Minimal stimulation IVF options for various patients groups. Is it a “money saver” or valuable IVF protocol?

Elias Tsakos MD, FRCOG
Medical Director , Embryoclinic

IVF process, Low Ovarian Reserve

From this video you will find out:
  • What is mild/mini stimulation IVF protocol? What are its main advantages and disadvantages?
  • What are the differences between conventional IVF versus mild stimulation?
  • Who can benefit most from mild stimulation protocol?
  • What are the current guidelines/ recommendations regarding mild stimulation?

Mild versus conventional ovarian stimulation for IVF - what are the differences?

Dr Elias Tsakos, FRCOG, Medical Director at Embryoclinic – Assisted Reproduction Clinic in Thessaloniki, Greece, discussed mini/ mild IVF stimulation, its advantages over conventional IVF, and which group of patients would benefit most from that.

Conventional stimulation IVF aims to give drugs to the female patient to stimulate the ovaries and make them produce a sufficient number of eggs. Conventional stimulation dosages usually range between 200 and 400 units per day. This is the standard conventional protocol. That protocol aims to produce the maximum possible number of eggs. In the conventional stimulation cycle, there’s a trigger with beta HCG or with GnRH analogues or and then there’s an embryo transfer either in the first cycle or in a fresh cycle and a frozen cycle or just frozen cycles if we think that we should defer the fresh embryo transfer. In a standard patient, we would get enough embryos for a couple of embryo transfers. Such a patient would probably produce 5 to 10 eggs, and that would lead to a minimum of 2-3 or even up to 5 embryos. That would be enough for a minimum of 2 embryo transfers, sometimes more.

Mild stimulation IVF as a whole is a combination of either some oral treatments, Clomiphene or Letrozole or both alone or with a small dosage of FSH injections with a maximum of 150 units per day. The aim of mild stimulation is the production of a small number of eggs, so perhaps 1–4 eggs and then the trigger is the same the embryo transfer is the same. One of the differences is that invariably in the mild stimulation cycle, there are no surplus embryos. There’s no chance of a second embryo transfer, so 1 stimulation means 1 number transfer.

Mild stimulation IVF

What’s the rationale behind minimal stimulation? This is to balance the benefits and the risks. The benefits are sufficient ovarian stimulation, so to get enough eggs to produce embryos, at least 1 good embryo transfer with at least 1 or 2 good quality embryos, the production of 1 to 4 oocytes and the embryo transfer. One of the things the doctors wish to avoid is OHHS (Ovarian Hyperstimulation Syndrome), which is a production of a large number of eggs. This is usually associated with the production of maybe 12 or more eggs, and taking into account all the risks associated with that, the doctors want to avoid it. It’s very unlikely to have OHHS complications in a mild stimulation protocol. The doctors also want to avoid multiple pregnancies and the associated complications.

According to Dr Tsakos, nowadays, the majority of units in Europe don’t see that many cases of OHHS. The majority of modern, good-quality units don’t see more than perhaps 1 case every couple of years. However, when it happens, it’s associated with a lot of issues in most of the human organs, the respiratory tract (breathing difficulties), gastrointestinal tract (nausea, vomiting), the weight might be increasing rapidly, the ovarian organs are suffering, the urinary system is suffering (kidney failure), and the vascular system is suffering through dehydration and blood clotting, and potentially this could be a lethal complication.

The advantages of mild stimulation refer to the approach ‘less is more’. There’s a reduced chance of OHHS, in many studies and scientific publications, it shows 0 to 5% compared to conventional IVF. There is reduced risk of multiple gestations because perhaps 1 top-quality embryo is produced. Therefore, the chance of twins overall with mild IVF is much lower compared to conventional IVF, it’s 6 versus 32%. The pregnancy rates can be consistent in consecutive cycles, according to research, it’s about 50%. Another crucial advantage is fewer drugs, and fewer side effects, it’s not only a lower chance of getting OHHS but also less abdominal distension and pain, fewer gastrointestinal symptoms, less nausea, less vomiting and so forth. In general, mild IVF protocols are shorter and a bit more flexible.

Specific patient subgroups are more indicated to be managed with mild stimulation, in particular, poor responders, so women with a lower chance of response to medication and advanced reproductive age. Another benefit of mild stimulation is the better impact on endometrial receptivity. It has a smaller effect on endometrial receptivity. Mild stimulation is also associated with a lower cost of medication, which will translate to the opportunity to have more cycles and so forth. There’s always the option for oral medication only instead of injections. Then, there is also an option to start the cycle sooner, there’s no particular reason to wait a couple of months before the ovaries are stimulated again.

