During this event, Dr Marcel Štelcl, PhD, Chief Physician at ReproGenesis in Czechia, discussed what to do—and what to avoid—during ovarian stimulation. He covered various protocols, including agonist, flare-up, antagonist, mild stimulation, random start, PPOS (Progestin Primed Ovarian Stimulation), and DuoStim.
Dr Štelcl also explained the importance of personalisation and timing in IVF, emphasising how choosing the right stimulation protocol can make all the difference.
IVF stimulation is one of the most important and, at the same time, most questioned stages of fertility treatment. During his presentation, Dr Marcel Štelcl explained in detail how ovarian stimulation protocols work in daily clinical practice, what patients can realistically expect, and why individualisation is essential for achieving the best possible outcome.
Dr Štelcl emphasised that patients often ask which stimulation protocol is “the best.” His answer was clear: there is no universally best protocol. Each stimulation must be tailored to the individual patient.
He explained that during a first IVF cycle, it is not possible to guarantee an optimal response. In clinical practice, around 70% of patients respond optimally in their first stimulation, while approximately 30% do not. The main challenge is finding the right medication dosage, which is not always predictable in advance.
According to Dr Štelcl, ovarian response depends on many factors, including ovarian reserve, age, previous response to stimulation, and individual biological variability. This is why experience and careful monitoring are crucial.
Dr Štelcl outlined the main stimulation protocols used in IVF today and explained when each is typically recommended.
The antagonist protocol is currently the most commonly used worldwide, accounting for around 80% of IVF stimulations. It is often referred to as a “short protocol” and usually involves around 14–16 injections.
Its main advantage is safety. If the ovaries respond too strongly and there is a risk of ovarian hyperstimulation syndrome (OHSS), doctors can use an “emergency brake.” Instead of triggering ovulation with hCG, an agonist trigger can be used, significantly reducing the risk of OHSS. However, in this situation, a fresh embryo transfer is not possible, and all embryos must be frozen.
Dr Štelcl noted that this protocol is especially useful in cases where a higher number of eggs is desired, such as when preimplantation genetic testing (PGT-A) is planned.
Agonist and flare-up protocols are considered stronger stimulation approaches. They are typically used when a patient has shown a low or suboptimal response in a previous cycle or when a low response is expected from the outset, for example, in patients with low AMH levels.
Unlike antagonist protocols, emergency braking is not possible, and ovulation must be triggered with hCG. This means there is a higher risk of OHSS, although Dr Štelcl stressed that when used correctly and in appropriate patients, these protocols are still safe.
He also addressed a common misconception: switching from an antagonist to an agonist protocol does not dramatically increase egg numbers. For example, a patient who retrieved four eggs with an antagonist protocol should not expect 15 eggs with an agonist protocol. A small increase, such as from four to six eggs, is more realistic.
Patients often ask whether changing the type or brand of stimulation medication can improve results. Dr Štelcl explained that this is a frequent misunderstanding.
He discussed the role of LH in ovarian stimulation, noting that its benefits remain unclear. Although some medications combine FSH and LH, truly independent studies have not shown a clear advantage over FSH-only preparations. Many studies suggesting the benefits of LH are sponsored by pharmaceutical companies, which limits their objectivity.
In practice, Dr Štelcl sometimes uses LH-containing medications in older patients or adjusts medication in subsequent cycles if the initial response was suboptimal. However, he stressed that there is no reliable way to predict in advance which patients will benefit from LH supplementation.
Similarly, he explained that there is no proven difference in effectiveness between urinary and recombinant gonadotropins.
Mild stimulation protocols typically use lower doses of medication, usually up to 150 IU. Dr Štelcl explained that mild stimulation is most often recommended for low responders, particularly women around or over the age of 40.
In these cases, mild stimulation often produces a similar number of eggs as higher-dose protocols, but at a significantly lower cost. Increasing the dose beyond a certain point does not create more follicles; it only increases expense.
Dr Štelcl highlighted that doses above 300 IU of FSH rarely improve ovarian response and are generally unnecessary.
For many years, it was believed that stimulation had to start at the beginning of the menstrual cycle. Dr Štelcl clarified that this is no longer the case.
Stimulation can begin at almost any point in the cycle, including the follicular or luteal phase. Random-start protocols are especially useful when there is time pressure, such as before cancer treatment or for fertility preservation.
Dual stimulation involves performing two stimulations within the same cycle: one in the follicular phase and another shortly after egg retrieval in the luteal phase.
