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/

IVF Poor Responder With Endometriosis And Nightsweats

Question:

Hello, Dr.

I am from New Jersey , USA. and I have 2 questions for you.

I was diagnosed with stage 4 endometriosis in January of 2009. The surgeon removed all my endo in the operating room. Since the surgery I've been having nightsweats in the morning. From what I read from the internet, it can be due to the high estrogen level in my blood. I have 1.5cm cyst on my left ovary). Somehow the doctors I have seen so far don't know what is causing this.

1)What is the cause of my nightsweats?(I have it almost every morning)

My hormone levels were taken several times.

FSH=3.84 E2=92.3? in JULY 2009

FSH=10.4 E2=52 in October 2009

AMH=1.4 in November 2009

I tried IVF in October 2009 and failed.

I had only 1 immatrue oocyte at the retrieval even though on the ultrasound there were at least big 6-7 follicles. The doctor who retrieved the egg said the others could be chocolate cysts not real eggs. My RE used an antagonist protocol for IVF in October 2009. I had to take estradiol tablets for a week in the luteal phase just before the actual cycle.

Now I changed my RE, and she said she'll try something "flare protocol". This will take 2 months and I will have to start with estradiol patch for a week before the cycle. Isn't this almost similar to the antagonist protocol I tried before? How come the RE'S give me extra estrogen when they know that I have endometriosis? Wouldn't it make my cyst( 1.5cm cyst on my left ovary) grow bigger when they do this?

2)Will this micro flare protocol work for me? Thank you!

ANSWER:

Hello J. from the New Jersey,

First of all, "night sweats" can be from multiple causes such as decreased estrogen (menopause or ovarian dysfunction) or thyroid problems or cardiac problems.

In terms of your subsequent questions, there is some confusion. You had two FSH levels drawn, one was 3.84 and the other 10.4. Were these done on cycle day# 2 or 3 because that is when they need to done to interpret them correctly. From a fertility perspective, we want the FSH level to be less than 7 on cycle day #2 or 3. When it is higher, that signifies that the ovaries are "resistant" which means that they will not respond well to stimulation because they are not going to pick up the hormone adequately. As a woman ages, her ovaries become more and more resistant, but this can occur in younger ages as well. That may explain why you did not have very many follicles. Endometriosis does not and will not affect your response to stimulation. The problem with increasing estrogen is that endometriosis thrives and grows from estrogen, so that it can cause a recurrence of the endometriosis. Your first FSH level was actually very good and would indicate good ovarian response. In fact, you would probably not need too much medication (low protocol). Without having all the details of your IVF cycle, I cannot answer questions to it specifically, but your yield was very low. There could be multiple reasons for this.

I presume your new RE is going to try the "flare" protocol because you are a poor responder, low ovarian response. The flare is only another technique that is used to try to increase the egg yield, and is something different to try but has not shown any additional benefit is current studies. The antagonist protocol just means that an antagonist is used to suppress the ovaries instead of an agonist. The ovaries are suppressed so that they don't spontaneously ovulate or function on their own, so that the cycle can be better programmed, the ovaries can respond to stimulation better and don't short-circuit the stimulation. In addition, we don't want the ovaries to ovulate before we have the chance to retrieve the eggs. There is no difference between using an antagonist or agonist, in general, except there are less injections with the antagonist (3-4 vs 21). Antagonists are medications such as Ganerelix or Cetrotide and Agonist is Lupron.

I would advise that you not worry so much about your endometriosis. IVF is the treatment of choice and bypasses the endometriosis. If you become pregnant, pregnancy is a GREAT treatment for endometriosis so that is the goal. Quite often, Endo pain decreases dramatically after a successful pregnancy.

Your first cycle did not do very well because of the poor stimulation (which could be due to not enough medications) and low retrieval number. The fact that the egg was immature could be because the egg was not given enough time to mature ie. you were triggered too soon. So, I would advise that you keep trying. Your RE will adjust your protocol to give you the best chance of success. Studies show good cumulative pregnancy rates if a patient keeps trying, even in older women.

