Similar IVF Protocol But Different Results: Why?

Question:

Hi Dr. Ramirez,

I'm back again with a question about my recent IVF (second one). This IVF (in vitro fertilization) cycle we did the same protocol as last time (antagonist) but started off at a higher dose of Gonal-f based on my response last cycle. This cycle we started off at 300iu gonal-f and 75iu menopur whereas last cycle we started with 225iu gonal f and 75 IU menopur but had to increase to 300 IU gonal f after day 4 showed an E2 of only 90. Both cycles I started out with similar AFCs of 10 and 12 at suppression check. My usual AFC is between 16-20. Last cycle it seemed that I recruited more follies along the way and ended up with an E2 of 3030 and 23 eggs retrieved (17 of which were mature based on icsi and conventional fert rates as we did 50/50 split fertilization). This cycle my E2 was 2100 at trigger and they retrieved 12 eggs (still waiting on fert report today but we are doing all conventional fertilization).

My question is why did I have such a different response this cycle given that we started off at a higher dose this cycle compared to last? Last cycle we went up from 225iu gonal to 300 IU gonal at day 4 and stayed there until trigger. this cycle we started at 300iu gonal and stayed there until we added ganirelex on day 7. At that point my E2 stalled and do they increased my gonal f to 375iu gonal f and kept me there until trigger.

As always thanks for your advice/insight. S. from the U.S.A.

Answer:

Hello S. from the U.S. (Virginia).

The human body is not a consistent nor predictable structure so I can't explain why your response is different.  I have always explained to patients that have low response to stims that the ovaries can react differently each cycle and your experience is a case in point.  That being said, I would not have increased your dosage since your stimulation was so good the previous time and you bordered on entering OHSS territory.  In any case, IVF is not a contest where the person with the highest number of follicles or eggs wins the prize.  The goal is to find 1 or 2 perfect eggs that will lead to perfect embryos and a successful pregnancy.  So despite the fact that you stimulated less, that might be a better thing.  Bottom line is you only need one good one.  Also, there have been some studies showing that when a patient stimulates hard with lots of follicles, sometimes the egg quality suffers and the pregnancy rate drops.  This is especially true in PCO patients.  In those patients, our preference is to stimulate less and get fewer follicles.

So, in any case, as the saying goes: "I don't think you should sweat the nitty gritty" i.e the fine details.  Hope for the one perfect one.  That is the goal.

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.

