Stop Chasing the Perfect IVF Protocol

After a disappointing IVF retrieval, it is tempting to change everything. But does a new protocol actually explain a better next cycle—or is biology doing some of the talking?

In this episode, Dr. Mark Amols explains why IVF protocols absolutely matter, but why there is no single “perfect” protocol that can guarantee a certain number of eggs or mature eggs. Using the analogy of an Olympic runner and the right running shoes, he breaks down the physician’s role: optimize the medication plan, timing, trigger, and safety—without pretending we can fully control ovarian biology.

Dr. Amols reviews a 2026 Fertility and Sterility study of 801 consecutive IVF cycle pairs showing substantial cycle-to-cycle variation even when patients used the same stimulation protocol and dose. He also discusses why mature eggs matter more than total egg count, when a protocol change is purposeful, and why retrieval and lab workflow can influence the final egg number too.

If your last IVF cycle did not go as hoped, this episode will help you ask the better question: not “What can we change?” but “What did we learn, and what are we trying to improve?”

Referenced studies: Hochberg et al., Fertility and Sterility (2026); Mutlu et al., Nature Medicine (2026).

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Transcript

>> Dr. Mark Amols: 0:01

Today we talk about why the right IVF protocol matters, but why there's no such thing as a perfect IVF protocol. I'm Dr. Mark Amols, and this is Taco Bout Fertility Tuesday. In today's episode, I want to talk about one of the most common questions I get after an IVF retrieval that gives maybe fewer eggs or fewer mature eggs than expected. Maybe the fertilization is poor. Maybe you don't get as many embryos. The question is, was my protocol wrong? And then the next question that comes after that is, should we change everything next time? Now, this is a very reasonable question. IVF is expensive, it's emotionally draining, it's physically demanding, and every cycle feels like it has to count. When the results are disappointing, nobody wants to hear, well, sometimes biology is just variable, because that can sound like we're dismissing it. But there's a big difference between dismissing and being honest about what we can control. What spurred my desire for this podcast was a recent reflection in Fertility and Sterility, which is the reproductive journal for reproductive

