During this event, Dr Harry Karpouzis, Founder and Scientific Director of IVF Pelargos Fertility Group discussed natural and mild IVF protocols, how they work, and who they are best suited for.
He explained the differences between these approaches and conventional IVF, highlighting their advantages for women with low ovarian reserve. Dr Karpouzis also shared insights on how tailored protocols can improve fertility outcomes.
The event was hosted by Barbara Scott, Chair of the Association of Reproductive Reflexologists, Founder of Seren Natural Fertility, and author of Reflexology for Fertility. Barbara is an internationally recognised expert in reproductive reflexology who advocates an integrative, patient-centred approach to fertility care.
Natural, semi-natural, and mild IVF approaches are increasingly discussed as alternatives to conventional IVF, particularly for patients seeking more individualised treatment or reduced medication exposure. In this webinar, Dr Harry Karpouzis explained when and how these approaches may be used, their benefits and limitations, and which patients may be most suitable for each option, based strictly on clinical experience and current evidence.
Dr Karpouzis began by outlining the realities of conventional IVF, which typically involves injectable hormones given at moderate to high doses. He explained that while conventional IVF can be very effective, it is also physically and emotionally demanding. Patients may experience stress, discomfort, and a significant financial burden related to medication.
Although the risk of ovarian hyperstimulation syndrome (OHSS) has been significantly reduced in recent years due to vitrification, freeze-all strategies, and modern trigger injections, Dr Karpouzis noted that “the higher the dose of medication, the higher the risk,” even if that risk is now much better controlled.
These considerations raise an important question: why consider alternative IVF approaches that use lower doses of medication, oral drugs, or even no medication at all?
According to Dr Karpouzis, alternative IVF protocols may be considered for several reasons. They reduce overall drug exposure, are generally associated with fewer side effects, and may feel less intrusive for some patients. Importantly, they allow for a more personalised approach to treatment.
He emphasised that these protocols are not designed to replace conventional IVF but to complement it in selected cases. They may be appropriate when a woman does not wish to use high doses of medication, when there is a medical reason to avoid them, when there is a risk of hyperstimulation, or in women with poor ovarian response, where high-dose stimulation does not improve outcomes.
Natural IVF involves no ovarian stimulation medication. The clinic monitors the woman’s natural menstrual cycle and follows the development of the single follicle that normally matures each month. Ovulation may occur spontaneously or be triggered with an injection to better time egg collection.
Dr Karpouzis explained that natural IVF aims to retrieve one egg, reflecting what the body produces naturally. There is no risk of hyperstimulation, no medication cost, and no medication-related side effects. However, success rates per cycle are lower compared with stimulated IVF.
He also highlighted practical disadvantages, particularly for international patients. Timing can be unpredictable, and there is a 15–20% risk of cycle cancellation if ovulation occurs unexpectedly. Despite this, natural IVF may be beneficial for very poor responders who produce only one or two follicles, and cumulative success rates may improve when several natural cycles are performed consecutively.
Semi-natural IVF typically uses oral medications such as clomiphene citrate or letrozole. Dr Karpouzis explained that clomiphene acts at the level of the brain, stimulating the release of FSH, while letrozole works by reducing estrogen production, indirectly encouraging ovarian stimulation.
With these medications, it is often possible to obtain two or three eggs instead of one. Compared with natural IVF, semi-natural cycles have a lower risk of cancellation and still carry an almost negligible risk of hyperstimulation. Patients do not require injectable hormones, which many find more acceptable.
However, Dr Karpouzis noted that clomiphene may negatively affect the endometrium in some cases. For this reason, when a fresh embryo transfer is planned, letrozole is often preferred. He referred to evidence showing that, in selected cases, semi-natural IVF can achieve outcomes comparable to conventional IVF, but stressed that results depend heavily on patient characteristics, particularly the number of available follicles.
Mild IVF uses low doses of injectable gonadotropins, sometimes combined with oral medications. The goal is to stimulate the ovaries gently, usually resulting in fewer than seven eggs. Dr Karpouzis described mild IVF as an attempt to balance egg quality with egg quantity while reducing physical and emotional stress.
Medication costs are lower than in conventional IVF, and side effects are generally milder. He referred to randomised trials showing similar live birth rates in young women with normal ovarian reserve, although he noted that more than one mild cycle may be required to obtain the same number of eggs as a single high-dose cycle.
A key point emphasised throughout the webinar was the importance of cumulative live birth rates. Dr Karpouzis explained that while success rates per cycle may be lower with natural or mild approaches, repeated cycles can lead to comparable outcomes over time.
For example, several mild IVF cycles may result in similar cumulative success rates to one or two aggressive stimulation cycles. However, this approach requires careful consideration, especially for international patients who must factor in repeated travel, time, and costs.