We need to keep in mind that no protocol is perfect. There are some drawbacks to mild stimulation. The first thing is the inferior pregnancy rates, overall the success is 15% vs. 29% respectively. There’s less chance of success with mild stimulation because it has been shown that the success of IVF is directly related to the number of oocytes retrieved. According to meta-analysis, there’s probably about half chance of success compared to the standard stimulation protocol. There’s also lower oocyte yield, significantly fewer oocytes compared to conventional stimulation IVF, and there is an increased chance of cancellation rates (at about 15-20%).

Current recommendations

According to ESHRE guidelines from 2019, there are three types of patients, high responders, normal responders and poor responders. For example, there is no point in giving Clomiphene in addition to gonadotropins in high responders. For normal responders, there’s perhaps no place for mild IVF stimulation. When it comes to poor responders, there’s strong evidence to suggest that they could be treated either with Clomiphene alone or with Clomiphene and small doses of gonadotropins. There’s no point in adding more than 150 units daily of gonadotropin. Another thing is that a dose higher than 200 (IU) units daily is not recommended for predicted poor responders.


- Questions and Answers

What do you think about using an ovarian injection of platelet-rich plasma in low responders in combination with a mild simulation?

I think it’s a bit too early, I think the evidence we have is not very clear, but it may prove to be sufficient, in my opinion, I don’t think that the way it’s being performed at the moment is enough. I think it has to be modified a bit, it has to be fortified with other kinds of substances may be, and in another case, I don’t think it should be available in clinical practice, and I think it should only be available under very strict research protocols to get some data about it. At the moment, I’m not using it, I’m not recommending it because I don’t think there’s enough evidence of its use.

Doctors have told me there will be a difference in quality between high doses and low doses. Have you seen someone with poor eggs under conventional IVF getting good-quality eggs in mild stimulation?

There’s a debate about this, and the debate is still going on. I don’t have a clear answer to that. The egg is a potential cell, what we’re interested in is the quality of embryos and then again the quality of embryos depends at least 50% on the quality of the sperm, so it’s very difficult to compare similar situations. We can see good-quality eggs from either program. I think, in general, the quality of the egg is vastly depending on the age of the female. There’s a very clear relationship with that. On the other hand, it’s very clearly demonstrated that the success of IVF is directly related to the number of eggs retrieved. This is the case up to about 15 eggs and onwards. Think of what class of patient you may be falling into, so if you’re a normal responder, if you’re in your mid to late 30s with normal AMH, probably the conventional stimulation would be better for you. If you’re a poor responder of advanced productive age, probably the mild stimulation would be better because whether you use the mild or the high stimulation, you would still get the same number of eggs. But then, you will have saved all the costs.

Could a mini-simulation work better for me with diminished ovarian reserve? Age 35, AMH 6.1 pmol/l (when I was 34)m, BMI 20. First cycle, 300 units of FSH, 1 egg, second cycle 450IU, FSH and androgen priming with Tostran – 3 eggs. Initially, duo-stim was suggested by one specialist but only 2-3 smaller follicles came through on the day 10 scan, told another doctor that duo-stim is unlikely to be beneficial due to this. I had 5 blastocysts. There were thin-lining issues.

I would never use 450 units for a poor responder. In your case, I would go for a very standard mild stimulation protocol, perhaps with pre-treatment with DHEA, at the moment, DHEA is associated with a slightly better response to stimulation, so perhaps 6 weeks pre-treatment with DHEA. You had 5 blastocysts at the age of 35, if they were top quality, they would probably give us a cumulative pregnancy rate of nearly 90%. Perhaps you need to look into other factors as well, but in general, 5 blastocysts are very valuable. Every cycle has different variability and different potential, hold on to your blastocyst until you clarify exactly what’s happening with the endometrium, thin lining may be an issue, adhesions may be associated with that, infections, have a look at the microbiome situation of the uterus and go for it.

I’m wondering what is your opinion on using a mini simulation, eg., Letrozole or gonadotropin for FET in those with thin lining issues? My FER was cancelled due to thin lining with oral + transdermal high dose estrogen (3-5 mm past 2 cycles). Any other ideas for managing thin lining?

The thin lining is usually associated with some sort of damage to the endometrium, this is invariably the case. This can be very tricky because if there are adhesions or Asherman’s syndrome, these are situations and conditions that are not very easily treatable. However, this has to be evaluated and improved and optimized to the extent that it would be possible. Most units that don’t have the expertise would need to refer you to some sort of hysteroscopy specialist to do that. There are a lot of situations in which there are infections, microbiome testing has come into vogue, and that might be sufficient as well. Once we’ve optimized the endometrium as much as possible, then in terms of protocol, if you have normal cycles, is a natural cycle of frozen embryo transfer. That would be my number one priority, so if you’re ovulating normally, I would just let your own endogenous internal hormones do the trick and stimulate the endometrium as well. If that’s not the case, then I would probably use a medicated cycle in a natural cycle. Then again, if it’s not growing sufficiently, then we can change the route of administration of estrogen to oral, vaginal, or transdermal, and sometimes we are doing Viagra which may improve the vascularity of the endometrium as well. The shape of the endometrium is also important. Regarding EMMA and ALICE tests, I’m not a huge fan of them. If you’ve done it and you have some feedback, that’s fine. I prefer a natural cycle to be very precise in measuring the hormonal levels and then the time of the embryo transfer based on those and in the medicated cycle equally to ensure that I have a very nice hormonal balance before I do this.

