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/

35 Year Old Responds Well To Low Dose Clomid IUI Cycle: NOT A Low Responder!

Question:

Dr. Ramirez,

My husband and I have been infertile for more than 2 years now. We have gone through a wide variety of tests. I have had a polyp removed through operative hysteroscopy and we were asked to try on our own for 3 months afterwards (unsuccessfully). I am 35 years with borderline bad FSH (around 10 on day 3). I have a low antral follicle count (usually around 7 if they can see both ovaries during the ultrasound). We have tried 1 IUI (negative for pregnancy) and I was prescribed 50 mg Clomid on days 3 - 7 for the IUI. I ovulated 3 eggs with this dose and was triggered with an HCG shot when the 3 follicles were between 1.7 - 2.0 and IUI took place approximately 24 and 48 hours after this injection.

I have 2 questions:

1. Is the fact that I developed 3 eggs on Clomid a good or bad sign? My doctor says I will likely be what he calls a poor responder to medications because of my low antral follicle count and IVF may not be more worthwhile than IUI because of this. Does the fact that I got 3 with Clomid mean I might do better with injections then he thinks or are the 2 medications so different that my response to Clomid doesn't indicate anything?

2. What is the purpose of a blood test the day of my second IUI? I have a lot of problems with all the blood work that is required for monitoring due to bad veins (day 3 plus 4 more days of blood tests/ultrasounds before my IUI). I thought when I was triggered that would be my last blood test, but I was told I needed another blood test/ultrasound the day of my second IUI (48 hours post trigger). I asked the nurse if the blood test was essential and she said yes and it is part of the cycle monitoring that all fertility clinics require it so I forced another blood test through my already bruised veins. I understand the ultrasound was to show if the follicles released, but what would the purpose of this blood test be and is it really as essential as they say it is? (I was also on progesterone suppositories 200 mg twice a day following the IUI so I don't think it was to measure progesterone since those were prescribed regardless of the blood results).

I really appreciate you providing this service and if we do decide to travel for treatment, California will be our choice. Thanks again, A. from British Columbia

Answer:

Hello A. from Canada (British Columbia),

The fact that you responded well to low dose Clomid is very, very reassuring and I completely disagree with your doctor's opinion. FSH levels and Antral counts are indirect measures of ovarian response but not absolute. In other words, studies have shown that these numbers can vary from cycle to cycle and so the response can vary from cycle to cycle. Besides, an FSH level of 10 is not necessarily that bad. Sure, we prefer the level to be 7 or less, but it is much better than a level of 12 or greater, which I often see. Even these patients do respond to stimulation albeit only a few follicles.

So, considering that you responded well to Clomid, low dose Clomid no less, is more of an indication that you are NOT a low responder. A low responder would have only one follicle despite high dose (250mg) of Clomid. One thing these two levels do tell you, however, is that you may not have as much time to work with as you would have thought. You will need to use your time wisely and strongly consider a more aggressive approach (such as IVF). I would not recommend more than 4 IUI attempts. If that does no work (which is the number where most patients will be pregnant), then you have to go to IVF.

In terms of your second question regarding the blood test, I have absolutely no idea why it is being done. It must be something specific to your doctor. You will have to ask him. Now, I do an ultrasound after each IUI so that I can see if ovulation has occurred. That way I know that the timing was good. Since I don't know what test they did or what it could be, I can't try to explain why they would do it. It can't or shouldn't be a progesterone level, which is what we often use to determine if ovulation occurred, but that test is not valid if progesterone supplementation is given.

Thank you for your question and consideration...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.

You Can Do IVF With A Low AMH !