medicine, titled "Stop Fooling Yourself: 1:25

Protocol Changes Do Not Really Matter." And this was in response to an actual retrospective cohort study that was also in Fertility and Sterility, called intrapatient variability in the number of retrieved oocytes and ovarian response categories between consecutive in vitro fertilization cycles. What we're going to do is we're going to separate that fun and shocking title I talk about. What did the study actually show? Is it true that changing protocols does not matter at all? I'll give you a hint. It does matter, but selectively. Where the commentary got it correct was that if you are already optimized in a protocol, then changing the protocol is probably not going to do much to benefit for you. Matter of fact, what the study showed was that by just repeating the protocol more than once, you'll actually have different results. And these weren't minor changes. In 801 pairs of consecutive retrievals using the same stimulation approach, the median oocyte count difference was 40%. 50% of people had greater than 33% difference. And almost 50% of the people changed their ovarian response category. Category means how they grouped the responses. If it was 1 to 3 eggs, poor response, 4 to 9 suboptimal response, 10 to 14, normal response, 15 or more high response. So in this study, almost 50% of, people moved to a different category. So what this means is that better or worse egg count in your next cycle does not automatically prove the new medication plan caused it, because doing the same thing would also have changed it. But that doesn't mean that the protocols don't matter, because if you have the wrong protocol, you will affect how many follicles are going to be able to be retrieved. So there may not be the perfect protocol, but there definitely are protocols that may be wrong. Imagine an Olympic runner. If that runner is competing in a race, we want them in the best possible running shoes. We don't want to put them in cowboy boots or military boots. The wrong footwear can absolutely make a great runner perform worse. In that same sense, the shoes matter. But if you put me in those exact same Olympic running shoes, I'm still not going to even get close to the Olympian. The shoes optimize the athlete, they cannot create the athlete. And that's the point. A bad protocol may hold you back, but a good protocol doesn't mean you're going to do better than your body can. In this analogy, the protocol is the running shoes. We want to choose the best fit, the medication type, the dosage, how we suppress you or do not suppress you, and how we monitor growth and when to trigger the final maturation. If I match you with the wrong protocol, I may limit your performance. If I know someone has a lower AMH or high FSH, I'm not going to want to use lower dose medications. If I know someone has hypothalamic hypogonadism, it wouldn't make sense to not use LH activity. So as you can see, the wrong protocol can cause some damage. But even the best designed protocol cannot command the ovary to have a 15 recruitable follicle cycle. If that's not what the ovary is able to do that month. And that's the point, it things change; every month can be different. We can optimize the situation, but biology still decides the field of runners who show up on the race day. So when I say we should optimize a cycle, what do I actually mean by that? Well, as I mentioned a minute ago, we look at things like age, AMH, the antral follicle count, and any prior responses, and then using that information, we can determine if there's any changes that should be made or if it's the initial cycle. We make sure we pick the right protocol for that person. If the patient has hypothalamic hypogonadism, it means their pituitary gland is not sending the hormones down to be able to make follicles. So if you just give FSH, you may not get a response. You need to add the LH to it, to give the LH activity. So there the wrong protocol can have damning effects. If I know someone has a high FSH level, I'm going to start with a higher dose because I know their body needs more medication to get the same response I want. If they're on another cycle or even on their first cycle, and I notice the estrogen level is very high on cycle day three labs, they may have a lead follicle. So I'm going to use a protocol that can help me synchronize the cohort of follicles so they grow evenly. And it goes beyond just trying to get more eggs, because there is the safety. If a patient has polycystic ovarian syndrome, now called PCOS, I want to reduce the risk of ovarian hyperstimulation syndrome. That means I want to use a protocol that allows me to use Lupron as a trigger. Because if I use a protocol like a agonist protocol or a microdose Lupron protocol, I won't be able to use Lupron trigger, and we'd have to cancel their cycle if they're overstimulating. That is individualized care. That doesn't mean that we perfectly engineer the number of mature eggs in every situation. It means we use the evidence from the patient's prior responses or labs and data to give her ovaries their best opportunity to perform. So let's talk about this interesting 2026 study and how it is relevant to this podcast. It was published in Fertility and Sterility by Dr. Alyssa Hochberg and colleagues. The study looked at 801 pairs of consecutive IVF retrieval cycles in the same patients. And this is important, they were not random, completely unrelated cycles. They specifically looked at patients who had the same stimulation protocol, the same gonadotropin type, and the same starting and daily doses in both cycles for those patients. In other words, they tried to answer this simple question. If we keep the basic stimulation plan the same, how much can egg yield still change from one cycle to the next? The answer was quite a bit. As I mentioned, the median difference in retrieved eggs between cycles was 40%. And half of the patients had more than 33% difference in the number of eggs retrieved from one cycle to the next. As I mentioned, nearly half of the patients moved into a different ovarian response category. Basically, in one cycle you may be a suboptimal responder, in the next cycle you're a normal responder. And the crazy part is, nothing changed. And we're not just talking about egg number. We're

