Follow Up Question From 30 Yr Old Austrian Who Failed 5 IVF Cycles & Is Trying Once Again

This is a follow-up question from a young woman with possible PCOS in Austria, who first wrote me in March. Please view the first two questions she posed in order to fully understand the problems she and her husband face. See the March 18th blog post: http://bit.ly/cqXqAp

QUESTION:

Dear Dr. Ramirez,

I had asked you a couple of questions two months ago, and thought of you now as we are preparing to do another IVF. I copy below what you suggested in terms of protocol for me (PCO-like stimulator), since I discussed it with my doctor and he is not sure that this kind of protocol can be done with the medicines available in Austria. You said:"Patients start at a low dose of Follistim 150IU for three days then the estradiol level is checked for response. If there is not a high response then I step up the dosage to Follistim 150IU + Menopur 75. We continue the same pattern of checking and adjusting the dosage as needed. I don't use Lupron agonist suppression (long protocol), but instead use the Antagonist Ganerelix. When the follicles are appropriate sized, I trigger with Lupron 0.5 mg instead of Ovidrel. These combination and protocol has been shown to be effective in preventing hyperstimulation syndrome"

The protocol he gave me last time (Dec. 2009) (starting on day 3 of cycle) was:Day 3-5 Gonal-f (150IU)Day 6 Gonal-f (112 IU)Day 7 Gonal-f (112 IU) + Cetrotide (one shot 0,25 mg)Day 8 Cetrotide (0,25mg) + Pergoveris shotDay 9 Cetrotide (0,25 mg) + Pergoveris shotDay 10 Cetrotide (0,25 mg) + Pergoveris shotDay 11 Cetrotide (0,25 mg) + Pergoveris shot Triggering with OvitrelleEven though this protocol was substantially reduced in quantity of medication, I still had 15 eggs and mild-hyperstimulation (enough for being 3-4 days uncomfortable to breathe and in pain and swollen all around).

The doctor is now proposing a similar protocol to this, but reducing from 150 IU to 112 IU to start and see what happens. I showed him your suggestion and he was receptive but I don't know if the medicines you suggested can't be found here or if what he is suggesting is similar to what you suggested. We are thinking of not having a treatment here anymore and moving onto a treatment in the States. In an ultrasound on day 19 of my cycle, he saw that I had ovulated recently and noted that I have/had around 15 follicles (or left overs of follicles) in my two ovaries. I was really shocked since I have been medication free for 6 months, so I didn't expect that's normal to have so many follicles on a natural cycle, he said that could mean I have a high ovarian reserve and could be a sign of why I hyperstimulate every time no matter what medicine they have given me.

My questions:

Is the protocol he proposes similar to what you wrote above?

What do you think about this empty follicles in my ovaries now?

Also, he has me taking Thyrex for my thyroid (one pill of 50 mg per day) since I started treatment with him over 10 months ago because my TSH level was over 4, and he wants to keep it at around 1, but am I supposed to take this pill forever? for Hypothyroidism? That's what he said, that until I achieve a pregnancy and give birth, I should be taking that pill.

Another question: What do you think about that? My TSH has been at around 1 since i started taking the pill. Regarding my husband's sperm (CF gene), they have been using his frozen samples for all treatments, saying that the freezing and thawing act as natural selection, whatever survives is better for ICSI than trying with fresh sperm. Do you think is better to use fresh sperm for ICSI? or frozen?

Finally, we are thinking of going to a US clinic because in Austria PGD is prohibited, and for us they have been doing polar biopsy of my eggs to only transfer the embryos which fertilized with the better eggs, but as you noted in your previous emails, the embryos should be checked as well to eliminate any effect by my husband's sperm...correct?

So thank you so much for your answers, we are about to cancel the cycle here which starts in one week and move on to make an appointment in the States with you or another clinic which can take us.

Receive my warm regards, L. from Austria

Answer:

Hello Again,

I am happy, yet surprised to hear that your doctor was receptive to my suggestions. I do not dispense recommendations with the expectation that patients will share it with their Physicians. It is mainly for patient knowledge. I do not mean to intrude on that doctor-patient relationship, nor your doctor's judgement, since they usually know you better, and many doctors will be offended.

The medications Gonal-f and Follistim are the same, but made by different companies. Cetrotide is the same as Ganerelix. Gonal-f and Cetrotide are made by Serono, whereas, Follistim and Ganerelix are made by Organon. They are interchangeable. Based on the protocol you showed me, you were already on a pretty low dose protocol. Since, despite this, you hyperstimulated, I would reduce the dose further to a starting dose of 75IU or 37IU Gonal-f. I would probably fight the inclination to increase the dose above this because you seem pretty sensitive and 75IU may be all that you need to get an adequate number of mature eggs.

