Low ovarian reserve and IVF treatment explained

Alejandra Aguilar Crespo, MD
Gynecologist at Equipo Juana Crespo , Equipo Juana Crespo

From this video you will find out:

What actually is a low ovarian reserve? How low is very low?
How doctors measure the ovarian reserve?
What are the causes of low ovarian reserve apart from age?
What is a poor ovarian response?
What are the strategies to improve the outcome in such patients?

Low ovarian reserve and IVF treatment explained

All you need to know about IVF and low ovarian reserve

Watch the webinar with Dr Alejandra Aguilar Crespo, a Gynaecologist and Consultant Specialist at Equipo Juana Crespo, Valencia, Spain, where she discussed how patients can achieve a successful outcome with IVF and low ovarian reserve. Dr Alejandra Aguilar Crespo started with the definition of ovarian reserve and explained that it is defined by the number of available eggs that a woman has at a given moment in her life and is closely related to the potential to reproduce. It’s a prognostic marker for both a woman’s fertility and the time remaining until menopause. Ovarian reserve decreases throughout life. When a woman is born, there are more or less 2 million oocytes, but then at puberty, there is only 4 000 among them, only 400 will mature and ovulate, and the rest of them will reach atresia. On the contrary, male sperm regenerates through life, and the quality also decreases with age, but they always have some fertility capacity. Dr Aguilar pointed out that in each menstrual cycle, there is follicular recruitment, but only one will be in charge of maturation and releasing the oocyte. The rest of them reach atresia, which means that they die. If there is no fertilization 40 days later, the period comes and another cycle. As age increases, the probability of pregnancy decreases per month. The quality and the quantity of eggs decreases with age. Due to this, fertility is maximum at the age of 20 to 25 years old. The probability of pregnancy when a woman is around 20 to 25 years old is 30%, but then after the age of 20 to 35 years old, this probability drops considerably, and then at the age of 40 years old this probability decreases drastically and therefore also miscarriage probability increases. From the age of 38 to 40 years old, the prevalence of infertility increases and the probability of going ahead with an assisted reproductive technique.

Measurement of ovarian reserve

There are several tools to measure ovarian reserve. The first one is to measure the Anti-Müllerian hormone (AMH), which is done by a blood test. We can perform this test anytime during the cycle. If the level is below 1.1 nanograms per millilitre, it means we are facing a low ovarian reserve. Then we can also perform an ultrasound scan and to check the number of antral follicles. If we see there are fewer than 3 follicles in each ovary, that probably means we are looking at the low ovarian reserve. It depends on the time the scan is performed during the cycle and if the woman is taking the contraceptive pill. The third tool we have is to measure the Oestradiol and FSH levels on day three of the cycle. This tool is not very used because the previous ones give a more accurate measurement of ovarian reserve. As Dr Aguilar suggests, we should take into account that the measurement of the ovarian reserve has to predict the response to an ovarian cycle to an IVF treatment, and it doesn’t inform us about the quality of the oocyte.

Causes of low ovarian reserve

Several causes are leading to a low ovarian reserve, and the most frequent one is age. As age increases, the quantity and the quality of oocytes decrease. However, some other causes can provoke low ovarian reserve, and they are not related to age.

The first one is a genetic cause. Some genetic diseases, such as the X-fragile syndrome, BRCA mutation, can lead to ovarian failure. When we are facing a woman with a low ovarian reserve, and she’s young, we have to perform those genetic tests. We also have to perform a karyotype test.

Other causes are autoimmune diseases. The most frequent one is thyroid problems, which can cause a low ovarian reserve. There are also some environmental factors, such as the smoking habit, this one is controversial, but it has been correlated with a low ovarian reserve. It’s important to decrease the smoking habit. The treatment with chemo or radiotherapy for any cancer treatment is also associated with a low ovarian reserve. Especially, breast cancer, Hodgkin lymphoma (HL) and leukaemia. The chemotherapy and radiotherapy treatments are gonadotoxic, which means they kill or can mutate the reproductive cells. Another cause is ovarian surgery, for example, for an ovarian cyst or endometriosis. Especially, if those treatments are not performed by a reproductive surgeon. Sometimes, when we remove an ovarian cyst, we can also remove healthy ovarian tissue. Then we can decrease the ovarian reserve. Finally, there are also idiopathic causes. It means that despite ruling out every possible cause of low ovarian reserve, we still do not know the cause.

