First IVF Magazine
15 articles about IVF and Donor Conception by top IVF experts worldwide!

Stimulation protocols – what can possibly go wrong?

Halyna Strelko, MD
Co-founder& Leading Reproduction Specialist at IVMED Fertility Center, IVMED

Category:
IVF process, Low Ovarian Reserve

ovarian-stimulation-protocols
From this video you will find out:
  • What are the different protocols for IVF?
  • What is the main goal of controlled ovarian stimulation (COS)?
  • What do doctors call ‘normal response’?
  • How can we avoid Ovarian hyperstimulation syndrome (OHSS)?
  • What IVF protocol is best for low AMH?
  • What are the differences between hCG and GnRH agonists?

What to expect from ovarian stimulation in IVF?

In this session, Dr Halyna Strelko, Chief physician, Reproductive specialist at IVMED, Kiev, Ukraine, focused on stimulation protocols, she explained what ovarian stimulation is, how it works, what kind of protocols are used, and what happens during this phase of your IVF journey.

The main goal of controlled ovarian stimulation (COS)

Statistics say that only 23% of all embryo transfers lead to delivery. This data is from 38 countries and, 1169 clinics in Europe. The main goal of controlled ovarian stimulation (COS) is to harvest enough eggs with acceptable quality, which can permit to obtain live birth.

The quality of oocytes depends on the female’s age and individual peculiarity. Generally, we need more eggs when the age advances. How many eggs is considered a good number? It depends on the woman’s age. On the graph shown, if a woman is less than 35 years old, she has a 50% of chance to achieve a pregnancy. It’s expected that she would have approximately 7-8 eggs. However, if a woman is 40 years old, she will have the same chance with around 20 eggs. If she is 43 years old, it is around 50 eggs. Normally at this age, we never get to this number. It means that the more advanced reproductive age we have, the more eggs we should receive to have an acceptable pregnancy rate.

What is a ‘normal response’

We need to get around 10-20 eggs until the age of 40 to have a 50% chance to have a live birth. The number of eggs depends on the protocol, Anti-Müllerian hormone (AMH), body mass index (BMI), medication dosage, sensitivity, and a lot of other things.

Dr Strelko then presented a slide with all available protocols used nowadays. It is a short protocol, classical short antagonist protocol, long protocol, short agonist protocol, protocol from luteal phase, natural cycle, mild stimulation, flare-up protocol, stock protocol. What kind of problems we can have during ovarian stimulation?

It may be an excessive response, we call this response ovarian hyperstimulation syndrome (OHSS), and we expect this when the Anti-Müllerian hormone (AMH) is more than 3.5. Sometimes, there is also a possibility for non-expected ovarian hyperstimulation syndrome (OHSS) to occur. We can get the OHSS even without having a high ovarian reserve, it can happen in a natural cycle, it is rare, but it can happen. We can have poor egg quality, it may be expected, as we have mentioned, it mostly depends on a woman’s age. Over 38-40, eggs are not of very good quality more often, but sometimes we can have poor egg quality in younger patients. It may depend on the protocol or some mistakes as well. There is also a chance of having a poor response, it is expected when AMH is quite low, less than 1, although it can also occur in patients with normal AMH and young age.

If the AMH level is less than 1 ng/ml, we can expect a reduced response to stimulation. If, for example, you have 1 ng/ml at 25, it is not good, but if you have the same number at 45, it’s normal. The normal range of AMH depends on age. However, if we’re talking about the ovarian response, there is a different classification.

From the point of COS:

  • ≤ 1 ng / ml – reduced response (≤ 0.2 ng / ml – critically reduced prognosis)
  • 1 – 2.5 ng / ml – normal response
  • ≥ 2.5 ng / ml – very good response
  • ≥ 3.5 ng / ml – OHSS
  • ≥ 5 ng / ml – PCOS

We can also look at Antral Follicle Count (AFC), and we can see that if we have a low antral follicle count, we can expect a poor response, and if we have a lot, we can expect hyperstimulation syndrome.