Although there were expectations that eggs retrieved in the luteal phase might be of better quality, Dr Štelcl stated that this has not been proven. The main advantage of dual stimulation is saving time, not improving egg quality.
Dr Štelcl explained that progesterone can also be used to suppress the natural LH surge, replacing antagonist injections. This approach reduces the number of injections and lowers treatment costs.
However, progesterone-based protocols are only suitable when a fresh embryo transfer is not planned, as progesterone affects endometrial receptivity. They are commonly used in donor cycles or freeze-all cycles.
A central message of Dr Štelcl’s presentation was that IVF stimulation must always be individualised. There is no standard dose that works for everyone.
Clinics aim for an optimal number of eggs, generally between 8 and 14. While slightly higher numbers are acceptable, very high responses increase the risk of OHSS, and very low responses can be disappointing for patients.
Although some medication calculators and algorithms exist, Dr Štelcl explained that they are not precise. Artificial intelligence may improve this in the future, but for now, clinical experience remains essential.
Triggering ovulation is necessary to schedule egg retrieval. The most commonly used trigger is hCG, which closely mimics the natural LH surge and allows for fresh embryo transfer.
Alternatively, a GnRH agonist trigger can be used, especially in antagonist protocols, to reduce the risk of OHSS. In this case, a fresh transfer is not possible due to hormonal conditions.
In some situations, a double trigger (hCG plus agonist) may be used, particularly when egg maturation was suboptimal in a previous cycle. Dr Štelcl noted that this approach can be helpful for some patients, but not all.
Dr Štelcl concluded by emphasising that ovarian stimulation is one of the most complex aspects of IVF. While many patients achieve an optimal response in their first cycle, others require adjustments based on how their ovaries react.
Careful monitoring, realistic expectations, and an individualised approach are essential. As he explained, stimulation protocols are not about following rigid rules, but about adapting treatment to each patient’s unique biology and clinical history.
We maximise the number of eggs in the shortest time. We can start in the follicular phase, and we will have two eggs, and then in the luteal phase, we will maybe have two eggs, or we will have four eggs.
Or we can start 14 days later, and again, we will have two eggs. In a short time, we will have more eggs, but total, in 2 months, we may have more eggs. In general, I can’t see any other advantage.
I recommend double trigger much more. Double trigger is usually quite risky because it can occur before egg collection. So it is necessary to discuss with the patient. Usually, we use an antagonist. We use agonist 37 to 40 hours before egg collection and hCG 36 hours before egg collection.
The biggest advantage is lower price, so for clinics, it is an advantage. Then we can use it for donor eggs and spend less money on stimulation.
Yes. I use a dosing calculator. The medication Rekovelle was developed to be used with a specific dosing algorithm or calculator. As I told you, AMH and body weight are important for the dosage of this preparation. There are other types of calculators. But the problem is that there are 3 levels of sensitivity of ovarian receptors.
Imagine that on the surface of follicles are receptors which are accepting the drug, and there are three levels of sensitivity. We can test it with a genetic test, but usually it doesn’t help. Because finally, even if it is a low level of sensitivity, you don’t know how many times you should use a higher dose.
So yes, in the future, we are expecting it because it is a crucial question, optimal stimulation. We believe AI will help us, but not yet.
I also believe that it will be much easier for me. I will show the patient: “AI is telling me 175 units.” It will be helpful.
This question is in connection with the success of IVF with own eggs in different age groups. There are also low responders in younger patients with very low AMH. If AMH is under 0.3, usually this stimulation doesn’t make sense. There are usually one or two follicles. Then we can try natural cycles, but with low effectiveness.
The upper age limit is between 43 and 44. There is an extreme decrease in the success rate of IVF. Around 20% at age 40, around 15% at 41, around 10% at 42, around 5% at 43, and around 2% at 44. In my opinion, to do one cycle when the patient is 43 or more doesn’t make sense.
In my practice, I had patients with very good AMH at 46, for example. We had 20 eggs and no embryos. If we have an embryo, usually it’s not euploid. Usually, beta is negative. It’s a very sad story.
I had several patients who were 43, and they finished with the delivery of a healthy baby. I have been doing IVF for almost 20 years, and I can remember every case. But 44, I never saw. That’s why I wanted to ask, just to give you an idea.
A patient who is 44 and comes for the first time has expectations. Maybe we will do IVF. She has not decided. The results surprise her. So we do the stimulation for the patient to be sure that it doesn’t work. I understand the patient doesn’t believe us that it’s so bad. So minimally, one time, she should try it to be really sure that she did the maximum with own eggs.
