Protocol/ Egg/Embryo quality
14 Replies
jmr67 - November 15

Dr. Smith,
I know it is widely used, but I also understand there is some controversy with regards to the MDL flare protocol with respect to the resulting egg/embryo quality. What I heard is the high levels of androgens specifically in older patients can be detrimental. Can you give me your thoughts on this?


Dr Smith - November 16

Any association between the MDL protocol and egg quality probably has more to with the dianosis of the patients requiring the MDL protocol (reduced ovarian reserve, advanced maternal age, unresponsive ovaries, etc) than the stimulation protocol per se.

The hypothesis that elevated androgens have a direct effect of egg maturation and quality has yet to be fully substantiated. From a scientific point of view, there are big differences between an association between two variables, a correlation between two variables and a direct effect of one variable on another. I don't think the androgen story is ready for prime time yet.


Woolie - November 25

Dear Dr Smith

Firstly I have to commend you on your excellent feedback on all issues. This is by far the best website and so informative and believe me I have researched many.I'm 41.2 DH-40 have 2 failed IVF. 1st IVF- long protocol with 450 Puregon & 75 Menopur protocol- 9 fertilized eggs and 2 embryos 5&6 cells excellent grade 3dT-BFN-none suitable for freezing- 2nd IVF Re decided to do flare protocol due to me being a 'poor responder' & increased Puregon to 600. They retrieved 33eggs, of course it had to be cancelled due to fear of OHSS- of the 33 eggs 8 were frozen at pronuclear stage and 5 made it to blasts- 2 very good blast transferred on controlled FET -BFN , the remaining 3 blast grown to day 6 but were not suitable for freezing. My re says now that it is probably Anuploidy problem, in my country they do not do PGD. I contacted another RE that I know and he said that I was not a poor responder, that I may have a quality issue/implantation problem but by increasing my puregon to 600 compromised my second cycle. I am presently on my 3rd long protocol IVF with 450 of Menopur only no puregon as the RE that I got hte opinion from has a 39% success rate in 39-41y/o with menopur only. I am also on Heparin/ Prednisone/ Haparin/ folic 5mgs/ B complex this time around as it may also be a implantation issue, my lining on my previous IVF were 10 & 12 respectively. I am worried now that I may not respond at all or that I amy have too much LH on board- do you have any experience with older people on Menopur only or do you have any thoughts about what maybe my problem of course apart from my aging eggs. I know you are always honest and I would really appreciate your opinion. Many many many thanks


Dr Smith - November 28

Thanks. Flattery will get you everywhere (with me). My wife has long since given up flattering me. Sigh. That's what 20 years in on a life sentence will do...

O.K. Down to business. The fertilization/embryo development of first cycle was within the expected range and I'm not sure why they decided to change the protocol (you are not a "poor responder"). The second stimulation was way over the top. When too many follicles develop, the quality of the eggs suffers. Beyond a certain point, say 20 eggs, more is not better. I agree with the new RE. The second cycle was compromised by "overstimulation" and I'm sure the LH got a pretty high because of the number of follicles. Whether or not that had a direct effect on the eggs is difficult to tell.

Just curious, but why are you doing another fresh cycle when you have 8 frosties at the 2PN stage? I wouldn't give up hope completely on the frozen embryos. You did have good quality blastocysts for transfer (albeit nothing to freeze at the blastocyst stage) and that not bad for 41. There may be a couple of good ones in the frozen batch.

Anueploidy is an issue for you. However, by waiting until the embryos reach the blastocyst stage there is a better chance that the embryos that are transferred are "normal". Some embryos that reach the blastocyst stage are abnormal - that's one of the reasons for first trimester miscarriages. However, the first genetic "check point" is on Day 3-4 when most of the anueploid embryos stop growing. You can't tell by looking at them on Day 3, so you really don't know what your transferring on Day 3. I would continue to recommend blastocyst transfer in your case so that you at least know that the transferred embryos made it over the first genetic hurdle. Don't sweat the PGD (or lack thereof). The current technology for testing anueploidy is not very accurate and biopsying embryos on Day 3 may do more harm than good. As you might guess, I'm not a big fan of PGD for "advanced maternal age".

Its not so much the medications (or combination of medications) as the skill of the RE using the medications. If they have good success with Menopur only, they must be doing something right. No worries. A moderate stimulation is better than a low or high one. Its a Goldilocks thing. Third time is the charm?

An endometrium thickness of 10-12 is fine. However, it says nothing about what may be happening at the molecular level between the embryo and endometrium We don't know very much about this aspect of reroduction. It is a very difficult thing to study. There is no clinical test available to determine the receptivity of the endometrium.


Woolie - November 28

Thank you so much for your response and I will continue to flatter you! as really this is a fabulous site. I did not make in clear in my last mess that when I over stimulated they cancelled the transfer and put the 8 fertilized embryos on ice- as mentioned 5 made it to blast after thaw and 2 were transferred in a controlled FET 2 months later- so I have no frosties left as the remaining 3 were not suitable for re freezing. Please God 3rd time lucky- Thank you so much


Dr Smith - November 28

Aha! Now I get it. When I re-read your post, you were clear. It was me that was befuddled. Wow, from 33 to 8. That's a pretty big drop (although not entirely unexpected). Only 8 fertilized? Did they tell you the number of mature eggs? Only mature eggs will fertilize, so that would account for some of the drop. Did they use ICSI? Sometimes ICSI improves fertilization in hyperstimulated cases. I'm not sure how much further ahead you get using ICSI in these circumstances, because you can't make a bad egg good by sticking a sperm inside. It does, however, look better on paper to have a higher fertilization rate.

Cancelling the transfer was a good idea. For reasons that no one really knows, the endometrium is not very receptive in cycles where the E2 goes sky high. And, if you did become pregnant, your risk of OHSS was really high. Good call in terms of damage control.