Ovarian Hyperstimulation Syndrome (OHSS)

Why is Ovarian Hyperstimulation Syndrome a problem of the protocol? This Ovarian hyperstimulation syndrome is triggered by exogenous administration of hCG (Human chorionic gonadotropin). Two main medications produce the final egg maturation – it is hCG, such as Ovitrel, e.g., this molecule looks like LH (Luteinizing Hormone) it activates the same receptors, but it stays in your body for around 10 days and has, what we call FSH effect. It means that it acts like Follicular Stimulation Hormone (FSH), and during these 10 days, this molecule continues to stimulate the ovary, not only maturate eggs, which we take out during the collection, and that’s why it produces all these symptoms of ovarian hyperstimulation syndrome.

How is OHSS prevented? With hCG, the risk of having mild, moderate or severe ovarian hyperstimulation syndrome is more than 5%. If we use GnRH agonist, it is less than 2%.

Different studies show that the use of a short protocol instead of the classical protocol may decrease the probability of OHSS significantly. The main factor that can prevent OHSS is to use the agonists as a trigger.
In a recent paper published in 2021, 2 groups of patients used agonists and the other hCG. We can see that with agonists, the probability of OHSS is 0.5, so almost 0, and with hCG, it was mostly 1.5 with the symptoms of ovarian hyperstimulation syndrome.
GnRH agonist trigger and freeze-all strategy is the main instrument to prevent OHSS.

To avoid OHSS, it is necessary to identify the patient of high risk. Especially, if there were previous cycles with OHSS, the patient suffers from PCOS, is of a young age, stimulation protocol. Stimulation should be done with antagonists, the trigger should be done with (a-GnRH) antagonist like Diphereline. It is necessary to use a minimal dose of FSH for the stimulation, but even with high response, even if we have 30-40 follicles with agonist triggering, we will never have OHSS. It is also necessary to exclude the chance of pregnancy in this case and choose a freeze-all strategy.

Age and poor prognosis

As Dr Strelko mentioned, egg quality is individual, and it depends on a woman’s age. As stated by the American Society for Reproductive Medicine – ASRM, over the age of 35, the quality of eggs and pregnancy rates start to decline. It is mostly related to maternal meiotic abnormality, which means the egg quality. If we calculate the probability of having a genetic abnormality of the embryo, we can see if it is related to eggs and sperm. Mostly it is related to the age of the woman, the more advanced age, the probability of genetic abnormality is higher. Paternal age is not so directly related, and the percentage of meiotic abnormality is mostly the same in all ages. Therefore, the main problem is woman’s age because, with age, the number, and quality of mitochondria decrease dramatically due to some damage, and as we know, mitochondria are the main battery of eggs. When the number and quality of mitochondria decreases, we have less potential for fertilization, cleavage stage and so on.

Other factors may also be involved in this process, such as shortening of the telomere, coenzyme dysfunction, spindle degradation and abnormality. This increases the number of genetically abnormal eggs, and in this case, we will have low egg quality.

Low response & AMH

The prognosis of potential response of COS is mostly based on AMH and AFC levels. Both of the parameters are not very stable. Sometimes, we have a good prognosis patient, we have a good number of antral follicles, we have a young patient, we have a good level of AMH, and yet we retrieve only 1 egg. Why does it happen? We have a lot of mechanisms of discordance between ovarian response and AMH levels which we have measured. We can see that the follicular AMH and AMH levels we receive from the lab are two different numbers. We have different sources of variability of AMH, for example, there might I be some systemic problem like physiological, e.g. day of the cycle, it may also be a pathological problem like some tumours, some abnormalities. It could be the administration of some hormonal medication like estrogens, progesterone, contraceptive pills during ovarian stimulation. Another thing would be pre-analytic variations like temperature, or it may be some preparation protocols that are not correct, be freezing and thawing of blood or plasma before they analyze it at the laboratory. Finally, there may be some analytical variability due to some kind of machines and so on. In this case, we will have some level of AMH in blood circulation, but we will receive another number in your analysis, and it may be quite a big difference.