32 Yr. Old Losing Hope After One IUI Miscarriage and One IVF Chemical Pregnancy: I Say Don't Give Up!!!

Hello, I don't even know how to begin because my infertility process has been so exhausting. I suppose I have diminished ovarian reserve. My last FSH check was 8.5. My AMH is 1. My stimulation cycles response seem to change--one time will be a nice response and the subsequent ones won't be. I started my first IVF this year and I fear repeating the same pattern as last year. Last year, my first IUI on 75 follistim/femara produced 4 mature eggs. I conceived, hcg was high, but ultimately a miscarriage due to trisomy 3. Did a complete RPL work up (I had a chemical pregnancy unmedicated 6 mos earlier). Nothing was abnormal, even karotyping. I had two more IUIs after that, producing 2 eggs, then only 1 egg. No success. I battled recurrent simple follicular cysts for about six months (would bounce from one ovary to next, two cyst aspirations and they would still come back) and finally had a cystectomy and laparoscopy in early February 2013. He found very mild endometriosis and treated it. I had started birth control pills in early January, on for 5 weeks, and then carried on with an antagonist protocol later in February with 150 follistim/75menopur. My day 4 E2 was over 700, thought I had another cyst, but instead had several follicles, dropped follistim to 75, then E2 dropped to 500, then up to 100 follistim and eventually my growth balanced out. Ultimately, I had 14 follices, 12 mature, 9 eggs retrieved, 6 fertilized, 4 day 3 embryos, then 2 highest grade blastocysts, 1 morula. Transferred the two blasts. Positive beta, 175 14 days after transfer. But my 48 hour beta dropped to 77. So I'm having another chemical pregnancy/miscarriage. This is exactly a year from my last miscarriage. I am terrified that in continuing IVF I will repeat this same pattern--that the next IVFs will not work. I just don't know what to do. I don't want to be 32 and have bad eggs when I know I don't have a translocation. I feel like I do respond to lower doses of medications, which should be indicative of decent reserve, but I don't know why I would keep having such problems likely due to embryo abnormalities. I suppose my uterus may have not been ready after the surgery and it wasn't the embryo but I took the good stuff-PIO, vivelle, dexamethasone, prednisone. Anyway, can these protocols be causing me an increased risk for aneuploid embryos? What could be changed? Any comforting words that I won't face the same fate with more IVFs that I did with the repeat IUIs? With it happening the same way all over again, I am believing I'll never have a baby. Last year was so hard, this IVF was hard. I’ve had to miss so much work, surgeries, U/S, procedures, etc. And I love my husband so much. I hate that I put him through this. Thank you, L. from Oklahoma Answer: Hello L. from the U.S. (Oklahoma), First let me clarify and emphasize to you that the IVF cycle worked, and you certainly have a good chance that it will continue to work in the future.  Your doctor probably did not explain that IVF only gives you the "chance" to get pregnant.  It, in fact, cannot MAKE you pregnant because the last three steps of the reproductive process are still beyond our technology to make happen.  These steps have to happen naturally (that part is still in God's hands).  So the fact that you got pregnant on your first IVF cycle is significant because it shows that you can get pregnant!  It is unfortunate, however, that it ended as a miscarriage. In terms of going through all of your previous pregnancies and this one, that would involve a more comprehensive analysis and explanation, that is beyond this venue.  I can do that by private consultation only. Second, I think you need to get the terms "decreased ovarian reserve" and "never" out of your vocabulary.  You DON'T have decreased ovarian reserve.  Keep in mind that in IUI cycles, we only want up to three mature sized follicles so that you don't get triplets, quadruplets, etc.  So, your responses were appropriate.  With your IVF cycle you were on a very low dose protocol and the yield was appropriate. . . not too strong and not too light.  You certainly could have been stimulated a little stronger, but it looks like your ovaries are very sensitive to the fertility medications so some care needs to be taken, as your doctor did. Finally, there is no technology that can predict or evaluate for internal embryo quality.  We can evaluate chromosomes so one option you certainly could consider with IVF is to have preimplantation genetic screening (PGS).  If you decide to do PGS, I would recommend a D#5 biopsy to reduce harm to the embryo, but your embryos would need to be frozen and transferred at a different cycle.  But that would allow you to evaluate the genetics of the embryo prior to transfer.  Your doctor would also need to stimulate a little stronger to have more embryos to work with and test since surely some will return abnormal.  This will then allow you to transfer normal embryos. All clinics, doctors and the protocols they use differ and that is what influences the pregnancy rates which vary from clinic to clinic.  There are other treatment protocol options; for example, I use low dose aspirin and low dose heparin in my recurrent pregnancy loss patients.  It has been well documented to help.  You might want to discuss that with your doctor. I want you to not lose hope.  You are young, your ovaries are still responsive and you've been pregnant, so now the goal is just to get a perfect embryo so that you can have the perfect baby.  Statistically, your chances are very very high, so you will eventually be successful.  You just need to hang in there and get the best treatment that you can.  Then once you have your baby, let me know so that I can celebrate your success as well.  You are on the road to success.  The only way you will surely fail, is if you deviate from than road.  Like Law school, this is a hard road, and it may not be fair, but in the end, it will be the most wonderful experience you've ever had in your life!  Greater than falling in love.  It was for me, and I thank God for his blessing that gave me my beautiful soon to be 16 year old IVF daughter.  Keep the faith in your path and in yourself.  Sorry for the long answer...good luck! Dr. Edward J. Ramirez, M.D., FACOG Executive Medical Director The Fertility and Gynecology Center Monterey Bay IVF Program www.montereybayivf.com

A Step By Step Guide To The IVF Process: Step Two -- Follicle Growth And Egg Maturation

Dear Readers:

This is the third 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 also 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 TWO: FOLLICLE GROWTH AND EGG MATURATION

Under the influence of FSH (follicle stimulating hormone), dormant follicles within the ovary start to grow. Measurement of the dormant follicle number is called the “antral follicle count (AFC)” and also measured by the “Anti-Mullerian Hormone (AMH)”. Both these measurements are used to give one an idea of the ovarian capacity to be stimulated, also known as ovarian reserve, similar to the FSH level. They are additional indirect measurements. Many physicians and patients believe that these two measurements actually tell them how many eggs are left within the ovaries, but that is too broad an interpretation. We do not have the technology to know how many eggs are present without doing a careful dissection of the ovaries. So these are indirect measurements that serve to give warning about your fertility. Their only use is to help predict, as much as possible, whether the ovaries will yield many follicles upon the hyperstimulation that occurs with giving increased amounts of FSH.

So the real interpretation of a low AFC or AMH is that there might be a lower number of follicles produced, and consequently less eggs retrieved. As explained previously, these are additional measurements of “ovarian reserve.” They only predict success from a statistical point of view because part of how IVF enhances your chances of fertility is by increasing the number of eggs that are available for fertilization and hence the number of embryos and hence the increased chance of finding the perfect embryo that will lead to a pregnancy as explained in the previous segment. It is a total misunderstanding or misinterpretation to say that a low AFC or low AMH indicates that you are infertile, that your ovaries won’t stimulate or that you won’t have good eggs! Taken together with an elevated FSH, these measurements serve as red flags from a time point of view. It means that you may not have as much time to get pregnant using your own eggs as you might have thought. Since we cannot predict when you will run out of time, time becomes a critical consideration.

