that this is going to be the true solution and that this is going to be the one that works. They are spending a lot of money and time, and psychologically, they are being affected as well. We have to be very honest.
The most important predictive factor is your age and then your ovarian reserve. You must be very clear about what you can offer. If you are 40 years of age, around 60% of your eggs are abnormal. Your pregnancy rate maximum could get to 20%, only if you can get the embryo, then you will have a good probability of achieving a birth rate. I think it’s very significant that all these things are very clear to our patients. There are some strategies, for example, we receive in our centre many patients with endometriosis. Endometriosis is a chronic inflammatory disease, and we see in these patients not that we are improving the quality, but we are improving their lives because we can use diet, we can use supplements, antioxidants that will make them feel better, reduce the level of inflammation, and that’s going to make things easier when we do the stimulation. They are not going to be in such pain; they are going to follow the whole therapy in a much easier way. So you have to be very careful when you advise things and be very clear that there’s nothing that will improve the quality of the eggs.
Dr Elena Puente, Clinica Fertia: That is an important question. We are trying to get antioxidants because we think that as you get older, you have more oxidative stress and mitochondrial function isn’t as good. There are lots of free radicals of oxygen that can damage not the genetics, but at least the way the egg is working. Sometimes I explain to patients, that when they are getting older, they may have an egg that is genetically abnormal but still somewhat competent. It’s like comparing a very old car to a brand-new car—you are getting to the place, but with the old one, you are doing things more slowly. Your metabolism is not as good. Antioxidants can help in general, and a healthy lifestyle is very significant. We have to work on weight because obesity is a very significant factor. There are more cytokines and inflammatory factors that can compromise the quality. Smoking has been proven to have an important effect, even diminishing and advancing the age of menopause. But antioxidants are good. Watching our diet, having a Mediterranean diet, avoiding high levels of sugar or carbohydrates, and fast foods—things like that will improve your general inflammatory state and can improve competence, but never genetics. You cannot think that you are eating your way out of it.
I remember like 2 months ago, there was a lady who came in, and the whole table was covered with vitamins. She was taking them for everything: her thinking, her sleeping, her egg quality. This is wrong. The most important thing is to have a good diet, and a good lifestyle, avoid smoking, watch your weight, and have a balanced diet. That’s the key.
Dr Nicole Mardešićová, MHA, PRONATAL Group: When I read the question further, she said that she already had 2 failed rounds of high stimulation, with 3 eggs collected each time, minimal response to medication, and 1 blastocyst failed embryo transfer. So now, that we know the history behind this, we understand how much time, money, effort, and emotions she has invested until now. Given her age and AMH levels right now, I think I would probably advise the same thing, and that is the donor program. We wouldn’t be able, using any stimulation that we can imagine, to get as many eggs as would be needed for her age to get a genetically euploid blastocyst—that means a genetically healthy embryo. So yes, I agree. After all, she has done already, I would also advise a donor egg. But of course, we have very little information. I didn’t see the uterus; I didn’t see the ovaries, so we must be careful with that. But given the information that I have now, I agree; I would advise the donor program.
Dr Evangelos Sakkas, PhD, MSc, MD, Gyn Care IVF: I’m convinced that she shouldn’t continue the same way. Egg donation should be the logical decision. If the patient wishes to continue with her own eggs, of course, we cannot say no, but in that case, I would add PGT-A, so the patient could be convinced that the embryos are euploid or abnormal. In that case, the decision to move to egg donation might be easier. All the other stuff, like PICSI, Zymot, etc., I’m not convinced that’s going to help the situation. It’s not a patient who had only 1 IVF stimulation; if I got it right, she had many IVF stimulations. They tried to go from blastocyst to day 3, from day 3 to day 5, but that didn’t help. Egg donation is the best way to resolve this problem, and if she wants to continue with her own eggs, PGT-A would provide proof of the embryo’s genetic status.
I was working for years in Brussels, where I got my education and specialization. In Brussels, they had something like 5,000 to 6,000 cycles per year. For women after 44 years old, from 44 to 50, of course, they had no pregnancy with their own eggs. No pregnancy. It wasn’t a centre with one or two cycles per year; they had huge experience. There was no pregnancy at 44.
Dr Nicole Mardešićová, MHA, PRONATAL Group: That’s a hard question—I would have to be a witch to know the future and the answer. I will try to think of a good answer. An antral follicle count (AFC) between 7 and 9 is very nice; it shows us a good ovarian reserve. On the other hand, Clomid and Letrozole are anti-estrogens; this is not an FSH stimulation. Anti-estrogens can help you have more follicles and poly-ovulation in this one cycle, but still, I do not think that Clomid or Letrozole in standard dosing would lead to more than 7 or 9 follicles. This is just an opinion. Many variables come into play, but based on my experience, I do not think that only Clomid or Letrozole would give us more than 9 follicles.
