During this event, Dr Kristýna Frühaufová, PhD, Head Physician at GYNEM Fertility Clinic, Czechia, discussed various ovarian stimulation protocols in IVF. Dr Frühaufová discuss different types of ovarian stimulation protocols, how they are personalised for the best outcome.
Dr Frühaufová explored how protocols are selected based on individual patient profiles, including age, ovarian reserve, and previous IVF responses. She discussed how stimulation protocols are monitored and adjusted to maximise the chances of success while minimising risks such as ovarian hyperstimulation syndrome (OHSS).
Dr Frühaufová explained that ovarian stimulation involves administering hormonal medication to encourage the ovaries to grow multiple follicles within a single menstrual cycle. The goal is to retrieve more than one egg, increasing the chances of creating viable embryos.
In natural cycles, only one follicle typically ovulates. In IVF, stimulation allows clinicians to collect multiple eggs during one ovarian cycle, improving the overall probability of success.
In the Czech Republic, stimulation is monitored primarily by ultrasound. Some clinics also measure hormone levels, while others combine both approaches. On average, stimulation lasts around 11 to 14 days.
Several types of medication are used during stimulation, each with a specific role.
The main drugs are gonadotropins, which stimulate follicle growth. These can be:
recombinant gonadotropins, produced in laboratory conditions (pure FSH or FSH combined with LH)
urinary gonadotropins, derived from the urine of postmenopausal women
Both types are administered via injections.
In addition, anti-estrogens may be used in tablet form to support stimulation in certain protocols.
To prevent premature ovulation, clinics use GnRH agonists or antagonists. Finally, ovulation timing is controlled using a trigger shot, most commonly hCG or a GnRH agonist, depending on the protocol and patient response.
Dr Frühaufová stressed that protocol selection is always individualised. Several factors are taken into account, including:
ovarian reserve (measured by AMH and antral follicle count)
ultrasound appearance of the ovaries
hormonal profile
response to previous IVF cycles, if any
body weight and BMI, particularly body fat percentage
Higher body fat can reduce medication effectiveness, meaning higher doses may be required. For this reason, stimulation must always be tailored to the individual patient. There is no “one-size-fits-all” protocol.
For most patients today, the short antagonist protocol is considered the gold standard.
Stimulation usually begins on day two of the menstrual cycle. A GnRH antagonist is added around day seven, or earlier if indicated by ultrasound findings, to prevent premature ovulation. Final oocyte maturation is triggered using either hCG or a GnRH agonist, depending on follicle number.
When more than 20 follicles are present, a GnRH agonist trigger is preferred to reduce the risk of ovarian hyperstimulation syndrome (OHSS).
Advantages of this protocol include:
shorter duration
lower risk of OHSS
flexibility to adjust medication doses during stimulation
Possible disadvantages include the need for close monitoring and, in some patients, a slightly lower yield of mature oocytes.
Another option for normal responders is the long protocol. This begins with pituitary down-regulation using a GnRH agonist in the mid-luteal phase of the previous cycle (around days 20–22).
After approximately two weeks, ovarian stimulation with gonadotropins begins. This protocol often results in better follicular synchronisation and a higher proportion of mature eggs.
However, Dr Frühaufová explained that it has important limitations:
the total duration is longer (around one month)
there is a higher risk of OHSS
it is not suitable for patients with low ovarian reserve
This protocol is mainly used in patients who previously showed poor follicular synchronisation with antagonist protocols.
For patients with low ovarian reserve, different approaches may be used.
The flare-up protocol starts on day two of the cycle using a GnRH agonist to stimulate endogenous FSH and LH production, combined with gonadotropins. While useful for poor responders, it carries a higher risk of premature ovulation and requires careful monitoring.
Soft stimulation is another option. This involves lower doses of gonadotropins combined with anti-estrogens. It may reduce costs and side effects while still achieving an acceptable follicle yield in selected patients.
Dual stimulation is designed for patients who wish to accumulate more embryos in a short period of time.
The first stimulation starts on day two of the cycle and ends with egg retrieval. A second stimulation then begins during the luteal phase of the same cycle, followed by another egg retrieval.
Dr Frühaufová explained that this approach can increase the number of eggs retrieved within a single menstrual cycle. However, it is only suitable for embryo freezing, as fresh embryo transfer is not performed in these cycles.
Letrozole-based stimulation combines letrozole with gonadotropins throughout the cycle. Dr Frühaufová noted that this protocol is particularly useful for oncology patients with hormone-sensitive cancers, as it helps control estradiol levels during stimulation.
