Monday, July 13, 2009

“Empty Follicles” – An IVF Egg Retrieval Mystery Explained

It is not uncommon to hear women report that their IVF-egg retrieval yielded far fewer eggs than was expected and that when asking for an explanation they were told by their doctor that many of their follicles were “empty” and contained no eggs. This is at best an oversimplification of a complex situation, or at worst a flagrant misstatement! All follicles by definition must contain eggs.

True, it is not unusual or irregular for egg retrieval to yield a few less eggs than the number of follicles would suggest. However, when less than 50% of follicles >15mm fail to yield eggs, something is wrong. So how and why does it happen?

First, a little background information…With the LH surge that precedes spontaneous ovulation and also with the hCG trigger shot given to induce ovulation following the use of fertility drugs, the egg undergoes “ripening” to prepare for fertilization. This involves (among other events) a rapid halving in the number of its chromosomes (meiosis). At the same time, enzymes are released that loosen the cells (cumulus oophorus) that surround and bind the egg to the inner wall of the follicle. This is necessary to enable the egg to come free at ovulation and/or at the time of egg retrieval.

The problem is that with poorly developed eggs, the latter mechanism often fails, leaving such eggs tightly “stuck” to the follicle wall and unable to come free, often in spite of vigorous attempts to flush them loose. That is why the more difficult it is to successfully aspirate an egg at egg retrieval, the more likely it is that such an egg is chromosomally abnormal and “incompetent” (i.e. incapable of developing into a normal pregnancy). This state of affairs is most commonly encountered in women with diminished ovarian reserve (i.e. “poor responders”), women over 40 and in women with polycystic ovarian syndrome (PCOS) who do not receive an optimal protocol of controlled ovarian hyperstimulation (COH).

So the term “Empty Follicle Syndrome” is a misnomer! Yet the circumstances surrounding failure of numerous follicles to yield the eggs they contain at the time of egg retrieval only serves to underscore the need to individualize COH protocols and to time the administration of the “hCG trigger”, precisely.

23 comments:

  1. Hello Dr Sher
    I am 41 y/o. My two first long luppron protocol produced respectively 3 and 7 embryos (40 y/o at the time), the latter one with a pregnancy that ended at 7 weeks. A third long luppron protocol ended with a cancelled cycle which looked like oversuppression (with one ovaries that shut down and the other were only 2/3 follicles that developed). On my fourth attempts on a GnRH antagonists protocol, it seems that I ovulated 2 or 3 hours before the retrievals (while the last US indicated something like 8 /9 follicles)over 15 mm day 12 of the cycle. It seems my best cycle in term of stimulation but ended with no eggs retrieved. What can have happened ? how could this be avoided ? should I change protocol ?
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  2. It sounds as if you experienced a "premature LH surge", a condition where high LH levels cause “follicular exhaustion” resulting in poor egg quality and often failure of the egg to come free with aspiration . But the term “premature LH surge” is a misnomer since it suggests a sudden unanticipated rise in LH that occurs as a “terminal event” or an isolated occurrence. In actuality, what happens is the result of a progressive escalation in LH (the so called “staircase effect”) that through a persistent rise in stromal androgens, ultimately exhausts the follicle and damages the egg irreparably.
    A more accurate term might be “premature luteinization.”

    Geoff Sher
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  3. hai dr
    my sister undergone for ivf 2 times . both time , the dr said there was no egg in follicles .is empty follicle syndrome and the above condition are same ?
    what are the remedies other than doner / surrogacy .
    also i am trying for 3 years , is it genetically happen or only coz of hormones
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  4. I just finished a donor cycle. Can you tell me if missing 1 of the gonnul and 2 of the menopur injections could cause empty follicles? I confused my calendar and started both medicines a day and days (respectively) late. I didn't mention it to the doctor as I thought I still had time to make up the injections. However, seeing many follicles he called for retrieval 2 days later and so I was told to discontinue the medications and take the trigger shot. I didn't realize that not all follicles would produce eggs. We only retreived 3 eggs and I feel terrible, like I really messed this up. Please advise.
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  5. I suspect that the protocol of stimulation could have played a role in egg "competence" and that in turn might have prevented the eggs from detaching from the inner wall of the follicles after the hCG trigger. As this article indicates, tThere is really no such thing as an empty follicle.
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  6. One of the commonest reasons for "empty follicle syndrome" is, in my opinion, a less than ideal protocol for ovarian stimulation.