In her next slide, Dr Strelko focused on physiological variability. The graph represented a different colour for each patient. In the study, AMH levels were checked every 7 days during the menstrual cycle. It shows that some patients have quite stable levels of AMH, but some others have a very big difference in different phases of the cycle. It may be due to waves of follicle growing, it means that follicles grow by some cohorts, and in some cycles, you have more or fewer antral follicles. This may be due to the issue we have mentioned before. It happens quite often, and the difference may reach 20-30% in the same cycle. We should also be aware that when women take oral contraceptive pills, it may decrease AMH levels up to 30%. The pregnancy rate can also decrease, on the other hand, ovarian tumours may increase AMH levels. Surgical interventions and chemo or radiotherapy can also influence AMH levels. When we get an AMH level, we get the prognosis of a good or bad ovarian response. In 30% of cases, our prognosis may not be correct. It is not because the protocol was wrong, it is because the prognosis was only based on AMH, due to its variability, it would not be very correct.

The next slide showed that different conditions may change AMH levels dramatically. For example, the effect of long-term storage at -20, AMH level may increase by 230%. It means that if at the beginning you have an AMH level at 1, you would get 3, and after with low dose stimulation protocol, you will receive 2 follicles, and it will be a big problem. So as you can see quite a lot of things may influence the AMH level, and it may change the final result. Therefore, it is necessary to know that, and for example, if your doctor sees that you have a good follicle number and you receive a bad AMH level or just the opposite, it is probably necessary to change laboratory and repeat the analysis once more.

Unexpected low ovarian response

If you expect to have 10 eggs and receive 3 it is a problem. Therefore, a group of doctors divided patients with the low response into 4 groups. This classification is called the Poseidon group. Two first groups are patients under 35 years old and over 35 with good AMH levels, low response to normal standard stimulation. What is the reason behind it? It may be due to mutation of FSH receptors, and in these cases, women may have delayed puberty, decreased breast development, sometimes primary amenorrhea. Other factors include FSH gene variant, LH receptor mutation, polymorphism of FSH and LH, also polymorphism of their reception. There are a lot of mutations and polymorphisms that were described. It is quite difficult to know about that before, and even if we suspect it, we would need to do 10 or 20 different genetic tests, which would be quite difficult from a practical point of view. On the other hand, we should be aware that sometimes it is not related to a bad protocol or bad product, sometimes patients say that they had a bad response, for example, with Puregon, and they want to change it to Gonal-F. We can change it, but this may be due to this kind of thing and not medications.

What to do in this case? The recommendation for the Poseidon’s group I and II for patients with normal AMH levels and bad responses is to increase the dose of FSH and LH and add Growth Hormone to use what we call double or dual triggering. Sometimes we also suggest doing the egg banking program, so we want to collect the eggs in several cycles, 2-3 times and then use them for fertilization. We can also use advanced embryological techniques for egg maturation to improve the probability of fertilization and cleavage.

In situations where we have an unexpected low egg quality and maturity, the cause might be the product, the dosage, protocols, and the triggering. Premature ovulation may also be due to late triggering. Normally it is 3-4%, but in some groups of patients, if we don’t have a sufficient maturity of oocytes of more than 50% of immature eggs, normally it should be 75% or more MII eggs, but if we have less than 50%, it means that something was wrong or the trigger was premature, or it was an insufficient dose, or it was not a good type of triggering. We also can have postmature oocytes, which means late triggering, and we would have what we call empty follicle syndrome, so no eggs at all. The empty follicle syndrome is a very rare condition, and in most cases, it is due to not appropriate triggering. We see Empty Follicle Syndrome in clinical practice much more often, and it is due to some errors and mostly triggering mistakes.

Suboptimal response to an a-GnRH trigger

In this group, we can include:

  • low maturity rate
  • low fertilization rate
  • cleavage arrest
  • low blastulation rate, normally, it should be around 40%
  • low pregnancy rate and live birth rate

When it comes to a low maturity rate, it means that the nucleus and cytoplasm should be matured at the same time, but those are two different processes. When we have a lot of non-mature eggs, some parts of eggs we consider as mature have immature cytoplasm. In this case, we will have a problem with fertilization cleavage and so on. Statistics and scientific papers show that when we have low maturity rates, even eggs considered mature end up with lower fertilization and worse quality. One of the risk factors for suboptimal response to a-GnRH is the contraceptive pill. When can we expect this not adequate response to a-GnRH triggering? It is when we see a very low LH, and quite often, it occurs when women take oral contraceptive pills for a long time.

