QuestionQUESTION: Hi Dr. Ramirez,
I am 44 turning 45 this June. I have had 3 failed ivf's - 1 didn't go beyond retrieval because I pre-ovulated so no eggs to retrieve. My recent failed ivf cycle I had 3 follicles 19mm, 18mm and 16.5mm. The biggest follicle had no egg, the second largest had a degenerative cell and the third an immature egg. I took 300 iu's of follistim and 1 vial of menopur increased to two mid cycle.
Can taking too little or too much meds (follistim/menopur) cause this outcome?
We are trying a gentler dose and using follistim instead of gonal f. My first few cycles I was taking 600 iu's of gonal f and 150 iu;s of menopur. They had me doing this protocol for months and I started to respond poorly to it. I insisted on changing the meds or trying a gentler dose.
We also interviewd Dr. Zhang at New Hope and his approach is less is more, less meds and get better quality vs. quantity eggs. And is it true that the smaller follicles esp. women my age will have bad eggs? My last cycle debunked that whole theory because the dominant follicle or the two largest didn't have any eggs? And the smallest follicle did have an egg but it was immature.
I know that on the average I produce 5-8 follicles per cycle. I think it's important to save as many of the follicles we can, we can't afford not to even if they have bad eggs in them. I am not young and producing 20 follicles. How much do you recommend women my age take in meds (follistim/menopur)? Dr. Zhang wanted to put me on 150iu's of follistim every other day or maybe everyday? That did not seem enough? He only wants to stimulate the dominant follicle or larger follicles. I don't want to take too little that it doesn't stimulate enough or take too much that I can get overstimulated and not respond well. I know my body and I am very sensitive to the drugs. I have also used micro-dose lupron and I responded poorly to it.
What protocol do you at your clinic use on women my age? My recent baseline fsh is 8.6, E2 is 30 and my AMH 0.27. It started low and increased up to 0.7 taking dhea and in the last few months started to decrease. I have no other issues other than my age and thyroid disease but it's under control. Do you change dosage depending on blood levels, number and size of follicles? The doctors I went to never did that.
Do you use clomid or birth control pills? I am not fond of either of them but I have heard and read that if you are on clomid you third ivf cycle will be successful? I prefer to use estrace or patches over the birth control pill to suppress - or is it to suppress? Why do clinics use birth control pills? I have read clomid was found to give cancer to lab rats?
Your help is greatly appreciated. I don't have time to waste anymore.
Thank you,
Christine
ANSWER: Hello Christine from the U.S.,
In general I don't comment on specific protocols because each doctor has their personal preferences and there are none that are perfect or better than others. However, I don't think I like Dr. Zang's recommendations or protocols and I'll explain why.
The biggest hurdle that you are facing is an age related decline in egg quality AND a decreased ovarian reserve. There is nothing that can be done about the egg quality but the goal with IVF is to increase the number of eggs recruited and available in the hope that a good egg is still present and we can find it. So, the protocol is always to try to stimulate an increased number of follicles and hopefully eggs. I have read studies where the argument is if you use a natural cycle (no stimulation# or decreased stim cycle, the egg quality will be better, but I believe that to be nonsense. Why would decreasing the number of follicles or relying on a natural cycle #only one follicle# produce better eggs? That is illogical. The quality of the eggs are already predetermined. Stimulation or lack thereof does not influence its quality. Again, I believe that the only way to overcome the age factor is to try to get the maximum number of eggs out at a time. For this I use a high protocol that is 450IU of follistim and 150IU of Menopur #called a mixed protocol#. I also Do Not use Lupron #called the long protocol) because I think it is inhibiting the ovaries too much at the time of follicle recruitment. Instead I use an antagonist protocol where the antagonist is given for only 1-3 days.
The only time I will decrease the amount of medication is if the patient has gone through one or two IVF cycles and still the number of follicles encountered or eggs retrieved are few. I decrease the protocol because I don't want her to spend lots of money on medications if the increased amount is really not doing too much. The ovaries do get to a point where they won't stimulate much despite increased dosage of medications. Your ovaries sound like they are there already. Again, the reason for doing this is to reduce the cost of medications.
I do alter my dosages as the cycle goes on, but only if I am starting from a lower dose and the patient is not stimulating, in which case I increase the dosage, or if I start on a higher dosage protocol and she is stimulating too strongly, in which case I decrease the dosage. Other than that, the dosage stays the same for most of the cycle without alterations.
I would not even consider Clomid for an IVF cycle. Some clinics do again to decrease the cost of medications but multiple studies show that the injectables are superior to Clomid.
