Ovulation Induction With Follistim Keeps Failing & Estradiol Remains Low

Question:

We are currently TTC our 2nd baby. My daughter who is 2 was conceived on our second cycle of follistim75iu. We are currently on our 4th cycle of Follistim 75iu. Each cycle I'm told my estradiol is low and they end up increasing my dose of Follistim to 150 iu and even by the time I trigger it's still on the low side.

I understand that ideally estradiol should be 200-250per mature follicle. But this cycle it is 110 with follicle sizes of a 14 and a11. So at this point of my cycle what should it be since they are not mature follicles? Also last cycle they had me do hcg booster shots after ovulation because I had a low estradiol (it was 80) 7 days after ovulation the cycle prior. The boosters helped increase my estradiol to 354. My concern is do the boosters really help achieve pregnancy or are they just masking a bigger problem?? Thanks in advance, S. from Pennsylvania, U.S.A.

Answer:

Hello S. from the U.S. (Pennsylvania),

There is no fixed protocol when using gonadotropins such as Follistim. Basically, these medications are the hormone FSH which is the hormone that your brain produces to stimulate the ovary to produce a mature follicle for ovulation. If the amount of hormone is insufficient to do this, then it has to be increased and this is usually done on an incremental basis. Please see how I do ovulation inductions here: "Ovulation Induction".

For example, it may be started at 75IU but every three to four days, and estradiol level can be drawn and checked to see if it is increasing. If it is increasing then starting on cycle day #9, an ultrasound is done to evaluate the ovaries and see how many follicles are present, what their sizes are and when to trigger. In your case it sounds like that is not being done. For some reason, your doctor is fixated on keeping the same dosage. I'm not sure I understand why.

You are correct about the estradiol level of a mature follicle. If your follicle does not reach the mature size18-20 mms, then the estradiol level will not reach the appropriate size either. Basically the follicle increases in size by increasing the number of cells. Think of it as a chain of cells in a circle. These cells to increase in size, rather, more cells are added to the chain and each cell produces some estradiol. That is why as the follicle increases, more estradiol is emitted. In order for the follicles to grow more cells, increasing amounts of FSH is required. So, if your doctor stops the dosage at 150IU and it is not enough FSH to stimulate follicular growth, then nothing will happen. He needs to keep increasing the dosage until the follicle grows appropriately. Once the follicle reaches the ovulatory size of 18-24 mms, then ovulation can be triggered with HCG (a substitute for the LH surge you would produce in a natural cycle).

The "HCG booster shots" do nothing to help the estradiol rise. Rather, this was merely a coincidence. The growing follicle causes the increased estradiol. The HCG can be used after ovulation to help prime the enodmetrial lining for ovulation. Some clinics use this instead of progesterone. It is also used to trigger ovulation, as I've mentioned previously.

Based on the information you have given me, I'm wondering if you are seeing the right doctor. Your doctor may be comfortable with using Follistim, but is he really an infertility specialist i.e. have a thorough knowledge of the gonadotropins to use them for IVF (in vitro fertilization) if he has to? There are many Ob/Gyn docs that feel comfortable with ovulation induction and use gonadotropins like Follistim on a protocol basis, but in reality, don't know what they are doing. Could you be in that type of situation? Maybe it is time for a second opinion. The best way to find an infertility specialist is to simply ask the clinic or doctor, "Do you do IVF?".

Good Luck,
Dr. 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.

Secondary Infertility: Decreased Ovarian Reserve And Low Morphology May Be The Culprits

Hello,

I just turned 33 and I have one beautiful 18 mo little girl who is the love of my life. She was conceived on our 3rd iui using 5mg of Femara. My husband has low morphology (6%) and I have no regular periods. We both exercise / eat as we should and have no other health issues. We are considered unexplained infertility.

For the past 6mos we have been trying to conceive. I just had a large polyp removed and my fsh levels were tested. 2 1/2 years ago they were 7.0. 6 weeks ago they were 12.1. We are trying to figure out what to do next. We definitely want another child (And we would be open to 3). My questions are:

1) What do you recommend for medication? Is Femera a good starting point? Should we use the same dosage or higher?

2) Should we try an IUI or go straight to IVF?

3) Are there any "rules of thumb" for why FSH increases and how quickly it increases? I've heard stress can impact it. Thanks in advance for your help. C. from Washington State

Answer:

Hello C. from the U.S.,

Congratulations on achieving your first baby relatively easily. You do not have "unexplained" infertility as you have two reasons: sperm abnormality/low motility and irregular periods (ovulation dysfunction). Those are reasons enough to prevent spontaneous pregnancies.