For patients with PCOS or a high risk of OHSS, antagonist protocols are preferred. Lower gonadotropin doses or step-up stimulation (gradually increasing doses based on ultrasound findings) are commonly used.
In these patients, ovulation is triggered with a GnRH agonist rather than hCG. This necessitates a freeze-all strategy, as the endometrium is not optimal for immediate embryo transfer after an agonist trigger.
Freeze-all is also used when embryos undergo genetic testing, such as PGT-A, regardless of the stimulation protocol.
Dr Frühaufová explained that freeze-all is the most effective preventive strategy against OHSS. In addition, when genetic testing is performed, embryos must be frozen while waiting for results.
In these cases, egg retrieval and embryo creation are followed by deferred embryo transfer in a later cycle under optimal conditions.
In conclusion, Dr Frühaufová emphasised that stimulation protocols must always be individualised. Key factors include:
ovarian reserve
patient age
previous stimulation outcomes
Even in the same patient, responses can vary from cycle to cycle due to natural hormonal fluctuations. Consecutive stimulation cycles may also reduce ovarian responsiveness over time.
For this reason, if multiple cycles are planned, clinics often recommend a break of at least three months after back-to-back stimulations to allow ovarian receptors to recover.
As Dr Frühaufová concluded, there is no “golden bullet” in ovarian stimulation. IVF success relies on careful protocol selection, close monitoring, and continuous adjustment based on each patient’s unique response.
Understanding how and why stimulation protocols differ can help patients feel more informed, supported, and confident throughout their IVF journey.
If we speak about stimulation in different phases of the cycle, for example, during the luteal phase, you need higher doses of medication because when the corpus luteum is present, you have to top up the hormone levels. Sometimes we combine soft stimulation with gonadotropin stimulation.
Regarding different brands of medication, there are studies comparing them. For example, Menopur is different from Bemfola because it is a completely man-made medication consisting of FSH and LH in a 2:1 ratio (FSH to LH). Menopur contains FSH and LH, while Bemfola is a urinary product with hCG that acts on receptors like LH but binds differently.
Studies show that the number of follicles growing on ovaries is similar, but pregnancy rates are lower with urinary products, which might refer to lower egg quality at the end of stimulation. So, the number of eggs is similar, but egg quality might differ due to the difference in hCG binding compared to LH.
The third part is tricky because the main factor is age. At this age, it’s not only about AMH or ovarian reserve but the eggs themselves. We know it takes about 8 to 9 blastocysts to have one good one, meaning around 25 to 30 eggs obtained by stimulation. Usually, several cycles are needed to obtain a single good quality blastocyst.
Looking at statistics from last year, IVF clinics measure success with pregnancy rates, including biochemical and clinical pregnancies, and also the take-home baby rate, which is the number of healthy newborns.
Generally, for women up to age 35, the success rate is about 40%, meaning 40% get a positive pregnancy test with a low miscarriage rate. So, many patients actually give birth. This is reversed for women aged 42 and older.
Last year, there was only one live birth in the 40-44+ age category. The pregnancy rate was about 8%, but the abortion rate was high. So, only one patient had a live birth. This shows how difficult it is at that age.
Usually, the number of mature eggs does not equal the number of follicles seen during stimulation. More insight is needed, for example, if the six follicles were the same size. If they differed in size, I would go for a long protocol in this patient to get follicles starting to grow at the same time.
AMH 0.9 is not very low, and a good antral follicle count might still give a chance to grow a decent number of follicles. If you decide to continue with a short antagonist protocol, sometimes a combination of trigger shots with GnRH and hCG can help to get more eggs in one cycle.
Omnitrope is considered off-label for IVF and is not allowed in the Czech Republic.
Well, I think that this is the perfect patient for the soft stimulation in my eyes.
It’s not the same thing. In the long protocol, we are actually using the GNRH agonist either in the form of a nasal spray or injections. To be honest, the long-term injections do work the best. It’s basically one injection introduced on days 20 to 22. Then its action lasts for four consecutive weeks. You have enough time to see the effect of the down-regulation on the ovaries and then start the stimulation.
You don’t actually need to add any other preventive measures to prevent premature ovulation during the stimulation. You just add the gonadotropins later on. The anti-baby pills are used in some centres, especially as a form of timing the IVF cycles, because some centres have a waiting list and it’s more difficult for them to squeeze the patients in randomly when they start their cycles. Or, as we spoke before, about the estrogen priming, the contraception basically works the same.
As I mentioned, you can do back-to-back within two cycles; that’s okay, depending on how much time you have. If you have to consider the age factor, then it’s better to do back-to-back than wait two to three months. If we’re speaking of a woman less than 35 years, then I would suggest giving a break between the cycles.