As a doctor, I can understand. I understand the patient. It’s necessary to do it before accepting a donation.
There is no age limit. It can be dangerous because there are some types of mutations that are more common in older men, over 43–44. But these mutations are still very rare. The information that there is a legal limit is not correct.
Sometimes yes, but the question is: if we have, for the first time, five eggs and the second time seven eggs, is it significant? The patient is usually happy that we have more eggs, but in general, it doesn’t make a big difference.
Another question is whether using the pill makes egg quality better, worse, or the same. If contraception pills are used for many years, for example, 10 years, and then we do stimulation directly, usually we have fewer eggs. But using it for a few weeks or two to three months usually doesn’t change the number of eggs.
I will tell the story about low responders. Every second year, we have a congress like “Update in Infertility Treatments.” There is always the same person presenting on low responders.
In 2010, we believed that DHEA could achieve better results in poor responders. In 2015, DHEA didn’t work. Maybe testosterone would make better results. In 2018 or 2020, DHEA and testosterone don’t work. Maybe growth hormone will be better.
Now, the situation is: DHEA, testosterone, and growth hormone don’t work. So we are waiting for what will be next. Of course, I would like to be in the first group to use something new if it works. But if something really worked, we wouldn’t have an increase every year in the number of donor cycles worldwide. That’s the reality.
Yes, of course. There are more expensive preparations, but, for example, in our country, they have better coverage from insurance. There are preparations which are less expensive with less payment. So it’s a very complicated situation. It depends on whether the treatment is covered by insurance or if it’s fully paid by patients. But every time, I prefer the same results and a lower price. So, the optimal equilibration price and manual activity.
Agonist protocol means that agonists lead to the ovaries from the hypothalamus. In the brain, some centres lead to the ovaries. Agonists from the hypothalamus produce hormones which activate the pituitary to produce FSH and LH. When we use agonists (substances like those produced in the hypothalamus), the first effect is a large production of FSH and LH. But if you use them for several days, the production of FSH and LH goes down through the pituitary.
Usually, after 10 or 14 days, the pituitary is completely blocked. Then we start to use exogenous FSH or FSH and LH. Usually, I recommend FSH and LH together in a long agonist protocol. We use it for 14 days—agonists and the preparation with FSH and LH—to make ovarian stimulation.
You can imagine that after 14 days, the ovaries are “cold,” and then we use a high dose of FSH and LH. Sometimes it works like a big impulse for the ovary, and we have more follicles than in the antagonist protocol, but only sometimes.
I did my best in explaining the agonist protocol.
Because the pituitary is blocked, we can use an agonist for triggering. But in agonistic protocols, we should use only hCG for triggering. If we have many follicles, it can be very dangerous because of OHSS.
Usually, patients with AMH higher than 3.9 or 4. In these cases, we must be very careful in stimulation. These are difficult cases for optimal stimulation. It’s easy to stimulate a woman with AMH 1—300 units, and it’s clear. But it can be difficult to stimulate a woman with AMH 5.3.
Basic rule: do not use agonistic protocol but the antagonist protocol—short protocol. When you see more than 20 follicles during ultrasound monitoring, use agonist triggering and avoid OHSS. It won’t be a fresh transfer, but it doesn’t matter. Vitrification of embryos works very well, and then we can do frozen embryo transfer without any problems.
So, for patients with high AMH, it’s necessary to use the antagonist protocol.
Very rarely. We see it maybe 1 or 2 times per year. Usually, it’s when the patient is not in the clinic, and we have limited info, 10 follicles around 17 mm, and we do distance treatment. The patient comes directly for collection, and we see it’s a problem.
In the past, like in 2005 or 2008, we had it twice per month. Now, it’s twice a year.
Sometimes, OHSS can happen even in normal, optimal stimulation. It’s not preventable. For example, a patient with 12 follicles and still severe OHSS, but it’s very rare.
Especially in cases with high AMH, we can see that new follicles keep growing. At first scan, 5 follicles, second scan—ten follicles. If we continue, they keep growing.
The rule is: if there are three or more follicles ≥17 mm, it’s an indication for triggering. The reality is more complicated. If we have several follicles at 17 mm and others at 14 mm, we wait. But if we have four at 17 mm and the rest are 11–12 mm, we don’t wait. It’s a difficult situation, and there is no strict advice. It depends. It’s still an area open to discussion in ART.