I did 3 cycles with an okay number of eggs, but only a few could be fertilized. I’m 41 now. Could the protocol help me to improve good quality?

Fertilization issues mean problems with eggs or sperm, or both. I don’t know what sperm quality is like and whether it’s your partner’s or the donor’s sperm, but definitely, I would look into the sperm factor. Traditionally, we’ve been looking into a standard semen analysis, and many more factors in sperm could affect fertilization. I would look into the sperm in much more detail. Regarding the egg quality, I would use ICSI as opposed to Conventional IVF if there’s a fertilization issue. Then again, I would look into the timing of a collection, there are a lot of units only doing pickups perhaps 3 or 4 times a week, they don’t pick up on the weekends or they don’t have residents every day and so forth, so that could affect the maturity of the eggs, the number of eggs, the quality of eggs and all that. Just make sure that you discuss with the unit doctors to ensure that there are 7 days a week covering for the collections and make sure that you have very close monitoring to ensure that you would get at least the number of eggs that are there. At 41, I would most likely use DHEA again for 6 weeks and provided that your BMI is normal, I would give some mild stimulation cycle plus minus Clomiphene or Letrozole, plus 150 units of FSH.

Does DHEA improve egg reserve for someone with low ovarian reserve?

There’s no evidence to support the mechanism exactly, but it seems that it probably doesn’t improve the reserve, but it improves the response to stimulation. It makes the follicles even, as you know, the follicles could be of various sizes, and the very small ones maybe are not responsive, and the bigger ones become cysts and so forth. It seems that DHEA improves the ovarian response to stimulation. At the moment, in my opinion, this is one of the very few safe, inexpensive and possibly effective tools in our hands, so yes, 6 weeks of DHEA before stimulation would probably not harm and may give you this extra egg that may make the difference.

Would you use Letrozole in mild stimulation, and do you prefer Clomiphene to Letrazole?

I’ve been trying to make up my mind for the last few weeks. I’m very reluctant to use Letrazole outside the concept of cancer patients. There was some data relating to Letrazole with teratogenicity in early pregnancy, so I wasn’t prepared to take the risk unless I had to. If you had an incident-dependent or progesterone-dependent breast cancer patient, you have no other choice, when you do the fertility preservation cycle, than to use Letrozole to suppress the circulating estrogens.

Do you have an opinion on my Duo stim protocols for poor responders?

I don’t like it, to be honest, they never made sense to me. The costs are the same because it’s a second cycle, it’s back to back. I don’t think there’s a huge place for it, I’ve never used it, and I’ve never been convinced. I think it’s confusing for the patients, it’s very difficult to counsel them. There might be a bit of benefit of this in fertility preservation, or in cases where there are only 1–2 follicles. Overall, I don’t think that, generally, the IVF community are very convinced about its value.

Do you start Clomiphene and FSH together? What does the protocol look like?

I don’t is the answer because I’m trying to mimic physiology, so I always start Clomiphene with a standard dosage of 100 milligrams per day, sometimes we go to 300 if the female weight is perhaps more than 80-85 kg kilos first. That’s from either day 2 to day 6, this is the standard protocol, so 5 days of Clomiphene, we let it kick in for a couple of days before we start the FSH simulation. In my protocol, I would start on day 2, I would start with Clomiphene, and perhaps on day 4 or day 5, I would start the FSH.

What can be done to improve the thin uterine lining, or will the doctor deal with this during the IVF procedure?

Firstly, you have to identify a hysteroscopy specialist, and again you have to discuss it with your IVF doctor, it may not be the same person. It has to be assessed hysteroscopically, invariably, I like to assess the fallopian tubes as well. They are often neglected in IVF because we think that they don’t contribute to either of success, they’re there, it doesn’t matter if they’re blocked if they’re inflamed or whatever, I don’t see any issues on the scan, so probably they’re okay, they don’t have hydrosalpinx, but that is not enough for me. If there is a suspicion of infection, that infection may have affected the tubes and may have produced hydrosalpinx, which is not diagnosed. I would definitely look into the tubes as well. How would I do that? Either with the standard HSG or with the laparoscope. Once I have evaluated the lining, invariably there are some issues there, then I would specifically work to improve it, and again I would always keep in mind the microbiology testing, which is not the standard testing. It’s also the microbiome testing, there’s a new technique of assessing the endometrium, and we may find some dysfunction which may not be clearly associated with an active infection but more of a chronic dysfunction that may affect the lining and the implantation. There are a lot of why’s and question marks hiding in the lining, but the good thing about IVF is that we can disconnect two factors, if we have good-quality embryos and we have a failed implantation, we need to look into the lining as well.