Patients with low LH levels on the day of the trigger had a 25% chance of suboptimal LH surge. In the past, it was quite often that doctors prescribed contraceptive pills a few months before IVF treatment. Nowadays, it is changing, and in most cases, we can start stimulation any day of the cycle, and there is no need to take these pills during 2-3 months and decrease LH dramatically. Other possible causes of suboptimal response to triggering maybe some inner conditions such as early oocyte atresia due to folliculogenesis dysfunction, a mutation of LH or hCG receptors, some abnormal activity of some medication. Also, increased hepatic hCG clearance where the body destroys hCG more quickly. There also may be a very low LH level at the beginning of the stimulation, as it was mentioned, it may be due to taking contraceptive pills, as well as possible mistakes during the administration of medication, especially self-administration.

How can we check if trigger injection was not done or done incorrectly? The next day after trigger injection, so after 8-12 hours, we can do the ovulation test, if it is positive, it means that your LH level is high and all is fine, but if it is low, it means that the medication is not doing its job or you have done it incorrectly. We can repeat a new triggering, it is a good method to control. Other risk factors of low egg quality and maturity can be due to high body mass index (BMI) and the dosage of stimulation. In patients with a very high dosage of stimulation, this problem of maturity occurs 4 or 5 times more often than in patients with a normal response. Patients with very low BMI and patients with low LH levels more often can have not a good response to the agonist triggering. Sometimes, oocyte maturation failure can be caused by some inner inherited genetic problem. Lots of mutations and mistakes are hereditary, and we cannot change them with the stimulation protocol, triggering or medication. When we don’t have a good maturity of oocytes, there are some ways to deal with that. If the patient is a poor responder, we can do what we call double triggering, it means that we are using hCG and agonists at the same time. If we have a normal response, we can do the same, and it may increase the number of mature eggs. The difference between poor and normal responders is that in poor responders, there is a higher risk of premature ovulation. It would be better to do the triggering a bit later, a few hours earlier before the egg retrieval, around 34 hours earlier.

The third category is abnormal oocytes maturation, and in this case, we can get agonists 40 hours before the egg retrieval and hCG 34 hours before. It lets us stimulate the LH receptors for some more hours, and sometimes it can improve the number of mature eggs.

There are a few treatment options that we can use for oocyte maturation failure and these are:

  • dual or double triggering
  • LH control in 12 hours after agonists of GnRH triggering
  • discover mistakes
  • repeat the triggering if the LH level after triggering is not good
  • advanced embryological techniques and approaches for oocyte maturation

Conclusions

Theoretically, we can divide poor results into 2 categories: expected and unexpected poor prognosis. The unexpected poor prognosis may be due to some objective patterns like receptor mutations, genetic problems, age and whatever we would do, we wouldn’t be able to change a lot. Some problems with Controlled Ovarian Stimulation (COS) we can improve and resolve by some supplements addition, change of the final trigger injection, using advanced embryological techniques. It is also crucial to avoid mistakes because, unfortunately, quite a lot of problems may be due to some simple technical mistakes and miscommunication between medical staff and patients.

What to expect from ovarian stimulation in IVF? - Questions and Answers

What protocol is recommended for a 35-year-old with ICIS? About to start a new round, last 3 rounds of egg collection we’ve got 19 eggs and between 7-9 embryos.

It is necessary to know the quality of the embryos and eggs, and after that, decide which protocol will be better. Why? It’s because if we receive, for example, 19 eggs but half of them were not mature or degenerated, it is one question. Another question is if all those 19 eggs were good and not fertilized, and the 3rd question is if all were fertilized, did they expand to the blastocyst stage? If we have more than 25% of MI, so not mature eggs, we can try double triggering, hCG triggering or growth hormone, we can prolong the stimulation and try to achieve more mature eggs. However, if, for example, half of the eggs have degenerated, this will not change a lot.