In terms of your FSH level, I have to presume that it was drawn on cycle day #2 or 3, because that is the proper time to do this test and the only way that it an be interpreted. If it was, the elevated FSh level of 12.1 is not a good finding. This is called "decreased ovarian reserve", which basically means that your ovaries will be more resistant and less productive if stimulated with fertility medications. It is not an indication of ovarian function, but is somewhat of a time clock. Once the FSH level reaches 15, most IVF clinics will require you to use donor eggs. When it reaches 20, it means you are in menopause, which in your young age would be classified as premature ovarian failure. So from a time perspective, that means you don't have a lot of time to waste.

Certainly IUI is an option for you, and somewhat reasonable since it worked before. The FSH level will have no bearing on its chances of success. Chances of success depends on age and the sperm problem. If you wanted to do IUI first, I would limit it to no more than 4 attempts. You can use Femara, Clomid or injectables for these attempts and even alternate them, but don't waste a lot of time. Keep in mind that the chances of pregnancy with IUI in your age group is 20% per attempt. By four attempts you should be pregnant, otherwise the statistical chances drop dramatically after that.

If the IUI's fail, then you need to progress aggressively and quickly, especially if you want to have more than one more child. In that case I would recommend proceeding to IVF with ICSI. This will give you a 74% chance of pregnancy per attempt in my clinic (and is the treatment level that most infertility specialists would recommend with an FSH level above 10. Most would recommend not even to try the IUI).

I can't tell you why the fSH is elevated. That is an unknown.

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.

Use Of Prednisone And Lovenox For IVF Cycle With Donor Eggs: How Long?

Question:

Dr. Ramirez:

I am a 44-yr old with a history of numerous IVF attempts. Miraculously, cycle 1 (2007) with my own egg (yes, only one egg was retrieved) resulted in a healthy baby. 1 additional IVF attempt (2009) with my own egg - unsuccessful. Subsequently, 4 IVF attempts with two different donors (some fresh, some frozen cycles) were also unsuccessful. With each attempt, the blastocysts were high-grade, and other recipients of same donor's eggs resulted in pregnancies.

For my current cycle, which begins this week, we will be using a cryopreserved embryo, and physician is adding two medications: Prednisolone 25 mg daily, starting 10 days before transfer, and Lovenox 40mg daily, starting 2 days prior to transfer. If successful, plan is to continue both meds (along with Estrogen and Progesterone injections) for the first trimester. This seems like an extremely large dose of prednisolone and lengthy duration. I am concerned about the potential side effects on me, as well as the developing fetus, assuming a positive outcome. Do you have any experience and/or information regarding the prednisolone and Lovenox? Thank you, C. from the U.S.

Answer:

Hello C. from the U.S.,

In my patients that fail 2 IVF cycles, I automatically add prednisone, Heparin (lovenox can be used as well). All my IVF patients get the prednisone (I use medrol), low dose aspirin, progesterone and estrogen, so in reality the only thing that is new is the heparin/lovenox. Because of the potential effects on the developing fetus, I do not use the prednisone longer that the first pregnancy test. The heparin, aspirin, progesterone and estrogen are continued until the patient reaches 10 weeks gestational age. In patients that have a history of recurrent miscarriages, I will sometimes continue the medications until 12 weeks gestational age.

I start the heparin (lovenox) with the start of the IVF cycle, just like I do with the prednisone and aspirin.

Incidentally, your experience with a pregnancy in the first IVF cycle with only one embryo transferred, at the age of 40, is the reason why I DON'T ever cancel a cycle if there is only 1-3 follicles. My belief is that this one egg may lead to the one perfect embryo left and I would hate to lose the opportunity to get a pregnancy from it. It may be a lower chance, but it is still the best chance that you've got. So I am glad to hear that your docs continued the cycle and did not cancel it like so many do!

Good luck with your upcoming donor cycle.

Dr. 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.

Comment: Thank you very much for your expert opinion and extremely timely response! I greatly appreciate your time and expertise.

Progesterone Supplementation During An IUI Cycle

Question:

Hello Doctor,

I have been TTC since the past 15 months, I have irregular menstrual cycles. My husband has no fertility issues. I have been undergoing treatment - clomid, ovidrel followed by IUI (intra uterine insemination) since the past 3 months.

My luteal phase is 14 days long. I get a .8/1 degree increase in temperature the day after ovulation.This time ( 3rd IUI ), my RE asked me to take a vaginal progesterone supplement 2 days after the IUI.