Implications of low ovarian reserve

As Dr Aguilar explained, most women with low ovarian reserve don’t know about it. If they look for pregnancy when they are young, they will probably succeed because when they are young, the oocytes have very good quality, and probably they will get pregnant in the first year of trying to conceive. Nowadays, women are delaying pregnancy until their mid-30s or even older, and therefore they are sometimes struggling with getting pregnant, and they have to use the assisted reproductive techniques. Any woman over the age of 30 years old who wants to delay motherhood should check her ovarian reserve. If they have a low ovarian reserve, she needs to organize the family planning. A low ovarian reserve can lead to premature ovarian failure and early menopause. The low ovarian reserve represents a major challenge in reproductive medicine. It is often associated with a poor ovarian stimulation response, a high cycle cancellation rate and a low pregnancy rate. The number of oocytes is a direct indicator of the ovarian reserve and ovarian response to ovarian stimulation. Dr Aguilar emphasized that:

Having a low ovarian result doesn’t necessarily mean that conception is impossible, but it can lead to an increase in FSH levels, and this is associated with impaired oocyte quality and decreased number of follicles that are ready to be stimulated. It’s vital to perform any screening before trying to conceive.

Low ovarian reserve (LOR) & Poor ovarian response (POR)

We should not confuse a low ovarian reserve with a poor ovarian response. Women with poor ovarian response are those, who have a reduced number of follicles responding to the FSH, the hormones – gonadotropins. This results in poor IVF outcomes. Normally, women with a low ovarian reserve have a low ovarian response, and this is because they have less amount of follicles. They will produce a low amount of eggs. To define the poor ovarian response, there is ‘The Bologna criteria‘, which was created in 2011 and these criteria include:

advanced maternal age
the previous cycle cancelled or less than 3 oocytes retrieved in a stimulation
low AMH or low antra follicle count

To diagnose a poor ovarian response, we need 2 of these 3 criteria. The expert criticized these criteria because they didn’t give tools for the physicians to help these patients. Therefore, in 2016, ‘The Poseidon criteria‘ was created, and these criteria will serve as a guide to personalized treatment protocols, and it was a set of newly established criteria for low prognosis patients, and they took into account:

the age
the antral follicle county (AFC) & AMH
the ovarian response provided that the previous stimulation cycle was performed

With that, the Poseidon group created 4 groups. For each group, they had a specific treatment for improving the outcomes.

Strategies for improving the outcome

If the woman has a low ovarian reserve and doesn’t want to get pregnant soon, we have to inform her about fertility preservation through oocyte vitrification. The first step is to prevent it. When we are facing a couple with a history of infertility and a low ovarian reserve, we have several tools to try to improve the outcome. Some strategies can help those patients. It’s very important to personalize the treatment, as every patient is different. The treatment should be based on age, BMI, previous treatment, etc. Examples of treatments that can improve the oocyte yield:

androgen pre-treatment

It has been demonstrated that the treatment with testosterone or with DHEA (testosterone precursor) offered before the stimulation (at least 21 days before) can improve the oocyte yield, and so it can improve the embryo yield. Every single oocyte matters in these patients because they have a very low number of them, so if we can improve the oocyte yield, we can always improve the embryo yield. Therefore, the pregnancy rate increases.

personalized ovarian stimulation protocols

We have different protocols where different drugs are used. They are non-standard drugs for this kind of patient. The use of high doses of hormones doesn’t help. If we gave a high dose, it wouldn’t mean we will get more eggs, we could even do more harm to the patient.

embryo accumulation

It means that we perform a few cycles and then only perform an embryo transfer when we have at least 2 or even 3 good quality embryos. To get to that point, we sometimes have to repeat several cycles.

double stimulation; DuoStim

It means we would perform two stimulations in a single menstrual cycle. It’s one stimulation in a follicular phase, and then 5 days later, we start stimulation during the luteal phase. In this kind of patient, it has been demonstrated that it can improve the oocyte yield, and therefore, the pregnancy rates. Dr Aguilar added that at Equipo Juana Crespo, they offer this to foreign patients when they have a very short frame of time to do their stimulation. It’s always better to perform two cycles in a short time than just wait 1 or even 2 months to perform another cycle.

PGT-A (Pre-implantation genetic testing)

Dr Aguilar advice is to perform PGT-A if there is advanced maternal age. Dr Aguilar added that some authors argue that in women with less than 4 oocytes retrieved, the PGT-A doesn’t help because sometimes they can’t even get any blastocysts to be biopsied, so it doesn’t improve the pregnancy rates, although it can decrease the miscarriage rate. However, as she mentioned, performing PGT-A in a patient of advanced age who has low ovarian reserve can increase the pregnancy rate.

experimental treatments

One of them is called ovarian rejuvenation. We can perform an ovarian surgery to do some cuts on the ovary, and these cuts help to increase some molecules, some growth factors that can increase the antral follicles. There is also another treatment called Platelet Rich Plasma (PRP) infusion. It contains a lot of growth factors that can activate the primordial follicles and then can improve the number of follicles.

egg donation

In the end, if we have performed all available options and we have not been successful, there is an egg donation option, but it’s only advised when we have tried everything up to that point. Dr Aguilar concluded that low ovarian reserve is an entity with several causes. The most frequent one is the one related to age. The older the woman is, the lower quantity of eggs we have. It’s very important to perform a screening of the ovaries before trying to spontaneously conceive, and if we see that we have a low ovarian reserve, we have to consider family planning. This entity represents one of the most challenging issues of assistive reproduction, but there are some strategies to improve the result. It’s crucial to individualize treatments according to patients’ characteristics. RELATED ARTICLES Facing Low Ovarian Reserve – Success Stories

All you need to know about IVF and low ovarian reserve - Questions and Answers

What are my possibilities of getting pregnant using IVF with AMH at 0.44? I am 39.

