Understanding IVF and Protocol Basics

What happens in a normal cycle?

The first thing that is really important to understand if we're going to talk about IVF, is you have to understand briefly what is normal and what we are trying to do in general with the protocol. Then that's going to allow you to understand why we might choose one or what is really different in these protocols. So if we think about IVF, most people have heard or they understand IVF to some extent, but really we need to talk about the ovary. So remember, inside the ovary, you are born with all the eggs you are ever going to have. If you've been around here, or you've seen me in clinic, you know that I use a reference imagining that there is a vault inside your ovary where all of your eggs are kept. Inside that vault, you're born with all the eggs you're ever going to have. They are going to run out at some point, and that is menopause or ovarian failure. Every single month you are going to have a group of eggs coming out of the vault, and each of these eggs grows inside of follicle. A follicle is a small, fluid-filled structure you can see on ultrasound. So the brain is going to send out follicle stimulating hormone, or FSH. FSH is well named. This actually starts to be sent out from the pituitary gland while you're on your period. So while you are bleeding, this FSH is being sent out because the body knows you are not pregnant because you're on your period, and it wants to get another egg ready for ovulation. FSH is so well named because what it does is stimulate just one follicle to grow. There is amazing feedback between the ovary and the brain, meaning the brain doesn't see what is happening inside the ovary. Imagine you and your best friend live in different places, but you talk on the phone all the time. The brain has no idea how many eggs you have, how many are outside the vault, how many are growing that month, but it can hear estrogen, that is the signal or feedback to the brain to tell it a follicle is growing and is ready for ovulation. If a follicle is not growing, we are not pregnant. So estrogen is what an egg makes as it becomes more and more mature. So throughout the course of a normal cycle, your FSH will rise. This will stimulate one follicle to grow. As that follicle grows, it starts making estrogen your FSH, then drops, so you don't get more follicles growing when your estrogen is high enough for long enough, this signals to the brain we are mature, and that is going to allow your brain to send out a surge of LH or luteinizing hormone, which is going to then allow you to ovulate. When you ovulate, that follicle is rupturing, the egg is being released, and then that follicle is reforming into the corpus luteum. The corpus luteum is going to make progesterone based on LH pulses from the brain, up and down and up and down throughout the entire luteal phase. If you get pregnant, then that pregnancy is going to come in and implant and make HCG. We say this rescues the corpus luteum and allows it to keep making progesterone. If it doesn't, the HCG is going to not be present. So the corpus luteum cannot survive. It can only live about two weeks. It dies, progesterone drops, you get a period, and the process starts over. All of the eggs that were available in that month that did not ovulate, they die. So any given month you are losing many eggs, more than just the one egg that you ovulate. This is important, because this ties into ovarian reserve, but also how many eggs you can get.

What happens during IVF?
So if we are being as simple as possible in IVF, the whole goal is to try to get all of the eggs that are outside the vault in that given month to grow at the same pace and reach maturity together, and then take them out of the body so we can fertilize them, grow them in the lab to an implantation stage embryo called a blastocyst and/or do genetic testing. Then we can either do a fresh transfer five days later, after we have retrieved them, or we can proceed with a frozen embryo transfer. So there's intricacies to the IVF process. Do you do ICSI? Do you do genetic testing? These are different than what is your protocol? So when we really talk about your protocol, we're talking about the type of medications that we are using to get the job done, and the job is to get all of the eggs that are outside the vault to grow. Your protocol should be selected for you based on your age, your antral follicle count, your AMH prior response in any cycles you've had in the past and your medical history now, the decision about certain things about IVF is extremely important.

Fresh Vs. Frozen Transfer

Are you doing a fresh transfer or frozen transfer? Are you doing genetic testing or not? These are separate yet important IVF questions that should be answered. I have some videos on fresh and frozen transfer so you can look at transfer intricacies. The short answer difference is a fresh transfer is one embryo is not getting frozen, it's getting put into your body. We have fallen less and less in favor of doing that, because we see that obstetrical outcomes for the vast majority of people are going to be better when an embryo is implanted in a more normal environment, which is not when your estrogen level is 3000 from a fresh IVF cycle. We also do not do genetic testing if you're doing a fresh transfer, and you also don't have the full information about what you've gotten from the cycle. So when IVF started an embryo freezing wasn't really good, a fresh transfer was where it was This is when we put tons of embryos inside people. This pre-dates me, and I've been in the field for 10 years. This is where people would do transfer of high order of embryos because they didn't trust their freezing process. Now the freezing is so good I will tell you that an embryo does not survive a biopsy, a thaw in a freeze about 1% of the time, and clinically, it is less than that. Meaning, at least in our lab, I do well over 100 transfers a year, and our clinic will have one embryo not survive the freeze thaw. So it's well less than that. Most clinics will quote you about a 1% non survival rate for a blastocyst embryo, even with PGT testing. That's really different than it used to be. So it makes sense that fresh transfer used to be the standard, it would save you money, and it'd save you embryos if they didn't have good freezing thawing. But now that we do, most of us are doing a frozen transfer, synchronizing embryo to endometrium, normalizing the environment, getting better pregnancy rates and better birth outcomes, allowing for understanding how many blastocysts you really have, and are they genetically normal. So to me, it is, by far and away, my preference for most people.

