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/

39 Yr Old TTC With Previous Miscarriage: Clomid Vs. Gonadotropins? Flare Vs. Antagonist Protocol?

Question:

Dear Doctor,

I am from India. I am 39. I had two missed abortions at 36 and 37 both in the eighth week and after the heart beat was felt.After leaving a gap of four months I have been trying to conceive naturally for 14 months without any result.

Subsequently I started Clomid 100 mg (day 3-7) at the advice of doctor.I did 3 cycles with Clomid out of which I got two follicles of ovulatory size (more than 18mm) in two of the cycles and one follicle (20mm) in one of the cycles.I did not conceive. My FSH and other hormones are normal.

I consulted a IVF specialist who examined me and said that my ovary volume is good and said that she will go for two cycles of IUI, if they are not successful she will go for IVF.

In my first cycle of IUI, the doctor did a trans-vaginal ultra sound on day 2 and gave the following medications from day 2 to day 5 (1) Suprefact 10 markings in the insulin syringe with 100 markings (BD 100 mark syringe) (between 1 to 2 pm daily)(2) GMH (human menopausal Gonadotropins (FSH+LH)) 225 IU (between 7-9 pm daily)

On day 6 she checked and told me that there is no response and the follicles have not grown.She changed the medication to GMH 375 IU per day on day 6 and day7 (between 7-9 pm daily) (She stopped Suprefact)

On day 8, she checked and told me that the follicles have not grown and advised cancellation of the cycle.Further she said that my follicles are not good enough for future trials of IVF or IUI and advised IVF with donor egg.

I asked her how I could get two ovulatory sized follicles (above 18mm) with Clomid in two of my three monitored cycles but nothing in this cycle and she is ruling out the possibility of the future trials. Her answer was that with Clomid or Letrozole even empty follicles grow and give a false impression that the follicles are growing and ovulating. But with Gonadotropins only follicles with good eggs will grow and that is the reason why my follicles did not grow with Gonadotropins. Is the above statement about Clomid and Gonadotropins correct. I will be grateful for your answer. R. from India

Answer:

Hello R. from India,

The simple answer is "NO. Her explanation is NOT correct." The gonadotropins are more effective than Clomid or Letrozole in recruiting and growing follicles because it IS the hormone the brain sends to the ovary for that purpose. Clomid and Letrozole work by an indirect method to cause the brain to increse its FSH output.

Also, she is NOT correct that gonadotropins only grow "good" follicles whereas Clomid grows "false" follicles. This explanation is made up and not scientific at all. In fact, no such thing exists. Sorry.I am not sure why your doctor cancelled your cycle. If the CD#8 ultrasound (which is early) or Estradiol level are showing a low response, the proper protocol is to continue going. Sometimes the follicle can grow slower. I have had patients get up to 21 days before ovulation occurs. In addition, the FSH should be increased if the stimulation is slow. I do not expect to have ovulatory sized follicles until at least CD#12.

I agree with you that since you stimulated with Clomid previously, you should readily stimulate with Gonadotropins as well. Maybe you should find a new IVF specialist. One thing to keep in mind, however, although your chances are still good at 39 years old, your previous miscarriage show what part of the problem is, which is that the eggs have aged and more and more of them are not of good quality. As a result, there is a higher chance of abnormal embryos which increases the miscarriage rate. IVF should help that because it increases the amount of eggs that are retrieved which in turn increases the possibility of finding an egg that is still good quality. You probably will need a high dose protocol using up to 600IU of FSH. IVF is definitely the way to go!

Follow-Up Question:

Dear Doctor,Thanks for your kind advice.The IVF specialist said the protocol given to me is the flare protocol meant for poor responders. Is that so? Then I do not understand why I did not respond to the protocol.

During my Clomid cycles my follicles reach ovulatory size by day 12. Do you think the poor response in the Gonadotropins cycle could be due the Suprefact Injection which was given from day 2 to day 5 along with Gonadotropins? Also kindly advise if it is necessary to add Suprefact or lupron early in the cycle or giving only FSH will help. Besides doctors here give Gonadotropins (FSH+LH) not Recombinant FSH. Is it better to give Recombinant FSH?

Kindly advise. R.

Follow-Up Answer:

Hello Again,

I do not like to comment on protocol specifics because there is no one way to do things. Please keep that in mind as I answer your questions. The "flare" protocol is one type of protocol used to stimulate the ovaries with IVF. It has no advantage over other protocols, but sometimes is used in patients that are designated as "poor responders". Studies have not shown it to be any better. I personally do not use the flare protocol. My preference is to use an antogonist protocol so that there is no suppression of the ovaries during the initial recruit phase, but I am in the minority in terms of centers that use this type of protocol.