    Geoff Sher
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  7. Dr Sher,

    Thanks for such a great blog. I have just done my first round of IVF and with about 8 follicles between 13 & 16mm on day 12, I didn't get any eggs. Egg pick up was on day 15 with trigger 36 hours beforehand.

    My E2 levels were 1020 on day 5, 1100 on day 9 and dropped to 700 on day 12. I was on 125iu of puregon, but they dropped it to 75iu from day 5 due to my PCOS and a risk of OHSS.

    Is there any hope for me in future cycles? How can this be avoided in the future? I'm devastated and looking for answers.

    Thanks, Kim
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  8. Thanks for your kind words. It sounds to me as if your last cycle was doomed because of premature luteinization (early LH rise). Clearly the protocol of stimulation needs to be seriously modified. Call 800-780-7437 and set up a free telephone consultation with me so we can discuss what needs top be done.

    Geoff Sher
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  9. Hello Dr Sher,

    My partner has just completed her IVF cycle, with no egg retrieved from just one follicle. Her age is 42. She has been on Agnus Castus/natural herbs/acupuncture for two months to lower FSH levels. Day 2 FSH have been progressively lowering - from 30 to 21 and then 7 on Friday 24 September 2010 (LH had also lowered to 5 from levels in the teens and before that in the 20s and 30s. So with FSH 7 and LH 5 we decided to try IVF. As one failed IVF five months ago (one egg from one follicle, fsh injections of 300, no fertilization). So partner this time was placed on higher 375 fsh injections. At day seven scan we were told that partner had a 22mm x 16mm follicle and that 'she was ready'. But it was our decision to go ahead as only one follicle and chances were low. We went ahead due to partner's age etc. How can partner have such a mature follicle after just five nights of fsh injections. This seems far too early for any follicle to be ready. What implications does this have on egg maturity? The same morning as day seven scan partner was given first and only antagonist injection by clinic, and that evening we administered the hCG trigger. Saizen GH was injected on day seven (day of scan, antagonist and trigger) and day eight.

    Thank you

    Colin and Laetitia
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  10. Dear Dr Sher,

    I have recently undergone my 7th ICSI attempt. I am a poor responder with good FSH but high E2. All my previous cycles (all bar one SP with SP giving best results) ended in transfer of 1-2 embryos. The last cycle, with 5 follicles, ended in retrieval of 1 immature egg. The other follicles were 'empty'.
    I was down regulating for about 3 weeks and started stimulating on CD5 - I was on Merional during almost the entire cycle (which surprised me as, given that I am a PR, I thought it would be Follistim or something similar). I also had Clomid for 5 days and Cetrotide for about 4 days. I was stimulated for 11 days in total. I had a urinary HCG shot (10K IU) 36 hours prior to the retrieval.

    Dr Sher, could you please give me your opinion of what could have happened here?
    Thank you ever so much.
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  11. Dear Dr Sher,

    I have recently undergone my 7th ICSI attempt. I am a poor responder with good FSH but high E2. All my previous cycles (all bar one SP with SP giving best results) ended in transfer of 1-2 embryos. The last cycle, with 5 follicles, ended in retrieval of 1 immature egg. The other follicles were 'empty'.
    I was down regulating for about 3 weeks and started stimulating on CD5 - I was on Merional during almost the entire cycle (which surprised me as, given that I am a PR, I thought it would be Follistim or something similar). I also had Clomid for 5 days and Cetrotide for about 4 days. I was stimulated for 11 days in total. I had a urinary HCG shot (10K IU) 36 hours prior to the retrieval.

    Dr Sher, could you please give me your opinion on what could have happened here?
    Thank you ever so much.
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  12. This sounds as if it could be related to thje protocol of stimulation. I suggest you call 800-780-7437 so we can talk.

