A Step By Step Guide To The IVF Process: Step One -- Stimulation

Dear Readers,

This is the second part in the series I have begun to help answer what In Vitro Fertilization (IVF) is and how it works with my world-wide Blog audience. What you read here is what I also provide my patients with on a daily basis. I plan on going into some detail but in a way that is understandable to the normal (lay) audience, and not the medical or scientific one. I hope that this will not only clarify what you will go through, but explain why things are done a certain way and what the goals of each step are. I also want to convey that IVF is actually a replacement for some of the “natural” steps required to get pregnant and not some miraculous high tech fertility treatment that gets patients pregnant artificially, as many think it is. It is somewhat of a miracle that we can do as much as we can, but there are still lots of things/steps that we cannot do or influence. I hope this discussion will benefit you. This series will be posted over the next few weeks in installments.

STEP ONE: STIMULATION

As explained in the natural process, the first step in your body is for the hypothalamus and pituitary to send a hormone to the ovary to stimulate the growth of a follicle and maturation of the egg within.

The hypothalamus sends a hormone called GnRH or gonadotropin releasing hormone to the pituitary. This in turn, causes the pituitary to give off follicle stimulating hormone (FSH) and a little luteinizing hormone (LH). For now, I won’t go into detail regarding LH since it is not as important in this stage of the process. The FSH, or follicle stimulating hormone, stimulates the growth of a follicle, hence the name. The ovaries already have all the follicles they are going to have from birth. These follicles are in a dormant state until they are stimulated. In a natural cycle, several follicles are stimulated but only one is designated to grow to ovulation. The FSH goes through the blood stream and makes its way to the ovary. The ovary then picks up this hormone from the blood. It then processes the hormone and a follicle grows causing the production of estradiol and progesterone, and maturing the egg within. The egg is normally in an immature state in the dormant follicle.

In the IVF process, we take over the function of the hypothalamus and pituitary. In fact, we shut down the natural process so that we can control how the process goes and to help with timing. Timing is critical in IVF, as it is in the natural process. Many programs use birth control pills to shut down the ovaries and thereby shut down the hypothalamic-pituitary axis. Some clinics use leuprolide acetate or Lupron, Synarel or a similar drug, to shut down this axis. These drugs are known as GnRH (gonadotropin releasing hormone) agonists which is essentially adding GnRH but the brain monitors the levels of this hormone and if it reaches a certain threshold, shuts down production in the hypothalamus. Using Lupron from the luteal phase of the previous cycle is known as the “long protocol”. Some programs will go into IVF directly from an natural menstrual cycles and this is sometimes called “Natural cycle” IVF.

As I was explaining, in the IVF process we take over this step by giving FSH and LH hormone directly. These are known as injectable fertility drugs, but in actuality are not “fertility” drugs but merely the hormones your body would naturally produce to induce follicle growth in the ovary but at a higher dosage. So in reality, these drugs don’t increase your fertility or make you more fertile, they actually just give you more of an opportunity to become pregnant. Some of the medication used in IVF, such as Gonal-f or Follistim are now recombitant, or genetically produced FSH (in the old days, all FSH used to be natural FSH that was extracted from elderly women’s urine). These medications are pure FSH and have no LH within. There are other medications such as Pergonal, Menopur, Repronex that contain both FSH and LH. These are still derived from urine. Some clinics will use only FSH but most will use a “mixed” protocol, meaning they use both an FSH only drug in combination with an FSH/LH drug taken together.