OHSS is primarily a concern in young women with polycystic ovaries. Dr Karpouzis explained that with modern IVF practices, including freeze-all strategies and appropriate triggers, the risk is now very low, even with high-dose protocols.
Low-dose protocols may still have a role when a fresh embryo transfer is planned, as high hormone levels can negatively affect endometrial receptivity. In such cases, mild or semi-natural approaches may help maintain a more favourable implantation window.
Dr Karpouzis outlined several patient groups for whom natural, semi-natural, or mild IVF may be appropriate. These include women of advanced reproductive age, women with diminished ovarian reserve, patients with previous hyperstimulation, and those who prefer minimal medication for personal or ethical reasons.
He stressed that in cases of severe male factor infertility or when preimplantation genetic testing for aneuploidy (PGT-A) is planned, obtaining a higher number of eggs may be advantageous. In such situations, conventional stimulation may still be preferable, particularly in women with normal ovarian reserve.
The strongest evidence supporting mild and low-dose protocols applies to women with diminished ovarian reserve. Dr Karpouzis highlighted an important principle: follicles that do not exist cannot be stimulated. If a woman has only three or four follicles, increasing medication doses will not increase egg numbers but may increase cost, stress, and the risk of cancellation.
He explained that in these cases, lower-dose or combined protocols are often preferable, as high-dose stimulation has not been shown to improve live birth rates. Repeated low-dose cycles or dual stimulation strategies may help increase the total number of eggs collected over time.
Dr Karpouzis addressed the debate about whether high-dose stimulation affects egg quality. Egg quality, he emphasised, is primarily related to age. One theory suggests that retrieving more eggs increases the chance of finding a chromosomally normal embryo, while another proposes that excessive stimulation may increase oxidative stress and negatively affect quality.
He noted that although high-dose protocols do not appear to improve outcomes in poor responders, there is also no definitive evidence that they harm egg quality. What is clear, however, is that they do not improve live birth rates in women with diminished ovarian reserve.
In conclusion, Dr Karpouzis stressed that there is no single “best” IVF protocol. Each approach has advantages and limitations, and decisions must be individualised. Factors such as age, ovarian reserve, follicle count, treatment goals, travel considerations, and patient preferences all play a role.
He emphasised the importance of open discussion between patients and their fertility specialist, ensuring that choices are based on evidence, realistic expectations, and personal circumstances.
This is something that your doctor will decide. There is plenty of evidence nowadays that between the different categories of medication, there is not a big difference. The recruitment to the follicles initially still has a bit of evidence behind FSH medication, like Gonal rather than HMG and LH-including medication. In poor responders who do not have a lot of eggs, in mild protocols at Pelagros IVF, we usually start with FSH medication in low doses.
We combine this possibly with different ways of stimulation like Clomiphene or Letrozole, and if needed, we check throughout the process the LH blood tests and the estradiol blood tests. Depending on the case, we might add some LH as well. The doses and alternatives to all these protocols are too many. The important thing is to try to individualise it and for the doctor to know why to use each of the medications. It doesn’t have a big difference. We usually work in a different way, using FSH medication initially and then adding the LH medication later on, depending on the blood tests.
This is a very good question, and this is something that I have noticed as well. Antagonist is a bad medication. Antagonist can stop the growth of some follicles, can reduce a lot the LH levels during a stimulation, and this might cause immature eggs at the time of the trigger. If you don’t check throughout the process and cycle the LH and estradiol levels, this is information that you do not get. At Pelargos IVF, we do not use antagonist at the same dose throughout the cycle. We prefer to start late. We use an antagonist only when it is needed by the LH blood tests. Many times, we use half doses of Orgalutran or Cetrotide. Many times, we omit the antagonist. We are very careful whether we will use an antagonist on the day of the trigger because this can cause immature eggs. This is a personalised approach that needs a blood test and follicular growth monitoring to decide if and in what does it will be used.
There are some new protocols that use progesterone medication like Duphaston instead of an antagonist. It can cause negative feedback and help prevent ovulation, which is the point, but it doesn’t reduce the growth of the follicles initially. This is also an approach when using mild-dose medication.
Yes, in every scan we do blood tests to know if we will use the full dose of antagonist or half dose or no antagonist. It depends on the blood tests and the size of the follicles. If LH levels are very high, you will need to use the antagonist to prevent ovulation. If LH levels are low, you don’t have a risk of ovulation. In cases like that, if you give an antagonist at a high dose, you might stop the growth of a follicle or prevent the growth of other follicles.