Currently, transvaginal ultrasound is used to monitor the follicular growth by simply measuring the follicles. This measurement is usually an average diameter taken from a horizontal and vertical measurement of the follicle and reported in millimeters (mms). As the ovary is stimulated with FSH, some of the follicles will grow. Follicles grow approximately 2 mms per day so there is some predictability of when the follicles will reach the appropriate size for ovulation or retrieval. As the follicle expands, Estradiol hormone is produced in increasing amounts by the growing follicle and so estradiol levels can be monitored to also help determine progress as well. With IVF, the goal is to have 15-20 total follicles and estradiol levels between 2000-4000. Each mature follicle will produce approximately 150-250 of estradiol. In IVF, we want to keep the estradiol level at less than 4000 because if there are more than 20 growing follicles and the estradiol level goes above 4000, there is an increased risk for an illness called “ovarian hyperstimulation syndrome”. That is a whole other topic so it won’t be explained here. Suffice it to say that OHSS has the potential to cause death in its worst form. A competent physician with experience doing IVF will take appropriate precautions to prevent this from occurring.

It is known that the follicle has to reach an average diameter of a minimum of 15 mms for the egg within to be mature. We cannot see the egg because it is microscopic size. Therefore, maturation is assumed by the size of the follicle, as has been shown in early IVF studies. With most IVF clinics, a follicle is deemed to be mature size and appropriate to trigger once it has reached at least 18 mms, but it can be as low as 15 mms based on previous studies. Because the follicles will grow unevenly, meaning there will be some that grow faster and some that grow slower, most physicians will trigger with HCG when the largest 2-4 follicles reach maturity size, or when the highest number are between 15-24 mms. My preference is for the larger follicles to be 20-24 mms which I have decided to use based on my long term experience. I don’t necessarily trigger when the largest ones reach that size but, rather, I want to get as many follicles into the mature stage as I can without losing the larger ones or have too many smaller ones. The problem with smaller sized follicles is the eggs within them will not have had adequate time to mature and so will be unusable. Also, follicles that grow to over 24 mms tend to have eggs that are over-mature and therefore not viable. Once the majority of the follicles reach a size of 20-24 mms, then you are ready for the “trigger” shot. The decision of when to give this shot is determined by the experience of the doctor part of the art of IVF. If given too soon, you may lose eggs because they will not be mature. Too late and you may lose them because they will be over-mature. The goal is to try to get the majority number of mature eggs as possible because only mature eggs will fertilize.

Until the trigger shot is given (or the body goes through an LH surge if allowed to occur naturally) the egg within the follicle does not go through its final phase of maturation, meiosis stage 2. Eggs within the follicle are usually in the “germinal vesicle (GV)” stage. Once stimulation occurs, they then go through meiosis phase 1 (M1) and then are mature at meiosis phase 2 (M2). In the natural reproductive process, the “trigger” occurs under the influence of a hormone called LH (luteinizing hormone) and is known as the LH surge. This is what is being checked when you use an ovulation detector kit. There is a sudden rise in the LH hormone which then signals the ovary to begin the ovulation event.

In IVF, HCG (human chorionic gonadotropin) hormone, which is chemically similar to LH, is substituted for the LH to make the eggs go through their final maturation phase and begin the process of ovulation. There are three sources for this medication:

(1) Urinary HCG extracted from human urine,
(2) Recombitant HCG (synthesized HCG) and
(3) Lupron, another drug that has a similar chemical structure to LH.

Lupron can only be used if you are on an antagonist protocol, with Ganerelix or Cetrotide, and not in a long Lupron protocol. This trigger shot will also cause the ovary to begin the ovulation process but because we don’t want the ovulation to occur, and thereby lose the eggs into the pelvis, the egg retrieval procedure is timed to occur before ovulation will take place. This is usually scheduled for 35-36 hours from the trigger shot.

We will continue this discussion soon with the next installment, "Step Three And Four: Egg Retrieval". 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 Protocol For High FSH

Question:

Dear Dr. Ramirez,
I am 39 years old in 2 weeks and about to undergo my first ivf (in vitro fertilization). I have only one fallopian tube, which an hsg has shown to be blocked, probably by adhesions (my other tube was removed due to damage from extensive adhesions - a reaction to previous surgery to remove a dermoid cyst on my left ovary).


My FSH level was 14 in March. Two weeks ago my FSH dropped to 8 and my AMH level was 7.42. An ultrasound scan and follicle count showed 9 follicles on my right ovary and 3 on my left (the ovary which the cyst was removed from).

My consultant has suggested the long protocol, as he thinks I will respond ok. I have read much about the short protocol being better for my age group, and if fsh has been high. I am anxious to get the correct protocol from the outset. What do you think my response might be, based on my levels? Do you think a short protocol would be better in my case? Many thanks, R. from the U.K.

Answer:

Hello R. from the U.K.,

The worst thing you can do is try to second guess your doctor, especially with information that you read on the internet. You are not an expert and don't have sufficient knowledge to make a proper decision. However, it is good to be educated regarding what you will be going through, and certainly, I have the knowledge to answer questions, so you can trust my input. But, given that you are not my patient, I don't have all your medical information and am not doing the procedure, the answers I give you have to be generalities and cannot be specific.