The amount of medication given is what determines how many follicles your ovaries grow, and is dependent on how aggressive your doctor wants to be, i.e. how many follicles they want to try to get, and how well he/she thinks your ovaries are functioning or going to respond to the stimulation. We call the latter “ovarian reserve”. A younger patient will usually, but not always, have a very good ovarian reserve and therefore require less medication, whereas as a woman ages, her ovaries become more resistant or less likely to pick up the FSH from the blood, i.e. decreased ovarian reserve. Logically you can see that if the ovaries are more responsive, less medication is required and vice versa. The best way to picture this, as I explain to my patients, is to imagine a golf “wuffle” ball. If you don’t know golf, this is a practice ball with lots of holes in it so that it doesn’t fly far. Imagine that all the holes are open and you put the ball in a bowl of fluid (which is the FSH). The wuffle ball readily admits the fluid into its center. Now imagine that you block off most of the holes in the ball. You can see that less fluid gets into the ball (you also have to imagine that you have a time limit as to how long the ball gets to sit in the bowl of fluid). That is ovarian resistance. No matter how much drug you give, the ovary will only pick up as much FSH as it can and thereby only stimulate as well as it is going to stimulate. There is no technology that can change this. That leads to a lower ovarian response to the stimulation, and less follicles and eggs to work with. It is called “ovarian resistance” once stimulation has been attempted and only a few follicles grow. That is different from “ovarian reserve” which is the anticipated ovarian response or ovarian response potential before stimulation. “Ovarian resistance” is what you see once the stimulation is done and the ovary does not stimulate well.

The stimulation step is important because part of the success of IVF is an enhanced statistical chance by having lots of eggs to work with. Take for instance, if you have one dice and you want the number five. You have a 1 in 6 chance with each roll of the dice. Of course, your chances increase with rolling the dice more times, which is a different statistical chance and the statistic that changes as you attempt IVF repetitively. But taking just one roll into consideration, as in one IVF cycle, your chance is 1 in 6. Now, if you add three, four or five dices to that one roll, you can see that you have increased your chances 3, 4 or 5 fold. That is the same with each IVF cycle. In a natural cycle, you give off only one egg, so if that egg doesn’t go through each step perfectly, you don’t get pregnant. IVF increases your chances of pregnancy by accomplishing more of the steps of the process for you, but more importantly, you still need to have a perfect egg that forms a perfect embryo. If you only have one egg, the chances of having a perfect egg are significantly decreased. It increases by having more eggs to work with. That is how IVF increases your chances of pregnancy statistically. So the goal of stimulation is to try to maximize the number of eggs that you have available in order to increase your chances of getting/finding the perfect egg/embryo.

Now there is a caveat to this. You don’t necessarily want too many eggs because over stimulation can not only cause a major illness, but the egg quality may suffer. This is where the “art” of IVF lies. It is up to the doctor to try to make an educated guess as to how much stimulation would be ideal for each patient. Under-stimulate and you decrease the chances. Over-stimulate and you also decrease the chances, as well as, risk making the patient sick. Doctors get better at making this decision through experience. And this is part of what makes each doctor and each clinic different.

We will continue this discussion soon with the next installment, "Step Two: Follicle Growth and Egg Maturation". Thank you for joining me today!

Edward J. Ramirez, M.D. F.A.C.O.G.
Medical Director, Monterey Bay IVF
Monterey, CA
http://www.montereybayivf.com/

A Step By Step Guide To The IVF Process: Overview

Dear Readers,
I get many  many questions regarding what In Vitro Fertilization (IVF) is and how it works that I thought I would share the information with my world-wide Blog audience. What you read here is what I also provide my patients with on a daily basis. I plan on going into some detail but in a way that is understandable to the normal (lay) audience, and not the medical or scientific one. I hope that this will not only clarify what you will go through, but explain why things are done a certain way and what the goals of each step are. I also want to convey that IVF is actually a replacement for some of the “natural” steps required to get pregnant and not some miraculous high tech fertility treatment that gets patients pregnant artificially, as many think it is. It is somewhat of a miracle that we can do as much as we can, but there are still lots of things/steps that we cannot do or influence. I hope this discussion will benefit you. This series will be posted over the next few weeks in installments.