The Pergoveris is the same as Menopur (FSH/LH). If it is added, as your doctor did previously, he might want to reduce the dose to 37.5 IU (half-dose), but it isn't absolutely necessary. Some studies have shown decreased hyperstimulation in PCO patients when the FSH/LH is left off because PCO patients tend to have an elevation in LH production.

Once your lead follicles reach 15 mms (at least 20% of the follicles), Cetrotide should be started at 0.25 mg per day and continued until the trigger shot. The Gonal-f may need to be increased because of this ovarian suppression, and you should expect a decrease/drop in the estradiol level initially because some of the smaller follicles will stop developing due to the suppression and stop producing estradiol. That is okay and the cycle should be continued (this is contradictory to current thought, where if the estradiol drops the cycle is usually cancelled).

The trigger should NOT be HCG or Ovidrel. Instead, Lupron 0.5mg (50 mcg) should be used subcutaneously as the trigger. This has been shown, in European studies, to be just as effective as HCG but because of a shorter 1/2 life (the amount of time the drug is in your system), there is a decreased incidence of hyperstimulation.

In addition, to the above, I will also sometimes use "drifting/coasting" if it looks like the estradiol level will go above 4000 before the lead follicles are at a mature size. This requires that the doctor predict the levels on a daily basis and the drift/coast is not started until the lead follicles are at least 16 mms. You doctor should understand what this technique is. But, just in case he is not familiar with it, it is where the stimulationn with Gonal-f and/or FSH/LH is stopped but the ultrasound surveillance continues until the lead follicles reach 18-24 mms, then the trigger is given.

Finally, your doctor is correct that the TSH (thyroid hormone) levels have to be in the normal range, otherwise this can have an adverse effect on your pregnancy chances. As I said previously, PGD is the only way to rule out your husband's CF gene from the embryo, as egg polar body biopsy only evaluates the egg (your genes), and frozen sperm is just as good as fresh sperm. I am flattered that you would consider us for a second opinion, thank you. If you do decide to come to the U.S. I would certainly enjoy meeting you and your husband and be assured that our center would do anything that it can to accommodate you and help you succeed.

In closing, tell you doctor that I have had patients where I even start the Gonal-f/Follistim at 37.5IU and step up to 75 or 150IU, so he might want to consider that in you since you are so sensitive.

The very best of 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.

Young PCO Austrian Had 5 IVF Cycles Over 3 Years And Is Ready To Give Up - Short Protocol, CGH Advised & Keep Trying!

Dear Dr. Ramirez,

Thanks for taking the time to do this, I have read several of your previous answers on the website and I am looking forward to hear your thoughts on our case. I am writing from Austria. Both my husband and I are 30, we have been doing IVF/ICSI for the past 3 years (5 cycles) with no success. My husband has the CF gene and no vas deferens (0 count). Everything is fine with me (blood work, hormones, etc). I had a laparoscopy/hysteroscopy in 2006 (prior to the treatments) where an endometrial cyst was removed from one ovary, as well as one polyp from the uterus and some adhesions from the tubes. I have been getting continuously checked since then and my uterus, ovaries are clear from anything. My husband has had 3 TESE procedures, and good looking sperm was found each time and lots of it has been frozen.

We had 2 treatments in 2007, 1 in 2008, and 2 in 2009. In the first cycle (with fresh sperm) I had 14 eggs, 3 fertilized, and 2 grade A embryos were transferred. In my second and 3rd cycle I had 20 eggs (different protocols used in each of the treatments) and none fertilized. I hyperstimulated severely in cycle # 2 and ended up in the hospital. I was told we had an egg issue and to try with donor eggs. We took a year off to think about it and switched clinics. In 2009, cycle # 4, we had 15 eggs (frozen sperm), 3 fertilized and 2 grade A embryos were transferred on day 3. In cycle #5, we had 15 eggs again (frozen sperm), 7 fertilized, and we had 2 morulas transferred. We have a lot of trust in our doctor and clinic used for the past 2 treatments, and have a great relationship. The clinic is a stat of the art building with all new technology. This doctor does not think I have egg quality issues since I had good embryos (although very few of them) in the last two cycles, and thinks we should keep trying. However, we know it is not normal that within our age group we have not succeeded yet. It is hard to not think that there is something wrong with us. I stimulate very well in terms of numbers, and the protocol has been decreased (amount of drugs) with each treatment (always yielding a high number of eggs). We have tried acupuncture, yoga, bed rest, no bed rest, and all kinds of things. We do have a possibility to try one treatment in the US (due to the expenses), but are not sure of what we should do.

Any thoughts would be appreciated. What do you think of my egg quality issue? Would a US clinic suggest donor eggs? I would really like to try with mine...Best regards from Austria.