Egg Quantity

The group of eggs that comes out of the vault is considered your ovarian reserve. We can check that number by doing a vaginal ultrasound and counting the follicles that we see. This is called your antral follicle count, or your AFC. Your goal is to get all those follicles to grow. So your AFC is probably the very best you're going to do because it's hard. Your ovary does not want to have 20 babies at one time, so it doesn't want to allow 20 eggs all to grow to maturity at the same pace. We are trying to do something your body doesn't want to do because it is wired to not have 20 babies at one time. Your unique ovarian reserve is really important. AMH is another micro ovarian reserve, and I use both of these together. AMH is anti-mullerrian hormone and is made from the cells that surround all of the follicles outside the vault. When you have more eggs in the vault, more come out every month. Therefore, when you are generally younger, you will have a higher egg count and a higher AMH, and you can get more eggs in an IVF cycle than if you are older or you have fewer eggs. Remember that everybody is born with a number, and that number is different. Everybody runs out of eggs, and the pace of the decline is different. Things like chemotherapy, smoking cigarettes, and endometriosis can impact your ovarian reserve. There's a lot of other things like autoimmune disease, genetics, environmental toxins that also can impact your ovarian reserve. We typically do not know why people go into premature ovarian failure. So just because you're young doesn't mean you're going to get a normal number of eggs. Generally, the whole process is going to be easier when you are young because you also are going to have the best egg quantity that you're ever going to have.

Egg Quantity and IVF
So egg quality and egg quantity are separate things. When we check your AFC and your AMH, we're trying to get an estimate that's going to help us choose the protocol. Remember that your antral follicle count can change by 30% any given month. So if you come into my clinic and I count fourteen, and then you go through your cycle and we get eleven, it's not that we didn't get three. It's a different month and it's a 30% difference. It's just how the cards fell that month. If I count fourteen and we only get three, something is well off, and you would be mind blown that clinics do not have open dialog and communication with patients, and they do not cancel a cycle when they should. To me, a protocol's goal is to try to get as many eggs as possible. We look at that range of normal based on your AMH and your AFC, and we're trying to gage during the monitoring. Are we achieving that goal? If we're not, we should cancel the cycle and try a different protocol. There are exceptions. If your endurance is running out, and this is your only time, or you're going through chemotherapy, and this is just whatever we get is what we get, or you have unlimited benefits. So any eggs are better than none. So there's always extreme examples, and it's ultimately something that should be discussed. Too often I will look through somebody's records and see somebody who underperformed an IVF cycle, who never had it discussed with them, and it's just mind blowing.

The Protocol and Success

So the goal of the protocol is to get all the eggs we think we can to grow. When we think about what is really happening, I gage a protocol's number one sense of success by how many mature eggs did we get. Then, based on that, I might make some tweaks if we're doing another cycle. I may change the dose of medication, length of the trigger, or the exact type of the protocol. Ultimately, the protocol has some influence on your embryo quality, but really not as much because that's all determined by egg quality and sperm quality. So progression and culture is generally not really related to protocol. There are always exceptions, and somebody who gets a high egg number, but is having really poor progression and culture. Sometimes we don't have many tools, and changing a protocol is something we might try. When thinking about your protocol, I’m wondering “did I get as many mature eggs as possible?” This confuses people, and I'll just say this: success is relative because we think of success as getting normal embryos or getting pregnant. However, If you're older and your antral follicle count of six, and we get six mature eggs, but you had no normal embryos because four fertilized and two grew out, and you're age 38. In this case, we would expect a third of them to be normal and a third of them happened to be zero. That is a sad outcome, but it's not an unexpected outcome. The protocol actually did it’s job perfectly because we were expecting to get six mature eggs, and we did. So remember that success from a protocol standpoint might feel different than success from a cycle standpoint, so understanding the end point is really important in evaluating the protocol.