What your possibilities are, we don’t know. If I don’t perform a scan, I cannot be sure about your chances because as I said before every patient is different and every patient has own possibilities. I can only tell you that at 39 years old the probability of having normal embryos is around 40%. It means that at least 60% of the embryos, which are issued from an IVF treatment would be abnormal, it means that they won’t have the correct number of chromosomes. In women who are older than 37 years old, the quantity matters. If I know that among all those embryos I will have only 40% normal embryos, it’s important to have at least more than 2 embryos. With a low AMH, which is 0.44, it is sometimes difficult to get at least 2 or 3 embryos in a single IVF. If we see that we won’t have at least 2 good quality embryos, it is best to repeat another cycle, it means to perform an embryo accumulation to get at least 2 good quality embryos. If we have 2 good quality embryos and of course we can’t forget about the uterus, we need to see that your uterus is okay and the embryos are okay, of course, your chances of having a baby are okay. It also depends on the ovarian reserve, it depends on how the uterus is and this kind of things, but I will never ever reject any patient or any IVF treatment with a low AMH.

What is your opinion/experience about human growth hormone for oocyte quantity or quality?

I’ve used that before, I’ve used that several times but there are some controversial papers regarding the growth hormone, some say that it can improve the oocytes yield and others that they don’t. Even though they have more oocytes, it doesn’t correlate with good pregnancy rates. So we’ve stopped using it because I prefer to use the DHEA because from my own experience there is more evidence regarding DHEA and we have good results with that. It won’t harm the growth hormone, this is used only during the ovarian stimulation, but it has not been demonstrated. I mean we lack evidence of that.

Would you recommend placing a single fertilized egg in a blastocyst culture (5-day egg)? In my last 3 IVF (ICSIs) I received them back on day-3. Would you recommend doing an IUI with only one fallopian tube and an AMH of 0.19 ng/ml? What do you think about taking prednisolone and granulocyte without specific findings?

It depends, it means if we have a good quality blastocyst, I will put it in the patient, depending though on the patient. Depending on the age of the patient and depending on if the uterus is well prepared. Then, of course, I would prefer to put the blastocyst, which means that the embryo is more developed, also if we have 2 good quality embryos on day-3, it will probably be the same. The answer to your second question again depends on the age of the woman. If you have a low AMH, but you are young, it means that probably your oocytes could be in of good quality, so why not. It’s better if you ovulate from the tube that you have patterned, but we can think about an IUI. If you don’t have a history of infertility and has not done a lot of previous treatments, I can go ahead with IUI. The problem is that if we see that there is a low AMH and there is a young woman – I prefer to do a cycle to preserve her embryos. Sometimes we do that because we want to preserve her fertility, we do a cycle, and then we get some embryos because if we see that she has a low ovarian reserve, and she’s young probably she will have an early menopause and if she gets pregnant with an IUI and then she comes back for the second child probably we won’t get any oocytes, so, therefore, she will be two years older and the oocytes will not be of good quality. Sometimes it’s better if we perform an IVF treatment and then if she wants to go ahead with IUI, she can. But first I want to have those embryos frozen. Regarding your third question, well without specific findings, we don’t like to give drugs if there is no indication. Prednisolone we give to patients that have some immunity disease or they have several implantation failures. If they have any immunity status that can lead to implantation failures, such as the KIR or the HLA discordance. We can give it, but if there is a first IVF cycle, if there is no indication of getting prednisolone or granulocyte, we don’t think that this can improve the outcome, so probably we won’t give it. Only if it’s indicated.

Why do typical hormones/stims hurt egg quantity and quality in people w/ DOR (Diminished ovarian reserve)?

They don’t hut the egg quality and quantity, the only thing that hurt egg quality and quantity is the age. The hormones that we use, they, don’t hurt because when we do the stimulation, we try to save those follicles that are ready to die because, in each menstrual cycle, there is only one. We have recruitment of eggs, among those eggs that are recreated only one would be in charge of ovulating, so the rest of them die. With an IVF treatment, we give hormones, we give gonadotropins to try to rescue those follicles, so there are no future implications, and with more stimulation that it doesn’t hurt the quantity and quality. It’s very important to stimulate properly, it should be prepared, we cannot forget that because the high dosage can hurt the egg quality. The egg quality also depends on when we give high doses of hormones or where we stimulate. For example in a PCOS patient when we don’t give the correct dose of the trigger or sometimes we get low-quality eggs, but this is not because we have given stimulation drugs, it is because we have not used them correctly.