I personally don't criticize "protocol" questions because there is not one way or best way to do IVF. There are many different protocols and usually the specific protocol is based on the training and experience of your doctor. They all have the possibility to work. Some doctors stimulate less, some more, some use only pure FSh, some use mixed protocols, some use the long Lupron protocol, some use the antagonist protocol and some use the micro-dose flare protocol. There is not way to predict how any one will respond to any given protocol. But studies have shown no benefit to the micro-dose flare protocol (short protocol) in comparison to any other protocol, just as there is no study that shows that the long protocol is better than the antagonist protocol. I prefer the antagonist protocol because there are less injections in comparison to the long protocol.

Because you have had an elevated FSh level, despite it being lower more recently, you would still be considered a poor responder (or at least have the potential of being a low responder). For that reason, my preference would be to NOT inhibit your ovaries with Lupron in the stimulation phase, and only begin ovarian suppression once the lead follicles are at least 16 mms. This is the technique used in the antagonist protocol. With the long protocol, your ovaries are suppressed by the lupron starting from the previous cycles and may not respond as well. Before the antagonist protocol was developed, the micro-dose protocol was developed to reduce that suppression phase. Without criticizing your doctor's choice of protocols, my personal choice would have been different. But that is what makes Infertility doctors and clinics different and gives them different pregnancy rates.

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/

Third Failed IVF Cycle: New Protocol Needed? Compare SART Stats?

Question:

Dr. Ramirez,

I just had my 3rd failed IVF cycle and I'm looking for some guidance. A little history:

I am 31 have a short luteal phase but PIO and estrace seem to do the trick. Day 3 testing normal. My husband has low morphology.

My 1st IVF attempt I responded very well (long lupron) to low doses of meds. Stimmed for 7 days. They obtained 10 eggs and 9 fertilized with ICSI... all were very good quality on Day 3. Transfered 1 and 5 frozen on Day 3.

2nd IVF attempt- Antagonist Protocol- very slow to respond on highest doses of meds. Didnt have any measureable follicles until Day 10... stimmed for 15 days. Obtained 6 eggs and only 3 fertilized with ICSI. Transfered 2 embryos on day 3. Negative beta 10dp3dt and stopped meds. Discovered 2 weeks later that I was pregnant and miscarried.

3rd IVF attempt- back to Long Lupron- very slow to respond again on highest doses. Stimmed for 15 days- obtained 8 eggs- 4 fertilized and only 2 were viable on Day 3. Beta negative.

Questions:Any thoughts on why I would have such a different response from cycle #1? All 3 cycles were done in 2011.Would you suggest trying a different protocol? Do you think I may be a good canidate for Micro-Flare Protocol?In both 2nd and 3rd cycles my e2 level was 22 and 24 at suppression check compared to 59 in cycle 1. Any insight? Could this mean that I am oversuppressed? Also AFC was lower in past 2 cycles.How much time do you suggest in between fresh cycles?Any thoughts that you would be willing to share would be greatly appreciated. I am getting very discouraged and you have been so helpful in the past. Thank you, D. from Massachusetts

Answer:

Hello D. from the U.S.(Massachusettes),

It is difficult to critique protocols and I generally do not. There are many different ways to accomplish the same thing so any one particular protocol may not be better than another.I do not favor the long protocol, however, for two reasons. I think there is too much ovarian suppression at the beginning of the stimulation and you have to take many more injections. For that reason I use the antagonist protocol, which usually only required 2-3 injections. So, I would not go back to the long protocol. There is not question that the long protocol is the classic method, in fact, most REI's use this protocol because they are not familiar with the antagonist protocol.

In terms of your stimulation, there can be significant differences from one cycle to the next. For example, I have a patient who only produced one follicle in her first cycle with the maximum dosage of medication, yet in the second cycle, with a reduced protocol, she produced 8 follicles. This shows that each cycle is unique and the ovaries will respond differently. You don't mention of these cycles were done back to back i.e. consecutive months, but in general there should be a one month rest period between IVF cycles to allow the ovaries to recover. A stimulation of 12-14 days is not unusual and sometimes preferable. Sometimes a short stimulation phase leads to less quality eggs. Also keep in mind that you were successful in the second cycle, which means that you can be successful again. You have to be persistent. You are lucky that you are in an insurance mandated State for IVF.

I would strongly recommend against the Micro-flare protocol. This has been shown to not be of any benefit.Finally, there are other reasons for failure of an IVF cycle. You are young and had good embryos to transfer. So maybe it was something else? Implantation failure can occur if the transfer technique is not good by the Physician, as an example. Or you may need some additional meds to reduce your immune response or increase blood flow. There are differences between IVF clinics/centers. We are not all the same and therefore pregnancy rates differ.