If we have post mature eggs, it is probably necessary to do the triggering earlier. There is no better protocol for 35-year-old or 40-year-old, it is necessary to see the exact condition, eggs and embryo quality. Normally, the standard recommendation for patients over 35 years old is to add Luteinizing Hormone (LH) or Menopur or recombinant like Pergoveris. It may improve the egg quality and quantity. Some authors recommend using growth hormone for such a category of patients. It may improve their egg number and quality. In most cases, there are no benefits of using a long protocol if there are a lot of eggs. In such a situation, the risk of OHSS is higher. It’s because, in a long protocol, we can only use 1 type of triggering, which is hCG, and we know it can cause OHSS. Therefore, a long protocol is probably not a good option for poor responders. First, we should do this suppression and then we should do the stimulation, and when we have a very suppressed ovarian reserve after this suppression, we can have a very poor response. If we have a good reserve, we will receive a good response, but in the end, we should do hCG, and it can cause OHSS.

In the last round, there were 5 embryos. Two of them were transferred and went to live birth. Three were frozen, two have failed, and one is left.

If you have as minimum as 40% of blastulation, it is considered as quite a good result, it means that if you have 10 eggs, for example, and 8 of them fertilized (fertilization should be around 80%) till the blastocyst stage you should have as minimum as 3 embryos, it is considered normal. Around 40- 50% of all eggs at the age of 35 may be genetically abnormal in general, but individually it may be 30%, but it may be also 60%. If the egg is genetically abnormal, it will not fertilize, and expand to blastocyst.

In low AMH, does DHEA help increase AMH and can give a better outcome? Or does it further reduce the egg reserve?

There are different publications about DHEA supplementation. Some of them, it was around 10-12 years ago when we had a boom of DHEA. If there was a problem of poor ovarian reserve, DHEA was recommended. In some publications published, they showed that the number of antral follicles increases after 2-3 months of DHEA but on the other hand, antral follicle count may change from cycle to cycle, it may change without any treatments. As we have seen, variability is around 30%, even without any treatments from time to time, we can have a better number of eggs and sometimes fewer eggs after DHEA.

Transdermal testosterone also may be helpful, and more recent publications show that it works even better than DHEA. Both those molecules help decrease the atresia of antral follicles. With this kind of medication, like DHEA or transdermal testosterone, we may decrease atresia a bit. In this case, we will receive more antral follicles, and get a bit higher AMH level, which may improve the outcome. The problem is that if you have, for example, 1 egg more and you had 8 eggs before and after that DHEA is taken, you will have 9, it will not change the result a lot. However, if you had, for example, 1 egg in the previous protocol and within 2-3 months of this treatment, you will get 3, it will probably statistically make a significant difference. There is still a little study done, only on some small groups of patients studies don’t show a big difference.

Can you do stimulation and freeze egg back to back, or do you have to have a break between cycles?

It depends. In some cases, when patients don’t have too much time, especially foreign patients who cannot stay at the clinic for 3-5, we are doing 2 consecutive stimulations in 1 cycle, and the second stimulation sometimes works even better than the first one.

There are no recommendations where they say it is necessary to wait 2-3 months, only if you have a very high response probably it would be necessary to wait up to 3 months.

I’m 40, and my AMH is 0.033. Which kind of protocol would you recommend? Or would you recommend going for egg donation?

Your AMH is very low, it is mostly 0, but on the other hand, we have seen that it may change from cycle to cycle, You can have 1 follicle in some cycles 0 in some cycles too. It is necessary to follow your cycles. Secondly, it may be a problem in the laboratory. Some machines that measure AMH have a different threshold of sensitivity, so in one laboratory, they can show this level, in some laboratories, it is below.

It is necessary to see the ovary by ultrasound and check if there are 1 or 2 antral follicles. Stimulation, in this case, is mostly useless because the stimulation will not produce more follicles. At this AMH level, it means that you have probably 1-2 follicles that will grow with stimulation, or without it. In this case, a natural cycle will be probably the best option, and pre-treatment with CoQ10, DHEA, testosterone, sometimes replacement hormonal therapy may be useful.