There are those factors to take into consideration. Generally, doing two consecutive stimulations one after another shouldn’t result in a lower egg yield.
There’s no hard data on the use of any supplements having any benefit for the IVF stimulation itself. DHEA differs because you have different manufacturers, different doses, and it’s a supplement, not a medication. You don’t have hard recommendations—what dose to use, when to use it, or how long. No clinical studies have proven that it helps to improve the results.
In terms of lifestyle changes, there are no dietary restrictions during the stimulation. You can imagine that egg quality is influenced by your whole lifestyle so far. If you accumulated any DNA changes to the eggs, it was done some time ago. We have to pay the price for our lifestyles in our 20s, for example. There’s no magic drug that would reverse those changes, if there have been any. Unfortunately, males have the advantage that they might influence the semen quality, but women are not the lucky ones.
If I understand correctly, the 150 Gonal and Menopur was the first part of the stimulation, and now in the luteal phase you’re using 225 Menopur.
Well, I would honestly go for at least the same dose using Menopur only or a combination. I don’t know why this was chosen—whether it was an economic matter or limits on what medication can be used for stimulation, which does apply to some countries.
As I said, generally in the luteal phase, we need high doses of medication to get at least the same response. Personally, I would go for 300 units of Menopur or any combination of that, at least. I hope it works well, of course.
The BMI is a bit of an issue here because the higher the weight, the higher the dose of the medication we have to use. You already tried high doses. I understand it ended up with the same result. So again, I might suggest soft stimulation IVF in those cases.
This is usually difficult to handle. AMH gives you some idea of how the ovary is going to respond, but the other parameters used to suggest the dose of the medication give different information. In the first place, I would test the AMH again to see if there was any lab error.
AMH is quite unstable parameter and sometimes dependent on the time of day or even the phase of the cycle when it was measured.
When there’s a discrepancy between the ultrasound findings and AMH, it’s always better to double-check. Typically, in those kinds of patients, we go for high doses to start with. I would go for the antagonist protocol as my first choice of protocol for those patients.
This is quite a big topic at any IVF conference. We see that the proportion of mature eggs versus the number of follicles is affected by age.
In older women, we unfortunately see fewer mature eggs yielded during IVF stimulation. Generally, if you have a lower number of eggs than expected, the double trigger or dual trigger is suggested.
In some patients, the answer might be in the choice of a different protocol. I’ve seen patients on antagonist protocol end with fewer oocytes, and then after switching to long protocol, they had a better egg yield. So again, factors such as age, response, AMH, and if you’re suitable, going for a long protocol may help.
I personally don’t use the progesterone primed stimulation protocols, but it might be used in PCOS patients, especially in those when you’re expecting to freeze all, so the freeze strategy. Then yes, you can go for that, because there are some savings on medication costs. So it’s one of the options.
In terms of setting, it is a form of short antagonist protocol. But what we refer to by using mini or soft protocol is usually the combination of anti-estrogens with a low dose of gonadotropins. So it means lower doses and softer stimulation using gonadotropins.
Yes, most likely I would say let’s go for the same type of stimulation that you had. It’s not only about the number, it’s also about the quality of the eggs. Having half of the embryos euploid is actually a good result. I wouldn’t necessarily say that 300 units of Pergoveris is a high dose. I would agree with that.
There are different aspects. With an antral follicle count of 8, realistically, we can expect to have 5 or 6 mature eggs at best. For patients with endometriosis, the long protocol might be suited, or something called ultra-long. With a lower antral follicle count, the response might not be great. I would focus on getting as good a response as possible. I would opt for the antagonist protocol using around 300 units of FSH or Pergoveris and try a double trigger for oocyte maturation in the end.
The first choice would be the soft or mini IVF.
It’s a new topic. I don’t think we’re there yet. AI is emerging in all medical fields and can be helpful. There are apps developed to calculate proper doses based on body weight and AMH. When some medications were introduced, they were expected to help prevent OHSS in PCOS patients, but it didn’t work as expected. I no longer use such dose calculators. I do the dosing myself. Different patient aspects need to be considered. For example, two women with the same BMI can metabolise medication differently, depending on muscle mass versus fat. That’s something AI can’t yet take into account. So, we’re not there yet.
Generally not. We noticed that if you’re a long-term user—more than 6 months—AMH and antral follicle count drop, and you get a lower response. If you use it for one month to time IVF, it shouldn’t have any negative impact.
When I use letrozole protocol, I go for 2.5 mg twice a day, so 5 mg per day total, which is the general recommendation.
