Tuesday, September 29, 2009

Multiple Failed IVF cycles

Dear Dr Ramirez

Welcome back from your holiday ! I’m Australian but am writing to you from sunny Singapore, one degree north of the equator, which is where I work and where I am now having IVF (after 6 failed cycles in Australia).

I had metastatic cancer (melanoma) at 35 so had no choice but to stop trying for a baby back then, and I received the "all clear" to try again just before my 41st birthday (this would be my first/only). I tried 3 IUI cycles (because my hormone levels were apparently great) but when they failed, I went to IVF with ICSI and assisted hatching. I am now 43 and trying for what will probably be my last (or next to last) attempt. I very much want to try with my own eggs (my medical history makes me ineligible to adopt).

I wasn’t told, but have recently discovered, that I have what appears to be very high E2 levels (I’ve discovered that from the web sites I’ve visited…..my first clinic just told me I was "too old"). My D2 bloods this month were similar to every other non-stim month: FSH 6.5, LH 5.6, E2 168.8, P4 .76 and Prolactin 12.8. Those numbers have changed little since my first tracking cycle in Jan 06 and it’s common for me – at ovulation – to have E2 levels of 900-1800 on unstimulated cycles. On stimulated cycles (I’m using 250IU Puregon with Nafarelin/buserelin as downregulation) I’m getting E2 at trigger of 9000-21 000 (21000 was on a flare protocol). I get good response usually (10-17 eggs so far, with about 70% mature and about 75% of those fertilise) but apart from one chemical pregnancy, no good outcomes despite some AA grade blasts last year. I usually get mild OHSS but last cycle, it was so bad I had trouble breathing (due to the abdo swelling….it made it hard to expand my lungs).

The only other significant background I can think of is that my periods became light to non-existant (spotting only some months) after the first IVF cycle and despite the excellent efforts of my naturopath and acupuncurist who work together and work with my new clinic), they’re still really light. Even after the chemical pregnancy ended, there was no bleeding. I had some spotting as the HCG hit 500 but then as the numbers went down, nothing. I just ovulated again 2 weeks later (confirmed with a P4 blood test) and it seems to me you can hardly expect a pregnancy with minimal endometrium. I’m otherwise really healthy – normal weight, and work out 3 times a week with a personal trainer.
My questions are
1. If I have such high E2, why aremy periods so light ? My P4 at 14 days post transfer is usually 40 (with crinone pessaries) but is that too low in view of the high E2 ?
2. My new doctor has suggested birth control pills (Gynera: gestone + estradiol) for a month to quieten down my ovaries and then a long downreg to try and suppress the E2 level. His plan is that if E2 becomes too high, we can just freeze any embryos and transfer later but I don’t expect that to do much more than kill any embryos, so any suggestions you have for controlling the high E2 would be great. (not sure if there is a particular type of BCP/downregulation that’s better than others ?) 3. What protocol would you suggest for someone with that profile ?
Thanks for any help you can suggest. I realise we’re going through a lot in the hope of "one good egg" but I want to make sure I’ve tried everything possible before I give up. I’ve been reading your previous responses (to make sure I don’t ask something you’ve already answered !) and have been quite cheered up by your "20% chance of success" stats. That’s more than I’d expected and a little under the chance I was given of surviving 5 years from metastatic cancer, so I hope to be "queen of the small percentages" one more time ;) Thank you so much for volunteering your time for this – I guess you can tell that it’s enormously appreciated.



Hello Allison,

Thank you for all the information. You are certainly in a tough spot because you are trying to "beat the odds", but since your ovaries respond so well to stimulation, there is certainly hope. The major obstacle for you at this point is the age related changes to your eggs. This passage of time has rendered them quite debilitated, and therein is the problem. Finding that one good egg will be difficult and make take many more attempts. Fortunately, you provide your clinic with lots of eggs to work with and that increases your chances.

It is curious that your baseline estradiol is elevated, and certainly not normal. I am surprised your doctor has not tried to find the source of that elevation. It is not normal, and something has to be producing the estrogen. In most cases it is an ovarian cyst, but that would easily be seen by ultrasound. Ovarian tumors can do the same. That certainly needs to be followed up in an unstimulated cycle. If your doc is going to proceed anyway, I would definitely recommend suppression with the birth control pill for at least three weeks prior to the start of the cycle. That, hopefully, will suppress the estrogen and it should be under 100 at the start of the cycle. If it starts out elevated, how can the clinic know exactly what your real estradiol level is to make decisions. By the way an estradiol of 21,000 is the highest I have ever seen. I watch my patients very very carefully to prevent hyperstimulation syndrome, which is the most dangerous complication of IVF, so I have never had a patient get so high.

In term of protocol suggestions, other than the BCP, I can't think of any specific protocols for your situation except the following:
1. Your doctor might want to consider using an antagonist instead of the "long protocol" with Naferelin (a GnRH agonist) such as Ganerelix or Cetrotide. This uses less medication, and is used extensively in European protocols, but the major advantage, and the reason I use it in high stimulators, is that Lupron can be used to trigger, instead of HCG. Since Lupron has a shorter half-life, there is a significantly decreased incidence of hyperstimulation syndrome. Lupron is a GnRH agonist so it can't be used when you are already on one.
2. I would recommend post-retrieval day # 3 transfer and NOT blastocyst transfer. I am not confident that culturing to blastocyst is entirely perfected yet and your good embryos may not make it to the point. There is not change in pregnancy rates between the two transfer dates, but you lose more embryos going to blastocyst. In addition, I don't know if they allow it in Singapore, but they should put back up to 8 embryos to give you the best chances. The chance of a super-multiple (>2) is low at your age.
3. Because of your age, you are at an increased chance of miscarriage, which includes chemical pregnancies, due to spontaneous chromosomal breakages. That is part of the age factor. You'll have to be prepared for that if you use your own eggs.
4. Because you have gotten pregnant before, that is a big positive on your side. That means that if you can get a good embryo into your uterus, you have a good chance of having a successful pregnancy. That is the hard part. Instead of adoption, have you ever considered using donor eggs? Is it allowed where you are. I think that if you switch to donor eggs, and this can be done at any age because the uterus does not age, you would have an excellent chance of pregnancy. In our center the pregnancy rate is 62% per cycle with donor eggs. It would be genetically your husband's and biologically yours, since you would be pregnant, nurture it in utero and deliver the child. No one would ever dispute that it isn't your genetic child. It is a better alternative to adoption, and would give you the highest chances of success. It is an alternative that you should keep in mind.

I hope this helps,
Edward J. Ramirez, M.D., FACOG
Executive Medical Director
The Fertility and Gynecology Center
Monterey Bay IVF Program
Monterey, California, U.S.A.

check me out on Facebook and twitter with me at @montereybayivf

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