In terms of your stimulation, I still think that a higher amount of medication may be warranted.

Both Suprefact and Lupron are medications called "gonadotropin agonists" and what they do is suppress the brain from producing FSH and LH.Gonadotropins are either pure FSH, pure LH or mixed FSH/LH. This is the name for that class of medications. Some IVF clinics only use FSH, some will use a mixed protocol of FSH and FSH/LH. Examples are Follistim (pure FSH) and Menopur (FSH/LH). My preference is the mixed protocol but many clinics will use FSH only protocols and some will use only the mixed FSH/LH medications. Studies have not show a necessary benefit of any of these protocols so they cannot be compared or criticized. Each doctor and/or clinic has their preferences. The most important aspect is how much FSH is being given because FSH (follicle stimulating hormone) is the hormone that stimulates follicle growth in the ovaries. Also, Natural vs Recombinant forms are equal. There is no difference.

Wishing you good luck with your TTC journey,

Dr. Edward J. Ramirez, M.D., FACOG
Executive Medical Director
The Fertility and Gynecology Center
Monterey Bay IVF Program
www.montereybayivf.com
Monterey, California, U.S.A.

Why Do I Need HCG Injections After Ovulation During IUI Cycle?

Question:

Dr. Ramirez,

My husband and I have been trying to start our family for a few years. I have been pregnant and miscarried 3 times, but is has been over a year and a half since my last miscarriage. I am seeing a Reproductive Endocrinologist and their diagnosis for not getting pregnant again is unexplained infertility. We have are trying the IUI process now using Letrozole and I have also been given a prescription to do HCG injections on days 3, 6, and 9 past my LH surge. I am not finding very much information about using HCG after ovulation. I know their reasoning is to supplement my progesterone... but not sure why then, they don't just use progesterone? Please help!

Thank you! G. from Colorado

Answer:

Hello G. from the U.S. (Colorado),

HCG (human chorionic gonadotropin) injections can be used to support the luteal phase in place of progesterone and there is nothing wrong with that protocol. Most don't use that method because you have to take it as injections and the medication is considerably more expensive. There are many progesterone alternatives such as Crinone, Endometrin, Prometrium that can be used vaginally as a supplement. You should ask your doctor why they don't just use a progesterone supplement.

The other question to ask is "what are they treating or trying to achieve"? Do they suspect that your miscarriages are due to a luteal phase defect i.e. decreased progesterone? In that case testing by an end of cycle endometrial biopsy for dating and/or b-integrin would have diagnosed luteal phase defect and your diagnosis would not be "unexplained infertility." I am not a strong believer in "unexplained infertility" as a real entity. I think it is more like undiagnosed infertility. The cause just has not been found because either a test has not been done to find it or doesn't exist. Often we find that many of these cases of fertilization failures or defects with the sperm (found at the time of IVF) or endometriosis found on laparoscopy. Sometimes age is the problem as well leading to poor embryo quality.

Your question is a good one and you should ask your doctor. Be sure they explain everything to you!

Good Luck,
Dr. Edward J. Ramirez, M.D., FACOG
Executive Medical Director
The Fertility and Gynecology Center
Monterey Bay IVF Program
www.montereybayivf.com
Monterey, California, U.S.A.

Comment: Thank you so much... for all of your information and quick response! I will follow up with my doctor.

Marathon Runner Has Amenorrhea And Is Trying To Conceive: May Need Gonadotropins

Question:

Hi, I am a 25 year old, PhD student and I am a competitive marathoner. My husband and I would like to get pregnant over the next 8 months. I was on the pill until last April, when I went off the pill. I had been on the pill for nine years and my cycle was regular before I went on the pill. During the years I was taking the pill my cycle was fairly regular, light and short in duration, but still regular. I have not had a period since I went off the pill 6 months ago. I am 5 7' and about 108lbs.

I have met with my Dr and she suggested that I go on the pill for a month so I can at least have my period to shed my uterine wall. Then she said if my period does not stick around I may need to gain a bit of body fat. I have also done blood work to make sure there are no other issues. Do you think that I will have to gain weight before I can get pregnant? Or can I just cut back on my training and lose some muscle mass and avoid gaining weight? Also can I get pregnant with my period being absent? Thanks! A. from Canada

Answer:

Hello A. from Canada,

The problem with competitive runners is that they lose a tremendous amount of body fat and so cannot produce hormones. They develop a disorder called hypogonadotropin hypogonadism. For this reason, they do not cycle normally. The birth control pill artificially takes over ovarian function and so you have an artificial period, but it is not because the ovaries are working. Having stopped the BCP (birth control pill), you are now at your normal state and your ovaries are not working. This is the reason your doctor recommended that you gain fat weight. Hormones are made from cholesterol. It is the chemical basis for all hormones. Unless you gain fat weight, you will not ovulate naturally and so will be unable to get pregnant.