I am 34, one living child (3.5 yo) from a naturally conceived pregnancy. Since then, I had 2 miscarriages due to a balanced translocation. Unfortunately, I also have a low ovarian reserve (or borderline, I don’t remember the values now). I had 2 egg retrievals now with 8 and 10 eggs, however, the quality was poor, leading to only 2 and 1 blastocysts. All had several mosaic errors. Are there any tests that I should do before trying another IVF? Or how to change my treatment protocol? I had GONAL-f 300 IU the first time, and plus GONAL-f 150 IU, menopur the second time.

On one hand, you do have a borderline ovarian reserve but having 10 eggs retrieved at 44, that’s a good result. Then it’s different because it can be a lot of causes, the first one if you have a balanced translocation we have to perform the PGS to just try to get a normal embryo and to improve the property of pregnancy, and then knowing how to stimulate this kind of patients is very important, so from my point of view, I don’t know the cycle, the doses of hormones, the levels of estrogen but for me, I think you had high doses of hormones. This maybe has not helped you. It’s very important to do proper stimulation. Sometimes even if we perform correct stimulation, we only have 2 and then 1 blastocyst. If those blastocysts are of good quality, probably that would be a good stimulation, depending also on how many eggs were mature, how many got fertilized because we have to know the whole pathway. If you had 2 miscarriages, you should do a karyotype. If the miscarriage were because of chromosomal abnormality, you have to perform a karyotype just to confirm that you don’t have any balanced translocation. Then you can also perform the recurrent miscarriage test, it can be by a blood test so we can see if the fallopian tubes are okay, if there are no hydrosalpinx and of course we need to see your uterus because your miscarriages were caused by balanced translocation, so we have the causes of the miscarriage, but also we have to check the uterus. In your case, performing a good stimulation, not with high doses, probably 150 and 75 will be okay. Just to perform a correct protocol and to give you also other drugs to try very slowly to get good follicles and therefore good oocytes and to try to get more blastocysts. The more blastocysts you have, the more probability of a normal embryo you have. If you have a balanced translocation, you have to know that at least 25% of the embryos won’t be good, so it is important to do that.

I’m 40 and ith AMH 1.2 have done 3 IVF cycles Microflare Lupron and was able to have 4 embryos (from 8 eggs retrieval) in round 2, and 2 embryos (from 9 eggs retrieved) in 3rd round, but none were viable. I’m open to doing another cycle, but what would you recommend? I did PGT-A test – chromosome issues.

At 40 years old having 4 abnormal embryos is what we can expect. At 40, the probability of having an abnormal embryo is at least 60-65%, it doesn’t mean that we will never have a normal embryo. The more cycles you get, the probability of having a normal embryo is higher, but I think doing another stimulation cycle sometimes it’s exhausting, sometimes it can be psychologically very difficult, so it all depends if you are open to doing another cycle. Some papers say the long protocol used with the agonist in low ovarian reserve patients is better, but in our case, we prefer to do a personalized treatment to try to stimulate the person when the ovary is ready to get the injections. So in your case, we would try to do a cycle with different protocol to try to improve, a short protocol, but it’s difficult because sometimes it takes even a day to understand why those treatments have failed and how to manage this kind of changes and sometimes we need to think and discuss it within our team. After all, that is what we do. Sometimes, it is very difficult to stimulate a patient properly. If you have 2 stimulations with no viable embryos, we have to change everything, we have to do a pre-treatment to try to improve the quality and also a stimulation protocol with different drugs. Also, we need to manage the stimulation to see how are your estrogen levels, if they are good etc. Having an AMH of 1.2 and having 4 embryos and those embryos reach day-5, that’s not a bad stimulation. The problem is the chromosomal abnormality, and this is related with the age, so, unfortunately, we cannot go back to be 30 years old, so it’s difficult. We have several patients that have had abnormal embryos in the previous cycles, and then with us, they have normal embryos.

Is mild IVF suitable for someone with low ovarian reserve?

Yes, as I’ve mentioned in the presentation, there are some protocols where they explain that mild stimulation can help these patients. They think that if they only stimulate a very low quantity of follicles, so those that are growing are of the best quality, so probably they will have the best quality embryos. It depends on the patient for example if we see that we have done a mild stimulation and we have a good embryo probably we’ll say, let’s repeat the cycle because we have a good embryo. Sometimes if it is the first IVF stimulation and we see that the patient has low ovaries, but at least we can expect to have more than 2 embryos, I will go ahead with a short protocol, not with a mild one. If we see that even if we give the patient low doses, I can’t expect to have only 1 or even 2 embryos. I will try the mild stimulation, but it depends because sometimes that doesn’t have good results.

Do you know if there is any relationship between LOR (low ovarian reserve) and intestinal microbiota (dysbiosis)?

