Mini IVF: minimal hormonal stimulation in IVF – indications, limits and outcomes explained

You know, when I think of IVF conventionally or traditionally, the way IVF is done is that physicians will use primarily injections of hormones to try and stimulate the ovaries to produce lots of eggs or lots of follicles. It’s probably best to go through whether what a natural cycle is first and then to kind of move into what IVF is and what conventional stimulation is. So, in a natural cycle your body puts out just a little bit of hormone every day and that hormone is enough to grow one egg, and typically women will ovulate or grow one follicle during that cycle. So, for a typical 28-day cycle you’re growing month follicle, the patient is ovulating around day 14 and ideally they have intercourse during that time and they’re able to get pregnant. But during every month more than one egg is recruited or wakes up, so there’s a whole group of eggs every month that wake. As women age, that group of egg gets a little bit smaller in quantity and potentially even smaller in quality. The whole point of IVF is to try to exploit so that we don’t just wake up one egg but we actually wake up and stimulate that entire group. So, we make the process of ovulation a little bit more efficient, and that is why the conventional IVF approach was initially developed for. So the idea here is that we are giving excess or super physiological amounts of hormones traditionally something like FSH or follicle stimulating hormone which is an injection, potentially along with some other injections like Menopur, which is a combination of FSH and LH, which is luteinizing hormone. Then those high doses of hormones really allow for not just the one egg to grow but maybe five eggs or ten eggs or the entire group of eggs, if possible. That’s the conventional. There are risks to that, as well. Probably, the biggest risk is what’s called ovarian hyperstimulation syndrome, that’s the most common thing that people get. You often hear stories that someone does an IVF cycle and they’re nauseous throughout the cycle, vomiting and their belly gets bloated, they build up a fluid or their ovaries can twist. That can lead to problems with blood supply and they developed numerous cysts. That’s something that we really would love to avoid and I think that’s really what started the whole trend to do minimal stimulation. So the way you should think about minimal stimulation is we are trying to do a more gentle, controlled and holistic approach to IVF. We feel that bigger is not always better. It may not necessarily fit every person to take ten times the normal hormones and take three injections a day, and go through this procedure that puts you at significant risk for hyperstimulation. With many other centers around the world, especially in Japan, we have pioneered this idea of mini stim which lets us try and personalize the medicine, understand how many follicles the patient actually has and what’s the required amount of medication. In general, a mini protocol is typically a combination of some injectables and then some oral medication to supplement, and allows us to really get excellent quality stimulation without the use of these really high conventional doses. Of course, the biggest benefit is that we avoid a lot of these severe side effects that we see with conventional IVF. We’re focusing on quality as opposed to quantity by supplementing the injections or we’re reducing the injections and supplementing it with some oral medication, which is certainly easier to take. We can even avoid certain injections like trigger shots, we have various nasal sprays, and also we avoid the high risk of hyperstimulation.

This is one of the most common questions we get and it’s not simple to answer it. The real answer is: “ It depends”, and it primarily depends on the patient’s age and her existing ovarian reserve. If we focus on out typical patient, who is 37 or 38 years old, with a pretty good ovarian reserve, and maybe the reason she’s not pregnant is because there’s a sperm quality issue or maybe there’s a fallopian tube issue, then I would say with a mini IVF approach using a combination of some injectables and some pills we would probably expect to get between 6 and 10 eggs from one cycle. However, you need to understand that it can vary significantly. The bottom line of how many eggs are expected I would say in patients who are under the age of 37-38, maybe between 6 to 8 eggs or 6 to 10 eggs. In those who are a little bit older , with mini IVF it may be slightly around the 2 to 5 or 2 to 6 eggs.

This is a great question. To make it simple to understand, I would like to split IVF into 4 phases. The first phase just happens before the period. If it was to have their period on June 1st, then we actually start preparation before the 1st of June, and lasts 7 days where we usually give them something like a birth control pill in order to help to increase follicles. The preparation is over, it’s day 1 of your period. So when follicles are mature, you have a trigger, you take it home, and then 36 hours later, when all phases finished , the fourth phase is agreeable. We do the egg retrieval, we will take sperm and will fertilize the egg, we generate embryos and we allow those embryos to grow in the incubator, and at that point they’re frozen. That really kind of cycle end for the patient.