There have been no tests performed to find if there is Luteal phase defect. I am scared/apprehensive about taking the progesterone supplements and I think my hormonal levels should be okay as my LP is 14 days long. Can you advise ? Your advise/suggestion on this matter will be much appreciated. Thanks in advance ! S. from California

Answer:

Hello S. from the U.S. (California),

I prescribe progesterone to ALL my infertility patients undergoing treatment. It is an easy medication to use, will cover any possible deficits in progesterone level that could impair implantation or continuation of the pregnancy and has no side effects. I think you should have been doing this from the first IUI treatment. I usually start it the day after the IUI.

You are correct that you don't have a luteal phase defect because your luteal phase is 14 days, but the additional progesterone won't hurt and it will make sure that you have adequate b-Integrin development, which is what is needed for implantation at the cellular level.

Good Luck,
Dr. 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.

After 11 IUI's, Canadian Fails 1st IVF cycle: Poor Embryos, Bleeding Or Implantation Failure?

Question:

Dear Dr. Ramirez,

I'm writing to you from Toronto, Canada. Thank you in advance for your answer!

My husband and I are both 37 years old. I was diagnosed with mild PCOS due to the shape of my ovary (pearl-like follicles) and irregular cycle (28-36 days), and as result was prescribed Metformin. My husband has low sperm count and motility. Last year I was pregnant after 5 attempts of IUI (intra uterine insemination), but unfortunately ended up in miscarriage due to chromosome abnormality. The protocols include Letrozole Femara on its own, Letrozole Femara in combination with Gonal-f and Hcg Ovidrel, and one unstimulated cycle. In all cycles, we only worked with 1 follicle. My husband's sperm ranged from 1-5 million after washed during those cycles. During our pregnant cycle, Letrozole Femara in combination with Gonal-f and Hcg Ovidrel were used, his sperm was 1.6 million after washed.

Three months after the miscarriage we tried again, with 6 rounds of IUI with similar protocols as before, but also include doubling Letrozole Femara with Gonal-f and Orgalutron, as well as Gonal-f injection only but none resulted in pregnancy. With the exception of 1 cycle where we worked with 2 follicles, the rest we only worked with 1 follicle. My husband's sperm ranged from 1-7 million after washed during those cycles.

Recently we went through an unsuccessful round of IVF-ICSI (in vitro fertilization with intra cytoplasmic sperm injection), with 5 days transfer. Protocols include Gonal-f, Repronex, Orgalutron, and Hcg Ovidrel. I was also put on a birth control pill the cycle prior to IVF cycle, and had an endometrium biopsy during the luteal phase of the birth control cycle. Post retrieval include antibiotics and vaginal natural progesterone 100mg in the morning and 200mg in the evening. Post transfer include vaginal natural progesterone 200mg in the morning and 200mg in the evening, and 81 mg aspirin daily.15 eggs were retrieved with 11 matured. 3 were IVF and 8 were ICSI. 1 out of the 3 IVF fertilized, and 4 out of the 8 ICSI fertilized. Since more than 3 eggs fertilized, the clinic's policy is to do 5 days transfer. By day 3 the quality of the 5 embryos were as follows: 10-12 cells grade 2 (good), 8 cells grade 1 (excellent), 8 cells grade 1 (excellent), 8 cells grade 2 (good), and 6 cells grade 2 (good).Unfortunately only 1 of the 8 cells (ICSI) turned into a blastocyst (with quality "not bad" according to my doctor).

The day 5 transfer include the only blastocyst we have and the 10-12 cells embryo. We ended up having no embryos to freeze. I started bleeding 7 days after the transfer.

Sorry for the long background story, my questions are as follows:

What should we do to ensure successful IVF next time? Failing the IVF, do I have an implantation problem?

What could have been done to prevent the early bleeding, could the progesterone injection prevent it? I didn't seem to have luteal phase defect in the past since my period normally come 14-16 days after ovulation.

What would have caused the poor embryo development after day 3? My doctor mentioned about possible sperm DNA fragmentation issue although this still need to be tested. Are there any other tests we should do?

What could have caused sperm DNA fragmentation, my husband doesn't smoke or drink, or exposed to any chemical environment in his day to day.

What protocol would you suggest for an IUI? Just want to mention that I didn't respond well to clomid and therefore my doctor prescribed letrozole. Why did IUI work for us last year and the last 6 attempts didn't? Also, I started taking Chinese herbs subsequent to miscarriage, therefore for the first 5 attempts out of the 6 IUI attempts I was also taking Chinese herbs at the same time, would that be why the IUI's failed?

I very much appreciate your time and help.Yours sincerely, E. from Canada

Answer:

Hello E. from Canada,

Thank you for all the information, it helps a great deal. Let me get to your questions directly.