Finally, in terms of the birth control pill, I do use it. Several studies have shown a better response if preceded by birth control pills. It suppresses the ovaries in the cycle preceding the IVF cycle and there may be a rebound effect so that the ovaries stimulate better. Estrogen does not suppress the ovaries unless given in very high amounts such as with the birth control pill. I have read of clinics trying to do IVF after a natural "unsuppressed" cycle, but I don't think it makes much difference. The other reason to use the birth control pill is that it allows us to take control of your cycle so that we can be sure that timing is correct. Timing is absolutely critical with IVF. There is a very small window of opportunity for the embryo to implant and if you miss it, then the cycle will fail. Also, using the birth control pill helps with scheduling if you batch patients (put them in the same group).
I think it is meritorious that you are trying to achieve pregnancy with your own eggs at 45 years old, but you have to understand that pregnancies rarely occur after 43 even with IVF unless donor eggs are used. However, I always remind my patient that the oldest woman to achieve pregnancy through IVF using her own eggs was 49 years old. It did take her two years of doing IVF, so persistence can count if you can afford it. But you also have to be realistic and not let your expectations be too high.
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.
for additional information check out my blog at http://womenshealthandfertility.blogspot.com check me out on twitter with me at @montereybayivf and facebook @montereybayivf
---------- FOLLOW-UP ----------
QUESTION: Hello Dr. Ramiez,
Thank you for taking the time to answer all my questions. I feel so much better knowing that I wasn't too far off. I feel like I have been around the ballpark enough to really understand the various protocols and more importantly to trust my instincts.
I forgot to mention that I had 3 consecutive ivf cycles last year all at 600 iu's of gonal f and 150 iu's menopur. My last cycle I mentioned I pre-ovulated so no eggs were retrieved. This really freaked me out so we stopped for almost 6-7 months to give my body a break and to try naturally again to no avail. We went back to taking the injections but I noticed the cycles were getting worse (fewer and fewer follicles) so we opted for IUI's instead. This went on for months until finally I insisted on trying follistim or gentler dose. The point of this is that I wanted you to know that we had breaks in between so it wasn't like I was having injections every month. You mentioned you thought my ovaries may already be there - that more stimulation isn't going to make a difference - do you still believe this is the case since my last cycle with meds was 4 or 5 months ago? Also we aborted a few ivf cycles to IUI's because I wasn't responding well to gonal f anymore. We did about 4 natural IUI cycles (no injections) and used.OV home kit to test when I was OV to go in for the IUI procedure. We finally got our insurance to approve follistim.
Our first IVF cycle with follistim was last month. I took 300 iu's of follistim and 75 iu's of menopur and then midway increased it to 150 iu's of menopur. So really this was our first iv cycle on follistim and first IVF cycle in several months. Should I increase my next cycle to 450 iu's of follistim or keep it the same at 300 iu's because you mentioned that if by first or second ivf cycle produce same amount of follicles or similar size eggs then you decrease the dose but really for sake of saving client money on meds. I was told that each cycle builds on each other like my first 3 consecutive cycles last year - each cycle did produce more follicles unfortunately the last one where I pre-ovulated we lost the eggs. I definitely should not decrease the dose from 300 iu's?
The antagonist protocol - you mentioned using antagonist 1-3 days. Do you use centrotide or ganirelix? Antagonist is started after 4-5 days of ovarian stimulation and is continued everyday afterward until the day of HCG. When do you start the antagonist and why do you do only 1-3 days instead of everyday until day of HCG? Now that we are on the subject of antagon I was told and I am the perfect example that older women tend to pre-ovulate - is this why you use antagonist protocol? Then the antagon should be given when the follicle is around 14 mm? Or 2-3 days before expected natural ovulation? For example my last cycle where I almost pre-ovulated my doctor had me take full dose of ganirelix day 9 of injections skip a day and take another full dose of ganirelix day 11 but I started surging my lh level doubled and my estrogen started to drop. Instead of triggering on day 12 they triggered me on day 11 the same day I took a full dose of ganirelix in the morning. And that night I took the HCG shot and went in for retrieval the next day day 12.
I just want to make sure this doesn't happen again and that I don't pre-ovulate. If I do the antagonist protocol when do you suggest I take the antagon and for how many days? In hindsight the doctor realized that he should of had me take full dose ganirelix 3 days in a row Day 9, Day 10 and Day 11 instead of having me skip a day.
Importantly you mentioned timing is critical and I have heard this many times. Do you mean in regards to when your retrieve and when you do the transfer like day 3 or day 5 transfer? How do you get the timing right and what are the factors? Do you recommend I do a cycle with birth control? I think I did it once two years ago at another clinic but I don't remember it being an improvement. But I am older and wiser now and open to trying it again if you think it can help me optimize my cycle.
Thank you for your help, it's reassuring and gives me more hope. I have already put into motion and set my course to conceive there is no turning back. I hope my situation with your expertise opinions can help other women try to understand and to ask questions and be involved in the process.
Warmest Regards,
Christine
ANSWER: Hello Again,
Thanks for the additional information. I don't think that the hiatus' that you took have improved your situation. Time is actually your enemy and the passing of time but itself may have worsened the outlook.