2 good blastocysts out of 8 frozen-thawed 2PNs... Hmm. I still think that anueploidy is an issue. However, there is some data out there to suggest that hypertimulation can cause anueploidy. Just a thought.


Woolie - November 29

Hi Dr Smith

They also feel that it is aneuploidy issue- They do not feel that ICSI would make much of a difference at this point and they didn't say how many were mature. My Dh did ask perhaps about checking him out again but the RE said that the embryologist would have requested that if they felt it was necessary, so I'm assuming from that that his Sperm is ok. I will ask though the next time I go there about how many mature eggs I did have. On this present cycle I seem to be stimming ok on the menopur 450- Day 6 scan today showed 7 follies on the right & 9 follies on the left & good size for this day-I am due a scan on Friday again and they said they might decrease the stimms, I am very nervous of over stimming again- what do you think?

Thanks a million


Dr Smith - December 5

Sorry for the delay. Trust the RE to adjust the dose accordingly. Hindsight is 20/20 and a second stimulation usually corrects any problems that occurred during the first stimulation.

Best of luck.


Woolie - December 8

Hi Dr Smith

I just have one more question for you, my RE did drop my Menopur to 300 as I had 18 good size follicles on my last scan. Had my EC on Wednesday and only 10 eggs retrieved of which only 4 fertilized- of the remaining 6-4 were immature and 2 mature but failed to fertilize. Pretty poor eh. They have planned a blast cycle but I don't know now with only 4 eggs should I go for day 3 transfer tomorrow!!!. I am of the believe that if they don't make it to day 5 blast in lab that they probably wouldn't make it in utero either.I feel the writing is on the wall but I'd love to know what you would do at this stage considering that this is probably what am I saying definitely our last go.

I am so well informed due to this site, I just wish I found you earlier- maybe your glad I didn't,

Thanks a million


Dr Smith - December 9

You are correct that the number of immature eggs (including the ones that were "mature" but didn't fertilize) was high. It could have been a result of dysynchrony in the growth rate of the follicles. That is, there were a few larger follicles and a bunch of smaller ones. The mature eggs came from the mature follicles while the immature eggs were retrieved from the smaller follicles. RE's usually trigger wit hCG when the largest follicles are ready, but will aspirate eggs from the smaler follicles too. This can lead to a disporportionately high number of immature eggs.

At our program, we plod on through to Day 5-6 to see what happens. When a lab has significant experience in culturing embryos to the blastocyst stage, the major reason why the embryos either go or don't go is their genetic normalacy. If you are comfortable with the notion that putting genetically compromised embryos in the uterus will not change their genetics nor increase their chances of continued development, then I say plod on to Day 5 and see what happens. If this is your last attempt and no embryos make it to the blastocyst stage, I believe it will bring true closure and allow you to move on.


Woolie - December 10

Thanks Dr Smith

We have decided to wait to day 5 which is tomorrow and just got a call to say that 3 of the 4 are 'doing great' and will be ready to transfer tomorrow, the other one is at 10-12 cell today no fragmentation and looking that it may catch up. Obviously we are delighted and cautiously optimistic at this point, ( I have being reading you correspondence on blast development and that they are not all are created equal & number of stem in the inner cell mass is vitally important to ongoing development etc). They would like to transfer 3 but I am a nervous about it, would you at my age (41) and with a failed blast cycle last time go for gold and get the 3 back in?

Thank you so much for your opinion


Dr Smith - December 11

Sorry. Too late for my advice - you already had your transfer. Anyway, either 2 or 3 would be O.K. At 41, you also have to compensate for an increased chance of loss during the first trimester. So, if you transferred 3 and 3 implanted, it is unlikey that all 3 would develop beyond the first trimester.

Best of luck.


Woolie - December 11

Thank you for your responce Dr Smith and I'm glad you would have gone for putting 2 or 3 back, we did go for the 3 considering the last blast cycle failure of 2 potential good blasts. I guess I have to let nature take it's course now but I want to say thank you again! Ye guys are fantastic on this site.

I promise this is my last question, I asked about assisted hatching of the Blasts ( you know considering my age etc (41)( they didn'd do it the last time) and the Embryologist said that it was too close to hatching itself that they would damage the embryo- does this sound right!!! bit late now if it dosen't eh!!!

The RE said it has too work this time, he was surprised at how well we did considering only 4 fertilized- he said by putting back 3 we have a 40% chance of getting pregnant-


Dr Smith - December 13

I have to go with the embryologist's call on that one. I think he/she may be unaware of a technique for hatching fully expanded blastocysts and decided it was too risky. If they aren't expereinced with the technique, your blastocysts are not the place to try it out.

Sometime RE's can be a little over confident in their predictions (i.e. "has to work"). It sets the patients up for a giant let down if it fails. I consider myself a realist and I don't entirely agree with the "keep the patient upbeat and positive" approach. In cases such as yours, I would remain cautiously optimistic. It looks good so far, but there are a lot of things down line from embryo transfer that have to fall into place for it to be a success. I do agree with your RE that you have about a 40% chance of pregnany; term delivery is another matter. I don't want make you overly anxious, so hang in there and see how things go. Best of luck.


Woolie - December 13

Thanks Dr Smith.

I have been accused of being way to realistic in the past about things so I think that is kicking in this time too. I agree with you about the 40% possibility of pregnancy been correct but take home % is another thing. Ah well I'll hang in there and hope for the best-I do believe as I have done in the past that there is always a reason if it dosen't happen and sometimes we just never get to find out. It's a big expectation for 41y/o eggs anyway!!Thanks for all your help, I really do appraciate it. So I'll sign off and remain cautiously optimistic that Santa may come early.



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