I’m 43, I will have an egg donation cycle. I have a blood disease. What will be the most appropriate protocol in my case to facilitate the implantation of embryos? I have had a genetic mutation with secondary amenorrhea for 35 years. I started this year, and they recommend taking estrogen. I have a cycle planned for April 11th.

It will be good to know about the blood disease whether it is increased or decreased coagulation, it makes a difference. If it is increased coagulation, it will be necessary to give something like Heparin, Aspirin, and if it is the opposite, other specific treatment will be needed.

About oestrogens, if it is a premature ovarian failure (POF) normally, before doing the transfer, it will be good to prepare the endometrium and uterus to do replacement hormonal therapy for 2-3 months. First, to see if the endometrium responds well, and second to improve the blood circulation and the growth of the endometrium. If all is okay, prepare the uterus for the transfer.

Do you use estrogen priming to synchronize follicles in advanced maternal age patients? When in the cycle do you start, and for how long?

There are a lot of strategies to synchronize the cohort of follicles with the long protocol. Why do we propose a long protocol for poor responders? It’s because they switch off the ovary, and we can try to synchronize follicles. We can also do that with oestrogens because high estrogen levels will decrease the FSH level, and we know that FSH levels change during the cycle. There is the first wave in the first part of the cycle. Then the second wave is after ovulation, before the next menstruation. When we add oestrogens, we decrease the second wave, and that’s why follicles stay more or less at the stable size. I’m using that from time to time.

We can also start this simulation in the second phase of the cycle if, for example, on 19 or 20 days, we can see that all follicles are more or less of the equal size, there is no need to wait for the beginning of the cycle, we can start immediately. There are different strategies, we can also use antagonist injection at this moment. For how long? It is 5-7 days, around 1 week, it is enough in most cases.

Why do FSH regimes lead to a good amount of eggs but few blastocysts compared to regimes with FSH and LH?

It does not always lead to a low blastocyst number. It may happen in some categories of patients, like patients over 35, if they have some LH receptor mutations and some problems with low LH, e.g., after contraceptive pills. In a normal physiological cycle, FSH increase at the beginning of the cycle and when follicles start to grow and produce estrogen, FSH drops, but LH starts to increase. The second part of follicles growing, they are more sensitive to LH than to FSH and need more LH than FSH. For normal egg maturation and normal follicle growing, we require FSH and LH.

When a woman is young, she has a lot of receptors to FSH and the LH and has a normal hormonal level, a very little amount of inner LH is enough. However, when a woman becomes older and is over 35, the number of LH receptors decreases, sensitivity to FSH decreases and in this case, we require a bit different amount of hormones. Therefore, FSH is sometimes not enough for the follicles to grow but not enough for proper egg maturation.

My first IVF failed, with 2 eggs retrieved, none was fertilized. It was a long protocol, my AMH is 1.4. Should I get a short protocol for the next IVF? I’m 40.

I think it would be a good option, but first, it is necessary to see if your AMH 1.4 is real and if it corresponds to 7-9 antral follicles. With this AMH level, there should be more or less 7-9 follicles. If, for example, we can only see 2-3, it means the AMH level is not done correctly in the laboratory, or there is some other problem.

We can expect only a few eggs, but if we can see a lot of follicles, much more than 2, in this case, it is necessary to use another medication like FSH plus LH or increase the dose. As for me, a better option would be to do the short protocol. However, it is crucial to see all of these things before understanding which tactic will be the best.

What would you do after stimulation with empty follicle syndrome? Which stimulation protocol and which embryological techniques?

First, it is necessary to understand if it is a mistake or a real problem. To understand that, we need to see the day of egg retrieval if you have done hCG triggering, it’s necessary to take blood to hCG and progesterone. Your progesterone level should be high if your injection was done correctly. Your hCG should be around 40, maybe 60 units. You can even do a very simple thing like a pregnancy test. If your injection was done correctly, the pregnancy test should be positive.