    Geoff Sher
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  13. We underwent 2 ICSI .In the first ICSI i had 5 follicles and out of which only 2 could be retrieved and others were empty.Both fertlilsed but failed to cleave.In the second Icsi again 5 follicles but only 1 egg retrieved and others were empty.The egg fertilised again but failed to cleave.The Dr. asked us to do karyotyping but came out normal.Day 2 E2 , FSH , testosterone and AMH are normal.We used short protocol both times..tried Recagon and Gonal-F..Pls give us an answer
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  14. I am 32 and have done 2 IVF cycles, produced several follicles in each and no eggs were retrieved in either. I have always had very low estrodiol levels considering the number of follicles I have. I have also done a unstimulated cycle with just an egg retrieval. An egg was retrieved, and although it was mature, through in vitro maturation, it reached maturity, fertilized, and divided, just didn't make it to blastocyst. Have you seen any cased like this or have any thoughts on the cause of why my eggs don't respond to stimulation despite producing so many follicles?
    ReplyDelete
  15. One thing is very likely and that is that failure to harvest an egg in the vast majority of cases has to do with egg aneuploidy (irregular numerical chromosome component). I would need to know much more about your case to comment. I suggest you call 800-780-7437 or 702-699-7437 and set up a free telephone consultation with me.

    Geoff Sher

    Geoff Sher
    ReplyDelete
  16. Hi Dr Sher,
    I am hoping you can offer some advice on guidance on what we should do next. Here is my background on our IVF journey.

    Me: 33 (had a fibroid removed mar 10 - discovered mild adenomyosis / laparoscopy dec 10: found mild endometriosis / tubes all clear

    Husband: poor motility/morphology

    Specialist advised to go straight to ICSI.

    Jan 11: ICSI#1 - FSH 9 /Puregon 150iu / Orgalutran / Ovidrel trigger. Didnt respond particularly well, but still retrieved 7 eggs. 6 mature. 5 fertilised. 1 Blasto implanted / 1 frozen. BFN :(

    March 11: ICSI#2 - FSH 13 - Synarel cycle / Puregon 225iu then upped to 300iu as not really going to well. Progesterone was 6 on day 8 so was told i couldnt have an embryo transfer, but could still go for an egg collection even though i only had 3 measurable follicles. Decided to go ahead with it anyway as nothing to lose.
    Retrieved 2 eggs! I fertlised and made it to day 6 but was highly fragmented so not suitbale for freezing.

    This cycle was disastarous from word go, and i dont even like to include this in the list!!! Synarel and me didnt get on!!!

    I then had my AMH level tested and got the awful news that it is 3.1! This would explain why im not responding very well.

    FS imeadiately put me on DHEA 75mg per day and said we would be going agressive from now on.

    May 11 - ICSI# 3 (advised to do fresh to try and get more frosties due to low amh):

    FSH 9 / Changed to Gonal f - 300iu / Orgalutran / Ovidrel trigger:

    Responded much better with 15 follicles.

    Retrieved 8 eggs (woohoo!) however only 4 were mature. Then the awful news that NONE of these fertilsed! Whats going on??

    So, we transferred our frozen embryo from cycle 1 and would you believe it but i got BFP!!!!!

    However, i had a missed miscarriage at 7 weeks and was absolutely devestated.
    Had a D&C on June 29.
    Chromosone analysis: extra chromosone 21 and extra chromosone 11.

    SEPT 11: Currently i am in ICSI# 4.

    This has been my best cycle to date in terms of stimulation. Gonal f 300 / orgalutran / ovidrel.

    I had 22 follicles and all looked sooo good. On day 13 i had an estrogen level of 5235 / P4- 3 / LH 1/ Follies ranged from 2.05 - 1.1

    They let me stim an extra day as they wanted the middle cluster to grow more, and it would be worth it to gain say 6 eggs but lose the top 2.

    Triggered at 8pm on cycle day 14 with egg collection on 15 September.

    This cycle has now crashed.. i woke up to hear they only got 3 eggs!!!??????? Only 2 were mature. They said the rest were empty follicles????? How can this be happening after the stims went so well???