I’m not sure, I will try to find out. I’m pretty sure that the microbiota, the dysbiosis can affect the ovarian stimulation, it can affect the pregnancy rate. It has been demonstrated that when we do a stimulation cycle the vaginal and the endometrial microbiota changes. This is due because of the higher levels of the estrogen and the changes with the progesterone. In our patients, when we are performing an ovarian stimulation, we get them probiotics, and this is because we want to avoid the dysbiosis. We give them probiotics, once we are doing the stimulation, and then we change the probiotics with the vaginal probiotics for the embryo transfer. So I think it could be correlated, but I’m not sure if there is a direct cause of a low ovarian reserve. I don’t think so, this is more related to the quality and also with the fresh embryo transfer, but not with the low ovarian reserve. I will find out though to make sure.

I’m 38 with AMH of 3.5 – will I get any eggs?

An AMH of 3.5 depending on if it’s in picomoles or if it’s in nanograms. If it is in nanograms, it means that your ovarian reserve is really good. If this in picomoles, it is a low ovarian reserve. But it also depends on your FSH levels because if your FSH levels are not very high and we perform a stimulation, we think about your personalized stimulation protocol, I think that we will have a chance of getting oocytes. We have had a lot of pregnancies with an AMH at 0.02, but it does depend, sometimes we have to wait at least 4 or even 6 months to get at least a good cycle. Sometimes if the FSH is very high, we need time to decrease the FSH level and therefore to get the ovaries ready for the stimulations, and this takes time, but once the ovary is ready of course, we can start with appropriate stimulation, and retrieve some oocytes.

My AMH level is 5 (41years old), and we need surgical sperm retrieval. What are our options?

It’s difficult, an AMH of 5, I think it would be 5 picomoles, as I’ve said, it depends on your FSH levels, also depends on your antral follicle count because sometimes if they are very accurate the antral follicle and antimullerian hormone, there are some differences and when we see that there is a very low anti-Müllerian hormone, and we see the antral follicle count, the prognosis is better. To answer the second question if you have sperm collected at least, the chances of getting embryos are high. At your age probably it’s better to have at least between 2 to 4 embryos because of the probability of embryos with chromosomal abnormalities. An AMH of 5, if this is 5 nanograms, it means it is very good because probably we’ll have a lot of embryos. If it is 5 picomoles at your age and with the sperm retrieval, you have to be aware that probably we will have to repeat 1 or 2 cycles to get between 2 two to 3 embryos.

I am 35 years old with an AMH of 0.52. We have one failed cycle (6 eggs collected, one 7-day blastocyst). Looking at our next cycle, are we better using higher stimulation drugs to increase egg quantities? Or should we consider lower stimulation drugs to improve the quality of the few eggs we produce?

In that case, I wouldn’t probably use high doses high. A long time ago we thought that when we give more stimulation drugs, you will respond better, and that’s not true. It has been demonstrated that in this kind of patient if we give low doses between 2 to 5 and 150, it’s better for them. We’ll avoid high doses of estrogen, and these high doses of estrogen can affect the implantation rate if we are going ahead with a fresh embryo transfer. The higher doses of estrogen can affect the uterus, so if you had an AMH of 0.52 and you got 6 eggs collected, that’s good. When we see that at 35 years-old, 6 eggs were collected and we only got one day-7 blastocyst, it means that the quality is not very good, so in your case, I would try a different protocol with a short one or even a long one but with low doses. In a stimulation we have to take into account that in a stimulation, lots of things have to be taken into consideration, the drugs, the pre-treatment, the triggering the trigger, the dose, which we’ll be using. If we’re using LH or FSH, we have to take into account also the trigger if we are using Ovitrelle or Decapeptyl because every step matters, so we have to consider everything because if one of this step fails, the whole cycle fails.

I have had 2 IVF cycles and only managed 3 eggs on the first cycle and 1 on the next. I am 41. Would you recommend looking at egg donation?

When we’re going ahead, we need to think about the easy way or the difficult pathway. In your case, egg donation will give you a higher chance of pregnancy. It’s very high, at least 80% of probability to succeed. If you want to get pregnant soon, my advice will be let’s go for egg donation, but if you want to fight and still try with your own eggs, it would be difficult because you have to take into the account that you have only had 3 eggs on the first cycle, and then 1, it means that your ovarian reserve is very, very low, but not only that, at 41 years old we need at least 4 embryos to get a single one that is healthy, so it’s extremely difficult. If you want to go ahead, we can try to improve everything, we can try, here in our clinic the average age of the patients is 39-40, and we always want to try with their own eggs, but sometimes it’s not possible because of the quality and the quantity. If you are open to an egg donation, it will be my advice, but if not, we can try, we have tools for low responding patients, and we can try to improve the oocytes yield, but if we improve the oocyte yield, but then the chromosomal abnormality rate is still there, it is difficult.

What IVF protocol do you suggest for AMH 0.33, 41 years old? No previous IVF or pregnancy trials.