talking about mature eggs: 8:25

a 50% difference between cycles using the same protocol. So that means if a patient had six mature eggs in one cycle and nine or 10 in the next, that improvement may reflect a thoughtful protocol adjustment. It might, but the study tells us that we cannot automatically give all the credit to the new protocol because there is a real month to month biological variation. Now, keep in mind this was a retrospective study. It's possible that the doctor decided not to go for the next month because they noticed the antral follicle count was lower. So we cannot automatically say this is absolute truth. But that doctor's opinion about are we really helping anything by changing the protocol is a belief held by many in the reproductive community. Not that protocols don't matter, but that when you have an optimal protocol, if your outcome is not what you wanted, does changing the protocol actually benefit it? And that's a fair question to ask. Now, as I just mentioned, total egg count is important, but what really matters is mature eggs, because those are the ones that can be fertilized. I don't want to know just how many eggs did we get. I want to know how many mature eggs did we get? And I want to know, depending on what I expected to get, did we get that? If I expected 12 mature eggs and only got five, then the question I need to ask is, were the follicles growing evenly? Were the follicle sizes averaged up? In other words, was it 14.5 millimeters? And we called it 15 and they really weren't mature? Maybe the trigger shot needs to be changed. These are the clinical questions that we need to ask. But again, we need humility. The study didn't say that making changes isn't helpful. It just said that even without changes, there may be changes that occur in the next cycle, and it may not be due to the protocol change. And what that means is that if you do another cycle and there's a lower mature egg number, it's not automatically proof that the physician made a mistake. And the higher mature egg number next time doesn't mean that they did a great job. I tell patients this all the time, that sometimes they do a better cycle. And I don't take credit. I said your body just performed better this month. That doesn't mean there aren't correctable issues. If there is an issue with the cohort having asymmetry and being unsynchronized, then yes, making changes fixes that. If you triggered the patient at 18 millimeters and most were immature, then you're going to let them get bigger the next time. You might even add a dual trigger. But what you wouldn't do is just change it to change it, because that isn't going to help based off of this study. And that's really the way a lot of us practice medicine. We don't just change to change. Matter of fact, I spend more time in a failed cycle talking about having the patient step away from the edge before they jump off, that changing everything feels good, but it doesn't always benefit you. And that every change should have a diagnosis or hypothesis attached to it and that they are purposeful adjustments, not random adjustments. So when should we change the protocol? Well, my rule is simple. A protocol change should have a reason attached to it, not just, well, that was disappointing. We should change something. I got 800 more protocols we can use. Instead, I look and go, what can we learn? What specific issue are we trying to improve? If the patient was already taking, let's say, a lower dose than anticipated, and I had to crank it up halfway through, then I'm going to start at a higher dose from the beginning. If I need to look at trigger timing, then I adjust that. If I need to look at synchronization of the cohort, then we'll adjust for that. Doctors are not perfect. We are going to pick the wrong protocol at times. And that's not because we might have, made a mistake. It could be because the data we got showed something else. For example, people with endometriosis can have elevated AMH levels, making the doctor think that your egg reserve is better than it is, and all of a sudden, you don't do as well. That's a point where data caused the doctor to make the wrong choice. And, yes, we're not perfect. We can sometimes make the wrong decision, too. And that's when protocols should change. But the point is not lost in that editorial. We should not confuse better or worse results with proof that someone did something wrong and the protocol was wrong. Sometimes it's just biology. Now, to really throw a wrinkle into this discussion is that the number of eggs on the retrieval report is not always determined just by the ovary and the medications. Sometimes it can reflect the retrieval itself and how the follicular fluid is handled by the embryology lab. Now, this is not a diss on embryologists. They're amazing. They look through a microscope and they can find these little tiny eggs. But there was an interesting study in 2026 in Nature Medicine by Dr. Baris Mutlu and colleagues that tested a microfluidic device that reprocessed the follicular fluid, which had already been manually screened by the lab. And in this clinical study of 582 patients across multiple IVF centers, the device found additional oocytes in more than half of the cases. Half the cases had eggs that were not seen by the embryologists. Now, that does not mean that every lab is missing eggs and that this technology is now routine care. It's just saying there's a lot of hands in this and that sometimes it could even be a reduction due to the eggs not being found. And that reinforces this important point. The final number of eggs retrieved is not a pure scorecard for the stimulation protocol. It reflects ovarian biology, the retrieval procedure, and the laboratory workflow. So, as a patient who just went through IVF that gave you fewer mature eggs than you hoped for, what should happen next? Well, not dismissal, but not blame and not automatically start from scratch again. There should be a real review of the cycle. And what issues were there? You look at what did we expect and what actually happened? Did we identify a specific issue that could be improved? And is there a meaningful reason to adjust the protocol? And if the answer is yes, then we should make the purposeful change. But we should also be honest that the protocol is not the ultimate decision maker. Our job is to put the runner in the best possible shoes. We want to make sure we optimize the situation because what we don't want to do is get in the way of the ovaries doing their best work, because we can't promise how many follicles biology will make every month. But what we can do is make sure we don't get in the way of those follicles giving their best chance to become mature eggs. So when your doctor doesn't want to change things, that's not doing nothing. That is practicing IVF with both intention and humility. Sure. Do I want to raise my arms and say, I did it. I made it better when I made a change, that's fine. If the area I found was bad got improved, then yes. What I'm not going to do is I'm not going to sit there and take the award for improving your cycle when I know there is intercycle variability that is going to occur naturally. Maybe you went through an IVF cycle and didn't have a good cycle that time, and you spoke to your doctor and you felt disappointed that, how come they're not changing everything? Or maybe you went to another doctor who said, oh, we'll change everything. But the question is, did you need to? Well, hopefully this episode helped you and maybe you have a friend who's in the exact same situation and let them know about this episode because it may help them not make changes that aren't needed. As always, if you like this episode and this podcast, please give us a five star review. Tell your friends about us. But most of all, keep coming back. I look forward to talking again next week on Taco Bout Fertility Tuesday.