OVERVIEW:
Before I begin explaining each step, let me give you an overview of IVF. As I mentioned earlier, IVF or "In Vitro Fertilization" is actually a replacement for the natural steps your body would go through in order to get pregnant, and it still relies on many of those natural steps to occur before you become pregnant. “In Vitro” means in the laboratory versus “In Vivo” which means in the body. As I’ll explain, IVF is not all done in the lab. Some parts of the process still are required to be in the body, so in actuality, it is both an “In Vitro” and “In Vivo” procedure.

There are basically nine steps that your body goes through in order to achieve a pregnancy:

(1) Your brain (hypothalamus and pituitary) sends a signal to the ovaries to stimulate the growth of a follicle and maturation of the egg within.

(2) The designated follicle grows, and the egg matures, until it reaches a critical size, whereby there is an LH surge to induce ovulation.

(3) The follicle surface ruptures and an egg is expelled with the rush of fluid within (ovulation) and enters a space behind the uterus called the culdesac, the lowest point in your abdomen.

(4) Through fluid motion (this part is not exactly known so it is my personal belief that this is how it happens), the egg contacts one or the other fimbria of the tube, which is hanging into the culdesac in its natural position, and now lies within this puddle of fluid. The egg is then brought into the tube by the fimbria and tubal motility.

(5) The egg moves into a part of the tube where, hopefully, the live sperm are waiting to attach to the egg, and then fertilization occurs.

(6) The fertilized egg slowly moves down the tube, dividing and forming into a blastocyst.

(7) The blastocyst then enters into the uterine cavity and settles there.

(8) The inner portion of the blastocyst then hatches out of the shell and attaches to the uterine lining.

(9) The uterine lining then engulfs the embryo, which is known as implantation and at this point bHCG begins to be produced.

These are the steps that your body goes through to get pregnant, but does not do it exactly or perfectly each month. That is why it may take several months before a human woman gets pregnant. IVF is basically accomplishing most of these steps for you, NOT doing some artificial process. Yes, it is not within your body, or at least some of it is not, but the same processes have to occur. If you know and understand IVF you can see that IVF basically accomplishes steps 1-7. Two steps then have to occur naturally for pregnancy to occur. So as you can see, IVF is still basically a “natural” process because it still relies on natural processes within your body.

In other words, we give fertility drugs to stimulate the ovaries to grow and mature eggs but the ovaries still have to pick up and process these hormones on their own, and growth and maturation of the eggs still have to occur naturally. We can put the egg and sperm together but fertilization still has to occur by itself. Even ICSI (intra cytoplasmic sperm injection) is only putting the sperm into the egg. The actual fertilization process, the merging of the egg nucleus and sperm nucleus, among other processes; still have to occur on their own. We cannot make that happen. We can put a grown embryo into the uterus but we cannot make it hatch out of its shell, attach to the uterine lining or make the lining engulf the embryo (implant). All of these steps are left up to nature or, as I tell my patients, are in God’s hands and the way He reminds me that I am but His humble servant. This keeps my head and ego from becoming too big!

Many patients are devastated when an IVF cycle fails, because they have the false belief that it is the ultimate and perfected technological way to become pregnant, and therefore works every time. It is certainly more technological but not even close to being the ultimate or perfect method, and it doesn’t work every time. For that reason we cannot achieve 100% pregnancy rates, and much research and technological advances still need to be developed before we will get there. Make no mistake, however, we have improved greatly since the first IVF success with Louise Brown, but that took years to occur as well.

Sixteen years ago when my wife and I did IVF, she was 37 years old, and her statistical chances were about 12-15% but now a 37 year old in my center has a 65% chance of pregnancy per cycle. We have improved greatly and come a long way. We can now help a couple acheive a pregnancy where previously there would have been no other option but adoption. IVF is certainly better than trying naturally because more steps are accomplished, whereas in natural cycles, the body does not always do each and every step correctly. For example, ovulation may occur but the egg may never find the fimbria so that month pregnancy will not occur. Just to put things in perspective, a 37 year old has a 5% chance of pregnancy per month of trying by natural means. When trying naturally, women have to keep trying for several months before a pregnancy occurs. In fact it will take 85% of women under 30 years old 8 to 12 months to achieve a pregnancy. In the same way, because IVF is just replicating the process, it can take several attempts before the body does its part of the process correctly. In my center 55% of patients (not adjusted for age), achieve pregnancy in their first attempt. Most patients will be pregnant by three attempts rather than the 12 months it may take to achieve a pregnancy naturally.