    Anyway, only 1 of the 2 has fertilised and i am now waiting to see if it makes it to day 3 and then blasto by tuesday. I know the chances are slim.

    What is going wrong with me??? Should i be going straight to Donor eggs or try a different protocol??

    I cant understand why my first cycle was so good compared to the rest, and, I have successfully managed to get pregnant on only my 2nd transfer.

    I know my AMH must have a lot to do with it, but i have friends who are alot older than me, with FSH numbers in the 20's who are getting much better yields of eggs.

    Any advice on what i should suggest to my FS would be gratefully appreciated. The fact i have got pregnant is making me want to keep trying with my own eggs as im only 33, but, in the last 2 cycles combined i have had 11 eggs retrieved/ 6 mature and only 1 fertilise so im starting to panic.

    I think the DHEA is responsible for the increase in follicle numbers, but im wondering if perhaps it is affecting egg maturity/quality.

    Please help me!

    Ziz
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  17. Thank you for taking the time to reveal all this information. That having been said, I recognize that you are looking for substantive input and I am afraid that after all you have been through I can only contribute properly if we talk. I suggest that you call 800-780-7437 and set up a free medical telephone consultation with me so we can effect this.

    Until then,

    Geoff Sher
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  18. hello dr geoffry
    thank you for this nice informative blog
    iam 47yr old :(
    yesterday i had my egg retrival appt >>> i had 5 follicles b/w 20-17 size
    they told me all were empty no egg
    should i take any cotraception now in case b/c i want to think about before i try again
    today is day 12 of the current cycle
    any advice
    best regards
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  19. Not really . If you start taking a BCP it should be with the onset of your next period.

    This having been said...at 47 you should not be using your own eggs. You really need an egg donor. See the articles I wrote elsewhere on this site re:

    1. Age and IVF outcome
    2. Egg Donation
    3. Egg donation with "Staggered IVF".

    When you have read these (and any others that might interest, you might consider calling 800-780-7437 or 702-699-7437 to set up a free telephone consultation with me so we might discuss your case in detail.

    Geoff Sher
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  20. I recently underwent my first ivf cycle with 450 gonal injections for 10 days. At day 10 there were 6 follicles (all apparently good size). The trigger was cetrotide on day 11 followed by egg pick up on day 13. After surgery I found only one follicle produced an egg, the rest were apparently empty. Doctor said this can happen. Egg fertilized, was a good quality embryo and was transferred at day 3 but unfortunately did not take.
    Currently I am taking dhea 3 times a day for next cycle in 4 months. What sort of changes to cycle protocol would you recommend to ensure no empty follicles at retrieval? I am 33 with a low amh level.
    Ellen
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  21. To the best of my knowledge, Cetrotide (an Antagonist) cannot be used as a trigger because it blocks LH. Are you sure you were not triggered with an "agonist" (Lupron or Superfact") That might be doable, but using an antagonist to trigger with makes no sense to me. Hopefully you are mistaken here. However, if not, that would explain the "empty follicle situation".

    Geoff Sher

    P.S. Call 800-780-7437 if you wish to have a free telephone consultation with me to discuss your case in detail.

    Geoff Sher
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  22. First if all, thank you for your reply. This forum is great and you ate very kind to respond to all our questions so fast.

    Second of all, you are right and I am confused about medication names. I confirmed with the clinic nurses and found out proper procedure I underwent.

    For my first ever ivf cycle I was given 450 of Gonal f till day 11 of cycle, starting day 2 os cycle (10 days total in morning). I then added 250 of Cetrotide from day 8 (evening) to day 11. On day 11 I was also given a trigger injection of 250 Ovidrel.

    Egg pick up was day 13 of cycle. Scans indicated 6 mature size follicles, but egg retrieval only gave one egg - rest were apparently empty. My one egg fertilized, was transferred as a good quality embryo 3 days later, but unfortunately did not take.

    Currently I am taking dhea supplements of 25mg thrice daily and clomid. Dr suggests I use a nose spray in next cycle called Synarel in next cycle - Feb or March 2011.

    What protocols do you think should be followed to help eliminate empty follicles? I have a low amh and am 33 years of age.

    Kind regards
    Ellen
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