Question:

Hello Dr. Ramirez,

I am 36 and have been unable to conceive for 3 years. The diagnosis we have been given is diminished ovarian reserve. I have tried 3 IUIs (intra uterine insemination) with clomid. Each time I ovulated only 1 egg (I already ovulate on my own). I decided to move on to IVF. I went to a new clinic because they have very high success rates (30% higher than my current clinic). Over the last year, my antral follicle count has only been between 6 - 8. FSH has been between 7.6 to 9.5 (my very first cycle a year ago it was 12.5, but that was tested on day 4, so I'm hoping that made a bit of a difference). Estrogen is always low on day 3, so my FSH is not artificially suppressed. The new RE insisted on an AMH test (my previous clinic offered it, but I declined as it is not covered by insurance and wouldn't have changed my treatment plan - only possibly caused more worry - my previous clinic was okay with my decision).The AMH test came back with very bad results (2.4 pmol/L - I understand there are 2 units for measuring this and for pmol/L this is very low). The new RE says there is no point doing IVF with that AMH result. He said my chances of success are less than 2%. He said you usually get half the number of eggs of your AMH (so I would be lucky to get 1). He would only do IUI with injectables if I wanted to, but recommends I move straight to donor eggs based on the AMH test.

I am wondering if the new clinic has such great results because they exclude patients from IVF that may not respond so well OR if the doctor really does know what he is talking about and I would just be throwing money away. Obviously, I would prefer to have a chance at a biological child and wanted to move to IVF ASAP. In your opinion, should I visit another clinic that would allow me to do IVF (understanding with low AFC and low AMH, my results may not be positive) or do you think this doctor is right and it would be a waste of time to try my own eggs and move to donor eggs immediately. I know donor eggs would have a better success rate, but there is not a time limit on this option (as there is on my own eggs) so that could be a future option. Thank you very much for your time, L. from Toronto, Canada

Answer:

Dear L. in Toronto

It always angers me when Doctors draw these type of conclusions. A recent study that I read showed that despite a low AMH number or an elevated FSH, there is still a pregnancy rate of about 20%. What that basically shows, as I have always argued, is that it only takes ONE good egg to be successful. When a woman tries on her own naturally each month, she only has one egg to work with. I often get letters from patients whose doctor has cancelled their cycle because they only have 1-3 follicles. But, what if the perfect egg was in one of those follicles? FSH levels and AMH are only indirect measures of ovarian function. They are NOT measures of egg quality or your chances of pregnancy. Please see more on AMH here: Understanding Infertility: Age Factors.

Naturally, part of the statistical chances with IVF occurs from being able to get many eggs to work with i.e. more eggs increases the statistical chances. Imagine that you have a dice and want the number 6. If you only have one dice, you have a 1 of 6 chance. Two dices double your chances, three dices etc. So with IVF, since we can't predict if the egg that is retrieved will be the perfect egg, and because we don't want to have to do this over and over again due to cost, we want to have lots of eggs. But that doesn't necessarily mean it won't work if you have fewer than is ideal. It might take more than one try (statistically). But, as I ALWAYS tell my patients, who are usually older than you, it only takes one good egg to be successful.You might want to find a clinic that is more willing to work with you instead of make decisions for you. I can see that you are good at analyzing the situation and I am confident that you will make the right decision.

Good luck and don't give up!

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

Follow-Up To This Post:

Please scroll down to November 6, 2013 to see this writer's good news and how by persevering she conceived with a low AMH :)!

"I am the one that originally submitted this question to you and I want to thank you for being positive as even with the low AMH we did end up getting pregnant and are currently 4 months away from meeting our 'miracle' baby."

31 Year Old With DOR Advised To Keep Trying: Adjust Protocol To "Mixed" FSH & FSH/LH

QUESTION:

Hi Dr Ramirez

I am on my first round of IVF and my day 9 scan showed no follicles on left ovary and 3 tiny follicles on right. I am on 375 menopur which has now been upped to 450. Priot to starting treatment i was on the combined pill for irregular periods. I am 31 years old with FSH level of 6. My question is, can being on the pill interfere with follicles growing and am i on te right meds? When they scanned me prior to starting treatment i had more follicles than when doing IVF which doesn't make sense to me? I am having treatment in London, England.

Thanks, N. from England

ANSWER:

Hello,  N. from England,

With your age and FSH level, I would have expected a much better stimulation response. I think you are not being adequately stimulated. Menopur is not adequate. There needs to be more FSH in my opinion, but keep in mind that each doctor does things differently and one way is not necessarily better than another. If you were my patient, my preference is to use a "mixed" protocol using both FSH (Follistim or Gonal-f) and FSH/LH (Menopur or Repronex). I would have started at 300IU Follistim and 150IU Menopur (450IU total of FSH), then possibly decreased to the dosage you started at. But, that is my personal preference (and of course something that makes each clinic different with different results).