We will continue this discussion soon with the next installment, "Step One: Stimulation".

Thank you for joining me today!

Edward J. Ramirez, M.D. F.A.C.O.G.
Medical Director, Monterey Bay IVF
Monterey, CA
http://www.montereybayivf.com/

3-D Animation Of The IVF Process

A very nice 3-D animation on In Vitro Fertilization from Schering-Plough (2009).  It details the procedure as well as the fertilization process.

More Questions Regarding IVF and ICSI: Can I Have Twins, SET, And Other Post Retrieval And Transfer Questions

Question:

Hello again, this is S. with some follow-up questions from my earlier email.

Thanks for answering my questions. I have a few more. I know that obviously it depends upon the number of viable eggs removed during egg retrieval for IVF with ICSI but how many of the eggs would they try to fertilize and use at a time? How does it work with the frozen embryos? What are the chances of twins or triplets with this type of procedure? Can I decide if I want twins if I have more than 1 egg that is ready? After the egg is fertilized and put back do I have to be off of my feet for a time? How long does it take for the process to take place?

Sorry I'm just really unclear about all of this. Do I have to go back for ultrasounds afterwards and if so how often do I have follow up appts? Thanks again!

Answer:

Hello S.,

You're welcome to follow up with additional questions any time. I probably did not address the ICSI (intracytoplasmic sperm injection) question you had in your first email. With ICSI, all mature eggs are injected since not all with fertilize. If they only took a few and did ICSI, which I understand some clinics will do, that could impair the number of embryos you have to work with if they don't fertilize.

These are then allowed to divide over a 3-5 day period. An appropriate number is then chosen to transfer. That number is decided between you and your doctor. With frozen embryo transfers, the embryos are thawed, allowed to expand, and if they survive, are transferred. Usually the number thawed are the number transferred because re-freezing is not necessarily a good thing.

If three embryos are transferred, the risk of twins is about 35% and triplets less than 10%. This risk declines as the number of embryos transferred decreases. Because of the high pregnancy rates these days, many clinics have moved to doing a single embryo transfer, or SET, in order to minimize the risk of twins or more. This is based on new recommendations that have come out from the American Society for Reproductive Medicine and the Society for Advanced Reproductive Technology. There has been strong political pressure for IVF centers to reduce the incidence of a multiple gestation (twins or more). If you want twins, then you have to discuss this with your doctor and see if that is something the doctor feels comfortable with. Depending on your age, either two or three embryos would be transferred to try to achieve twins.

Once the embryos are transferred, you do not have to "rest" for any period of time. I have my patients do light activity for three days after the transfer to allow for implantation to take place, but I do not want them to be at bedrest. From that point it is a natural process and is the same that your body would go through if you were trying on your own.

In terms of your last two questions, these are answers that you should be getting directly from your IVF center. You pay them a lot of money for this procedure and they should be giving you almost royal treatment. If they are not, then you should demand it. The IVF process is a three week process, basically mimicking your natural process. The ovaries are stimulated, which takes 10-12 days, the eggs are retrieved at the mid-cycle and allowed to fertilized, then they are allowed to grow in culture for 3-5 days, then they are transferred back into the uterus. 8-10 days later a pregnancy test is done, which usually coincides with the end of the month if you started at the beginning of the month. (You should check out my website and I have an outline of the IVF process.) In the first 10-12 days, ultrasound and blood tests are done periodically to evaluate how you are responding, how many follicles you have, how big the follicles are and when to trigger for the retrieval. These ultrasounds can be done daily, every other day or farther apart depending on how big the follicles are and how close you are to the trigger day (generally as you get closer, the appointments get closer). The egg retrieval is usually done two days after the trigger (35-36 hours from the trigger injection) then the transfer is done 3-5 days after that.