Follow-Up Question #1:


Thank you so much for your thorough response. I have a few more follow up questions if you do not mind...What are your thoughts on the Estrogen Priming Protocol? Do you usually use a FH and FSH while stimming? I have read that adding Menopur in too soon can effect egg quality. The article that I read suggested adding it in after 4-5 days of stims and then lowering the FSH dosage. Any thoughts on this? My current RE had me starting Menopur on the 2nd day of stims.The past 2 cycles fertilization was only 50% with ICSI compared to 100% my 1st cycle. The embryologist noted that my eggs were "brownish". Any thoughts on this? Do you think it was due to egg quality? Lab issues?You mentioned additional meds to reduce your immune response and increase blood flow... what type of meds do you usually prescibe?How much emphasis do you put on SART scores.

I am contemplating switching clinics and I am looking for some guidance. Mass General has the highest success ratings in my age group but I have heard that they are very focused on scores, etc. I have heard great things about a RE at Boston IVF but there SART scores are lower. Would this be a deciding factor for you?Yes, I agree... I am very lucky to have insurance coverage! Again, I really appreciate your help. This process is so stressful and I am so overwhelmed!

Follow-up Answer #1:

Hello Again,

Let me take your questions sequentially for ease.

1. I don't have any feelings one way or the other regarding estrogen priming. I don't use it because I don't think it has been shown to be of any benefit. By I lack the experience to know for sure.

2. I am a believer in the "mixed protocol" which uses both pure FSH and a combination FSH/LH (my preference is Follistim/Menopur). Many studies have shown benefit to having LH present in the follicular phase. It has been found to increase the egg quality although there is not real technology to determine egg quality. I was trained on this method and my experience has been that the stimulation is better i.e. higher number of follicles. My pregnancy rates are pretty good as well. I don't agree that it will decrease egg quality. That has not been my experience.

3. Brownish or discolored eggs signify a basic egg quality issue. This may be why the fertilization rate was not as good. The minimum fertilization rate should be 50% and will vary from cycle to cycle because the eggs will be different each time. I don't think anyone has any explanation for why the eggs would have a "brownish" or "discolored" appearance.

4. I use low dose aspiring (81mg), Medrol (16 mg) and low dose heparin (2000 units twice per day). These all start with the start of the stimulation and continue through the cycle. The aspirin and heparin are stopped on the day of the trigger injection and not restarted until the day after the retrieval.

5. SART scores are certainly one thing I would look at. The problem with SART scores or the CDC scores is that they only look at one year, not cumulative scores which is more revealing. That's because clinics can have a good year and bad year depending on the types of patients they have, embryology problems, change in personnel, etc. But since these two organizations don't give cumulative statistics, you might have to ask the clinics if they have them. If you are going to use SART scores, then try to look at the last three years and compare. Also the problem with these scores is that they are 2 years behind and IVF technology is ever-changing.

Also, if you are going to look at the SART/CDC stats, the only one you should look at is the implantation and pregnancy rates per cycle and transfer in patients under the age of 35. Don't necessarily look at your specific age group. Those two statistics are the important ones and we use under 35 years old as the gold standard because those are inherently the most fertile patients (ie no age factor). Certainly your age group statistics are also important because you want a clinic that does well with your age group. If I were going to a new area and had no idea which clinic to go to, I would use the SART/CDC statistics to help me decide. Then I would go check them out, ask about their program and see how personal the care is (just like you would if you were buying a car). I don't recommend going to a factory type program. You want a program where you have one doctor attending you through the entire process and don't get a different doc for the transfer, which is one of the most critical steps. Sometimes smaller clinics are better than larger ones because of this, as long as the pregnancy rates are equivalent. Try to get the clinic's current statistics if you can or the most recent ones, and not necessarily the ones from two years ago submitted to SART. Most clinics will have the previous year's stats.


Follow-Up Question #2:

Thank you very much for your response. The info that you provided re: the SART scores is very helpful. I appreciate the tips!!One more follow up question re: the "mixed protocol". Do you usually start the Menopur at the same time as Follistim? Or do you wait a couple of days.Also, would you reccomend that I try any supplements? I have done some reading about DHEA? What are your thoughts?

Follow-Up Answer #2:

Hello Again,

The Menopur (FSH/LH) is started at the same time as the Follistim (FSH). I don't recommend any supplements. There are none, especially DHEA, that have been proven to work but I did see a recent article touting DHEA is older women. They claimed it increased embryo quality, but I am doubtful. That shouldn't be a problem for you because you are young.

Things that I do add in patents that have failed a previous cycle:
1. Acupuncture (it is not proven, but some studies show benefit and it doesn't hurt to try everything after failures.)
2. Low dose aspirin - 81 mg orally per day starting at the beginning of the cycle.
3. Low dose heparin - 2000 units SQ twice per day starting at the beginning of the cycle.
4. Medrol 16 mg orally per day starting at the beginning of the cycle and decrease to 8 mg on the day of transfer (you would stop this at the time of the pregnancy test).
5. Both progesterone injections and progesterone suppositories. I don't start the suppositories until the day after the transfer.

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: Dr. Ramirez is always very kind and helpful. I am very thankful for all of his help.

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.