Dr Elena Puente, Clinica Fertia: I mean, if you want to have 7 to 9 eggs, I would use gonadotropins or at least a combination of Letrozole and gonadotropins. I agree with Dr Nicole; you are not getting good levels of eggs if you are using Clomid on its own. Only if you have a huge ovarian reserve—sometimes we use Letrozole, for example, for inseminations because the problem we have with gonadotropins is the risk of hyperstimulation. Only in very certain cases. If we want to get those 9 eggs, I would use gonadotropins.
Dr Evangelos Sakkas, PhD, MSc, MD, Gyn Care IVF: Actually, the average we see with Letrozole or anti-estrogens is 2, 3, or a maximum of 4 follicles. I’ve never seen much more than that. So if she wants to get all 9 of them, that’s not the solution.
Dr Nicole Mardešićová, MHA, PRONATAL Group: It would be interesting to know the reason she is asking this question. I mean, if I want 9 follicles, maybe nine oocytes, I would probably stimulate.
Dr Evangelos Sakkas, PhD, MSc, MD, Gyn Care IVF: We’re trying to collect all the data in order not only to provide the IVF stimulation protocol, but also to give an answer to the patient and the couple. It should be a project that, in the end, tells us, “Okay, given all that data, you have a 50% chance with your own eggs, 70% with egg donation,” etc.
This is something that is being studied every day. I repeat, we’re doing this to give an answer to the patients about the best strategy to follow. Of course, in the future, we’re going to use AI for IVF stimulation, and it’s already being used for the selection of blastocysts. We’re inputting data now to determine which blastocyst is the best one to transfer, based on data from the embryologist, who knows this better than I do—factors like time-lapse, timing, sequences, and velocity that we get from the technology. So yes, AI is going to be used in IVF stimulation and all other fields.
Dr Nicole Mardešićová, MHA, PRONATAL Group: I think we all are already using the easiest AI, and that is the predictor for the dosage of FSH in PCOS patients. This is an AI system that helps us with the dosage of gonadotropins in a PCOS patient based on her AMH and weight. Yes, because weight is an important factor when it comes to dosage. So this is a very easy and very helpful AI that we use in daily practice.
Dr Elena Puente, Clinica Fertia: All of us—started to use it in the lab, but I’m convinced, as Dr Sakkas has said, that we are going to use it more and more in our stimulation protocols for our patients. I think it’s a very nice hope. I remember when we first thought about time-lapse, our biologists were spending hours looking at oocytes, and it helped. It will be the same for us as doctors in the stimulation field.
Dr Elena Puente, Clinica Fertia: First of all, both conditions are inflammatory diseases in the bowel. The best thing is to be under control because one of our main concerns is that when you have comorbidities before starting your cycle, you need to be under good control. If you have colitis or problems like those, we must make sure that your illness is under control. Normally, after they enter the IVF system, they have been on a diet and use drugs for the inflammation process, and we start stimulation when the inflammation is under control. I don’t think it’s going to affect the AMH level or ovarian reserve, but we have understood that if you have inflammation in the digestive system, you will also have more inflammation in the pelvic area, which is going to affect the process as well.
Inflammation in the pelvic area will mean higher levels of proinflammatory cytokines, which can impact embryo implantation. For patients with inflammatory issues, diet is very important. We make sure they are free of disease before starting the process, whether it’s Crohn’s, colitis, or even endometriosis. We must make sure they are stable and that we can reduce the level of inflammation, either with diet or lifestyle changes. AMH will be the same, but the condition of the uterus will be better, and the process of stimulation will be smoother. We must always remember that quality of life is very important. If she is having a very inflammatory process, we shouldn’t do any IVF therapy. First, we treat her illness, and then we proceed with IVF. Diet and lifestyle are, as I mentioned previously, really significant. Therefore, I don’t think one month is enough.
If a woman has a good ovarian reserve, we will try to get her in the best condition, but we can never postpone more than 2 to 4 months for an older lady because then the effectiveness decreases completely.
Dr Nicole Mardešićová, MHA, PRONATAL Group: DuoStim or Dual stim is short for dual stimulation. What it is are 2 consecutive stimulations. The first stimulation starts as usual; the patient stimulates for, let’s say, 9 to 10 days, and then she has her oocyte pickup. After the oocyte pickup, let’s say 4 days later, she starts with a new stimulation. There is no fresh transfer; the embryos from the first cycle have to be frozen or vitrified. So, 4 days after her first pickup, she starts stimulating again and can repeat it up to 3 times—that would be the TriStim.