Every cycle is unique. They don't "build" on eachother or affect eachother. The ovary can respond differently every time, the eggs that result will be unique and the result unique. What I meant by "more stimulation may not make a difference" is that as the ovary ages, it's function slowly declines until it stops working, which we call menopause. I explain to my patients to picture a golf practice ball, called a waffle ball (I think the spelling is right), that has lots of holes in it. That represents your ovary. This sits in the body and blood flows through the ball. As long as the holes are open, the blood flows through the ball and the hormones enter the middle. Now picture these holes slowly plugging up. Because the holes are the same size and can't be increased, still only a certain amount of blood (and hormone) can pass through the ball (ovary) and enter the middle, so no matter how much you increase the amount of blood or hormone, still only a certain amount gets in. That is what I mean by what I said. Even if you increase the FSH my larger and larger amounts, the ovary may still only respond as much as it can or that it is going to respond. So, giving more medication may not be of any benefit. This is the reason why whey we measure a day#2 or 3 fSH level we worry about an increased level. It is basically showing that less and less of the FSH is being taken up by the ovary from the blood stream. Because you have consistently had a decreased response, and had to convert several IVF cycles into IUI (which I do not believe in doing by the way), it shows that the ovaries are probably very resistant now, and an increase in amount of meds won't necessarily give you more follicles or eggs. Also, I don't know if you "pre-Ovulate or prematurely ovulate", but we do know that as a woman ages, less and less of her follicles have eggs within.
In terms of the antagonist protocol, I use Ganerelix but have also used Cetrotide. Either one is fine. There is not a set day that I start the medication. I base it on follicle sizes. The rule of thumb is to start the medication when approximately 30% of the lead follicles are at least 16 mms. However, this is a rule of thumb. It has to be tailored to the situation, so for instance, if one lead follicle is 17 mms but the rest are 14mms or less, I would start the antagonist on that day to prevent the large follicle from becoming the sole dominant follicle and ovulating before the smaller ones have a chance to mature. Once I start the Ganerelix, I continue it daily until HCG. In most cases, since I will trigger when I have two follicles of 20 mms, that will only be a day or two (follicles grow at 2 mms per day). Of course, this again will vary depending on the situation. This is part of where the art and experience come into play. This is why clinics and doctors are different and have differing pregnancy rates.
I mainly do day#3 transfers because I believe that the uterus is a better incubator and culture media than the lab. I have seen, and read, many embryos not survive to Day#5 (blastocyst), that potentially would have led to a pregnancy. In terms of timing, the timing of the transfer is very critical and is dependent on the day that HCG is given.
Well this has been a long answer, so I will stop here.
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.
for additional information check out my blog at http://womenshealthandfertility.blogspot.com check me out on twitter with me at @montereybayivf and facebook @montereybayivf
---------- FOLLOW-UP ----------
QUESTION: Hi Dr. Ramirez,
Thank you again. Words can't express my gratitude for your help to better understand the complexities of IVF protocol.
I mentioned to you my last ivf cycle did not go any further then retrieval. I almost prematurely ovulated because my doctors did not tell me to take antagon properly. The morning I went in for day 11 of meds I had 3 follicles 18mm, 17mm and 16mm. I also took full dose of antagon that morning before going in for AM monitoring. They decided to trigger the next day (day 12) and have me come in for retrieval on day 14. That same day I got a call from doctor saying the my blood results show I am surging and that I need to take the trigger shot that same night (day 11, I took antagon in the morning) and come in for retrieval the next day. They retrieved no eggs from the two largest follicles and wanted to give the smaller 16.5mm follicle another day to grow so they had me come in the next morning to do another retrieval if sonogram showed I did not already ovulate. I hadn't ovulated so they retrieved one immature follicle which did not continue to grow.
I am giving you all this info because I just started spotting tonight and it's only been 10 days since I took the antagon in the morning and hcg (trigger shot) that evening. This is a short luteal phase and I have never had this before. Does this mean I have no follicles for the next cycle or that the quality of eggs will be bad? What does this mean? I am usually 28 day cycle - did the last cycle really mess my body up? Do you recommend I take a break this cycle and start next cycle? I really don't have the time as I mentioned I turn 45 in June and my insurance stops covering meds. Your advise and opinions is greatly appreciated.
Warm Regards,
Christine
AnswerHello Again,
Remember that this is an artificial cycle and not your normal one. This spotting could just be premenstrual spotting since nothing was replaced. I presume you were placed on progesterone to complete the cycle. Once this medication is stopped the period usually ensues. If you were not placed on progesterone then it could be some form of dysfunctional bleeding that will herald a period.
In general, I don't do back to back cycles. I will usually let the ovary rest for one cycle before proceeding into another IVF cycle. This lets everything get back to normal before starting up again.
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.
for additional information check out my blog at http://womenshealthandfertility.blogspot.com check me out on twitter with me at @montereybayivf and facebook @montereybayivf
