Question:
Can you help figure out what the next step should be? I'm 39 but have day 3 tests of 6.4 FSH, 53 estradiol and 25 antral follicles. Also great uterine ultrasound. We're doing IVF due to severe male factor. Just finished our first cycle, during which I somewhat overstimmed (16 eggs, sky-high E2 levels) but we got 3 good embryos, froze 1 and implanted 2 (my lining was 10.2 if I recall correctly), but they didn't take. I feel like I got a bit of a "cookie cutter" treatment from current RE and am wondering what changes you might recommend.
What felt "cookie cutter" was that despite my great day 3 tests, RE put me on microdose Lupron flare protocol with 300 units of Follistim (150 twice a day). Isn't that kind of an aggressive protocol for someone with day 3 numbers like that? Couldn't that risk sacrificing egg quality to quantity? I just feel like all they saw was my birthday (almost 40), not the day 3 numbers, good health and family history (women in my family stay fertile pretty late).
Anyway, after 4 days of 300 units of Follistim I had tons of follicles and my E2 was too high--almost 900--so that day and the next they had me skip the PM dose of Follistim (in other words on days 4 and 5 I had 150 of Follistim once a day). The E2 kept climbing, to 1100+ on day 5 and 1900+ on day 6. So on day 6 they had me go back to two 150 unit doses of Follistim. The next day (day 7) my E2 shot up to 4300+ so they had me coast. By day 8 E2 had spiked to over 7300, but it fell to 5300+ on day 9.
In order not to lose the cycle they had me do HcG on day 9, even though apparently a lot of clinics won't do the HcG shot unless the E2 is under 4000 due to the OHSS risk. (To prevent OHSS they had me use a half-dose of HcG and also gave me albumin.) Out of 16 follicles we got 16 eggs, of which 14 were mature, and 7 fertilized. On day 3 after retrieval, we had 4 embryos. Two looked great--we transferred them, both 7 or 8-cell--and two didn't look so great. They let those continue growing; one made it to blastocyst and is frozen now.
My RE said, of my response to the protocol, that I "reacted WAAAY more than any of our testing led us to expect." I don't understand what part of my testing suggested that I would have any problem producing enough eggs. Do you see anything that suggests that? I am just trying to figure out if I can trust my RE... I don't know if they actually are less worthy of trust or if I'm just feeling that way because I'm upset at the failed cycle.
More importantly, do you think these estrogen spikes and/or the overly aggressive protocol damaged my egg quality? I've seen some things on the web saying that excess E2 can kind of "toast" the eggs. What would you do now, if I were your patient? My RE wants to switch me to a more standard Lupron downregulation cycle with 225 units of Follistim a day. She said it's up to me whether to precede the Lupron with birth control pills. I don't want to take the pills--it just seems like going from one extreme to another, IVF protocol-wise, and I don't want to risk being over-suppressed. What do you think? Also, is this a situation where you would lean towards antagonists instead of Lupron to avoid over-suppression?
Sorry for the long post. I just wanted you to know enough to comment. And thanks in advance for your help. M. from the United States.
Answer:
Hello M. from the U.S.,
Before I answer the specifics of your questions, let me precede with the disclaimer that (1) there are lots of variations of protocols and opinions in the world regarding stimulation and none are absolute (meaning apply to all people) and none are better than others, and (2) the opinions I give are my own opinions based on my knowledge and experience and (3) the first IVF cycle is hard to predict with everyone because there are too many unknowns as to how a person will respond until you do it the first time and (4) pregnancy does not occur every time a woman does IVF for many reasons.
In answer to your questions, the protocol you were on (300IU per day) is actually a low dose protocol. Medication can be given up to 600IU per day. However, based on your response, it seems that your ovaries have a tendancy toward PCO-type response even if you are not a classic PCO. That is to say, your ovaries were very sensitive to the stimulation and hyperstimulated. For that reason you had to coast. I don't use the microdose flare protocol, which is indicated for "poor responder" patients or patients with "decreased ovarian reserve", neither of which you fit. Your FSH level was fine and your antral follicle count was more like a PCO. If I see ovaries with PCO-type characteristics in the pre-IVF ultrasound, I will usually defer to a PCO protocol because I don't want to put the patient at risk for hyperstimulation syndrome.I think that the adjustment of the medications was appropriate.
One thing to keep in mind, which I think you already know and have read, is that PCO patients that hyperstimulate have a reduced pregnancy rate because many of the eggs within don't mature. In addition, there does seem to be a reduction in egg quality, and that is further enhanced when coasting is required. That is part of the reason why we try to avoid coasting, but the risk of hyperstimulation is much greater so we sacrifice the egg quality for preventing OHSS.
I also will differ with your doc in that I prefer to use a "mixed protocol" (using both FSH + FSH/LH) because there have been some studies that show that LH is required for egg development and quality. In addition, I ALWAYS precede my patients with the birth control pill to help with quieting the ovaries (putting them at rest) prior to the IVF stimulation, to assist me with stimulation (studies have shown better stimulation) and to help with scheduling/controlling the cycle. Also, I strongly differ with your doc in the number of embryos I would have transferred. I would have transferred or recommended transferring all four of the embryos on day#3 just based on your age (that is totally based on whether or not you would be willing to take the risk of a twin pregnancy). We know that just based on your age, even with the family history of retained fertility at an older age, your chances of quality eggs are reduced, so the goal is to have a lot of eggs and embryos to work with in the hope of getting a good embryo in the end (keep in mind that "good looking embryos" does not necessarily mean that the embryo has good internal quality. We have no technology to access that at this time.) In my 39 year olds, I will transfer 4-6 embryos in order to get one implantation.
Finally, since we now know that you respond like a PCO patient, I would use a PCO protocol. In my practice, I exclusively use the antagonist protocol rather than the long protocol (Lupron), so that I can trigger with Lupron instead of HCG (which has been shown to reduce the chances of OHSS), and decreases the number of injections required. I call my PCO protocol the "low slow protocol", where I start with a low dose of medication and slowly increase it based on response.
Thank you for providing detailed information, it helps a great deal in formulating my response! I hope this answers your questions and that any subsequent cycles go better than the first.
Good Luck,
Edward J. Ramirez, M.D., FACOG
Executive Medical Director
The Fertility and Gynecology Center
Monterey Bay IVF Program
Monterey, California, U.S.A.
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