It’s the same person who asked before, I think. We can try a double trigger. I don’t know how many follicles were growing. What is concerning is that low AMH is often connected with low egg quality. What does it look like? Follicles with no egg. Follicles with eggs, but not mature. Follicles with mature eggs, but no embryos. There are many levels where it can fail.
Typically, women ask why they don’t have mature eggs. Unfortunately, I often have to say I don’t know. But we know now that this is one reason why pregnancy doesn’t happen—egg maturity. At 31, with AMH 0.7, something is wrong with the ovaries.
Sometimes we get lucky and get mature eggs. Sometimes we try everything, double triggers, and so on, and still no success. Eventually, it can end in donor egg treatment. It’s necessary to try several times. I know it’s very hard for patients to go through 3 or 4 attempts and have no eggs or embryos. I also have patients in this exact situation.
Yes. We have the germinal vesicle stage. This stage is usually not usable or available for fertilisation. Then there is the M1 and M2 stage. M2 is clear. M1 is possible to wait. Now there is also the question of fluorescence and microscopy to see the spindle, if it is developed. And it’s also the magic of the laboratory: sometimes the spindle is present, and then we have a chance for embryos. Sometimes the spindle is not present.
There is something called in vitro maturation. It was designed for patients with PCOS, with very high AMH, to retrieve oocytes and do in vitro maturation. And it works—but it doesn’t work in cases with normal-sized follicles and only germinal vesicles. The problem is the quality. There are no structures responsible for meiotic processes and later for mitosis. So, if we have germinal vesicles in normal stimulation, in vitro maturation doesn’t work.
Yes, it’s connected to the previous question. There are two things: AMH and age. Age is a very good parameter for measuring the quality of eggs.
We can have a 45-year-old woman with good AMH but a very bad prognosis for pregnancy with own eggs. And then we can have a 25-year-old woman with low AMH, but usually good-quality eggs, and she can conceive naturally—she doesn’t know she has any problem.
The usual recommendation for a 25-year-old woman with low AMH is to start conceiving naturally, and usually it works.
If AMH is very low, is it also connected with bad quality? Sometimes yes, and sometimes no. It’s difficult. Usually, young patients with low AMH and good-quality eggs do not come to my practice. The patients with low AMH who have problems conceiving naturally probably also have poor egg quality.
Unfortunately, I don’t have a satisfying answer, but it’s a typical case in my practice. If we have good AMH, we try full stimulation. The first discussion is usually: we will do PGT-A to identify which embryos are good. The patient expects 4 embryos, with 2 good and 2 bad.
The usual result of such stimulation is 2 blastocysts, not good enough for PGT-A, maybe good for freezing. We often see low egg quality. We cannot change it. We just hope that maybe next time we’ll find that 1 out of 20 or 25 eggs, which is good. There is no other advice.
You can see that the double trigger didn’t work. Agonist or antagonist protocols—if the eggs are bad, we can try anything and still have bad eggs. Excuse me for this answer, but this is the reality.
Endometriosis—sometimes the egg quality is poor, sometimes not. I had a patient with endometriosis. We used Pergoveris and got very poor quality eggs. Then we tried Rekovelle, and it was much better.
I don’t want to say Rekovelle is better than Pergoveris. Sometimes I start with pure FSH, and we are satisfied, sometimes not. So the second time, I tried FSH and LH. In this case, one patient had a very bad result with Pergoveris and a very good one with Rekovelle. Another had the opposite. AMH is good, so I recommend trying another medication. I don’t think the problem is with the type of protocol.
Egg donation is my advice. We’ve discussed the statistics. In my practice, at 45, the chance of success is about 1% to a maximum of 3%. That means, 97% to 99% of the time, the treatment won’t be successful.
It’s a similar situation. AMH 7.9 is a little over 1 ng/ml—quite good ovarian reserve. But bad quality eggs. The result is poor embryo development, usually lost between days 3 and 5. Patients often say the worst part of the process is waiting for the pregnancy test. But I think if we don’t have embryos, it’s a result. It’s better to know we have no embryos than to transfer 1–3 and wait three times for negative pregnancy tests.
So if embryos are lost between days 3 and 5, it’s due to egg quality. Cultivation today is very good, not detrimental to embryos. If embryos are lost, it’s due to egg quality. 90% of embryo quality is the egg, 10% sperm. 80% of success is the egg, 10% sperm, and 10% uterus. The egg is the crucial cell. These cases show that the problem is in egg quality.
We are young—I’m 48, I feel young—but for reproduction, it’s too much. Nature is not fair. But this is how it is.