I would not recommend another course of BCP's at this time, however. You can wait and see if you get a period, which you only need to have every three months at a minimum, and if it does not occur by itself, then you can take progesterone for 5 days to start the period. That way you will have the opportunity to become pregnant should ovulation occur.

The only other option for getting you pregnant would be to give you the hormones that your brain is not making to stimulate the ovaries. This is a medication called a gonadotropin. We would use a medicine called Menopur that is FSH and LH hormone. These hormones stimulate the ovaries to ovulate. You cannot use Clomid or Femara because the hypothalamus needs to be working for these to work and yours is not working.

Although there are many reasons for primary & secondary amenorrhea (absence of menstruation), I believe yours is due to your pattern of exercise and has a good chance of being corrected. See the Mayo Clinic website for more information: "Amenorrhea: Causes".

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.

Infertility Patient Worried About Side-Effects From Lupron Trigger Shot

Question:

Hello. I am about to undergo a cycle in which we will use Lupron as a trigger. I recently have read frightening stories of women who have had long-term, debilitating physical and cognitive side effects after using Lupron even once (usually to treat medical conditions). I am wondering if using Lupron as trigger shot could subject me to the same permanent, debilitating side effects. (I do have endometriosis, and I don't know if that makes one more susceptible to the dangerous effects of this drug)?

Thank You. L. From the U.S.

Answer:

Hello L. from the U.S.,

The lupron you are reading about is for the treatment of endometriosis and not the same dose that is used for the trigger. The endometriosis dosage is 3.75 mg or 11.25 mg, whereas the trigger dose is 0.5 mg. There are no known serious side effects from the Lupron trigger. Some mild side-effects might include: hot flashes, vaginal dryness, and headaches. If these side effects occur they will usually resolve after you start taking gonadotropins. After ovulation is triggered, there is no further need to continue on Lupron.

Besides, I and many other docs use full-dose Lupron for the treatment of endometriosis all the time and I have yet to have a patient with the horror stories that are published on the internet. Keep in mind that internet stories are not edited or filtered so you have to believe them carefully and with a little reservation.

Good Luck and don't worry,

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.

Injectables with IVF - Is Metformin Indicated?

Question:

Hello-I am from the US and I am 33 years old. My husband is 34. We have been trying for almost a year and saw an RE. I was told I have a fibroid that I am having removed laparoscopically the end of March. I was told by my doctor that since my huband's sperm is below where it needs to be (both count and motility) that I can begin IVF (in vitro fertilization) with injectable treatments about 2 cycles after the surgery. Which drugs are used? She mentioned ICSI (intracytoplasmic sperm injection) also. Will I have side effects from these injectable medications and if so what will they possibly be?

She also mentioned my possibly taking Metformin to try to enhance the IVF to work. I have heard mixed reviews on this medication actually working and was wondering what your take is on it. Can you please advise? I have heard of some unpleasant side effects from Metformin/Glucophage so I am not sure what to do.

What is the chance of IVF or IVF with ICSI to work? She said around 50% which I believe is much better than the 20% chance it would be which we were told if it would happen naturally. Is this true? I have had an ultrasound with saline and an HSG with dye- both came back fine other than the fibroid. I have been put on Synthroid to regulate my thyroid which I was told was slightly elevated. I am also on the birth control pill until I have the surgery to remove the fibroid the end of next month. I have had several blood tests testing my FSH, LH, Prolactin, Estradoil, glucose, etc all which have been normal results. Any additional info. you could provide would be appreciated.

Thanks!- S.

Answer:

Hello S.,

Let me answer your questions sequentially to make it easier:

1. Lots of different medications are used with IVF cycles. This is a question best answered by your doctor, or her IVf coordinator. Each doctor has different protocols, depending on their preferences and how they are trained. The main medications are called gonadotropins and are synthetic versions of the FSH and LH that your brain produces to stimulate the ovary to ovulate. We give higher dosages of these medications in order to make the ovary produce/prepare more that one egg. The goal with IVF, in order to maximize the chances of pregnancy, is to get more than one egg out. Preferably 10-20. This is because not every egg is a good egg.