The pill should not and does not interfere with ovarian stimulation. I presume that you are also on a Long lupron protocol? Lupron will suppress the ovaries as well.

I have also been surprised by the lack of stimulation in a younger patient, such as your doctors were pretty surprised. Sometimes it is hard to predict what will happen. If the cycle fails, then I greatly increase the medications in the next cycle. Such a finding is called a "poor responder". But keep two facts in mind:

(1) each cycle is unique and the stimulation results can vary from cycle to cycle. One does not necessarily predict the next.

(2) it only takes one good embryo to be successful.

Good Luck!

Follow-Up Question:

Hi Dr Ramirez,

Thank you so much for your prompt reply. I carried on with the 450 Menopur until day 16 and they decided to cancel the cycle as the one follicle was not responding as they would have liked. The consultant at the IVF clinic told me that my chances of conceiving are zero per cent even with IVF. To say I was shocked was an understatement. I spoke to him about the possibility of a different protocol or different meds but he was adamant that I shouldn't try again. I don't quite know where to go from here. I have been under the care of a gynae at my local hospital for fertility investigations for 5 years and he kept telling me IVF was the answer. I got pregnant with Clomid two years ago but now I am at zero fertility, I mean not even 1% according to the IVF consultant.

My question to you would be, in America do you do things differently? I spoke to him about Gonal F and he said it wouldn't have made a difference. I also said about Synarel and he said it wouldn't have made a difference. I have low ovarian reserve and that is that. He is a highly regarded doctor here in England (Mr Tim Child) so I am sure he wouldn't have said zero if he didn't believe it. I know it's hard for you to give an opinion without knowing my full history, but have you seen seomeone with such a poor first reposne go on to do better second time around or should I just draw a line under it all?

Thank you so much for your guidance on this, as my husband and I are a bit shell-shocked. Over here in the UK we always consider the Americans to be further forward in medicine and cutting-edge treatments. We would be prepared to travel if we thought it was worth it. If only one follicle is growing very slowly under high stimulation, would you be inclined to say zero chance too? I appreciate your honesty.

Kind regards, N.

Follow-up Answer:

I am sorry for all the grief you have had to endure. I am afraid that I don't completely agree with your doctor. First of all 450IU is not the maximum dose of medication. You certainly have "decreased ovarian reserve", which means that your ovaries don't stimulate well, but given your age, I would expect you to have a good chance even with only ONE egg. So I would recommend trying with a higher protocol and even if there are only a few follicles, you should continue the cycle and give it a try. It stands to reason, if the cycle is cancelled you certainly won't get pregnant, so in my opinion if there is a follicle present the patient deserves to give it a chance.
In terms of decreased ovarian reserve, there have been several studies, including one that was just published, that showed that ovarian response will vary even in patients with decreased ovarian reserve. Therefore, it is still recommended to continue trying in a patient with decreased ovarian reserve. The next cycle may be completely different than this one, especially if a different protocol is applied.

In addition, I am a firm believer that there is a difference between a mixed protocol (using FSh + FSH/LH such as is found in Gonal-F or Follistim (pure FSh) and Menopur (FSH/LH). I know that there is no standard protocol and studies contradict each other, but FSH is the hormone that stimulates follicle growth (that is why it is called follicle stimulating hormone)and LH is not. In a normal natural cycle, the LH does not rise until just before ovulation whereas the FSh is rising all of the first half of the cycle.

I would encourage you not to give up.. . at least not yet anyway. It is possible that down the road you might have to resort to using donor eggs, for instance if your ovaries shut down completely (premature menopause/premature ovarian failure) or you have failed several attempts with your own eggs, but until then, hope is not lost, every cycle is a new and different cycle and every egg is a new and different egg; all with their own potential. I will never tell a patient that there is "zero" chance because there are always exceptions to the rule and I also believe in miracles. I've seen them happen many times. If you wish to come to California, I would be pleased to assist you in the best of my abilities.