The IVF protocol depends on the BMI, on what we are expecting to get, on the ovarian reserve and on patients characteristics, so if I see that your AMH is very low, and you are 41, and this is your first IVF cycle, I probably would try with a short protocol, not very high doses and also I would perform some blood tests before the stimulation just to be sure that your ovaries are ready to receive the hormones, and this is a personalized treatment. It means that we will only start the stimulation protocols once your hormone levels are okay, so probably I would do that. I want to stress that here our clinic when we do the first consultation, we don’t give the treatment protocol straight away because this is a very important issue, so we need to think about that, once we have performed the scan, once we know the patient, once we know all their background, all characteristics, we think about the treatment protocol because it’s very important, and not everyone knows how to stimulate the ovary correctly. We have to go inside the ovaries, we need to focus on that, so it’s very difficult. I cannot give you what protocol is the best for you because I don’t know you nor your background. So I’ve mentioned that I would probably use a short protocol, but sometimes if I do a scan and then I see something different, I might change my mind, so we need to be very careful with this.

Is there any medication I can take to increase the AMH level?

Unfortunately, not. The AMH measures the antral follicles and these decrease with age. If you smoke, you have to stop because it has been demonstrated that smoke can decrease the ovarian reserve, then if you see that your ovarian reserve is very low and you don’t want to get pregnant, my advice would be to perform fertility preservation. If not, and you are looking for a pregnancy, you can go for IVF treatment. You can also take antioxidants, this is not to improve the quantity, but at least if you have a low quantity, that way you can try to increase the quality. There are no tools to improve the quantity, we’ve seen that there are some experimental treatments with ovarian rejuvenation. With this surgery, some dormant antral follicles are activated and with that, it can increase the AMH. That is in the context of an investigation. We have to perform a lot of trials regarding that.

What is your opinion about the recommendations of the book ‘It starts with the egg’. It recommends many different supplements (f.e. CoQ10, NAC, R lipoic acid, vitamin E) as well as lifestyle changes (f.e. changing of cosmetic products and diet to lower carb intake)

I’m pretty fond of CoQ10 it can increase the quality, it doesn’t increase the quantity but can increase the quality of the oocytes. The diet and low carb intake, I’m pretty fond of that, especially low gluten, low lactose intakes because the gluten and lactose can provoke a bowel inflammation and can provoke inflammation of the ovaries, it can also lead to a low quality. To all our patients, I recommend, at least during the stimulation or preparation for the cycle, to take a gluten-free diet and low lactose. Sometimes, for example, women with endometriosis, when they feel that they have stomachaches etc. , and sometimes when they reduce the gluten and the lactose, they feel better, so this means that it’s working. The lipoic acid, I don’t really know, if it’s not harmful, you can use that, and vitamins like vitamin E, D are indicated for the stimulation cycle.

I am 42 years old and AMH 0,20 ng/ml, 4-5 AFC. Do I have any chance to get pregnant? What other test do you recommend beside AMH and AFC count for identifying the right ovarian reserve? What option do I have?

Two most common measurement of the ovarian reserve nowadays is the antral follicle count (AFC) and the AMH. There were a lot of previous ones that were used like clomiphene test, which is the basal estradiol. There were a lot of tests, but nowadays the most common are the ones I’ve mentioned, they give an accurate measurement of the antral follicle count and the AMH. With an AMH of 0.20, it correlates with 4-5 follicles, so I have to be honest at 42, it’s difficult with such a low ovarian reserve, but of course, we can try, every patient is different, and we have a lot of patients that are 42-43 with a low ovarian reserve and with a good stimulation they have had 2 or 3 good quality embryos, and they achieved pregnancy, but it’s not always the case. I don’t know if you have any chance to get pregnant, I cannot tell you that you can’t get pregnant. If you want to get pregnant quickly and soon, you can go ahead with egg donation, that’s for sure, but with your own eggs there is an option, there is not a zero per cent of chances, but we have to think of a good stimulation and to perform one, or more than one cycle because we have to take into account that if you have 4 to 5 eggs, those eggs need to fertilize if the sperm is okay at least 80% of the eggs will be fertilized, so for example, if you have 4, we will have 3 eggs fertilized in the best-case scenario, and then those eggs need to develop in embryos, so sometimes it’s very difficult because 50% of the embryos will develop until day-3 or day-5, so it’s difficult. We do have a lot of patients of your age with your AMH, and they get pregnant, so we just have to try. If you don’t try, we won’t succeed.

I have a friend who is worried about the quality of her embryos as she did 2 cycles in a hurry when she was told she had to have a kidney transplant. Would the medications she took to accept the kidney have impacted her embryos, she is 30yrs old?

She was probably with medications that are in high immune super source and also high doses of antibiotics I suppose, so yes those can affect it. We have to take into account that if the body is okay if your mind is okay, the oocytes are going to be of good quality, but if there’s something wrong, we have a basal pathology, such as endometriosis, cancer, for example, it can cause the loss of quality, but I need to see the development of the embryos. I need to see how the cycle was going, so I cannot tell you that there is a 100% chance that IVF before the kidney transplant caused the poor quality of the eggs. I’m not sure, but of course, some drugs can affect the quality.

If stimulation day 6 the estrogen is 1288 is it high? It can cause problems with embryos? Was the stimulation too strong? It was Fostimon 450.