The reason for dual stimulation was especially for women who do not have the time, such as those needing fertility preservation in oncological patients, patients with low ovarian reserve who need more embryos in a shorter time, or patients who just want more embryos in a shorter period.
To be honest, we use it very rarely. There is a lot of data on Dual stimulation; some studies are very positive, while others are not so favourable. Our experience is that in these patients, usually those with a low ovarian reserve, even dual stimulation does not bring us closer to a healthy pregnancy. There was another reason for dual stimulation, which was the potential difference in embryo quality. Some data showed that embryos from the second stimulation might be of better quality than those from the first, but not all data confirm this, so I can’t say it’s true. There is still a lot of uncertainty. This is the definition, and no, we are not using it regularly because, in our experience, it is a financial burden for the patient that does not bring us closer to success.
Dr Evangelos Sakkas, PhD, MSc, MD, Gyn Care IVF: I agree with Nicole. First, to consider dual stim, you must ask if the health system or the National Health System can afford it. If we are talking about private medicine, you must see if the patient can afford the dual stim because, in Greece, it means buying the medication twice, doing the pickup twice, and cryopreservation twice. For a Greek patient, it’s a huge burden.
It’s not a bad idea, but I confirm what Nicole said. Yes, it’s a great idea for fertility preservation, but that’s it. I know studies promote this idea of collecting more eggs, but I believe every cycle has its own quality. Each cycle—March, April, May—has a different quality of eggs. So, dual stim, in my view, trying to squeeze the ovaries into one cycle, doesn’t give me better results. I’ve tried it in the past, but I didn’t see more clinical pregnancies; the results were more or less the same.
Regarding the studies Nicole mentioned the second half having better blastocysts, it’s controversial. Some studies even say the opposite, that the second half has worse blastocysts. I know it’s fashionable in Italy; they do it a lot there because it probably started there. But I don’t know many other countries where it’s done so much. For me, it’s good for fertility preservation, not so much for low AMH, so we don’t do it.
The only time we do something similar is for patients who do natural cycles, meaning they don’t take medication, just monitor their cycle. We do the oocyte pickup on the 12th or 14th day of the cycle, and we might ask them to come again after seven days to see if there’s another oocyte coming naturally. But we don’t use IVF stimulation, just monitoring naturally.
Dr Elena Puente, Clinica Fertia: We use dual stim, but it’s something we discuss with the patient very thoroughly. If we have a patient with low ovarian reserve, we first need to explain her probability of becoming pregnant, depending on her age and the number of eggs we can get. Then, we explain upfront that there could be this possibility. Once we have done the pickup and culture to blastocysts, if we just get 1 blastocyst and the quality is not very good, we discuss again whether we should try a second round of stimulation. We do get good blastocysts from the second stimulation.
We published that the quality rate between the first and second stimulations is pretty much the same. Of course, there’s no randomized control trial, but we discuss it with the patient.
Sometimes, if we ask her to do it immediately, she might say, “Okay, I want to try to give myself the best opportunity to have a healthy embryo.” If she fails the first time, and she’s 40 and hasn’t got any blastocysts, she might not try again. The dropout rate is very high, which has been established by many authors, especially in Italy, as Dr Sakkas mentioned.
We don’t plan dual stim; we explain the probability, and then once we know what has happened with the first one, we decide whether to go for the second stimulation or not. It’s always the patient’s choice. Our experience with low ovarian reserve patients is that we get a higher number of eggs and blastocysts in the same menstrual cycle, and for these patients, time is very important. When they are in their 40s, they want to do things very quickly. But of course, we have to sit down and, depending on the result of the first one, decide whether to go for the second one or not. But yes, we do use dual stim.
Dr Nicole Mardešićová, MHA, PRONATAL Group: Thyroid health is very important, not so much for getting pregnant, but for keeping the pregnancy. If there is a thyroid issue, the main problem will not be getting pregnant but maintaining the pregnancy and avoiding miscarriage. Unfortunately, there are no real supplements that help the thyroid gland if it’s not healthy. If there’s a hypo or hyperfunction, the only solution is medication to stabilize thyroid health.
Regarding oocyte quality and quantity, I don’t think there is any impact on quantity. I haven’t read any study confirming that thyroid health affects quantity. Quality, however, is a different question. If a patient has an autoimmune disorder affecting the thyroid, then the antibodies produced against the thyroid cells could also affect the oocytes, potentially impairing their quality.