2. Most women tolerate these medications very well since they are essentially the same as the hormones your body produces. Of course, all medications have side effects and each person is different and can react differently to each medication. The biggest side effect of these stimulation drugs is that the ovaries will enlarge and become tender because so many eggs are being recruited. In addition, some patients will feel bloated. If the ovaries are stimulated too strongly, or the ovaries respond too strongly, you can develop an illness called "hyperstimulation syndrome." This is a very serious and dangerous problem that has to be prevented and managed appropriately. If you have PCO, which I suspect you might have since your doctor recommended Metformin, you are at increased risk for hyperstimulation syndrome. You need to discuss this with your doctor and ask her what she does to prevent this. There are methods that we use to prevent this from occurring such as using lower dosage protocols, close monitoring of blood levels, coasting or drifting if necessary, antagonist protocol, triggering with Lupron instead of HCG.3. Metformin is only indicated in 30-40% of patients that have PCOD. It is NOT indicated in all patients AND, it takes 6-8 months to work so starting it with an IVF cycle is not appropriate. I would not recommend it unless you have been found to have insulin resistance by blood testing.

4. In terms of IVF working, you have a 50-70% chance of pregnancy with each IVF cycle in your age group. You should ask you doctor what her statistic is. Pregnancy rates do vary depending on the clinic and the doctor, so be sure to check both out.5. With a severe sperm disorder, the chances of pregnancy would be much less than 20%. Your natural chances of pregnancy at your age, if there were absolutely no problems, would be about 15% per month of trying. With the sperm problem it would drop it to less than 10%. That is why IVF is the treatment of choice. With IVF and ICSI, we had a 75% pregnancy rate per transfer in 2009. Most clinics are reaching that level as well.

I hope this information helps. Be sure to ask lots of questions. You will be paying a lot of money for this treatment and you should make sure you have had ALL your questions answered to your satisfaction. This type of procedure is like shopping at Saks 5th Avenue. You should demand and get the highest level of service!

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.

More On Luteal Phase Defect

After the January 10th Q & A regarding Luteal Phase Defect while on Clomid, I received another question which I would like to include to further enlighten those who struggle with this problem and are not receiving an adequate explanation or treatment for it..

Question:

Hi Dr. Ramirez, My question is that I have a LP (luteal phase) of 8 days. I ovulate on day 23. I always spot beginning of cycle, mid cycle and after cycle for 2-4 days. I started taking 100mg of B6 vitamins last month and progesterone cream immediately after ovulation. Last month, I began spotting two days post-O (I stopped the cream at that time).

The problem is my spotting has increased (menstruation CD 1-9, spotting CD 10, 11, 15-18, 25-31 and menstruating during new CD 1-10). What can I do about this? I am taking my BBT (temps are elevated post-O, I am also taking OPKs so I know I am ovulating. My Dr has done pelvic u/s (ultrasound), ovarian u/s, etc. everything is normal, so are hormone levels. Is there anything I can do on my own to increase my chances of conception? Or is there anything I can bring to my Dr.'s attention? Help! Thx..

Answer:

Thank you for your question. I would like to explain a little about what the luteal phase is before addressing your concerns. The luteal phase is one of the most exact parts of a woman's cycle, if she is ovulatory. It is the second half of the menstrual cycle after ovulation. The corpus luteum secretes progesterone which prepares the endometrium for the implantation of an embryo. A normal luteal phase is 14 days. However, there is a disorder of the luteal phase whereby this part is short. It is called a luteal phase defect. It sounds like you may have a luteal phase defect, which is cuased by hormonal asynchrony. Hence the abnormal bleeding. The uterine lining (endometrium) is very dependant on appropriate hormonal synchrony to keep it stable. If it is unstable, it breaks apart, hence the bleeding at odd times during the month.

The luteal phase can be supported by using supplemental progesterone. It is generally used beginning on cycle day #16 and extending for two weeks. Of course, a pregnancy test will have to be done because the period may be suppressed. If it is positive, you continue the progesterone until 10 - 12 weeks gestational age.

However, based on your scenario, LPD is not the only problem. You may actually need to go an an ovulation induction protocol with Clomid, Latrezole or Gonadotropins in addition to the progesterone supplementation. These medications will help your ovary to perform normally and synchronize the hormonal situation. It may also alleviate the luteal phase defect.

I hope this helps!

Edward J. Ramirez, MD, FACOG

Executive Medical Director

Fertility and Gynecology Center

Monterey Bay IVF

http://www.montereybayivf.com/

Monterey, CA