I think it’s very good estrogen level if you had at least more than 6 follicles, I think it’s pretty good. Sometimes when the estrogen is very high at the beginning, and you have a low quantity of follicles, it means that they are growing very fast and it is associated with impaired quality. It depends on your age because if you are over 37 years old, my advice would be to use a combination of FSH, which is Fostimon and LH activity, such as Menopur or Meriofert because the LH activity can increase their follicular recruitment. But I don’t think that this estrogen level can affect the embryo quality, it depends on the number of follicles, it depends on how much bigger they were, so I cannot tell you 100%.

I am 41 years old, AMH 0,7 and I had 2 IVF stimulation protocols first last year with 3 mature eggs fertilized, but unfortunately, all the embryos had aneuploidy. The second stimulation protocol this January produced no mature eggs. I also had a natural cycle with one mature egg with an aneuploidy as well. I had an ovarian cyst removed 5 years ago, but I developed a cyst again on the ovary which was aspirated when the eggs were collected. Should I keep trying?

Here we are facing a low ovarian reserve and also a low ovarian response, and then there is a problem with the chromosomal abnormality of the embryos. If you want to keep trying, I mean, of course, it’s up to you. If you feel that you can try again that you want to try and fight to try with your own eggs, you can try, but with 4 embryos that had an aneuploidy it’s very difficult, I have to be honest that to improve that, it will be very difficult, but you can try and change several things. In your case, you have to at least be open-minded regarding the egg donation because I don’t know if you will get a better chance or better embryos.

I have adenomyosis on the top part of the uterus. I will be having a surgical hysteroscopy to open the space so implantation could happen in an IVF treatment. How big could the chances be of getting pregnant after that surgery?

In our clinic, we perform this surgery as well to improve the implantation rate, to remove the uterine fibrosis and to improve the vascularization of the uterus, so that we can improve the implantation rate. Sometimes 20% of our patients having unexplained infertility and having previous cycles, they get pregnant spontaneously, and this is because they had a uterine problem. I cannot tell how big your chances are after the surgery exactly, but the chances increase, it’s better to do the hysteroscopy to improve the implementation than not doing it, so go ahead with that.

I asked my fertility doctor about my AFC. She said to me, she can’t really count the follicles, but she sees them. Can the doctor count the follicles on an ultrasound?

Yes, and they have to do it. The ovaries are more or less between 2 and 3 centimetres, and the small black area, the small black bubbles that you see inside the ovaries are the antral follicles, they measure between 2 and 9 millimetres, so they are easy to see on the ultrasonic scan. However, sometimes it’s difficult to count the antral follicle count because it depends on the cycle. If you have already ovulated, it means that one of those follicles have been already selected, has reached maturation and you have ovulated, and the rest are dying, so sometimes you cannot see. To check the antral follicle count it’s better to perform it with the period between day 1 and day 5 of the menstrual cycle. If the gynaecologist has some experience, it’s pretty easy to count the follicles.

Can you do PGT-A, PGT-M and PGT-SR from the same embryo/biopsy?

Yes, we can do it. If you have to do that because of a genetic condition, and you have to perform the PGT-SR or PGT-M, you can do it in a single biopsy, you can perform those 3 tests. So just one single biopsy and then one same goes for the PGT-A and then with the same we go for the PGT-M.

What exactly is a ‘mild stimulation’? Is it only about the lower dose, or does the protocol also differ in another way? How long (how many days) can stimulations be done? And an unrelated question: do you prefer HCG or Decapeptyl to trigger ovulation?

Regarding the mild stimulation, it is a modified natural cycle, it means just to follow the oocytes, the follicle is growing by your own hormones and sometimes just push it a little bit with some kind of stimulation drugs, just a little bit. There are some other protocols with low doses of hormones. There are also different drugs, which are the Clomiphene Citrate or Letrozole that are not commonly used in a patient with a good prognosis, like young women with a good ovarian reserve and we can try this with such patients. A mild stimulation means that sometimes we use different drugs, different conventional drugs, and also they are with low doses of hormones like 150 or even lower. Regarding the second question, it also depends because the Decapeptyl is very good to avoid hyperstimulation syndrome. Sometimes in patients that have higher levels of estrogen at the day of the trigger injection or they have a polycystic syndrome sometimes we have to use the Decapeptyl to avoid this hyperstimulation. From my point of view in low ovarian reserve patients, I prefer HCG because it can give a better maturation, nowadays, we are performing the dual trigger, which is a combination of HCG and Decapeptyl together because they do the same action but in different ways. So sometimes just to control everything, to control all the pathways, we do a dual trigger, and with that the maturation rate of the oocytes increases. In low prognosis patients, sometimes we perform a dual trigger, which is HCG plus Decapeptyl.

I am 42, I had 2 failed IVF. My AMH is 1.4. I have a low ovarian reserve and a cyst which is gel-like. Should I remove it now or will it affect fertility? In the first cycle, I had 5 embryos, 1 good quality day-5 blastocyst and 2nd had 1 good quality day-5 blastocyst. My endometrium lining was 11-12. Was the failure due to chromosomes? Would natural IVF be better?