Failed IVF Cycle With Drop in Estrogen & Progesterone Levels & PCO Type Response: Might Benefit From Adjustment In Protocol

Question:

HI, I have a question regarding spotting 5 days post transfer with full period bleed on 6 days post transfer. Here is our history:-I am 32 and my husband is 41. He has a daughter from a previous relationship.-I was diagnosed with diminished ovarian reserve in January, and also stage III endometriosis in June with a laparoscopy. They were able to clean out almost all of the endometriosis except for some on the colon because I did have some bowel in my colon and they didn't wan to rip it. They also found a polyp in my uterus that they removed. Also, I have a luteal phase defect as I always would spot around 9dpo and would have an 11 day luteal phase with 24-26 day cycles.

- January/February 2011 - First treatment cycle. Letrozol with monitoring and intercourse and prometrium 50mg 1x a day. Luteal phase increased to 14 days with 29 day cycle. Negative.


-February/March - An ovulatory cycle - went in on day 3 and never came down to baseline. Ovulated day 8 (which has never happened) so couldn't do meds. Prometrium again, but only 11 day luteal phase, obviously negative.


-March/April. Anther cycle on Letrozol and prometrium - same as first cycle but negative.


-April/May - Moved to injections. Follistim 150mg and then decreased to 75 due to good response and high estrogen. Ganirelex 3-4 days prior to IUI. HCG trigger with 6 follicles developed and 1 mature. IUI with crinone (prometrium was causing depression). Luteal phase 14 days with 28 day cycle - negative.-Laproscopy in June.


-IVF June/July - Long protocol - BCP, 10mg Lupron for 10 days, Follistim 150mg day's 3-6, increase to 175 day 7-9 (estrogen at 840 after this). Decrease to 150mg days 10-11(estrogen shot up to 3400) Decrease Follistim to 75mg day 11-12 (estrogen 6000). All along with 5mg Lupron. HCG shotday 13(only half dose b/c estrogen so high. Retrieval on day 15. Starteg Crinone that day. 15 eggs retrieved with 14 fertilizing without assistance (husbands sper is great quality). Day 5 transfer, 1 blastocyst very good quality. All other embryo's taken to day 6 to freeze, but all but 1 poor quality so couldn't freeze. The 1 completely hatched so couldn't freeze and they didn't want to disrupt other embryo by transferring it. I had a follow up on day 5 post transfer to just check me for OHSS and they took my levels and my progesterone was 3 and estrogen 60 (at baseline they have never seen it below 72).


I knew something was wrong b/c I started spotting that day and a full period started that night. It is very heavy bleed which I usually don't have, but not nearly as much pain as I have had int he past, most likley from the endo surgery. I am taking a little while off, but it sounds like they think I have a true luteal phase as they never see this response to IVF. I want to be as edcuated as possible when I meet with my doctor.


What would your suggestion be for a luteal phase protocol to address this? I am nervous about the shots. The nurse said possibly estrogen patch, prometrium, and crinone or something along those lines with 2 progeteron meds. I have also asked to have my levels monitored during the next luteal phase. I am taking a cycle or two off before jumping into the next cycle. I am lucky to have the flexibility b/c my insurance covers this. I appreciate your feedback on this.


Thank you! K. from New York

Answer:

Hello K. from the U.S. (New York),

You had an awkward IVF cycle to say the least, was my first impression. There were several interesting moments in your cycle. First, your response was very characteristic of a PCO-type response, very sensitive ovaries. I don't know if your doctor was expecting this or not, but hitting an estrogen level of 6000 put you at very high risk of OHSS. Despite this, your doctor continued the cycle and triggered with HCG, which further increases the risk. I think you are lucky to not have developed full blown OHSS.

Second, I found the up and down of your meds to be unusual.

Third, a PCO type response would explain the decrease in embryo quality. When the ovaries are hyperstimulated they often lead to a deficit in embryo development or quality. That would explain why there were so few embryos to freeze. If they had to culture to day#6 that means that the embryos had not reached blastocyst stage by day#5, which is not necessarily a good sign. For the one that did, I was surprised it wasn't just frozen at day#5 so there would not have been a hatching problem. Why did they wait an extra day?

Finally, the abrupt drop in estrogen and progesterone levels was sure curious. I have never seen such a precipitous drop in a patient that is receiving supplementation. Surely, the problem with serum (blood) hormone levels is that they don't accurately reflect the levels within the endometrium, but there will be some levels and there are minimum levels in the blood that we know usually mean there is adequate levels in the endometrium. Neither of your levels met these minimum levels, but there should have been hormone in the blood because of the medications you were taking. You were taking medications weren't you? I would be very surprised if they didn't supplement you. Basically the bleeding that you had was the onset of your period because the hormone levels had dropped so precipitously. That is how it works in a natural cycle.

Certainly in the next cycle, I would recommend that you take progesterone injections (50mg) per day beginning with the retrieval, then add vaginal progesterone (Crinone or Endometrin) after the embryo transfer (because it is messy and interferes with the transfer), I also would add estrogen supplementation by patch starting with the transfer as well, but in your case, your levels should have been high from the hyperstimulation. I'm still thinking of possible causes for the drop. . . did you not stop the lupron?