With an AMH of 0.2 and with one ovary only, especially if the number of follicles initially at the start of the IVF cycle is less than four, if I decided to go with own eggs, most probably I would use a low-dose protocol. Whether it will work or not depends on many different things. It depends on the number of eggs collected. If someone has only 3 or 4 follicles in one go, they will get up to 3 or 4 eggs. The more eggs you get, the more you increase the chances of finding one that will be normal. But implantation depends on other factors. This woman has endometriosis. Other things need to be checked. She even had egg donation and failed, which is unusual. We don’t know why an egg donation would fail. Maybe there are other reasons for IVF failure here. We need to check the hysteroscopy. We need to make sure there are no other reasons preventing implantation. In a situation like this, egg donation gives much better chances of success.
Now, if someone wants to try one or two more times with own eggs, they need to know from the beginning that things are very difficult. There are things we can try in the protocol. But yes, the answer is most probably it will be a low dose of medication.
Yes. We don’t know about the sperm. We have no information. The sperm needs to be checked as well, because when an egg donation is also failing, and some embryos do not survive, it might be a common factor related to the sperm. It needs to be investigated for DNA fragmentation, oxidation, and things like that.
We always work step-down when we start high. When we choose to do a high-dose protocol, we prefer to start high and then step down because when you start high initially, it helps with the follicular recruitment. Now, when we talk about a low-dose protocol, there is no step down. You start with a low dose like 150, maximum 225, and you keep pushing either by itself or with other medications as well, like Clomiphene and Letrozole. You continue, and you see the growth.
Yes. It’s very difficult. We need information from past protocols. We need all the information about the number of follicles, the AMH, everything plays a role. There are some things we can talk about. This is definitely a low, this is definitely a high, but every time it’s personalised.
We don’t have the number of follicles in the ovaries, but with an AMH like that at 43, I suspect the number of follicles will be low as well. In cases like that, we usually prefer low doses unless there’s a surprise with the antral follicular count, and the antral follicular count is much better, like 7, 8, 9. In cases like that, we might consider starting high to get more eggs in one go, because this plays a role, especially with medical tourism. People don’t want to travel for two or three low-dose protocols if they can’t get the same number of eggs in one go.
Of course. Even the antral follicular count might be changing in the same cycle. Nowadays, many times in poor responders we do an antral follicular count at the beginning of the cycle and see only two follicles, then we check in the luteal phase after ovulation and suddenly see five or six. We say, okay, this is a better antral follicular count, let’s start stimulating here. So, even in one cycle, the number of follicles plays a role in when you start stimulation.
I cannot know that. I need to go through the doses and everything you had in the previous cycle. In women about 40, the best thing would be to proceed with PGT-A to find out the reason for failing. When someone at 40 proceeds with PGT-A, the point is to get as many eggs as possible. If the antral follicular count corresponds to the AMH, which is said here to be good, but I don’t know exactly what it is, let’s say the AMH is indeed good for the age of 40, and the antral follicular count is also good. So this woman, despite being 40, has like seven, eight, nine follicles, maybe 10, 11, which is very good for 40. In that situation, we prefer to go high and try to get as many eggs as possible.
The more eggs we get, the greater the chances increase for one being chromosomally normal and giving a normal embryo. The point is to get as many as possible in one go. Then do PGT-A, take a biopsy if they reach day 5, because it depends on fertilisation, sperm, and other factors. First, find out if we can achieve a chromosomally normal embryo or not. If we cannot, the reason is the quality of the eggs. Then you either persist and get more in a second cycle, or start thinking about other options like egg donation, which gives better chances.
Yes. In an antagonist short cycle, people have scans on day two, then another scan 2 or 3 days later. Every time they have a scan, they have blood tests. You start with a high dose, check follicular growth and blood tests, and depending on results, you adjust doses, increase or reduce, give antagonist or not. You can play around and change during the cycle to achieve better results. The total number of eggs depends on the number of follicles at the beginning. The quality depends mainly on age. The number of eggs is significant because statistically, the more eggs, the higher the chance one is chromosomally normal. If AMH and follicular count are low, we try to prevent high doses because some theories say they might affect quality.
Antagonist is an injectable medication, antagonist of GnRH, used to prevent ovulation. During stimulation, follicles increase in size. When a follicle reaches 12, 13, 14 mm, if left alone, it will ovulate. We don’t want ovulation because we want to bring all follicles to the right size at the right timing. So we use antagonist, a quickly acting medication, to prevent ovulation.
Given the information, I would start high dose again. It’s a very good AMH for your age. The medication depends on previous cycles. Every cycle is diagnostic and provides information. You might start with 300 FSH and 75 LH. Sometimes even more than 300. The most important thing is not the initial dose, but the right timing of the trigger and how you bring follicles to the right size for more eggs. Eleven eggs at your age is not bad. Check sperm well on a high-dose protocol—DNA fragmentation, oxidation, and rule out sperm factors. Fertilise as many eggs as possible, leave them to day five, then PGT-A. Find out if the problem is the embryo or not.