From our point of view, it’s better if the ovarian cyst is a benign one, I mean it is like a simple cyst or an endometrioma, and we probably would know by doing a scan that it is a benign cyst, we’d prefer not to touch it – if it’s less than 6 centimetres and it doesn’t affect the egg collection because sometimes we have to remove the ovarian cyst if it is affecting the egg collection techniques because we cannot retrieve the eggs. If we see that the cyst is very big and other follicles cannot grow because the other cyst is growing and is taking healthy tissue. In your case, if you have done previous cycles and you got blastocyst, my advice would be not to touch this cyst because if we touch it, there is a risk of getting a healthy tissue and we can decrease the ovarian reserve. At your age, if we decrease, your ovarian reserve, even more, it probably would be catastrophic. If you had 5 embryos and 1 blastocyst, it’s a good response. It’s what we normally can expect, and there were 2 failed attempts with 2 good quality blastocyst, it can be different, but in that case, it is probably related to a chromosome abnormality. At 42 years old, at least 75% of the embryos will be abnormal. Every patient is different, but I’m talking about the vast majority of people. We also have to take into consideration your uterus, your fallopian tubes, your endometrial lining, your endometrium was 11-12, I think it’s a little bit thick, I mean it is a good one, but from our point of view, we prefer for it to be a little bit thinner. When it comes to a natural IVF, if it would be better, it depends because if we see that the stimulation was done properly and in the end, you got 2 good quality embryos – it was not a bad stimulation. In that case, probably you will benefit from the PGT-A to be sure that it is because of the embryo. If we see that the embryo was normal, we have to go and to think about all the causes of implantation failure.

What do you think the live birth success rate would be with 23 yrs old donor eggs that have been PGD24 tested with ‘good to excellent’ sperm if they are transferred to a healthy surrogate? Can you provide the percentage?

You have a donor egg who is 23 years old, it means that she will probably have excellent embryos, and then if the sperm is excellent, you will have even more good quality embryos. Then if the surrogate is health, Her uterus is okay, we are facing the best quality of everything, better quality embryos, a better quality of the uterus, so the chances of being pregnant are excellent, in that case. The percentage depends on if we put just a single one embryo, it also depends on the endometrium, but normally with that first attempt it will be between 70-75%, then the 2nd attempt if the first fails will be 85%, and the 3rd attempt would be around 90%. I cannot tell you exactly, of course, but this is our experience.

Should the Surrogate Mother be tested for the MTHFR gene?

She can, of course, but a long time ago this mutation was very controversial because nowadays we don’t treat this mutation. If we have this mutation, we give her high doses of acid folic, and that’s all. If she’s a healthy woman if she has previous pregnancies and she has a good uterus, and she’s healthy probably I wouldn’t test her. When we are trying to conceive spontaneously we don’t even look at this type of mutation, so probably in the first attempt, I wouldn’t check it. In case, the attempt fails, or we see that there is something wrong, then we will check it but not in the first attempt.

What are your thoughts on ovarian rejuvenation procedures for improving low AMH?

In fact, we are carrying our own study regarding the ovarian rejuvenation, and we have promising results, but we’ve also seen a that in woman over the age of 40 years old this surgery doesn’t improve the outcome. It can improve 1 oocyte or slightly increase the quality of the embryos, but that doesn’t increase the quantity. In younger women who have failed IVF treatment or if they had poor quality embryos, we offer it, and we try it but in a context of an investigation, it means that if the woman needs any surgery because she has hydrosalpinx or she has a fibroid we offer it, we don’t indicate this type of treatment to only perform the ovarian rejuvenation because it is a surgery, it can have its risks like the risk of bleeding, so we have to be very careful with that, but if there is an indication of any surgery, we can perform it but in the context of an investigation. Our results are promising, and we do such procedure more and more, but we’re trying to perform it in younger patients below the age of 30 years old.

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Authors

Alejandra Aguilar Crespo, MD

Dr Alejandra Aguilar Crespo is a Gynaecologist and Consultant Specialist at Equipo Juana Crespo, Valencia, Spain. She holds two Master’s Degrees in human reproduction and advanced gynaecological endoscopic surgery. Dr Alejandra Crespo has published several national and international publications in scientific journals and has attended numerous national and international congresses. She speaks English, Spanish and French.

Event Moderator

Caroline Kulczycka

Caroline Kulczycka is managing MyIVFAnswers.com and has been hosting IVFWEBINARS dedicated to patients struggling with infertility since 2020. She's highly motivated and believes that educating patients so that they can make informed decisions is essential in their IVF journey. In the past, she has been working as an International Patient Coordinator, where she was helping and directing patients on their right path. She also worked in the tourism industry, and dealt with international customers on a daily basis, including working abroad. In her free time, you’ll find her travelling, biking, learning new things, or spending time outdoors.

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