Protocols are highly different between centers and there is not one protocol that is necessarily better than another. These are just suggestions. Your doctor may want to do something entirely different. Also, because you had a PCO-type response, I would recommend that you not use the long protocol and instead use an antagonist protocol with Lupron 0.5 mg as the trigger instead of HCG. This will reduce your chances of developing OHSS.

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.

"What FET Protocol Do You Use For Difficult PCOS Patients?" UK Patient Asks

Dear Dr Ramirez,

Firstly, thank you so much in advance for taking the time to read my question.

Brief History: Dx with PCOS at 17 y/o. HSG clear. My husband has severe m/f, so our only chance of conceiving is through IVF with ICSI. On my fresh cycle in 2008, I had 30 eggs retrieved and due to OHSS, couldn't have an Embryo Transfer. We had 13 embryos, all of which were frozen at the 2PN stage. I have gone through six FET cycles since, but only got to transfer three times, b/c the drugs used to suppress my ovaries (ProstapSR, Buserelin, Synarel) have actually stimulated my ovaries, leading to OHSS a further three times!

My treatment is in the UK and I cannot switch clinics b/c a) my treatment is free and b) since it's free I can't choose where to have my IVF/FET's. The Drs at my clinic have put their heads together to try to come up with an individualized protocol for me, since I keep suffering these rare responses to the suppression meds. I am naturally frightened and sceptical about this new protocol since it hasn't been tried and tested in the UK as yet (but apparently it has in other countries with good success for challenging PCOS patients).

The new protocol would not involve the usual suppression medications. On day 3 of my period, I would inject a long acting Cetrotide shot (sub-q) and also commence 6mg Progynova (estradiol valerate). On Day 5, I would commence daily Cetrotide shots, whilst continuing daily with the Progynova. All in all, this protocol should only take around 13days, then I would commence Progesterone, 3-4days before Embryo Transfer. I am terrified of hyperstimulating again. Is this likely to happen with the Cetrotide at all? Have you had any PCOS patients who have ever responded like I have to suppression medications?

If you were my Dr (I wish you were :D ), what protocol would you suggest for a FET? It may be helpful to add that I have always been a slim PCOSer (BMI 21) and have an AMH of 98.5. I also got pg on our first FET with twins, which I sadly miscarried at 8 weeks. My subsequent two transfers resulted in a negative beta. Thank you so much for reading and for any input you may be able to give! G. from the U.K.

Answer:

Hello G. from the U.K.,

I have never heard of such as thing as OHSS with an FET cycle. I'll have to do some research on that and see if that actually happens. If not, your docs might want to write your case up as an unusual case. Since you have been using GnRH "agonists (stimulators)" in your previous cycles, it sounds like maybe the dosages were not high enough to suppress the hypothalamus (which is what they are supposed to do and prevent ovarian function), but instead stimulated FSH production and ovarian stimulation leading to the OHSS.

I think the change to an "antagonist" is certainly the best way to go. I converted to using the antagonist, Cetrotide and now Ganerelix, over 5 years ago (mainly because it is less injections). I have not used it with an FET cycle (because it is more expensive), but it can work just as well with the protocol you have outlined. The antagonist will definitely suppress any ovarian function, so you should not be able to mount an OHSS response. This is definitely a good plan.

I thank you for the compliment :) and wish that you could be my patient as well. For many reasons, such as the fact that some like you can get IVF for free where they live, patients feel that they are stuck in the clinic near their home. This cannot be further from the truth. I have a patient from Serbia and South Korea in my IVF cycle this month. I have patients come from out-of-state, one from as far as Montana, which is like the difference between the UK and Poland. You can travel to the best center to do your IVF, thereby saving you years of frustration & grief. I had one patient who failed five times at a Los Angeles center only to succeed the first time with us. It is not that difficult to do or arrange IVF afar. There are additional costs involved, which is the biggest factor, but heck, you could plan a vacation at the same time. The IF community calls this "Reproductive Tourism" or "Cross-Border IVF", I believe.

An IVF cycle can be done so that you only have to come here for the minimum necessary time, which for an FET cycle would be 1 week or less or 10 days for a fresh cycle. Also, remember the old adage, "you get what you pay for." Free cycles are all well and good, but as you mentioned above, you are stuck with one center, one protocol, one embryology lab (and there quality can differ greatly), governmental restrictions and that is unfortunate. In the U.S., particularly in California, we have few restrictions and can do embryo donation, donor egg, donor sperm, frozen eggs, surrogacy, and are given leeway on the number of embryos we can implant. I wish that I could just outfit a 747 jet with an IVF clinic and jet all over the world where patients want to see me. I think that would be fun as well :D !!!

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.

Possible PCO Patient Adjusting IVF Antagonist Protocol For Fear Of OHSS: Decrease Gonal-F Dosage?