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/

Australian Undergoing Natural Cycle FET: Timing Is Everything!!!

Question:

Hi Dr Ramirez, I am 32 from Australia. I am about to embark on my first Frozen Embryo Transfer, using my natural cycle. I have one child (5yrs old) who was conceived spontaneosly after removing my endometriosis 3 months earlier. My doctor will be conducting ultrasounds and blood tests to determine ovulation and progesterone levels. This starts on day 12. My embryos (which were all top rating) were frozen on day 2.

What is the latest time (post ovulation) they could transfer these soon to be 3 day old embryos? I'm just worried because 3-4 days post ovulation would most likely be on a Saturday or Sunday and the lab is not open on a Sunday. Is delaying it or doing it too early acceptable?

Thank you for your time. Kind Regards, Z. from Australia

Answer:

Hello Z. from Australia,

First let me say that I am very surprised that your doctor has chosen to do this with a natural cycle. Implantation is very time sensitive, meaning the timing of the transfer has to be pretty exact. If the development of the lining is out of sync with the embryo stage, then implantation will not occur. The timing of the endometrial lining development is very dependent on progesterone stimulation and that cannot be measured by blood tests because the blood levels do not reflect the endometrial levels or the endometrial architecture.

In terms of your question, I cannot believe that an IVF center would not be open on a Sunday if they have to be because of timing. Again, I know I'm being redundant, timing is EVERYTHING in a frozen embryo transfer. The embryos can be transferred at any cell stage, as long as it coordinates with the stage of endometrial development. In a normal cycle, the embryos are transferred one more day than the number of days you have been on progesterone. For example, for a Day 3 embryo, it is transferred on the 4th day of progesterone. For a Day 5 embryo, it is transferred on the 6th day of progesterone. What I would suggest for you, if the 3rd day falls on a Sunday and the clinic cannot do a transfer on that day, culture out the embryos until Day #5 and transfer at that time. They will have developed into blastocysts by then which might help your chances for implantation since the embryos will be closer to the stage they need to be in for implantation.

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.

Israeli Woman Pregnant With IUD In Place: Are There Risks?

Question:

Hello, Sorry for my poor English. I live in Israel, so English is not my mother-tongue :) I had a Mirena placed at late November 2011. Ultrasounds showed that it was placed well. To make thing short: I've got pregnant in February. My ginecologist didn't succeed to get Mirena out. After doing more ultrasound tests with two different specialists: no one is sure if it is in or out.

I was checked by professor (who has very high reputation and I know him for several years and trust his opinion). He says that it might happen that Mirena has gone out of womb but not completely. He suspects that it is half-out (all this is very surreal for me). No one can tell what end of Mirena is out (I mean no one knows if it still secrete Progesteron into the womb) . We planned to have more children, so I'm not against the idea of pregnancy. Hence no one wants to perform laporascopy test to discover what is going on.

Now, suppose the Mirena is still in (half or complete) and it secretes the Progesterone into the womb. I know there is a risk of miscarriage and there is nothing I can do about. The question is: can these dose of Progesteron harm the embryo? Are there statistics or researches on that?

And say the embryo will be boy, can Progesterone influence him and his hormone levels as to even change the "orientation"? Sorry for that last question, but I can't help thinking of that.

Please make some order in my situation. Of course I'm observed by ginecologists and he is checking relevant information for me right now. Thanks in advance. LT from Israel

Answer:

Hello LT from Israel,

I'm sure that your gynecologist is doing the same research that I had to do to answer this question. It is a good question, but I don't think there is any real clear answer. This is what I found out and it is from the following website: http://www.drugs.com/pro/mirena.html

Based on the information from the above site, if an IUD is in place when pregnancy occurs, you have the following risks:

1. There is a two fold increased risk of miscarriage.
2. There is a four fold increased risk of preterm labor, delivery and loss.
3. There is an increased risk of 2nd trimester infection (chorioamnionitis) and maternal death.
4. Few congenital anomalies have been noted (there is no statistic).
5. Regarding your last question: There has been some reports of and there could be an increased risk of masculinization of a female fetus.