That’s a great question. We have to remember that when women go through cycle after cycle their body really only wants to ovulate one egg, and what we are trying to do is exploit their body a little bit and select more than one egg to grow, and that’s where the birth control pill comes in. I won’t say that’s a requirement, but it’s definitely highly recommended because when we give a patient some birth control just before her cycle is expected to start, it suppresses the brain a little bit and allows all of the follicles to synchronize. By taking a little bit of birth control pill, and I’m not talking about a month but literally five to seven days, what we can do is we can synchronize all the follicles so that when we’re ready to start phase two, and they all grow equally together. So that’s why it’s very import and I will add that there are patients that for whatever reason don’t want to take a birth control pill or can’t for some medical reasons, and that’s totally OK. It does mean that just before we start the IVF cycle we want to make sure that all the follicles are indeed the same size and that the hormone levels, particularly estrogen levels, are nice and low, ideally below the 85 range.

I think, this really is a personal choice. There is some sort of medical opinions that you’ll read here and there. When we test embryos, we have to remember that we are not changing embryos, we’re not taking a good embryo and making it bad. We also can’t, unfortunately, take a bad embryo and make it good. However, what we can do is we can try and better select an embryo so that the likelihood of pregnancy is higher from the start. E.g. someone has six embryos, how do you know which one to put in? In the past ,we transferred embryos based on grading. But today, we know that the embryo grading does not always predict success. You could have A grade embryo but it might have Down syndrome, and we want to avoid that. So that’s where testing comes in play, it’s when a patient has a group of embryos, and they’d like to get pregnant and would like their first try to be the best shot. So, that’s where we will test the embryos for genetics and that will increase our per transfer pregnancy rate significantly because we are not just randomly picking embryos, we’re picking embryos that have the highest chance of getting pregnant. So, how many embryos should you test? In an ideal situation – all of them. But we know that testing embryos is expensive and time-consuming. So you should test where you’re able to test.

I would say there is no standard of care, at least none in the US, about whether a partner needs to take antibiotics just before a cycle. Probably the most common antibiotic, that’s given to men, is called Doxycycline. However, if there’s a small undetected asymptomatic bacterial infection in the sperm it could affect the quality of the embryo. We can even see that in the various practice patterns in some IVF centers in the US antibiotics are just mandatory. Here, at New Hope, we don’t routinely give all partners antibiotics unless there’s some other medical application.

I would say that you are probably one of the most common patients we see at New Hope. By far, the vast majority of patients we see are those that have gone to other centers and have failed because a conventional protocol is not appropriate for someone in your situation. You’re at a point where you’ve got one or two, or maybe three follicles whether we give you 600 units of injectables, which is a full stimulation or we give you minimal stimulation, the maximum eggs that you’ll probably achieve in that one cycle. So, what I would say is I would tailor a protocol to that, your FSH is already a little bit high to have some good follicular growth. So, in this case, at New Hope, we have a protocol called an ultra mini protocol and it requires no injections. I think that whether you take high-dose objections or you do an ultra mini protocol, where you really just take some tablets, a combination of, probably, Clomid and Letrozole, you would have a very similar outcome. In fact, you may even have a better outcome with that ultra mini protocol because we have less outside injections, which we know, could affect the quality of eggs.

There’s some data on this, but unfortunately a lot of the data is what I would call sort of grade B or grade C data. It’s what we call retrospective data. Unfortunately, a really good controlled study has not been done. However, there are some retrospective studies, where they look at a whole group of patients, but they’re different, and some got lower stim, and some got higher stim. There’s some evidence there, that potentially lowering the dose of Gonadotropins, especially in patients with diminished reserve, could improve egg quality.

It’s very hard to set a certain number because everyone is a little bit different. Going back to that example, where we have a patient who’s 37 or 38 years old with a pretty good reserve, I would say with a conventional IVF you should probably get somewhere between 12 to 14 eggs. But again, that comes with the risk of some ovarian hyperstimulation, which is some of the things we talked about. From mini IVF we can expect more kind of like at 6,8 to 10.

I would say that sometimes it’s good to take a little bit of a break, not just for your kind of physical body, but also for some emotional break. IVF is not an easy process to go through, there are financial, psychological and emotional implications, so aside from the medical reason, there’s lots of other reasons why some people take breaks. I think that it’s perfectly safe to do 3 or 4 cycles in a row. Except again that some people do need a mental break and sometimes it’s a good thing. Sometimes we will do a mini cycle and then we’ll do a conventional, and sometimes we’ll start with a conventional IVF and then do a mini, if the conventional didn’t work very well. I can’t really speak to other IVF senders, but we are definitely very dynamic here and we personalize care, so we don’t have one specific protocol that we push on everyone.