Dr Elena Puente, Clinica Fertia: I don’t think there is a real impact on the quality. I mean, while it’s been published, some authors agree or disagree about double triggering with GnRH agonists and hCG. It’s believed that this could help in achieving more mature eggs when using the analogue. The LH and FSH surge is similar to what happens physiologically. Many authors believe this could help with steroidogenesis and final maturation of the egg, leading to more mature eggs.
However, this approach comes and goes. There’s even a meta-analysis on women with very low ovarian reserve, involving 1,000 patients using double stimulation and 1,900 using the conventional method with hCG. The study showed more eggs, better fertilization, and better pregnancy rates with double stimulation. I believe that for those with low ovarian reserve, we try everything to get the best results, and dual triggering might be something we can do. But it doesn’t necessarily mean it will always improve quality. We might get more eggs, but it very much depends on the patient. I don’t think it will have a significant impact on quality.
Dr Evangelos Sakkas, PhD, MSc, MD, Gyn Care IVF: Actually, 2 things come to my mind. First is something that you cannot change: environmental pollution. Unfortunately, this, along with climate change, can affect our quality of life and possibly ovarian quality, though I’m not sure if there are many studies on that. But I can presume there is a correlation. Then, there are substances, I believe they are called endocrine disruptors. These are produced by chemical processes, end up in the ground, and enter our food supply. So, of course, living a healthier lifestyle can improve ovarian quality, but I don’t think there are extremely many studies on that, and I doubt there’s going to be a huge improvement from making changes like that. As for the male partner, yes, if someone works in a toxic environment, exposure to toxic products can harm sperm, but I don’t think it’s as impactful on ovarian quality.
Dr Elena Puente, Clinica Fertia: Endocrine disruptors are all over our environment. It’s not only in the food industry but also in plastics. For example, if we use a microwave with plastic containers, these chemicals can leach into our food. For instance, in the clinic, we use crystal bottles to avoid these disruptors, but it’s just small steps. Avoiding non-stick pans and being aware of pollution are also good practices. However, it’s very challenging because whatever we eat—meat, fish, vegetables—has those biochemicals, making it hard to control. Still, education is key, and if we know, we can avoid certain things. But we must also consider the financial aspect, as not everyone can afford organic food and similar choices. It’s not easy.
Dr Evangelos Sakkas, PhD, MSc, MD, Gyn Care IVF: The take-home message I would like to give is that as doctors, embryologists, and as a society, we should try to better inform women—and their partners—about the concept of ovarian reserve. Fortunately, it’s a topic that’s being discussed more and more, and it should be even more prominent. It’s really unfortunate when a woman in her early 30s has a low AMH and no one informed her earlier, not even her gynecologist. Whether we measure it with AMH or FSH, the idea of ovarian reserve should be better understood. We should also promote social freezing for patients who seem to have a rapid decline in their ovarian reserve.
Dr Elena Puente, Clinica Fertia: I think it’s very important, as Dr Sakkas just mentioned, for us as doctors to be very clear about the options for becoming pregnant with low ovarian reserve. That is the main thing. If patients have accurate information, they will have better options to make the right decision. For example, if a woman has had 10 cycles, she might find a clinic that says, “Okay, I’m going to try this or that.” I don’t think that is honest because, in the end, what happens is that she may end up with no children, as she will be so fed up with all the processes she’s gone through that she won’t pursue the option that could truly make her a mother. Being honest, being clear about the results, and understanding the chances are crucial.
Prevention is also very important. We are delaying childbearing and experiencing low ovarian reserves about age. We need to explain the importance of vitrification. Social freezing should have more support. It’s a pity when we see patients with endometriosis who have never been told that they could vitrify their eggs before they end up needing egg donation at 36 or 37 years of age. We need to consider all this, and we must inform society and even our colleagues. They do ultrasounds, count follicles, and should be saying, “Okay, do you want to become a mother? Then you should do something about it.” Information is the basis of everything.
Dr Nicole Mardešićová, MHA, PRONATAL Group: I will finish up with a message for our patients. For women and couples who either will be treated for infertility, are being treated, or are thinking about your reproductive health: AMH as a marker of ovarian reserve is a great marker. It is the best we can get right now, so get it tested. Even if you have to pay for it, it is just one hormone. Get it tested. Educate yourself about fertility. Educate your children and your future daughters about fertility. Fertility doesn’t last forever; it can be gone very quickly, and you can lose your fertility in the blink of an eye. So, please educate yourself and your children.
The last point I would like to close with is that all we talked about—AMH, ovarian reserve, ICSI, all the techniques of assisted reproduction—is all great. But the most important factor is your age. Please do not postpone pregnancy. If you have a prospective partner, trust your doctor and the advice we give you because we want you to get pregnant as soon as possible.