Good Luck,

Edward J. Ramirez, M.D., FACOG

Executive Medical Director

The Fertility and Gynecology Center

Monterey Bay IVF Program

www.montereybayivf.com

Chances Of Conceiving At 39 After TTC For Three Years: IUI Cycles Cancelled Unnecessarily

Question:

I am 39 years old and have been TTC (trying to conceive) for 3 years and 4 months now. I had a Laparoscopy done in March 2007 which showed healthy patent tubes, clear ovaries and a normal uterus. I normally have irregular periods ranging in length from 32 days to sometimes 42 days but in general around every 35 days. I usually get my positive on an OPK around day 21.After trying naturally for 1.5 years we went to a fertility clinic where I was put on Clomid 100mg with mid-cycle scanning plus trigger shot and I conceived on my second cycle but unfortunately miscarried in January 2008 at 10 weeks. I took a break of 3 cycles after the miscarriage and then went back on Clomid for 4 months. On each of the clomid cycles I produced 2 to 3 dominant follicles but each cycle resulted in a negative result. I took a break after Clomid for another few cycles and then started into IUI (intra-uterine insemination) just before Xmas 08.

On my first IUI cycle I was on Gonal F 75iu and after 7 days of injecting the cycle was cancelled because I produced 8 dominant follicles. My meds were then changed and I was put onto Purgeon 50iu for 2 further IUI cycles and on each of these cycles I produced 3 dominant follicles and my husbands sample was good yet both cycles produced a negative result. My most recent IUI cycle (June 09) had to be cancelled again as I produced 5 dominant follicles.

My question to you is this? Is it just bad luck that I haven't conceived since my miscarriage or is my age a factor? I had a day 3 hormone profile done in April 2009 and my results were as follows: FSH 5.9, LH 3, Oestradiol 22 pg/mg - do these results look ok to you? Is there any chance my eggs may be of poor quality or would my day 3 results have reflected that?

We still have 2 more IUI cycles to complete and failing those we will be moving to IVF (in vitro fertilization), but I thought I would ask your advice in the meantime.

I hope you can help.

Answer:

Hello,

The hurdle you seem to be facing is probably due to poor egg quality as a result of age. Your natural chances of pregnancy at 39 is 1% per month/12% per year and 3-5% per month with IUI. Not very good odds. This is strictly due to age. Your miscarriage was probably age related as well, as the miscarriage rate increases with increasing age due to spontaneous chromosomal abnormalities (i.e. spontaneous breaks in the chromosomes as they are dividing).

You have been wasting a lot of time and now it is time to become more aggressive if you want to have a child. You have done more than enough Clomid and IUI cycles (six IUI cycles are too many! 3 - 4 cycles are what are recommended before proceeding to IVF). I would recommend that you move directly to IVF as soon as you can, since you are stimulating well. Pregnancy rates with IVF are 50-60% (it is 71% so far in 2009 in our clinic), but this will go down to 27-30% at age 40. Your lab results are good and show that you still have good ovarian function, but that is not a measure of egg quality. Egg quality is the issue. I often tell my patients that with IUI's it's not the sperm that are an issue it's the egg factor. We need to have one good egg to acheive that pregnancy. Because of that, I allow more eggs to ovulate in an IUI cycle (5-8) if the patient is over 37 years old. I would not have cancelled the cycle that you just went through. I have never had a problem with multiple pregnancies since the chances of a multiple are minimal in the 37 plus age group. If a patient with your history proceeds to IVF I will transfer 5-7 embryos.

I hope this helps,

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.

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PCOS Patient Beginning IVF Treatment, What Questions Should She Ask Her Doctor?

Question:

I have PCOS and I've started IVF (in vitro fertilization). I have concerns because I don't really understand what is going on. They say they want my estrogen level up and that it is going in the right direction but they keep increasing my medication. Why? How can I tell if it is working?