Question:

I am about to start my first IVF protocol (today is CD2). I am concerned about the recombinant FSH dosage prescribed and would like your opinion regarding appropriate dosage. I believe I am at higher risk for OHSS for several reasons (described below), however my recent ultrasounds are not showing definitive signs of PCO. Here is the protocol prescribed by my doc:

No pre-cycle BCPs (they make me very ill)
CD2: gonal-f 225
CD3: gonal-f 225
CD4: gonal-f 150
CD5: gonal-f 150
ultrasound on day 6
addition dosing determined following this ultrasound
Gonarilex to prevent premature ovulation

I called the doctor today because I was nervous about taking the first two days of 225IU gonal because of the risk of OHSS. After very little discussion, he switched me to 150IU for 4 days.

The difference between 225 and 150 is a big change. I wonder if I will get good results with a dosage that is this low. What is your opinion? I feel like there might be some sort of middle ground that is more appropriate? I would appreciate any thoughts. I would like to get the "best" results without complications of OHSS.

I believe I am at higher risk for OHSS than the normal woman for many reasons:

1) my ultrasound yesterday (on CD1) shows 9 follicles on right and 16 on left

2) I responded well to low doses of gonadotropins (6 IUI cycles some with letrozol/femera at 5mg/day?, others with clomid at 25mg/day all cycles gave 3-5 mature follicles on CD12),

3)I am petite (5'2", 100 lb.s)

4) in 2006 a doctor told me I had PCOS based on ultrasound results, a history of severe PMS, and moderate acne(two additional doctors I consulted with gave no diagnosis - I am not hairy or pear-shaped)

5) cancelled IUI due to elevated estrogen associated with a small complex cyst on cd2 (and another very uncomfotable IUI cycle when a different OBGYN proceeded with an IUI when I had a cyst at the start of my cycle).

6) grandma had type 2 diabetes

7)early male baldness runs in my family.

Answer:

Hello J. from the U.S.,

First of all, I have to caution you about trying to second guess your doctor. Sometimes that may not be good. I would presume that your doctor had a logical reason for selecting your protocol.

You were originally scheduled to be on a 3 down protocol (75IU x 3 for two days then decrease). That is a standard protocol and is on the low side. Because of your concern, your doc decreased you to 150IU and will make adjustments based on the response. The only down side to the lower protocol is that you may not recruit as many follicles as the higher dose, but there is no way to know this when it is the very first cycle. In most cases we determine the protocol based on an educated guess. The adjustment at CD#6 is still early enough to increase the dosage and recruit more follicles if necessary, and if you are indeed a PCO, then you will already have an increased number of follicles and the decreased dosage will be safer for you.

I am glad to see that your doc is using the "antagonist" protocol with ganerelix. I am a firm believer in this medication and its ability to decrease the risks of OHSS. With the antagonist, instead of using HCG to trigger ovulation, Lupron can be used to trigger and because of its shorter half-life, the risk of OHSS is dramatically reduced. This is the protocol I use with my PCOD patients to reduce their risk, in addition to careful monitoring, lowered FSH dosage, Drifting (if necessary) and Coasting (if necessary). My goal is to keep the Estradiol level less than 4000 at the time of trigger. With this protocol, I have had no incidence of OHSS in my center for the past 5 years. Most the reasons that you gave for being PCOD are not valid criteria, but my concern would be the same as yours based on the high number of antral follicles seen on ultrasound. I treat patients as a PCO patient if they have PCO-appearing ovaries even if they don't meet the strict criteria for PCO. And, I find that they do stimulate like a PCO ie have a high number of follicles (>25).

In your case, I think that being safe is better than being sorry and the lower dose is probably the way to go. I call your new protocol a 2up protocol and it is a standard protocol that I use with my PCO patients. I check estradiols at CD#5, however, and adjust from there.

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.

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

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...

ELONVA, A New Sustained Follicle Stimulant Just Approved In Europe!

Dear Readers,

I just read a news release from the big drug manufacturer Merck that they have been approved by the European Commission to market a new drug for IVF patients that will make their lives remarkably easier! It is a sustained release follicle stimulating hormone called Elonva, the first of it's kind! Whereas women undergoing IVF now have to have daily subcutaneous injections of FSH, with Elonva they will only have to have a subcutaneous injection ONCE a week. This is a significant improvement, thanks to the Organon division of Merck pharmaceuticals.

From what I have read in their press release, this new long-acting FSH lasts for 7 days. It has to be used with an antagonist so that doctors that already use antagonist protocols will have an easier time adapting to the new regimen. Those that use the long protocol will be less amenable to use it because they will have to get comfortable with two new meds. It will replace the first 7 days of injections required by currently available medications. Hopefully, the cost of medication will be equivalent or less, but for sure patients will appreciate the reduced number of injections! I can't wait for an FSH/LH equivalent for my mixed protocols. I hope the FDA approves it ASAP for U.S.A. use. Otherwise, I might have to take a lot of trips to Europe :-)

See the following link to get more information: http://bit.ly/cQpXn5

Here's hoping for a quick release for our patients in the United States!

Edward Ramirez, MD, FACOG

Executive Medical Director

Fertility & Gynecology Center

Monterey Bay IVF

http://www.montereybayivf.com/