ANSWER:

Hello S. from Austria,

Based on the history you have given me, it sounds like you may be a PCO-type ovarian stimulator. That is why you have so many eggs, and had hyperstimulation syndrome. The good part of that is that you yield lots of eggs. There have been some studies that show a decrease pregnancy rate in PCO patients, however, and it is thought that it is because they stimulate too much. This leads to unequal maturation of the eggs within. Certainly, you seem to have had good quality (albeit external quality) embryos in the latter two cycles. At your age, I would have expected a pregnancy, easily. One concern is whether the sperm is contributing to poor embryos (again internal quality/genetically), because of your husband's CF gene. The embryo could still look good but be genetically abnormal. The only way to know this is to do preimplantation genetic screening, preferably by polar body biopsy and CGH, to verify that only normal embryos are transferred. CGH, or "comparitive genomic hybridization" is a genetic test that analyzes the chromosomal integrity of an egg or embryo. In IVF, it is ideally done in women under the age of 39 who have more than 6 healthy embryos after fertilization. They can be her own or donor eggs.

I would not recommend that you give up yet. If you give up, you certainly will fail. Since your ovary stimulates so well, and you are young, I think your chances of pregnancy are still high. The alternative to the above genetic testing on the embryos, would be to go to donor sperm, rather that donor eggs, in order to eliminate that paternal genetic factor. I know that you husband would probably prefer a genetic child, however, so in that case, you just have to keep trying.

If you came to me or any other clinic in the U.S., I don't think we would be ready to give up with your eggs. I think we would continue to encourage you to keep trying with your own eggs. I recently had a patient, similar to you that seemed to have poor embryo quality in another clinic. They did three IVF cycles there and then were recommended to use donor eggs. Fortunately, her husband got transferred to my locale and they came to me for consultation. I encouraged them to try at least one more time with her own eggs, again since her ovaries stimulated well. They decided to go with my recommendation and in their first attempt, became pregnant.

Follow-Up Question:

Thank you Dr. Ramirez for your answer.

In the meantime, I just had a hysteroscopy 3 days ago and a polyp removed from the uterine wall, this polyp was not showing up on ultrasounds. Could you please elaborate on why you think I have PCO? I do ovulate every month, no diabetes issues, no acne, no absence of menstruation, none of the signs I have read are present in me, but since it is the first time I hear that, please explain me how I could have it and how does it affect stimulation? How is it better to deal with it?

I forgot to mention that in the last two treatments (with 2 embryos/morulas transferred each time) we did polar biopsy of the eggs and only the 2 perfect/healthy ones were transferred each time, still no success. My doctor recommends that we continue to do this polar biopsy and we will. What kind of stimulation would you recommend for me? What could have caused this polyp I just had removed? Could it be the same stimulation drugs (estrogen), which is given to me as part of the treatments that made my uterine tissue grown into a polyp? (it was a long, flat polyp, not the regular ones that can be seen by ultrasound).

With regards to the couple you mention in the last paragraph, what did you do different from their 3 previous treatments that could have led to success? Is it just a matter of numbers/attempts, that we need to keep trying? The more one fails, the harder it is to believe it could happen....and I know mental power can do lots for either direction.

We might try one more treatment here (much more affordable) and then have a final treatment in the States. We are definitely not ready to give up! Thanks again!

Follow-Up Answer:

Hello Again,

There are many variations of PCO. Not all fit the classic descriptions. In your case, what makes me think that you have a PCO tendency is the fact that you overstimulated and developed hyperstimulation syndrome. I have had many patients that have surprised me in the same way. They are thin, have regular menstrual cycles, don't have any other PCO-type tendencies, yet they stimulate like a PCO patient. That is, their ovaries are very sensitive to the fertility medications. Since you don't have any of the other PCO findings, the only thing to keep in mind is that your ovaries are very sensitive to stimulation, so that the next time, a low dose protocol will be used and you don't develop hyperstimulation syndrome.

In terms of stimulation protocols, with my PCO patients I use a "step-up" protocol. Patients start at a low dose of Follistim 150IU for three days then the estradiol level is checked for response. If there is not a high response then I step up the dosage to Follistim 150IU + Menopur 75. We continue the same pattern of checking and adjusting the dosage as needed. I don't use Lupron agonist suppression (long protocol), but instead use the Antagonist Ganerelix. When the follicles are appropriate sized, I trigger with Lupron 0.5 mg instead of Ovidrel. This combination and protocol has been shown to be effective in preventing hyperstimulation syndrome.

Polyps are normal. It is very common and is due to an overgrowth of endometrial tissue. The finding is probably not significant in terms of pregnancy chances, but we prefer to remove them anyway so that they can't potentially interfere.

In terms of my couple, I used a completely different protocol than what she used previously, and some additional medications. Different clinics have different success rates because of differences in their protocols and techniques. "Failing" is when you stop trying. As long as you continue to try, you have a chance of success and that is what you have to focus on. Focus on the goal, not the pathway.

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.

***See continuing follow up to this question on May 16th, 2010...