I have started since January 22nd. Is it normal to continue and what questions do I ask my doctor to see if my chances remain good?

Answer:

Thank you for your question, it's always good to know exactly what is going on so don't hesitate to ask your doctor as many questions as you can. Take a pad of paper with you and write down the answers if you need to.

Let me begin with our protocol at our clinic for patients such as yourself. With PCOS patients we have to be very careful because if you over-respond, you could develop and illness called ovarian hyperstimulation syndrome (OHSS). Many IVF programs use a protocol called a "step-up" protocol whereby you start on a lower dose and it is slowly increased based on your estradiol levels and ovarian response. They should be doing ultrasounds at the same time to see how many follicles are growing and what size the are. Once it looks like you are stimulating, the dose is usually kept constant until the follicles reach the appropriate size for retrieval (18-24 mms).

If you started on the 22nd of January, your cycle is definitely going kind of slow. Most patients will respond within 10-16 days. I would presume you are getting closer.

If your doctor is not explaining these things, then you need to be more insistant that you want an explanation at each visit. Most doctors, or their respective nurses, will then explain how things are going and what the goal and timeline is. We can usually predict, within a day or two, when you will be ready to retrieve.

What you should ask is:

1. How am I doing?

2. Am I responding to this dose or protocol? Are my follicles increasing?

3. How many growing follicles do I have?

4. When are you expecting me to be ready to retrieve? Transfer? Explain that you need to plan the date.

5. What if I have too many follicles? Will you cancel me? Do you Coast? Will you trigger with HCG or Lupron? (Lupron is what I use because it has a shorter duration of action and has been shown to decrease the incidence of OHSS if there are too many follicles and the estradiol is too high (over 4000).

6. What is my estradiol level? (the goal is to have a level of 2000-4000 at the point that the follicles are ready for retrieval. If the estradiol level is over 4000, then the risk for OHSS is higher).

I hope this gives you enough questions to ask for now. Keep informed and stay in touch! Good luck!

Sincerely,

Edward J. Ramirez, M.D.

Executive Medical Director

The Fertility and Gynecology Center

Monterey Bay IVF program

http://www.montereybayivf.com/

Monterey, California, U.S.A.

Birth Control pills before IVF

Question:

Hi Dr Ramirez,
I am 42 y/o with an fsh of 6. I am to start IVF soon. Before I start stimming, my RE wants to put me on birth control pills for one month .

Is there any benefit to being on BCP for 1 whole month before
IVF? I feel like this is delaying my Ivf for too long.

Thank you, Lisa from Tustin.

Answer:
Hello Lisa from the U.S.,
　
You certainly don't need to go on the birth control pill, however, previous studies have shown it to be an advantage for several reasons:

1. It puts your ovaries in a stasis mode so that it will be more responsive to stimulation.
2. It allows us to take control of your ovaries more tightly when the stimulation begins
3. It allows us to program your cycle.

I too use BCP prior to starting IVF for the above reasons. Other than having to wait a little, it has no other detrimental effects. If you trust your IVF doctor, then you need to trust him completely so that you will get the best possible outcome. Your age is already a significant factor, and we do all that we can to try and overcome this and have developed specific protocols for that. The best you can do is follow your docs advice and not try to second guess him, especially via the internet (which has too much nonspecific information). If you don't trust him/her, then you should find a doc and/or clinic that you have complete trust in. After all, it is a very expensive process you are going through.

Good luck,

Edward J. Ramirez, M.D., FACOG
Executive Medical Director
The Fertility and Gynecology Center
Monterey Bay IVF Program
http://www.blogger.com/www.montereybayivf.com

Monterey, California, U.S.A.

for additional information check out my blog at http://womenshealthandfertility.blogspot.com/ check me out on facebook and twitter with me at @montereybayivf

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.