Good Luck,

Edward J. Ramirez, M.D., FACOG

Executive Medical Director

The Fertility and Gynecology Center

Monterey Bay IVF Program

http://www.montereybayivf.com/

Monterey, California, U.S.A.

What Is In Vitro Fertilization?

In Vitro Fertilization is a high technology infertility treatment. Couples who have trouble conceiving, having failed to conceive for more than two years, often need to turn to a reproductive specialist who can evaluate and prepare them for this delicate procedure. With this procedure, most of the steps required to become pregnant are basically done outside the body in a specialized laboratory. The basic steps are as follows:

1. The ovary is stimulated to mature many egss. In a normal natural cycle, only one egg is matured an ovulated. With IVF, the goal is to have many, though not too many, eggs because the quality of eggs varies and we want to make sure we have at least one or two good quality eggs. The goal is not to have to repeat the IVF cycle again.

2. The ovary is evaluated by sequential ultrasound examinations to evaluate the response and measure the follicles. Follicles are what contain the eggs. They look like a black circle on ultrasound. The eggs are too small to be seen so we indirectly evaluate the egg by looking at the size of the follicle.

3. Once the follicles, that contain the eggs, are of appropriate size, indicating that the egg within is mature, the aspiration of the follicles is performed. This is a minor procedure whereby a needle is inserted through the vagina into the ovary under ultrasound guidance and the entire contest of the follicle, which includes the egg, is suctioned. Most clinics use some form of sedation for this because it can be painful. The eggs are aspirated into test tubes that the embryologist evaluates and isolates the eggs. These are then placed individually into petri dishes.

4. Sperm is either added to each egg (natural fertilization) or injected into each egg (ICSI) so that fertilization may occur. This will take 24 hours.

5. The eggs that fertilize are now placed into their individual petri dishes to allow for incubation. Incubation is done over a 3-5 day period. During this time, the fertilized egg will divide many times to evolve into a 6-8 cell embryo at 3 days or a blastocyst at 5 days. It's progress is monitored daily.

6. At 3 days from the retrieval or 5 days from the retrieval, the transfer is performed. The patient, with recommendations from the Physician, chooses which embryos to transfer and how many to transfer. These specific embryos are then isolated and placed into a very small and very flexible catheter in the embryology laboratory. The patient is placed into a transfer room, placed into the standard position for doing pap smears, and the cervix is prepared. The embryologist brings the embryo(s) into the transfer room and the Physician very gently slides the catheter into the uterus to a specific place. This location is verified by abdominal ultrasound examination. The embryo(s) is then deposited and the catheter gently and carefully removed. The embryologist will then take the catheter to the lab to verify that the embryo has not been re-aspirated.

7. The patient then takes medications to help support implantation of the embryo.

8. 8-12 days after the transfer, the pregnancy test is performed. If positive, we do pregnancy tests every-other day for four consecutive pregnancy tests. Since these tests measure the pregnancy hormone, BHCG, levels, we can see if the pregnany is progressing well by these four values.

9. If all goes well with the pregnancy tests, then the first ultrasound is scheduled in two weeks to confirm an intrauterine pregnancy and the number. This will be about 6 weeks gestational age based on the transfer date.

10. We then do a second ultrasound at 8 weeks gestation to verify a viable pregnancy.

At this point, the patient is then transferred to her Obstetrician to begin her prenatal care. For all infertility specialists this is a joyous occasion tempered by some sadness at not being able to follow the patient all the way through to delivery. When I began doing IVF, I was still practicing obstetrics and has the rare opportunity to deliver the babies that were conceived with our help. At this point in my practice career, I still do gynecology and I have much more time to focus on the infertility side of my practice as well. My patients benefit from still being able to receive gynecological advice as well as infertility advice.