When I hear stories about how either we have empty follicles or immature eggs, I often think that there might be issues with the timing of the trigger – that’s probably the number one answer there. Then the second thing to look at is the type of trigger that was used. You’re a 37 and you’re very young, that’s that actually goes to your favor. Assuming you mean 4 follicles were developed, that’s not great, we would expect ten follicles for a 37 year in a conventional IVF cycle. When I hear that one egg or one follicle was empty and that there were some immature eggs, one thing that could lead to it is timing. So, perhaps, they didn’t allow the follicles to get big enough if you were triggered a little bit early. Another thing is that maybe there were some bigger follicles and some smaller follicles, so eggs were not really synchronized. And the last thing is the type of trigger. When I hear about immature or maturity issues, I often will do a dual trigger. And typically the combination of those together along with adjusting prevents maturity issues.

If the antral follicle count in the beginning of the month is really around six or seven, like I mentioned before, that’s going to be the maximum follicles that you can get. If we’re talking about a synchronous follicle growth, one thing I would recommend is trying some type of preparation either a birth control preparation or sometimes, if there is a component of diminished reserve, which it sounds like there, maybe I would try Estrace preparation, which is Estradiol that is typically dosed at two milligrams, it’s given at the same time seven days before your expected cycle. The reason I mentioned Estradiol or Estrace preparation as opposed to a birth control is because there’s some recent data that has shown that especially in women with diminished reserve and Estrace preparation that helps prepare those follicles to accept a good stimulation. Why you got four retrieved the first time and only one the second time? That could just be cycle a cycle variation, something in terms of the retrieval and how the retrieval was done, maybe there are some complications with the location of the ovaries. It sounds like you are developing follicles and getting eggs, so I would say yes.

I would say about 10% of women or 10% of couples really fall into this category called unexplained, and it’s a very frustrating category. The success rate for patients with unexplained varies and it’s slightly lower than perhaps some of the other fertility or infertility categories. When I have patients with unexplained infertility and they get a normal embryo the success rate is not much different. At New Hope, when we transfer one single normal embryo, the success rate is about 65% which is pretty good and that doesn’t change whether your diagnosis is unexplained or e.g. a male factor.

It’s a little bit of a myth, taking the pill does not make the corpus luteum go away. It will probably go away on its own. The reason that birth control pills work very well is that they prevent new cysts from forming.

I would say, if there’s still a corpus luteum and the progesterone level is elevated, then you may want to wait for that progesterone to come down. If there is a cyst, that’s there at the baseline, and the progesterone is low, as long as the estrogen is equally in the low range less than 85 at US units, then I think it’s pretty much safe to go ahead.

I wish I could give you one off top my head but I don’t have them. We do have a department in our clinic that deals a lot with what we call outside monitoring, and we have a whole list of clinics all around the world that we’ve been happy where we’ve sent our patients there. I’m sure that we have some London clinics listed, so we can send recommendations later.

The quality of embryos does not dependent on just one variable. Unfortunately, the quality of embryos depends on the patient’s age, the quality of eggs and sperm, the quality of the lab, what type of protocols and what type of embryology culture medium they use, and how frequently they open the incubators, how well they are at making sure that the embryos are growing according to protocol, if various parameters of the incubators are maintained appropriately. I would say that probably the quality of embryos and mini IVF is slightly better and that’s primarily because we’re not using as much medication and we’re allowing the body to self-select eggs.

Yes, absolutely. I think that as long as the medication doesn’t contain any specific hormones that would alter our test, then I think it’s totally OK to add or supplement the IVF cycle with herbal medicine.

What I would say is it’s age dependent, but again going to that example of 37- 38 year old patients with 8 mature eggs, we would probably expect something like 90% of a fertilization rate. so that would bring you to seven fertilized eggs, and then from there, if we’re talking about day five blastocyst, we would probably expect something like a 50% blast rate, so maybe something around three or four embryos from eight mature oocytes. The older the patients are the percent of embryos, that lead to full day five day blasts, goes down. If you are 44 years old and you have eight mature oocytes, and they were frozen at that time, then the chance of a blast is about 20%. So from eight eggs you’re looking at something like one or two, from donor eggs the blast rate should be about 50%.

The answer to that is it may actually lead to more eggs and it depends on what your FSH is. If you are 45 and your FSH is fairly high on your baseline, maybe your FSH is 15 or 16, then your body is really pumping out quite a bit of FSH. And that’s really where mini IVF shines, because what we can do is we can prepare your body and keep FSH in a very narrow controlled window so that we’re not over stimulating.