1. Unfortunately, I don't comment on specific protocols because each doctor, clinic and country use different protocols. There is no right one or wrong one. These variations will often determine pregnancy success, however, and is the reason why some clinics are more successful than others. So, despite what I might advise you as to protocols, inevitably it will be your doctor's opinion, based on his training, knowledge and experience, that determines what protocols you use. Given that, it looks like you stimulated well, had a good number of eggs and embryos formed. The only changes I might suggest, which you have control over is (1) ICSI ALL eggs to allow for maximum fertilization and embryo number, (2) DO NOT PROGRESS TO BLASTOCYST CULTURE without at least 5 8-cell grade 1 or 2 embryos.There is an inherent attrition rate from day#3 embryos to blastocyst that may have nothing to do with inherent embryo quality. Based on preimplantation genetic testing data, sometimes even genetically normal and healthy embryos may not make it to blastocyst. Keep in mind that blastocyst culturing is still in its early development stages and not perfect. If you don't have enough embryos to lose, don't do it.

2. The bleeding after embryo transfer is very very common. I would refer you to my blog where that particular topic is the most often viewed. There is more information to this than I can give in this forum. Basically, however, it is not clear why or where this bleeding is from and how to prevent it. The good thing is that in many, if not most cases, it is of no consequence.

3. As mentioned above, the lack of embryo development does not necessarily have to be due to poor embryo quality. But, embryo quality can certainly affect the ability of an embryo to develop to blastocyst. The sperm fragmentation part . . . I'm not sure I would agree with that. Your age affects egg quality and therefore embryo quality more significantly.

4. Unknown what causes sperm fragmentation.

5. If you were going to return to IUI (which is an option but you have to consider that you will be lowering your chances of pregnancy) I would probably go to injectables only stimulation and not a combination protocol. The goal would be for you to have three to four ovulatory sized follicles (n0t one like you have been having), which will increase your chances of a successful pregnancy. The fact that you have gotten pregnant in the past is an indication that your reproductive system works but you have to overcome the sperm factors and the age factor. For these two, I would probably recommend IVF.

I would caution against adding herbal regimens. These are just un-purified pharmaceuticals. They could certainly have adverse affects.

Follow-Up Question:

Thank you so much for your reply.

In reading your blog on early bleeding, I mentioned to my doctor about using injectable progesterone. She wasn't on board and she still recommends vaginal progesterone. She explained that based on numerous researches, the vaginal progesterone is as effective as injectable, and the injectable create much discomfort. Instead for the next IVF, she will add estrogen patch. Should I insist on the injectable, I'm worried that I won't have enough progesterone support for implantation. Is it possible that's what might have caused the early period bleeding in my last IVF (7 days post 5 days transfer)?

Lastly, could the miscarriage that happened last year after IUI was also caused by lack of progesterone? That cycle I was only prescribed 100mg vaginal progesterone daily. However there was no bleeding whatsoever and after the fetal heartbeat stopped at 2.5 months pregnancy, I had a D&C done.

We will be doing another IVF 2 months later, in these 2 months, 1st month will be natural cycle and the 2nd month will be birth control cycle. Will doing the next IVF this early affect the eggs quality (the quality will be worse) and therefore reduce the pregnancy chance? Best regards, E.

Follow Up Answer:

Hello Again, Your doctor is correct in that studies have shown that vaginal progesterone is just as effective as injectable, and doesn't have the discomfort of the injection (Injectable progesterone has to be given intramuscularly). Injectable progesterone is still the gold standard, however, and if that is the form that you want, I don't see why your doctor can't change. But these kinds of things are what make each doctor different. Extra progesterone does not hurt, so why not? You could continue to argue with her but it sounds like she has her preferred way and will stand by it. The estrogen is a different hormone. I don't see any benefit to that for the bleeding but I certainly supplement with estrogen in my protocols.

Remember, I said that you cannot compare protocols because there is no one way, right way or wrong way. Protocols differ between doctors and clinics and that is okay.In the IUI pregnancy, which found a heart beat, progesterone was definitely not the cause. The lack of progesterone will result in very early pregnancy loss. Way before the placenta develops to produce its own progesterone. After that point, losses are usually due to abnormal pregnancies or fetal development.

The answer to your last question is NO. One can do an IVF cycle as quickly as every other month. Each cycle is different and unique and the eggs retrieved are unique. They can be good eggs or bad eggs, which is already predetermined prior to the IVF cycle depending on the state that the egg is in prior to stimulation.

Good Luck,

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.