Do you often see no embryos resulting from my IVF protocol?

Yes, absolutely. This is one of the reasons why mild IVF has lower success, perhaps overall, 50% less success than conventional IVF. This is one of the first things we counsel our patients about, I mean especially international patients when they come over to Greece from a different country, and we have no embryos, that’s an absolute disaster. That’s one of the first things we talk to them about, this is what we want to avoid, but sometimes it’s unavoidable. If you have a poor responder or a woman of advanced reproductive age, then it is on the cards. It’s one of the risks of mild stimulation.

What do you count as the optimal BMI for my stimulation? I have been under 18.5, trying to get over 19.

I wouldn’t like to give a figure, I mean, health is not just related to BMI, somebody can have a normal BMI on junk food, then somebody could be on a lower BMI with a normal diet and normal exercise. I don’t think 18.5 is bad provided that you’re fit and healthy and you’re taking your vitamins, and all your blood levels are normal. There’s no such thing as optimal BMI, I think BMI is normal if someone is supporting them with a good lifestyle which is important in IVF, we must be aware of that. I’d rather have someone with a BMI of 30 with healthy exercising and eating well than someone with perhaps a BMI of 20 who is eating junk food. It’s not a matter of optimal BMI, it’s a matter of optimal lifestyle.

Would you use Clomiphene for a woman with PCOS and hypothyroidism?

The answer is maybe. Generally, PCOS is very common in the world, it’s even more common in the south of Europe, especially Greece, Italy, and Spain. PCOS seems to be of the higher incidence compared to the north of Europe. My team and I have very extensively started to do some research on diagnosing PCOS with 3D scanning and Doppler, we have published papers, and we’ve been awarded by the old college for a presentation on that subject. The answer is not easy, if it’s combined with hypothyroidism, it can become more complex. Hypothyroidism could be quite complex to diagnose and to communicate with our patients to make them understand. We shouldn’t be sticking to figures, I’ve recently had someone who got upset because she was treated although she had a TSH of 2.7, and she read everywhere that 2.5 is the normal range. There’s no huge difference, there’s no difference at all between 2.5 and 2.7, in particular, when somebody is under treatment. When someone has Hashimoto, high antibodies, then yes, this could be one of the issues, but unfortunately at the moment, there’s no particular medication to suppress the antibodies following COVID-19, we seem to see even more hypothyroidism in young patients, in infertile patients. To answer your question, this is an endocrinopathy, I would look into it very carefully, there are different levels of PCOS, and different degrees of hypothyroidism, so I would evaluate all that and decide.

Would having a laparoscopy and hysteroscopy to remove mild endometriosis ever improve poor response?

Probably not is the answer. I don’t know if you suspect endometriosis or if you have endometriosis. Endometriosis is one of the pathologies that my group are evaluating and studying at the moment. If you lasered it 2 years ago, again depends on where it was if it was on the ovaries stage 1, I don’t think I would bother with another laparoscopy if I were you. Endometriosis damages fertility through various factors and various mechanisms. One of them is a poor response, but it’s not the only one. In general, if you’ve had laparoscopy and laser 2 years ago and now you have no symptoms, and you have normal scans, I wouldn’t bother with another laparoscopy, and I don’t think it would improve the outcome.
Understanding the Importance of Carrier Genetic Testing
Hysteroscopy before IVF:  can it improve outcomes?
Recurrent Pregnancy Loss challenges: causes and solutions
How to prepare for an embryo transfer to improve your chances: There’s more to consider than just the endometrium
Endometrial factor and recurrent failures in IVF: diagnosis and treatment
How old is too old for my IVF treatment?
Elias Tsakos MD, FRCOG

Elias Tsakos MD, FRCOG

Dr Elias Tsakos, FRCOG, is a Medical Director of Embryoclinic - Assisted Reproduction Clinic in Thessaloniki, Greece. He has received extensive and certified training in the United Kingdom and is a Fellow of the Royal College of Obstetrics & Gynaecology. Dr Tsakos is also a Board Member Representative of the Royal College for Greece and Cyprus and a Board Member of the Hellenic Society of Assisted Reproduction. He is a Member of the British, European and American Fertility Societies (BFS, ESHRE, ASRM). Dr Tsakos has been living and working in Thessaloniki, Greece, since 1999.
Event Moderator
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.
Have questions about what factors will affect your IVF success?
Join our live event to directly ask your questions to three IVF experts.