The point is to try to figure out why did the pregnancies end in miscarriage three times in a row. By definition that puts you in a category called recurrent pregnancy loss and therefore your problem may not be getting pregnant but your problem is staying pregnant. There’s a whole recurrent pregnancy loss workup that we would recommend, and part of that is looking at some hormonal issues, uterus, etc. You mentioned that one of them was Edwards syndrome, so that’s a classic chromosome abnormality. So the way to avoid that is to test the embryos and put back a genetically normal embryo. Also pre-implantation genetic testing lowers the miscarriage rate, so we would put back one embryo of known good genetic quality. There are two most common supplements we have data on them: DHEA which is a type of male hormone but seems to improve egg quality and Coenzyme Q10.

That’s kind of just what we talked about. It’s a supplement that is a derivative of testosterone, it has been shown in numerous trials to help improve quality. Most of the time here in the US we start at about 25 milligrams, that’s a single tablet, and then we work our way up to two tablets a day and the maximum of three tablets a day or 75 milligrams a day. Ideally, you do this for six weeks before starting the IVF cycle.

Yes, it’s completely OK.

There isn’t data to support the use of them without diminished ovarian reserve, I I’m not sure that that’s recommended, it’s not a standard of care. I doubt that it would be harmful, but I’m not sure that there would be much benefit.

There’s a couple of reasons that you want to stop. First and foremost, as if you’re symptomatic e.g. if you start getting hot flushes or heat, waves, or you are developing nausea, vomiting or having headaches, then you should stop it because you’re just not responding well. Another reason to stop it is if you’re gonna do a transfer cycle, if you’re done with your treatment and you already produced follicles and eggs, now you have embryos and you’re ready to continue to transfer, then you should definitely stop the DHEA.

This is a very tricky case. Borderline tumors called such because they are not considered to fully malignant ,it’s not a full ovarian cancer. The patients with borderline tumors can develop a second tumor and that can be completely independent of any kind of stimulation, so that’s just something to keep in mind. From the data and the knowledge that we have and given the types of medications that we use in IVF, which is primarily FSH, which is something that your body makes anyways, there really shouldn’t be a huge risk to stimulation.

You can do it, it’s not our standard protocol. For sure, the levels will go up after you start taking it, so don’t be shocked at that. I wouldn’t make a big deal out of it. Unless you have PCOS, there’s no clear indication to check baseline levels.

2 mg daily for seven days is a very common traditional dose, and it should not suppress you too much. Alternatively you could use patches, typically we use 0.1 milligram patches and we get one patch every other day. I try to stay away from shots. I could probably either stick with the pills or the patches, and both of those doses sound good.

We use picograms per milliliter, deciliter.

I think what we’re talking about here is a mock transfer a cycle, that’s typically how we use that terminology, and the answer is: not really. It depends what you’re trying to get out of it. If you’re trying to see how thick the lining is, then no, I mean you have to have a cycle either a natural cycle or an estrogen. If the goal is to see if the transfer will be smooth, then yes.

As I mentioned, we really personalize our care, so we don’t have one simple protocol that we use for everyone, we use a variety of factors. If you’d like to know, probably, what’s the most common protocol is something like a hundred milligrams of Clomid and five milligrams of Letrozole to start with. If we’re gonna add back some injections probably 75 units a day is the most common. But we tailor that up and down as we need to.

I probably would not fix it, I would let you go right into an IVF cycle. There’s probably very little benefit to measuring testosterone level.

I almost never tell anyone to take DHEA or Co Q10 for 2, 3, 4 months and then come back. That’s probably not the best idea. If anything we tell is to start the DHEA and Co Q10 and IVF up right away. Because every month that goes by your AMH is gonna to drop and drop, the number and the quality of follicles will drop and drop, so I would rather you do them simultaneously as opposed to trying to really optimize everything upfront because age at the end of the day is gonna be the biggest factor here.

This is becoming such a common question. I think the true answer to this is that no one really knows exactly why, but it seems that just like estrogen climbing improves the follicles ability to respond to FSH, seems that something probably similar is happening where we’re giving this hormone called DHEA, which is a testosterone derivative. It probably just improves the follicles response to FSH. So, having DHEA on board probably improves the ability for that follicle to grow and hopefully get a better quality egg , and getting the egg and the sperm to meet better.

Coenzyme q10 is it’s another one of those cofactors that various enzymes and the cells use. So when the cell is combining with the sperm and it’s trying to segregate that DNA and make sure that the right amount of DNA and chromosomes are going to the right spots. I think things like Coenzyme Q10 and other cofactors are of really help for cell growth and support the division of the cells.

I couldn’t tell you the dose off the top of my head, but I’m sure that’s something that can we can provide later.