In your case, it would be very important to know if the IUD is in place. If it can't be seen easily by ultrasound, then a pelvic x-ray would probably be indicated, not a laparoscopy. The IUD should be seen and the amount of radiation is very small and won't affect the fetus or pregnancy.

I hope all goes well and 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: My question required some serious research and was answered very clearly Thank you very much!

How Can I Overcome Implantation Failure After Failing Multiple Fresh & Frozen Cycles?

Dear Dr Ramirez,

I'm a 43 years old female (from Australia) and for the last 2 years have been unsuccessful with IVF (in vitro fertilization) after 3 stimulated cycles and 10 Embryo transfers. I produce a good number of eggs (approx 18) with a stimulated cycle of 300iU/day of Gonal F. This egg number usually decreases at each stage; eg of 19 eggs, 13 are mature to fertilise, 6 fertilise and finally 1 or 2 reach day 5 blastocysts which can be transferred or frozen. All frozen eggs have always thawed well and transferred.

The pattern each cycle is similar however I'm finding that in this latest cycle only one embryo was transferred and the 2 remaining did not reach an acceptable stage for freezing. Implantation has always failed, even with the use of progesterone pessaries after transfer. I've also tried implanting 2 embryos with no positive result.

My specialist has resigned to the fact that my eggs are not of good quality due to my age. No testing on this has been suggested.

In terms of health I have PCO's and have a BMI of 30 (90kgs). I find it difficult to lose the weight which has been gradually gained in the last 8 years, have mild anxiety on the odd morning upon waking and trouble getting quality sleep 2 -3 nights per week. At times I suffer from low mood but put it down to the drugs and loss of hope. But I pull though with the support from family but use no medication. I do take a prenatal multivitamin 150mg of CoenzQ10 and fish oil. In your experience are there other treatments that could be explored for recurring implantation failure? Thank you, S. from Australia

Answer:

Hello S. from Australia,

Based on your embryo development and transfer of at least one good blastocyst, the cause of your failures is not determinable. We classify this as implantation failure but in reality there are two steps that have to occur naturally after the embryo is transferred. These are embryo hatching and attaching to the uterine wall and the endometrium growing around the attached embryo (implantation). We have no way to confirm that these steps are occurring. For that reason, there are no specific therapies to overcome failure at this point, but there are many suggestions for things to try. I say "things to try" because these are not proven remedies either. Also keep in mind that IVF success is not only dependent on embryo quality/normality and endometrial processes, but also on the doctor's transfer technique.

I think that what I would do if you were my patient is:

(1) Abandon the blastocyst transfer. Blastocyst culturing does not guarantee a quality embryo or success. Laboratory techniques, media, etc are not perfect. I wholly believe that the uterus is a better culture media and environment than the lab. Also, some embryos that might be the normal and healthy ones may not develop to blastocyst, as has been shown by numerous studies looking at preimplantation genetic screening.

(2) You could consider PGS to determine which embryos are genetically normal, and therefore have the highest chances for success.

(3) I empirically add low dose aspiring 81 mg per day, Medrol (Prednisone) 16 mg per day and Heparin 2000 Units twice per day starting at the beginning of the IVF cycle in my patients that have had repetitive failures. This is a formula that has been proven to decrease recurrent miscarriages with the thought that adequate micro blood flow and immunological factors may be leading to failure. I also increase my progesterone supplementation by using both injectable and vaginal supplementation, and add estrogen supplementation after the transfer by patch. Acupuncture has also been found to increase success in some studies, possibly by increasing blood flow or by reducing stress. All of these latter treatments are, as I said earlier, unproven. We call it "throwing the kitchen sink in" which basically means trying everything under the sun.

Finally, if you really suspect that it is an embryo problem, then donor embryos would be the remaining option, or you could consider using a surrogate if you think your embryos are okay but the uterus is not hospitable (my presumption is that a diagnostic hysteroscopy was already done to make sure of this).

Keep trying and 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.