Another thing that can happen with hCG injection, for example, your egg collection is on Wednesday and your triggering is on Monday evening, but sometimes the patient mixes dates and may do the injection, for example, on Tuesday evening. The next day the patient comes for egg retrieval, and it is not 36 hours, but like 12 hours and in this case, we will have empty follicle syndrome, you will have high progesterone and hCG in the blood, but there wouldn’t be enough hours for final egg maturation. In this case, it would be necessary to repeat egg collection in one day. If it was triggering with a-GnRH it is again necessary to control it 12 hours later to do the ovulation test or blood test, LH level should be more than 12. If it is more than 12, it should be normal egg maturation. If it is less than 12, it would mean that it doesn’t act correctly, or for example, there is some technical problem in this case. If all tests are correct, there is a normal number of follicles duration of stimulation, so 9-10 days, we can use a double triggering hCG and then agonists but hCG 40 hours before because individually sometime eggs may become mature a little later.

Normally, the maturation of eggs starts 32 hours after triggering, but sometimes it is 35, sometimes it is a bit more, and in some individual cases, it is 40 hours. We can also use the flushing technique, so we aspire follicle then put inside some specific liquid-like washing and take it out, and after 2-3 times of washing, sometimes we receive an egg.

I have endometriosis, and I am 40. Does endometriosis impact the ovarian reserve? My AMH is 1.4.

Yes, of course, endometriosis can impact your ovarian reserve. In this case, the AMH will drop, which means that if you have endometriosis, the amount of normal follicular tissue in the ovary will decrease, and your AMH will drop. Endometriosis will not produce a higher AMH than it is in reality, in this case, we will see a simultaneous decrease of the Anti-Müllerian Hormone level.

Do you recommend transferring a day-3 embryo when you have a poor responder or are of advanced age with a few oocytes?

Some Cochrane database recommends that if you have only 1 or 2 eggs or 1 or 2 embryos and are of advanced maternal age, it is slightly better to transfer after 72 hours. On the other hand, when we transfer 72 hours after, we don’t understand the situation, for example, we won’t know if this embryo will go till the blastocyst stage or not and in this case, there will be no implantation.

When we transfer at the blastocyst stage, we understand that it is either the problem of an embryo or the problem of the endometrium. If we have a nice blastocyst, we are searching for some implantation issues, but if we have no blastocyst, we understand that whatever we will do with the endometrium, nothing will happen.

I am 38, and I just went through the IVF process. I got 17 oocytes, 13 matured eggs were fertilized, and 7 embryos were frozen. Is this a good outcome?

It’s quite a good outcome. Seventeen oocytes and 13 mature eggs, I don’t know the result of the other 5 oocytes, it might have degenerated, but it is quite a good outcome. You got 7 embryos frozen, which means that probably you’ve got 7 blastocysts, and it means that in around more than 50% of the situation, it can increase the result. It is necessary to see the morphology of these blastocysts, but it is normal.

I am 41, AMH 0.47, AFC 6-8. I had a duo stim short protocol for my 9th and 10th egg retrieval. On FPS, we used Pergoveris 225 from CD2, and my baseline was FSH 6, LH 4, estrogen 0.016, but progesterone was 5. We used single trigger Gonapeptyl 0.2 mg. We got 7 follicles of good size, and for the first time, 4 follicles were empty. From 2 eggs, 1 was mature and made to 4AA day-5 blastocyst. Can high baseline progesterone have anything to do with a poor response? After the 10th egg retrieval a week ago, I got my period after 5 days break, the baseline test shows all good numbers. I asked for double trigger and Femara 5 mg & Pergoveries 150, Menopur 75. Finally, for the first time, I got 6 eggs, but I was triggered on day 9 because my clinic does not work on weekends, so 2 eggs were not mature, the other 4 all fertilized with ICSI and 2 managed per today’s day-4 and have a good chance to make it day-5.

For me, high progesterone won’t influence the response a lot. In most of the publications, they say it won’t influence it. A lot of protocols propose to do it without antagonists and agonists at the same time with progesterone. Progesterone prevents spontaneous LH increase, spontaneous ovulation. Normally, it should not influence it.

Sometimes, it may be due to a lot of different things, for example, the way of follicle growing may not be very good because some cohorts of follicles are sometimes better and sometimes worse. It may also be due to single triggering because sometimes when we add hCG to agonist, it may increase the number of mature eggs.

Now, lots of clinics start to do the stimulation protocol from the second phase of the cycle, and we are doing it as well, especially for the egg donation program for egg donors, we are not waiting, we start when they come. We don’t see a big difference between the egg quality.

I had 8 egg retrievals, and I never get more than 1 egg to fertilize made it to an embryo. I live in Norway, and they do not do baseline blood tests now after the 6th cycle, I insist on doing baseline blood tests. I noticed that even my progesterone is over 3, they just run the cycle, and from 6-8 AFC, I never get more than 1 egg. From the last 3 cycles, as my progesterone was very high, so they were not fresh, I managed to bank 3 embryos. Do you have any experience with DuoStim protocols? I had 6 embryo transfers that failed. Now I’m going to do an ERA test to find my receptive endometrium. I always had nice blastocysts.

About DuoStim protocol, we are doing it quite often, especially for foreign patients because they come for a short period, they cannot stay for a long time. We try to stimulate during 1 menstrual cycle, and sometimes the second stimulation is working better than the first one. It is a good option when we have a low number of follicles. When you have 6-8 antral follicles, and for example, only 1 embryo, it is necessary to see if they are empty follicles or not mature eggs or doesn’t grow, and in all these 3 cases, there would be a different approach.

If, for example, we can see 8 follicles and only 1 is growing, and in each protocol, you receive the same number, it is probably necessary to increase the dosage. If they all grow and, in the end, they are empty, we’d probably try to do double triggering or, for example, give more hours after the triggering and retrieval. If, for example, we receive 8 eggs and all are immature, we’d probably try in vitro maturation (IVM). Again, it is crucial to see all the details.

Could I do another DuoStim right after the first time or I should wait?

We can do the DuoStim protocol only in case the first protocol, first retrieval and first triggering were with agonists. In this case, in 2 days, all hormones drop, we can start the second stimulation, but if your triggering was done with hCG, it is necessary to wait as many as 10- 12 days. Your ovary will not be sensitive to stimulation, hCG will occupy all receptors, and it will not work. DuoStim is possible in the case if first is done with agonists.

In double triggering, do you give GnRH 36 hours before oocyte retrieval?

It depends on patients, especially in patients of late reproductive age and decreased ovarian reserve, who tend to have earlier spontaneous ovulation, so it is better to do it 35 or even 34 hours earlier. We need to see it case by case, but in some patients, we receive eggs but not of good maturation.

Why is the cycle after the stim cycle so long? Mine is at least 10 days longer than usual.

Normally, it is like that. It also depends on triggering. If your triggering is done with agonists, your cycle will arrive in 4-5 days. However, if your triggering was with hCG, as we have seen hCG stays in blood circulation for more than 12 days, so before your hCG will disappear, your ovary will still actively produce progesterone hormone. Menstruation starts when your progesterone drops. Progesterone will drop when your hCG will drop, so your cycle after hCG triggering may arrive 2 weeks later.

You need time to restore hormonal activity. Menstruation starts when there is a difference between progesterone. If you have big stimulation, progesterone will not drop a lot, so your corpus luteum disappears, then starts growing the new follicles, and these take a little more time than a normal cycle. The next cycle after bleeding, after stimulation, is normally longer than your standard cycle.

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Authors
Halyna Strelko, MD

Halyna Strelko, MD

Dr Halyna Strelko is the Co-founder & Leading Reproduction Specialist at IVMED Fertility Center, Kiev, Ukraine since 2012. Dr Strelko is a certified member of ESHRE (European Society of Human Reproduction and Embryology) and ASRM (American Society of Reproductive Medicine), UARM (Ukrainian Association of Reproductive Medicine). She had a medical practice in France and medical practice in leading Kyiv’s infertility clinics with over 23 years of experience. She speaks English, French and Italian.
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Caroline Kulczycka

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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